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ISSN 1995-1892 (print) ISSN 1680-0745 (online)

Vol 27, No 2, MARCH/APRIL 2016

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial 59

Cardiovascular disease in pregnancy: the South African perspective J Anthony • A Sarkin • K Sliwa

Cardiovascular Topics 60 The importance of cardiovascular pathology contributing to maternal death: Confidential Enquiry into Maternal Deaths in South Africa, 2011–2013 P Soma-Pillay • J Seabe • K Sliwa 66

Electrocardiographic predictors of peripartum cardiomyopathy KM Karaye • K Lindmark • MY Henein

Review Articles 71 Pre-eclampsia: its pathogenesis and pathophysiolgy P Gathiram • J Moodley 79 Pre-conception counselling for key cardiovascular conditions in Africa: optimising pregnancy outcomes L Zühlke • L Acquah 84

Medical disease as a cause of maternal mortality: the pre-imminence of cardiovascular pathology AO Mocumbi • K Sliwa • P Soma-Pillay

89 Physiological changes in pregnancy P Soma-Pillay • C Nelson-Piercy • H Tolppanen • A Mebazaa 95 Diagnosing cardiac disease during pregnancy: imaging modalities NAB Ntusi • P Samuels • S Moosa • AO Mocumbi 104

Hypertensive disorders of pregnancy: what the physician needs to know J Anthony • A Damasceno • D Ojjii

INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Guest Editor prof karen sliwa Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

111 Valvular heart disease in pregnancy J Anthony • A Osman • M Sani

Case Report 123 Pregnancy and childbirth in a patient after multistep surgery and endovascular treatment of cardiovascular disease P Buczkowski • M Puślecki • S Stefaniak • J Kulesza • O Trojnarska • T Urbanowicz • M Jemielity

Vol 27, No 2, MARCH/APRIL 2016

CONTENTS

119 Assessing perinatal depression as an indicator of risk for pregnancy-associated cardiovascular disease L Nicholson • S Lecour • S Wedegärtner • I Kindermann • M Böhm • K Sliwa

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CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 27, No 2, March/April 2016

Editorial Cardiovascular disease in pregnancy: the South African perspective John Anthony, Andrew Sarkin, Karen Sliwa Maternal mortality in South Africa, as in many developing nations, is avoidably high. The causes of death are well documented because statutory notification of mortality, happening during pregnancy and for 42 days after delivery, has been in place for 15 years now. The mortality data have been compiled into a triennial report (Saving Mothers) published by the National Department of Health.1 These reports map the epidemiology of avoidable maternal mortality, for which there are diverse causes, none more significant than the dual failure on the part of attending clinicians to correctly identify potentially life-threatening illness, together with recurrent failure to provide an adequate standard of care to ill pregnant women. The death of a pregnant woman may adversely affect the chance that her surviving children will thrive. In South Africa approximately 1 600 women die every year because of pregnancy complications. Many others suffer the burden of on-going morbidity related to childbirth. Preventing premature death and disability among women and children is a priority to which the National Department of Health has committed itself. Given the pivotal role of women in society, especially within poorer communities, this targeted intervention is one with which few would take issue. The epidemiology of maternal mortality informs a variety of proposed recommendations aimed at reducing the risk of death related to childbirth. The burden of disease is described by SomaPillay and Sliwa in this issue (page 60). The contribution of cardiac disease in pregnancy is recognised to be the single most prevalent medical disorder giving rise to death during pregnancy among South African women. Reducing deaths due to cardiac disease has not yet been accomplished. The need for accurate diagnosis and appropriate management depends on identifying women with some evidence of cardiac disease, followed by referral to an appropriate level of medical care where the greatest available level of expertise may be employed in the further management of such patients. However, such a simple principle is difficult to implement. Often those providing care at the community level (where most South

Division of Obstetrics and Gynaecology, Groote Schuur Hospital, University of Cape Town, South Africa John Anthony, MB BCh, FCOG, MPhil, john.anthony@uct.ac.za

Hatter Institute for Cardiovascular Research in Africa, and IDM, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa; Soweto Cardiovascular Research Unit, University of the Witwatersrand, Johannesburg; Inter-Cape Heart Group, Medical Research Council South Africa, Cape Town, South Africa Karen Sliwa, MD, PhD, FESC, karen.sliwa-hahnle@uct.ac.za

Department of Cardiology, Faculty of Health Sciences, University of Pretoria, South Africa

African women deliver their babies) are ill-equipped to recognise significant disease and even less able to provide the necessary medical management. Innovative approaches have been necessary and are also part of the recommendations made in the triennial report. Sliwa et al. have described the function of a combined obstetric and cardiac clinic where multi-disciplinary care is provided to women with suspected heart disease.2 The object of this clinic is to diagnose, triage and implement care during pregnancy and to ensure that those who present with undiagnosed disease during pregnancy have ongoing access to care after childbirth. Preconception counselling and contraceptive advice are all provided within the same clinical environment. The triennial report has endorsed this type of combined clinic that encompasses the skills of both obstetricians and cardiologists as a means to eliminate any failure to recognise problems correctly and to ensure that the incidence of substandard care is kept to a minimum. Such clinics are feasible in metropolitan areas of the country where the greatest concentration of people live. Smaller towns and rural communities have less access to the same level of care. Nevertheless, co-responsibility for patient care between practitioners with different skills sets is recognised to be beneficial, and combined obstetric and medical clinics have been suggested as an attainable goal throughout the country. Monthly joint clinics would enable more considered evaluation of suspected medical disorders during pregnancy and an enhanced level of care together with appropriate referral to regional hospitals. The difficulty of discerning between normal pregnancy physiology and clinical disease, as well as understanding the impact of pregnancy physiology on underlying medical disease has not been taught or examined in the post-graduate training curriculum of general physicians. The anticipated benefits of combined care would only be realised once essential aspects of pregnancy physiology and pathophysiology and their influence on the expression and management of medical disease complicating pregnancy is incorporated into the university curriculum. Such changes are under consideration at present and to that end, this publication establishes a template for understanding the epidemiology of cardiac problems in pregnancy, understanding the (patho)physiology of pregnancy and how interventions, both obstetric and medical, may influence the outcome of these pregnancies. The broader object of this process still remains the targets set 15 years ago and enunciated as the millennium development goals.3

References 1.

Andrew Sarkin, MB BCh, FCP (Med) 3.

National Department of Health. Saving Mothers 2011â&#x20AC;&#x201C;2013: Sixth report on confidential enquiries into maternal deaths in South Africa. Short report, 2015. Sliwa K, et al. Spectrum of cardiac disease in maternity in a lowresource cohort in South Africa. Heart 2014: p. heartjnl-2014-306199. United Nations Declaration. Millennium Development Goals, 2000.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

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Cardiovascular Topics The importance of cardiovascular pathology contributing to maternal death: Confidential Enquiry into Maternal Deaths in South Africa, 2011–2013 Priya Soma-Pillay, Joseph Seabe, Karen Sliwa

Abstract Aims: Cardiac disease is emerging as an important contributor to maternal deaths in both lower-to-middle and higherincome countries. There has been a steady increase in the overall institutional maternal mortality rate in South Africa over the last decade. The objectives of this study were to determine the cardiovascular causes and contributing factors of maternal death in South Africa, and identify avoidable factors, and thus improve the quality of care provided. Methods: Data collected via the South African National Confidential Enquiry into Maternal Deaths (NCCEMD) for the period 2011–2013 for cardiovascular disease (CVD) reported as the primary pathology was analysed. Only data for maternal deaths within 42 days post-delivery were recorded, as per statutory requirement. One hundred and sixty-nine cases were reported for this period, with 118 complete hospital case files available for assessment and data analysis. Results: Peripartum cardiomyopathy (PPCM) (34%) and complications of rheumatic heart disease (RHD) (25.3%) were the most important causes of maternal death. Hypertensive disorders of pregnancy, HIV disease infection and anaemia

Department of Obstetrics and Gynaecology, Maternal and Foetal Medicine, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa Priya Soma-Pillay, MB ChB, MMed (O et G) Pret, FCOG, Cert (Maternal and Foetal Med) SA, Priya.Soma-Pillay@up.ac.za

Department of Obstetrics and Gynaecology, Tembisa Hospital, Tembisa, South Africa Joseph Seabe, MD

National Committee for the Confidential Enquiry into Maternal Deaths, South Africa Priya Soma-Pillay, MB ChB, MMed (O et G) Pret, FCOG, Cert (Maternal and Foetal Med) SA Joseph Seabe, MD

were important contributing factors identified in women who died of peripartum cardiomyopathy. Mitral stenosis was the most important contributor to death in RHD cases. Of children born alive, 71.8% were born preterm and 64.5% had low birth weight. Seventy-eight per cent of patients received antenatal care, however only 33.7% had a specialist as an antenatal care provider. Avoidable factors contributing to death included delay in patients seeking help (41.5%), lack of expertise of medical staff managing the case (29.7%), delay in referral to the appropriate level of care (26.3%), and delay in appropriate action (36.4%). Conclusion: The pattern of CVD contributing to maternal death in South Africa was dominated by PPCM and complications of RHD, which could, to a large extent, have been avoided. It is likely that there were many CVD deaths that were not reported, such as late maternal mortality (up to one year postpartum). Infrastructural changes, use of appropriate referral algorithm and training of primary, secondary and tertiary staff in CVD complicating pregnancy is likely to improve the outcome. The use of simple screening equipment and point-of-care testing for early-onset heart failure should be explored via research projects. Keywords: cardiac disease in pregnancy, valve disease, valve thrombosis, rheumatic heart disease, cardiomyopathy, peripartum cardiomyopathy Submitted 31/8/15, accepted 1/2/16 Published online 19/2/16 Cardiovasc J Afr 2016; 27: 60–65

www.cvja.co.za

DOI: 10.5830/CVJA-2016-008

Cardiac disease is emerging as an important indirect cause of maternal death globally. Cardiac conditions may be pre-existing, such as rheumatic heart disease (RHD) or congenital heart disease and may be unmasked by the increased haemodynamic load in pregnancy, or may be caused by the pregnancy, for example hypertensive disorders or peripartum cardiomyopathy (PPCM).1 Compared with child mortality, maternal mortality has been more difficult to track over time at a national level, in particular in middle- to lower-income countries (LMICs). Major challenges include incomplete data sets, inexperience of the physicians in applying the classifications, misclassification of maternal deaths to other causes in countries with complete vital registration and

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

medical certification of causes of deaths.2 However, many cases remain unreported due to lack of linkage to the causality of the pregnancy. Maternal death is rarely reported beyond six weeks postpartum. The ICD 10 classification (version 10) defining late maternal death (six weeks to one year) is often not applied. This leads to the fact that death due to, for example PPCM, which often only presents three to five months postpartum, death due to left ventricular dysfunction and heart failure related to hypertensive disorders in pregnancy, or death related to right heart failure in complex congenital heart disease remains unreported and, therefore, not adequately addressed. There is a profound lack of knowledge on cardiac disease contributing to morbidity and mortality, which impacts on foetal outcome, not only in South Africa but on a global level. The objectives of the study were to determine the cardiovascular causes and contributing co-morbidities of maternal death in South Africa, and to identify avoidable factors and missed opportunities. The goal is to develop strategies to improve quality of care, with the ultimate aim to reduce maternal death due to cardiovascular disease.

Methods This study was an audit of maternal deaths due to cardiovascular disease in South Africa for the period 2011–2013. Maternal death is defined as the death of a woman while pregnant, or within 42 days of termination of pregnancy, irrespective of the duration and site of pregnancy, from any cause related to or

Maternal death Report completed within 7 days

Sent Provincial assessor

MaMMA entry (provincial assessor)

Provincial MCWH

Provincial assessor’s report sent

Death notified and a unique number given

NCCEMD secretariat

NCCEMD Distributed to provinces who distribute information to regions and districts

Results Overall demographic data, antenatal risk factors and mode of delivery The demographic information of the study population is shown in Table 1. The majority of the women were black African, with a mean age of 28.6 years and a parity of less than 2. More than one-third of the patients were HIV positive. Most patients had a low systolic blood pressure of 116 ± 28.6 mmHg and an elevated heart rate (HR). Table 1. Demographic data of the study population (n = 118) Parameters

Returned within 30 days Anaesthetic assessments

aggravated by the pregnancy or its management, but not from accidental or incidental causes.3 In South Africa it is currently not a statutory requirement to document and record late maternal deaths (up to one year postpartum, ICD 10 code, version 10). Maternal deaths are notifiable by law in South Africa. Following the death of a mother, it is the responsibility of the clinician caring for the mother to fill in the Maternal Death Notification form (MDNF). This form, together with a copy of the patient’s clinical notes, must be sent to the Provincial Maternal Child and Woman’s Health Office within seven days of the maternal death. Fig. 1 describes the process of the Confidential Enquiry into Maternal Deaths.4 One hundred and sixty-nine cases of maternal deaths related to cardiac disease were reported to the National Committee for the Confidential Enquiries into Maternal Deaths (NCCEMD) and entered on the MaMMA’s database for the triennium 2011–2013. One hundred and eighteen hospital case files with complete data were available for assessment, data extraction and analysis. Permission was obtained from the NCCEMD and the Department of Health of South Africa for this audit to be conducted and presented.

Report

All basic data destroyed MCWH: Office for Maternal Child and Women’s Health. NCCEMD: National committee for the Confidential Enquiry into Maternal Deaths. MaMMA: Maternal Mortality and Morbidity database.

Fig. 1. T he process of Confidential Enquiry into Maternal Deaths.

Demographic data

Race African, n (%)

104 (88.2)

Coloured, n (%)

7 (6.9)

White, n (%)

5 (3.9)

Indian, n (%)

2 (1.7)

Age (years) Mean (± SD) Range

28.6 (6.49) 17–43

Obstetric history Parity median (range)

1 (1–6)

Gravidity median (range)

2 (1–6)

HIV disease status, n (%) HIV positive

50 (42.4)

HIV negative

56 (47.5)

Unknown disease status

12 (10.2)

CD4 count median (SD)

275 (18-839)

Haemoglobin at presentation Haemoglobin (g/dl), mean (± SD) Range

9.5 (1.8) 5–12

Heart rate at presentation Heart rate (bpm), mean (± SD) Range

115 (25.7) 69–180

Blood pressure at presentation Systolic blood pressure (mmHg), mean (± SD)

116.3 (28.6)

Diastolic blood pressure (mmHg), mean (± SD)

65.1 (20.7)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

Table 2. Antenatal risk factors (n = 118) Risk factor

70 Number (%)

With known heart disease

46 (39.7)

Smoking (past and current)

11 (9.3)

60 50

8 (6.8)

Hypertension

43 (36.4)

Proteinuria in current pregnancy

22 (18.6)

Glycosuria in current pregnancy

12 (10.2)

Anaemia (haemoglobin < 10 g/l)

30 (26.8)

Tuberculosis (past and current)

0 Specialist

Table 2 summarises the antenatal risk factors (as reported in the MDNF) as documented at the first antenatal visit of the pregnant mother. Some patients had more than one risk factor. Ninety-two (78%) patients attended antenatal clinics, but only 44.3% of patients booked for antenatal care before 20 weeks’ gestation. Fig. 2 describes the level of antenatal care received by the women who died. Forty (33.7%) mothers delivered vaginally, 31 (26.3%) by Caesarean section, and 47 (39.8%) mothers were undelivered. The average gestation at delivery was 32 weeks. Fifty-one (71.8%) babies were born preterm (< 37 weeks’ gestation). The average birth weight of babies born alive was 2 558 g. Of the babies born alive, 37 (64.5%) were low birthweight (< 2.5 kg) babies.

Cardiovascular conditions and co-morbidities leading to death An electrocardiogram and echocardiogram was performed in only 42.9% (n = 50) and 34% (n = 40) of patients, respectively. The mean heart rate of the patients who died was 115 beats per minute (Table 1); 19 were hypertensive (systolic BP > 140 mmHg) and eight were hypotensive (systolic BP < 100 mmHg). The majority of women (69%, n = 71) died after delivery, while the remaining 47 (31%) died during the antenatal period. For the mothers who died in the postpartum period, death occurred 11 ± 10.7 days postpartum. Seventy-two per cent of mothers presented to the health institutions in a critically ill condition, while 6% of the mothers were dead on arrival. The maternal deaths occurred at the following health localities: community health clinics, five patients (4.12%); level one hospital, 25 (21.7%); level two hospitals, 34 (28.9%); level three hospitals, 50 (42.3%) and private hospitals, four (3.1%). The diagnosis contributing to cardiac death is illustrated in Fig. 3. PPCM (34%) and complications of RHD, which includes un-operated cases, as well as cases with prosthetic valve disease Peripartum cardiomyopathy 19 (6.2%) 2 (1 . 7 3 (2 %) .5% ) 6 (5.1%)

Rheumatic heart disease Other cardiomyopathies 41 (34%)

9 (7.6%)

Prosthetic heart valves Pulmonary hypertension Congenital heart disease Myocardial infarction

9 (7.6%) 10 (8.4%)

19 (16%)

Infective endocarditis Other

Fig. 3. C ardiovascular conditions contributing to cardiac death (n = 118).

General practitioner/ Advanced midwife/ medical officer professional nurse

Number

Specialist: a person registered with the Health Professionals Council of South Africa (HPCSA) in an appropriate speciality. General practitioner/medical officer: a doctor with a medical degree registered with the HPCSA. Professional nurse: a person who is qualified as a midwife. Advanced midwife: a professional nurse who has completed a further year of training in midwifery.

Fig. 2. Antenatal care provider.

(25.3%), were the most important diagnoses leading to maternal death.

PPCM and other cardiomyopathy There were 41 deaths due to PPCM. All cases were newly diagnosed as none of the maternal records documented a previous history of cardiomyopathy. Twelve (29.3%) deaths occurred at level three institutions, 14 (34.2%) at level two facilities and 15 (36.6%) at level one or community health clinics. Twenty (48.8%) mothers presented with acute symptoms in the postpartum period. Death occurred in nine (22.0%) patients who were undelivered, and 32 (78.1%) were postpartum. The most important antenatal co-morbidities identified among the women who died due to a cardiomyopathy were: hypertension, 22 patients (53.7%), HIV infection, 17 (41.5%) and anaemia, 15 (36.6%). Twenty (48.8%) mothers however had a haemoglobin level of < 10 g/dl when they presented in acute cardiac failure. In most cases, a clinical diagnosis was made, in only 12 (30%) cases was an electrocardiogram performed, and an echocardiogram was done in five (13%) cases to confirm diagnosis of a cardiomyopathy.

Rheumatic heart disease There were 35 maternal death files due to complications of RHD available for assessment. There were 19 cases of valvular heart disease, four deaths due to complications of prosthetic heart valves (presumed to be rheumatic in origin in this South African population), two deaths due to infective endocarditis and five cases of underlying valvular lesions complicated by pulmonary hypertension. Mitral stenosis was the most common valvular lesion contributing to maternal death (> 50% of cases with valvular lesions), followed by severe tricuspid incompetence (n = 4), mixed mitral valve disease (n = 2), aortic stenosis (n = 2), and one case of isolated severe mitral regurgitation. All four patients with mechanical heart valve prostheses died due to valve thrombosis. Two patients were non-compliant with anti-coagulant medications. One patient was treated with

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

low-molecular weight heparin without any monitoring of antiXa levels and no anti-coagulant was prescribed in the other patient post-delivery. The average age of the mothers who died was 28.1 ± 6.49 years. Twenty-four (68.5%) mothers presented for antenatal care with a known history of cardiac disease, while 11 (31.5%) mothers had undiagnosed cardiac lesions prior to pregnancy. Twenty-six (74.1%) mothers booked for antenatal care but only 12 (34. 3%) were managed at a tertiary institution during the antenatal period. Death occurred in the following institutions: level one facility, two patients (5.7%); level two hospitals, 11 (3.4%), and level three hospitals, 22 (62.9%). Table 3 summarises the factors contributing to death for the entire study population, as well as women with PPCM and RHD. This information was obtained from the MDNF and is the opinion of the clinician reporting the death. Some patients had more than one avoidable factor. In 24.3% of cases, the assessors believed that different management could reasonably have been expected to affect outcome. The problems of failure to make a diagnosis, incorrect management and delay in referring patients to the appropriate level of care were important factors that contributed to cardiac mortality (Table 4).

Discussion This study has shown a disease pattern markedly different to that seen in high-income countries, with cardiomyopathies and RHD most commonly leading to death, often complicated by HIV/AIDS, hypertension and anaemia as co-morbidities. Confidential inquiries on maternal death reports from European high-income countries and the European EURObservational Research Programme registry on cardiac disease in pregnancy typically report operated congenital heart disease as the most common mode of death.5

Access to care, avoidable factors and late maternal death The majority of patients attended antenatal care but booked late. Only one-third had access to a specialist as an antenatal care provider. The most important avoidable factors contributing to death included: delay in patients seeking help (> 50% of patients), lack of expertise of medical staff managing the case (30%), delay in referral to the appropriate level of care, and inappropriate action. A recent single-centre prospective cohort study from Groote Schuur Hospital6 has reported that most deaths were due to different forms of cardiomyopathies, with only two related to complications attributable to sepsis and thrombosis affecting Table 3. Factors contributing to death for the two major disease groups Whole group

Peripartum cardiomyopathy

Rheumatic heart disease

n (%)

Patient delay in seeking help

49 (41.5)

16 (39.0)

16 (45.7)

Lack of expertise by medical staff managing case

35 (29.7)

16 (39.0)

12 (34.3)

Delay in referral to appropriate level 31 (26.3) of care

13 (31.7)

8 (22.9)

Delay in appropriate action

15 (36.6)

15 (42.9)

Avoidable factor

43 (36.4)

prosthetic heart valves. However, eight out of the nine deaths reported in this 152-patient cohort with a six-month post-delivery outcome period would not have been reported if the definition of death within 42 days had been applied. This highlights the underestimation of the number of cardiac deaths related to pregnancy as a result of the late presentation, and these deaths are especially important among women with familial or PPCM. The European Society of Cardiology working group on PPCM has defined PPCM as an ‘idiopathic’ cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy, or in the months following delivery, where no other cause of heart failure is found.7 Patients most commonly present two to three months postpartum and therefore outside the 42 days reporting period.8 This condition may be difficult to distinguish from other forms of cardiomyopathy, such as familial or pre-existing idiopathic dilated cardiomyopathy, which usually presents prior to pregnancy or in the second or third trimester. Reported incidence for PPCM varies among different geographic regions, with potential hotspots in Africa (1:100 to 1:1 000).9 There has been an increase in the reporting of PPCM in high-income countries in the past decade and this is probably due to increasing awareness created by a large prospective international registry on PPCM, the ESC EURObservational Research Programme (http://www.eorp.org).10 At present the overall mortality rate is between 10 and 25%. The fact that more than two-thirds of all deaths occurred post-partum and that PPCM was the most common condition leading to death in this tri-annual report is an important finding. It also implies that the maternal death rate in South Africa, which is already estimated to be 176/100 000,2 is underestimated, as death could only be reported until 42 days postpartum. Cardiomyopathies or other causes of left ventricular dysfunction that often present with heart failure or severe arrhythmia leading to death beyond that period is of major concern. These deaths are pregnancy related, even at late presentation. Interventions to prevent these deaths include adequate counselling about the risks of future pregnancy, access to adequate contraceptive services, termination of breastfeeding, and use of the medication bromocriptine8 in patients with PPCM. This is crucial as available data strongly suggest that subsequent pregnancy in patients with PPCM is associated with a high risk of relapse and death.11

Improving care for women with undiagnosed, diagnosed and operated RHD Valvular heart disease in pregnant women, whether due to congenital or acquired aetiologies, such as RHD, poses a challenge to clinicians and their patients. Significant valve Table 4. Foetal outcome for all pregnant women (n = 118), women with peripartum cardiomyopathy (n = 41) and rheumatic heart disease (n = 35) Whole group

Peripartum cardiomyopathy

Rheumatic heart disease

n (%)

In utero death

11 (9.3)

4 (9.8)

3 (8.6)

Gestation, mean (± SD)

32 (7.7)

35.6 (6.9)

27.2 (8.9)

Born preterm (< 37 weeks gestation) 51 (71.8)

14 (34.1)

15 (42.9)

37 (64.5)

10 (24.3)

11 (31.4)

Low birth weight (< 2 500 g)

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disease increases the risk of pregnancy to the mother and foetus and requires a careful preconception risk assessment and, subsequently during pregnancy, specialised care to minimise maternal and foetal morbidity and mortality. All women with valvular heart disease should ideally have preconception evaluation, including advice on risk prediction and contraception by a joint cardiac–obstetric team. Zühlke and co-authors reported recently from the REMEDY study that among 1 825 women of child-bearing age with RHD, only 3.6% were on contraception.12 A recent publication by Sliwa et al.13 summarises how counselling on maternal and offspring risk should be carried out in women with valvular heart disease, according to the modified World Health Organisation (WHO) classification, and should include information on complications such as heart failure and valve thrombosis, which can occur during and beyond the immediate delivery period. Management of the patients in our cohort was clearly sub-optimal. Many patients presented late to healthcare providers and this was possibly due to lack of knowledge of the underlying cardiac problem. This could potentially be improved by providing better information by a counsellor, cell phone/ web-based information or via short featured video clips, e.g. www.heduafrica.org and MomConnect website (www.rmch. org/wp-content/uploads/2014/08/MomConnect-Booklet.pdf). Appropriate guidance in referral to secondary and tertiary care hospitals with dedicated cardiac disease in maternity clinics should be implemented and is currently being explored in South Africa.

Cardiac disease contributing to institutional maternal mortality rate in South Africa There has been a steady increase in the institutional maternal mortality rate (iMMR) for cardiac disease over the last decade in South Africa.14 The iMMR for cardiac disease in 2005–2007 was 3.73 and this increased to 5.64 during 2008–2010, and to 6.00 per 100 000 during 2011–2013. After non-pregnancy-related infections, cardiac disease is the second most common cause of indirect maternal death. The Saving Mothers reports of 2002–2004 and 2005– 2007 have grouped all cases of cardiomyopathy (peripartum cardiomyopathy and other cardiomyopathies) in one category when analysing causes of cardiac death.4,15 In these reports, complications of RHD and cardiomyopathy were the most important and equal contributors to cardiac deaths. In the triennium 2011–2013, the number of deaths due to peripartum cardiomyopathy was more than double that of complications related to RHD, and formed 34% of the total number of cardiac deaths. Our data suggest that care in the postpartum period needs to be improved, possibly including earlier referral to the general cardiac clinic or cardiomyopathy clinic. However, joint obstetric– medical–cardiac clinics would be the optimal approach for these patients. Medical physicians and cardiologists need to be actively involved in the postpartum care of women with cardiac disease. A need to provide focused training to medical registrars has already been identified. Most tertiary level hospitals in South Africa, such as Steve Biko Academic Hospital, Pretoria and Groote Schuur Hospital, Cape Town, now provide a bi-weekly cardiac–obstetric clinics and regular obstetric medicine lectures in their registrar training programmes.

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The use of simple screening equipment, such as hand-held echocardiography and point-of-care testing for early-onset heart failure, should be explored via research projects. A recent publication evaluated the ability of medical students who had previously received training in echocardiography (eight hours) to detect RHD. The students’ averaged sensitivity for diagnosing RHD was 81%, while specificity was 95%.16 Handheld echocardiography as a routine diagnostic facility should be considered as a training module for students and could improve detection of significant cardiac disease in primary and secondary care.17 Research on the use of simple point-of-care testing on NT-proBNP, a marker of early heart failure, could lead to earlier detection of heart failure related to various forms of CVD.

Limitations The retrospective analysis of patients’ files, and the limited number of investigations that can be performed in primary or secondary care or due to the emergency condition itself clearly impacts on the quality of data that can be collected via such a retrospective audit. It is a major limitation that not all patients’ files were accessible. In many cases the diagnosis, often made by a junior doctor, could not be verified or the patient died prior to reaching a higher-level hospital.

Conclusion The pattern of CVD contributing to maternal deaths in South Africa was dominated by cardiomyopathies and complications of RHD, which could have been avoided to a large extent. There is most likely an underestimation of maternity-related death, as late maternal mortality (up to one year postpartum) is not recorded. Infrastructural changes, use of an appropriate referral algorithm and training of primary, secondary and tertiary staff in cardiovascular disease complicating pregnancy is likely to improve the outcome. The authors thank the National Department of Health of South Africa for the use of the data. K Sliwa acknowledges the Medical Research Council of South Africa, the University of Cape Town, the Maurice Hatter Foundation and Servier South Africa for institutional support.

References 1.

Mocumbi AO, Sliwa K. Women’s cardiovascular health in Africa. Heart 2012; 98: 450–455.

Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, Shackelford KA, Steiner C, Heuton KR, et al. Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 980–1004.

World Health Organization. Evaluating the quality of care for severe pregnancy complications: The WHO near-miss approach for maternal health. Geneva: 2011.

Saving Mothers 2008–2010. Fifth report on the confidential enquiries into maternal deaths in South Africa. Pretoria: 2012.

Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K, et al. Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. Eur Heart J 2013; 34: 657–665.

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Sliwa K, Libhaber E, Elliott C, Momberg Z, Osman A, Zuhlke L, et al. Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa. Heart 2014; 100: 1967–1974.

peripartum cardiomyopathy. J Am Coll Cardiol 2014; 64: 1629–1636.

Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B,

Cupido B, et al. Characteristics, complications, and gaps in evidence-

Buchmann E, et al. Current state of knowledge on aetiology, diagnosis,

based interventions in rheumatic heart disease: the Global Rheumatic

management, and therapy of peripartum cardiomyopathy: a position

Heart Disease registry (the REMEDY study). Eur Heart J 2015; 36:

of Cardiology working group on peripartum cardiomyopathy. Eur J Heart Fail 2010; 12: 767–778.

1115–1122a. 13. Sliwa K, Johnson MR, Zilla P, Roos-Hesselink JW. Management of valvular disease in pregnancy: a global perspective. Eur Heart J 2015;

Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nature Rev Cardiol 2014; 11: 364–370.

11. Elkayam U. Risk of subsequent pregnancy in women with a history of 12. Zuhlke L, Engel ME, Karthikeyan G, Rangarajan S, Mackie P,

statement from the Heart Failure Association of the European Society

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Hilfiker-Kleiner D, Haghikia A, Nonhoff J, Bauersachs J. Peripartum cardiomyopathy: current management and future perspectives. Eur Heart J 2015; 36: 1090–1097.

36: 1078–1089. 14. Saving Mothers 2011–2013. Sixth report on confidential enquiries into maternal deaths in South Africa. Pretoria: 2015. 15. Saving Mothers 2005–2007. Fourth Report on Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: 2009.

10. Sliwa K, Hilfiker-Kleiner D, Mebazaa A, Petrie MC, Maggioni AP,

16. Shmueli H, Burstein Y, Sagy I, Perry ZH, Ilia R, Henkin Y, et al. Briefly

Regitz-Zagrosek V, et al. EURObservational research programme: a

trained medical students can effectively identify rheumatic mitral valve

worldwide registry on peripartum cardiomyopathy (PPCM) in conjunc-

injury using a hand-carried ultrasound. Echocardiography 2013; 30:

tion with the Heart Failure Association of the European Society of Cardiology working group on PPCM. Eur J Heart Fail 2014; 16:

621–626. 17. Sliwa K, Zilla P. Rheumatic heart disease: the tip of the iceberg. Circulation 2012; 125: 3060–3062.

583–591.

Register now 5th Annual COngress of the faculty of consulting physicians of south africa 27 – 29 may 2016 Century city conference centre

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Electrocardiographic predictors of peripartum cardiomyopathy Kamilu M Karaye, Krister Lindmark, Michael Y Henein

Abstract Objective: To identify potential electrocardiographic predictors of peripartum cardiomyopathy (PPCM). Methods: This was a case–control study carried out in three hospitals in Kano, Nigeria. Logistic regression models and a risk score were developed to determine electrocardiographic predictors of PPCM. Results: A total of 54 PPCM and 77 controls were consecutively recruited after satisfying the inclusion criteria. After controlling for confounding variables, a rise in heart rate of one beat/minute increased the risk of PPCM by 6.4% (p = 0.001), while the presence of ST–T-wave changes increased the odds of PPCM 12.06-fold (p < 0.001). In the patients, QRS duration modestly correlated (r = 0.4; p < 0.003) with left ventricular dimensions and end-systolic volume index, and was responsible for 19.9% of the variability of the latter (R2 = 0.199; p = 0.003). A risk score of ≥ 2, developed by scoring 1 for each of the three ECG disturbances (tachycardia, ST–T-wave abnormalities and QRS duration), had a sensitivity of 85.2%, specificity of 64.9%, negative predictive value of 86.2% and area under the curve of 83.8% (p < 0.0001) for potentially predicting PPCM. Conclusion: In postpartum women, using the risk score could help to streamline the diagnosis of PPCM with significant accuracy, prior to confirmatory investigations Keywords: peripartum cardiomyopathy, electrocardiogram, predictors, risk score Submitted 25/1/15, accepted 7/12/15 Cardiovasc J Afr 2016; 27: 66–70

www.cvja.co.za

DOI: 10.5830/CVJA-2015-092

Although peripartum cardiomyopathy (PPCM) was first described in 1880, much remains unknown about it.1,2 Electrocardiography (ECG) is an inexpensive and important tool for evaluating cardiac electrical function and is widely Department of Medicine, Bayero University and Aminu Kano Teaching Hospital, Kano, Nigeria Kamilu M Karaye, MB BS, DIC, MSc, FWACP, FESC, FACC, kkaraye@yahoo.co.uk

Department of Public Health and Clinical Medicine, Umea University, Sweden Kamilu M Karaye, MB BS, DIC, MSc, FWACP, FESC, FACC Krister Lindmark, MD, PhD, FACC, FESC Michael Y Henein, MD, PhD, FACC, FESC

Department of Cardiology, Umea Heart Centre, Umea, Sweden Krister Lindmark, MD, PhD, FACC, FESC Michael Y Henein, MD, PhD, FACC, FESC

available, even in limited-resource settings. A recent study found the majority (96%) of PPCM patients had ‘abnormal’ 12-lead ECGs at presentation and highlighted the usefulness of the ECG in screening and prognosticating patients at risk in resource-poor settings.3 To the best of our knowledge, there is a paucity of ECG data in PPCM, and no data on its use in the diagnosis of PPCM in women presenting with clinical features of heart failure towards the end of pregnancy or during the puerperium. The aim of this study was to determine potential ECG variables that predict the diagnosis of PPCM. If proved, such variables could help to streamline the diagnosis of PPCM prior to confirmatory investigations, particularly in limited-resource settings.

Methods This was a case–control study carried out in the Murtala Mohammed Specialist Hospital (MMSH), Aminu Kano Teaching Hospital (AKTH), and a private cardiology clinic in Kano, Nigeria. The research protocol was approved by the ethics committees of each of the study centres, and the study conformed to the ethics guidelines of the Declaration of Helsinki, on the principles for medical research involving human subjects.4 The inclusion criteria for the patients were: (1) confirmed diagnosis of PPCM; (2) onset of symptoms towards the end of pregnancy or within the puerperium, and presentation to hospital within nine months postpartum; (3) age of at least 18 years; and (4) written informed consent. Patients were excluded if: (1) their symptoms could be explained by diagnoses other than PPCM; (2) their symptoms started in early pregnancy or after the first five months postpartum; (3) they were younger than 18 or older than 45 years; (4) they denied consent to participate. To be included, the controls had to satisfy the following criteria: (1) be apparently healthy; (2) no past history of any cardiac disease or systemic hypertension (except pregnancyinduced hypertension); (3) normal ECG (except for flat T waves in leads III or aVF, and inverted T waves in aVR, V1 or V2, which are considered non-specific);5 (4) present to the study centres within nine months postpartum for routine immunisations for their children; and (5) give written informed consent. Subjects taking drugs known to affect ECG intervals were excluded from the study.6 T-wave inversion with or without ST-segment depression were considered abnormal in all leads except aVR, V1 and V2.5 In addition, flat T waves in leads III or aVF were also considered non-specific.5 Controls were excluded if: (1) they presented their children for immunisation after five months postpartum; (2) they presented to the hospital as patients; (3) they were younger than 18 or older than 45 years; (4) they were known or found clinically to have any cardiac disease; (5) they denied consent. The sample size for

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the controls was estimated at 1.5 × the total number of patients (± five patients). PPCM was defined according to the recommendations of the Heart Failure Association of the European Society of Cardiology working group on PPCM, and left ventricular (LV) systolic dysfunction was defined as LV ejection fraction < 50%.7 At the study centres, physicians in the Internal Medicine, and Obstetrics and Gynaecology Departments were approached and requested to refer all patients with suspected PPCM to the principal investigator (PI) for further evaluation. Patients were then interviewed, clinically evaluated and recruited consecutively. Hospital in-patients with PPCM were clinically assessed and underwent investigations within the first 48 hours of admission. Demographic data, relevant aspects of the history and physical signs, results of investigations, co-morbid conditions, and complications were included in a detailed questionnaire. Baseline levels of serum urea, electrolytes and creatinine were carried out in the laboratories of AKTH, while 12-lead ECGs at rest, and transthoracic echocardiograms (for PPCM patients only) were all carried out by the PI at the study sites, according to standard recommendations.8 The echocardiographic examination was performed using a Sonoscape S8 Doppler ultrasound (Shenzhen, China, 2010) and the ECG was recorded using a Mindray DECG-03A digital electrocardiograph (Shenzhen, China, 2008).8,9 All ECG recordings were studied and interpreted by the investigators in the standard fashion, and ECG intervals/ durations were measured using manual callipers.10,11 The controls were evaluated using the same protocol as the patients, including the ECGs, but an echocardiogram was not performed.

