12 Pregnancy

SECTION 12

Pregnancy 102.

Anaemia in Pregnancy K Tewary, Anubha Singh

485

103.

Thyroid Diseases in Pregnancy Padmavathy S Menon

488

104.

Management of Hypothyroid in Pregnancy Sarita Bajaj

490

105.

Heart Diseases in Pregnancy Monotosh Panja, Arindam Pande, Madhumanti Panja, Ajanta Samanta

493

106.

Peripartum Cardiomyopathy AN Rai, Mritunjay Kumar Singh

500

107.

Acute Infections in Pregnancy Niteen D Karnik, Priya Bhate

503

108.

Jaundice in Pregnancy Saurabh Srivastava, Payal Jain

509

109.

SLE and Pregnancy Sirisha K, Narasimulu G

513

110.

Rational Use of DMARDS During Pregnancy and Lactation RN Sarkar, Chandan Kumar Das

518

111.

Drugs in Pregnancy Mandish K Dhanjal

524

Anaemia in Pregnancy

C H A P T E R

102

K Tewary, Anubha Singh

increased physiological demands, chronic blood loss due to inflammation and infections like malaria, HIV, Tuberculosis and worm infestation.

INTRODUCTION

Anaemia is one of the most frequent observed nutritional deficiency diseases in world, affecting around 800 million children and women , with pregnant women at particular risk. The World Health Organization (WHO) 2011 data shows that anemia in pregnancy is a significant problem throughout the world with a prevalence of 38.2% ( 32 million) for pregnant women. Anaemia in pregnancy is one of the major causes of maternal complications, morbidity and offspring mortality in almost all the developing countries of the world. In India, National Family Health Survey -3 in 2005-2006 shows that 55% of women are anaemic; more prevalent in breastfeeding and pregnant (59%) women.

2.

Vitamin B12 & folic acid deficiency - Vitamin B12 and folate deficiency can affect DNA replication leading to derangement of red cell maturation with production of abnormal precursors known as megaloblasts. Combined deficiency of iron and Vitamin B12 or folic acid produces dimorphic picture on peripheral smear.

3.

Protein deficiency - Caused due to malnutrition and less dietary protein intake

C.

Hereditary - Hemoglobinopathies of genetic origin such as Sickle cell disease and Thalassemia; Hereditary hemolytic anaemias (RBC membrane defects); Microangiopathic haemolytic anemia (HELLP syndrome.)

D.

Aplastic anaemia – Bone marrow hypoplasia or aplasia due to radiation, drugs or idiopathic.

ANAEMIA IN PREGNANCY

Pathophysiology

Nutritional Iron Deficiency (ID), accounting for more than half the cases is the commonest cause of anaemia during pregnancy. A 55 kg pregnant woman is estimated to need approximately an additional 1200 mg of iron over the whole pregnancy. The daily iron requirement increases from approximately 0.8 mg in the first trimester to 4–5 mg during the 2nd trimester and > 6 mg in the 3rd trimester.

Types of Anaemia

Several types of anaemia developed during pregnancy are: A.

Physiological anaemia of pregnancy: During pregnancy there is a disproportionate increase in plasma volume, RBC volume and haemoglobin mass as plasma volume increases more than RBC mass hemodilution occurs.

B.

Nutritional deficiency:

1.

Iron deficiency Anemia (IDA) - IDA can occur as a result of low dietary intake of iron, less absorption from diet rich in phytates and phenolic compounds, deficient iron stores from adolescence to postpartum stage due to multiple pregnancies,

Table 1: WHO categories of anaemia in pregnancy Category

Hb level (gm/dl)

Non -anaemia

11 or higher

Mild

10-10.9

Moderate

7- 10

Severe

<7

Clinical features of iron deficiency anaemia

The clinical features depend on the degree of anaemia and majority of patients with mild to moderate anaemia may be symptomatic with the entity being an accidental finding during examination. The categories of anaemia in pregnancy are listed in Table 1.

Symptoms – Lassitude and a feeling of exhaustion or weakness, indigestion and loss of appetite. Other features are palpitation, dyspnoea, giddiness, pedal oedema and rarely, generalized anasarca and even cardiac failure in severe cases.

Signs- Pallor of varying degree, glossitis, stomatitis, oedema of the legs due to hypoproteinaemia. A soft systolic murmur in the mitral area due to hyper dynamic circulation.

Diagnosis

The underlying reason for the reduced Hb production should be sought by taking a detailed medical history, proper clinical assessment or by means of further investigations.

TREATMENT OF IRON DEFICIENCY ANAEMIA IN PREGNANCY

Prophylactic 1.

Avoidance of frequent child births, teenage pregnancy and high parity.

486

Table 2: Diagnostic workup for diagnosis of anaemia Lab. Parameters

Comment

Haemoglobin & Erythrocyte indices

A typical iron deficiency anaemia shows following: Hb - < 10gm%, RBC - < 4 million/cmm3, PCV - < 30%, MCV < 75fl, MCH < 25 pg.

PREGNANCY

Peripheral Smear

In typical iron deficiency anaemia, Peripheral smear shows, anisocytosis, poikilocytosis, microcytic, hypochromic picture.

If the MCV is >100 fl, and the peripheral blood picture suggests the possibility of folate or Vitamin B12 deficiency, appropriate investigations should be carried out to establish the diagnosis

Serum ferritin

Levels of < 15 µg/L confirm the presence of iron deficiency regardless of the Hb level.

Serum iron, transferrin Iron deficiency – serum saturation(TSAT), iron < 60mg/dl, TSAT transferrin receptors(sTfR) <15%, sTfR > 8.5mg/L Bone marrow examination ID - Absence of hemosiderin granules; helps to rule out kala azar and aplastic anaemia

3.

4.

Oral iron therapy

For mild to moderate anaemia, oral iron therapy is gold standard treatment.

For therapeutic iron supplementation various iron preparations are available – iron salts e.g. Ferrous sulphate, ferrous ascorbate, ferrous gluconate, ferrous fumarate, ferric ammonium citrate; Iron complexes e.g. Iron dextran complex, Iron polymaltose complex. Depending upon anaemia severity international guidelines recommend elemental ferrous iron 120 mg daily or 100-200 mg daily for IDA treatment.

Haematologically, there is reticulocyte response in 5-10 days with a rise in Hb concentration from 0.3 gm to 1.0 gm per week and haematocrit subsequently. If clinical or haematological improvement does not occur within 3-4 weeks, diagnostic re-evaluation is needed.

Oral therapy, however, can suffer from compliance issues (up to 10% of patients). About a third of women also suffer with significant gastrointestinal side effects like epigastric pain, nausea, vomiting, diarrhoea or constipation which make some women intolerant of oral iron. Depending on the degree of anaemia and iron deficit, especially in the presence of risk factors for IDA; like inflammatory bowel disease, multiple pregnancy, a short inter-pregnancy interval, teenage status, grand-multiparity oral iron may not successfully correct anaemia before birth of the baby.

Parenteral Iron Therapy

The indications for the parenteral administration of iron Include: •

Insufficient or no response to oral iron

•

Severe anemia

•

Insufficient absorption of oral iron due to intestinal disease

A balanced diet, rich in iron and protein should be prescribed. The foods rich in iron include liver, meat, egg, green vegetables, green peas, figs, beans, jaggery, whole wheat etc. Iron utensils should preferably be used for cooking.

•

Intolerance of oral iron

•

Poor compliance

•

Combination with rhEPO (for the prevention of functional iron deficiency)

Iron Supplementation: Government of India, Ministry of health and family welfare recommends 100 mg of elemental iron and 500 µg of folic acid daily for 100 days during pregnancy, followed by same dose for 100 days in the post-partum period.

Deficit can be calculated using Ganzoni’s formula-

Stool & Urine examination To rule out worm infestation and schistosomiasis 2.

anaemia include oral iron, parenteral iron, erythropoiesis stimulating agents and blood transfusion.

Adequate treatment to eradicate hookworm infestation, malaria, bleeding piles and urinary tract infection. All infections and chronic inflammatory conditions should ideally be controlled prior to pregnancy.

Curative

An accurate diagnosis (Table 2) of the cause of anaemia and type of anaemia should be made before starting treatment. At present the main treatment options for

Body weight (target Hb – Actual Hb gm/dl) 2.4 + 500 (for refilling body stores) Various parenteral iron formulations are available for correcting iron deficiency e.g. Iron dextran (low molecular weight), iron gluconate, iron sucrose, ferric Carboxymaltose, iron isomaltoside, ferumoxytol. Iron dextran is associated with risk of anaphylactic reactions, so a test dose is needed prior to infusion. Iron sucrose causes rapid rise in Hb levels and replenish iron stores faster.The introduction of newer intravenous formulations like Ferric Carboxymaltose, iron isomaltoside, Ferumoxytol offer administration of higher doses in single administration making it as an effective, rapid and safe treatment for IDA avoiding the use of blood transfusion. However a

careful risk/benefit evaluation is required before use in pregnancy.

Blood transfusion is required in patients with severe anaemia after 36 weeks, associated infection, refractory anaemia, to correct anaemia due to blood loss and to combat post-partum haemorrhage.

Megaloblastic Anaemia

487

Iron deficiency anaemia is a major public health problem, especially in countries like India, and is associated with increased maternal and perinatal morbidity and mortality.

Majority of women do not have adequate stores of iron to meet the increased demands during pregnancy. Strategies like nutritional education, iron & folic acid supplements and ensuring maximum compliance, deworming, treatment of chronic diseases and universal antenatal care to pregnant women will help in overcoming this serious issue.

REFERENCES

1. Dutta Dc. Anaemia in pregnancy. Text book of obstetrics including perinatology & contraception, 6th ed. Calcutta: New Central Book Agency (P) Ltd.; 2004. p. 262-7.

2. Lopez A, Cacoub P, McDougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet 2016; 387:907-16.

3. Breymann C. Iron deficiency anemia in pregnancy. Expert Rev Obstet Gynecol 2013; 8:587–596.

4. Goonewardene M, Shehata M, Hamand A. Best Pract Res Clin Obstet Gynaecol 2012; 26:3-24 5. Sharma JB, Shankar M. JIMSA 2010; 23:253-260.

CHAPTER 102

It occurs due to deficiency of either Vitamin B12 or folate or both. Vitamin B12 deficiency is rare in pregnancy.

Folate deficiency can occur as a result of inadequate intake, diminished absorption or increased demands. A prophylactic dose of 400 µg is recommended for all women, in the preconception period and throughout pregnancy.

Treatment of established folic acid deficiency by giving 5 mg oral folate per day which should be continued for at least 4 weeks in puerperium. When response to folic acid is not adequate supplementary intramuscular vitamin B12 100 µg daily or on alternate days may be added.

CONCLUSION

Thyroid Diseases in Pregnancy

C H A P T E R

103

Padmavathy S Menon

INTRODUCTION

Pregnancy results in hormonal and metabolic alterations.

In this chapter, we are going to deal with thyroid disorders in pregnancy and to this end; we need to know the alteration of thyroid functions in pregnancy. The commonest clinical situation faced in clinical practice is Hypothyroidism followed by Hyperthyroidism in pregnancy and their management will be dealt in detail.

Other disorders that require treatment are goiter, thyroid nodules and malignancy of thyroid.

THYROID FUNCTION ALTERATIONS IN PREGNANCY

Human chorionic gonadotropin (hCG) levels increase in pregnancy and this stimulates the thyrotropin receptor resulting in increase in T4 and T3 and a suppression of TSH. The Thyroid Binding Globulin (TBG) increases in pregnancy due to large amount of Estrogen and also due to sialyation of TBG molecule increasing its half-life. The net result is an elevation of T4 and T3 (nearly 2 fold) and a low or suppressed TSH. Hence a low or supressed TSH in pregnancy can be a normal finding.

TFT in pregnancy

TSH: Trimester specific ranges for TSH has been evaluated in many studies and American Thyroid Association ATA (2011) and Endocrine society (2013) on the basis of these studied have suggested the normal values for pregnancy (Table-1).

The individual population norms in pregnancy, if available, should be used for deciding the normal values (as well as laboratories), but this being absent we may follow the ATA/Endosociety recommendations.

T4 is elevated in pregnancy – the method of estimation being not ideal and many variations in kits, FT4 is done by many. This too has problems as the ideal measurement of FT4 is LCMSMS (still a research tool) and hence the combination of T4 and TSH is used for deciding the management in practice. T3 is also elevated in pregnancy and of limited value as a test for deciding management of thyroid disorders in pregnancy.

Table 1: Trimester specific TSH values Trimesters

ATA 2011

Endosociety 2013

I

0.1 – 2.5 mIU/L

≤ 2.5 mIU/L

II

0.2 – 3 mIU/L

≤ 3 mIU/L

III

0.3 – 3 mIU/L

≤ 3 mIU/L

Hypothyroidism in Pregnancy

Most of the times, a TSH is done by the obstetrician and referred for abnormal values. Hence no patient comes with any clinical symptoms suggestive of hypothyroidism.

Patient at risk for hypothyroidism are those with a history of thyroid disorder in the past or abortion, goiter, radioactive iodine treatment for toxicosis or a history of neck irradiation.

The adverse effects of hypothyroidism include hypertension, eclampsia, placental abruption, miscarriage, risk of C-section and postpartum haemorrhage. Fetal adverse outcome described in literature are: preterm delivery, low birth weight, increased perinatal and neonatal mortality and neuropsychiatric and cognitive impairment.

Subclinical hypothyroidism (SCH) in pregnancy is diagnosed when the TSH is > 2.5 mIU/L and the FT4 is normal. There is some difference of opinion regarding treatment. Both ATA and Endocrine society recommend treatment when thyroid peroxidase antibodies are positive, but differ when anti bodies are negative (ATA advocates no treatment). In those where antibodies are positive, the TSH tends to rise on follow up by third trimester and hence treatment by thyroxin is recommended by Endocrine society.

Overt hypothyroidism (OH) is diagnosed when TSH is > 2.5 mIU/L to 10 mIU/L and FT4 is low (pregnancy specific ranges if available). Generally, treatment with thyroxin is indicated.

Goal of treatment of SCH and OH is to normalise TSH values to trimester specific ranges. The starting dose will depend on the TSH level and can be from 25 – 50 μg/day.

TSH should be monitored every 4 – 6 weeks and when TSH remains stable for 2 or 3 successive time monitoring can stop and thyroxin continued till delivery. This usually happens around six months.

If pregnancy occurs in a subject who is already on treatment for Subclinical hypothyroidism (SCH) or Overt hypothyroidism (OH), there is likely to be an increase in dose requirement within 4 – 6 weeks of pregnancy. Hence patients on thyroxin are advised to do TSH and report to endocrinologist/physician as soon as pregnancy is detected and the dose revised and followed up as above.

After delivery – she goes back to her pre-pregnancy dose.

Positive thyroid antibodies (anti TPO) and pregnancy loss is a matter of controversy as some studies showed

an association and some did not. A meta-analysis of 10 studies showed a clear positive association. However causality is not determined.

Certain unanswered questions remain: (1) should we screen all pregnant thyroid patients? some studies favour and some do not. I personally feel all should be screened as tests are easily available and not too costly. (2) Is there a TSH value above which we should terminate pregnancy?

No recommendations from any of the scientific bodies advocating termination of pregnancy, no matter what the TSH level is.

Prevalence of thyrotoxicosis is rare (0.1- 1%). Most are Graves’ disease (85%). 0.5 – 1% of pregnancies may have Gestational Thyrotoxicosis (GTT), a self - limiting disorder requiring no specific therapy. It should be remembered that 5 – 10% of normal subjects can have an undetectable TSH during the entire 9 months. MNG with toxicosis and autonomously secreting thyroid nodules are very rare and management is similar to Graves’ disease (GD).

The clinical manifestations of mild thyrotoxicosis can be difficult to distinguish from that of pregnancy and hence require laboratory tests: Elevated FT3, FT4, suppressed TSH with positive TRAb. The management will depend on when patient consults you for GD: before, during or after pregnancy:

Patient of GD planning pregnancy

A definitive treatment for GD should be advised; surgery (subtotal or total thyroidectomy) or Radio Active iodine ablation (RAIA). After RAIA, pregnancy should be planned only after six months for obvious reasons. The dose of RAI should be large enough so that thyrotoxicosis is controlled – a resulting hypothyroidism is acceptable in this situation. A definitive line of treatment is recommended because of adverse effects of antithyroid drugs (ATD) during pregnancy as all drugs cross placenta.

The methimazole (MMI) and carbimazole (CBM) exposure causes congenital malformations such as aplasia cutis, choanal atresia and others. Propyl Thiouracil (PTU) had significantly lesser prevalence of embryopathy than MMI & CBM, hence given in first trimester; but it is associated with liver damage and hence not entirely safe.

First suspected to have GD in pregnancy

Graves’ disease (GD) usually presents with severe symptoms of toxicosis and presence of goiter and positive TRAb, which is a very specific for GD. In GD, the accepted drug for management is PTU (100 – 200 mg three times daily) in the first trimester and MMI/CBZ after that. The smallest dose of required to keep FT4 & FT3 just above the normal nonpregnant range is ideal.

Symptomatic treatment with beta-blockers (propranolol 20mg eight hourly) or atenolol 25 -50 mg/day can be given for 2 – 4 weeks, Too much of MMI/CBZ can produce hypothyroidism and goiter in the fetus and this needs to

489

During pregnancy, the TRAb crosses placenta and this leads to transient neonatal toxicosis, fortunately this is very rare.

A close differential diagnosis of mild GD presenting first time in pregnancy is Gestational thyrotoxicosis (GTT) mediated by very high hCG levels. GTT is more common than GD in pregnancy; there is usually no goiter and the Thyroid receptor antibody (TRAb) is negative. The usual manifestation is exaggerated morning sickness causing dehydration with suppressed TSH. If severe, may require admission for IV fluids; this condition should not be treated with anti-thyroid drugs.

Patient on treatment for GD becomes pregnant

If well controlled for some time with CBM or MMI the antithyroid treatment is recommended to be changed to PTU (100 mg three times daily) in the first trimester and reinstitute methimazole or carbimazole in the second trimester by the ATA as in first suspected to have GD in pregnancy. FT4 should be maintained at higher normal range. There is a good chance of remission during the third trimester of pregnancy and hence when this is achieved, omit the antithyroid drug.

Other thyroid disorders

Goiter and Thyroid nodules discovered first time in pregnancy can await management till after delivery.

Their evaluation is similar to non - pregnant women. In extremely rare cases, immediate management may be required and should be left to the specialists.

REFERENCES

1.

Terry F Davis, Peter Laurberg, Rebecca S Bahn, Hyperthyroid disorers, Shlomo Melmed, Kenneth S Polonsky, P Reed Larsen, Henry N Kronenberg. Williams Text Book of Endocrinology, 13th Edition, Elsevier; Philadelphia, 2016, 369- 415

2.

Vimal Nambiar, Varsha S. Jagtap, Vijaya Sarathi, et al., “Prevalence and Impact of Thyroid Disorders on Maternal Outcome in Asian-Indian Pregnant Women,” Journal of Thyroid Research, vol. 2011, Article ID 429097, 6 pages, 2011. doi:10.4061/2011/429097

3.

Alex Stagnaro Green et al Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum.

Thyroid 2011; 21:1081 -1125.

4.

Leslie De Groot et al, Management of Thyroid disorders during pregnancy and postpatum: An Endocrine Society Clinical Practice guidelines. J Clin Endocrinol Metab 2012; 97:2543-2565.

CHAPTER 103

Hyperthyroidism in pregnancy

be avoided. Patient should be monitored with FT4 and TSH 2 to 4 weekly in the initial period and when goals are achieved, once in 4 to 6 weeks. If remission occurs, drug should be discontinued. Thyroidectomy during pregnancy is rarely required and RAIA is contraindicated.

There can be aggravation of GD after delivery as immune suppression of pregnancy disappears. Patients can safely continue ATD during lactation.

C H A P T E R

104 INTRODUCTION

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. 10% to 20% of all pregnant women in the first trimester of pregnancy are thyroglobulin (Tg) or thyroid peroxidase antibody (TPOAb) positive and euthyroid.

16% of the women who are euthyroid and positive for TPOAb or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPOAb or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception.

CHANGES IN THYROID FUNCTION ASSOCIATED WITH PREGNANCY

A normal pregnancy results in a number of important physiological and hormonal changes that alter thyroid function. These changes mean that laboratory tests of thyroid function must be interpreted with caution during pregnancy. Thyroid function tests change during pregnancy due to the influence of two main hormones: hCG and estrogen. hCG can weakly turn on the thyroid and high circulating hCG levels in the1st trimester may result in a slightly low TSH (subclinical hyperthyroidism).