Statistical analysis Frequencies, mean, median and inter-quartile ranges were used to describe patients’ characteristics. Chi-square, Fisher’s exact probability, Student’s t- and Mann–Whitney U-tests were used to compare categorical and continuous variables as appropriate. Binary logistic regression models were used to determine predictors of PPCM among the ECG variables, and values were expressed as odds ratios (OR) and 95% confidence intervals (CI). Pearson’s correlation coefficient and linear regression models were used to further assess relationships between variables of interest. A simple score assigning 1 to each identified independent ECG predictor was composed and its accuracy in predicting PPCM was determined using the area under the receiver operating characteristics (ROC) curve (AUC), and AUC > 0.75 was considered satisfactory. A p-value < 0.05 was considered statistically significant. The statistical analysis was carried out using SPSS version 16.0 software.

Table 1. Baseline characteristics of PPCM patients and controls PPCM patients (n = 54)

Controls (n = 77)

Mean age (years)

26.6 ± 6.7

25.7 ± 5.7

p-value 0.450

Body mass index (kg/m2)

21.6 ± 4.3

21.8 ± 4.3

0.836

Systolic BP (mmHg)

119 ± 24

123 ± 16

0.293

Diastolic BP(mmHg)

86 ± 18 16 (41.0)

82 ± 12 14 (28)

0.099

Pregnancy-induced hypertension, n (%) 0.197 Serum creatinine (µmol/l) 0.045* 93.2 ± 67.1 74.7 ± 19.3 Serum sodium (mmol/l) 0.009* 136.9 ± 5.9 139.6 ± 4.4 Serum potassium (mmol/l) 3.9 ± 0.8 4.6 ± 0.7 < 0.001* *p-value statistically significant; values are expressed as means ± standard deviations or as numbers with percentages in parentheses.

pregnancy-induced hypertension were not significantly different between the two groups (p > 0.05). However, mean serum level of creatinine was higher (p = 0.045), and mean serum sodium and potassium levels were significantly lower (p = 0.009 and < 0.001 respectively) in patients compared to controls. ECG findings are presented in Table 2. All subjects were in sinus rhythm, and ectopic beats and PR interval were not significantly different (p > 0.05) between the two groups. However, patients had significantly faster heart rates, broader QRS durations, prolonged QTc intervals, and more frequent tachycardia and ST–T-wave abnormalities (T-wave inversion with or without ST-segment depression in all leads except aVR, V1 and V2) than the controls (p < 0.004 for all comparisons).

ECG predictors of PPCM The results of the logistic regression models are presented in Table 3. In the univariate analysis, heart rate, ST–T-wave abnormalities, and QRS and QTc durations were all predictors of PPCM (p ≤ 0.003). In addition, heart rate < 100 beats/min reduced the risk of having PPCM by 89.7% (p < 0.001). The presence of ST–T-wave abnormalities increased the odds of PPCM almost 12-fold (p < 0.001), while QRS duration > 110 ms and QTc duration > 460 ms increased the odds 5.2-fold (p < 0.001) and 9.5-fold (p < 0.001), respectively. Stepwise multivariate regression analyses were then carried out to control for confounding factors. In the initial model, including heart rate, ST–T-wave abnormalities, QRS duration Table 2. ECG features of PPCM patients and controls

Sinus rhythm, n (%) Premature ventricular or atrial extrasystoles, n (%) Heart rate, beats/min

Results

Tachycardia, n (%)

A total of 54 PPCM and 77 controls satisfied all the inclusion criteria and were consecutively recruited. PPCM patients were recruited at the time of confirmation of diagnosis, when specific heart failure treatment was also commenced. The baseline characteristics of the subjects are presented in Table 1. The mean age, body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), and prevalence of

QRS duration ≥ 110 ms QTc duration (ms)

QRS duration (ms)

QTc duration ≥ 460 ms PR interval (ms) ST–T-wave abnormalities

PPCM patients (n = 54) 54 (100) 5 (9.3)

Controls (n = 77) 77 (100) 4 (5.2)

p-value

111 ± 16 36 (66.7)

90 ± 16 17 (22.1)

< 0.001*

109.9 ± 23.6 19 (35.2)

98.6 ± 12.8 8 (10.4)

445.0 ± 34.2 12 (22.2)

421.2 ± 18.9 3 (3.9)

< 0.001* 0.001*

148.1 ± 20.4 37 (68.5)

149.1 ± 21.1 13 (16.9)

< 0.001*

0.365

< 0.001* 0.004* 0.001*

0.799

*p-value statistically significant; values are expressed as means ± standard deviations or as numbers with percentages in parentheses.

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and QTc interval, the former two maintained their statistical significance (p < 0.001 each), while the latter two lost their prediction of PPCM (p > 0.05 for each). The addition of serum sodium or potassium levels to the models with heart rate and ST–T-wave abnormalities did not influence the results, as the two ECG variables maintained their predictive value (p < 0.001), although serum potassium exerted greater influence than sodium levels. Therefore after controlling for confounding variables, including serum sodium and potassium levels, a rise in heart rate of one beat/min increased the risk of PPCM 6.4% (p = 0.001), while the presence of ST–T-wave changes increased the odds of PPCM 12.06-fold (p < 0.001).

180 160 140 LVESVI

120 100 80 60

Relationship between ECG and echocardiographic variables The patients were evaluated echocardiographically. Mean end-diastolic and end-systolic dimensions (LVEDD and LVESD, respectively), LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF) were 61.4 ± 8.8 mm, 51.0 ± 9.1 mm, 85.1 ± 33.1 ml/m2 and 34.4 ± 9.9%, respectively. The relationship between these echocardiographic and ECG variables are presented in Table 4, which shows that QRS duration was the only variable that modestly correlated with LV dimensions and LVESVI, and showed a trend towards a significant relationship with LVEF (r = –0.27; p = 0.065). Fig. 1 shows the relationship between QRS duration and LVESVI, which was responsible for 19.9% of its variability (R2 = 0.199; p = 0.003).

ECG risk score for PPCM Three variables, namely tachycardia, ST–T-wave abnormalities and QRS duration, were included in the risk score, counting 1 Table 3. Binary logistic regression models for predictors of PPCM Variables Univariate analysis ECG heart rate, beats/min

Odds ratio

95% CI

< 0.001* 0.003*

Normal heart rate

0.103 0.044–0.241

QRS ≥ 110 ms

5.241 2.057–13.355

< 0.001* 0.001*

9.471 2.548–35.199

0.001*

ST–T-wave abnormalities QRS duration, ms QTc interval, ms B (included variables: heart rate, ST-Twave abnormalities, serum potassium level) ECG heart rate, beats/min ST-T-wave abnormalities C (included variables: heart rate, ST-Twave abnormalities, serum sodium level) ECG heart rate, beats/min ST–T-wave abnormalities

125

150 ECG QRS Observed

175

200

Linear

Fig. 1. Relationship between QRS duration and LV endsystolic volume index. R2 = 0.199; B = 0.571 (CI = 0.200–0.943); p = 0.003. LVESVI, left ventricular endsystolic volume index.

for each if present and 0 if absent (see Table 5). Tachycardia was defined as heart rate > 100 beats/min, ST–T-wave abnormalities as T-wave inversion with or without ST-segment depression in all leads except aVR, V1 and V2, and broad QRS duration > 110 ms. A total of 46 patients and 27 controls had a score of ≥ 2. This score had a sensitivity of 85.2%, specificity of 64.9%, positive predictive value (PPV) of 67.7%, negative predictive value (NPV) of 86.2% and AUC of 83.8% (CI = 76.4–91.2%; p < 0.0001) (see Fig. 2) for predicting PPCM.

Table 4. Correlation between ECG and echocardiographic variables 1.078 1.048–1.109 1.038 1.013–1.065 1.036 1.019–1.054

Multivariate analyses A (included variables: heart rate, QRS, QTc, ST–T-wave abnormalities) ECG heart rate, beats/min

100

p-value

QRS duration, ms QTc interval, ms

QTc ≥ 460 ms ST–T-wave abnormalities

< 0.001*

11.970 5.160–22.770 < 0.001*

1.073 1.036–1.112 < 0.001* 14.591 4.581–46.480 < 0.001* 1.028 0.994–1.062 0.105 1.014 0.993–1.035 0.202

1.066 1.029–1.104

< 0.001*

12.056 3.507–4.443

< 0.001*

13.415 4.203–42.825 < 0.001* 1.064 1.029–1.101 < 0.001*

*p-value statistically significant; ECG, electrocardiogram.

ST–T-wave ECG ECG ECG abnormalities QRS QT HR LVESD Pearson correlation +0.033 +0.446 +0.096 +0.109 p-value 0.822 0.002* 0.515 0.460 LVEDD Pearson correlation +0.072 +0.420 +0.073 +0.039 p-value 0.624 0.003* 0.624 0.793 LVEF Pearson correlation +0.015 –0.268 +0.009 –0.231 p-value 0.920 0.065 0.949 0.115 LVESVI Pearson correlation +0.012 +0.446 +0.065 +0.095 p-value 0.936 0.003* 0.685 0.553 *p-value statistically significant; ECG, electrocardiogram; HR, heart rate; LVESD, left ventricular end-systolic dimension; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index.

Table 5. The ECG risk score for PPCM ECG variable Heart rate, beats/min ST–T-wave abnormalities QRS duration, ms

Value < 100 ≥ 100 Absent Present < 110 ≥ 110

Score 0 1 0 1 0 1

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1.0

Sensitivity

0.8 0.6 04 0.2 0.0 0.0

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Diagonal segments are produced by ties.

Fig. 2. R OC curve of PPCM risk score. Area under the curve = 83.8% (CI = 76.4–91.18%); p < 0.0001.

Discussion This study describes, perhaps for the first time, the use of postpartum ECG variables in a simple risk score that seems to predict PPCM diagnosis among women at risk for the disease. PPCM patients and controls had similar age, systolic and diastolic blood pressures and body mass index. Therefore, the findings could not have been influenced by these possible confounders. Our findings show that the presence of heart rate less than 100 beats/min reduced the risk of diagnosing PPCM to 89.7%, while the presence of ST–T-wave abnormalities, QRS duration more than 110 ms and QTc duration longer than 460 ms increased the odds of PPCM 12.0-, 5.2- and 9.5-fold, respectively. In the initial multiple regression model, heart rate and ST–T-wave abnormalities maintained their high statistical significance in predicting PPCM but not QRS duration and QTc interval. This finding was not influenced by serum sodium or potassium levels. None of our patients had malignant arrhythmia, and ectopic beats were equally uncommon in both groups. These results are supported by previous reports in women with PPCM as well as in healthy pregnant women.3,12 Serum sodium and potassium levels were significantly lower in the patients than the controls, possibly because of water retention caused by heart failure syndrome.7 It should be noted that patients were all recruited at the time of confirmation of the diagnosis, when most heart failure treatments were commenced, and none was on drugs that could affect ECG measurements. For the first time, we have developed a simple scoring system using three ECG variables that could potentially predict PPCM with an accuracy of 83.8%. A risk score of ≥ 2 had a sensitivity of 85.2%, specificity of 64.9% and NPV of 86.2%. The score’s satisfactory accuracy in predicting the diagnosis of PPCM makes it appealing for routine use, particularly in areas where the disease is prevalent and more expensive diagnostic facilities are limited. Our results have shown that in the patients, ECG measurements were related to cardiac structure and function, suggesting diffuse pathological changes. QRS duration modestly correlated with LVEDD, LVESD and LVESVI, explaining 19.9% of the variability of the latter, but had only a trend towards a relationship with LVEF. Furthermore, QRS duration of > 110

ms significantly increased the odds of PPCM 5.2-fold, in spite of the faster heart rate in patients compared to controls. These results are supported by a previous study, which showed an association between QRS duration and mortality among predominantly male (98%), elderly Caucasians with moderate to severe LV systolic dysfunction caused by a variety of diseases (LVEF < 40%).13 Therefore in patients presenting with clinical features of heart failure, QRS duration > 110 ms could be used to suggest significant LV dilatation and systolic dysfunction, as well as a poor prognosis. T-wave abnormalities were identified in 68.5% of our patients. Similar findings were reported by Ntusi et al. in dilated cardiomyopathy patients, with a lower prevalence in idiopathic (68.8%) compared to those with familial disease (87.5%), but there was no association between such electric disturbance and survival.14 It seems therefore that T-wave changes, which reflect disturbed repolarisation, may have a less detrimental effect on a patient’s survival compared with QRS duration, which, in most, mirrors the impact of systolic dysfunction. In our series, QRS duration was the only ECG variable that correlated with LV dimensions and end-systolic volume index, while heart rate and ST–T-wave abnormalities had higher sensitivity in predicting PPCM. Longitudinal follow-up studies would determine the prognostic impact of ECG variables in the setting of PPCM. Heart rate and ST–T-wave changes seemed to independently predict the diagnosis of PPCM. In addition, a simple score of ≥ 2, counting 1 for each of three ECG abnormalities (tachycardia, ST–T-wave abnormalities and QRS duration > 110 ms) had 83.8% accuracy for predicting PPCM in women at risk. These findings could help to filter out patients requiring additional investigations in areas with limited resources. This study has some limitations. Firstly, serum levels of calcium and magnesium were neither assessed nor controlled for, but deficiencies of these electrolytes have not been reported to be common in PPCM patients.7 Secondly, PPCM patients were not directly compared with patients with other conditions, such as dilated cardiomyopathy, but we relied on published evidence; therefore the findings cannot be considered specific to PPCM. The sample size was small but our results are consistent and seem to provide evidence for using easily measured ECG variables to predict PPCM in women at risk of the disease. Finally, echocardiography was not performed on the controls. They were screened using clinical evaluation and ECG only, which can be used to identify healthy women after delivery.3 Our findings should be considered as representative of the early stage of the disease, while long-term electrical abnormalities remain to be determined.

Conclusion This study shows, for the first time, that in women presenting within the first nine months after delivery with symptoms of heart failure, heart rate and ST–T-wave abnormalities were potential predictors of a diagnosis of PPCM. QRS duration modestly correlated with LV dimensions and LVESVI. A simple ECG-based score could potentially predict the diagnosis of PPCM, a finding that could help to streamline the diagnosis of PPCM prior to confirmatory investigations, particularly in limited-resource settings, where the disease is common.

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We acknowledge the efforts of Dr Hadiza Saidu and Mr Ibrahim Armaya’u,

Standards Committee; Task Force on Chamber Quantification; American

both of Murtala Mohammed Specialists Hospital, Kano, during the recruit-

College of Cardiology Echocardiography Committee; American Heart

ment of patients at the Hospital. This study was supported by funds received

Association; European Association of Echocardiography, European

from Umea University, Sweden.

Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7: 79–108.

References 1.

phy. A Report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of

Porak C. De l’influence réciproque de la grossesse et des maladies du

CD, et al. ACC/AHA clinical competence statement on electrocardiog-

Tibazarwa K, Lee G, Mayosi B, Carrington M, Stewart S, Sliwa K. The

raphy and ambulatory electrocardiography: a report of the American

12-lead ECG in peripartum cardiomyopathy. Cardiovasc J Afr 2012;

College of Cardiology/American Heart Association/ American College

23(6): 322–329.

of Physicians − American Society of Internal Medicine Task Force on

World Medical Association Declaration of Helsinki. Ethical principles

Clinical Competence (ACC/AHA Committee to Develop a Clinical

for medical research involving human subjects. J Postgrad Med 2002;

Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol 2001; 38: 2091−2100.

Goldberger AL, Goldberger ZD, Shvilkin A. Understanding the

11. Buxton AE, Calkins H, Callans DJ, DiMarco JP, Fisher JD, Greene

normal ECG. In: Goldberger AL, Goldberger ZD, Shvilkin A (eds).

HL, et al. ACC/AHA/HRS 2006 key data elements and definitions for

Goldberger’s Clinical Electrocardiography, A Simplified Approach. 8th

electrophysiological studies and procedures: a report of the American

edn. Philadelphia: Elsevier Saunders; 2013: 26–34.

College of Cardiology/American Heart Association task Force on

Woosley RL. Drugs that prolong the QT interval and/or induce torsades

Clinical Data Standards (ACC/AHA/HRS Writing Committee to

de pointes. http://www.azcert.org/medical-pros/drug-lists/browse-drug-

Develop Data Standards on Electrophysiology). Circulation 2006; 114:

Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, et al. Heart Failure Association of the European

Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. 10. Kadish AH, Buxton AE, Kennedy HL, Knight BP, Mason JW, Schuger

Coeur, thesis, Paris, 1880.

list.cfm (accessed on 13th December 2014). 7.

Recommendations for quantification of Doppler echocardiogra-

by Porak C. De l’influence réciproque de la grossesse et des maladies du

48: 206–208. 5.

Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA.

Virchow R. Sitzing der Berliner Geburtshilflisher Gersellskhalt. (Cited Coeur, thesis, Paris, 1880.)

2523–2570. 12. Salisu AI, Karaye KM. Electrocardiographic indices in a rural pregnant Nigerian women population. Sahel Med J 2010; 13(3): 147–152.

Society of Cardiology Working Group on Peripartum Cardiomyopathy:

13. Silvet H, Amin J, Padmanabhan S, Pai RG. Prognostic implications

Current state of knowledge on aetiology, diagnosis, management and

of increased QRS duration in patients with moderate and severe left

therapy of peripartum cardiomyopathy: a position statement from

ventricular systolic dysfunction. Am J Cardiol 2001; 88(2): 182–185, A6.

the Heart Failure Association of the European Society of Cardiology

14. Ntusi NB, Badri M, Gumedze F, Wonkam A, Mayosi BM. Clinical

Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010;

characteristics and outcomes of familial and idiopathic dilated cardio-

12(8): 767–778.

myopathy in Cape Town: a comparative study of 120 cases followed up

Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka

over 14 years. S Afr Med J 2011; 101(6): 399–404.

PA, et al. American Society of Echocardiography’s Nomenclature and

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016

Review Articles Pre-eclampsia: its pathogenesis and pathophysiolgy P Gathiram, J Moodley

Abstract Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 5–8%. It is one of the main causes of maternal and perinatal morbidity and mortality globally and accounts for 50 000–60 00 deaths annually, with a predominance in the low- and middle-income countries. It is a multisystemic disorder however its aetiology, pathogenesis and pathophysiology are poorly understood. Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors. This review covers the latest thoughts on the pathogenesis and pathology of pre-eclampsia. The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors. This imbalance in favour of anti-angiogenic factors leads to widespread endothelial dysfunction, affecting all the maternal organ systems. In addition, there is foetal growth restriction (FGR). The exact aetiology remains elusive. Keywords: pre-eclampsia, major cause of maternal mortality and morbidity, placenta Submitted 6/7/15, accepted 17/2/16 Cardiovasc J Afr 2016; 27: 71–78

www.cvja.co.za

DOI: 10.5830/CVJA-2016-009

Pre-eclampsia (PE) is a disorder of pregnancy with a worldwide prevalence of about 5–8%. It is characterised by new-onset hypertension with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, measured on two occasions at least four hours apart, and proteinuria of > 0.3 g per 24 hours or ≥ 1+ proteinuria, detected by urine dipstick after 20 weeks of pregnancy, or in the absence of proteinuria, new-onset hypertension with new onset of any one of the following: thrombocytopaenia (platelet count < 100 000/μl), renal insufficiency (serum creatinine

Department of Physiology, Women’s Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa P Gathiram, PhD

Department of Obstetrics and Gynaecology and Women’s Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa J Moodley, FCOG, jmog@ukzn.ac.za

concentration > 1.1 mmg/dl or a doubling of the serum creatinine concentration in the absence of other renal disease), impaired liver function (raised concentrations of liver transaminases to twice normal concentrations), pulmonary oedema, or cerebral or visual problems.1 PE is one of the main causes of maternal mortality, resulting in about 50 000–60 000 deaths annually worldwide.1 In addition, it is associated with an increased risk of the mother and her child developing cardiovascular complications and diabetes mellitus later in life.2 Furthermore, PE is a multi-systemic syndrome, involving genetic and environmental factors in its pathogenesis and pathophysiology and the only known treatment is delivery of the foetus and placenta.3 In addition, there are subtypes of PE, which are based on the time of onset or recognition of the disease. It is generally divided into two main types, early- and late-onset PE.4 The latter comprises the majority (> 80%) of pre-eclamptics. In the earlyonset type, the clinical signs appear before 33 gestational weeks, while in the late-onset type they occur at and after 34 weeks. However, it is the early-onset type that is responsible for most of the high maternal and foetal mortality and morbidity rates. The main pathological feature of early-onset PE is incomplete transformation of the spiral arteries, resulting in hypoperfusion of the placenta and reduced nutrient supply to the foetus. This results in signs of foetal growth restriction (FGR).5 On the other hand, in late-onset type, the spiral arteries, if at all, are slightly altered in diameter and there are no signs of FGR.6 This is because early-onset pre-eclampsia is related to placental hypoperfusion, while in the late-onset type there is either no change or a shallow modification of the spiral arteries, leading in some cases to hyperperfusion of the placenta.7-9 Therefore, it seems that early- and late-onset PE have different pathophysiological and aetiological pathways.9 In normal pregnancy, the extracellular fluid and plasma volumes increase by 30–50% and 30–40%, respectively, perhaps due to a decrease in systemic vascular resistance and increase in cardiac output.10 The decreased systemic vascular resistance is thought to be due the presence of nitric oxide.11 In early-onset PE, there is a decrease in plasma volume, occurring at 14–17 gestational weeks,9 before the clinical onset of the disorder.12 This aspect is discussed more fully later under the role of the renin– angiotensin–aldosterone system (RAAS). Despite decades of research, the pathogenesis and pathophysiology of PE are still poorly or incompletely understood.4 The pathogenic process of PE begins during the first trimester, long before clinical signs are apparent. Hence it is difficult to identify early biomarkers. The main reason for this is perhaps ethical in nature, as it is difficult to conduct studies in early pregnancies, as these may compromise both the mother

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and child, and furthermore the pathogenic processes could be multifactorial. In any event, it is generally felt that lack of adequate placental development is the root cause of early-onset PE because the only known treatment of the disorder is delivery of the foetus and placenta. It is, however, essential to understand the features of placental development in normal pregnancies in order to understand the pathophysiology of PE.

Role of the placenta in normal pregnancies Placentation and trophoblast invasion of the maternal tissue involves two processes, firstly vascularisation to establish a foeto-placental vascular network, and secondly, invasion of the maternal spiral arteries by the cytotrophoblasts or endovascular trophoblasts (EVTs).13 At the time of implantation, trophoblastic cells differentiate into cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form the extravillous trophoblasts (EVT), which invade the decidual and junctional zone myometrial segments, the inner third of the myometrium and the spiral arteries. The EVTs induce remodelling of the latter, perhaps by causing loss of the elastic lamina, most of the smooth muscle cells, and temporarily replacing the endothelial cells,13 thus transforming a high-resistance, low-flow vascular system into a low-resistance, high-flow type, essential for normal foetal growth.13,14 Therefore, the cytotrophoblasts, epithelial in nature, replace the endothelial cells and in the process, the epithelial-like receptors are replaced with maternal adhesion molecules such as vascular endothelial (VE) cadherin vascular adhesion molecule-1, platelet-endothelial molecule-1, and αVβ3 integrin.13 This perhaps accounts for the prevention of foetal rejection. The trophoblasts therefore take on the phenotype of endothelial cells and are in direct contact with maternal blood, but the maternal and foetal blood do not mix. The syncytiotrophoblasts are multinucleated, line the chorionic villi, and act as an interface between maternal and foetal blood. However, according to Brosens et al. (2011),15 trophoblast invasion of the spiral arteries is preceded by oedema of the vessel wall, disintegration of the elastic fibres and changes in the smooth muscle layer, leading to a loss of myofibrils.15 Hence it is not the generally believed concept that the trophoblastic cells themselves cause disintegration of the elastic fibres and loss of myofibrils. In addition, development of the foetus initially occurs under low oxygen tension and placental perfusion is only from the intervillous space, and unplugging of the maternal spiral arteries occurs at about the 12th gestational week.16 The migration of trophoblasts into the spiral arteries is influenced by a number of factors such as cytokines, growth factors, oxygen tension, and the local cellular environment, for example immune cells such as macrophages and decidual/ uterine natural killer (dNK) cells.17 The dNK cells are thought to play an important role in regulating placentation but the exact mechanism of action is still unclear.18

Systemic inflammatory response in normal pregnancies The foetal trophoblast is regarded as an allo-antigen and the mother reacts to this and mounts a sterile, low-grade systemic inflammatory response.4,19 It is thought that syncytiotrophoblast

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microparticles (STMBs) detected in the maternal circulation could be the cause.20 However, it is known that utero-foetal perfusion only begins towards the end of the first trimester, while increased levels of STMBs in the maternal circulation are detected during the second and third trimesters.21 The initial inflammatory response during the first trimester could be due to an interaction between the decidual immune cells and trophoblast cells, and that a secondary inflammatory response during the second and third trimester could be due to syncytiotrophoblast microparticles released into the mother’s vascular system.21,22

Placental blood flow in pre-eclampsia and its consequences In PE, it has almost been established that there is reduced blood flow to the placenta, especially in the early-onset type, because of defective spiral artery remodelling and acute artherosis.23,24 In vivo techniques (magnetic resonance imaging and Doppler low-flow measurements) have confirmed this in early- but not late-onset PE.7 In PE the defects in spiral artery remodelling are restricted to the distal segments of the spiral arteries, that is the proximal decidua and the junctional zone (JZ) myometrial segments, and hence the myometrial spiral arteries still have much of their smooth muscle cells and elastic lamina, with absent or partial transformation of the arteries in the JZ myometrial segment.4,15 The exact mechanism for this is not known but various factors, such as abnormal genetic variations, biology of the trophoblasts or defective trophoblast differentiation acting together with extrinsic factors, such as maternal constitutional factors, action of macrophage defense mechanisms, impaired action of dNK cells and maternal endothelial cells have been advanced.18,23,25 Recently, it has been proposed that proteolytic activity of the different populations of the EVTs could be involved in invasion of the decidua and spiral arteries.26 Studies conducted in our laboratories showed that a PE-like syndrome can be produced in a rat model by reducing the placental blood flow through the administration of nitro-L-arginine methyl ester (L-NAME).27,28 In addition, co-administration of sildenafil citrate, which blocks the action of L-NAME, prevented the PE-like syndrome. Furthermore, we have shown that once the administration of L-NAME is discontinued, the pathophysiology of PE continues until birth of the pups, and thereafter the high blood pressure and proteinuria return to almost normal levels.29 The question then arises as to what the effects of the reduced placental blood flow or hypoperfusion on the maternal syndrome, namely hypertension, proteinuria and oedema, are. Is it the reduced blood flow per se that triggers events leading to the maternal syndrome, or is it some other factor/s associated with ischaemia? It is believed that reduced placental blood flow could result in hypoxia of the placenta, which has been suggested as the ultimate cause of PE.19,30 However, no in vivo measurements of oxygen tension in the intervillous space have been made to claim that hypoxia does occur.31 Nevertheless, it is believed that that reduced blood flow or chronic hypoxia on their own are not the direct cause of the placental lesions seen in PE but could be a contributing factor. It has therefore been assumed that

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the lesions could rather be due to an ischaemia–reperfusion or hypoxia–reoxygenation (HR) type of injury caused by free radicals such as reactive oxygen species (ROS).31 Furthermore, it has been speculated that an intermittent type of blood flow occurs in the intervillous space, which could be responsible for the HR type of injury.31 To support this, Yung et al. in 201432 showed that high levels of activation of unfolded protein-response pathways due to HR damage to the endoplasmic reticulum occurred in placental samples taken from early- but not late-onset PE. Accumulation of aggregates of unfolded protein response (UPR) or misfolded proteins has been observed in PE placentas and it is believed that these may contribute to the pathophysiology of the disorder.33 However, no measurements have been made to show that blood flow to the intervillous space is indeed intermittent. We believe that it is the pulsatile nature of blood flow from the spiral arteries that could be responsible for the HR type of injury. The defective spiral arteries lead to further deterioration in placental perfusion, ischaemia and worsening of the already hypoxic condition seen in normal pregnancies.10 The HR damage to the placenta, however, results in increased stress of the syncytiotrophoblasts, causing necrosis, apoptosis and release of excess placental debris (STMBs and vesicles), compared to a normal pregnancy, into the maternal circulation.34 In addition, soluble endoglin (sEng) is the extracelluar component of Eng, which is highly expressed in the syncytiotrophoblasts, and shedding of STMBs causes either mechanical disruption or proteolytic cleavage of sEng, and excess amounts of it are present in PE. The details of this are discussed later in this review. It is therefore believed that placental ischaemia–reperfusion injury is central to the development of PE. In addition to STMBs, pro-inflammatory cytokines, responsible for endothelial dysfunction and increased inflammatory responses, lead to the clinical signs of PE, such as hypertension, proteinuria and thrombotic micro-angiopathy, presenting as haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, pulmonary or cerebral oedema and seizures.35,36 However, there is no clear evidence that this really occurs and it has not been conclusively proven that STMB vesicles, and micro- and nanoparticle levels are significantly raised in PE compared to normal pregnancies, and that these substances give rise to the inflammatory disorder seen in PE.

Pro-angiogenic and anti-angiogenic factors in pre-eclampsia Pro-angiogenic factors, VEGF, PlGF and TGF-β Vascular endothelial growth factor (VEGF) and platelet growth factor (PlGF) play a key role in placental angiogenesis and are believed to be secreted by trophoblast cells. VEGF is thought to be essential for integrity of the maternal endothelial cells.37 Both elevated and reduced levels of VEGF in the maternal circulation have been reported in PE.38 These conflicting results could be due to the methodologies used. Elevated levels could perhaps be due to the use of commercial kits that measure both the bound and the soluble forms of VEGF in the maternal circulation. A longitudinal study showed that serum PlGF concentrations increased from 15–19 pg/ml through to 21–25 gestational weeks, and peaked at 27–30 weeks in uncomplicated pregnancies, in

women with small-for-gestational-age (SGA) neonates and PE without SGA neonates, and thereafter the levels declined towards 35–36 gestational weeks.39 However, in PE complicated by SGA, the peak occurred at 21–25 gestational weeks, but at all times the levels were lower than in women with PE only.39 The transforming growth factor-β (TGF-β) family, especially TGF-β1 and TGF-β3,40 have also been implicated in pre-eclampsia,40,41 but their exact mechanism of action is not known except to say that they are expressed in the pre-eclamptic placenta and reduce trophoblast proliferation, migration and invasion.41

Anti-angionenic factors sFlt-1 and sEng The anti-angiogenic factors are VEGF receptors (VEGFR1 and VEGFR2) and Eng. VEGFR1 is also known as fms-like tyrosine kinase-1 (Flt-1), which is membrane bound, while VEGFR2 is known as kinase insert domain receptor (KDR).42,43 It is known that sFlt-1, a spice variant of Flt-1, is the free form found in the circulation.43 Soluble Eng has anti-angiogenic effects, and as it has binding sites for TGF-β1 and β3,44 it is thought to play a role in PE.45 Venkatesha et al. found that Eng mRNA expression was significantly up-regulated in placental tissue (obtained at delivery), particularly in syncytiotrophoblasts in PE at 25 and 40 gestational weeks compared to age-matched control pregnancies.44 These researchers also found that this was accompanied by a significant rise in sera levels (obtained before delivery) of sEng in PE women compared to control pregnancies, and concluded that both sEng and sFlt-1 could be blocking the actions of TGF-β1 and VEGF, respectively. However, no significant differences in serum TGF-β1 levels were detected between normal-pregnancy and PE women.44 Venkatesha et al. further showed that administration of sEng to pregnant rats significantly increased the mean arterial pressure at 17–18 days of pregnancy but it had mild to modest effects on proteinuria. However, co-administration of sFlt-1 caused high levels of proteinuria, hypertension and evidence of the HELLP syndrome.44

Imbalance in angiogenic and anti-angiogenic state in PE There is increasing evidence that suggests an imbalance between pro-angiogenic and anti-angiogenic factors are responsible for the pathophysiological effects seen in PE,46,47 and these appear before clinical signs are apparent.48 However, it is not exactly known why some women develop PE while others with similar features, such as placental ischaemia and endothelial dysfunction, give birth only to SGA neonates without classical clinical signs of the disorder.49 Serum samples taken at the time of delivery have shown significantly increased sFlt-1 and decreased VEGF and PLGF concentrations in PE, compared to normotensive controls.50 In vitro studies showed that serum from PE inhibited tube formation in human umbilical vein endothelial cell (HUVEC) lines compared to that from controls, and administration of adenovirus expressing sFlt-1 to pregnant rats caused hypertension, albuminuria and glomerular endotheliosis, similar to that observed in PE.50

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Cross-sectional studies conducted in our laboratories among black African women at term before delivery demonstrated that variations in plasma levels of pro-angiogenic (PlGF and TGF-β) and anti-angiogenic (sEng and sFlt-1) factors indicated an association with PE.51 In a similar study, we observed that serum sFlt-1 concentrations were significantly raised in early-onset PE and higher in late-onset PE compared to normotensive controls and chronic hypertensives, while VEGF was not detectable in all groups.52 A longitudinal study showed that patients with SGA neonates had significantly higher plasma sEng concentrations throughout their pregnancies, but in those who developed early- and late-onset PE, the levels were significantly higher at 23 and 30 gestational weeks, respectively, compared to normal pregnancies.49 In the case of plasma sFlt-1 levels, early- and late-onset PE had higher levels at 26 and 29 gestational weeks, respectively, compared to normal pregnancies.49 However, those with both early- and lateonset PE and those with SGA neonates had lower levels of PlGF throughout pregnancy, compared to controls.49 Other studies show similar findings.53,54 In addition, it was reported that plasma sFlt-1 levels were elevated in pre-eclamptics compared to normal pregnancies at 6–10 weeks and more so at 2–5 weeks prior to the development of a clinical diagnosis.55 A pilot study showed that extracorporeal removal of 17–34% of sFlt-1 from pre-eclamptic women between gestational ages 27 and 31 weeks lowered the blood pressure and reduced proteinuria and other complications.56 The disproportionate levels of anti-angiogenic factors such as sEng and sFlt-1, and pro-angiogenic factors such as VEGF, PlGF and TGFβ, are believed to cause generalised maternal endothelial dysfunctions, leading to hypertension, renal endotheliosis and blood coagulation.

Immune factors and inflammation, cytokines and chemokines There is increasing evidence suggesting that both innate and adaptive immune processes are involved in the pathogenesis of PE.57,58 Predominance of Th1 immunity is not only related to poor placentation but also to the exaggerated inflammatory response and endothelial dysfunction seen in PE.59 In a recent study it was shown that between 14 and 18 gestational weeks, serum tumour necrosis factor-α (TNF-α), interleukin 10 (IL-10) and interferon-γ (INF-γ) levels were significantly lower in PE than in normal pregnancy.60 In another study, it was shown that serum levels of circulating cytokines, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, INF-γ, TNF-α and chemokine interferon-γ-inducible protein (IP-10), monocyte chemotactic protein-1 (MCP-1) and adhesion molecules [intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1)] were raised in PE compared to controls.58 In early-onset PE, the plasma TNF-α and its receptors TNFR1, IL-1β and IL-12 levels, and heat shock protein-70 (Hsp-70) were significantly higher than in late-onset PE, while IL-10 concentrations were higher in late-onset than early-onset PE.61 Controversial findings have therefore been reported in the levels of some of the cytokines. The differences noted could have been due to the time of taking blood samples. For example, in the study by Kumar et al.,60 the samples were taken between

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14 and 18 gestational weeks because 24 hours before delivery, raised levels of IL-4 and TNF-α were found, while the levels of INF-γ were not significantly different between those with PE and controls.60 However, it is believed that in PE compared to normal pregnancy, there is a shift to Th-1 type from Th-2 type of immunity. It is known that Th-1 type produces INF-γ and TNF-α, and hence it would be expected that the latter cytokines would be raised in the circulation. A meta-analysis and a systematic review of published articles on concentrations of TNF-α, IL-6 and IL-10 in the maternal circulation showed that the concentrations were significantly higher in PE compared to controls.63 It is noteworthy that in one study in which TNF-α levels were measured, there was also no significant difference between PE patients and controls.63 From these data, Lau et al. concluded that in the third trimester, PE is associated with higher levels of TNF-α, IL-6 and IL-10 in the maternal circulation, compared to normal pregnancies, but they found insufficient evidence to state that this was so in the first and second trimesters as well.62 A recent study conducted at a mean gestational age of 34 weeks demonstrated that plasma IL-6, IL-8 and INF-γ levels were significantly higher in PE compared to age-matched normal pregnant and non-pregnant women. The level of TNF-α was not significantly different but the level of IL-10 was significantly higher in normotensives than pre-eclamptics.63 In addition, it was found that severe PE was associated with increased plasma levels of IL-8, IL-6, TNF-α, IL-12 and INF-γ, linking these cytokines with the exaggerated inflammatory response in this condition.63 Studies from our laboratories have just recently shown that blood levels of Th-1 (TNF-α, IL-2, IL-12p70), INF-γ and granulocytemacrophage colony-stimulating factor (GM-CSF), and Th-2 (IL-4, IL-5, IL-10 and IL-13) cytokines are similar in PE and normotensive pregnant women.64

Low oxygen tension, oxidative stress in gene expression levels in PE In early-onset PE, oxidative stress caused by low oxygen tension or by disruption of the oxygen-sensing mechanism in placentas is believed to cause over-expression of hypoxia inducible factor-1 (HIF-1α) in placental tissue, and also to the release of increased levels into the circulation.65 In normal pregnancy, placental expression and formation of HIF-1α increased in a hypoxic environment during the first trimester and this was paralleled by TGF-β3, of which early trophoblast differentiation and placental expression of both molecules remained high until about the 10th gestational week when placental O2 levels began to increase.66 This was speculated to be responsible for extravillous trophoblast (EVT) outgrowth and invasion of the spiral arteries. However, it was noted that in PE the expression and formation of HIF-1α and consequently TGF-β3 remained high, resulting in shallow trophoblast invasion of the spiral arteries.66 These findings were confirmed by other researchers. Increased expression of the haeme (Hb) gene in the presence of hypoxia or oxidative stress has also been noted in PE placentas, and together with foetal haemoglobin (HbF), is thought to be involved in the pathogenesis of PE.33 In a review article, Hansson et al. in 2014 showed that free Hb, in addition to causing oxidative stress, also caused placental and kidney damage.33

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Placental hypoxia and perhaps oxidative stress, which occurs in PE, is also known to upregulate the gene expression and formation of Eng in placental tissue, perhaps via TGF-β3.67,68 The action of Eng and its receptor sEng have already been discussed. Perhaps in a similar manner, there is over-expression of genes responsible for the formation of sFlt-1, PlGF and VEGF in PE placentas.65,68 However, it has to be noted that for ethical reasons, it is difficult to study gene expression in placentas prior to actual clinical diagnosis of PE.

The RAAS and angiotensin II AT-1 receptor auto-antibodies In a recent review article Verdonk et al. presented a detailed account of the involvement of RAAS and Ang II AT-1 receptor auto-antibodies (AT-1AA) in the pathophysiology of pre-eclampsia.10 Readers are advised to refer to Verdonk et al.10 for details. They stated that in normal pregnancies, particularly in the early stages of gestation, there is an increase in maternal blood volume and a decrease in total resistance, and to counteract a fall in blood pressure, the RAAS is activated, resulting in sodium and water retention. However, in PE in contrast to normal pregnancy, the intravascular blood volume and cardiac output are reduced, while the total peripheral resistance is increased, and most components of the RAAS are downregulated.10 These findings led them to conclude that in pre-eclampsia, the suppression of most components of the RAAS could lead to increased response to Ang II and AT-1AA. They reported that the exact role of the RAAS and AT-1AA systems in PE remains unanswered, suffice to state that the sensitivity of Ang II receptors to Ang II is increased, and angiotensinogen synthesis is stimulated by high circulatory oestrogen levels in the first 10 weeks of pregnancy.10 High-molecular weight angiotensinogen levels were found to be about 25% higher than total angiotensinogen levels in PE, compared to 16% in normal pregnancy.69 However, it has been found that plasma renin activity, Ang II and aldosterone levels were decreased.70 At present, evidence of the exact role of the RAAS in PE is therefore lacking. Circulating auto-antibodies to AT-1AA have been shown to increase after 20 weeks of gestation.71 Others have shown that AT-1AA was more predictive in late-onset than in early-onset PE.72 It is possible that Ang II, by activating the AT-1 receptors on human trophoblasts, could play a role in shallow trophoblast invasion of the spiral arteries through secretion of plasminogen activator inhibitor-1 (PAI-1). Similar findings for AT-1AA were noticed in in vitro studies using human mesangial cells, where it caused increased secretion of PAI-1 and IL-6, compared to IgG from normotensive patients.73 It was further speculated that the latter actions of AT-1AA could account for the renal damage seen in PE patients.73 Xia and Kellems have presented a detailed review on the pathophysiological role of AT-1AA.74 They have shown that that these auto-antibodies play a critical role in PE, and blockade of AT-1 receptors in animal models reversed the signs and symptoms of PE by reducing the circulatory levels of sFlt-1 and IL-6.74 However, it remains to be shown conclusively that in human patients, AT-1AA plays an important role in the pathophysiology

of PE, since most of the experiments were conducted in animal models, which may not represent what happens in PE. In addition, it has not been conclusively shown that in every pre-eclamptic woman, the levels of AT-1AA are raised.

Hydrogen sulphide Hydrogen sulfide (H2S) is a gaseous signalling molecule in humans and animals. It is produced in endothelial cells.75 It has vaso-relaxant properties and is involved in uterine contractility.76,77 Endogenously produced H2S also has angiogenic75 and antiinflammatory properties.75,78 In the latter case, H2S acts at the endothelial–leukocyte interface.78 Chronic administration of H2S was found to have hypotensive effects in a rat model and reduced infarct in ischaemic–reperfusion injury in experimental rats.79 The production of H2S requires one of two enzymes: cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS).80 Both these enzymes are localised in foetal endothelial cells of both the stem and chorionic villi, and the Hofbauer cells express CBS mRNA.80 In early-onset but not late-onset PE, CBS mRNA expression was down-regulated.80 A recent study showed that mRNA expression of CSE was reduced in pre-eclamptic placental tissue and in women with SGA neonates, compared with normal pregnancy.81 The reduction in CSE expression was accompanied by reduction in the concentration of H2S in the maternal circulation.81 In addition, it was found that trophoblasts and mesenchymal cells in the core of the chorionic villi were the sites for expression of CSE.81 Inhibition of CSE by DL-propargylglycine (PAG) in pregnant mice resulted in hypertension and elevation in sFlt-1 and sEng levels in the circulation, and also caused placental abnormalities, while administration of GYY4137, which inhibits the action of PAG, reduced the levels of circulating sFlt-1 and sEng and restored foetal growth.81 This illustrates that H2S is required for placental development. Furthermore, it was also shown in in vitro studies that dysregulation of the CSE/H2S pathway affected spiral artery remodelling and placental development.81 In addition, it was found that inhibition of CSE with PAG in placental explants taken from first-trimester pregnancies reduced PlGF production. Wang et al. are of the view that their findings imply that endogenous H2S is required for placental development and foetal and maternal well-being.81 These findings perhaps show that H2S plays a role in the pathogenesis and pathophysiology of PE. However, it is felt that plasma H2S levels were overestimated in some of the above studies and may not reflect the true values.82 Nulliparity has been suggested as a risk factor for PE.83 The risk of pre-eclampsia was 26% in nulliparous patients versus 17% in parous [RR and 95% CI: 1.5 (1.3–1.8)] subjects. The risk of PE is also increased with a history of abortion and changed paternity. There seems to be a genetic component. Both mother and foetus contribute to the risk of PE, the contribution of the foetus being affected by paternal genes. An immune-based pathology is also proposed, whereby prolonged exposure to foetal antigens protects against PE in a subsequent pregnancy with the same father.84,85 Finally, a reason why PE is more common in nulliparous than multiparous women could be that in the latter, the uterine and spiral arteries develop a larger bore, which is easier for trophoblastic invasion.83

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uNKC

Cytotrophoblasts

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Fig. 1. A spects of pathophysiology of pre-eclampsia. VEGF: vascular endothelial growth factor; PlGF: placental growth factor; sFlt-1: soluble film-like tyrosine kinase.

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Conclusion

liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160(4):

The exact aetiology of PE remains elusive but much of the pathophysiology has been explained. The current theory is one of balance between angiogenic and anti-angiogenic factors. Measurement of circulatory angiogenic and anti-angiogenic proteins as biomarkers could possibly indicate placental dysfunction and differentiate PE from other disorders, such as gestational hypertension and chronic glomerulonephritis. In addition, biomarkers such as those stated above are reproducible, linked to the disease, and above all, are easy to interpret. See Fig. 1 for some aspects of the pathophysiology of pre-eclampsia.

1405–1423. 14. Valenzuela FJ, Perez-Sepulveda A, Torres MJ, Correa P, Repetto GM, Illanes SE. Pathogenesis of preeclampsia: the genetic component. J Pregnancy 2012; Article ID: 632732: 8 pages. http://dx.doi. org/10.1155/2012/632732. 15. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204(3): 193–201. 16. Foidart JM, Schaaps JP, Chantraine F, Munaut C, Lorquet S. Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia – a step forward but not the definitive answer. J Reprod Immunol 2009; 82(2): 106–111.

Key messages • The exact aetiology of pre-eclampsia remains elusive. • Much of the pathophysiology has been explained. • Treatment remains empirical and cure is dependent on stabilisation of high blood pressure and other specific organ complications, followed by delivery of the foetus and placenta.

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Pre-conception counselling for key cardiovascular conditions in Africa: optimising pregnancy outcomes Liesl Zühlke, Letitia Acquah

Abstract The World Health Organisation (WHO) supports pre-conception care (PCC) towards improving health and pregnancy outcomes. PPC entails a continuum of promotive, preventative and curative health and social interventions. PPC identifies current and potential medical problems of women of childbearing age towards strategising optimal pregnancy outcomes, whereas antenatal care constitutes the care provided during pregnancy. Optimised PPC and antenatal care would improve civil society and maternal, child and public health. Multiple factors bar most African women from receiving antenatal care. Additionally, PPC is rarely available as a standard of care in many African settings, despite the high maternal mortality rate throughout Africa. African women and healthcare facilitators must cooperate to strategise cost-effective and cost-efficient PPC. This should streamline their limited resources within their socio-cultural preferences, towards short- and long-term improvement of pregnancy outcomes. This review discusses the relevance of and need for PPC in resource-challenged African settings, and emphasises preventative and curative health interventions for congenital and acquired heart disease. We also consider two additional conditions, HIV/AIDS and hypertension, as these are two of the most important co-morbidities encountered in Africa, with significant burden of disease. Finally we advocate strongly for PPC to be considered as a key intervention for reducing maternal mortality rates on the African continent. Keywords: pre-conceptual counselling OR counselling, Africa, sub-Saharan Africa OR Afric* Submitted 1/9/15, accepted 2/3/16 Cardiovasc J Afr 2016; 27: 79–83

www.cvja.co.za

DOI: 10.5830/CVJA-2016-017

The World Health Organisation (WHO) recently stated that four out of 10 women report that their pregnancies were unplanned. As a result, 40% of pregnancies miss the essential health interventions required prior to pregnancy. Despite the laudable gains achieved by some countries in the United Departments of Paediatric Cardiology and Medicine, Red Cross War Memorial Children’s and Groote Schuur Hospitals, Cape Town, South Africa Liesl Zühlke, MB ChB, DCH, FCPaeds (SA), Cert Cardiology (Paeds), MPH, FESC, PhD, liesl.zuhlke@uct.ac.za

Department of Medicine, Division of Hospital Internal Medicine, Mayo Clinic Hospital, Saint Mary’s Campus, Rochester, Minnesota, USA Letitia Acquah, MD, MSc, FACP

Nations’ millennium development goal 5 target 5A, ‘Reduce by three-quarters, between 1990 and 2015, the maternal mortality ratio’, maternal morbidity remains a critical concern and public health issue in Africa.1 The WHO strongly supports the need for optimal pre-conception care (PCC) or counselling, followed by comprehensive antenatal care.2 PCC is defined as the continuum of promotive, preventative and curative health and social interventions.3 In addition to health interventions, other sectors and stakeholders need to be engaged to ensure universal access to PPC. PCC aims at improving the health status of prospective parents and reducing behaviours and individual and environmental factors that contribute to poor maternal and child health outcomes. Its ultimate aim is to improve maternal and child health, in both the short and long term. It is important to note that although PCC aims primarily at improving maternal and child health, it brings health benefits to adolescents, women and men as individuals in their own right (not just as potential parents).4 Among others, PCC can improve a variety of important health outcomes including: reducing maternal and child mortality; preventing unintended pregnancies, perinatal complications, reducing the vertical transmission of HIV/STIs, and co-morbid infections such as rubella; and reducing the risk of type 2 diabetes mellitus and cardiovascular disease later in life. PPC identifies current and potential medical problems of women of childbearing age, in order to strategise optimal pregnancy outcomes. The WHO has developed a package of PPC interventions that focuses on information and perspectives on important issues, target groups, delivery mechanisms and specific regional considerations. These are focused around 13 areas and provide an evidence-based package of interventions addressing the following areas: nutritional conditions, vaccine-preventable diseases, genetic conditions, environmental health, infertility/ subfertility, female genital mutilation, too early, unwanted and rapid successive pregnancies, sexually transmitted infections, HIV, interpersonal violence, mental health, psychoactive substance abuse, and tobacco use (Table 1).2 It is clear that addressing non-medical and medical causes and correlates of maternal morbidity and mortality will optimise healthy pregnancy outcomes.5 Various authorities have studied key non-medical issues, namely, women’s education and family planning, which directly impact on the general welfare of childbearing women and enhance pregnancy outcomes.6 Of note is the importance of key collaborations and multisector engagement in order to devise a local strategy for PCC. Such a strategy would need to be informed by an assessment of the strengths and weaknesses of the PCC system in place. It will need to be supported by key stakeholders and partnerships to ensure political commitment, and it has to leverage on existing public health programmes. It would also need to be adapted to country priorities and target populations, while identifying

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Table 1. Pre-conception care WHO package of evidenced-based interventions • Nutritional conditions • Genetic conditions • Vaccine-preventable conditions • Environmental health • Infertility/subfertility • Female genital mutilation • Too early, unwanted and rapid successive pregnancies • Sexually transmitted infections • HIV • Interpersonal violence • Mental health • Psychoactive substance use • Tobacco use

Components of pre-conception care

Specific conditions addressed by pre-conception care only

• Medical history • Psychosocial issues • Physical examination • Laboratory tests • Family history • Nutritional assessment

• Conditions that need time to correct prior to conception • Interventions not usually undertaken in pregnancy • Intervention considered only because a pregnancy is planned. • Conditions that might change the choice/timing or method to conceive • Conditions requiring early post-conception pre-natal care

Adapted from: Preconception care to reduce maternal and childhood mortality and morbidity. Meeting report and packages of interventions: WHO HQ, February 2012; Preconception care: Greater New York Chapter of the March of Dimes Preconception Care Curriculum Working Group 2015.

service-delivery mechanisms within existing programmes. Innovative programmes have to be explored to highlight PCC. Consequently, adequate financial resources should be mobilised to support strategic implementation, monitoring and evaluation of viable PCC programmes.2 Having outlined the vision for PPC and the specific need within the African continent, we will focus our attention on some specific conditions requiring comprehensive PPC and assessment. Given the burden of disease of congenital, rheumatic and hypertensive heart disease, as well as HIV/AIDS, we will discuss these conditions by suggesting clear guidelines for clinicians caring for such patients, as well as strategies to improve outcomes relating to these conditions. Although we describe specific medical interventions to optimise health prior to pregnancy, the general evidence-based interventions should be the platform upon which these are based. These include screening for anaemia, nutritional supplementation (iron and folate), information, education and counselling, food supplementation, promoting exercise and a healthy diet, and family planning and child spacing (Table 2).

Systematic review We performed a literature review of publications in PubMed, employing no language restriction, on the use of pre-conception counselling in Africa. Search terms included combinations of ‘((preconceptual[All Fields] AND (‘counselling’[All Fields]

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OR ‘counseling’[MeSH Terms] OR ‘counseling’[All Fields])))’ and ‘Africa OR sub-Saharan Africa’ or Afric*. We identified no previous studies that report pre-conception counselling in Africans. This review responds to the need for pre-conception counselling in African women. It provides an overview of the need, details and goals of such counselling and then describes specific important conditions. There are several studies detailing pre-conception counselling in different situations similar to the ones described. However, these are all from developed countries, therefore the findings cannot be generalised to the African context. Our review highlights the need for multidisciplinary team approaches to pregnancy and for pre-conception clinics in specific key disease groups. We anticipate that this review will be an important resource for physicians, obstetricians and gynaecologists working in developing country settings.

Congenital heart disease The story of congenital heart disease is one of the major successes of medicine in the last 50 years. The vast majority of lesions are amenable to surgery and neonatal surgery is now the norm rather than the exception.7 Many women with congenital heart disease are currently in their childbearing years, and desire pregnancy to bear their own children; however, there is a startling difference in the situation in Africa.8 With very few specialised cardiothoracic centres in Africa, the majority of children requiring congenital heart surgery have no access to these centres.9 Adults with congenital heart disease in Africa fall into two categories, namely, those who are ‘postoperation’ or ‘post-intervention’, and adults with ‘previously undiagnosed’ congenital heart disease (recognised for the first time at pregnancy, or in early adulthood). The latter category is seldom encountered in the developed world. Both categories of women should be offered comprehensive PPC by a dedicated multidisciplinary team, because each category presents a unique set of cardiac and obstetric challenges, requiring an individualised assessment of risks and a carefully documented care plan.10 A large proportion of women attending cardio-obstetric clinics have documented congenital heart disease. A recent review of one clinic in Cape Town, South Africa, showed that almost a third (32%, 15 with previous operations) had congenital heart disease.11

Table 2. Clinical pearls: planning pregnancy with certain medical conditions Medical condition

Preventative measures and supplementation

Contra-indications to pregnancy

Key points

Congenital heart disease

Rubella vaccination

WHO IV risk score Needs comprehensive risk assessment before pregnancy

Rheumatic heart disease

Primary prevention of group A streptococcus with penicillin Institute secondary prevention with penicillin after a diagnosis of ARF/RHD

WHO IV risk score Needs comprehensive risk assessment before pregnancy

Hypertension

Identify and treat secondary causes, treat sleep-disordered breathing, lifestyle changes

ACE inhibitors and Normalise pre-pregnancy blood pressure ARBs

HIV

Treat co-morbidities

None

General

Screen for anaemia Food supplementation, iron and folate supplementation

As per examination Information, education and counselling Promote exercise and healthy diet Family planning and spacing Weight control Substance and tobacco control

Avoid efavirenz if possible Optimise ART to maximal suppression of viral load Improved ART adherence Advise appropriate contraception

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Several scoring systems are used to risk stratify women contemplating pregnancy. The most commonly used are the cardiac disease in pregnancy (CARPREG) score, the ZAHARA (Zwangerschap bij Aangeboren Hartafwijking) score, and the WHO classification, which offer categories of risk.12 Class IV in the WHO score is extremely high risk, which contra-indicates pregnancy. Class IV includes: pulmonary hypertension, severe systemic ventricular dysfunction, dilated aortopathy and severe left-sided obstructive lesions.6 PPC must evaluate the potential risk posed by pregnancy to the woman, and include information regarding smoking, anticoagulation and anaemia, medication and recurrence of congenital heart defects in offspring. Late presentation of left-to-right shunts in the African setting often results in Eisenmenger syndrome or pulmonary vascular disease, associated with cyanosis. Eisenmenger syndrome is associated with a high maternal and foetal risk, so the affected should be advised against pregnancy. Specialist counselling and contraceptive advice are essential to their care. Although treatment has improved, the maternal mortality rate remains in excess of 20% in developed countries, and probably closer to 50% in African settings.13 Unoperated tetralogy of Fallot is commonly found in Africa in association with cyanosis and severe right ventricular hypertrophy and significant antenatal risks. The most common left-sided lesion is coarctation of the aorta, which is usually repaired in the neonatal period. Because of late complications, such patients need lifelong surveillance due to high rates of hypertension, the need for re-intervention and decreased survival rates.14,15 Unoperated coarctation may cause severe hypertension, which can complicate pregnancy. Management of the hypertension may be difficult and reduction of maternal upper-body blood pressure may compromise the foeto-placental unit. These present significant challenges to the cardio-obstetric and cardioanaesthetic teams, so they are best managed before conception, with individualised patient-care plans, based on their anatomy and physiology.16 All patients with known cardiac disease should preferably be counselled before conception. Pre-pregnancy evaluation should include a comprehensive risk assessment for the mother and foetus, including medication use and information on heredity of the cardiac lesion. In cases of late diagnosis of congenital heart disease, combined with limited specialised cardiac resources, PPC is crucial A

to assessing pregnancy risks. Safe contraception options should be considered with a multidisciplinary management team. Continued attention should remain on the critical elements of PPC, such as nutritional support, family spacing and genetic conditions.

Rheumatic heart disease Rheumatic heart disease remains an endemic condition on the African continent, with an incidence of 27 per 100 000,17 and a prevalence of over 20 per 1 000 in sub-Saharan Africa.18,19 Moreover, recent studies demonstrate the severity of the disease in tertiary institutions in Africa, with the majority of cases presenting with established heart failure, atrial fibrillation and pulmonary hypertension.20,21 The pathognomonic lesion in established rheumatic heart disease is mitral stenosis, which is associated with complications such as atrial fibrillation, stroke and death (Fig. 1). Valvular heart disease, especially stenotic valvular lesions, results in significant physiological effects during pregnancy, and is associated with maternal mortality and foetal loss.22,23 A previous study of 46 pregnant Senegalese women with rheumatic heart disease reported 17 maternal deaths (34%), six foetal deaths, and five therapeutic abortions.24 Severe mitral stenosis is classified as extremely high risk, therefore contra-indicating pregnancy. It is critical to evaluate all women of childbearing age with severe mitral stenosis, in order to provide family planning advice. In cases where pregnancy is strongly desired, pre-pregnancy interventions should be considered.25 Although mitral regurgitation is better tolerated during pregnancy, patients with severe symptomatic mitral regurgitation and impaired left ventricular function should be considered for timely surgery.26 Two final scenarios must be considered. The first scenario is the woman with a prosthetic heart valve desirous of pregnancy. Clear information on choices of anticoagulation therapy (e.g. heparin, warfarin or enoxaparin) during a potential pregnancy should be discussed with health professionals, with a clear plan to prevent complications and mortality.27 The second scenario is the patient with moderate mitral stenosis and a dilated left atrium, which increases the risk of stroke due to the lesion and the pregnant state.28 Once again, treatment options should be discussed prior to conception. B

Fig 1. S evere mitral stenosis (A) Doppler echocardiography; mean gradient 15 mmHg and (B) dilated left atrium with reduced excursion.

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The evaluation of a woman with rheumatic heart disease prior to pregnancy should include taking a careful history and performing a detailed physical examination, 12-lead ECG and comprehensive echocardiogram, which should focus on the degree of left-sided valvular obstruction and systolic function. Finally, careful counselling to address both the general points of PCC and the specific risks of pregnancy (including the risk of miscarriage, early delivery, foetal losses and small for-gestationalage babies) should be paramount in this population.

Hypertension Blood pressure (BP) control before pregnancy should improve the effects of chronic hypertension on pregnancy outcomes. The weight of evidence indicates that chronically hypertensive women are at a higher risk of developing complications. Specific antihypertensive agents used by the chronically hypertensive woman should be titrated, discontinued or changed to other agents, in order to optimise her BP prior to pregnancy. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are contra-indicated during pregnancy and must be discontinued when pregnancy is being planned.29-32 Whenever possible, pre-pregnancy BP should be normalised with lifestyle changes before pregnancy. These comprise: dietary changes (low-salt intake, increased intake of fresh fruits and vegetables), healthy weight modification to avoid obesity, and adherence to anti-hypertensive medications, which should improve health and pregnancy outcomes. When ACEIs or ARBs are discontinued before initiating a pregnancy, they could be replaced with other medications, e.g. hydralazine, alpha-methyldopa, nifedipine, diltiazem, labetalol or clonidine, if the benefits of the chosen drug outweigh its risks.

HIV/AIDS HIV/AIDS is a major public health concern and cause of death in many parts of Africa. The worst HIV/AIDS-affected people live in sub-Saharan Africa (SSA); 69% of all people living with HIV and 70% of all AIDS-related deaths in 2012 were from SSA,33 which had approximately 1.6 million new HIV infections and approximately 1.2 million AIDS-related deaths. Globally, AIDS-related illnesses are the leading cause of death among childbearing women. SSA women are disproportionally affected; the percentage of those aged 15–24 years living with HIV is twice that of young men.34 HIV-infected women have many HIV-related medical and psychosocial issues, which may increase the risks of adverse HIV-pregnancy outcomes, perinatal and sexual transmission. While advances in HIV treatment and perinatal transmission have resulted in prolonged survival, improved quality of life and an increased number of pregnancies, PPC is required to optimise management to improve perinatal outcomes and minimise transmission risks (Table 2). Key objectives for HIV/AIDS-related PPC are necessary. Firstly, maximal viral suppression should be achieved before conception. Detectable HIV plasma viral loads (PVL) and lack of effective antiretroviral treatment (ART) are associated with increased perinatal and sexual transmission.35 Furthermore, uncontrolled viral replication and non-adherence to ART cause viral resistance and overt disease. Sustaining high levels of adherence to ART with maximal viral suppression challenges

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resource-limited SSA, yet several programmes have demonstrated achievability.36 Secondly, PPC should explore the fertility desires of serodiscordant couples and offer options for safer conception. Early patient–provider communication about fertility goals could decrease peri-conception risks to HIV-uninfected partners.37 Although PPC is usually directed at women, exploring fertility goals with HIV-positive men in serodiscordant relationships could decrease peri-conceptional seroconversion in women.35 Exploring contraception needs informed, educated, reversible and irreversible contraception choices.38 An HIV-positive woman with excellent disease control and fertility control (reversible contraception) could have a healthy child at an optimal time, while preventing HIV transmission to her sexual partner and child. Thirdly, PPC facilitates the appropriate choice of ART regimens. WHO guidelines recommend prescribing the same group of drugs to HIV-infected pregnant and non-pregnant women.39 Efavirenz has been associated with an increased risk of teratogenicity in recent studies conducted among infants exposed to efavirenz-containing regimens,40 however, WHO guidelines recommend the use of efavirenz as first-line therapy.41 Finally, PPC allows the assessment of common HIV-related co-morbidities before pregnancy, e.g. cardiovascular, kidney and liver diseases, cognitive dysfunction and mental health,42 malignancies and metabolic bone disease, and infections (viral hepatitis, HPV).39 A comprehensive assessment of metabolic and mental capacity before conception would improve general health-related outcomes (Table 1).

Conclusion Providing PPC in Africa is challenging at best. Due to the complexities barring access to PPC, the task of providing such care should be shared corporately among all healthcare providers who may have any appreciable encounter with women of childbearing age. There should be a concerted effort to position PCC as a public health intervention for maternal and child health, and it should aim at improving the general health status of women beyond perinatal care. Public health educational campaigns should target at-risk groups to discuss the importance of reducing adverse pregnancy outcomes in order to optimise PPC. Beneficiaries and indirect stakeholders of the advantages of improved pregnancy outcomes should endeavour to provide cost-efficient and cost-effective PPC, within their resource-challenged settings, towards the reduction of maternal morbidity and mortality rates. There is a clear need for research into PPC in African countries, particularly to explore novel and innovative ways to deliver PPC within existing traditional maternal and health programmes. We call on all cardiac professionals to integrate PCC into their standard of practice in order to improve pregnancy outcomes for their patients.

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anticoagulation. Rev Port Cardiol 2015; 34: 71.e1–5. 28. Wang D, Liu M, Lin S, Hao Z, Tao W, Chen X, et al. Stroke and rheumatic heart disease: a systematic review of observational studies. Clin Neurol Neurosurg 2013; 115: 1575–1582. 29. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 2005; 73: 123–130. 30. Lavoratti G, Seracini D, Fiorini P, Cocchi C, Materassi M, Donzelli G et al. Neonatal anuria by ACE inhibitors during pregnancy. Nephron 1997; 76: 235–236. 31. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215–216. 32. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–2451.

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2015; 33(8): 544–556. Epub 2015 May 26. 40. Prestes-Carneiro LE. Antiretroviral therapy, pregnancy, and birth defects: a discussion on the updated data. HIV AIDS (Auckl) 2013; 5: 181–189. 41. World Health Organisation (Geneva). Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants, 2010 version. URL: http://apps.who.int/iris/bitstream/10665/75236/1/9789241599818_ eng.pdf access date 31 March 2016. 42. Nachega JB, Mutamba B, Basangwa D, Nguyen H, Dowdy DW, Mills EJ,

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Medical disease as a cause of maternal mortality: the pre-imminence of cardiovascular pathology AO Mocumbi, K Sliwa, P Soma-Pillay

Abstract Maternal mortality ratio in low- to middle-income countries (LMIC) is 14 times higher than in high-income countries. This is partially due to lack of antenatal care, unmet needs for family planning and education, as well as low rates of birth managed by skilled attendants. While direct causes of maternal death such as complications of hypertension, obstetric haemorrhage and sepsis remain the largest cause of maternal death in LMICs, cardiovascular disease emerges as an important contributor to maternal mortality in both developing countries and the developed world, hampering the achievement of the millennium development goal 5, which aimed at reducing by three-quarters the maternal mortality ratio until the end of 2015. Systematic search for cardiac disease is usually not performed during pregnancy in LMICs despite hypertensive disease, rheumatic heart disease and cardiomyopathies being recognised as major health problems in these settings. New concern has been rising due to both the HIV/AIDS epidemic and the introduction of highly active antiretroviral therapy. Undetected or untreated congenital heart defects, undiagnosed pulmonary hypertension, uncontrolled heart failure and complications of sickle cell disease may also be important challenges. This article discusses issues related to the role of cardiovascular disease in determining a substantial portion of maternal morbidity and mortality. It also presents an algorhitm to be used for suspected and previously known cardiac disease in pregnancy in the context of LIMCs. Submitted 6/9/15, accepted 2/3/16 Cardiovasc J Afr 2016; 27: 84–88

www.cvja.co.za

DOI: 10.5830/CVJA-2016-018

The 2010 Millennium Development Goals summit concluded with an action plan to accelerate progress on maternal and child Instituto Nacional de Saúde and Department of Medicine, Universidade Eduardo Mondlane, Maputo, Moçambique AO Mocumbi, MD, PhD, FESC, amocumbi@gmail.com

Inter-Cape Heart Group, Medical Research Council South Africa; University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa P Soma-Pillay, MB ChB, MMed (O et G) FCOG, Cert (Maternal and Foetal Med) SA

health. The target of the millennium development goal 5 was to reduce by three-quarters the maternal mortality ratio and achieve universal access to reproductive health between 1990 and the end of 2015. A 2013 report by the United Nations states: ‘The maternal mortality ratio dropped by 45 per cent between 1990 and 2013, from 380 to 210 deaths per 100 000 live births. All regions have made progress but accelerated interventions are required in order to meet target.’1 The maternal mortality ratio in low- to middle-income countries (LMIC) is 14 times higher than in high-income countries (HIC).1 Problems such as lack of antenatal care, the need for family planning and education, and the low rates of birth managed by skilled birth attendants contribute to the high maternal deaths rates in LMICs. Direct causes of maternal death, such as complications of hypertension, obstetric haemorrhage and sepsis remain the largest cause of maternal death in LMICs. Cardiovascular disease however is an important contributor to maternal mortality in both the developing and developed world, justifying a better understanding of its profile and relative burden in both regions.

Cardiac disease and maternity in high-income countries HIC such as the United States of America and the United Kingdom have reported decreases in direct causes of maternal mortality, but deaths due to cardiovascular disease have remained unchanged or are increasing.2,3 Considering the surveillance period in the United States (2006–2009), cardiovascular conditions accounted for a third of all pregnancy-related deaths (Fig. 1), while cardiac disease is currently the leading cause of maternal mortality in the United Kingdom.3 The most common causes of maternal death in the United Kingdom for the period 2006–2008 were sudden adult death syndrome, peripartum cardiomyopathy, aortic dissection and myocardial infarction.4 There were no deaths due to rheumatic heart disease and a decrease in deaths due to congenital heart disease. Lifestyle factors such as advanced maternal age, obesity and smoking were important contributors to maternal mortality.

Sudden adult death syndrome (SADS) SADS is defined as sudden death in an adult where no cause is identified. It is believed that obesity, cardiac hypertrophy and severe atherosclerosis can cause arrhythmia and sudden death.5 The condition is also associated with the presence of high concentrations of circulating non-esterified fatty acids, and women with central obesity are at greater risk than those with a peripheral pattern of obesity. There were 10 maternal deaths due to SADS in the United Kingdom during the period 2006–2008; four mothers were obese (BMI 30–45 kg/m2) and seven had an enlarged heart (the median heart weight at autopsy was 390 g).

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Percentage of deaths

35 30 25 20 15 10 5 0 Haemorrhage Hypertensive disorder

Infection

1987–1990

Thrombotic pulmonary embolism

Amniotic fluid embolism

1991–1997

Anaesthesia

Cardiovascular condition

1998–2005

Cardiomyopathy

Cerebrovascular accident

Other medical condition

2006–2009

Fig. 1. C auses of pregnancy-related mortality in the United States, 1987–2009 (from Creanga et al., 20142).

Peripartum cardiomyopathy (PPCM)

Aortic dissection

PPCM is a potentially life-threatening heart disease emerging towards the end of pregnancy or in the first months postpartum in previously healthy women.6 In most patients, cardiac function recovers, however, the mortality rate is up to 5–32%, and many patients develop chronic heart failure.7 In the acute phase, PPCM manifests as acute heart failure (AHF) and the diagnosis relies on exclusion of other causes of AHF. A novel finding is the discovery that oxidative stress-mediated cleavage of the nursing hormone prolactin into a smaller biologically active sub-fragment (16-kDA prolactin) may be a major factor initiating and driving PPCM. Treatment recommendations rely on standard acute heartfailure therapy. After the acute phase, in addition to the standard treatment of chronic heart failure, novel disease-specific strategies, such as bromocriptine, should be considered. PPCM in itself is a prothrombotic condition and embolic events leading to strokes are common. Therefore, all patients with an ejection fraction (EF) < 35%, those receiving bromocriptine, and particularly if a thrombus has been visualised on echocardiography, should be anticoagulated with intravenous heparin or low-molecular weight heparin antepartum, and receive warfarin after delivery.

In the same United Kingdom registry for the 2006–2008 triennium there were seven maternal deaths due to aortic dissection. In most cases, patients presented with severe chest or interscapular pain requiring opiate analgesia, and the diagnosis was delayed as appropriate investigations were not performed. Hormonal changes and increased haemodynamic stress predisposes to aortic dissection in pregnancy, but the exact mechanism is unclear.9 Obesity, multiparity, raised systolic blood pressure, heart conditions and pre-existing connective tissue disorders such as Marfan and Turner syndrome, Ehlers– Danlos type IV, coarctation of the aorta and bicuspid aortic valve increase the risk for aortic dissection. This diagnosis must be considered in the differential diagnosis of pregnant women who present with chest pain, particularly in the presence of systolic hypertension. Appropriate imaging includes computed tomography chest scan, magnetic resonance imaging, as well as transthoracic or transoesophageal echocardiogram.

Ischaemic heart disease during pregnancy The incidence of fatal ischaemic heart disease (IHD) in pregnancy ranges between 0.48 and 0.76 per 100 000 pregnancies. The most common presenting symptom in pregnancy is chest pain, which is present in 95% of women with IHD.8 In a systematic review of IHD in pregnancy, 93% of women who had an acute myocardial infarct (AMI) due to atherosclerosis had risk factors, compared with AMI caused by coronary dissection (43% had risk factors) and thrombus or emboli (68% had risk factors).8 Therefore lifestyle factors such as obesity and smoking are important risk factors in pregnancy. Coronary artery dissection and thromboembolic coronary events are the most common causes of IHD reported in pregnancy.8 Diagnosis in pregnancy is based on ECG (ST-segment deviation will be seen in about 89% of cases) and laboratory investigations. In the United Kingdom sub-standard care due to delayed diagnosis occurred in 46% of cases of maternal death. Therefore, a high index of suspicion is needed for IHD in pregnant women who present with chest pain and risk factors.