When this occurs, TSH will be slightly decreased in the 1st trimester and then return to normal throughout the duration of pregnancy (Fig 1). Estrogen increases the amount of thyroid hormone binding proteins which increases the total thyroid hormone levels in the blood since > 99% of the thyroid hormones in the blood are bound to these proteins. However, measurements of “free” hormone (that are not bound to protein, representing the

Management of Hypothyroid in Pregnancy Sarita Bajaj

active form of the hormone) usually remain normal. Table 1 lists effects of pregnancy on thyroid physiology.

INTERACTION BETWEEN MATERNAL AND FETAL THYROID FUNCTION

For the first 10-12 weeks of pregnancy, the baby is completely dependent on the mother for the production of thyroid hormone. By the end of the 1st trimester, the baby’s thyroid begins to produce thyroid hormone on its own. The baby, however, remains dependent on the mother for ingestion of adequate amounts of iodine, which is essential to make thyroid hormones. WHO recommends iodine intake of 200µg/day during pregnancy to maintain adequate thyroid hormone production.

HYPOTHYROIDISM IN PREGNANCY

Primary maternal hypothyroidism is defined as the presence of an elevated TSH concentration during gestation. Historically, the reference range for serum TSH was derived from the serum of healthy, non-pregnant individuals. Using these data, values greater than 4.0 mIU/L were considered abnormal. More recently, normative data from healthy pregnant women suggest the upper reference range may approximate 2.5–3.0 mIU/L. When maternal TSH is elevated, measurement of serum FT4 concentration is necessary to classify the patient’s status as either subclinical (SCH) or overt hypothyroidism (OH). This is dependent upon whether FT4 is within or below the trimester-specific FT4 reference range. The distinction of OH from SCH is important because published data relating to the maternal and fetal effects attributable to OH are more consistent and easier to translate into clinical recommendations in comparison to those regarding SCH.

DEFINITIONS OF OH AND SCH IN PREGNANCY

Elevations in serum TSH during pregnancy should be defined using pregnancy specific reference ranges. OH is defined as an elevated TSH (>2.5 mIU/L) in conjunction with a decreased FT4 concentration. Women with TSH levels of 10 mIU/L or above, irrespective of their FT4 levels, are also considered to have OH (0.2%). SCH is defined as a serum TSH between 2.5 and 10 mIU/L (in 80-90%) with a normal FT4 concentration. TPOAb may be positive in 6080%. SCH is more common in women (7.5% against 2.8% in men) and is found in 2.3% of pregnant women. SCH is common in diabetes, goiter, and spontaneous abortion.

TPOAb positivity is seen in 10.8% of all pregnant women.

patients who are pregnant or are planning pregnancy, including assisted reproduction. The policy is for “aggressive case finding” ie in women with past history of thyroid disease, PPT, or thyroid lobectomy, with a family history of thyroid disease, with a goiter, known positive thyroid antibodies, with symptoms or clinical signs suggestive of thyroid hypofunction or hyperfunction, including anemia, elevated cholesterol, and hyponatremia and with type 1 diabetes.

Fig. 1: Thyroid hormone levels during pregnancy Infertility and miscarriage are more common if TPO positive.

COMMON CAUSES OF HYPOTHYROIDISM IN PREGNANCY

Hypothyroidism can occur during pregnancy due to the initial presentation of Hashimoto’s thyroiditis, inadequate treatment of a woman already known to have hypothyroidism from a variety of causes, or over-treatment of a hyperthyroid woman with anti-thyroid medications.

Postablative hypothyroidism following radioactive iodine or surgical therapy and iodine deficiency may be seen.

Table 2 lists the causes of hypothyroidism in pregnancy.

RISKS OF MATERNAL HYPOTHYROIDISM TO THE BABY

Even mild (subclinical) thyroxine deficiency in early pregnancy is detrimental to mother & fetus. Thyroid hormone is critical for brain development in the baby.

Untreated severe hypothyroidism in the mother can lead to impaired brain development in the baby. This is mainly seen when the maternal hypothyroidism is due to iodine deficiency, which also affects the baby. Children born with congenital hypothyroidism can have severe cognitive, neurological and developmental abnormalities if the condition is not recognized and treated promptly. These developmental abnormalities can largely be prevented if the disease is recognized and treated immediately after birth. Consequently, all newborn babies in the United States, Europe and Japan are screened for congenital hypothyroidism.

There is 20% incidence of maternal and perinatal complications with untreated, or inadequately treated hypothyroidism viz anemia, CHF, pre-eclampsia, gestational hypertension, placental abruption, preterm birth, LBW, congenital malformations, impaired intellectual and psychomotor development and fetal death. With subclinical hypothyroidism the same problems exist, but they are one-third as common.

SCREENING FOR HYPOTHYROIDISM DURING PREGNANCY

At this time universal screening is not recommended for

The optimal method to assess serum FT4 during pregnancy is measurement of T4 in the dialysate or ultrafiltrate of serum samples employing on-line extraction/ liquid chromatography/tandem mass spectrometry (LC/MS/ MS). If FT4 measurement by LC/MS/MS is not available, clinicians should use whichever measure or estimate of FT4 is available in their laboratory, being aware of the limitations of each method. Serum TSH is a more accurate indication of thyroid status in pregnancy.

In view of the wide variation in the results of FT4 assays, method-specific and trimester-specific reference ranges of serum FT4 are required.

TREATMENT OF HYPOTHYROIDISM DURING PREGNANCY

Apart from symptomatic improvement benefits of treatment are prevention of progression to overt hypothyroidism, reduction in lipid levels with a subsequently lower risk of cardiovascular events and prevention of poor developmental outcomes in children born to women with subclinical disease.

The treatment of choice is levothyroxine (LT4). Once hypothyroidism is diagnosed (overt or subclinical) treatment should be started with LT4 in doses of 50 µg daily with gradual increments of 25 µg every week, until the serum TSH level becomes normal.

For women on thyroid replacement therapy before pregnancy check serum TSH level as soon as pregnancy is confirmed with a preemptive dose increase by 25 mg. Higher doses may be required for postablative and postsurgical hypothyroidism.

TARGET LEVELS OF TSH AND MONITORING DURING PREGNANCY

Emphasize pre conceptional control (TSH<2.5 mU/L) in known hypothyroid women. The goal of LT4 treatment is to normalize maternal serum TSH values. The upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges for TSH are not available : the targets are <2.5 mIU/L in the first trimester, <3 mIU/L in later pregnancy.

For previously diagnosed hypothyroid women, monitor TSH every 3-4 weeks during the first half of pregnancy and every 6-8 weeks thereafter. After delivery decrease LT4 dose to pre pregnancy dose and check TSH in six weeks.

If the original indication for T4 therapy is unclear this can be sorted out by stopping it for 6 weeks postpartum for re-evaluation.

CHAPTER 104

THE OPTIMAL METHOD TO ASSESS FT4 DURING PREGNANCY

491

PREGNANCY

492

Table 1 : Effects of pregnancy on thyroid physiology

Table 2 : Causes of hypothyroidism during pregnancy

Physiologic Change

Thyroid-Related Consequences

Primary hypothyroidism

 Serum thyroxinebinding globulin

 Total T4 and T3;  T4 production

• Circulating TSH-receptor-blocking antibody

 Plasma volume

 T4 and T3 pool size;  T4 production;  cardiac output

• Thyroid destruction (Hashimoto’s disease) Asymptomatic (euthyroid) autoimmune thyroid disease Postpartum thyroid disease

 Deiodinase expression in placenta and (?) uterus

 T4 production

• Hyperthyroidism

First trimester  in hCG

 Free T4;  basal thyrotropin;

• Combinations

 T4 production

• Pre-existing

 Renal I- clearance

 Iodine requirements

 T4 production; fetal T4 synthesis during second and third trimesters

 Oxygen consumption by  Basal metabolic rate;  fetoplacental unit, gravid cardiac output uterus, and mother Separate iron, calcium, soy products by at least four hours after LT4 ingestion to ensure adequate absorption.

Women who are TPOAb positive are susceptible to subclinical hypothyroidism. They should be monitored during pregnancy and postpartum for the development of thyroid dysfunction.

REFERENCES

1.

http://www.thyroid.org/wp-content/uploads/patients/ brochures/HormoneTreatment_brochure.pdf accessed on 24/08/2016

2.

http://www.ijogr.com/blog/2015/thyroid-disease-inpregnancy-clinical-considerations-and-recommendations/ accessed on 25/08/2016

3.

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum.The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Thyroid 2011; 21:1081–1125.

4.

Donny C Elizabeth N. Screening for Maternal Thyroid Dysfunction in Pregnancy: A Review of the Clinical Evidence and Current Guidelines. Journal of Thyroid Research 2013.

5.

Roberto Negro. Clinical Aspects of Hyperthyroidism, Hypothyroidism, and Thyroid Screening in Pregnancy.

Endocr Pract 2014; 20:597-607.

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http://www.thyroid.org/thyroid-disease-pregnancy/ Accessed on 24/08/2016

• Hypothyroidism Graves’ disease • Gestational exacerbation and remission PP exacerbation 7.

http://thyroidnodule.in/index.php/thyroid-disease-andpregnancy/ accessed on 24/08/2016

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http://www.thyroid.org/wp-content/uploads/patients/ brochures/Thyroid_Disesease_Pregnancy_brochure.pdf accessed on 23/08/2016.

9.

http://www.thyroid.org/wp-content/uploads/publications/ ctfp/ct_public_v98.pdf accessed

10. Toft AD. Beckett GJ. Measuring serum thyrotropin, thyroid hormone, assessing thyroid hormone transport. In: Braverman LE, editor; Utiger RD, editor. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 9th.

Lippincott, Williams & Wilkins; Philadelphia: 2005. pp.

329–344 11. Anckaert E. Poppe K. Van Uytfanghe K. Schiettecatte J. Foulon W. Thienpont LM. FT4 immunoassays may display a pattern during pregnancy similar to the equilibrium dialysis ID-LC/tandem MS candidate reference measurement procedure in spite of susceptibility towards binding protein alterations. Clin Chim Acta 2010; 411:1348– 1353 12. Mestman J. H., Goodwin T. M. and Montoro M. M. Thyroid disorders of pregnancy. Endocrinology and Metabolism Clinics of North American 1995; 24:41-71.