Cardiac disease and maternity in the developing world Heart disease is a common problem in pregnancy in LMICs;10 it increases the risk of morbi-mortality in these women and, as in HICs, seems to be the leading non-obstetric cause of maternal death. Similarly to the situation in HICs, risk factors such as hypertension and diabetes are contributors to maternal morbidity and mortality in LMICs, owing to their prevalence in the general population.11-16 However, a unique disease profile is found in LMICs due to the existence of poverty-related cardiovascular diseases. Risk factors such as hypertension, obesity and diabetes are increasingly important, occuring in high numbers in some countries, urban settings and specific sub-populations in sub-Saharan Africa, Asia and Latin America. In Africa, hypertension is most frequently observed in both rural and urban communities, with prevalence rates in young populations ranging from 9.3 to 48.1%.11,12 Smaller variations were found in India, where the overall prevalence for hypertension was 29.8% (95% confidence interval; range 26.7–33.0%) and significant differences were noted between rural and urban areas.13 A metaanalysis of published studies on the prevalence of hypertension in Chinese cities found an average of 21.5%,14 while in Iran

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the prevalence was 41.8% in women.15 The Latin American Consortium of Studies in Obesity (LASO), in its study on the major cardiovascular risk factors in Latin America, found that the prevalence of diabetes mellitus, hypertension and low levels of high-density lipoprotein (HDL) cholesterol in Latin American countries were 5, 20.2 and 53.3%, respectively.16 In this study, women had a higher prevalence of obesity and lower HDL cholesterol levels than men and, compared to the region’s average, the prevalence of each risk factor tended to be lower in Peru and higher in Chile. In LMICs, a search for cardiac disease in pregnant women is not performed routinely although hypertensive disease, rheumatic heart disease and cardiomyopathies are recognised as the largest drivers of maternal mortality. Among the cardiomyopathies, peripartum, Chagas disease and endomyocardial fibrosis present specific challenges due to their poor prognosis and high prevalence in some geographical areas. Cardiovascular manifestations of HIV/AIDS is a major concern due to the higher prevalence of infection in African women and lower mean age of those affected, compared to men.17 Undetected or untreated congenital heart defects continue to be diagnosed during pregnancy, which is witness to the fact that advances in paediatric cardiology and cardiac surgery over the last decades have benefited disproportionately women from developed countries, compared to those living in the developing world. In fact, pulmonary hypertension and severe heart failure complicating pregnancy are a common presentation when surviving girls reach their reproductive years. In specific endemic regions, sickle cell disease and other haemoglobinopathies may constitute important challenges by increasing the risk of thromboembolic complications due to the hypercoagulability caused by enhanced platelet function, activation of the coagulation cascade and impaired fibrinolysis in pregnant women.18

Current data on morbidity and mortality rates Data on mortality rates of pregnant women with cardiac disease vary widely among LMICs, as data from hospitalbased studies with variable designs and different geographical contexts suggest. Hypertension (pregnancy in hypertensive women and hypertension aggravated by pregnancy) is probably the single most important cardiovascular risk factor linked to adverse maternal and neonatal outcomes in LMICs.19 Regarding non-obstetric (indirect) causes, a retrospective analysis on 144 pregnancies in women with cardiac disease who delivered in a single centre in Turkey showed that rheumatic (87.5%) and congenital heart disease (12.5%) were the only causes of disease, with 44.4% of patients presenting in New York Heart Association classes II–IV. Although there was no maternal mortality, morbidity was observed in 16 (11.1%) cases, strongly related to the severity of cardiac disease.20 In India, cardiac causes were responsible for 27 of the 277 (9.75%) maternal deaths that underwent a pathological autopsy in a tertiary healthcare centre.21 Data from Iran revealed a maternal mortality rate of 4.0% (n = 8), with pregnant women with congenital heart disease experiencing higher mortality rates.22 Although data from Africa are scarce, maternal morbidity and mortality related to heart disease may reach unacceptably high rates. A systematic review of pre-existing cardiac disease in

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pregnant women in South Africa found seven studies where the prevalence of heart disease ranged from 123 to 943 per 100 000 deliveries, with a median prevalence of 616 per 100 000.23 In this African country, maternal mortality has quadrupled over the last decade, being responsible for 41% of the indirect causes of death; 77% of cardiac deaths occurred in women who attended antenatal clinics, showing major gaps in care and loss of opportunities to diagnose and adequately manage when women contact health services.24 Postmortem autopsy findings from cases of maternal death at a tertiary hospital in Nigeria over a five-year period revealed that 84 cases (28.6%) of maternal deaths were due to non-obstetric causes, with 20.8% of them being linked to pre-existing hypertension.25 Sliwa et al. studied 225 women presenting to a single tertiary care centre in South Africa with cardiovascular disease in pregnancy or within six months’ postpartum, showing that 54% of pregnant women presented to specialised care for the first time with a gestational age over 24 weeks.26 This study also showed that women present at late stages of disease, since only 73 (32.4%) were in World Health Organisation (WHO) class I. The most common problems in the 152 women in WHO class II–IV were congenital heart disease (32%), cardiomyopathy (27%) and rheumatic heart disease (26%). Maternal mortality rate within the six-month postpartum follow-up period was 9/152 (5.92%) with all deaths occurring in symptomatic women (WHO class III or IV risk group). The main diagnoses leading to death were familial and peripartum cardiomyopathy (n = 7) and prosthetic valve complications (n = 2). Interestingly, eight out of nine deaths occurred outside the 42-day maternal mortality report period, meaning that they were not considered in the statistics as maternal deaths. In LMICs, rheumatic heart disease contributes to 30% of the cardiovascular disease seen in pregnancy and remains an important determinant of morbidity and mortality.27-29 Rheumatic valvular lesions were the commonest abnormalities found in South Africa, where the most frequent complications were pulmonary oedema, thromboembolism and major bleeding related to warfarin use.26 In the global prospective registry of rheumatic heart disease (REMEDY), which enrolled 3 343 patients presenting at 25 hospitals in 12 African countries, India and Yemen, young females were highly represented (median age 28 years, females 66.2%) and had a higher prevalence of major cardiovascular complications.30 The participating countries were grouped into three income categories according to 2011 World Bank definitions: low-income countries (Ethiopia, Kenya, Malawi, Rwanda, Uganda and Zambia), lower-middle-income countries (Egypt, India, Mozambique, Nigeria, Sudan and Yemen), and uppermiddle-income countries (Namibia and South Africa). There was no difference in the predominance of females in the three groups: 728/1 110 (65.8%) 867/1 370 (63%) and 616/863 (71.3%), respectively. However, a statistically significant difference was found in the proportion of women in child-bearing years between the three groups of countries (86.5% in low-income countries, 90.3% in LMIC and 66.9% in upper-middle-income countries; p < 0.01). Among 1 825 women of childbearing age (12–51 years), only 65 (3.6%) were on contraception, reflecting the poor provision of family planning and pre-pregnancy advice for women with heart disease that occurs in many regions of the world.31,32

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Socio-demographic and health systems issues In LMICs, delays in enrolment for antenatal care and lack of adequate healthcare hamper the recognition of life-threatening conditions and the control of preventable factors that lead to cardiac decompensation during pregnancy. Low capacity for diagnosis at peripheral levels of the health systems and lack of awareness of the risks related to pregnancy result in few pregnant women being identified as having heart disease, therefore determining inadequate management and considerable impact on maternal and foetal outcome. On the other hand, acute and chronic complications and common endemic diseases may also further contribute to increase the risk of pregnant

Primary and secondary care maternal facility

Modified WHO classification I • Previously diagnosed hypertension, diabetes, morbid obesity (BMI > 35 kg/m2) • Successfully repaired simple lesions • Uncomplicated, small or mild mitral valve prolapse, pulmonary stenosis • Palpitations – no dizziness

Tertiary care maternal facility Tests: BP, ECG, echocardiogram and assess for murmurs Normal Follow up with maternity service

Modified WHO classification II • Unoperated ASD and VSD • Repaired tetralogy of Fallot and coarctation • Arrythmias and dizziness • Mild left ventricular impairment (EF > 45%, NYHA FC II) due to newly diagnosed PPCM or HT heart failure • Previously diagnosed RHD with murmurs and/or recently assessed asymptomatic mechanical valve

Abnormal

Non-urgent referral

Modified WHO classification III–IV • Mechanical valve and symptoms • Complex congenital or cyanotic heart disease • Pulmonary hypertension any cause • Previously diagnosed peripartum cardiomyopathy • Severe ventricular impairment (EF < 45%, NYHA FC > II) • Severe mitral stenosis and aortic stenosis • Aortic dilataion > 45 mm (bicuspid AV, Marfan)

Urgent referral

Joint cardiac–obstetric– anaesthetic CDM team Consulting with paediatric cardiologist, endocrinologist, radiologist, HIV specialist and others

Postpartum referral to main cardiac clinic, if indicated, for management and possible cardiothoracic surgery BMI: body mass index; ECG: electrocardiogram; ASD: atrial septal defect; VSD: ventricular septal defect; EF: ejection fraction; NYHA FC: New York Heart Association functional class; PPCM: peripartum cardiomyopathy; HT: hypertension; AV: aortic valve

Fig. 2. R eferral algorithm for suspected and previously known cardiovascular disease in maternity.

women dying during pregnancy, such as the case with cardiac tuberculosis, schistomosmiasis and syphilis.33 For the identification and management of pregnant patients with cardiovascular disease, we would therefore recommend that (1) all pregnant women should be screened at booking for underlying medical or surgical conditions; (2) women with known or recently detected cardiovascular disease should undergo risk assessement based on an algorithm (Fig. 2); (3) women presenting with difficulty in breathing, systolic blood pressure of < 100 mmHg, heart rate > 120 beats per minute or appearing cyanotic, need to be transferred by ambulance to a tertiary centre within 24 hours; those presenting with signs of fluid overload should receive a bolus of lasix 40 mg IV and oxygen per face mask prior to transfer; (4) clinicians should have a low threshold for investigating pregnant or recently delivered women (up to six months postpartum), especially those with cardiovascular risk factors (hypertension, diabetes), suspected rheumatic heart disease or with symptoms such as shortness of breath or chest pain; appropriate investigations include ECG, chest X-ray, echocardiogram and CT pulmonary angiography; (5) certain patients with high-risk cardiovascular disease may need careful monitoring for up to one year postpartum due to the high risk of developing heart failure, serious arrhythmia and embolic events. Socio-economic and demographic factors such as persistently high fertility rates, social pressure to conceive, insufficient access to contraceptive methods, as well as social or familial ostracism towards women who use contraception, may further contribute to increasing the risk of death due to cardiac disease, even in women who have been diagnosed.34

Conclusions Available data on maternal mortality rates reveal the pre-imminence of cardiovascular disease as the most important medical cause of non-obstetric maternal death in both developed and developing countries. Failure to systematically search for cardiac disease in pregnant women has led to late diagnosis and high rates of fatal complications. Therefore active screening for cardiac disease in pregnant women is warranted, if the millennium development goal of reducing the maternal mortality ratio is to be achieved. In LMICs algorithms for cardiac screening of pregnant women should consider the unique profile of cardiovascular disease, including rheumatic heart disease, cardiomyopathies, HIV/AIDS, haemoglobinopathies and undetected/untreated congenital heart defects. Such active strategies for suspected and previously known cardiac disease in pregnancy are expected to prevent a substantial proportion of maternal morbidity and mortality.

References 1.

The Millennium Developent Goals Report 2013.United Nations, 2013; UNDP, UNFPA; UNICEF; UN Women; WHO.

Creanga AA, Berg CJ, KO JY, et al. Maternal mortality and morbidity in the United States: Where are we now? J Women’s Health 2014; 23: 3–9.

Nelson-Piercy C. The UK maternal death report. Obstet Med 2015; 8: 3.

Nelson-Piercy C. Cardiac disease in Centre for Maternal and Child Enquiries (CMACE). Br J Obstet Gynecol 2011; 118 (suppl. 1); 109–115.

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Zollner J, Curry R, Johnson M. The contribution of heart disease to maternal mortality. Curr Opin Obstet Gynecol 2013; 25: 91–97.

Sliwa K, Hilfiker-Kleiner D, Mebazaa A, et al. EURObservational Research Programme: a worldwide registry on peripartum cardiomyopathy (PPCM) in conjunction with the Heart Failure Association of the European Society of Cardiology Working Group on PPCM. Eur J Heart Fail 2014; 16(5): 583–591.

Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nature Rev Cardiol 2014; 11: 364–370.

Thrombol 2013; 35(3): 352–358. 19. Paily VP, Ambujam K, Rajasekharan Nair V, Thomas B. Confidential review of maternal deaths in Kerala: a country case study. Br J Obstet Gynecol 2014; 121(Suppl 4): 61–66. 20. Madazli R, Sal V, Cift T, Guralp O, Goymen A. Pregnancy outcomes in women with heart disease. Arch Gynecol Obstet 2010; 281(1): 29–34. 21. Panchabhai TS, Patil PD, Shah DR, Joshi AS. An autopsy study of maternal mortality: a tertiary healthcare perspective. J Postgrad Med 2009; 55(1): 8–11.

Lameijer H, Kampman MAM, Oudijk MA, Pieper PG. Ischemic heart

22. Yaghoubi A, Mirinazhad M. Maternal and neonatal outcomes in preg-

disease during pregnancy or post-partum: systematic review and case

nant patients with cardiac diseases referred for labour in northwest Iran.

series. Neth Heart J 2015; 23: 249–257. 9.

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J Pak Med Assoc 2013; 63(12): 1496–1499.

Koul A, Hollander G, Moskovits N. Coronary artery dissection during

23. Watkins D, Sebitloane M, Engel M, Mayosi B. The burden of antenatal

pregnancy and the postpartum period: two case reports and review.

heart disease in South Africa: a systematic review. BMC Cardiovasc

Catherization Cardiovasc Intervent 2001; 52: 88–94. 10. Naidoo P, Desai D, Moodley J. Maternal deaths due to pre-existing cardiac disease, Cardiovasc J Afr 2002; 13(2): 17–19. 11. Hendriks ME, Wit FW, Roos MT, Brewster LM, Akande TM, de Beer IH. Hypertension in sub-Saharan Africa: cross-sectional surveys in four rural and urban communities. PLoS ONE 2012; 7(3): e32638. 12. Kayima J, Wanyenze RK, Katamba A, Leontsini E, Nuwaha F.

Disorders 2012; 12: 23. 24. Saving mothers 2005–2007: fourth report on confidential enquiries into maternal deaths in South Africa. Department of Health, Pretoria, South Africa, 2009.   25. Dinyain A, Omoniyi-Esan GO, Olaofe OO, Sabageh D, Komolafe AO, Ojo OS. Autopsy-certified maternal mortality at Ile-Ife, Nigeria. Int J Womens Health 2013; 6: 41–46.

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26. Sliwa K, Johnson M, Zilla P, Roos-Hesselink J. Management of valvular

review. BMC Cardiovasc Disorders 2013; 13: 54. doi:10.1186/1471-2261-

disease in pregnancy: a global perspective. Eur Heart J 2015, Mar 2. pii:

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E, Prabhakaran D. Hypertension in India: a systematic review and

Spectrum of cardiac disease in a low resource cohort in South Africa.

meta-analysis of prevalence, awareness, and control of hypertension. J Hypertens 2014; 32(6): 1170–1177. 14. Ma YQ, Mei WH, Yin P, Yang XH, Rastegar SK, Yan JD. Prevalence of hypertension in Chinese cities: a meta-analysis of published studies. PLoS ONE 2013; 8(3): e58302.

Heart 2014; doi: 10.1136/ heartjnl-2014-306199.   28. Diao M, Kane A, Ndiaye MB, Mbaye A, Bodian M, Dia MM, et al. Pregnancy in women with heart disease in sub-Saharan Africa. Arch Cardiovasc Dis 2011; 104: 370–374. 29. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden

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interventions in rheumatic heart disease: the Global Rheumatic Heart

16. Miranda JJ, Herrera VM, Chirinos JA, Gómez LF, Perel P, Pichardo R, et al. Major cardiovascular risk factors in Latin America: A comparison with the United States. The Latin American Consortium of Studies in Obesity (LASO). PLoS ONE 2013; 8(1): e54056. doi:10.1371/journal. pone.0054056. 17. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort. Eur Heart J 2012; 33(7): 866–874. 18. Naik RP, Streiff MB, Lanzkron S. Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know. J Thromb

Disease Registry (the REMEDY study). Eur Heart J 2015; 36(18): 1115–1122a. 31. Sliwa K, Mocumbi A. Women’s cardiovascular health in Africa. Heart 2012; 98: 450–455. 32. Thorne S, MacGregor A, Nelson-Piercy C. Risks of contraception and pregnancy in heart disease. Heart 2006; 92: 1520–1525. 33. Mocumbi AO, Ferreira MB. Neglected cardiovascular diseases in Africa: Challenges and opportunities J Am Coll Cardiol 2010; 55; 680–687. 34. Adongo PB, Phillips JF, Kajihara B, et al. Cultural factors constraining the introduction of family planning among the Kassena-Nankana of Northern Ghana. Soc Sci Med 1997; 45: 1789–1804.

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Physiological changes in pregnancy Priya Soma-Pillay, Catherine Nelson-Piercy, Heli Tolppanen, Alexandre Mebazaa

Abstract Physiological changes occur in pregnancy to nurture the developing foetus and prepare the mother for labour and delivery. Some of these changes influence normal biochemical values while others may mimic symptoms of medical disease. It is important to differentiate between normal physiological changes and disease pathology. This review highlights the important changes that take place during normal pregnancy. Keywords: hypercoagulable state, diabetogenic, uterine contractions Submitted 31/8/15, accepted 4/3/16 Cardiovasc J Afr 2016; 27: 89–94

www.cvja.co.za

DOI: 10.5830/CVJA-2016-021

During pregnancy, the pregnant mother undergoes significant anatomical and physiological changes in order to nurture and accommodate the developing foetus. These changes begin after conception and affect every organ system in the body.1 For most women experiencing an uncomplicated pregnancy, these changes resolve after pregnancy with minimal residual effects. It is important to understand the normal physiological changes occurring in pregnancy as this will help differentiate from adaptations that are abnormal.

Haematological changes Plasma volume increases progressively throughout normal pregnancy.2 Most of this 50% increase occurs by 34 weeks’ Department of Obstetrics and Gynaecology, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa Priya Soma-Pillay, MB ChB, MMed (O et G) Pret, FCOG, Cert (Maternal and Foetal Med) SA, Priya.Soma-Pillay@up.ac.za

Department of Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners; Guy’s and St Thomas’ Foundation Trust, and Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare Trust, London, UK Catherine Nelson-Piercy, MA, FRCP, FRCOG

INSERM UMRS 942, Paris, France Heli Tolppanen, MD Alexandre Mebazaa, MD

Heart and Lung Centre, Helsinki University Central Hospital, Finland Heli Tolppanen, MD

University Paris Diderot, Sorbonne Paris Cité, Paris; Department of Anesthesia and Critical Care, Hôpital Lariboisière, APHP, France Alexandre Mebazaa, MD

gestation and is proportional to the birthweight of the baby. Because the expansion in plasma volume is greater than the increase in red blood cell mass, there is a fall in haemoglobin concentration, haematocrit and red blood cell count. Despite this haemodilution, there is usually no change in mean corpuscular volume (MCV) or mean corpuscular haemoglobin concentration (MCHC). The platelet count tends to fall progressively during normal pregnancy, although it usually remains within normal limits. In a proportion of women (5–10%), the count will reach levels of 100–150 × 109 cells/l by term and this occurs in the absence of any pathological process. In practice, therefore, a woman is not considered to be thrombocytopenic in pregnancy until the platelet count is less than 100 × 109 cells/l. Pregnancy causes a two- to three-fold increase in the requirement for iron, not only for haemoglobin synthesis but also for for the foetus and the production of certain enzymes. There is a 10- to 20-fold increase in folate requirements and a two-fold increase in the requirement for vitamin B12. Changes in the coagulation system during pregnancy produce a physiological hypercoagulable state (in preparation for haemostasis following delivery).3 The concentrations of certain clotting factors, particularly VIII, IX and X, are increased. Fibrinogen levels rise significantly by up to 50% and fibrinolytic activity is decreased. Concentrations of endogenous anticoagulants such as antithrombin and protein S decrease. Thus pregnancy alters the balance within the coagulation system in favour of clotting, predisposing the pregnant and postpartum woman to venous thrombosis. This increased risk is present from the first trimester and for at least 12 weeks following delivery. In vitro tests of coagulation [activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT)] remain normal in the absence of anticoagulants or a coagulopathy. Venous stasis in the lower limbs is associated with venodilation and decreased flow, which is more marked on the left. This is due to compression of the left iliac vein by the left iliac artery and the ovarian artery. On the right, the iliac artery does not cross the vein.

Cardiac changes Changes in the cardiovascular system in pregnancy are profound and begin early in pregnancy, such that by eight weeks’ gestation, the cardiac output has already increased by 20%. The primary event is probably peripheral vasodilatation. This is mediated by endothelium-dependent factors, including nitric oxide synthesis, upregulated by oestradiol and possibly vasodilatory prostaglandins (PGI2). Peripheral vasodilation leads to a 25–30% fall in systemic vascular resistance, and to compensate for this, cardiac output increases by around 40% during pregnancy. This is achieved predominantly via an increase in stroke volume, but also to a lesser extent, an increase in heart rate. The maximum cardiac output is found at about 20–28 weeks’ gestation. There is a minimal fall at term.

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An increase in stroke volume is possible due to the early increase in ventricular wall muscle mass and end-diastolic volume (but not end-diastolic pressure) seen in pregnancy. The heart is physiologically dilated and myocardial contractility is increased. Although stroke volume declines towards term, the increase in maternal heart rate (10–20 bpm) is maintained, thus preserving the increased cardiac output. Blood pressure decreases in the first and second trimesters but increases to non-pregnant levels in the third trimester. There is a profound effect of maternal position towards term upon the haemodynamic profile of both the mother and foetus. In the supine position, pressure of the gravid uterus on the inferior vena cava (IVC) causes a reduction in venous return to the heart and a consequent fall in stroke volume and cardiac output. Turning from the lateral to the supine position may result in a 25% reduction in cardiac output. Pregnant women should therefore be nursed in the left or right lateral position wherever possible. If the woman has to be kept on her back, the pelvis should be rotated so that the uterus drops to the side and off the IVC, and cardiac output and uteroplacental blood flow are optimised. Reduced cardiac output is associated with a reduction in uterine blood flow and therefore in placental perfusion, which could compromise the foetus. Although both blood volume and stroke volume increase in pregnancy, pulmonary capillary wedge pressure and central venous pressure do not increase significantly. Pulmonary vascular resistance (PVR), like systemic vascular resistance (SVR), decreases significantly in normal pregnancy. Although there is no increase in pulmonary capillary wedge pressure (PCWP), serum colloid osmotic pressure is reduced by 10–15%. The colloid osmotic pressure/pulmonary capillary wedge pressure gradient is reduced by about 30%, making pregnant women particularly susceptible to pulmonary oedema. Pulmonary oedema will be precipitated if there is either an increase in cardiac pre-load (such as infusion of fluids) or increased pulmonary capillary permeability (such as in pre-eclampsia) or both. Labour is associated with further increases in cardiac output (15% in the first stage and 50% in the second stage) Uterine contractions lead to an auto-transfusion of 300–500 ml of blood back into the circulation and the sympathetic response to pain and anxiety further elevate the heart rate and blood pressure. Cardiac output is increased between contractions but more so during contractions. Following delivery there is an immediate rise in cardiac output due to relief of the inferior vena cava obstruction and contraction of the uterus, which empties blood into the systemic circulation. Cardiac output increases by 60–80%, followed by a rapid decline to pre-labour values within about one hour of delivery. Transfer of fluid from the extravascular space increases venous return and stroke volume further. Those women with cardiovascular compromise are therefore most at risk of pulmorary oedema during the second stage of labour and the immediate postpartum period. Cardiac output has nearly returned to normal (pre-pregnancy values) two weeks after delivery, although some pathological changes (e.g. hypertension in pre-eclampsia) may take much longer. The above physiological changes lead to changes on cardiovascular examination that may be misinterpreted as pathological by those unfamiliar with pregnancy. Changes may include a bounding or collapsing pulse and an ejection systolic

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murmur, present in over 90% of pregnant women. The murmur may be loud and audible all over the precordium, with the first heart sound loud and possibly sometimes a third heart sound. There may be ectopic beats and peripheral oedema. Normal findings on ECG in pregnancy that may partly relate to changes in the position of the heart include: • atrial and ventricular ectopics • Q wave (small) and inverted T wave in lead III • ST-segment depression and T-wave inversion in the inferior and lateral leads • left-axis shift of QRS.

Adaptive changes in renal vasculature The primary adaptive mechanism in pregnancy is a marked fall in systemic vascular resistance (SVR) occurring by week six of gestation. The 40% fall in SVR also affects the renal vasculature.4 Despite a major increase in plasma volume during pregnancy, the massive decrease in SVR creates a state of arterial under-filling because 85% of the volume resides in the venous circulation.5 This arterial under-filling state is unique to pregnancy. The fall in SVR is combined with increased renal blood flow and this is in contrast to other states of arterial under-filling, such as cirrhosis, sepsis or arterio-venous fistulas.3,6 Relaxin, a peptide hormone produced by the corpus luteum, decidua and placenta, plays an important role in the regulation of haemodynamic and water metabolism during pregnancy. Serum concentrations of relaxin, already elevated in the luteal phase of the menstrual cycle, rise after conception to a peak at the end of the first trimester and fall to an intermediate value throughout the second and third trimester. Relaxin stimulates the formation of endothelin, which in turn mediates vasodilation of renal arteries via nitric oxide (NO) synthesis.7 Despite activation of the renin–angiotensin–aldosterone (RAA) system in early pregnancy, a simultaneous relative resistance to angiotensin II develops, counterbalancing the vasoconstrictive effect and allowing profound vasodilatation.8 This insensitivity to angiotensin II may be explained by the effects of progesterone and vascular endothelial growth factormediated prostacyclin production, as well as modifications in the angiotensin I receptors during pregnancy.9 The vascular refractoriness to angiotensin II may also be shared by other vasoconstrictors such as adrenergic agonists and arginine vasopressin (AVP).10 It is possible that in the second half of pregnancy, the placental vasodilatators are more important in the maintenance of the vasodilatatory state.6

Changes in renal anatomy and function As a consequence of renal vasodilatation, renal plasma flow and glomerular filtration rate (GFR) both increase, compared to non-pregnant levels, by 40–65 and 50–85%, respectively. In addition, the increase in plasma volume causes decreased oncotic pressure in the glomeruli, with a subsequent rise in GFR.11 Vascular resistance decreases in both the renal afferent and efferent arterioles and therefore, despite the massive increase in renal plasma flow, glomerular hydrostatic pressure remains stable, avoiding the development of glomerular hypertension. As the GFR rises, both serum creatinine and urea concentrations decrease to mean values of about 44.2 μmol/l and 3.2 mmol/l, respectively.

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The increased renal blood flow leads to an increase in renal size of 1–1.5 cm, reaching the maximal size by mid-pregnancy. The kidney, pelvis and calyceal systems dilate due to mechanical compressive forces on the ureters. Progesterone, which reduces ureteral tone, peristalsis and contraction pressure, mediates these anatomical changes.11 The increase in renal size is associated with an increase in renal vasculature, interstitial volume and urinary dead space. There is also dilation of the ureters, renal pelvis and calyces, leading to physiological hydronephrosis in over 80% of women.12 There is often a right-sided predominance of hydronephrosis due to the anatomical circumstances of the right ureter crossing the iliac and ovarian vessels at an angle before entering the pelvis. Urinary stasis in the dilated collecting system predisposes pregnant women with asymptomatic bacteriuria to pyelonephritis.12 There are also alterations in the tubular handling of wastes and nutrients. As in the non-pregnant state, glucose is freely filtered in the glomerulus. During pregnancy, the reabsorption of glucose in the proximal and collecting tubule is less effective, with variable excretion. About 90% of pregnant women with normal blood glucose levels excrete 1–10 g of glucose per day. Due to the increases in both GFR and glomerular capillary permeability to albumin, the fractional excretion of protein may increase up to 300 mg/day and protein excretion also increases. In normal pregnancies the total protein concentration in urine does not increase above the upper normal limit. Uric acid excretion also increases due to increased GFR and/or decreased tubular reabsorption.11

Body water metabolism Arterial under-filling in pregnancy leads to the stimulation of arterial baroreceptors, activating the RAA and the sympathetic nervous systems. This results in a non-osmotic release of AVP from the hypothalamus. These changes lead to sodium and water retention in the kidneys and create a hypervolaemic, hypoosmolar state characteristic of pregnancy.6 Extracellular volume increases by 30–50% and plasma volume by 30–40%. Maternal blood volume increases by 45% to approximately 1 200 to 1 600 ml above non-pregnant values. By the late third trimester the plasma volume increases by more than 50–60%, with a lower increase in red blood cell mass, and therefore plasma osmolality falls by 10 mosmol/kg. The increase in plasma volume plays a critical role in maintaining circulating blood volume, blood pressure and uteroplacental perfusion during pregnancy.13 Activation of the RAA system leads to increased plasma levels of aldosterone and subsequent salt and water retention in the distal tubule and collecting duct. In addition to the increased renin production by the kidneys, ovaries and uteroplacental unit produce an inactive precursor protein of renin in early pregnancy.14 The placenta also produces oestrogens that stimulate the synthesis of angiotensinogen by the liver, resulting in proportionally increased levels of aldosterone compared to renin. Plasma levels of aldosterone correlate well with those of oestrogens and rise progressively during pregnancy. The increase in aldosterone is responsible for the increase in plasma volume during pregnancy.13 Progesterone, which is a potent aldosterone antagonist, allows natriuresis despite the sodium-retaining properties of aldosterone. The rise in GFR also increases distal sodium delivery, allowing excretion of excess sodium. Progesterone has antikaliuretic effects and therefore excretion of

potassium is kept constant throughout pregnancy due to changes in tubular reabsorption, and total body potassium increases during pregnancy.6,15 Hypothalamic AVP release increases early in pregnancy as a result of increased relaxin levels. AVP mediates an increase in water reabsorption via aquaporin 2 channels in the collecting duct. The threshold for hypothalamic secretion of AVP and the threshold for thirst is reset to a lower plasma osmolality level, creating the hypo-osmolar state characteristic of pregnancy. These changes are mediated by human chorionic gonadotropin (hCG) and relaxin.11,16 In middle and late pregnancy there is a four-fold increase in vasopressinase, an aminopeptidase produced by the placenta. These changes enhance the metabolic clearance of vasopressin and regulate the levels of active AVP. In conditions of increased placental production of vasopressinase, such as pre-eclampsia or twin pregnancies, a transient diabetes insipidus may develop.17 As a consequence of this volume expansion, the secretion of atrial natriuretic peptides increases by 40% in the third trimester, and rises further during the first week postpartum. The levels of natriuretic peptides are higher in pregnant women with chronic hypertension and pre-eclampsia.18

Respiratory changes There is a significant increase in oxygen demand during normal pregnancy. This is due to a 15% increase in the metabolic rate and a 20% increased consumption of oxygen. There is a 40–50% increase in minute ventilation, mostly due to an increase in tidal volume, rather than in the respiratory rate. This maternal hyperventilation causes arterial pO2 to increase and arterial pCO2 to fall, with a compensatory fall in serum bicarbonate to 18–22 mmol/l (see Table 1). A mild fully compensated respiratory alkalosis is therefore normal in pregnancy (arterial pH 7.44). Diaphragmatic elevation in late pregnancy results in decreased functional residual capacity but diaphragmatic excursion and therefore vital capacity remain unaltered. Inspiratory reserve volume is reduced early in pregnancy, as a result of increased tidal volume, but increases in the third trimester, as a result of reduced functional residual capacity (see Fig. 1). Peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV1) are unaffected by pregnancy. Pregnancy may also be accompanied by a subjective feeling of breathlessness without hypoxia. This is physiological and is most common in the third trimester but may start at any time during gestation. Classically, the breathlessness is present at rest or while talking and may paradoxically improve during mild activity.

Adaptive changes in the alimentary tract Nausea and vomiting are very common complaints in pregnancy, affecting 50–90% of pregnancies.19 This might be an adaptive Table 1. Reference ranges for respiratory function in pregnancy Investigations pH pCO2, mmHg (kPa) pO2, mmHg (kPa) Base excess Bicarbonate (mmol/l)

Normal values Pregnant Non-pregnant 7.40–7.47 7.35–7.45 ≤ 30 (3.6–4.3) 35–40 (4.7–6.0) 100–104 (12.6–14.0) 90–100 (10.6–14.0) No change +2 to –2 18–22 20–28

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mechanism of pregnancy, aiming at preventing pregnant women from consuming potentially teratogenic substances such as strong-tasting fruits and vegetables. The exact underlying mechanism is not clear but pregnancy-associated hormones such as human chorionic gonadotropin (hCG), oestrogen and progesterone could to be involved in the aetiology. The levels of hCG peak at the end of the first trimester when the trophoblast is most actively producing hCG, correlating with the nausea symptoms. Nausea is also more frequent in pregnancies with high levels of hCG, such as in twin pregnancies. Thyroid hormones may also be involved in the development of nausea symptoms, as a strong association with nausea and abnormal thyroid function tests has been found. Thyroidstimulating hormone (TSH) and hCG have similar biomolecular structures and therefore hCG cross-reacts with TSH, stimulating the thyroid gland.18 Psychological causes, genetic incompatibility, immunological factors, nutritional deficiencies as well as Helicobacter pylori infection have been proposed as aetiological factors of nausea and vomiting during pregnancy.20 The nausea symptoms usually resolve by week 20 but about 10–20% of the patients experience symptoms beyond week 20 and some until the end of the pregnancy.21 In most cases minor dietary modification and observation of electrolyte balance is sufficient. About 0.5–3% of pregnant women develop hyperemesis gravidum, a severe form of nausea and excessive vomiting, often resulting in dehydration, electrolyte imbalance, ketonuria, weight loss and vitamin or mineral deficiencies.19,21 In these cases intravenous fluid and vitamin substitution is commonly required. Thiamine supplementation is important in order to avoid the development of Wernicke’s encephalopathy.22 As pregnancy progresses, mechanical changes in the alimentary tract also occur, caused by the growing uterus. The stomach is increasingly displaced upwards, leading to an altered axis and increased intra-gastric pressure. The oesophageal sphincter tone is also decreased and these factors may predispose to symptoms of reflux, as well as nausea and vomiting.23 Changes in oestrogen and progesterone levels also influence the structural alterations in the gastrointestinal tract. These include abnormalities in gastric neural activity and smooth muscle function, leading to gastic dysrhythmia or gastroparesis. The alterations are pronounced in women with pre-existing

Inspiratory reserve volume Lung volume (ml)

Tidal volume Respiratory rate

Functional residual capacity

Fig. 1. P hysiological changes in respiratory function in pregnancy.

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gastrointestinal diseases such as gastroesophageal reflux disease, diabetic gastroparesis, gastric bypass surgery or inflammatory bowel disease.21,23

Endocrine changes Thyroid There is an increase in the production of thyroxine-binding globulin (TBG) by the liver, resulting in increased levels of thyroxine (T4) and tri-iodothyronine (T3). Serum free T4 (fT4) and T3 (fT3) levels are slightly altered but are usually of no clinical significance. Levels of free T3 and T4 do however decrease slightly in the second and third trimesters of pregnancy and the normal ranges are reduced.24 Free T3 and T4 are the physiologically important hormones and are the main determinants of whether a patient is euthyroid. Serum concentrations of TSH are decreased slightly in the first trimester in response to the thyrotropic effects of increased levels of human chorionic gonadotropin. Levels of TSH increase again at the end of the first trimester, and the upper limit in pregnancy is raised to 5.5 μmol/l compared with the level of 4.0 μmol/l in the non-pregnant state (Table 2). Pregnancy is associated with a relative iodine deficiency. The causes for this are active transport of iodine from the mother to the foeto-placental unit and increased iodine excretion in the urine. The World Health Organisation recommends an increase in iodine intake in pregnancy from 100 to 150–200 mg/day.24 If iodine intake is maintained in pregnancy, the size of the thyroid gland remains unchanged and therefore the presence of goiter should always be investigated. The thyroid gland is 25% larger in patients who are iodine deficient.

Adrenal gland Three types of steroids are produced by the adrenal glands: mineralocorticoids, glucocorticoids and sex steroids. The RAA system is stimulated due to reductions in vascular resistance and blood pressure, causing a three-fold increase in aldosterone levels in the first trimester and a 10-fold increase in the third trimester.25,26 Levels of angiotensin II are increased two- to four-fold and renin activity is increased three to four times that of non-pregnant values. During pregnancy there is also an increase in serum levels of deoxycorticosterone, corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), cortisol and free cortisol. These changes cause a state of physiological hypercortisolism and may be clinically manifested by the striae, facial plethora, rising blood pressure or impaired glucose tolerance.27 Total cortisol levels increase at the end of the first trimester and are three times higher than non-pregnant values at the end of pregnancy. Hypercortisolism in late pregnancy is also the result of the production of corticotropinreleasing hormone by the placenta – one of the triggers for the onset of labour. Diurnal variations in ACTH and cortisol levels are maintained. The hypothalamic–pituitary axis response to exogenous glucocorticoids is blunted during pregnancy. Table 2. Reference ranges for thyroid function in pregnancy37 Thyroid function fT4 (pmol/l) fT3 (pmol/l) TSH (mU/l)

Nonpregnant 9–26 2.6–5.7 0.3–4.2

1st trimester 10–16 3–7 0–5.5

2nd trimester 9–15.5 3–5.5 0.5–3.5

3rd trimester 8–14.5 2.5–5.5 0.5–4

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Pituitary gland The pituitary gland enlarges in pregnancy and this is mainly due to proliferation of prolactin-producing cells in the anterior lobe. Serum prolactin levels increase in the first trimester and are 10 times higher at term. The increase in prolactin is most likely due to increasing serum oestradiol concentrations during pregnancy. Levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are undetectable during pregnancy due to the negative feedback from elevated levels of oestrogen, progesterone and inhibin.28 Pituitary growth hormone production is decreased but serum growth hormone levels are increased due to growth hormone production from the placenta. The posterior pituitary produces oxytocin and arginine vasopressin (AVP). Oxytocin levels increase in pregnancy and peak at term. Levels of antidiuretic hormone (ADH) remain unchanged but the decrease in sodium concentration in pregnancy causes a decrease in osmolality. There is therefore a resetting of osmoreceptors for ADH release and thirst.29

Glucose metabolism Pregnancy is a diabetogenic state and the adaptations in glucose metabolism allow shunting of glucose to the foetus to promote development, while maintaining adequate maternal nutrition.30 Insulin-secreting pancreatic beta-cells undergo hyperplasia, resulting in increased insulin secretion and increased insulin sensitivity in early pregnancy, followed by progressive insulin resistance.31 Maternal insulin resistance begins in the second trimester and peaks in the third trimester. This is the result of increasing secretion of diabetogenic hormones such as human placental lactogen, growth hormone, progesterone, cortisol and prolactin. These hormones cause a decrease in insulin sensitivity in the peripheral tissues such as adipocytes and skeletal muscle by interfering with insulin receptor signalling.32 The effect of the placental hormones on insulin sensitivity is made evident postpartum when there is a sudden decrease in insulin resistance.33 Insulin levels are increased in both the fasting and postprandial states in pregnancy. Fasting glucose levels are however decreased due to: • increased storage of tissue glycogen • increased peripheral glucose use • decrease in glucose production by the liver • uptake of glucose by the foetus.34 Insulin resistance and relative hypoglycaemia results in lipolysis, allowing the pregnant mother to preferentially use fat for fuel, preserving the available glucose and amino acids for the foetus and minimising protein catabolism. The placenta allows transfer of glucose, amino acids and ketones to the foetus but is impermeable to large lipids. If a woman’s endocrine pancreatic function is impaired, and she is unable to overcome the insulin resistance associated with pregnancy then gestational diabetes develops.

Lipid metabolism There is an increase in total serum cholesterol and triglyceride levels in pregnancy. The increase in triglyceride levels is mainly as a result of increased synthesis by the liver and decreased lipoprotein lipase activity, resulting in decreased catabolism of adipose tissue. Low-density lipoprotein (LDL) cholesterol levels also increase and reach 50% at term. High-density lipoprotein levels increase

in the first half of pregnancy and fall in the third trimester but concentrations are 15% higher than non-pregnant levels. Changes in lipid metabolism accommodate the needs of the developing foetus. Increased triglyceride levels provide for the mother’s energy needs while glucose is spared for the foetus. The increase in LDL cholesterol is important for placental steroidogenesis.

Protein metabolism Pregnant women require an increased intake of protein during pregnancy. Amino acids are actively transported across the placenta to fulfill the needs of the developing foetus. During pregnancy, protein catabolism is decreased as fat stores are used to provide for energy metabolism.

Calcium metabolism The average foetus requires about 30 g of calcium to maintain its physiological processes. Most of this calcium is transferred to the foetus during the third trimester and is derived from increased dietary absorption by the mother.35 There is a decrease in total serum calcium concentration during pregnancy. This is mainly due to a decrease in serum albumin levels due to haemodilution, resulting in a decrease in the albumin-bound fraction of calcium. However the physiologically important fraction, serum ionised calcium, remains unchanged.36 Therefore maternal serum levels of calcium are maintained during pregnancy and foetal needs are met by increased intestinal absorption, which doubles from 12 weeks’ gestation. However the peak demand for calcium is only in the third trimester. This early increase in calcium absorption may allow the maternal skeleton to store calcium in advance.17 Serum levels of 25-hydroxyvitamin D increase and this is metabolised further into 1.25-dihydroxyvitamin D. The increase in 1.25-dihydroxyvitamin D is directly responsible for the increase in intestinal calcium absorption.36 Increased calcium absorption is associated with an increase in calcium excretion in the urine and these changes begin from 12 weeks. During periods of fasting, urinary calcium values are low or normal, confirming that hypercalciuria is the consequence of increased absorption.35 Pregnancy is therefore a risk factor for kidney stones.

Skeletal and bone density changes There is controversy regarding the effect of pregnancy on maternal bone loss. Although pregnancy and lactation are associated with reversible bone loss, studies do not support an association between parity and osteoporosis in later life.25 Bone turnover is low in the first trimester and increases in the third trimester when foetal calcium needs are increased. The source of the calcium in the third trimester is previously stored skeletal calcium.36 A study of bone biopsies in pregnancy has shown a change in the micro-architectural pattern of bone in pregnancy but not overall bone mass.36 The changes reflect the need for the maternal skeleton to be resistant to bending forces and biochemical stresses needed to carry the growing foetus. Other musculoskeletal changes seen in pregnancy include: • exaggerated lordosis of the lower back, forward flexion of the neck and downward movement of the shoulders

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• joint laxity in the anterior and longitudinal ligaments of the lumbar spine • widening and increased mobility of the sacroiliac joints and pubic symphysis.

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18. Castro LC, Hobel CJ, Gornbein J. Plasma levels of atrial natriuretic peptide in normal and hypertensive pregnancies: a meta-analysis. Am J Obstet Gynecol 1994; 171(6): 1642–1651. 19. American College of Obstatrics and Gynecology (ACOG) Practice Bulletin. Nausea and vomiting of pregnancy. Obstet Gynecol 2004;

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the puerperium. In Pavord S, Hunt B (ed). The Obstetric Hematology

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steroids throughout normal pregnancy. Am J Med 1980; 68(1): 97–104.

24. Glinoer D. The regulation of thyroid function in pregnancy: pathways

Davison JM. Renal haemodynamics and volume homeostasis in preg-

of endocrine adaptation from physiology to pathology. Endocr Rev

Tkachenko O, Shchekochikhin D, Schrier RW. Hormones and hemodyConrad KP. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol 2011; 31(1): 15–32.

Gant NF, Worley RJ, Everett RB, MacDonald PC. Control of vascular responsiveness during human pregnancy. Kidney Int 1980; 18(2): 253–258.

2002; 186(5 Suppl Understanding): S253–255. 23. Koch KL. Gastrointestinal factors in nausea and vomiting of pregnan-

Von Oeyon P, et al. Blood pressure, the renin-aldosterone system and sex

namics in pregnancy. Int J Endocrinol Metab 2014; 12(2): e14098. 7.

2012: 252676.

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nancy. Scand J Clin Lab Invest Suppl 1984; 169: 15–27. 6.

527–539. 21. Clark SM, Costantine MM, Hankins GF. Review of NVP and HG

Manual. Cambridge: Cambridge University Press, 2010: 3–12. 4.

gravidarum, a literature review. Hum Reprod Update 2005; 11(5):

Rodger M, Sheppard D, Gandara E, Tinmouth A. Haematological 671–684.

103(4): 803–814. 20. Verberg MF, Gillot DJ, Al-Fardan N, Grudzinskas JG. Hyperemesis

Irani RA, Xia Y. Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin Nephrol 2011; 31(1): 47–58.

10. Conrad KP, Davison JM. The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin? Am J Physiol Renal Physiol 2014; 306(10): F1121–1135. 11. Cheung KL, Lafayette RA. Renal physiology of pregnancy. Adv Chronic Kidney Dis 2013; 20(3): 209–214.

1997; 18: 404. 25. Dorr HG, Heller A, Versmold HT, et al. Longitudinal study of progestins, mineralocorticoids and glucocorticoids throughout human pregnancy. J Clin Endocrinol Metabol 1989; 68: 863. 26. Elsheikh A, Creatsas G, Mastorakos G, et al. The renin-aldosterone system during normal and hypertensive pregnancy. Arch Gynecol Obstet 2001; 264: 182. 27. Gordon MC. Maternal Physiology in Obstetrics: Normal and Problem pregnancies. 6th edn. Philadelphia: Saunders, Elsevier, 2012. 28. Prager D, Braunstein G. Pituitary disorders during pregnancy. Endocrinol Metab Clin North Am 1995; 24: 1. 29. Linheimer MD, Barron WM, Davison JM. Osmotic and volume control of vasopressin release in pregnancy. Am J Kidney Dis 1991; 17: 105. 30. Angueira AR, Ludvik AE, Reddy TE, Wicksteed B, et al. New insights into gestational glucose metabolism: lessons learned from 21st century approaches. Diabetes 2015; 64: 327–334.

12. Rasmussen PE, Nielsen FR. Hydronephrosis during pregnancy: a

31. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal

literature survey. Eur J Obstet Gynecol Reprod Biol 1988; 27(3): 249–259.

compared with gestational diabetes mellitus. Am J Clin Nutr 2000; 71:

13. Lumbers ER, Pringle KG. Roles of the circulating renin-angiotensinaldosterone system in human pregnancy. Am J Physiol Regul Integr Comp Physiol 2014; 306(2): R91–101. 14. Krop M, Danser AH. Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin. Curr Hypertens Rep 2008; 10(2): 112–118. 15. Gonzalez-Campoy JM, Romero JC, Knox FG. Escape from the sodiumretaining effects of mineralocorticoids: role of ANF and intrarenal hormone systems. Kidney Int 1989; 35(3): 767–777. 16. Davison JM, Gilmore EA, Durr J, Robertson GL, Lindheimer MD. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol 1984; 246(1 Pt 2): F105–109. 17. Davison JM, Sheills EA, Barron WM, Robinson AG, Lindheimer MD. Changes in the metabolic clearance of vasopressin and in plasma vasopressinase throughout human pregnancy. J Clin Invest 1989; 83(4): 1313–1318.

125S. 32. Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes 2011; 18: 409–416. 33. Mazaki-Tovi S, Kanety H, Pariente C, et al. Insulin sensitivity in late gestational and early postpartum period: the role of circulating maternal adipokines. Gynecol Endocrinol 2011; 27: 725–731. 34. Brizzi P, Tonolo G, Esposito F, et al. Lipoprotein metabolism during normal pregnancy. Am J Obstet Gynecol 1999; 181: 430. 35. Kovacs CS. Calcium metabolism during pregnancy and lactation. NCBI Bookshelf. http://www.ncbi.nlm.nih.gov/books/NBK279173/. 36. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS. Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology 2006; 147: 4010–4021. 37. Nelson-Piercy C. Handbook of Obstetric Medicine. 5th edn. London: CRC Press, 2015.

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Diagnosing cardiac disease during pregnancy: imaging modalities Ntobeko AB Ntusi, Petronella Samuels, Sulaiman Moosa, Ana O Mocumbi

Abstract Pregnant women with known or suspected cardiovascular disease (CVD) often require cardiovascular imaging during pregnancy. The accepted maximum limit of ionising radiation exposure to the foetus during pregnancy is a cumulative dose of 5 rad. Concerns related to imaging modalities that involve ionising radiation include teratogenesis, mutagenesis and childhood malignancy. Importantly, no single imaging study approaches this cautionary dose of 5 rad (50 mSv or 50 mGy). Diagnostic imaging procedures that may be used in pregnancy include chest radiography, fluoroscopy, echocardiography, invasive angiography, cardiovascular computed tomography, computed tomographic pulmonary angiography, cardiovascular magnetic resonance (CMR) and nuclear techniques. Echocardiography and CMR appear to be completely safe in pregnancy and are not associated with any adverse foetal effects, provided there are no general contra-indications to MR imaging. Concerns related to safety of imaging tests must be balanced against the importance of accurate diagnosis and thorough assessment of the pathological condition. Decisions about imaging in pregnancy are premised on understanding the physiology of pregnancy, understanding basic concepts of ionising radiation, the clinical manifestations of existent CVD in pregnancy and features of new CVD. The cardiologist/physician must understand the indications for and limitations of, and the potential harmful effects of each test during pregnancy. Current evidence suggests that a single cardiovascular radiological study during pregnancy is safe and should be undertaken at all times when clinically justified. In this article, the different imaging modalities are reviewed in terms of how they work, how safe they are and what their clinical utility in pregnancy is. Furthermore, the safety of contrast agents in pregnancy is also reviewed. Keywords: medical imaging, pregnancy, cardiovascular disease, X-ray, echocardiography, computed tomography, cardiovascular magnetic resonance, nuclear cardiology

Division of Cardiology, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa Ntobeko AB Ntusi, FCP (SA), DPhil, ntobeko.ntusi@gmail.com

Cape University Body Imaging Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Petronella Samuels, BTech Rad

Military Hospital, Wynberg, Cape Town, South Africa Sulaiman Moosa, FFRad Diag (SA)

Instituto Nacional de Saúde and Department of Medicine, University Eduardo Mondlane, Maputo, Mozambique Ana O Mocumbi, MD, PhD, FESC

Submitted 3/9/15, accepted 4/3/16 Cardiovasc J Afr 2016; 27: 95–103

www.cvja.co.za

DOI: 10.5830/CVJA-2016-022

Pregnant women with known cardiovascular disease (CVD) or a newly diagnosed cardiac condition in pregnancy often require cardiovascular imaging during the pregnancy to confirm the diagnosis, to assess disease severity and stratify risk, to prognosticate, to plan for appropriate management and to assess response to therapy (Table 1). A variety of cardiovascular imaging modalities are available for such purposes and include X-ray [which encompasses chest radiography, cardiovascular computed tomography (CCT), computed tomographic pulmonary angiography (CTPA), coronary computed tomographic angiography (CCTA), fluoroscopy and invasive angiography], echocardiography, cardiovascular magnetic resonance (CMR) and nuclear techniques. Of these, diagnostic X-ray and nuclear procedures emerge as the greatest source of concern for patients and clinicians alike. However, most diagnostic radiological procedures do not expose the pregnant woman to a degree of radiation that would threaten the well-being of the developing pre-embryo, embryo or foetus.1 Furthermore, as cardiological imaging focuses mainly on the chest, there is minimal direct exposure of the lower abdomen, where the baby may lie within the main X-ray beam; hence radiation doses to the developing foetus tend to be small.2 The mechanisms of action, safety and clinical utility of various cardiovascular imaging modalities in pregnancy are considered below. We performed a systematic search of the published literature on cardiovascular imaging in pregnancy, published in the English language, through PUBMED (January 1966 to December 2015), OVID, Cochrane Database of Systematic Reviews and hand search of reference lists from selected articles. All search engines were searched using the key words: ‘pregnancy’, ‘cardiovascular imaging’, ‘echocardiography’, ‘X-ray’, ‘angiography’, ‘fluoroscopy’, ‘computerised tomography’, ‘cardiovascular magnetic resonance’ and ‘nuclear cardiology’. Articles with important insights about cardiovascular imaging in pregnancy are included.

Ionising radiation and pregnancy Ionising radiation refers to electromagnetic radiation produced by X-ray equipment, the radioactive isotopes (radionuclides) used for radiation therapy (Table 2). The accepted cumulative dose of ionising radiation during pregnancy is 5 rad (which is also equal to 50 mSv or 50 mGy),3 and no single diagnostic study exceeds this maximum. For example, the amount of exposure to the foetus from a two-view chest X-ray of the mother is only 0.00007 rad.4

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Table 1. Rationale for use and indications for imaging of CVD in pregnancy Evaluation of biventricular structure, size and function Evaluation of native and prosthetic valve disease Evaluation of pregnancy-induced hypertension and hypertensive heart failure of pregnancy Evaluation of congenital heart disease Evaluation of myocarditis Evaluation of specific cardiomyopathies • Dilated cardiomyopathy • Peripartum cardiomyopathy • Hypertrophic cardiomyopathy • Arrhythmogenic right ventricular cardiomyopathy • Iron-overload cardiomyopathy • Restrictive cardiomyopathy • Myocardial infiltration (e.g. sarcoidosis) • Left ventricular non-compaction • Systemic rheumatic diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) • Other less-common diseases (e.g. Chagas disease, Churg-Strauss syndrome) Evaluation of pericardial disease • Pericarditis • Pericardial effusions • Pericardial tumours • Pericardial effusive-constrictive syndrome • Pericardial constriction Evaluation of great vessels and pulmonary veins Evaluation of cardiac masses (differentiation of tumour from thrombus) Evaluation of infective endocarditis Evaluation of ischaemic heart disease • Diagnosis of myocardial infarction and its sequelae • Assessment of myocardial viability • Assessment for inducible ischaemia • Coronary imaging • Assessment of suspected coronary artery fistula • Assessment of suspected anomalous coronary origins Differentiation of ischaemic versus non-ischaemic cardiomyopathy Evaluation of mechanical dyssynchrony Evaluation of unexplained heart failure or stroke

Possible deleterious effects of ionising radiation include (1) genetic consequences, the risks of which can be assessed only from animal studies; (2) carcinogenesis, which can be assessed from survivors of nuclear bombings and patients exposed for medical reasons; and (3) teratogenic effects on the developing embryo or foetus.2 Most cardiovascular diagnostic procedures expose the embryo and foetus to less than 50 mSv,5 which does not increase reproductive risks (either birth defects or miscarriage).6 The reported dose of radiation with consequent increased incidence of birth defects or miscarriage is above 200 mSv.7

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Termination of pregnancy on the grounds of ionising radiation exposure is not recommended unless there is sufficient documentation that the estimated foetal dose exceeds 15 rad (150 mSv).8 An important determinant of the consequence of radiation exposure in pregnancy is the stage in which the radiation exposure occurs.1,9 In the first two weeks following conception or the second two weeks from the last menstrual period, the developing embryo is resistant to the malforming effects of X-rays. However, the developing embryo is sensitive to the lethal effects of X-rays, although doses much higher than 5 rad (50 mSv) are necessary to cause a miscarriage.10 From the third to the eighth week of pregnancy, in the period of early embryonic development, the embryo is hardly affected, in terms of birth defects, pregnancy loss, or growth retardation, unless the exposure is substantially above 200 mSv.11 From the eighth to the 15th week of pregnancy, the embryo or foetus is sensitive to the effects of radiation, particularly on the central nervous system (CNS). However, for the development of microcephaly and other CNS malformations, the radiation exposure has to be sufficiently high. The threshold for an observed effect on intelligence quotient is estimated to be greater than 30 rad (300 mSv).12 Cardiovascular diagnostic studies do not reach these levels and, therefore, these effects are rarely of concern for patients. The most sensitive period for CNS teratogenesis is between eight and 15 weeks of gestation, therefore non-urgent radiological testing should be avoided during this time. Rare consequences of prenatal radiation exposure include a slight increase in the incidence of childhood leukaemia and, possibly, a small change in the frequency of genetic mutations.13 Such exposure is not an indication for pregnancy termination, however. Appropriate counselling of patients before radiological studies are performed is critical. After 20 weeks of gestation, the foetus is fully developed and it again becomes resistant to the effects of radiation exposure. At this late stage, there is no evidence of increased risk of birth defects or miscarriage from radiological diagnostic studies.14

Deleterious effects of ionising radiation Radiation-induced teratogenesis CNS malformations, in particular microcephaly and mental retardation, are the most commonly seen non-stochastic complications following high-dose radiation exposure. Following Hiroshima, many Japanese bomb victims who were exposed in utero to doses greater than 10 to 150 rad developed

Table 2. Measures of ionising radiation Measure Exposure Absorbed dose

Definition Number of ions produced by X-rays per kg of air Amount of energy deposited per kg of tissue

KERMA

Kinetic energy released per unit mass

Dose equivalent

A measure of radiation-specific biological damage in humans

Relative effective dose

Amount of energy deposited per kg of tissue normalised for biological effectiveness

Activity

Amount of radioactivity expressed as the nuclear transformation rate

Conventional units Roentgen (R) Radiation absorbed dose (rad)

SI units Coulombs/kg (C/kg) Gray (Gy) 1 Gy = 100 rad Radiation-absorbed dose (rad) Gray (Gy) 1 Gy = 100 rad Roentgen equivalents man (rem) Sievert (Sv) 1 Sv = 100 rem Roentgen equivalents man (rem) Sievert (Sv) (1 rem = 1 rad for X-rays) 1 Sv = 100 rem (1 Sv = 100 rad for X-rays) Curie (Ci) Bequerel (Bq) 1 Ci = 3.7 × 1010 Bq

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microcephaly.15 A linear, dose-related association between severe mental retardation and radiation was also found, with the important caveat that most cases followed exposure during weeks eight to 15 of gestation.16,17

Radiation-induced malignancy Exposure to as little as 1 or 2 rad has been associated with an increase in childhood malignancies, especially leukaemia, occurring in a stochastic fashion.13 For example, the background rate of leukaemia in children is about 3.6 per 10 000.18 Exposure to 1 or 2 rad increases this rate to five per 10 000.19 While these doses do fall within the range of some radiographic studies, the absolute increase of risk (~ 1 in 10 000) is very small.20 Therefore, physicians should carefully weigh the risks and benefits of any radiographic study and include the mother in the decisionmaking process whenever possible.

Radiation-induced mutagenesis Radiation can cause germ-line mutations, potentially affecting future generations. Although radiation is commonly believed to create bizarre new mutations, data show that it usually merely increases the frequency of mutations occurring naturally in the general population.21 The dosage required to double this baseline mutation rate is between 50 and 100 rad, far more than the radiation doses occurring in common cardiovascular radiographic studies.22 The most important factor for physicians to remember is that the currently accepted maximum limit of ionising radiation exposure to the foetus during pregnancy is a cumulative dose of 5 rad (50 mSv or 50 mGy).3,10,20,23

Non-ionising radiation and pregnancy The reproductive risk of non-ionising radiation, which includes electromagnetic fields from computers, microwave ovens, microwave communication systems, cellular phones, power lines, household appliances, heating pads and warming blankets, airport metal screening devices and diagnostic ultrasound has been studied extensively. Two national committees of scientists in the US evaluated the risk from these non-ionising radiation sources. The first report was published in 1993 from the Oak Ridge Associated University panel24 created by the White House, while the second was the product of the committee of the National Academy of Sciences.25 Both of these groups concluded that the reproductive risk of non-ionising radiation is minimal, if even existent.24,25

radiation to pass through and expose the X-ray-sensitive film).26 Dense bone absorbs much of the radiation while soft tissue, such as heart muscle, allows more of the X-rays to pass through. Consequently bones appear white on the X-ray, soft tissue shows up in shades of grey and air appears black. Medically indicated diagnostic chest radiographic studies can be safely performed in pregnancy (Fig. 1), provided the equipment works properly and the abdomen of the patient is adequately shielded. The risk of not making the diagnosis often far surpasses the risk of radiation in such instances.27

Fluoroscopy and invasive angiography Fluoroscopy is a type of medical imaging that shows a continuous X-ray image on a monitor, much like an X-ray movie. Fluoroscopy is routinely used to screen suspected stuck prosthetic valves and for percutaneous transvenous mitral commissurotomy (PTMC) in those with symptomatic mitral stenosis in pregnancy. Furthermore, fluoroscopy is the basis for imaging during invasive angiographic procedures (including coronary angiography and haemodynamic studies). There are many situations where the benefit of performing these procedures is much greater than any small possible harm that might arise from radiation exposure.20 For a typical fluoroscopic study, the amount of radiation occurring is in the range of 0.001 to 0.05 rad; dosage depends on duration of fluoroscopic time.28 As always with any medical exposure, each particular procedure must be clinically justified, including taking into account when the procedure needs to occur and the anticipated radiation dose to the foetus. Once justified, due diligence is taken to optimise when and how the procedure is performed to minimise radiation exposure to the foetus, consistent with achieving the desired clinical outcome. The radiation exposure to the foetus predominantly arises from scattered radiation within the patient.20,29 Some of the main methods for minimising the dose to the foetus include: (1) restricting the X-ray beam size to as small as is necessary; (2) choosing the direction of the primary beam so that it is as far away from the foetus as possible; (3) ensuring that the overall exposure time is as short as possible; (4) selecting appropriate exposure factors; (5) calculating the dose by a knowledgeable medical physicist, if there is concern; and (6) using a lead apron on the table to shield any primary beam from the X-ray tube reaching the foetus (Table 3).

Chest radiography The chest X-ray is the most commonly performed diagnostic cardiovascular radiographic examination, and is able to produce accurate images of the heart, lungs, airways, blood vessels and the bones of the spine and chest. The chest X-ray utilises small amounts of radiation (0.00002 to 0.00007 rad)4,9 when a focused beam of radiation is passed through the body, resulting in a black-and-white image recorded on special film or a computer. X-rays are able to differentiate tissues in the body because of varying densities (each tissue allows a different amount of

Fig. 1. Chest radiography of a pregnant woman with peripartum cardiomyopathy. (A) posterior lateral projection, (B) lateral projection.

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Table 3. Approaches to minimising foetal radiation during cardiovascular imaging in pregnancy Restricting the X-ray beam size to as small as is necessary Choosing the direction of the primary beam so that it is as far away from the foetus as possible Ensuring that the overall exposure time is as short as possible Selecting appropriate exposure factors Defer abdominal examinations if possible; imaging examinations of the thorax are associated with negligible risks to the conceptus Whenever possible, ultrasound is the preferred modality for abdominal imaging in pregnancy Magnetic resonance imaging is emerging as an alternative in centres where it is widely available Using a lead apron on the table to shield any primary beam from the X-ray tube reaching the foetus Calculations of dose by a knowledgeable medical physicist if there is concern The radiation dose should be kept as low as reasonably achievable (ALARA principle)

Echocardiography Echocardiography is an imaging modality that uses highfrequency (2–10 MHz) sound waves to image cardiac structures and to give reproducible information about cardiac structure and function. Ultrasound is produced when a piezo-electric crystal, mounted in a transducer, is stimulated by an electric current.30 Ultrasound waves are not audible and are harmless to tissue at the intensities used in diagnostic imaging. The passage of sound waves depends on the acoustic impedance of tissues. Most ultrasound waves pass through tissues to deeper structures further from the surface, but reflected sound returns to strike the crystal, deforming it and producing electric signals, which correspond to the degree of deformation.30 This electrical information is transformed so it can be displayed on a cathoderay tube as pulses of light. Due to the speed of sound within the body being relatively constant, the depth of the tissue interface can be calculated, and reflected echoes are displayed on the screen on a depth scale.31 Blood reflects little sound and appears relatively black/hypoechoic compared with the myocardium, which reflects more of the ultrasound and appears relatively white/hyperechoic. The heart valves are even more echogenic. Neither bone nor air is a good transmission medium for ultrasound waves; therefore as the heart is surrounded by lung and the bony cage of the thoracic cavity, the ultrasound beam must be aimed through specific gaps, known as acoustic windows (e.g. parasternal, apical, subcostal and suprasternal), to produce images of the heart and vasculature.31 Given the lack of ionising radiation, echocardiography is an attractive first-line investigation for most forms of CVD encountered in pregnancy. M-mode and two-dimensional (2D) echocardiography provide real-time imaging of heart structures throughout the cardiac cycle; more recently, three-dimensional (3D) echocardiography has been developed.32 Doppler echocardiography provides information on blood movement inside cardiac structures and on the haemodynamics33 (Fig. 2). Tissue Doppler imaging (TDI) provides information about movement of cardiac structures.33 The relationship between the dynamics of cardiac structures and the haemodynamics of the blood inside these structures provides information about cardiac diastolic and systolic function.33 Echocardiography is continuously evolving and constantly being augmented by newer modalities, such as tissue harmonics, speckle tracking, tissue Doppler strain and tissue characterisation.34

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Fig. 2. Echocardiography in a pregnant woman with mitral stenosis. (A) parasternal long-axis view showing a deformed, calcified and restricted mitral valve with a classic ‘hockey-stick’ deformity of the anterior mitral valve leaflet and a dilated left atrium. (B) continuouswave Doppler trace showing a mean gradient of 15.5 mmHg, indicating severe mitral stenosis.

To date, there have been no reports of documented adverse foetal effects from diagnostic ultrasound procedures, including duplex Doppler imaging.1 There are no contra-indications to echocardiography during pregnancy, and ultrasound is preferred over X-ray as the primary method of foetal imaging during pregnancy.35 Energy exposure from ultrasonography has been arbitrarily limited to 94 mW/cm2 by the US Food and Drug Administration (FDA).36 Doppler and colour echocardiographic scans work by concentrating a beam of sound in a small area, and therefore can cause heating of local tissues if held in the same place for a long time.37 Most scans automatically reduce the power of the ultrasound beam when Doppler is used, to decrease the intensity. Nowadays most echocardiographic machines have a low thermal index and so pose very little risk. Dobutamine is favoured in pregnancy over adenosine for stress echocardiography.38

Cardiovascular computed tomography (CCT) Computed tomography (CT) is a diagnostic imaging procedure that uses X-rays to demonstrate cross-sectional images of the body acquired in different orthogonal planes. The crosssections or slices are reconstructed from the measurements of attenuation coefficients of X-ray beams in the volume of the object studied.39 The fundamental principle of CT is premised on tissue density traversed by the X-ray beam, which can be calculated from the attenuation coefficient. In other words, CT permits reconstruction of tissue density by 2D sections perpendicular to the axis of the acquisition system. Unlike X-ray radiography, the detectors of the CT scanner do not produce an image, but rather measure the transmission of a thin beam (1–10 mm) of X-rays through a full scan of the body, and the image of that section is taken from different angles, allowing retrieval of information on the depth of the tissues imaged.40 Complex mathematical algorithms are used to construct an image from the raw data; a typical CT image is composed of 512 rows, each of 512 pixels, i.e. a square matrix of 512 × 512 = 262 144 pixels (one for each voxel). A typical CCT study gives 0.06 to 0.09 rad.41 Similarly, the effective radiation dose for CT pulmonary angiogram (CTPA) protocols is generally between 2.2 and 7 mSv (0.02–0.07 rad).42 Often, for CCT and CTPA, the imaging field of view includes the lungs and breasts; the radiation dose can be reduced by

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shielding, lowering the peak kilovoltage or lowering the tube current.43 In general, lower-dose protocols result in images with poor resolution and greater noise, therefore reductions must consider image quality and diagnostic confidence.44 CTPA remains the imaging modality of choice for diagnosis of pulmonary embolism in pregnancy and is preferred for its general superiority over ventilation-perfusion scintigraphy.45 Ventilation-perfusion scintigraphy may be indeterminate in up to 25% of patients imaged in pregnancy.46 In addition, the foetal radiation dose from CTPA is substantially less than that from ventilation-perfusion scintigraphy in all trimesters, even if halfdose perfusion-only scintigraphy is used.47,48

Cardiovascular magnetic resonance CMR is a remarkably powerful imaging modality, free of ionising radiation, with high spatial and temporal resolution, performed via excitation of hydrogen protons within a powerful magnetic field.49 The strong magnetic field aligns the nuclear magnetisation spin of the hydrogen protons, which are then excited by radiofrequency (RF) pulses (pulse sequences). After the RF pulses are switched off, the protons give off energy as they precess back to their equilibrium magnetisation; this dissipated energy is detected by the MR receiver coils. Fourier transformation is then used to convert frequencies into images. The signal from a given tissue (e.g. heart muscle) is determined by the proton density (PD) and by two specific relaxation parameters: longitudinal relaxation time (T1) and transverse relaxation time (T2).49 PD, T1 and T2 vary substantially for different tissues, and may vary substantially within the same tissue from health to disease; these differences are used to generate contrast in MR images.50 To prevent artifacts from cardiac motion, CMR images are generated with fast sequences gated to the R wave of the electrocardiogram. Respiratory motion may be eliminated by acquiring CMR images in end-expiratory breath-hold. A

MR has been used to evaluate obstetric, placental and foetal abnormalities in pregnant patients for more than 25 years. MR imaging is recognised as a beneficial diagnostic tool and is utilised routinely to assess multiple conditions that affect the pregnant patient (Fig. 3) as well as the foetus. To date, there has been a paucity of systematic studies directed towards determining the relative safety of using MR procedures in pregnant patients.51 There has been no evidence of harm from the use of CMR and other forms of MR imaging in pregnancy.51 Safety concerns include possible bio-effects of the static magnetic field of the MR system, risks associated with exposure to the gradient magnetic fields, the potential adverse effects of RF energy, possible adverse effects related to heating and to the combination of these three electromagnetic fields, possible acoustic injury from the vibration and noise in the scanner, and possible toxicity from gadolinium-based contrast agents used in patients with renal dysfunction.52 MR environment-related risks are difficult to assess for pregnant patients due to the number of possible permutations of the various factors that are present in this setting (e.g. differences in field strengths, pulse sequences, exposure times). However, several experimental and clinical investigations of the effects of MR in pregnancy showed no evidence of injury or harm to the foetus or the mother.53,54 Even the few human studies performed in pregnant human subjects exposed to MR imaging or the MR environment have not reported adverse outcomes for the subjects.55,56 In recent times, there has been increasing concern that acoustic noise associated with MR may impact on the foetus; however this remains unproven in recent large studies.57 In summary, CMR up to 3T appears to be safe in all stages of pregnancy.58 Higher field strengths have not been evaluated in the setting of pregnancy. CMR, where available, together with echocardiography, remains preferable to any studies using ionising radiation for cardiovascular imaging in pregnancy, in particular during the first trimester. Despite the lack of harm C

Fig. 3. CMR imaging in a pregnant woman with Marfan syndrome with previous spinal surgery and a prosthetic mitral valve (for severe mitral regurgitation). (A) anteriorâ&#x20AC;&#x201C;posterior projection of chest radiograph showing scoliosis, spinal rods and prosthetic mitral valve. (B) CMR showing coronal oblique view of the left ventricular outflow with a dilated aortic root (max. 49 mm at the sinuses), efacement of the sinotubular junction and a dilated proximal ascending aorta. (C) A right ventricular (RV) transverse stack showing a normal RV and right atrium, with a normal LV size, sigmoid septum and artifact from the mitral valve prosthesis and minimal artifact from the spinal rods. (D) MRI of thoracic spine showing an incidental finding of a thoracic cord syrinx.

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from MR in pregnancy, the current guidelines of the FDA require labelling of MR devices to indicate that the safety of MRI with regard to the foetus ‘has not been established’.

Nuclear cardiovascular imaging Diagnostic nuclear medicine investigations also involve ionising radiation. Unlike X-rays, nuclear techniques involve the inhalation, ingestion or injection of a small quantity of a radioactive isotope bound in a substance that targets a particular organ, for example the heart. The gamma radiation emitted by the radioactive isotope is detected outside the body by electronic receptors of a gamma camera, which displays images or functional data about the heart.59 The most commonly used radioisotope, technetium-99m (99mTc), is a metastable daughter product following negative beta decay of molybdenum-99. 99mTc decays to 99Tc with a halflife of six hours, releasing a mono-energetic gamma photon of 140 keV.60 Nuclear studies that may be performed during pregnancy include ventilation-perfusion scintigraphy for diagnosis of pulmonary embolism, myocardial perfusion imaging where 99mTc may be combined with several compounds that localise to active myocardial cells, allowing ischaemic areas of the heart to be determined, and, less commonly, cardiac ventriculography where 99m Tc can be used to evaluate cardiac function (ejection fraction) by imaging the ventricles. The dose of radiation passed on to the foetus during a ventilation-perfusion scan is about 0.05 rad.61 Along with conventional gamma scintigraphic imaging, the two major nuclear imaging techniques are positron-emission tomography (PET) and single photon-emission computed tomography (SPECT). Both imaging modalities are now standard in the major nuclear medicine services. PET is based on the principle of positron annihilation by using radionuclides that decay through positive beta decay.62 Positrons generated by the decay combine with an electron and annihilate, releasing two photons, with energies of 0.51 MeV, in the process. The photons are released in opposite directions. The most commonly used compound for PET imaging is fluoro-2-deoxyglucose (18FDG), which is initially metabolised within the cell, is unable to progress to the citric acid cycle, and is not easily excreted by the cell.62 Hence, cells that have a high glucose metabolism concentrate, 18FDG, can then be imaged. The sections are reconstructed by algorithms, similar to but more complex than those used for conventional CT, to accommodate the 3D acquisition geometries.63 Correction by considering the physical phenomena provides an image representative of the distribution of the tracer within the heart. In PET scanning, an effective dose of the order of 8 mSv is delivered to the patient.64 SPECT imaging is based on detectors that rotate around the patient to obtain a digital representation of a 3D radioactive distribution of the chest. The injected radioactive tracers emit during their disintegration, gamma photons, which are detected by an external detector after passing through the surrounding tissue.65 In SPECT, the main radioactive isotopes are 99mTc, iodine and thallium-201 (which is used primarily for studies on the heart). To increase the sensitivity and resolution of SPECT systems, converging channel collimators were developed.66 Both PET and SPECT benefit from electrocardiographic gating used to enhance tomographic myocardial scintigraphy.