13. Bishnoi A. and Sachmechi I. Thyroid disease during pregnancy. American Family Physician 1996; 53:215-220.

14. Mandel S. J., Larsen P. R., Seely E. W. and Brent G. A. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. New England Journal of Medicine 1990; 323:91-96.

15. Kaplan M. M. Monitoring thyroxine therapy treatment during pregnancy. Thyroid 1992; 2:147-152.

16. This NGC summary was completed by ECRI Institute on June 27, 2012. Theinformationwas verified by the guideline developer on July 16, 2012. https://www.guideline.gov/ summaries/downloadcontent/ngc-9019?contentType=pdf.

C H A P T E R

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Heart Diseases in Pregnancy Monotosh Panja, Arindam Pande, Madhumanti Panja, Ajanta Samanta

ABSTRACT

Heart disease is the leading cause of maternal mortality in the UK. Cardiomyopathy, myocardial infarction and aneurysm or dissection of the aorta are the leading causes of death from acquired heart disease while pulmonary hypertension is the leading cause of death from congenital heart disease. Congenital heart disease is the predominant form of heart disease encountered in pregnancy as most women with congenital heart disease now survive to adulthood due to the successes of pediatric cardiology and cardiac surgery. Patients with heart disease should receive multi-disciplinary counseling and risk assessment to enable an informed decision regarding pregnancy.

Appropriate contraceptive advice should also be given.

Physiological changes in pregnancy should be understood as they may precipitate de compensation in patients with previously well tolerated lesions. This article briefly reviews congenital and acquired cardiac lesions that are important because they are common conditions or because pregnancy poses a particular risk. Early involvement of a cardiologist is recommended in any pregnant woman with chest pain and ECG changes. Ischaemic heart disease and cardiomyopathy (dilated, peripartum, hypertrophic) are discussed. The management of pregnant women with prosthetic heart valves can be complex and choice of anti-coagulant needs to be individualized with close monitoring by a specialist team. Pregnancy is in-advisable in pulmonary hypertension, severe un-operated left sided stenosis, severely impaired ventricular function and Marfan syndrome with a dilated aortic root.

INTRODUCTION

At present, 0.2–4% of all pregnancies in western industrialized countries are complicated by cardiovascular diseases (CVD),1 and the number of the patients who develop cardiac problems during pregnancy is increasing.

Heart disease is the leading cause of maternal mortality in the UK, after psychiatric illness (maternal mortality rate of 2.2/100,000 maternities). Causes of maternal death include acquired and congenital heart disease; incidence 0.1% and 0.8%, respectively.2 Cardiomyopathy (predominantly peripartum), myocardial infarction and aneurysm or dissection of the thoracic aorta are the leading causes of death from acquired cardiac disease while pulmonary hypertension is the leading cause of death from congenital heart disease.2 The spectrum of CVD in pregnancy is changing and differs between countries.

In the western world, the risk of CVD in pregnancy has increased due to increasing age at first pregnancy and increasing prevalence of cardiovascular risk factors—

diabetes, hypertension, and obesity. Also the treatment of congenital heart disease has improved, resulting in an increased number of women with heart disease reaching childbearing age.3 In western countries maternal heart disease is now the major cause of maternal death during pregnancy.4 Hypertensive disorders are the most frequent cardiovascular events during pregnancy, occurring in 6–8% of all pregnancies.5 In the western world, congenital heart disease is the most frequent cardiovascular disease present during pregnancy (75–82%), with shunt lesions predominating (20–65%).6,7 Congenital heart disease represents just 9–19% outside Europe and North America.

Rheumatic valvular disease dominates in non-western countries, comprising 56–89% of all cardiovascular diseases in pregnancy.6,7 Cardiomyopathies are rare, but represent severe causes of cardiovascular complications in pregnancy. Peripartum cardiomyopathy (PPCM) is the most common cause of severe complications.8

PHYSIOLOGICAL CHANGES DURING PREGNANCY

An understanding of the basic haemodynamic changes that take place throughout pregnancy and delivery is essential. The total blood volume increases by up to 50% (up to 1500 ml), starting as early as the fifth week of pregnancy, with an increase in red cell mass (increased oxygen carrying capacity) and an even greater increase in total plasma volume resulting in a relative anaemia. To deal with the increased blood volume and the additional demand for oxygen, there is a 40% increase in cardiac output peaking at the 25th week. This is achieved via an increased stroke volume in addition to a 15–20% increase in heart rate. Failure to achieve this is marked by a resting tachycardia which may signal diminished cardiovascular reserve and may in turn be detrimental in conditions where left ventricular filling is slow. An increase in cardiac output across a stenosed valve will cause an increase in transvalvular gradient which often manifests with worsening symptoms in the second trimester. The increased cardiac output is balanced by peripheral vasodilatation (due to hormonal changes) with a subsequent reduction in systemic vascular resistance and reduction in after load. This may decrease the regurgitant fraction in regurgitant valve disease and explains why pregnancy is frequently well tolerated with valvular regurgitation.9 Other physiological changes include hypercoagulability with reduced antithrombotic factors (decreased protein C and protein S) and increased prothrombotic factors (fibrinogen, platelet activating inhibitor, platelet adhesion and aggregation) thus increasing the risk of valve thrombosis and other

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thrombotic complications. All of these physiological changes may precipitate de compensation in patients with previously well tolerated lesions.

PREGNANCY

CARDIAC PHYSICAL EXAMINATION DURING NORMAL PREGNANCY

The carotid upstroke is brisk and the jugular venous pressure is normal or slightly increased. The apex beat may be displaced and increased. The first heart sound is loud, the pulmonary component of the second may be prominent and an S3 may be heard. An ejection systolic murmur may be heard in 90% of pregnant women caused by an increase in pulmonary outflow. Benign venous hums and mammary murmurs can also be heard.

CARDIOVASCULAR EVALUATION

All patients with known or suspected cardiac disease should have a detailed clinical history and examination ideally prior to conception and then at regular intervals according to the underlying cardiac condition. ECGs and echocardiograms are very useful non-invasive investigations. Chest x-ray (CXR) and other radiological procedures are best avoided (particularly during the first trimester), however a CXR carries a negligible risk if the fetus is shielded and should be considered if the patient has chest pain.2 Caution should be used when considering computed tomography (CT) scanning due to the high maternal radiation dose involved. MRI is generally considered to be safe. Coronary angiography is occasionally necessary but should be avoided until at least 7 weeks gestation. Shielding should be used with an upper limb approach. No investigation should be withheld from a patient just because she is pregnant.

Pulmonary embolism, aortic dissection and myocardial infarction (MI) account for a number of maternal deaths each year, and failure to investigate correctly probably accounts for a significant proportion of these.

FETAL ASSESSMENT

First trimester ultrasound allows accurate measurement of gestational age and early detection of multiple pregnancy and of malformations. Diagnosis of congenital cardiac malformations can be made as early as 13 weeks, and, in families with heart disease, this timing is appropriate to start screening for congential heart disease. A review of the accuracy of first-trimester ultrasounds for detecting major congenital heart disease showed a sensitivity and specificity of 85% [95% confidence interval (CI) 78–90%] and 99% (95% CI 98–100%), respectively. Early examination in pregnancy allows parents to consider all options, including termination of pregnancy, if there are major malformations.10 The optimum time for screening of normal pregnancies for congenital heart diseases11 is 18–22 weeks of gestation when visualization of the heart and outflow tracts is optimal. It becomes more difficult after 30 weeks since the fetus is more crowded within the amniotic cavity. Second-trimester screening (18–22 weeks) for detection of fetal anomalies should be performed by experienced specialists, particularly in pregnancies with risk factors for congenital heart anomalies.12

INTERVENTIONS IN THE MOTHER DURING PREGNANCY

Percutaneous therapy: The effects of radiation on the fetus depend on the radiation dose and the gestational age at which exposure occurs. If possible, procedures should be delayed until at least the completion of the period of major organogenesis (<12 weeks after menses).

If an intervention is absolutely necessary, the best time to intervene is considered to be after the fourth month in the second trimester. By this time organogenesis is complete, the fetal thyroid is still inactive, and the volume of the uterus is still small, so there is a greater distance between the fetus and the chest than in later months.

Fluoroscopy and cineangiography times should be as brief as possible and the gravid uterus should be shielded from direct radiation. Heparin has to be given at 40–70 U/ kg, targeting an activated clotting time of at least 200 s, but not exceeding 300 s.

Cardiac surgery with cardiopulmonary bypass: Maternal mortality during cardiopulmonary bypass is now similar to that in non-pregnant women who undergo comparable cardiac procedures.1 However, there is significant morbidity including late neurological impairment in 3–6% of children, and fetal mortality remains high.13 For this reason cardiac surgery is recommended only when medical therapy or interventional procedures fail and the mother’s life is threatened. The best period for surgery is between the 13th and 28th week.14,15

TIMING AND MODE OF DELIVERY: RISK FOR MOTHER AND CHILD

High risk delivery

Induction, management of labour, delivery, and postpartum surveillance require specific expertise and collaborative management by skilled cardiologists, obstetricians, and anaesthesiologists, in experienced maternal–fetal medicine units.16,17

Timing of delivery

Spontaneous onset of labour is appropriate for women with normal cardiac function and is preferable to induced labour for the majority of women with heart disease.

Timing is individualized, according to the gravida’s cardiac status, Bishop score, fetal well-being, and lung maturity. In women with mild unrepaired congenital heart disease and in those who have undergone successful cardiac surgical repair with minimal residua, the management of labour and delivery is the same as for normal pregnant women.

Labour induction

Oxytocin and artificial rupture of the membranes are indicated when the Bishop score is favourable. A long induction time should be avoided if the cervix is unfavourable. While there is no absolute contraindication to misoprostol or dinoprostone, there is a theoretical risk of coronary vasospasm and a low risk of arrhythmias.

Dinoprostone also has more profound effects on BP than prostaglandin E1 and is therefore contraindicated in active CVD. Mechanical methods such as a Foley catheter would be preferable to pharmacological agents, particularly

in the patient with cyanosis where a drop in systemic vascular resistance and/or BP would be detrimental.18

Haemodynamic monitoring

Systemic arterial pressure and maternal heart rate are monitored, because lumbar epidural anaesthesia may cause hypotension. Pulse oximetry and continuous ECG monitoring are utilized as required.