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Therefore, the radioactivity from the myocardium and the electrical activity of the heart are coupled. Depending on the procedure, the mother and baby will generally receive a small radiation dose with SPECT. It is unlikely that any diagnostic nuclear medicine investigation would result in the radiation dose of the foetus approaching 20 mGy. It is ideal that radioactive isotopes are avoided during pregnancy. However, if there is a real clinical need for such imaging to be performed, the risk to the mother and foetus is minimal.20

Contrast agents A variety of oral and intravascular contrast agents are used with X-ray and MR procedures. Radiopaque agents used with CT and conventional radiography contain derivatives of iodine and have not been studied comprehensively in human pregnancy. However, iohexol, iopamidol, iothalamate, ioversol, ioxaglate and metrizamide have been studied in animals and do not appear to be teratogenic.67 Neonatal hypothyroidism has been associated with some iodinated agents taken during pregnancy.68 Therefore iodinebased contrast agents are relatively contra-indicated in pregnancy, unless absolutely essential for a correct diagnosis. Studies requiring views before and after the administration of contrast agents will necessarily have greater radiation exposure. While most contrast agents pass into the breast milk, they have not been associated with problems in nursing babies.67 Despite in vitro concerns, iodinated contrast agents seem safe to use in pregnancy.69 Radioactive isotopes of iodine are mutagenic and are absolutely contra-indicated during the pregnancy.70 Paramagnetic contrast agents used during CMR have not been studied systematically in pregnant women. Animal studies have demonstrated increased rates of spontaneous abortion, skeletal abnormalities, and visceral abnormalities when given at two to seven times the recommended human dose.71 It is not clear whether gadolinium-based contrast agents are excreted into human breast milk. It is important to emphasise that gadolinium-based contrast agents have not been associated with any harm in human pregnancy.72,73 The 2007 American College of Radiology (ACR) guidance for safe MR practices (expanded and updated in 2013) recommends that intravenous gadolinium should be avoided in pregnancy and should only be used if absolutely essential, until there is further information about these agents.74,75 Consequently, the FDA has classified gadolinium as a category C drug, meaning it can be considered in pregnancy ‘if the potential benefits justify the potential risks to the fetus’.

Safety counselling When a pregnant mother considers any radiation exposure, the most prominent question in her mind is likely to be, ‘Is this safe for my baby?’ To answer this question, the physician must carefully choose words that will help a patient understand the real, although very small, risks of exposure. The general population’s total risk of spontaneous abortion, major malformations, mental retardation and childhood malignancy is approximately 286 per 1 000 deliveries. Exposing a foetus to 0.50 rad adds only about 0.17 cases per 1 000 deliveries to this baseline rate, or about one additional case in 6 000.6 Such numbers often do not make much

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Table 4. Doses to the foetus from radiological and nuclear medicine examinations Examination Chest radiograph Pulmonary CTA CCTA (prospective gating) CCTA (retrospective gating) Abdominopelvic CTA Direct fluoroscopy (groin to heart catheter passage) Coronary angiography Electrophysiological procedures Lung perfusion Lung ventilation Myocardial perfusion Gated blood pool PET viability PET perfusion Maximum recommended dose

Estimated foetal dose (mGy) < 0.0001 0.01–0.66 1.0 3.0 6.7–56.0 0.094–0.244 mGy/min 0.074 0.0023–0.012 mGy/min 0.6 0.005–0.09 5.3–17 6.0 6.3–8.1 2.0 5 rad or 50 mGy

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foetal anomalies or pregnancy loss. Therefore concerns about possible effects of high-dose ionising radiation exposure should not prevent medically indicated diagnostic X-ray procedures from being performed on pregnant women. Consultation with an expert in dosimetry calculation may be helpful in calculating estimated foetal dose when multiple diagnostic X-ray procedures are performed in pregnancy. In general, the radiation safety principle, ALARA (as low as reasonably achievable), minimising radiation and release of radioactive materials should be employed at all times. In addition, the use of iodine-based contrast agents for X-ray, fluoroscopy and CT scanning, and the use of gadolinium-based contrast agents for CMR are safe in pregnancy and should be used when the potential benefit justifies the potential risk to the foetus. However, the use of radioactive isotopes of iodine is contra-indicated for therapeutic use during pregnancy. Dr Ntusi acknowledges support from the National Research Foundation and Medical Research Council of South Africa.

sense to patients, and it is incumbent on the clinician to take the time to allay fears, ensuring good and clear communication during counselling. ‘Safe’ is a relative term but one that physicians should not be afraid to use. When a radiographic study is needed for appropriate management of a pregnant patient, the ACR recommends that ‘health care workers should tell patients that X-rays are safe and provide patients with a clear explanation of the benefits of X-ray examinations.’74 One tool that physicians may consider using to reassure patients is Table 3, which compares the dosage of radiation provided by various common diagnostic studies with the accepted limit of 5 rad (50 mSv). A patient’s particular study could also be plotted on this graph, showing the clear margin of safety that exists for all single diagnostic studies.

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Conclusion Pregnant women with known or suspected CVD often require cardiovascular imaging. The accepted maximum limit of ionising radiation exposure to the foetus during pregnancy is a cumulative dose of 5 rad (50 mSv or 50 mGy). Concerns related to imaging modalities that involve ionising radiation include teratogenesis, mutagenesis and childhood malignancy. Importantly, no single imaging study approaches this cautionary dose of 5 rad (Table 4). Elective studies may be deferred until the pregnancy is over or the gestational period is beyond 20 weeks, and there are several strategies that may be employed to minimise radiation to the foetus (Table 3). Echocardiography and CMR appear to be completely safe in pregnancy and are not associated with any adverse foetal effects, provided there are no general contraindications to MR imaging. Current evidence suggests that a single cardiovascular radiological study during pregnancy is safe and should be undertaken at all times when clinically justified. As a general guide, centres where medical imaging is performed should have signs to remind mothers to notify the staff if they may be pregnant. The potential risks of each imaging modality must be discussed with the mother before she undergoes such imaging. Pregnant women must be made to understand that exposure from a single diagnostic procedure does not result in harmful foetal effects. Specifically, exposure to less than 5 rad has not been associated with an increase in

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outcomes. Arch Intern Med 2002; 162: 1170–1175. 47. Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, Lombardo GT. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology 2002; 224: 487–492.

Davis JL. ACC/AHA/ASE 2003 guideline update for the clinical appli-

48. Damilakis J, Perisinakis K, Vrahoriti H, Kontakis G, Varveris H,

cation of echocardiography: summary article. A report of the American

Gourtsoyiannis N. Embryo/fetus radiation dose and risk from dual

College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc

X-ray absorptiometry examinations. Osteopros Int 2002; 13: 716–722. 49. Pennell DJ. Cardiovascular magnetic resonance. Circulation 2010; 121: 692–705.

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50. Karamitsos TD, Francis JM, Myerson SG, Selvanayagam JB, Neubauer S. The role of cardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol 2009; 54(15): 1407–1424. 51. Ain DL, Narula J, Sengupta PP. Cardiovascular imaging and diagnostic procedures in pregnancy. Cardiol Clin 2012; 30(3): 331–341. 52. Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast agents. J Magn Reson Imag 1999; 10: 477–484. 53. Mevissen M, Buntenkotter S, Loscher W. Effects of static and timevarying (50 Hz) magnetic fields on reproduction and fetal development in rats. Teratology 1994; 50: 229–237. 54. Beers GJ. Biological effects of weak electromagnetic fields from 0 Hz to 200 Hz: a survey of the literature with special emphasis on possible magnetic resonance effects. Mag Res Imag 1989; 7: 309–331. 55. Schwartz JL, Crooks LE. NMR imaging produces no observable mutations or cytotoxicity in mammalian cells. Am J Roentgenol 1982; 139: 583–585.

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emission tomography. Prog Cardiovasc Dis 1989; 32(3): 217–238. 63. Saha, GB. Basics of PET Imaging: Physics, Chemistry and Regulations (2nd edn). New York: Springer, 2010. 64. Fazel R, Krumholz HM, Wang Y, Ross JS, Chen J, Ting HH, et al. Exposure to low-dose ionizing radiation from medical imaging. New Engl Med J 2009; 361: 849–857. 65. Khalil MM, Tremoleda JL, Bayomy TB, Gsell W. Molecular SPECT Imaging: An overview. Int J Mol Imag 2011: 2011: 796025. 66. Paul AK, Nabi HA. Gated myocardial perfusion SPECVT: Basic principles, technical aspects, and clinical applications. J Nucl Med Technol 2004; 32(4): 179–187. 67. Ralston WH, Robbins MS, James P. Reproductive, developmental, and genetic toxicity of ioversol. Invest Radiol 1989; 24(Suppl 1): 16–22. 68. Mehta PS, Metha SJ, Vorherr H. Congenital iodide goiter and hypothyroidism: a review. Obstet Gynecol Surv 1983; 38: 237–247. 69. Webb JA, Thomsen HS, Morcos SK; Members of Contrast Media

56. Wolff S, Crooks LE, Brown P, Howard R, Painter R. Test for DNA and

Safety Committee of European Society of Urogenital Radiology

chromosomal damage induced by nuclear magnetic resonance imaging.

(ESUR). The use of iodinated and gadolinium contrast media during

Radiology 1980; 136: 707–710.

pregnancy and lactation. Eur Radiol 2005; 15: 1234–1240.

57. Reeves MJ, Brandreth M, Whitby EH, Hart AR, Paley MN, Griffiths

70. Ginsberg JS, Hirsh J, Rainbow AJ, Coates G. Risks to the fetus of

PD, et al. Neonatal cochlear function: measurement after exposure

radiologic procedures used in the diagnosis of maternal venous throm-

to acoustic noise during in utero MR imaging. Radiology 2010; 257: 802–809.

boembolic disease. Thromb Haemost 1989; 61: 189–196. 71. Okuda Y, Sagami F, Tirone P, Morisetti A, Bussi S, Masters RE.

58. American College of Radiology. ACR-SPR practice parameter for the

Reproductive and developmental toxicity study of gadobenate dimeglu-

safe and optimal performance of fetal magnetic resonance imaging

mine formulation (E7155) (3) Study of embryo-fetal toxicity in rabbits

(MRI). Revised 2015 (Resolution 11). Available at: http://www.acr.org/~/ media/CB384A65345F402083639E6756CE513F.pdf 59. Berman DS, Hachamovitch R, Shaw LJ, Friedman JD, Hayes SW,

by intravenous administration. J Toxicol Sci 1999; 24(Suppl 1): 79–87. 72. Garcia-Bournissen F, Shrim A, Koren G. Safety of gadolinium during pregnancy. Can Fam Physician 2006; 52(3): 309–310.

Thomson LE, et al. Roles of nuclear cardiology, cardiac computed

73. Spencer JA, Tomlinson AJ, Weston MJ, Lloyd SN. Early report:

tomography, and cardiac magnetic resonance: assessment of patients

comparison of breath-hold MR excretory urography, Doppler ultra-

with suspected coronary artery disease. J Nucl Med 2006; 47(1): 78–82.

sound and isotope renography in evaluation of symptomatic hydrone-

60. Harper PV, Lathrop KA, Jiminez F, Fink R, Gottschalk A. Technetium 99m as a scanning agent. Radiology 1965; 85: 101–109. 61. Schembri GP, Miller AE, Smart R. Radiation dosimetry and safety issues in the investigation of pulmonary embolism. Semin Nucl Med 2010; 40: 442–454. 62. Camici P, Ferrannini E, Opie LH. Myocardial metabolism in ischaemic heart disease: basic principles and application to imaging by positron

phrosis in pregnancy. Clin Radiol 2000; 55: 446–453. 74. Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Jr., Froelich JW, et al. ACR guidance document for safe MR practices: 2007. Am J Roentgenol 2007; 188: 1447–1474. 75. Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Froelich JW, et al. ACR Guidance document on MR safe practices: 2013. J Magn Reson Imag 2013; 37: 501–530.

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Hypertensive disorders of pregnancy: what the physician needs to know John Anthony, Albertino Damasceno, Dike Ojjii

Abstract Hypertension developing during pregnancy may be caused by a variety of different pathophysiological mechanisms. The occurrence of proteinuric hypertension during the second half of pregnancy identifies a group of women whose hypertensive disorder is most likely to be caused by the pregnancy itself and for whom the risk of complications, including maternal mortality, is highest. Physicians identifying patients with hypertension in pregnancy need to discriminate between pre-eclampsia and other forms of hypertensive disease. Pre-eclamptic disease requires obstetric intervention before it will resolve and it must be managed in a multidisciplinary environment. The principles of diagnosis and management of these different entities are outlined in this review.

Pre-eclampsia Epidemiology

Keywords: hypertention disorders, pregnancy Submitted 14/1/16, accepted 14/4/16 Cardiovasc J Afr 2016; 27: 104–110

www.cvja.co.za

DOI: 10.5830/CVJA-2016-051

Hypertension during pregnancy is widespread, representing the most common medical complication of pregnancy and affecting 6–8% of gestations in the United States of America. Two hospital-based studies in sub-Saharan Africa have put the prevalence of this disorder at 11.5 and 26.5% of all deliveries, respectively.1,2 There are four categories of hypertension in pregnancy, chronic hypertension, gestational hypertension, pre-eclampsia, and pre-eclampsia superimposed on chronic hypertension, as defined by the National High Blood Pressure Education Program Working Group in Pregnancy. Hypertension during pregnancy is not only common but also associated with a risk of morbidity and mortality.3,4 The risk of adverse outcomes during pregnancy is largely but not exclusively confined to those pregnant women diagnosed to have pre-eclampsia.4,5 The separation of hypertension during pregnancy into pre-eclampsia or non-pre-eclamptic disease is a foundational consideration when determining the likely course of the disease, the necessary management and the probable outcome.3

Division of Obstetrics and Gynaecology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa John Anthony, MB, ChB, FCOG, MPhil, john.anthony@uct.ac.za

Department of Cardiology, Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique Albertino Damasceno, MD, PhD, FESC

Department of Cardiology, University of Abuja, Abuja, Nigeria Dike Ojjii, MD, PhD, FESC

Pre-eclampsia is uniquely manifest during pregnancy and is associated with a pathophysiological phenotype that encompasses placental disease, growth restriction of the foetus and the development of severe but reversible hypertension during pregnancy.4,6,7 Chronic hypertension, regardless of the precise diagnosis, is not specifically associated with placental vascular disease or severe intra-uterine growth restriction and will not remit after delivery.8 The necessary level of surveillance, hospitalisation and the need for preterm delivery rests upon the distinction between these hypertensive diagnoses.9 In this review we discuss the different types of hypertension during pregnancy, and the physician evaluation, including physical examination and laboratory investigations of the hypertensive pregnant patient.

Pre-eclampsia affects one in 30 primigravid women and one in 60 women in their second or subsequent pregnancies.10 Those who have suffered from the condition before are more likely to develop it in subsequent pregnancies (a one-in-seven risk) and women with underlying co-morbidity are also more likely to develop this complication of pregnancy. Specifically, women with chronic hypertension have a 25% risk of developing superimposed pre-eclampsia, and women with collagen vascular disease are also more prone to develop pre-eclampsia.8,9,11 There is also a hereditary component, and obesity is strongly associated with the risk of developing the condition.12 Obstetric risk factors include an increasing risk of developing pre-eclampsia related to multiple and even higher-order multiple pregnancies. A large placenta, such as those seen in women with trophoblastic disease or various kinds of foetal aneuploidy, are also associated with an increased risk of developing pre-eclampsia. Other risk factors that have been identified as leading to an increased probability of pre-eclampsia developing during pregnancy include antiphospholipid antibody syndrome, chronic hypertension, chronic renal disease, a maternal age over 40 years, nulliparity, incidence of pre-eclampsia in a previous pregnancy and pre-gestational diabetes. The highest incidence of pre-eclampsia is among women having their first baby, whereas the greater prevalence of the disease is in multiparous pregnant women. The disease is described as a condition of primigravidity but it is also, to some extent, associated with primipaternity.10

Clinical phenotype Pre-eclampsia is a syndrome characterised by the development of hypertension and proteinuria in the latter part of pregnancy, which then remits after delivery.3 Pre-eclampsia is unlikely to be the cause of hypertension or proteinuria developing before the 20th week of pregnancy.

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Hypertension is defined in different ways but the most widely accepted definition is the sustained elevation of diastolic blood pressure above 90 mmHg over a period of four hours. Proteinuria is similarly defined in different ways but dipstick proteinuria of 1+ or more merits further investigation. The 24-hour urinary excretion of protein greater than 300 mg is regarded as being pathological. Pre-eclampsia may present in an asymptomatic form. It may also develop acutely or progress to a phase of illness in which multi-organ disease becomes evident.13 This may include the development of eclampsia, cerebrovascular haemorrhage leading to stroke, renal failure either in consequence of acute kidney injury or associated with a progressive decline in renal function, pulmonary oedema for a variety of reasons, liver injury in the form of the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) or obstetric haemorrhage caused by abruptio placentae (commonly associated with pre-eclampsia). Many of these complications of pre-eclampsia may be lifethreatening to the foetus and the pregnant woman.14-16 Characteristically, the delivery of the baby signals the onset of disease resolution, although the mother may continue to exhibit worsening disease for up to 24 hours after delivery. The hypertension associated with pre-eclampsia may take up to six weeks to resolve completely, even if the risk of fulminant disease abates within 24 hours of parturition.

Pathology and pathophysiology Pre-eclampsia is a disease of defective placentation.6 The vascular adaptation in the vessels supplying blood to the placenta show signs of inadequate dilatation as well as evidence of lumina pathology, similar to atherosclerosis. The placenta itself is usually small and infarcted to a greater extent than is usually seen in normal pregnancy. The evolution of the clinical phenotype follows these pathophysiological events in the placental bed. The precise mechanisms are not fully elucidated but some combination of systemic immune activation in response to an increasing maternal circulatory burden of trophoblastic tissue released from the ischaemic placenta combines with components of oxidative stress and an imbalance in the production of angiogenic and anti-angiogenic factors to give rise to changes in systemic vascular endothelial function.17,18 The volume-overloaded circulation of normal pregnancy is offset by endothelial-dependent vasodilatation to such an extent that normal pregnancy is characterised by falling blood pressure, despite the volume overload.19 In pre-eclampsia, the endothelial mechanism is disrupted and hypertension based upon vasoconstriction ensues. The pattern of hypertension may evolve through stages where the increased systemic pressure may be partly based upon increased cardiac output, compensatory for the diminished perfusion of the placenta through narrow vessels in the placental bed.20 The later evolution of the disease is due to defective vasoregulation and vasoconstriction associated with loss of intravascular volume through leaky capillaries and the onset of multi-organ ischaemia.21-25 Specific organs show patterns of ischaemic change, and haemorrhage with or without oedema. These include the brain, kidneys, placenta and liver.26-28 In the brain, the oedema is seen in the watershed areas of perfusion of the occipital lobe and has been designated as ‘posterior reversible encephalopathy

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syndrome’.29 Large haemorrhages can arise from ruptured vessels, with consequent mass effects, including tonsillar herniation, leading to death. The liver shows periportal ischaemia and haemorrhage in women with the HELLP syndrome, whereas the kidneys show evidence of endotheliosis, associated in some cases with acute tubular and cortical ischaemic damage.21,28 The cardiovascular and pulmonary changes seen are those of pulmonary oedema in severe cases, usually without other overt signs of heart failure.13,30

Risk of morbidity and mortality There are two major causes of death among women with pre-eclampsia, cerebrovascular haemorrhage and pulmonary oedema, and each account for roughly half the number of deaths.16 Other rarer causes include the rupture of a subcapsular haematoma, which may complicate the HELLP syndrome. Cerebrovascular haemorrhage is related to severe hypertension.31 The threshold above which this risk escalates is the mean arterial pressure above which the cerebral autoregulatory function fails. This is commonly considered to be 140 mmHg. It is unusual for women to develop such severe hypertension without associated seizure activity. The development of eclampsia leads to severe hypertension during seizure activity and it is the reason why the case fatality rate for eclampsia is cited as one in 50, whereas the overall case fatality rate of pre-eclampsia is set at one in 1 500.14,32 The prevention of eclampsia is as important as the treatment of severe hypertension. Pulmonary oedema may develop for different reasons. The iatrogenic administration of excessive amounts of intravenous fluids may lead to an absolute increase in preload, resulting directly in interstitial pulmonary oedema.13,22 A very high systemic vascular resistance can also elevate the pulmonary capillary wedge pressure, leading to an increased risk of pulmonary oedema.33 The left ventricular function may also be abnormal and commonly demonstrates some degree of diastolic dysfunction, although left ventricular systolic dysfunction is unusual.22,23 The loss of protein in the urine may lower the colloid osmotic pressure and contribute to development of the generalised oedema so characteristic of pre-eclampsia, with similar effects on the lungs. Changes in capillary permeability and the lymphatic drainage of the lungs all modulate the risk of pulmonary oedema in women with variable changes in vascular resistance and ventricular function. Consequently, the precise mechanism of pulmonary oedema cannot be simply attributed to heart failure in this condition.

Management principles Pre-eclampsia is not a condition that can be managed adequately outside a hospital environment.4 The definitive management of pre-eclampsia is delivery.4 Once manifest, the condition tends to worsen and it is unusual for delivery to be delayed by more than 10 to 14 days once the patient develops symptoms or signs of the condition. Because the foetus is at risk of impaired growth and likely to deliver prematurely, management needs to take place in an obstetric unit with access to the best available level of paediatric care. Any improvement in neonatal outcome can only be secured by minimising the risks of prematurity. This is accomplished by delaying delivery for as long as the mother’s condition can be considered to be satisfactory.34,35

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The development of symptoms, an uncontrollable spike in blood pressure or the evolution of defined organ dysfunction signal the onset of life-threatening disease, requiring that the focus of treatment shift from the neonatal outcome to protecting the interests of the mother. Delivery at this point is inevitable and the neonate will need to be cared for in the best available circumstances. The second means of improving perinatal outcome revolve around the use of corticosteroids, given to the mother. These accelerate the maturation of the foetal lungs and lessen the likelihood of neonatal intraventricular haemorrhage in the newborn.36 In addition to the necessity of effecting delivery by either induction of labour or caesarean section, the obstetrician plays a role in preventing complications. The prevention of eclampsia is ensured by the use of magnesium sulphate, given as a continuous infusion or as intermittent intramuscular doses.37,38 This has been shown to be effective in reducing the risk of developing eclamptic seizures (and recurrent seizures) without adversely sedating the foetus. The mechanism of action is poorly understood and the use of magnesium sulphate needs to be weighed against potential risks. These include the development of toxicity, which is more common in women with renal failure. Toxicity leads to respiratory arrest, which can be reversed with intravenous calcium gluconate. Women who are fitting should have their seizures aborted with intravenous benzodiazepines. Women who continue to fit despite treatment or those who are unable to protect their airway because of a low Glasgow coma scale need intubation and mechanical ventilation until the pregnancy is over and the mother’s condition shows signs of improvement.13,39 Proper management of severe hypertension is always a priority. Drugs used to lower the blood pressure are a variety of agents, including direct-acting vasodilators (hydrallazine, dihydrallazine), calcium channel blockers (nifedipine), alphaand beta-blockers (labetalol), and combined arterial and venous vasodilators (nitroglycerine). Potent vasodilators such as sodium nitroprusside or diazoxide should not be used because they are associated with a risk of precipitous decline in blood pressure.

Specific organ failure is managed according to specific protocols • Eclampsia requires attention to seizure control as outlined above. Recurrent seizures may only be controllable by continuous infusion of propofol or diazepam; this usually requires intubation and ventilation for up to 24 hours after delivery has been effected. The co-morbidity associated with seizures needs individual management (see below); specific screening and treatment of aspiration pneumonia is important. Any focal neurological signs merit neuro-radiological investigation to exclude haemorrhage and infarction. The differential diagnosis of seizure activity also merits consideration and may extend to other possible diagnoses, including metabolic causes for seizure activity, thrombotic thrombocytopaenic purpura, systemic lupus erythematosis, cerebral venous thrombosis, malaria and amniotic fluid embolus.40 • Renal failure may be manifest on the basis of diminished preload together with peripheral, including renal, vasospasm. Acute renal injury may also cause oliguria and azotaemia. This is the consequence of ischaemia (due to pre-eclampsia

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or pre-eclampsia complicated by hypovolaemia caused by abruptio placentae) and haemoglobinuria. The principles of management are those of cautious intravascular volume expansion (no more than 300 ml of colloidal solution given as a bolus dose) and vasodilatation.41 Renal failure that fails to respond to these measures should result in a policy of fluid restriction, management of actual or incipient hyperkalaemia and expectant management in anticipation of gradual recovery after delivery.42 In the acute phase of the illness, dialysis may be necessary. • Liver injury is associated with the HELLP syndrome. This condition needs to be distinguished from other causes of micro-angiopathic haemolytic anaemia as well as other causes of liver failure. The differential diagnosis therefore includes thrombotic thrombocytopenic purpura, acute fatty liver of pregnancy, auto-immune disease, malaria and sepsis. The hallmark of the HELLP syndrome is that it reverses after delivery, with the nadir of thrombocytopaenia occurring on the third day postpartum.43 The management is obstetric, meaning delivery. Patients who do not exhibit the characteristic resolution of the thrombocytopaenia merit investigation for other causes of micro-angiopathic haemolytic anaemia. The only lethal complication of the HELLP syndrome is the development of a large subcapsular liver haematoma, which ruptures, causing massive intraperitoneal haemorrhage.44 The liver injury itself and the elevated liver enzymes seen in HELLP syndrome are not associated with failure of hepatic synthetic function and do not usually lead to coagulopathy or hypoglycaemia. These features, if present, indicate an alternative diagnosis. • Pulmonary oedema is the most difficult complication of severe pre-eclampsia in which to make a specific diagnosis.30 The mechanisms of pulmonary oedema are outlined above and the differential diagnosis will include other causes of acute dyspnoea, commonly infection and embolus. Pulmonary oedema itself may be the consequence of pre-eclampsia, or pre-eclampsia complicating underlying illness. These illnesses may include valvular heart disease and ventricular dysfunction due to cardiomyopathy. Regardless of the cause, emergency management is usually the same, involving supportive management of oxygenation and various combinations of diuretic and vasodilator therapy with a view to reducing both afterload and preload. This is commonly accomplished by using direct-acting vasodilators, such as dihydrallazine, together with intravenous furosemide. The development of pulmonary oedema is a signal for investigation by means of radiology, ECG and echocardiography to try to ascertain as closely as possible what the underlying cause may be. In some circumstances, the acute management of critically ill women may be facilitated by the use of pulmonary artery catheters to directly measure haemodynamic variables.45 Pulmonary oedema complicating pre-eclampsia is also an indication for immediate delivery, to begin reversing the underlying pathophysiology of pre-eclampsia.

Postpartum management Delivery of the pre-eclamptic pregnant woman will trigger reversal of the underlying disease. Generalised oedema begins to dissipate as the capillary leak reverses and the pregnancy

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preload is excreted. Commonly, 48 to 72 hours after delivery, the left ventricular preload may start to increase as the oedema resolves.46 This is an appropriate time to facilitate a diuresis. The hypertension itself may persist for up to six weeks after delivery, requiring management for this duration with diuretics and second-line agents. Whereas angiotensin converting enzyme (ACE) inhibitors are commonly used in non-pregnant hypertensives, often calcium channel blockers are more rapidly effective in these circumstances and are a good choice of treatment for the limited period for which they will be required. One of the most important aspects of managing the postpartum pre-eclamptic is that of counselling. Pre-eclampsia has been shown to be a marker of long-term risk. Specifically, there is an association between hyperinsulinaemia, dyslipidaemia and the risk of pre-eclampsia. These underlying metabolic disorders are also risk factors for early onset vascular disease (both coronary artery and cerebrovascular disease).47 Consequently, women with early onset pre-eclampsia are at risk of vascular arterial disease in later life. Attention therefore needs to be paid to primary prevention of these conditions through regular screening, and treatment for metabolic disorders. The second long-term consequence of pre-eclampsia is that of an increased risk of renal failure.48 This risk correlates with the number of pre-eclamptic pregnancies a woman may have and indicates a need to pay attention to aspects of care in later life that may have a renal protective effect, specifically the early and adequate treatment of hypertension.

Chronic hypertension in pregnancy Chronic hypertension during pregnancy may be divided into two groups: uncomplicated chronic hypertension and chronic hypertension with superimposed pre-eclampsia. The latter group requires management according to the principles outlined above, whereas the former requires out-patient care, often with an altered approach to therapeutic intervention. Chronic hypertension is defined as blood pressure of 140/90 mmHg or more on two occasions before 20 weeks of gestation or persisting beyond 12 weeks after delivery

Chronic hypertension with superimposed pre-eclampsia The risk of developing superimposed pre-eclampsia is estimated to be between 10 and 25%.49 The possibility of decreasing this risk merits consideration. The development of pre-eclampsia cannot be averted by controlling blood pressure and there is no therapy that has any major impact on the risk of developing superimposed pre-eclampsia. However, there is some evidence that the use of low-dose aspirin, given as a daily dose of 57 to 81 mg of aspirin, may reduce the risk of pre-eclampsia developing in about 10% of women who are at risk of the disease.50 It is not clear why aspirin is effective, and initial theories related to altered prostanoid metabolism have been discounted, with more recent speculation focused on the possible interaction between aspirin and the production of pro-inflammatory cytokines.51 Aspirin given in this dose is safe and has no effect on the foetus. Despite the modest effect on the incidence of the disease, it remains recommended therapy in women who are at risk. The second strategy used to reduce the occurrence of pre-eclampsia is based on the prophylactic administration of

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large doses of oral calcium. Meta-analysis of the studies conducted to date indicate that calcium administered in doses of up to one gram three times a day may significantly reduce the occurrence of pre-eclampsia and may also reduce the development of severe hypertension.52 The criticism of this data arises from the observation that the two single largest studies in the meta-analysis failed to reach statistical significance. Despite these reservations, calcium supplementation is widely accepted practice during pregnancy where there is a suspected risk of pre-eclampsia. Interventions that are not of benefit in preventing pre-eclampsia include bedrest, the use of anti-oxidant vitamins and antihypertensive therapy itself. Given the imperfect prophylactic measures aimed at preventing pre-eclampsia, care of pregnant women with chronic hypertension requires appropriate precautions to ensure that the development of superimposed disease is detected early in its development because of the attendant risks of foetal and maternal morbidity and mortality. Knowing who will develop superimposed pre-eclampsia before it becomes clinically manifest would be useful information. The clinical phenotype of pre-eclampsia arises from changes at the level of the foetoplacental unit and any early signs of intra-uterine growth restriction or abnormal uterine artery Doppler velocimetry may precede the onset of the clinical disease.49 The hallmark of superimposed pre-eclampsia is, however, the development of proteinuria. The difficulty with this is knowing when the proteinuria is a consequence of underlying pre-eclampsia rather than due to renal disease caused by longstanding hypertension or a priori renal disease with secondary hypertension (in many communities HIV-associated nephritis may be a major differential diagnosis). This distinction may not be easily made on a clinical basis and where a diagnosis of pre-eclampsia enters the differential diagnosis, the patient deserves in-patient care and management for presumptive pre-eclampsia until an alternative diagnosis can be made. The natural history of pre-eclampsia sometimes facilitates the distinction between pre-eclampsia and renal disease as a cause for proteinuria because pre-eclampsia tends to worsen as the pregnancy continues, whereas the chronically hypertensive patient has an indolent condition that changes little with the passage of time. The recent interest in biomarkers may provide an alternative way of diagnosing which hypertensive conditions have a placental origin. Angiogenic and anti-angiogenic factors [placental growth factor and the soluble receptor for vascular endothelial growth factor (sFlt)] have been shown to be good predictors of placental disease and may provide a ready means of discriminating between various types of hypertensive disease in pregnancy, specifically identifying those most at risk of adverse outcome.53

Uncomplicated chronic hypertension Uncomplicated chronic hypertension does not usually affect the pregnancy outcome to any significant degree. The drugs used to treat hypertension outside pregnancy may need to be revised and alternatives introduced in order to protect the foetus. Physiological changes during pregnancy have an impact on chronically hypertensive women as well. Specifically, they will vasodilate during the second trimester, leading to a fall in blood

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pressure and a reduction in the requirement for treatment at this point in the pregnancy. As the volume expansion during pregnancy continues and peaks at about 32 weeks’ gestation, the need for treatment may increase again. The goals of treatment also may need to be revised during pregnancy. Outside pregnancy, the aim of treatment is prevention of end-organ damage to the heart, vasculature and kidneys. The use of diuretics with ACE inhibitors is common and the goal of therapy is normotensive blood pressure. This strategy does not apply during pregnancy because the drugs may harm the foetus, and placental perfusion (in theory) may be adversely affected by antihypertensive drugs that diminish perfusion pressure. Diuretics, although used to treat cardiac conditions during pregnancy, are generally held to be contra-indicated in the management of chronic hypertension during pregnancy because pregnancy relies upon volume expansion to secure an accelerated rate of delivery of oxygenated blood to the peripheral tissues, including the placental bed. ACE inhibitors are also contra-indicated because they may interfere with the physiological regulation of uterine blood flow through local uterine mechanisms. More seriously, they are associated with neonatal renal failure in children of women treated with them during pregnancy. Of the other categories of antihypertensive drugs, beta-blockers are also relatively contra-indicated, being considered to be an independent risk factor for the development of intra-uterine growth restriction.54 Antihypertensive therapy during pregnancy in chronically hypertensive women is usually secured through the use of alphamethyldopa or calcium channel blockers. The aim of treatment is to reduce the occurrence of severe hypertension to safer levels of blood pressure. Practically, the threshold for introducing treatment is a sustained increase in blood pressure to above 160/110 mmHg to levels below this without seeking to reduce the pressure to normotensive levels. The complications of chronic hypertension during pregnancy may extend to various forms of cardiac decompensation, depending on the severity of the condition. Hence, hypertensive cardiomyopathy is rarely seen in relatively young women with chronic hypertension, although it may develop and can give rise to maternal mortality.55 More commonly, diastolic dysfunction caused by changes in left ventricular morphology may result in the onset of increasing dyspnoea in the third trimester as the volume expansion peaks out. Patients in this category are otherwise well, without any signs of superimposed pre-eclampsia. This is one circumstance where diuretic therapy may result in rapid clinical improvement and resolution of symptoms that will allow the pregnancy to continue to term. Obstetric intervention is not commonly required in chronically hypertensive women. However, some mild degree of foetal growth restriction may be present and the risk of superimposed pre-eclampsia cannot be excluded with absolute certainty. Consequently, induction of labour is usually recommended for women who do not labour spontaneously before 40 weeks’ gestation.

Latent hypertension Pregnancy may render overt hypertension that is not yet clinically manifest outside of pregnancy. Women who have a strong familial history of hypertension, whose genetic predisposition will manifest

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as essential hypertension in later life, may become hypertensive during pregnancy. The mechanism is thought to be related to subnormal pregnancy vasodilatation in vessels, with a hereditary defect in vasoregulation. In this circumstance, the increased intravascular volume of pregnancy cannot be accommodated by adequate vasodilatation, with a rise in blood pressure developing in the late second to third trimester of pregnancy.56 This condition should be managed according to the same principles as those outlined for women with chronic hypertension. The outcome of the pregnancy is usually unaffected and the only consideration might be the need for induction of labour in women not yet delivered by 40 weeks’ gestation.

Physiological hypertension Hypertension does not always indicate disease. Pregnancy is characterised by massive plasma volume expansion, and the cardiovascular adaptation needed to accommodate this increased intravascular volume is that of equally massive peripheral vasodilatation. The net consequence of this is a fall in blood pressure during the second trimester, with increasing levels of blood pressure closer to term. The entire adaptation is mediated by the placenta, and the adequacy of the pregnant physiological change depends on the amount of biochemically active trophoblast in the uterus. Hence women with multiple pregnancies or those who have singleton pregnancies with a large placenta will have a greater degree of volume expansion than those with a smaller placental mass. The consequences of this may be a supraphysiological increase in plasma volume that exceeds the degree of compensatory vasodilatation close to term. These individuals have normal pregnancies in every respect, with normally grown babies and no other signs of pre-eclampsia. This is not a condition requiring treatment or intervention and should be recognised as a variant of normal.3 The difficulty of managing these patients lies in being certain that the distinction can be safely made between physiological hypertension and pre-eclampsia. For this reason, many of these women would be allowed to continue to term but induction of labour would be justified at 40 weeks’ gestation

General evaluation of patients with hypertensive disorder of pregnancy Determining whether high blood pressure identified during pregnancy is due to pre-eclampsia or chronic hypertension is sometimes a challenge to the physician, especially if there are no recorded blood pressures available from the first half of the gestation. Clinical characteristics obtained through a good history, physical examination and some laboratory investigations may be used to help clarify the diagnosis.

Relevant history the physician must take The time of detection of hypertension is very important. Hypertension occurring before 20 weeks’ gestation is almost always due to chronic hypertension, while new-onset hypertension after 20 weeks’ gestation should lead to a suspicion of gestational hypertension. Worsening hypertension after 20 weeks of gestation should lead to careful evaluation for the manifestations of pre-eclampsia.

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Patients with pre-eclampsia may describe new-onset headache that is frontal, throbbing or similar to migraine headache. They may also have visual disturbances, including scintillations and scotoma, which has been linked to cerebral vasospasm. Gastrointestinal complaints, such as epigastric pain, may be moderate to severe in intensity and due to hepatic swelling and inflammation, with stretch of the liver capsule. Rapidly increasing or non-dependant oedema may be a symptom of developing pre-eclampsia. In addition, rapid weight gain as a result of oedema due to capillary leak, as well as renal sodium and fluid retention could be a pointer to pre-eclampsia. New-onset seizures in pregnancy suggest pre-eclampsia–eclampsia, but primary neurological disorders must always be excluded.

Signs the physician must look out for Pre-eclampsia is a multi-systemic disease with various physical signs. Oedema can be seen in non-dependent areas such as the face and hands, apart from the dependent areas. Maternal systolic blood pressure above 160 mmHg or diastolic blood pressure above 110 mmHg can occur and denote severe disease. In measuring the blood pressure, women should be made to sit quietly for five to 10 minutes before each blood pressure measurement, and blood pressure should be measured in lateral recumbency with the cuff at the level of the heart. Korotokoff sounds I and V should be used to define the systolic and diastolic blood pressure, respectively. In about 5% of pregnant women, an exaggerated gap exists between the fourth and fifth Korotokoff sounds with the fifth sound approaching zero. In this type of case, the fourth sound may more closely approximate the true diastolic blood pressure. Signs of secondary hypertension such as buffalo hump, wide purple abdominal striae suggesting glucocorticoid excess, systolic bruit heard over the abdomen or in the flanks suggesting renal artery stenosis, and radio-femoral delay or diminished pulses in the lower versus upper extremities suggesting aortic co-arctation should be looked for. The presence of a fourth heart sound on auscultation is not a normal finding in pregnancy and may suggest left ventricular hypertrophy from chronic hypertension. Carotid bruits may also reflect atherosclerotic disease due to longstanding hypertension. In addition, retinal changes of chronic hypertension may be noted. Retinal vasospasm and retinal oedema, which may manifest as severely impaired vision, generally reflects pre-eclampsia. In pre-eclampsia right upper-quadrant abdominal tenderness stemming from hepatic swelling and capsular stretch may be seen. Although brisk or hyperactive reflexes are common during pregnancy, clonus is a sign of neuromuscular irritability that usually reflects severe pre-eclampsia.

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Serum lipids usually increase during pregnancy and therefore measurement should be deferred until the postpartum period. Also, the increase in endogenous corticosteroids levels during normal pregnancy makes it difficult to evaluate for secondary hypertension due to adrenal corticosteroid excess. Useful blood tests when evaluating eclampsia and pre-eclampsia include urinalysis, a full blood count, serum electrolyte levels, urea and creatinine 24-hour urinary protein excretion, and serum uric acid, liver enzyme and bilirubin levels.

Follow up The long-term implications of having a pregnancy complicated by pre-eclampsia or hypertension have been highlighted above. It is important that pregnant women with hypertensive disease be given every opportunity to attend appropriate follow-up care in order to prevent long-term premature morbidity and mortality.

References 1.

Ebeigbe P, Igberase G, Aziken M. Hypertensive disorders in pregnancy: experience with 442 recent consecutive cases in Benin city, Nigeria. Niger Med J 2007; 48(4): 94–98.

Chowa P, Lin C, Goma F, South-Paul J. Prevalence of hypertension among women of child bearing age in Zambia. Med J Zambia 2011; 38(3): 3–8.

Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158(4): 892–898.

Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365(9461): 785–799.

Seely EW, Ecker J. Chronic hypertension in pregnancy. New Engl J Med 2011; 365(5): 439–446.

Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L, et al. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynecol 1991; 98(7): 648–655.

Lindheimer MD, Taler SJ, Cunningham FG. ASH position paper: hypertension in pregnancy. J Clin Hypertens 2009; 11(4): 214–225.

Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic hypertension. Obstet Gynecol 1983; 61(5): 571–576.

Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P, Klebanoff M, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. New Engl J Med 1998; 339(10): 667–671.

10. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. Br Med J 1998; 316(7141): 1343. 11. Chappell LC, Enye S, Seed P, Briley AL, Poston L, Shennan AH. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension a prospective study. Hypertension 2008; 51(4): 1002–1009. 12. Poon LC, Nicolaides KH. First-trimester maternal factors and biomarker screening for preeclampsia. Prenat Diagn 2014; 34(7): 618–627.

Laboratory investigations the physician must order

13. Anthony J, Johanson R, Dommisse J. Critical care management of severe

Laboratory investigations to evaluate chronic hypertension include testing for target-organ damage, and to exclude secondary causes of hypertension and co-morbid factors. For chronic hypertension in the first trimester, it is very useful to obtain a full blood count, electrolyte, urea and creatinine levels, liver enzyme concentrations and testing for proteinuria. These serve as baseline values to be referred to later in the pregnancy if there is a concern regarding superimposed pre-eclampsia.

14. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preec-

pre-eclampsia. Fetal Matern Med Rev 1994; 6(04): 219–229. lampsia and eclampsia. Obstet Gynecol 2001; 97(4): 533–538. 15. Lewis G. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–08. The eighth report on confidential enquiries into maternal deaths in the United Kingdom. Br J Obstet Gynecol 2007; 118(Suppl 1): 1–203. 16. National Fepartment of Health. Saving Mothers 2011–2013. Sixth report on confidential enquiries into maternal deaths in South Africa. Short report.

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2015. www.kznhealth.gov.za/.../Saving-Mothers-2011-2013-short-report 17. Dekker GA. Management of preeclampsia. Pregnancy Hypertens 2014; 4(3): 246–247. 18. Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens 2015; 24(2): 131–138. 19. Hytten F, Chamberlain G. Clinical Physiology in Obstetrics. Oxford: Blackwell Scientific, 1980. 20. Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol 1990; 76(6): 1061–1069. 21. Sibai BM, Taslimi MM, El-Nazer A, Amon E, Mabie BC, Ryan GM. Maternal–perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia–eclampsia. Am J Obstet Gynecol 1986; 155(3): 501–507.

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36. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Library 1996: 1: 1–8. 37. The Eclampsia Trial collaberative group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345(8963): 1455–1463. 38. The Magpie Trial collaberative group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359(9321): 1877–1890. 39. Anthony J, Johanson R. Critical care in pregnancy. Curr Obstet Gynaecol 1996; 6(2): 98–104. 40. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007; 109(4): 956–966. 41. Linton D, Anthony J. Critical care management of severe pre-eclampsia. Intensive Care Med 1997; 23(3): 248–255.

22. Belfort M, Anthony J, Kirshon B. Respiratory function in severe gestational

42. Drakeley AJ, Le Roux PA, Anthony J, Penny. Acute renal failure complicat-

proteinuric hypertension: the effects of rapid volume expansion and subse-

ing severe preeclampsia requiring admission to an obstetric intensive care

quent vasodilatation with verapamil. Br J Obstet Gynecol 1991; 98(10): 964–972. 23. Visser W, Wallenburg H. Central hemodynamic observations in untreated preeclamptic patients. Hypertension 1991; 17(6 Pt 2): 1072–1077.

unit. Am J Obstet Gynecol 2002; 186(2): 253–256. 43. Chandran R, Serra‐Serra V, Redman CW. Spontaneous resolution of pre‐ eclampsia‐related thrombocytopenia. Br J Obstet Gynaecol 1992; 99(11): 887–890.

24. Belfort MA, Anthony J, Saade GR, Wasserstrum N, Johanson R, Clark S,

44. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA.

et al. The oxygen consumption/oxygen delivery curve in severe preeclamp-

Maternal morbidity and mortality in 442 pregnancies with hemolysis,

sia: evidence for a fixed oxygen extraction state. Am J Obstet Gynecol 1993;

elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet

169(6): 1448–1455.

Gynecol 1993; 169(4): 1000–1006.

25. Belfort M, Akovic K, Anthony J, Saade G, Kirshon B, Moise K. The

45. Gilbert WM, Towner DR, Field NT, Anthony J. The safety and utility of

effect of acute volume expansion and vasodilatation with verapamil on

pulmonary artery catheterization in severe preeclampsia and eclampsia. Am

uterine and umbilical artery Doppler indices in severe preeclampsia. J Clin Ultrasound 1994; 22(5): 317–325. 26. Khong T, Pearce J, Robertson W. Acute atherosis in preeclampsia: maternal determinants and fetal outcome in the presence of the lesion. Am J Obstet Gynecol 1987; 157(2): 360–363.

J Obstet Gynecol 2000; 182(6): 1397–1403. 46. Hankins GD, Wendel GD, Cunningham FG, Leveno KJ. Longitudinal evaluation of hemodynamic changes in eclampsia. Am J Obstet Gynecol 1984; 150(5): 506–512. 47. Irgens HU, Roberts JM, Reisæter L, Irgens LM, Lie RT. Long-term mortal-

27. Richards A, Graham F, Bullock R. Clinicopathological study of neuro-

ity of mothers and fathers after pre-eclampsia: population-based cohort

logical complications due to hypertensive disorders of pregnancy. J Neurol

study. Pre-eclampsia and cardiovascular disease later in life: who is at risk?

Neurosurg Psychiat 1988; 51(3): 416–421. 28. Gaber LW, Spargo BH, Lindheimer MD. Renal pathology in pre-eclampsia. Bailliere’s Clin Obstet Gynaecol 1994; 8(2): 443–468. 29. Postma IR, Slager S, Kremer HP, de Groot JC, Zeeman GG. Long-term consequences of the posterior reversible encephalopathy syndrome in eclampsia and preeclampsia: a review of the obstetric and nonobstetric literature. Obstet Gynecol Surv 2014; 69(5): 287–300. 30. O’Dwyer SL, Gupta M, Anthony J. Pulmonary edema in pregnancy and the puerperium: a cohort study of 53 cases. J Perinatal Med 2015; 43(6): 675–681. 31. Belfort MA, Varner MW, Dizon-Townson DS, Grunewald C, Nisell H.

Br Med J 2001; 323(7323): 1213–1217. 48. Vikse BE, Irgens LM, Leivestad T, Skjærven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. New Engl J Med 2008. 359(8): 800–809. 49. Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29(3): 183–196. 50. Duley L, Henderson-Smart D, Meher S, King J. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007; 4: 1–121. 51. Roberts JM, Catov JM. Aspirin for pre-eclampsia: compelling data on benefit and risk. Lancet 2007; 369(9575): 1765–1766.

Cerebral perfusion pressure, and not cerebral blood flow, may be the critical

52. Hofmeyr G, Duley L, Atallah A. Dietary calcium supplementation for

determinant of intracranial injury in preeclampsia: a new hypothesis. Am J

prevention of pre‐eclampsia and related problems: a systematic review and

Obstet Gynecol 2002; 187(3): 626–634. 32. Douglas KA, Redman C. Eclampsia in the United Kingdom. Br Med J 1994; 309(6966): 1395–1400. 33. Belfort M, Anthony J, Buccimazza A, Davey D. Hemodynamic changes associated with intravenous infusion of the calcium antagonist verapamil in the treatment of severe gestational proteinuric hypertension. Obstet Gynecol 1990; 75(6): 970–974.

commentary. Br J Obstet Gynaecol 2007; 114(8): 933–943. 53. Chappell LC, Duckworth S, Seed PT, Griffin M, Myers J, Mackillop L, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation 2013; 128(19): 2121–1231. 54. Sliwa K, Anthony J. Cardiac Drugs in Pregnancy. London: Springer Verlag, 2014.

34. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJvW. Aggressive or

55. Sliwa K, Libhaber E, Elliott C, Momberg Z, Osman A, Zühlke L, et al.

expectant management for patients with severe preeclampsia between 28–34

Spectrum of cardiac disease in maternity in a low-resource cohort in South

weeks’ gestation: a randomized controlled trial. Obstet Gynecol 1990 76(6): 1070–1075.

Africa. Heart 2014: 100: 1967–1974. 56. Davey D, MacGillivray I. The classification and definition of the hyper-

35. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant

tensive disorders of pregnancy: proposals submitted to the International

management of severe preeclampsia at 28 to 32 weeks’ gestation: a rand-

Society for the Study of Hypertension in Pregnancy. Part B: Hypertension

omized controlled trial. Am J Obstet Gynecol 1994; 171(3): 818–822.

in pregnancy . Clin Exp Hypertens 1986; 5(1): 97–133.

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Valvular heart disease in pregnancy John Anthony, Ayesha Osman, Mahmoud U Sani

Abstract Valvular heart disease may be a pre-existing complication of pregnancy or it may be diagnosed for the first time during pregnancy. Accurate diagnosis, tailored therapy and an understanding of the physiology and pathophysiology of pregnancy are necessary components of management, best achieved through the use of multidisciplinary clinics. This review outlines the management of specific lesions, with particular reference to post-rheumatic valvular heart disease. Keywords: valvular, heart disease, pregnancy Submitted 9/2/16, accepted 14/4/16 Cardiovasc J Afr 2016; 27: 111–118

www.cvja.co.za

DOI 10.5830/CVJA-2016-052

Heart disease is one of the most common medical disorders in pregnancy. Pregnancy is associated with significant haemodynamic changes that may aggravate valvular heart disease and increase the risk of thrombo-embolic events. Valvular heart disease accounts for approximately a quarter of the cardiac diseases complicating pregnancy and is an important cause of maternal mortality, posing many challenges in management.1 In developing countries, valvular disease is almost exclusively the consequence of childhood rheumatic fever, although valvular dysfunction may also develop in some patients who have a prolapse of the mitral valve leaflets (Barlow’s syndrome), or ventricular dilation due to elevated afterload or cardiomyopathy.2 This review will be directed to the main source of valvular disease in developing countries, which is post-rheumatic disorders.

Epidemiology of rheumatic heart disease Rheumatic fever and its cardiac sequelae remain prevalent in developing countries.3 Although the Global Burden of Disease study demonstrated an overall reduction in deaths due to rheumatic heart disease (RHD) over a 20-year period, much of the change occurred in North America and Europe.4 The condition remains prevalent in other parts of the world, with an estimated global incidence of 282 000 new cases per year.5 On a global scale, the years lived with disability due to rheumatic fever, valvular heart disease caused by rheumatic disease, and heart failure related to valvular rheumatic heart disease are less encouraging, with increased rates of heart Division of Obstetrics and Gynaecology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa John Anthony, MB ChB, FCOG, MPhil, john.anthony@uct.ac.za Ayesha Osman, MB ChB, FCOG, MMed

Department of Medicine, Bayero University Kano and Aminu Kano Teaching Hospital, Kanu, Nigeria Mahmoud U Sani, MB BS, FWACP

failure evident.6 This epidemiology is significant because it defines a condition that is preventable within the context of socio-economic upliftment, limiting overcrowding and giving sufficient access to medical care; it is also a significant cause of premature mortality. The cited estimates of mortality reflect institutional rates due to clinical disease and take no account of the pre-clinical incidence of the disease. It has been projected that more than 15 million people suffer from RHD worldwide, which is likely a significant underestimation, according to the increasing data on subclinical RHD.7,8 RHD accounts for a major proportion of all cardiovascular disease (CVD) in children and young adults in African countries and for 17–43% of all cardiovascular disease in sub-Saharan Africa (SSA).9 The disease causes 400 000 deaths annually, mainly among children and young adults living in developing countries.10 The recently published Global Rheumatic Heart Disease registry (REMEDY) enrolled 3 343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India and Yemen. The majority (63.9%) had moderate-to-severe multi-valvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%) and major bleeding (2.7%). Among 1 825 women of childbearing age (12–51 years), only 3.6% were using contraception.11 In general, RHD accounts for about 8% of the clinical disease documented in an urban South African black population but is the presenting cardiac disease in a far higher proportion of pregnant women accessing maternity care in an African setting.12 In South Africa, cardiac disease in pregnancy is the most common medical disorder leading to maternal mortality and about 26% of those deaths have been attributed to complications arising from valvular heart disease. The physiological changes of pregnancy can precipitate symptoms of cardiac disease in women who were previously asymptomatic. The management of pregnant women with valvular heart disease combines and sometimes conflicts with obstetric management of the pregnancy. Perinatal outcome becomes an additional consideration superimposed on the need for good-quality medical care. These competing interests are best managed through collaborative, combined care in a high-risk clinic attended by both obstetricians and cardiologists.13

Physiology of pregnancy and heart disease Pregnancy results in the development of a hyperdynamic circulation. Increased circulating blood volume and increased cardiac output are necessary adaptations, allowing increased uterine and placental perfusion, combined with augmented perfusion of maternal organs, which is important in pregnancy homeostasis, especially for the kidneys and skin.14 The changes that take place are progressive and largely determined by placental endocrine function.

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The first trimester is characterised by increased cardiac output brought about by increased heart rate and stroke volume. These changes are partly induced by the onset of an expanded intravascular volume, set against peripheral arteriolar dilatation. Human chorionic gonadotrophin, which has some thyroid stimulating factor homology and activity, may also contribute to the rise in cardiac output. This is followed by progressive volume expansion secondary to physiological hyperaldosteronism with renal sodium and water retention.15 In the second trimester the volume expansion continues and peripheral vasodilatation dominates the pregnancy adaptation, leading to a fall in blood pressure.16 Early in the third trimester, the volume expansion peaks and vascular resistance rises. Labour is accompanied by a further increase in cardiac output, which may be catecholamine mediated as a result of painful contractions. Delivery has complex haemodynamic effects, including blood loss and autotransfusion of blood from the contracted uterus immediately after delivery. In the puerperium, the extracellular fluid retention of pregnancy dissipates, with resolving peripheral oedema, and the hyperdynamic effects of pregnancy persist for days to weeks. Further cardiovascular disturbance may arise from common morbidity such as postpartum anaemia. Pregnancy induces a procoagulant haematological profile with accelerated rates of thrombus formation and fibrinolysis.17 This is necessary to secure haemostasis within the choriodecidual space of the placenta and is also one of the mechanisms by which blood loss at the point of delivery is curtailed. This adaptation will increase the risk of thrombotic events in susceptible individuals. In summary, the cardiac consequences of pregnancy are those of increased preload, reduced afterload, and increased heart rate, stroke volume and cardiac output in a hypercoagulable circulation subject to progressive change throughout pregnancy but also confronted by acutely increased demands during labour and immediately after delivery.

Valvular heart disease Acute rheumatic fever is a possible complication of pregnancy but is rarely seen. Most patients present with established postrheumatic valvular disease. Valvular heart disease is present in 80% of patients with heart disease during pregnancy in developing countries, with rheumatic fever as the most common aetiology.18 It may present for the first time during pregnancy. Stenotic lesions that limit the ability to increase cardiac output may not be well tolerated during pregnancy and delivery. Regurgitant lesions are generally better tolerated, especially if the underlying cardiac function is normal.19 Occasionally, deterioration of regurgitation or left ventricular function is seen, requiring medical treatment.

Stenotic lesions The mitral valve is the most commonly affected valve following the development of acute rheumatic fever. A study of routine echocardiographic screening among a population of children under the age of 17 years in Mozambique and Cambodia identified mitral valve disease in 87â&#x20AC;&#x201C;98% of cases.20 An earlier South African study showed that overall, mitral stenosis was

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the single most prevalent abnormality, affecting 38% of those presenting with valvular disease, although mitral incompetence was more common in the first two decades of life.21 The latter study identified mitral incompetence in 30% of patients, with mixed lesions making up the balance. In the recently published REMEDY registry, children in the first decade of life presented predominantly with pure mitral regurgitation, with mixed mitral and mixed aortic valve disease emerging as a dominant mitral valve lesion from the second decade of life. Most of the cases of mitral stenosis and mitral regurgitation among other forms of valvular disease had moderate-to-severe disease.11

Mitral stenosis (MS) Rheumatic mitral stenosis is poorly tolerated in pregnancy, and it is the leading cardiac cause of maternal mortality in the developing world.22 It may be an incidental finding on physical examination, with many women unaware of the condition until the haemodynamic changes of pregnancy precipitate symptoms, usually in the mid-second trimester. They develop exertional dyspnoea and postural symptoms, including orthopnoea and paroxysmal nocturnal dyspnoea. Occasionally the condition may have been misdiagnosed as bronchial asthma. The classical signs of mid-diastolic rumbling murmur at the apex may be difficult to detect in patients with pulmonary oedema and a rapid tachycardia. Radiological signs of an enlarged left atrium and ECG evidence of a bifid P wave are all useful investigations. Pregnancy may, however, result in a mitralised cardiac shadow in the absence of any valvular pathology. Pregnancy-related tachycardia and the increased blood volume are less likely to be tolerated without an increase in pulmonary capillary pressures, with increasing degrees of mitral stenosis. The increasing systemic vascular resistance of the third trimester tends to increase left-sided filling pressures further and there is a risk of pulmonary oedema during pregnancy. This risk escalates further during labour and immediately postpartum because of an increasingly hyperdynamic circulation and the acute increase in blood volume during the third stage of labour. Significant mitral stenosis results in left atrial dilatation and an increased risk of atrial fibrillation. As pregnancy is already a hypercoagulable state, these patients are at an increased risk of developing intracardiac thrombus, and they should be anticoagulated with therapeutic low-molecular-weight heparin (LMWH). In a South American study of 88 women with rheumatic mitral stenosis (54 of whom had moderate-to-severe mitral stenosis), eight maternal deaths occurred as a result of heart failure.23 In sub-Saharan Africa, a study of 50 pregnancies in women with heart disease, most of whom had rheumatic mitral stenosis, the maternal mortality rate was high at 32%.23 The general principles of medical management are to control the heart rate, limit the volume expansion and prevent the development of co-morbidity due to anaemia, hyperthyroidism and sepsis. In addition to controlling heart rate, beta-blockade will preserve sinus rhythm and prolong diastolic filling of the left ventricle. Atrial fibrillation and atrial flutter should be treated promptly with rate control, and early cardioversion should be considered.24 All drugs should be given with caution. Afterload reduction can cause reflex tachycardia with declining diastolic

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filling of the left ventricle, promoting cardiac decompensation. In addition, preload reduction is associated with the risk of declining cardiac output.25 Patients with severe mitral stenosis (valve area < 1.0 cm2) have high rates of complications and are likely to decompensate. In these patients and those who remain symptomatic despite medical treatment, elective percutaneous balloon valvuloplasty should be considered if the valve is suitable for the procedure, ideally during the second trimester, before 20 weeks of gestation.19,26,27 Patients with moderate stenosis (valve area 1.0–1.5 cm2) should be monitored closely and may require intervention. Mitral regurgitation may develop following valvotomy but this is usually better tolerated than a stenotic disease.19 Whether or not a woman is suitable for mitral valvotomy depends on the findings of echocardiographic assessment of the mitral valve apparatus. The mobility, thickness and degree of calcification of the leaflets are assessed, as is the structure of the subvalvular apparatus. Those with calcification of the commissures or significant mitral regurgitation are generally unsuitable for the procedure.24 If percutaneous valvuloplasty is not available, closed commissurotomy remains an alternative. Open-heart surgery should be reserved for patients without other options, when the mother’s life is threatened.28

Aortic stenosis (AS) Aortic stenosis in pregnancy is a rare condition. It is mostly associated with congenital bicuspid aortic valve (which may be linked to aortopathy and risk of aortic dissection) and is not usually the result of rheumatic disease.29 A diagnosis of AS is generally made pre-pregnancy and this allows for counselling, optimisation of maternal care, and planning of antenatal care. Echocardiographic quantification of AS severity and measurement of aortic diameter should be performed before pregnancy. Exercise testing is recommended in asymptomatic patients to confirm asymptomatic status and evaluate exercise tolerance, blood pressure response, arrhythmias, and the need for interventions.28 Features that predict a favourable outcome during pregnancy include absent symptoms, normal ECG, normal exertional blood pressure rise, aortic valve area ≥ 1 cm2 and normal left ventricular function.30 Pregnancy is usually well tolerated in asymptomatic AS, even when severe, as long as the patient remains asymptomatic during exercise testing and has a normal blood pressure response during exercise.31,32 Pregnancy should not be discouraged in asymptomatic patients, even with severe AS, when left ventricular size and function as well as the exercise test result are normal. Cardiac deterioration due to AS may be indicated by worsening breathlessness, syncope, chest pain, deterioration in left ventricular ejection fraction, a reduction or failure to increase transvalvular gradient (it should normally increase by 20% during pregnancy), and/or ischaemic ECG changes. Symptomatic patients with severe AS or asymptomatic patients with impaired left ventricular function or a pathological exercise test should be counselled against pregnancy, and valvuloplasty or surgery should be performed before pregnancy.28,32 Medical therapy involves the use of diuretics and cautious betablockade at a low initial dose to avoid pre-syncope, syncope and hypotension. Vasodilators should be avoided. Failure of medical therapy can be managed, if gestational age allows, by delivery

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of the foetus, which results in significant improvement in the maternal cardiac status. Percutaneous valvuloplasty can be undertaken in non-calcified valves with minimal regurgitation when severe symptoms persist.33 Valve replacement should be reserved for life-threatening symptoms, after early delivery by cesarean procedure, if this is an option. Cesarean delivery should be considered in severe, particularly symptomatic aortic stenosis.34

Regurgitant lesions The effects of rheumatic mitral regurgitation are usually ameliorated in early pregnancy by the dominant physiological change, peripheral vasodilatation. The increased plasma volume is offset by the reduction in systemic vascular resistance and consequently, the extent of the regurgitation diminishes. The plasma volume, however, peaks in the middle of the third trimester and that, together with a rise in vascular resistance, may lead to worsening regurgitation and the onset of symptoms and signs consistent with fluid overload or pulmonary oedema. Hypertension may also precipitate similar cardiovascular symptoms at an earlier stage of plasma volume expansion. These patients respond well to diuretic therapy and usually no further intervention is necessary to secure the successful outcome of the pregnancy. Patients with severe regurgitation require expert evaluation to assess the risks and benefits of surgical intervention and the timing in relation to pregnancy. Severely symptomatic women, those with impaired left ventricular systolic dysfunction, or women with pulmonary hypertension are at high risk of maternal and foetal complications. An enlarged left atrium increases the risk of developing atrial fibrillation. If valve surgery is indicated in women of childbearing age who have severe mitral regurgitation, valve repair should be offered when possible, thus avoiding the risks of bioprosthetic valve degeneration and early repeat surgery or anticoagulation, thrombosis and embolism associated with a mechanical valve. A woman with symptomatic mitral valve disease who is not a candidate for repair or replacement of the valve should be advised against pregnancy. Aortic regurgitation (AR) is less common and those of rheumatic aetiology are usually associated with some degree of mitral incompetence as well.35 The most frequent cause of AR in women of childbearing age is also bicuspid aortic valve. The presentation during pregnancy is similar to that of mitral regurgitation and the management follows the same principles. Chronic, moderate or even severe aortic regurgitation is usually well tolerated if left ventricular function is preserved; nevertheless, women with severe aortic regurgitation are at a risk of developing pulmonary oedema and arrhythmias during pregnancy. Valve replacement during pregnancy for treatment of aortic regurgitation is rarely required and should be considered only in women with symptoms refractory to medical therapy.24 Isolated tricuspid and pulmonary valve incompetence is unlikely to be of rheumatic origin and therefore not considered further here.

Mixed lesions Generally, the risks of mixed valvular lesions depend upon the dominant abnormality. Left-sided cardiac valvular disease is

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associated with greater risk, and a dominantly stenotic lesion is more likely to develop complications than patients with predominantly incompetent valves.

Prosthetic valves Bioprosthetic valves are associated with minimal risks during pregnancy. Conversely, mechanical valves are associated with significant maternal and foetal complications.36 Mechanical prosthetic valves are exposed to two risks during pregnancy, namely the twin risks of thrombosis and sepsis. The procoagulant profile of pregnancy increases the likelihood of thrombotic events, and the need to maintain anticoagulation while protecting the foetus from exposure to anticoagulant drugs and preventing excessive haemorrhage at the time of delivery are contradictory therapeutic aims.37 The use of warfarin outside of pregnancy is both simple and cheap, with monitoring of anticoagulant effects made easy by measurement of the INR. In pregnancy, warfarin crosses the placenta and leads to embryopathy, foetal anticoagulation and an increased risk of pregnancy loss in all three trimesters. The alternative treatment with heparin protects the foetus from direct harm by anticoagulating only the mother; however, unfractionated heparin is only reliably used as an intravenous infusion and the use of LMWH requires monitoring of anti-Xa activity to know that the patient is in the therapeutic range.38 Notably, data from non-pregnant studies are not applicable to pregnancy, in which the procoagulant profile changes all the dosing schedules if a therapeutic level of anticoagulation is to be obtained. The contradictory literature pertaining to use of the different anticoagulants in pregnancy has been carefully review by Elkayam with reference to the risks of both pregnancy and the variable probability of valve thrombosis related to the specific prosthesis and the particular valve replaced.39 The recommendations of these authors are contained in Table 1. Of all the anticoagulants used, warfarin is the most effective agent for preventing maternal valve thrombosis but also has Table 1. Our recommended approach to anticoagulation therapy for women with MPHV during pregnancy Higher risk Lower risk New-generation MPHV in mitral Old-generation MPHV in mitral position and MPHV in aortic posiposition, MPHV in tricuspid position, atrial fibrillation, history of TE tion on heparin Warfarin (INR 2.5–3.5) for 35 to 36 LMWH SQ Q12 h (trough anti-Xa ≥ 0.6 IU/ml, peak anti-Xa < 1.5 IU/ weeks followed by IV UFH (aPTT ml) to 35 to 36 weeks, then UFH IV > 2.5) to parturition + ASA 81–100 (aPTT > 2.0) to parturition mg/day OR OR LMWH SQ Q12 h (trough anti-Xa LMWH SQ Q12 h (trough anti-Xa ≥ 0.7 IU/ml, peak anti-Xa < 1.5 IU/ ≥ 0.6 IU/ml, peak anti-Xa < 1.5 IU/ ml) or UFH SQ Q12 h or IV* (mid ml) or UFH SQ Q12 h or IV* (mid interval aPTT > 2.0) for 12 weeks interval aPTT > 2.5) for 12 weeks, followed by warfarin (INR: 2.5–3.5) followed by warfarin (INR: 2.5–3.0) until 35 to 36 weeks, then UFH IV to 35 to 36 weeks, then UFH IV (aPTT > 2.0) to parturition. (aPTT > 2.5) to parturition + ASA 81–100 mg/day. *IV preferred. aPTT = activated partial thromboplastin time; ASA = acetylsalicylic acid; INR = international normalised ratio; IV = intravenous; LMWH = lowmolecular-weight heparin; MPHV = mechanical prosthetic heart valve; Q = every; SQ = subcutaneous; TE = thromboembolism; UFH = unfractionated heparin.

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the highest risk of adverse pregnancy outcome. Consequently, intensive counselling is required to explain the relative risks of different treatment regimens and the anticipated complications of each approach. Long-term heparin therapy is associated with a risk of osteoporosis and heparin-induced thrombocytopenia; these adverse effects are less frequently seen with LMWHs. Both heparin and warfarin increase the risk of retroplacental haemorrhage during pregnancy, and warfarin-exposed foetuses in the first trimester risk the development of nasal hypoplasia and epiphyseal calcification. Intravenous heparin may also be complicated by line sepsis, which becomes a greater risk with increasingly prolonged periods of intravenous drug administration. There is therefore no uniform opinion on how best to approach anticoagulation in pregnancy. Many South African units would use unfractionated heparin before 12 weeks of gestation and after 36 weeks of pregnancy, in order to have monitored control of anticoagulation that is also rapidly reversible. Warfarin is used between these gestational ages as a compromise that allows domiciliary care with ease of administration and ready access to INR monitoring. There are other ways of approaching anticoagulation, including the use of continuous warfarin or continuous LMWH. In the latter case, access to anti-Xa assays is necessary to ensure therapeutic efficacy. The question of adjuvant therapy with aspirin has been considered and certain advocates of LMWH routinely combine aspirin with LMWH throughout pregnancy.39 Bioprosthetic tissue valves are significantly less thrombogenic than mechanical valves, and anticoagulation is not required, unless associated arrhythmias are present.36 Pregnancy may be well tolerated in the presence of a normal valve structure, normal left ventricular function and absence of other cardiac lesions. Pregnancy risks increase when the valve does not function normally. Tissue valves, however, degenerate over time. In general, mitral bioprostheses degenerate faster than aortic prostheses, and the rate of degeneration is more rapid in women under 40 years of age.40,41 Therefore, women of childbearing age with bioprosthetic valves are likely to require redo heart surgery, which is an important consideration when discussing the choice of valve implant before pregnancy.22 Sepsis is an ever-present risk in obstetric practice at the time of delivery, although the rate of endocarditis varies widely in the reported literature, from 0–10%.42 The pyrexial pregnant woman with prosthetic valves deserves careful evaluation to exclude endocarditis as a diagnosis. The development of endocarditis on mechanical prosthetic valves is commonly an indication for valve replacement. The avoidance of sepsis is a priority that requires strict protocols during and after labour. These protocols include minimising the number of vaginal examinations during labour, restricting instrumentation of the genital tract during labour and delivery, scrupulous attention to anti-sepsis during the conduct of labour, ensuring that delivery of the placenta is complete, and the use of prophylactic antibiotics.

Complicated disease Pulmonary hypertension, diagnosed on the basis of estimated pulmonary artery pressures, evident in increased peak regurgitant velocity across the tricuspid valve, may follow

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mitral or aortic valvular heart disease. The development of pulmonary hypertension in this setting does not necessarily imply a worsening prognosis. A prospective Canadian study identified rheumatic valvular disease as being the single most common cause for pulmonary hypertension, accounting for 52% of cases, but was not associated with any independent increase in risk for pregnant women with left heart obstruction.43 The authors of this article noted that reactive pulmonary hypertension may have a different prognosis from those with primary hypertension, although there is no clarity on this issue. The risk of maternal morbidity and mortality (17–50%) is however, generally reported to be high in all categories of pulmonary hypertension. Mortality occurs mainly in late pregnancy and after delivery, owing to heart failure, pulmonary thrombosis and arrhythmias.44 Recent evidence showed better outcomes in women with mild pulmonary hypertension (systolic pulmonary arterial pressure < 50 mmHg), however, no safe cut-off value is known.45 There is limited literature and research into the treatment of pulmonary hypertension during pregnancy.46 In a recent small series, no mortality occurred when nebulised iloprost was started early during pregnancy, upgraded to intravenous iloprost in some cases, with the addition of sildenafil when clinically indicated.47 These medications are favoured over endothelin receptor antagonists, which are teratogenic.34,47 Of the various treatment options, the use of pulmonary vasodilator therapy with sildenafil is currently under ongoing investigation and there is insufficient experience to make any recommendations. Heart failure complicating rheumatic valvular heart disease in pregnancy has been described in 22% of women with valvular rheumatic disease presenting for care in 12 different African countries, Yemen and India.48 The onset of pulmonary oedema may be related to fluid overload during pregnancy, resulting from the combined alterations in intravascular volume and peripheral resistance characteristic of normal pregnancy, but may be precipitated by the injudicious use of intravenous fluids. An increasingly hyperdynamic circulation caused by the development of anaemia, subclinical hyperthyroidism, infection or the onset of labour itself may also lead to pulmonary oedema. Hypertension, whatever the precipitating mechanism, will increase left-sided filling pressures during pregnancy, with an attendant risk of pulmonary oedema. Treatment is directed towards anticipation and prevention of precipitating causes; the treatment of the cardiac lesion itself is usually combined with diuretic therapy. Table 2. Risk classification Risk class Risk of pregnancy by medical condition I No detectable increased risk of maternal mortality and no/mild increase in morbidity. II Small increase risk of maternal mortality or moderate increase in morbidity. III Significantly increased risk of maternal mortality or severe morbidity. Expert counselling required. If pregnancy is decided upon, intensive specialist cardiac and obstetric monitoring needed throughout pregnancy, childbirth and the puerperium. IV Extremely high risk of maternal mortality or severe morbidity; pregnancy contra-indicated. If pregnancy occurs, termination should be discussed. If pregnancy continues, care as for class III.