Anaesthesia/analgesia

Lumbar epidural analgesia is often recommendable because it reduces pain-related elevations of sympathetic activity, reduces the urge to push, and provides anaesthesia for surgery. Continuous lumbar epidural analgesia with local anaesthetics or opiates, or continuous opioid spinal anaesthesia can be safely administered.

Regional anaesthesia can, however, cause systemic hypotension and must be used with caution in patients with obstructive valve lesions.

Labour

Once in labour, the woman should be placed in a lateral decubitus position to attenuate the haemodynamic impact of uterine contractions.22 The uterine contractions should descend the fetal head to the perineum, without maternal pushing, to avoid the unwanted effects of the Valsalva manoeuvre.23,24 Delivery may be assisted by low forceps or vacuum extraction. Routine antibiotic prophylaxis is not recommended. Continuous electronic fetal heart rate monitoring is recommended.

Delivery in anticoagulated women with prosthetic valves

OACs should be switched to LMWH or unfractionated heparin (UFH) from the 36th week. Women treated with LMWH should be switched to i.v. UFH, at least 36 h before the induction of labour or caesarean delivery. UFH should be discontinued 4–6 h before planned delivery, and restarted 4–6 h after delivery if there are no bleeding complicationsIf emergent delivery is necessary while the patient is still on UFH or LMWH, protamine should be considered. In the event of urgent delivery in a patient on therapeutic OACs, caesarean delivery is preferred to reduce the risk of intracranial haemorrhage in the fully

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Post-partum care

A slow I.V. infusion of oxytocin (2 U/min), which avoids systemic hypotension, is administered after placental delivery to prevent maternal haemorrhage. Prostaglandin F analogues are useful to treat post-partum haemorrhage, unless an increase in pulmonary artery pressure (PAP) is undesirable. Methylergonovine is contraindicated because of the risk (.10%) of vasoconstriction and hypertension.

[25, 26] Meticulous leg care, elastic support stockings, and early ambulation are important to reduce the risk of thrombo-embolism. Delivery is associated with important haemodynamic changes and fluid shifts, particularly in the first 12–24 h, which may precipitate heart failure in women with structural heart disease. Haemodynamic monitoring should therefore be continued for at least 24 h after delivery.27

Breastfeeding

Lactation is associated with a low risk of bacteraemia secondary to mastitis. In highly symptomatic/unwell patients, bottle-feeding should be considered.

INFECTIVE ENDOCARDITIS

Infective endocarditis during pregnancy is rare, with an estimated overall incidence of 0.006% (1 per 100 000 pregnancies)28 and an incidence of 0.5% in patients with known valvular or congenital heart disease.29 The incidence is higher in drug addicts. Patients with the highest risk for infective endocarditis are those with a prosthetic valve or prosthetic material used for cardiac valve repair, a history of previous infective endocarditis, and some special patients with congenital heart disease.

Prophylaxis

The same measures as in non-pregnant patients with recent modifications of guidelines apply.30 Endocarditis prophylaxis is now only recommended for patients at highest risk of aquiring endocarditis during high risk procedures, e.g. dental procedures. During delivery the indication for prophylaxis has been controversial and, given the lack of convincing evidence that infective endocarditis is related to either vaginal or caesarean delivery, antibiotic prophylaxis is not recommended during vaginal or caesarean delivery.30,31

ISCHAEMIC HEART DISEASE (IHD)

An acute coronary event occurs in 1 in 10–35,000 pregnancies, predominantly in the third trimester, caused by coronary thrombosis, spasm or dissection and less commonly atherosclerosis. Risk factors include increased age, diabetes, hypertension and eclampsia with greatest

CHAPTER 105

Vaginal or caesarean delivery: The preferred mode of delivery is vaginal, with an individualized delivery plan which informs the team of timing of delivery (spontaneous/ induced), method of induction, analgesia/ regional anaesthesia, and level of monitoring required. In high risk lesions, delivery should take place in a tertiary centre with specialist multidisciplinary team care. Vaginal delivery is associated with less blood loss and infection risk compared with caesarean delivery, which also increases the risk of venous thrombosis and thromboembolism.19 In general, caesarean delivery is reserved for obstetric indications. Caesarean delivery should be considered for the patient on oral anticoagulants (OACs) in pre-term labour, patients with Marfan syndrome and an aortic diameter >45 mm, patients with acute or chronic aortic dissection, and those in acute intractable heart failure. Cesarean delivery may be considered in Marfan patients with an aortic diameter 40–45 mm.20,21

anticoagulated fetus. If emergent delivery is necessary, fresh frozen plasma should be given prior to caesarean delivery to achieve a target international normalized ratio (INR) of ≤2.4 Oral vitamin K (0.5–1 mg) may also be given, but it takes 4–6 h to influence the INR. If the mother was on OACs at the time of delivery, the anticoagulated newborn may be given fresh frozen plasma and should receive vitamin K. The fetus may remain anticoagulated for 8–10 days after discontinuation of maternal OACs.

PREGNANCY

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risk occurring before and during labour. Mortality is 21– 37% increasing up to 50% in patients with diabetes. Fetal mortality ranges between 13–34%. Investigations include ECG and troponin I, 3 which are reliable biomarkers for myocardial injury during pregnancy (unlike creatinine kinase). Angina can be treated conventionally but an acute coronary syndrome (ACS) is a difficult problem with little data in pregnancy. Since the mortality of acute MI is so high, a ‘wait and see’ approach is not good practice. Thrombolysis carries a risk of maternal and fetal haemorrhage and will not be effective if the pathology is coronary dissection. The best option in a woman with an acute MI is urgent transfer to the catheter laboratory where angiography will reveal the pathology and allow effective intervention for dissection or ruptured plaque.

Early involvement of a cardiologist is recommended in any pregnant woman with chest pain and ECG changes.

DILATED CARDIOMYOPATHY

Pregnancy in patients with dilated cardiomyopathy is poorly tolerated and related to New York Heart Association (NYHA) class. Mortality in classes I–II is 1%, increasing to at least 7% in classes III–IV. Fetal mortality is strongly related to NYHA class (30% in class IV). Adverse prognostic features include left ventricular (LV) ejection fraction <20%, mitral regurgitation, right ventricle (RV) failure, atrial fibrillation and hypotension.

Most patients should be advised against pregnancy but if they do become pregnant they should be advised to limit strenuous exercise, to obtain adequate rest, restrict salt intake and attend for regular specialist review. Anaemia should be avoided. Diuretics, β-blockers and vasodilators can be used. ACE inhibitors should be avoided unless poor maternal cardiac status means that the risk of a poor maternal and fetal outcome is considered to be greater than the associated ∼17% risk of fetal renal agenesis.

PERIPARTUM CARDIOMYOPATHY

This rare condition is defined as cardiac failure in the last month of pregnancy or within 5 months of delivery with no identifiable cause of heart failure and no recognisable pre-existing heart disease. Mortality ranges between 6–50% with mortality risk in subsequent pregnancy estimated as: •

0–2% if normal ejection fraction (EF) before subsequent pregnancy

•

8–17% if depressed EF.

Adverse risk factors include age, multiparity, twins and persisting left ventricle (LV) dilatation and dysfunction.

Around 50–60% of patients show complete or nearcomplete recovery of clinical status and cardiac function six months post partum. Subsequent pregnancies should be discouraged if the LV does not recover.32,33

HYPERTROPHIC CARDIOMYOPATHY

Most women tolerate pregnancy well. In a study of 91 consecutive families with 199 live births, symptoms deteriorated in less than 10% of patients. Mortality was increased but confined to patients known to be at high risk

(massive LV hyperthrophy, severe restrictive physiology).

Maternal death was uncommon and risk of sudden death was not increased by the pregnancy.34 Vaginal delivery is generally well tolerated with careful fluid management in labour to avoid hypovolaemia-induced hypotension due to decreased left ventricular filling or pulmonary oedema due to overzealous fluid replacement.

MITRAL STENOSIS

Regurgitant lesions are generally well tolerated in pregnancy whereas left-sided stenotic lesions are not.

Impaired diastolic flow through a stenotic valve may cause tachycardia and increased stroke volume leading to increased left atrial (LA) pressure, pulmonary oedema and atrial fibrillation. Treatment includes bed rest, diuretics, rate control and heparin. Balloon valvotomy should be used if delivery is not advisable (e.g. fetal prematurity) or if the patient is haemodynamically compromised.

PROSTHETIC HEART VALVES

The high risk of thrombo-embolic complications means that choice of anticoagulant is extremely important. The interests of the mother and fetus are in conflict: •

warfarin is a more effective anticoagulant, but crosses the placenta and may cause embyropathy and fetal haemorrhage

•

heparin does not cross the placenta, so has no fetal adverse effects, but is associated with a 12–24% risk of valve thrombosis or embolism.35

Women with mechanical valves need care from a specialized team which includes a cardiologist, obstetrician and haematologist. The choice of anticoagulation regime needs to be individualized taking into account factors such as valve site and type and required warfarin dose (very low risk of embryopathy if <5 mg).36 The choice of regimens includes: •

warfarin throughout pregnancy with elective caesarean section at 38 weeks

•

heparin and aspirin for the 1st trimester, warfarin in the 2nd trimester, converting back to heparin for delivery

•

heparin and aspirin throughout.

There is no consensus about the type of heparin used and choice is controversial in the absence of good data.

Unfractionated heparin is associated with osteoporosis and thrombocytopenia whereas low molecular weight (LMW) heparin is not. It is also possible to more effectively control LMW heparin with 2–4 weekly antiXa levels. LMW heparin should be given as a twice-daily regimen.37,38

CONGENITAL HEART DISEASE

This section is not an exhaustive review of the congenital cardiac lesions that may be encountered in pregnancy. It includes some of those that are important because they are common conditions or because pregnancy poses a particular risk.

BICUSPID AORTIC STENOSIS

Most young people with aortic stenosis are asymptomatic and pregnancy is well tolerated if the patient has a: •

normal resting ECG or voltage increase only

•

normal exercise test

•

good LV function

•

pre-pregnancy echo gradient – peak <80, mean <50 mmHg.

AORTIC COARCTATION

In this condition the right ventricle supports the systemic circulation. Pregnancy is well tolerated but RV function may deteriorate during the course of pregnancy and systemic AV valve regurgitation may worsen. Treatment is as for any patient with heart failure. There is also a risk of complete heart block.