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An American study found that endocarditis has a rising incidence, with rates increasing from 11 per 100 000 population to 15 cases per 100 000 population.49 Similar trends have been seen in the United Kingdom, and the temporal relationship of this increase to the promulgation of a revised guideline advocating more conservative use of prophylactic antibiotics for individuals having interventions associated with bacteraemia is clearly demonstrable.50 Cardiac valves damaged by rheumatic disease are associated with turbulent blood flow, and bacteraemia triggers infection on the valve itself. The most frequently implicated organisms are Staphylococcus aureus, followed by streptococci and other gram-negative organisms. Fungi can result in infection of the valve. Obstetric practice is confronted by high rates of sepsis at the time of parturition; risk factors that identify a greater probability of infection include rupture of the membranes, prolonged labour, multiple vaginal examinations during labour, instrumentation of the genital tract, surgical delivery, co-morbidity with HIV infection, and exposure to virulent organisms, especially group A streptococcal infection. Consequently, prophylactic antibiotics should be administered routinely according to established guidelines.

Principles of combined obstetric and cardiac management Prior to pregnancy, the severity of the cardiac condition and the cardiovascular reserve of each patient should be assessed. All women who reach childbearing age should have a discussion with their physician about the maternal and foetal risks a pregnancy would pose. In addition, drug therapy should be reviewed with the patient, particularly when potentially teratogenic drugs such as warfarin are involved. These women should be made aware of the risks of an unplanned pregnancy and should have a safe environment in which to initiate a discussion about planning a pregnancy. Contraception should also be discussed and offered to these young women.51 A multidisciplinary team involving the obstetrician, cardiologist, anaesthetist, neonatologist and on occasion, a cardiothoracic surgeon, is vital to the successful management of the pregnant women with heart disease.51

ESC guidelines and WHO risk stratification The European Society of Cardiology (ESC) guidelines on the management of cardiovascular disease during pregnancy recommend that all women with maternal heart disease should have a risk assessment performed at least once prior to pregnancy and then again during pregnancy.34 This risk assessment should be according to the modified World Health Organisation (WHO) risk classification, which integrates all known maternal cardiovascular risk factors, illustrated in Tables 2–5. Table 3. WHO class I • Uncomplicated, small or mild –– pulmonary stenosis –– patent ductus arteriosus –– mitral valve prolapse • Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage). • Atrial or ventricular ectopic beats, isolated

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Table 4. WHO class II and III WHO II (if otherwise well and uncomplicated) • Unoperated atrial or ventricular septal defect • Repaired tetralogy of Fallot • Most arrhthmias WHO II–III (depending on individual) • Mild left ventricular impairment • Hypertrophic cardiomyopathy • Native or tissue valvular heart disease not considered WHO I or IV • Marfan syndrom without aortic dilatation • Aorta < 45 mm in aortic disease associated with bicuspid aortic valve • Repaired coarctation WHO III • Mechanical valve • Systemic right ventricle • Fontan circulation • Cyanotic heart disease (unrepaired) • Other complex congenital heart disease • Aortic dilatation 40–45 mm in Marfan syndrome • Aortic dilatation 45–50 mm in aortic disease associated with bicuspid aortic valve

Antenatal and obstetric care Antenatal care plans should be dependent on the risk stratification.34 Women in WHO class I have a very low risk and cardiology follow up during pregnancy can be limited to one or two visits. Women in WHO class II are deemed to be low or moderate risk and follow up once during each trimester of pregnancy is recommended. Women in WHO class III are high risk with an increased risk of complications. These women should be followed up at least monthly, then increasing to twice a month during the latter stages of pregnancy. Women in WHO class IV are extremely high risk. In these women, pregnancy is considered contra-indicated but if they do fall pregnant and decline termination of pregnancy, these women should have close cardiology follow up monthly if not twice monthly. In addition, factors that may contribute to cardiac decompensation, such as anaemia, infections, arrhythmias, hypertension and hyperthyroidism should be actively sought so they may be avoided or corrected.34,51 The foetal baseline scan, 13-week nuchal translucency scan and 20-week foetal anomaly scan should all be done routinely, with an extra emphasis given to excluding cardiac disease in the foetus. Growth scans should be performed as obstetrically indicated but in addition, those women with severe cardiac disease, cyanotic congenital heart disease or on medications known to cause growth restriction should have serial growth scans to detect foetal growth restriction. The combined cardiac and antenatal clinic visits are the time when decisions regarding timing and mode of delivery, and the analgesic and anaesthesia options available are discussed and preferences are documented. Cardiac monitoring, antibiotic prophylaxis and thromboprophylaxis will need to be individualised. The entire team, including the patient, should be involved in the decision-making process. In general, vaginal delivery with a short second stage and good analgesia is the preferred option. Caesarean section increases the risk of haemorrhage, postpartum sepsis and thrombo-embolic disease. Blood loss should be minimised at all costs and blood should be replaced promptly. Operative delivery

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Table 5. WHO class IV • Pulmonary arterial hypertension of any cause • Severe systemic ventricular dysfunction (LVEF < 30%, NYHA III–IV) • Previous peripartum cardiomyopathy with any residual impairment of left ventricular function • Severe mitral stenosis, severe symptomatic aortic stenosis • Marfan syndrome with aorta dilated > 45 mm • Aortic dilation > 50 mm in aortic disease associated with bicuspid aortic valve • Native severe coarctation

should be limited to those patients with obstetric indications and very specific cardiac conditions.34,51

Specific management for specific lesions Stenotic valve diseases carry a higher risk of maternal and foetal complications than regurgitant lesions. Patients with MS, even when asymptomatic, should be advised against pregnancy and interventions should be performed prior to pregnancy. In those patients who continue the pregnancy, there should be monthly follow up. When symptoms or pulmonary hypertension develop, activity should be restricted and beta-1 selective blockers should be commenced. Low-dose diuretics can be added if symptoms persist. Therapeutic anticoagulation is recommended in patients with atrial AF or those with documented left atrial thrombosis and should also be considered in those with a large left atrium on echocardiography. Vaginal delivery is the preferred method of delivery in mild, moderate or severe MS with NYHA class I/II with no pulmonary hypertension. Caesarean section can be considered in those patients with moderate or severe MS, with NYHA class III/IV or who have pulmonary hypertension refractory to medical therapy. Aortic stenosis, if asymptomatic, or mild or moderate disease in pregnancy is well tolerated. Of note though is that patients with severe AS may be asymptomatic, and echocardiography is important for this diagnosis. All symptomatic patients with severe AS or even asymptomatic patients with reduced left ventricular function should be counselled against pregnancy and in these patients, surgery should be performed first. In those patients who continue the pregnancy, regular monthly follow up with echocardiography is recommended. In those patients with worsening symptoms, diuretic therapy can be administered. A beta-blocker or calcium channel antagonist can be initiated for rate control in AF, and where both of these are contra-indicated, digoxin may be considered. In non-severe AS, vaginal delivery is preferred so as to avoid the decrease in peripheral vascular resistance during regional anaesthesia and analgesia. In patients with severe AS, particularly those who are symptomatic, caesarean section is advocated with endotracheal intubation and general anaesthesia. Regurgitant valve disease carries a lower risk for poor maternal and foetal outcomes than stenotic lesions. Maternal risk is dependent on the severity of the regurgitation symptoms and left ventricular function. Those patients with severe disease and symptoms, or impaired left ventricular function should be advised to have surgery prior to pregnancy. In those who continue with the pregnancy, close follow up on a monthly basis is recommended. Medical therapy

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is usually sufficient to manage symptoms of fluid overload. Vaginal delivery is the preferred method of delivery, and in those patients who become symptomatic, epidural anaesthesia and a shortened second stage is advisable. Most patients with simple congenital heart lesions (these are the vast majority attending general cardiology clinics) tolerate pregnancy well. However, for those patients with more complex lesions, or those who may be taking teratogenic drugs, the issues of contraception and planning a pregnancy should be raised as soon as the young woman reaches childbearing potential.52 Contraceptive options are diverse and the discussion should be tailored to the individual, taking into account her underlying medical history as well as her educational and social circumstances. The practitioner will have to balance efficacy against safety but it is reasonable that in patients with severe cardiac disease where pregnancy itself poses an unacceptably high risk for the mother, then it is probably justified in leaning towards efficacy in these patients.52

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10. World Health Organization. Rheumatic fever and rheumatic heart disease: report of a WHO expert consultation. 20 October – 1 November 2001. Geneva, 2004. 11. Zühlke L, Engel ME, Karthikeyan G, Rangarajan S, Mackie P, Cupido B, et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur Heart J 2015; 36(18): 1115–1122. 12. Sliwa K, Wilkinson D, Hansen C, Ntyintyane L, Tibazarwa K, Becker A, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study. Lancet 2008; 371(9616): 915–922. 13. Sliwa K, Libhaber E, Elliott C, Momberg Z, Osman A, Zühlke L, et al. Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa. Heart 2014; Sept: 1–8. 14. Thaler I, Manor D, Itskovitz J, Rottem S, Levit N, Timor-Tritsch I, et al. Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 1990; 162(1): 121–125. 15. Nolten WE, Ehrlich EN. Sodium and mineralocorticoids in normal

Conclusion Rheumatic disease is a common and serious complication of pregnancy in developing countries. Pregnant women suffering from the sequelae of rheumatic fever benefit from the combined expertise of specialist cardiologists, obstetricians and anaesthesiologists during the pregnancy. Undiagnosed disease may also be identified for the first time during pregnancy, and the process of delivering obstetric care provides an opportunity to secure continuity of postnatal care with an emphasis on preventive therapy and contraception.

pregnancy. Kidney Int 1980; 18(2): 162–172. 16. Carlin A, Alfirevic Z. Physiological changes of pregnancy and monitoring. Best Pract Res Clin Obstet Gynaecol 2008; 22(5): 801–823. 17. Brenner B. Haemostatic changes in pregnancy. Thrombosis Res 2004; 114(5): 409–414. 18. Watkins DA, Sebitloane M, Engel ME, Mayosi BM. The burden of antenatal heart disease in South Africa: a systematic review. BMC Cardiovasc Disord 2012; 12(1): 23. 19. Emmanuel Y, Thorne S. Heart disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2015; 29: 579–567. 20. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et al. Prevalence of rheumatic heart disease detected by echocardiographic

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2008; 52(8): 676–685. 51. Tan JY-L. Cardiovascular disease in pregnancy. Obstet Gynaecol Reprod Med 2007; 17(5): 131–139. 52. Swan L, Lupton M, Anthony J, Yentis SM, Steer PJ, Gatzoulis MA. Controversies in pregnancy and congenital heart disease. Congenital Heart Dis 2006; 1(1–2): 27–34.

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Assessing perinatal depression as an indicator of risk for pregnancy-associated cardiovascular disease Lauren Nicholson, Sandrine Lecour, Sonja Wedegärtner, Ingrid Kindermann, Michael Böhm, Karen Sliwa

Abstract Cardiovascular conditions associated with pregnancy are serious complications. In general, depression is a well-known risk indicator for cardiovascular disease (CVD). Mental distress and depression are associated with physiological responses such as inflammation and oxidative stress. Both inflammation and oxidative stress have been implicated in the pathophysiology of CVDs associated with pregnancy. This article discusses whether depression could represent a risk indicator for CVDs in pregnancy, in particular in pre-eclampsia and peripartum cardiomyopathy (PPCM). Keywords: cardiovascular disease in pregnancy, peripartum cardiomyopathy, depression in pregnancy Submitted 19/8/15, accepted 14/11/15 Cardiovasc J Afr 2016; 27: 119–122 www.cvja.co.za DOI: 10.5830/CVJA-2015-087

The physiological changes associated with pregnancy, such as increased oxidative stress and circulatory changes, place a burden on the cardiovascular system of pregnant women (Fig. 1).1 Cardiovascular conditions associated with pregnancy, such as peripartum cardiomyopathy (PPCM) and pre-eclampsia, could result in serious cardiovascular complications.2,3 Psychosocial factors, for example depression, are increasingly being recognised as risk indicators for cardiovascular diseases such as ischaemic heart disease.4 Mental disorders such as anxiety and depression are the third leading burden of disease

Hatter Institute for Cardiovascular Research in Africa and MRC Inter-University Cape Heart group, Department of Medicine, University of Cape Town, South Africa Lauren Nicholson, BSc (Med), Hons, MSc (Med), nchlau002@ myuct.ac.za Sandrine Lecour, PhD, DPharm

in women globally.5 Women of childbearing age have the highest prevalence of psychiatric disorders, in particular, anxiety and mood disturbances.6,7 Previous studies have explored the association between depression and cardiovascular disease (CVD),4,8 and have demonstrated that depression is a risk factor for CVD and increases both morbidity and mortality rates.8 This article discusses the potential contribution of depression during the peripartum period to the pathophysiology of CVD in pregnancy.

Physiological adaptations in pregnancy Major compensatory changes are made by the maternal heart to accommodate the demands of pregnancy and lactation.9 In pregnancy, the foreign material of the foetus is not rejected by the maternal immune system,10 as increased oxidative stress during the first trimester prevents this rejection.11 During pregnancy women experience a reversible adaptive cardiac hypertrophy (Fig. 1) and reduced relaxation of diastolic function, whereas in healthy women this regresses to normal following childbirth.12

Increase in oxidative stress during pregnancy In the first trimester, oxidative stress, which is an increased production of reactive oxygen species compared to antioxidant defence mechanisms,13 regulates the invasion of foreign trophoblastic material in the maternal body.11 These oxidative stress mechanisms also control normal and pathological embryogenesis.14 The hormone oestrogen mediates regulation of the balance between pro-oxidative and anti-oxidative molecules guarding this process.14 An increase in oxidative stress during pregnancy can be characterised by enhanced lipid peroxidation and the circulation of lipid hydroperoxides.14 The increase in oxidative stress in healthy women peaks around the second trimester.15 When

1st Trimester

2nd Trimester

3rd Trimester

4th Trimester

Increase in oxidative stress

Oxidative stress levels peak

Oxidative stress decreases

Oxidative stress normalises

Reversible cardiac hypertrophy

Normal cardiac function

Suppression of maternal innate and adaptive immune response

Immune function normalises

Karen Sliwa, MD, PhD, FESC, karen.sliwa-hahnle@uct.ac.za

Clinic for Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital of Saarland, Homburg/Saar, Germany Sonja Wedegärtner, Dip (Psychol) Ingrid Kindermann, PhD (Med) Michael Böhm, MD, FESC

Inflammatory cascade

Suppression of maternal innate and adaptive immune response

Fig. 1. The physiological changes associated with pregnancy.

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the pregnancy becomes advanced, disruption in this oxidative balance can lead to inappropriate activation of the inflammatory cascade, which produces harmful effects, including premature labour and complications such as pre-eclampsia.14

The inflammatory response in pregnancy At the start of pregnancy an inflammatory cascade is activated, which allows the formation and invasion of the foreign trophoblastic material into the maternal tissues.16 Medawar et al. proposed a model by which suppression of the mother’s immune system allows invasion of the foreign material.10 This model suggests that maternal lymphocyte suppression allows this invasion.10 The immune system uses two basic components: the non-specific inbuilt innate immune response and the specific ‘learned’ adaptive immune system.17 The innate immune system is primitive. Its primary function is to differentiate self from non-self and it only copes with the most fundamental immune challenges, such as pathogens.17 The innate immune system presents antigens in association with major histocompatibility complex (MHC) class I and II molecules to the lymphocytes. The more specific adaptive immune system has a delayed response. The cells learn and develop an acquired defence against external threats.17 Human pregnancy presents a unique challenge to the immune system.18 The uterus is surrounded by a mucosal barrier, the decidua.18 It is, however, not impenetrable to the maternal immune system.19 The trophoblast cells do not express MHC class I or II molecules, thereby escaping the maternal innate immune response. Imbalances in the innate immune response in the placenta and decidua have been implicated in the development of pre-eclampsia.20 Adaptive immune responses are suppressed by placental products such as prostaglandins and interleukins 4, 6 and 10 (IL-4, IL-6 and IL-10). IL-6 is an important cytokine in the immune inflammatory response in adaptive immunity during pregnancy.21 Excessive IL-6 response has been implicated in pathological conditions of pregnancy, such as miscarriage and pre-eclampsia.21

Women and cardiovascular disease Cardiovascular disease, once thought to be a ‘male problem’, is now recognised as equally affecting women.22 The American Heart Association published the first women-specific clinical recommendations in 1999, which led to an increase in awareness and prevention of CVD in women.22 The rate of deaths resulting from CVD are however still increasing, due to diseases of lifestyle leading to an increase in hypertension and diabetes.22 Around 81% of CVD deaths in women occur in lower-income countries.22 In women with pre-existing heart disease, changes in the circulatory system during pregnancy can cause decompensation or death of the foetus or mother.23 Atkins and colleagues investigated the differences in risk factors in American women of Caucasian and African racial groups.24 Caucasian women have been found to have higher rates of hyperhomocysteinaemia and higher body mass index (BMI). African women were found to have an increase in blood pressure, BMI and iron-deficiency anaemia. Physiological changes during pregnancy in women

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with no known pre-existing CVD may lead to the development of PPCM and pre-eclampsia. Pre-eclampsia occurring in late or early pregnancy is characterised by hypertension, oedema and the presence of protein in the urine.3 Hypertensive disorders are the most frequent complication in pregnancy and cause of maternal death in Africa.12 There have also been limited insights into the exact pathophysiological mechanisms of the disease.25 A suggested pathophysiological mechanism is an increase in oxidative stress during pregnancy.26 PPCM presents in the final month of pregnancy and during the first five months postpartum.2 Distinguished from other forms of cardiomyopathy by its rapid development in the peripartum period, the exact mechanism of PPCM is not well understood.27 In countries with large populations of African descent, such as South Africa and Haiti, the prevalence is higher, with one in 1 000 and one in 299 births, respectively.28 More epidemiological studies are needed to fully determine the prevalence rates in Europe and Asia.1 Studies have suggested that an increase in oxidative stress during pregnancy leads to the cleavage of the breastfeeding hormone, prolactin, into a 16-Kda pro-apoptotic, which may contribute to the development of PPCM.28 Increases in pro-inflammatory cytokines such as C-reactive protein (CRP) have also been suggested to contribute to the condition.29

Depression as a risk factor for cardiovascular disease Since the time of the ancient Greeks, affective dispositions have been thought to be associated with physical disease.30 The World Health Organisation (WHO) estimates that, by the year 2030, mental disorders will rise to first place in hospitalisation morbidity, overtaking road traffic accidents and heart disease.31 Depression is known to be a risk factor for the development of CVD, as well as a predictor of poor prognosis following a cardiac event.8 Established risk factors, such as hypercholesterolaemia, hypertension and smoking, leave unexplained inconsistencies in ischaemic heart disease data.32 It has been suggested that psychosocial factors may account for these differences.32 The mental and physiological changes of a depressive individual may also negatively affect the course of CVD.8 The decrease in the depressive patient’s motivation and inability to function in day-to-day tasks, as well as fear of side effects, may result in non-compliance with medical recommendations.8 Depression also increases the incidence of other risk indicators, such as smoking and hypertension.8 Previous animal and human models have suggested links in the pathways between depression and physiological responses, such as nervous system activation, an increase in inflammation, changes in sleep patterns and cardiac rhythm disturbances.8,30 Rosengren and colleagues investigated the association of psychosocial factors with the risk of myocardial infarction.4 This study found that patients with myocardial infarction reported high psychosocial stress factors, such as depression and financial and work stress, compared to healthy individuals.4 The increased risk for CVD is potentially due to the physiological response to these psychosocial stressors. Depression has been shown to increase inflammatory cytokines, which are known to contribute to CVD.33 Inflammatory markers

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such as CRP, tumour necrosis factor-α (TNF-α) and IL-6 have been associated with an increased risk for CVD.33 Vaccarino and colleagues investigated depression, inflammation and cardiovascular outcomes of women.33 Women with established depression had 70% higher CRP levels than women without depression.33 The study also suggested that the association between depression and CVD cannot be explained by inflammation alone.33 Kamarck and colleagues performed a prospective study to determine the directionality of the association between depression and inflammatory markers in both men and women.1 The study found that only BMI had a greater association with increased CRP and IL-6 than depression.1

Maternal/postpartum depression

Immune response

Innate

Adaptive

MHC I and II

Inflammatory cytokines (IL-6, IL-10 and CRP)

Depression during pregnancy and postnatal depression Perinatal depression is a serious and prevalent mental health condition occurring towards the end of pregnancy and up until the first year postpartum.34,35 Depression is disabling for women and is most common during the childbearing years.35 Postpartum depression refers to the depressive disorders occurring during the postpartum period, up until the first year following childbirth.35 In developed countries, studies have shown that the prevalence of postpartum depression is around 10–15%.36 However, in developing regions, the proportion is often double that of developed regions. A study in western Nigeria reported the incidence of perinatal depression during pregnancy to be 31.3%.37 A South African study found that 32% of the perinatal women screened for maternal depression qualified for referral to counselling.5 The case study found that there is a deficiency in screening for depression in primary healthcare in South Africa and many cases are not identified.5 They used the Edinburgh Postnatal Depression Scale (EDPS) as a screening tool.5 This is a validated 10-item questionnaire used for screening for a probable diagnosis of depression, both pre- and postpartum.6,36 A separate study performed in peri-urban settlements in Cape Town, South Africa, investigated the prevalence of depressed mood during pregnancy in these populations.6 The study found that 39% of the pregnant women showed signs of depression. The psychosocial risk factors for maternal and postpartum depression include past history of mental illness, mental disturbance during pregnancy, family history of depression, low socio-economic status and poor interpersonal relationships.38 Postnatal depression is sometimes preluded by depression during pregnancy.7

Depression as a potential risk factor for CVD during peripartum Depression has been confirmed to be a risk factor for CVD in general.30 The mechanism by which depression is thought to contribute to the development of CVD is through an increase in oxidative stress, as well as inflammation.33 Oxidative stress and inflammation have both been suggested to contribute to the development of PPCM and pre-eclampsia.26,29 Depression during pregnancy may contribute to hypertension via excretion of vasoactive hormones.39 A prospective population study suggested that depression in early pregnancy was a risk factor for pre-eclampsia later in pregnancy.39 Depression has been linked to a higher risk of heart failure as well as poorer outcomes.40

Cardiovascular risk

Oxidative stress

Lipid peroxidation

Peripartum cardiomyopathy

Pre-eclampsia

Fig. 2. A hypothetical mechanism by which depression during pregnancy and postpartum may contribute to the development of PPCM and pre-eclampsia.

A hypothetical mechanism by which depression during pregnancy and postpartum may contribute to the development of PPCM and pre-eclampsia is shown in Fig. 2. The pathological increase in oxidative stress and inflammation caused by depression during the last trimester of pregnancy or postpartum may contribute to left ventricular heart failure in women with PPCM or hypertension in women with pre-eclampsia.

The way forward The aetiology of pregnancy-related cardiovascular complications in conditions such as pre-eclampsia and PPCM remain unclear. Depression during pregnancy and the postpartum period is a common condition. Previous studies have linked perinatal depression as a risk factor for pre-eclampsia. There is also evidence in the literature that depression is a risk factor for and a predictor of poor outcomes in CVD in general. The data have shown that depression causes an increase in the release of pro-inflammatory markers such as CRP and IL-6, which may contribute to the development of CVD, in particular PPCM. Further studies are required to determine whether depression in the peripartum period is indeed a risk factor for cardiovascular complications of pregnancy, for example, assessing the depression levels in a large group of pregnant women and then assessing their postnatal outcome.

References 1.

Kamarck W, Stuwart J, Rand K, Muldoon M. A prospective study of the directionality of the depression inflammation relationship. Brain Behav Immunol 2009; 23(7): 936–944.

Sliwa K, Böhm M. Incidence and prevalence of pregnancy-related heart

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disease. Cardiovasc Res 2014; 4: 554–560. 3.

Moodley J. Maternal deaths associated with eclampsia in South Africa: Lessons to learn from the confidential enquiries into maternal deaths, 2005–2007 Causes of hypertensive maternal deaths in South Africa. Sth Afr Med J 2010; 100(11): 718–719.

Rosengren A, Hawken S, Ounpuu S, et al. Association of psychosocial

the health of childbearing-aged women. Medicine (Baltimore) 2012; 37(4): 263–268. related to the diagnosis, screening, prevention, and treatment of

control study. Lancet 2004; 364(9438): 953–962.

pre-eclampsia and eclampsia. Int J Gynaecol Obstet 2004; 85: 28–41.

Honikman S, van Heyningen T, Field S, Baron E, Tomlinson M.

doi:10.1016/j.ijgo.2004.03.009. 26. Villar J, Purwar M, Merialdi M, et al. World Health Organisation

mental health project in South Africa. PLoS Med 2012; 9(5): 1–6.

multicentre randomised trial of supplementation with vitamins C and

Hartley M, Tomlinson M, Greco E, et al. Depressed mood in pregnancy:

E among pregnant women at high risk for pre-eclampsia in populations

Prevalence and correlates in two Cape Town peri-urban settlements.

of low nutritional status from developing countries. J Obstet Gynaecol

Bunevicius R, Kusminskas L, Bunevicius A, Nadisauskiene RJ, pregnancy. Acta Obstet Gynecol 2009; 88: 599–605. Joynt KE, Whellan DJ, Connor CMO. Depression and cardiovascular disease: Mechanisms of interaction. Biol Psychiat 2003; 54: 248–261.

heart disease. Circulation 2001; 104: 515–521. 24. Arbour MW, Corwin EJ, Salsberry PJ, Atkins M. Racial differences in

13648 controls from 52 countries (the INTERHEART study): case-

Jureniene K, Pop VJM. Psychosocial risk factors for depression during 8.

prospective multicenter study of pregnancy outcomes in women with

25. Villar J, Say L, Shennan A, et al. Methodological and technical issues

Reprod Health 2011; 8(1): 9. 7.

23. Siu SC, Sermer M, Colman JM, et al. Clinical investigation and reports

risk factors with risk of acute myocardial infarction in 11119 cases and

Stepped care for maternal mental health: a case study of the perinatal 6.

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Clapp C, Thebault S, Martínez de la Escalera G. Hormones and postpartum cardiomyopathy. Trends Endocrinol Metab 2007; 18: 329–330.

10. Billingham R, Brent L, Medawar PB. “Actively acquired tolerance” of foreign cells. Nature 1953; 172: 603–606. 11. Romero R, Gomez R, Grezzi F, Yoon B, Mazor M, Eddwin S. A foetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. J Obstet Gynaecol Gynecol 1998; 179: 186–93. 12. Leinwand LA. Molecular events underlying pregnancy-induced cardiomyopathy. Cell 2007; 1: 437–438. 13. Sies H. Oxidative stress II. Oxidants and antioxidants. London: Academic Press, 1991: 10–20.

(Lahore) 2009; 116: 780–788. 27. Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol 2014; 11(6): 364–707. 28. Hilfiker-Kleiner D, Sliwa K, Drexler H. Peripartum cardiomyopathy: Recent insights in its pathophysiology. Trends Cardiovasc Med 2008; 18(5): 174–179. 29. Sliwa K, Förster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006; 27: 441–446. 30. Suls J, Bunde J. Anger, anxiety, and depression as risk factors for cardiovascular disease: the problems and implications of overlapping affective dispositions. Psychol Bull 2005; 131(2): 260–300. 31. The global burden of disease 2004 update. Geneva: WHO Press, 2008. 32. Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. Adults. Epidemeology 1993; 4(4): 285–294. 33. Vaccarino V, Johnson BD, Sheps DS, et al. Depression, inflammation,

14. Biondi C, Pavan B, Lunghi L, Fiorini S, Vesce F. The role and modula-

and incident cardiovascular disease in women with suspected coronary

tion of the oxidative balance in pregnancy. Curr Pharm Des 2005; 2:

ischemia: the National Heart, Lung, and Blood Institute-sponsored

2075–2089. 15. Casanueva E, Viteri F. Iron and oxidative stress in pregnancy. World Health 2003; 133: 1700–1708. 16. Davies CJ. Why is the fetal allograft not rejected? J Anim Sci 2007; 85(13 Suppl): E32–35. doi:10.2527/jas.2006-492. 17. Murphy K. Janeway’s Immunobiology, 8th edn. New York: Garland Science, 2011, ch 4: 20–40. 18. Ober C. HLA and pregnancy: the paradox of the fetal allograft. Am J Hum Genet 1998; 62: 1–5. 19. Sunami R, Komuro M, Tagaya H, Hirata S. Migration of microchimeric fetal cells into maternal circulation before placenta formation. Chimerism 2010; 1(2): 66–68. 20. Yeh CC, Chao CK, Huang SJ. Innate immunity, decidual cells, and preeclampsia. Reprod Sci 2013; 4: 339–343. 21. Al-Othman S, Omu AE, Diejomaoh FME, Al-Yatama M, Al-Qattan F. Differential levels of interleukin 6 in maternal and cord sera and

WISE study. J Am Coll Cardiol 2007; 50(21): 2044–2050. 34. Muzik M, Borovska S. Perinatal depression: implications for child mental health. Ment Health Fam Med 2010; 4: 239–248. 35. O’Hara MWO. Postpartum depression: What we know. J Clin Psychol 2009; 65(12): 1258–1270. 36. Lumley J, Austin M. What interventions may reduce postpartum depression. Curr Opin Obstet Gynecol 2001; 13: 605–611. 37. Adewuya AO. The maternity blues in Western Nigerian women: Prevalence and risk factors. Psychiat Interpers Biol Process 2005; 193: 1522–1525. 38. Verkerk GJM, Pop VJM, van Son MJM, van Heck GL. Prediction of depression in the postpartum period: a longitudinal follow-up study in high-risk and low-risk women. J Affect Disord 2003; 77: 159–166. 39. Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O. Depression and anxiety in early pregnancy and risk for preeclampsia. Obstet Gynecol 2000; 95(4): 487–490.

placenta in women with pre-Eclampsia. Obstet Investig 2001; 52: 60–62.

40. Rumsfeld JS, Havranek E, Masoudi FA, et al. Depressive symptoms

22. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for

are the strongest predictors of short-term declines in health status in

the prevention of cardiovascular disease in women – 2011 update. J Am Coll Cardiol 2011; 57(12): 1404–1423.

patients with heart failure. J Am Coll Cardiol 2003; 42: 1811–1817.

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Case Report Pregnancy and childbirth in a patient after multistep surgery and endovascular treatment of cardiovascular disease Piotr Buczkowski, Mateusz Puślecki, Sebastian Stefaniak, Jerzy Kulesza, Olga Trojnarska, Tomasz Urbanowicz, Marek Jemielity

Case report

Abstract Nowadays physicians see an increasing population of patients reaching reproductive age after surgery for complex congenital heart defects. Correction of congenital and acquired cardiovascular defects does not exclude experiencing a safe pregnancy. We present the case of a 27-year-old woman, who, after multistep surgery and endovascular treatment of her cardiovascular system, underwent successful pregnancy and uncomplicated childbirth. Recent developments in medicine and interdisciplinary involvement have allowed women with corrected cardiovascular disease the opportunity to become pregnant and experience safe childbirth. Keywords: pregnancy, childbirth, aortic aneurysm, congenital disease, coarctation, hybrid treatment Submitted 20/1/15, accepted 14/11/15 Cardiovasc J Afr 2016; 27: e1–e2

www.cvja.co.za

DOI: 10.5830/CVJA-2015-084

In the past, girls with complex congenital or acquired heart defects often did not reach reproductive age. Recent developments in intensive paediatric cardiac surgery mean that more girls reach the age of maturity. Interdisciplinary involvement has allowed women with corrected cardiovascular defects the opportunity to become pregnant and experience safe childbirth.

A 27 year-old woman in good physical condition was admitted to the operating room of the Department of Cardiac Surgery because of a planned pregnancy. When she was six years old, she was operated on for a defect in the interventricular septum. After 10 months, she underwent surgical correction of aortic coarctation using a Dacron patch. During childhood and adolescence, the patient was normotensive and without any cardiac disease. At the age of 22 years, new symptoms appeared in the form of hoarseness and periodic aphonia, which suggested the presence of a rare postoperative complication, aortic dilatation on the border of the aortic arch and descending aorta. This suspicion was confirmed by imaging with computed angiography, which demonstrated dilatation of the distal aortic arch and descending aorta, starting at a maximum of 65 to 70 mm, with a normaldiameter (19 mm) descending aorta. She was involved in two-stage hybrid treatment.1 Initially, via median sternotomy, anastomosis was performed between the ascending aorta, brachiocephalic trunk and left common carotid artery, using a bifurcated graft (FlowNit Bioseal 12 mm). Due to extensive collateral circulation, the left subclavian artery was not revascularised. After 10 days, the second endovascular step was executed. Two stent grafts (Zenith TX2 TAA 28 mm) were implanted in the aorta

Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, Poznan, Poland Piotr Buczkowski, MD, PhD Mateusz Puślecki, MD, PhD Sebastian Stefaniak, MD, PhD, seb.kos@gmail.com Tomasz Urbanowicz, MD, PhD Marek Jemielity, MD

Department of Radiology, Poznan University of Medical Sciences, Poznan, Poland Jerzy Kulesza, MD

First Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland Olga Trojnarska, MD

Fig. 1. Computed tomography angiography three days after surgery. The aneurysm sac was excluded from the circulatory system after thoracic stent graft implantation.

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Fig. 2. C omputed tomography angiography two years after childbirth, four years after the surgery, showing disappearance of the aneurysm sac and correct flow through the stent graft.

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Fig. 3. Computed tomography angiography, 3D reconstruction, and current status. This indicates proper functioning of the bifurcated graft sewn to the ascending aorta, proper functioning of the thoracic stent graft, and no leakage of contrast into the aneurysm sac.

using a femoral approach, covering all branches of the arch. The proximal ends of the stent grafts were positioned in the ascending aorta above the previously sewn bifurcated graft (in landing zone 0). The distal end of the graft was placed downstream of the congenital narrowing of the aortic isthmus (Figs 1–3). Postoperative hospitalisation and rehabilitation proceeded without complications. A low-dose cardioselective beta-blocker was used as pharmacotherapy. Thereafter, the patient was under the care of Heart Surgery Ambulatory. Despite the above conditions requiring multi-stage treatment, and the potential complications, the patient consciously decided to become pregnant and was under the constant supervision of an experienced cardiologist who specialises in congenital heart defects in adults. Echocardiography showed normal left ventricular function (left ventricular ejection fraction > 50%), there was no significant gradient of the descending aorta, and the patient was in NYHA functional class I. The cardioselective beta-blocker was discontinued. Pregnancy proceeded without any complications and a decision was made to terminate the pregnancy at 38 weeks’ duration by caesarean section, after an interdisciplinary discussion (cardiologist, obstetrician, cardiac surgeon, neonatologist and patient). A healthy baby with a birth weight of 2 900 g and 10 points in the APGAR scale score was transferred to the Department of Neonatology. The mother spent the first day in the intensive care unit of Cardiac Surgery. Further hospitalisation proceeded without any complications and she was discharged home on the fourth day. Two years after the birth, control vascular imaging studies confirmed the positive outcome of her previous treatment.

force at that time, took care of the gestation. The decision was made on the date of termination of pregnancy, taking into account maternal and foetal maturity. Normally, vaginal delivery has a lower risk of complications and the use of epidural anaesthesia is the method of choice. This has been well described in the literature.4 However in this case, after interdisciplinary discussion and consultation with the patient, and based on the 2011 ESC guidelines on the management of cardiovascular disease during pregnancy,2 some reports in the literature,5,6 and our experience, we decided to terminate the pregnancy by caesarean section under general anaesthesia.

Discussion

4. Kanakis MA, Mitropoulos FA, Katsetos C, Ntellos C. Successful vaginal

Conclusion The most difficult period for cardiac haemodynamics is the third trimester of pregnancy. Therefore, in the final stage of pregnancy, patients with a cardiovascular history should be treated in specialist departments.

References 1. Puślecki M, Buczkowski P, Perek B, et al. Hybrid procedures for aortic arch repair. Kardiochir i Torakochir Pol 2011; 4: 438–444. 2. Regitz-Zagrosek V, Blomstrom LC, Borghi C, et al. ESC guidelines on the management of cardiovascular diseases during pregnancy: the task force on the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC). Eur Heart J 32(24): 3147–3197. 3. Trojnarska O, Bręborowicz P, Markwitz W, et al. Pregnancy and delivery in women with congenital heart disease after cardiac surgery. Arch Med Sci 2006; 2: 108–113.

Due to different degrees of potential risk for complications during pregnancy, the European Society of Cardiology (ESC), in a recent guideline, established a four-scale risk score.2,3 Our patient, because of vascular complications, qualified in the third risk group. A cardiologist, cardiac surgeon and obstetrician specialising in congenital abnormalities, according to the rules in

delivery in a woman with tetralogy of Fallot and pulmonary atresia after four cardiac operations. Hellenic J Cardiol 2012; 53: 246–248. 5. Balint OH, Siu SC, Mason J, et al. Cardiac outcomes after pregnancy in women with congenital heart disease. Heart 2010; 96: 1656–1661. 6. Ross-Hesselink JW, Duvekot JJ, Thorne SA. Pregnancy in high-risk cardiac conditions. Heart 2009; 95: 680–686.

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