TRANSPOSITION OF THE GREAT ARTERIES POST MUSTARD OR SENNING

With atrial redirection the RV supports the systemic circulation and there is a risk of atrial arrhythmia as well as RV failure and systemic atrioventricular valve regurgitation. The patency of the pulmonary venous pathways must be checked (by echocardiography) since obstruction may mimic mitral stenosis. Pregnancy is well tolerated if patients are NYHA class I–II.

FONTAN PROCEDURE

Major complications are infrequent but are a cause for concern. Obstetric and neonatal outcomes are similar to the general population.39 Each patient should have formal preconception haemodynamic assessment (exercise stress test, echocardiogram, MRI aorta) with very close monitoring of blood pressure during pregnancy.

This is a palliative procedure for patients with univentricular hearts e.g. tricuspid atresia, pulmonary atresia with intact ventricular septum. Both atrioventricular valves are connected to a single ventricular cavity (doubleinlet ventricle) and the main ventricle is connected to a rudimentary chamber.

MARFAN SYNDROME

This changes a complex cyanosed patient into a complex patient who is now pink. With no pump to support the pulmonary circulation, it relies on phasic flow with limited ability to increase cardiac output. Atrial arrhythmias are poorly tolerated and the circulation is prothrombotic. If patients are in NYHA class I–II with good ventricular function, maternal risk is not excessively high. Strict care should be taken to maintain filling pressures, avoid dehydration or vasodilation. There is a high risk of fetal loss (30%). Most patients take warfarin and should be converted to LMW heparin for the duration of the pregnancy. Anti-arrhythmicsare often needed raising the issue of arrhythmia risk vs teratogenicity. These patients need multidisciplinary expert care.41,42

The main maternal risk in this condition is type A aortic dissection – 1%. Patients with the following are at high risk: •

poor family history

•

cardiac involvement

•

aortic root >4 cm or rapidly expanding

Every patient should receive appropriate pre-conception counseling with regard to maternal as well as fetal risk. β-blockers are frequently used with elective Caesarean section if at higher risk. Staff should remain vigilant about the possibility of dissection as a cause of chest or interscapular pain in pregnancy, particularly if the woman is hypertensive.

Aortic dissection should always be considered in pregnant women with atypical chest pain and features of pulmonary embolism who do not get better with treatment. Other diagnostic features include pulse deficits and signs of aortic regurgitation.

REPAIRED TETRALOGY OF FALLOT

Pregnancy is well tolerated if ventricular function is good and there is no significant right ventricular (RV) outflow tract obstruction.40 If the woman has significant pulmonary regurgitation, a successful pregnancy outcome may be anticipated, but she may become breathless earlier than expected in pregnancy and may need bed rest and diuretics.

497

PULMONARY HYPERTENSION

There is a high risk of maternal death and severe morbidity even if pulmonary artery pressures are half systemic. The risk of maternal death is 40–50% (unchanged in the last four decades) and therefore pregnancy is NOT advised.

If a woman chooses to continue with pregnancy, she should receive multidisciplinary specialist antenatal and peripartum care. There is no evidence that intervention reduces mortality, but bed rest, heparin, oxygen, prostacyclin, phosphodiesterase inhibitors and endothelin antagonists may all be considered. The risk of death continues for at least two weeks postpartum.

Appropriate contraceptive advice is extremely important.

While sterilization can be considered, there are other more effective methods which avoid a general anaesthetic e.g. Implanon (sub dermal implant).

RISK ESTIMATION: CONTRAINDICATIONS FOR PREGNANCY

Maternal risk assessment is carried out according to

CHAPTER 105

Signs of decompensation include disproportionate dyspnoea, angina, pulmonary oedema, new ECG changes and an unexpected fall in peak Doppler gradient.

Treatment includes bed rest and β-blockade while in severe cases aortic valvotomy and aortic valve replacement may need to be considered. Vaginal delivery is advisable with avoidance of vasodilators and hypovolaemia (as with all obstructive lesions).

CONGENITALLY CORRECTED TRANSPOSITION OF THE GREAT ARTERIES

PREGNANCY

498

the modified World Health Organization (WHO) risk classification.43 This risk classification integrates all known maternal cardiovascular risk factors including the underlying heart disease and any other co-morbidity. It includes contraindications for pregnancy. The general principles of this classification. A practical application. In women in WHO class I, risk is very low, and cardiology follow-up during pregnancy may be limited to one or two visits. Those in WHO II are at low or moderate risk, and follow-up every trimester is recommended. For women in WHO class III, there is a high risk of complications, and frequent (monthly or bimonthly) cardiology and obstetric review during pregnancy is recommended. Women in WHO class IV should be advised against pregnancy but, if they become pregnant and will not consider termination, monthly or bimonthly review is needed.

CONCLUSION

All patients should receive multi-disciplinary counselling and cardiac assessment prior to conception. They should all receive appropriate contraceptive advice. An estimate of maternal and fetal risk should be made to enable an informed decision regarding pregnancy. Pregnancy is inadvisable in: •

pulmonary hypertension

•

severe unoperated left sided stenosis

•

severely impaired ventricular function (EF<20%)

•

Marfan syndrome with a dilated aortic root.

Treatment and management approaches in pregnant women are similar to those in non-pregnant patients with awareness of altered physiology and careful attention to fetal and maternal effects of pharmacological agents.

All pregnant and recently delivered women with congenital heart disease should be appropriately supervised, preferably by a consultant cardiologist with a special interest in congenital heart disease in close conjunction with a consultant obstetrician.

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Peripartum Cardiomyopathy

C H A P T E R

106

AN Rai, Mritunjay Kumar Singh

INTRODUCTION

Heart failure during pregnancy was first noted in 1849.

But the first description as a distinctive form came only in 1930s. In 1971 Demakis described 27 patients with the disease and named this as a syndrome peripartum cardiomyopathy (PPCM).

The European Society of Cardiology recently defined PPCM as a form of dilated cardiomyopathy that presents with signs of heart failure in the last month of pregnancy or within 5 months of delivery, where no other causes heart failure is found. It is a diagnosis of exclusion. The LV may not be dilated but the ejection fraction is nearly always reduced below 45%.

It occurs 1 in every 2289 live births in the United States.

The rate varies in other populations with highest in Haiti, where 1 case occurs in every 300 live births. Environmental and genetic factors, differences in cultural practices, and standards of perinatal care may account for this regional disparity.

ranged from 9-78% in different studies. However the presence or absent of Myocarditis alone does not predict the outcome of PPCM.

Cardiotropic Viral Infection

After a viral infection, a pathologic immune response occur which inappropriately target native cardiac tissue, leading to cardiac dysfunction. Bultmann found several viral (parvovirus B19, HHV6, EBV, CMV) DNAs in endomyocardial biopsy specimen of patients of PPCM.

Chimerism

Cells from the fetus provoke an immune response in mother. Serum from patients with PPCM has been found to contain autoantibodies in high titres, which are not present in serum from patients with idiopathic cardiomyopathy.

Apoptosis and Inflammation

Etiology

Experiments on mice suggest that apoptosis of cardiac myocyte has a role in PPCM. Fas and Fas ligand are cell surface proteins that play a key role in apoptosis. Study from South Africa, 100 patients with PPCM followed for 6 months. 15 patients died, and those who died had significantly higher plasma level of Fas/Fas ligand.

Myocarditis

Recent studies suggest that PPCM is a vascular disease, with cardio angiogenic imbalance and an excess of antiangiogenic signalling that is accentuated by preeclampsia. The placenta in late pregnancy secrets vascular endothelial growth factor (VEGF) inhibitors like soluble Fltl, and plasma level of sFltl is abnormally high in women with PPCM.

The aetiology and path physiology are poorly understood, but inflammation plays an important role and markers of inflammation (CRP, TNF) are elevated in many patients.

Myocarditis, cardiotropic viral infection, chimerism, and apoptosis play a role.

The prevalence of Myocarditis in patients with PPCM

Other report suggest role of cleaved prolactin in PPCM, which is powerful atiangiogenic, proapoptotic, and proinflammatory agent.

Who is at Risk?

Multiparity

Advanced maternal age (>30 years) Multifetal pregnancy Preeclampsia and Gestational hypertension African- American race

Symptoms and Signs

Fig. 1

Common symptoms include breathlessness, cough, orthopnea, and paroxysmal nocturnal dyspnea. Most affected patients have New York Heart Association (NYHA) class III or IV function. Other symptoms include nonspecific fatigue, malaise, palpitations, chest and abdominal discomfort, and postural hypotension.

Anticoagulation should be continued till left ventricular function is normalized.

Fig. 2 Cardiac arrhythmias and sudden cardiac arrest have also been reported. Physician should consider PPCM in any peripartum patients with unexplained breathlessness with raised BNP.

Warfarin is probably safe during the first 6 week of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation. It is relatively safe during the 2nd and 3rd trimesters but must be stopped and switched to a heparin several weeks before delivery. warfarin can cause spontaneous fetal cerebral haemorrhage in the 2nd and 3rd trimesters. Unfractoinated heparin/low molecular weight heparin can be used safely during pregnancy.

Cadiac Transplantion

Investigation

Newer Therapies

ECG- Left ventricular hypertrophy, Non-specific ST- T changes, atria or ventricular arrhythmia and conduction defect (Figure 2).

Intravenous immunoglobulin – improves the ejection fraction and significantly reduces the level of inflammatory cytokines.

ECHOCARDIOGRAPHY- LV dilatation with global hypokinesia, Left Ventricular Ejection Fraction < 45%, mitral regurgitation, pulmonary hypertension with dilated RA, RV, and TR and Pericardial effusion.

Immunosuppressive therapy – may have a role in patients with proven myocarditis.

Management of PPCM

The treatment of PPCM is same as for other form of congestive heart failure, except that Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin receptor blockers (ARB) are contraindicated in pregnancy.

Aldosterone antagonist should be avoided, because of antiandrogenic effect on fetus.

NON PHARMACOLOGICAL – salt restriction (4gm/ day), water restriction ( < 2l/day)

Pharmacological

Preload reduction- diuretics and nitrates ( nitroprussides are not recommended due to potential cyanide toxicity) Afterload reduction- hydralazine, nitrates, amlodepine Ionotropes- digoxin, dopamine, dobutamine are used in severely low cardiac output cases.

Beta-blockers and Anticoagulant Anti arrhythmic – qunidine, procainmide and digoxin Early fetal delivery may be required in women with heart failure .Cesarean section is preferred mode of delivery in hemodynamically compromised patients.

Guidelines of Anticoagulant Therapy

Patients with evidence of systemic embolism, with severe left ventricular dysfunction, or documented cardiac thrombosis should receive anticoagulation.

It is indicated in patients with severe heart failure not responding to maximal drug therapy, however only 3000 hearts are available worldwide for transplantation.

Therefore ventricular assist devices are indicated as a bridge to transplantation. Patients with symptomatic ventricular arrhythmia should be considered for defibrillator implantation.

Pentoxyfyline – improves left ventricular function and outcome.

Bromocriptine – it is a novel drug for targeted therapy of PPCM. Recent data discovered that blockade of prolactin by bromocriptine prevented the onset of disease in an experimental model of PPCM and appeared successful in small pilot trials. Bromocriptine is associated with increase risk of thrmboembolism so Concomitant heparin anticoagulation should be given.

Duration of Treatment

Treatment for heart failure should continue for 6-12 month in patient whom ventricular function return to baseline within 6 month, others will require treatment till normalisation of LV function or life long.

Prognostic Factors

The measure determinant of prognosis is recovery of left ventricular function. 30% of patients return to baseline ventricular function within 6 months. The usual cause of death in patients with PPCM is progressive heart failure, arrhythmia, or thrmboembolism. Usually PPCM had good prognosis with 5 year survival rate of 94%. There is an initial high risk period with mortality of 25- 50% in the first 3 month postpartum. Patients with persistent cardiomegaly at 6 months have a reported mortality of 85% at 5 years. QRS duration >120ms or more and positive troponin T measured 2 weeks after PPCM carry bad prognosis. Increased Risk of persistent left ventricular dysfunction is associated with LVEF < 30%, LVEDD > 5.6cm, left ventricular thrombus, and African American race.

CHAPTER 106

Common signs of PPCM include pedal edema, hepatomegaly, raised juglar venous pressure, presence of tachycardia with gallop rhythm, evidence of mitral or tricuspid regurgitation, pulmonary crepitations, left ventricular hypertrophy. The differential diagnosis includes accelerated hypertension, diastolic dysfunction, pulmonary embolus, and obstetric complications such as preeclampsia, eclampsia, and amniotic fluid embolism.

CXRPA VIEW- Cardiomegaly with or without pulmonary venous congestion/pulmonary oedema (Figure 1).

501

PREGNANCY

502

Risk of Relapse and Recommendation for Future Pregnancies

Future pregnancies carry a risk of relapse of PPCM even after full recovery of LV function. If LV function came to baseline, next pregnancies have no contraindication, although carries high risk of relapse. If LV function has not recovered, subsequent pregnancies are contraindicated, If LV function has partially recovered, and then dobutamine stress echocardiography should be done and if there is nomal response then pregnancy is allowed.

warfarin in first trimester because of potential teratogenic effects. Targeted therapies (for example, intravenous immunoglobulin, pentoxifylline, and bromocriptine) show promise but need further clinical evaluation before they can be widely adopted. An initial left ventricular end-diastolic dimension less than 5.5 cm, a LVEF > 30%, may predict a better outcome. Subsequent pregnancies may carry a high risk of relapse, even in women who have fully recovered left ventricular function.

CONCLUSION

References

High level of suspicion is required when a pregnant woman presents with signs of heart failure. The prognosis is best when peripartum cardiomyopathy is diagnosed and treated Early. Pregnant women should receive standard heart failure therapy. It is better to avoid ACEI/ARBs,or

1.

2.

3.

4.

Heart failure association of the ESC working group in PPCM. (silva et al 2010) The national heart lung and blood institute and office of rare diseases. (1997) Elkayam et al. N Engl J Med 2001; 344:1567.

Braumwaldâ&#x20AC;&#x2122;s HEART DISEASE a Textbook of cardiovascular medicine 10th edition.

C H A P T E R

107

Acute Infections in Pregnancy

INTRODUCTION

Pregnant women are a special high risk group since acute infections in them present the following challenges: 1.

Maternal risk: The unique immunologically suppressed state of pregnancy makes infections like influenza, malaria, hepatitis E, and herpes simplex virus (HSV) infection severe. Evidence also exists for increased severity of measles, smallpox, malaria, HIV infection, and listeriosis.

2.

Fetal risk: Congenital infections, intra-uterine growth retardation (IUGR), abortion or fetal death.

3.

Diagnostic implications: Pregnant women may not mount an adequate febrile response masking the presence of infections. Acute febrile illnesses may mimic other conditions like acute fatty liver of pregnancy and haemolysis, elevated liver enzymes and low platelet count (HELLP) syndromes.

Certain diagnostic modalities (x-ray, CT scan) may not be appropriate in pregnancy.

4.

Treatment implications: Prophylaxis (live vaccines) and certain drugs may not be safe in pregnancy.

CLASSIFICATION

Malaria

Pregnant women have a high risk of severe falciparum malaria presenting with severe anemia, hypoglycemia and acute pulmonary edema. Other complications include cerebral malaria, metabolic acidosis, acute kidney injury (AKI), convulsions, disseminated intravascular coagulation (DIC), shock and hyperpyrexia.

Niteen D Karnik, Priya Bhate

Fetal risks include abortion, stillbirth, IUGR, low birth weight (LBW) and rarely congenital malaria.

In areas with high transmission, malaria in the setting of high levels of acquired immunity contributes to anemia and IUGR especially in first pregnancy. In areas with low transmission, low levels of acquired immunity cause severe malaria.

Diagnosis: Peripheral smear or Rapid Diagnostic Tests Treatment (WHO guidelines) First trimester: Quinine (10mg/kg q8h) plus Clindamycin (10mg/kg q12h) - 7 days Second and third trimester: Severe: •

Artesunate 2.4 mg/kg IV at 0, 12, 24 hr, then once daily plus Clindamycin (10mg/kg q12h)

•

Start oral artemisinin-based combination therapy (ACT) once tolerated to complete 7 days

Uncomplicated: •

Oral ACT – 3 days

Artemether + Lumefantrine, Artesunate + Amodiaquine/ Mefloquine, Dihydroartemisinin + Piperaquine

•

In chloroquine-sensitive areas - Vivax malaria: Chloroquine 10 mg/kg - 3 days

•

Other treatment - fluid therapy, 25% dextrose for hypoglycaemia, blood transfusion for severe anemia, sodium bicarbonate for metabolic acidosis, phenytoin or phenobarbital for seizures, renal replacement therapy for AKI, ventilator support

Based on Spectrum System

Syndrome

1

Multisystem

acute febrile illnesses, tuberculosis

2

Neurological

meningitis, encephalitis

3

Cardiovascular

infective endocarditis

4

Gastro-intestinal

amoebic liver abscess, viral hepatitis, enteric fever

5

Respiratory

pneumonia

6

Renal

7

Others

Based on Etiology Viral

Cytomegalovirus, Dengue, Hepatitis E, Herpes, HIV Influenza (H1N1), Measles, Mumps, Rubella, Varicella zoster, Zika virus

urinary tract infections

Bacterial

chorioamnionitis, post operative sepsis, puerperal sepsis, retained products of conception, septic abortion

Chlamydia, Gonorrhea, Group B Streptococcus, Leptospira Listeria, Tuberculosis

Protozoal

Malaria, Toxoplasmosis

Fungal

Candida, Aspergillus

504

Table 1: Comparison of Dengue and HELLP syndrome

PREGNANCY

Dengue

HELLP

Fever

Present

Absent

Bleeding

Can be present (mild to severe)

Absent, Present in DIC

Abdominal pain

Present/absent

Present/absent

Blood pressure

Low in dengue shock syndrome (with oliguria)

High (due to preeclampsia)

Ascites, pleural effusion

May be present due to plasma leakage

Absent

Leucocyte count

Decreased

No specific changes

Thrombocytopenia

Present

Present

Haematocrit

 In plasma leakage

Maybe normal / 

Haemolysis

Absent

Present

Liver enzymes

Mild to severe 

Mild to moderate 

for acute respiratory distress syndrome (ARDS), antibiotics for gram negative sepsis.

•

Primaquine for radical treatment- contraindicated during pregnancy. Weekly chemoprophylaxis with chloroquine till completion of pregnancy; followed by primaquine as per G6PD status.

•

In Africa, WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), as part of antenatal care.

Leptospirosis

This zoonotic disease is known for its abortive effect in animals. In humans, it may be asymptomatic or may cause jaundice, AKI, ARDS, bleeding abnormalities, aseptic meningitis, myocarditis and multiorgan dysfunction.

Leptospirosis in pregnancy can have vertical transmission and lead to fetal death, abortion, still birth and congenital leptospirosis. It is not known whether pregnant women are at a higher risk for complications from leptospirosis.

increased blood volume and vasodilation) can mimic hypotensive shock. Bleeding due to thrombocytopenia or coagulopathy or vasculopathy may complicate delivery or surgical procedures. The gravid uterus decreases the tolerance to fluid accumulation due to plasma leakage (pleural effusion and ascites) and also makes these difficult to detect on clinical examination. Dengue with multiorgan failure can mimic HELLP syndrome as seen in Table 1.

Diagnosis: NS1Ag and Dengue PCR (in 1st week), Dengue IgM later Treatment: •

Fluid therapy- goal should not be “normal BP and heart rate” as this may cause fluid overload in pregnancy. Urine output is a better indicator of adequate perfusion.

•

Platelet transfusion – if active bleeding, platelet count <20,000/cc, during/at delivery

•

Tocolytic agents /measures to postpone labour in the critical phase of dengue (no evidence, only case reports)

Treatment:

•

Mild: Amoxicillin (500 mg PO q8h) or Ampicillin (500 mg PO q8h)

Severe haemorrhage - transfusion of fresh whole blood/fresh packed red cells

•

Oxytocin to prevent PPH

Diagnosis: IgM based agglutination test

immune-assay,

microscopic

Moderate/severe leptospirosis: Penicillin (1.5 million units IV or IM q6h) or Ceftriaxone (2 g/d IV) or Cefotaxime (1 g IV q6h) x 10-14 days Chemoprophylaxis: Azithromycin (250 mg PO once or twice a week) (Doxycycline- avoided in pregnancy)

Dengue

Dengue may cause undifferentiated fever, dengue hemorrhagic fever or dengue shock syndrome. Vertical transmission of dengue may occur in the perinatal period. Hyperemesis in early pregnancy may resemble a warning sign and delay recognition of severe dengue.

The physiological low BP and tachycardia (due to

Hepatitis E Virus (HEV)

Hepatitis E is usually self-limiting with a case-fatality rate of <0.1%. India has reported a high incidence of HEV infection in pregnancy with a higher risk of acute liver failure (ALF) with a mortality upto 30−100%. However, in some countries (Egypt, USA and Europe), HEV infection in non pregnant and pregnant women does not differ.

Genotype 1 is associated with high mortality in pregnant woman but not HEV genotypes 3 or 4. Pregnant women in the second or third trimester seem to be at an increased risk of ALF, fetal loss and mortality. The reason why HEV mortality is high in pregnancy and why there is a geographical difference in outcomes is still not clear.

505

Table 2: TORCH Infections in Pregnancy Infection

Management

Toxoplasmosis: • Asymptomatic or flu like illness in mother

• IgM positive- acute infection (may take weeks to appear and persist for years)

• Fetal risk: chorioretinitis, hydrocephalus, microcephaly, intracranial calcification, hepatosplenomegaly, IUGR

• IgG positive- past infection; 4-fold rise suggests recent infection • Diagnosis of fetal infection: PCR of amniotic fluid

• Risk of vertical transmission increases with gestational age, (60% to 80% in 3rd trimester vs. 6% in 1st trimester)

• Spiramycin 3MU q8h throughout pregnancy to prevent fetal infection

• Consider MTP Diagnosis by

Rubella: • Self limiting illness with rash in mother

• 4 fold in rubella IgG Ab titre

• Fetal risk: highest in 1 trimester

• Positive rubella-specific IgM Ab

• Congenital rubella syndrome can cause:

• Treatment is supportive

• Sensorineural deafness (60–75%)

• Consider MTP in early pregnancy

• Cardiac defects(10–20%)- Pulmonary stenosis, Patent ductus arteriosus, Ventricular septal defect

• Live attenuated vaccine available; contraindicated during pregnancy

st

• Ophthalmic defects (10–25%)-Retinopathy, Cataracts, Microphthalmia • Neurological (10–25%)- Mental retardation, Microcephaly Cytomegalovirus: • Asymptomatic or flu like illness in the mother

• Serology: if sonographic findings suggestive of CMV infection

• Fetal risk:

• IgG positive: denotes past infection

• 10-15% symptomatic at birth: IUGR, microcephaly, hepatosplenomegaly, jaundice, chorioretinitis, thrombocytopenia, DIC

• High IgG avidity: recurrent infection • Low IgG avidity: recent primary infection

• 85–90% asymptomatic at birth, but may develop sensorineural deafness, delayed milestones, visual impairment

• Consider MTP in early pregnancy

• IgM positive: acute infection

Herpes Simplex Virus:

• Caesarean section to reduce risk of neonatal infection

• Genital vesicles/ asymptomatic in mother

• Antiviral therapy not recommended before 36 weeks

• Fetus may get infected transplacentally (congenital) or during delivery (neonatal)

• Suppressive antivirals after 36 weeks till delivery

• Congenital infection causes microcephaly, hepatosplenomegaly, IUGR and IUFD

• Valcyclovir: 500 mg q12h

• Acyclovir: 400 mg q8h or 200 mg q6h

• Neonatal infection causes skin, eye, and mouth infection, encephalitis and disseminated disease (90% mortality) Vertical transmission of HEV can cause severe hepatic dysfunction and mortality in fetus/neonates.

•

Diagnosis: Anti-HEV IgM antibodies

Expediting delivery may theoretically prevent ALF (no evidence).

Treatment: •

Treatment of metabolic complications (hypoglycemia, hyponatremia, hypokalemia), cerebral edema (Mannitol, 3% NaCl) and supportive care

Liver transplantation- the only validated treatment for ALF due to HEV

H1N1 (Swine Flu)

Pregnant women have a 4- to 5-times higher rate of serious H1N1 illness. Mortality appears to be higher in the third trimester with fetal morbidity. Risk increases with coexisting organ disease, steroid therapy, diabetes

CHAPTER 107

• If fetal infection present: daily pyrimethamine 1mg/ kg (contraindicated in 1st trimester) and sulfadiazine (100mg/kg) with folinic acid

506

Table 3: Management of UTI in Pregnancy Asymptomatic bacteriuria

PREGNANCY

Acute cystitis

Acute pyelonephritis

Positive urine culture (≥10 5 cfu/mL of a single uropathogen in a single midstream clean catch urine sample) without symptoms of UTI.

oral antibiotics – 7 days

Urgency, frequency, dysuria, pyuria and haematuria without evidence of systemic illness.

oral antibiotics – 7 days

Flank pain, nausea/ vomiting, fever (>38ºC), and/or renal angle tenderness with or without cystitis symptoms.

Start empirical IV antibiotics.

Ampicillin Cephalexin Nitrofurantoin

Ampicillin Cephalexin Nitrofurantoin

Change as per culture & continue till patient is afebrile for 48 hours.

Ampicillin + gentamicin Or cephalosporin

Then, oral antibiotics to complete 10–14 days and HIV/AIDS. Pulmonary complications include ARDS and secondary bacterial pneumonia. Extrapulmonary complications are myositis, rhabdomyolysis, myopercarditis, encephalomyelitis and AKI Diagnosis: throat/ respiratory secretion swab for RT-PCR. Specimens should be placed on ice (4˚C) and transported immediately.

Treatment: Pregnant women with mild illness need oseltamivir 75 mg q12h for 5 days. Those with ARDS/ other complications may need 150 mg q12h. According to the CDC guidelines, chemoprophylaxis may be given for 7 days to women who are pregnant and upto 2 weeks postpartum who have had close contact with someone likely to have influenza.

URINARY TRACT INFECTIONS (UTI)

Asymptomatic bacteriuria is usually benign in non pregnant women but may progress (upto 30%) to pyelonephritis in pregnancy. Bacteriuria is associated with preterm birth, LBW, and perinatal mortality. Pyelonephritis may lead to AKI, bacteraemia, ARDS, anaemia, hypertension, preterm labour and LBW. Escherichia coli is the most common cause of UTI in pregnancy.

Pathophysiology of increased risk of UTI in pregnancy is explained by

Pathophysiology of increased risk of UTI in pregnancy is explained by: Smooth muscle relaxation (progesterone) Mechanical compression (gravid uterus)

TORCH Infections

Toxoplasmosis, rubella, cytomegalovirus and herpes, though mild in the mother, may cause very severe fetal infection. Routine TORCH screening in all pregnant women is expensive and not recommended. The SOGC guidelines for TORCH infections are summarized in Table 2.

Zika Virus (ZV): Current global alert •

Neurotropic virus spread by Aedes mosquito

•

Usually mild flu like illness in pregnancy

•

Spatiotemporal association of cases of microcephaly with the ZV outbreak

•

ZV has been isolated from the brains and CSF of neonates born with congenital microcephaly and identified in the placental tissue of infected mothers

•

•

Other associations in neonates: craniofacial disproportion, spasticity, seizures, ocular abnormalities and ventriculomegaly No vaccines currently available

Decreased sensation of bladder distension (trauma of labor, epidural or spinal analgesia)

Decreased ureteric peristalsis Increased bladder Hydroureteronephrosis

Increased stasis of urine

Pregnancy-induced glycosuria & aminoaciduria

Facilitate bacterial growth

UTI

Most guidelines recommend a single urine culture at the first prenatal visit. In non-pregnant symptomatic patients Most guidelines recommend a single urine culture at the first prenatal visit. In non-pregnant with an identified uropathogen, a colony count of ≥ 102– symptomatic patients withindicate an identifiedinfection. uropathogen, aThis colonycut-off count of ≥though 102–103 cfu/mL 103 cfu/mL may not evaluated in pregnancy, seems reasonable. Repeating may indicate infection. This cut-off though not evaluated in pregnancy, seems reasonable. urine cultures monthly until completion of pregnancy may Repeating monthlypersistent until completion pregnancy may be used to diagnose be usedurine tocultures diagnose orofrecurrent bacteriuria.

Management UTI inManagement pregnancy isinoutlined Table 3. 3. persistent or recurrentof bacteriuria. of UTI pregnancy isin outlined in table

PUERPERAL SEPSIS (PS)

• Puerperal fever: PUERPERAL SEPSIS (PS) o

•

Rise of temperature above 38°C maintained over 24 h from the end of the first to the Puerperal fever: Rise of temperature above 38°C maintained over 24 h from the end of end of the tenth day after delivery. the first to the end of the tenth day after delivery.

The most common cause of puerperal fever is genital

o The most common cause of puerperal is genital tract infection. causes include tract infection.

Otherfever causes include UTI,Other mastitis,

wound infection and septic thrombophlebitis.

UTI, mastitis, wound infection and septic thrombophlebitis.

o PS is the third leading cause of death in pregnant women accounting for 15% of maternal mortality. o Risk factors: caesarean section, unhygienic delivery practices, poor socioeconomic

•

PS is the third leading cause of death in pregnant women accounting for 15% of maternal mortality.

•

Risk factors: caesarean section, unhygienic delivery practices, poor socioeconomic status, malnutrition, anemia, primiparity, prolonged labour, prolonged rupture of membranes, repeated vaginal examinations, obstetrical maneuovers, retained products of conception and postpartum hemorrhage.

pregnancy; and may cause intrauterine infection, abortion, chorioamnionitis, preterm delivery, and neonatal sepsis •

Empirical antibiotics for ABM: Ampicillin 12g/d, q4h + ceftriaxone 4g/d, q12h + vancomycin 4560 mg/kg/d, q12h. Drug of choice for listeriosis is ampicillin 12g/d for 3 weeks.

•

Adjunctive dexamethasone should be given

AMOEBIC LIVER ABSCESS

Maternal complications: peritonitis, pelvic abscess, septic shock, endotoxic shock

•

•

May be endogenous (from patient’s genital tract), exogenous (external contamination) or nosocomial

Rare complication in pregnancy in developing countries

•

•

Microbiology:

Gravid uterus makes abdominal examination difficult and diagnosis may be delayed

-

Aerobes: Streptococcus group A, B and D, Staphylococcus, Enterococcus, E.coli, Klelbsiella, Pseudomonas

•

Presents with fever, right lower chest and abdominal pain

•

Diagnosis: Abdominal ultrasound

•

Treatment: Metronidazole 750 mg PO/IV – 5-10 days; Chloroquine may be given

Anaerobes: Anaerobic Streptococcus, Bacteroides, Clostridia

•

Treatment: Antibiotics as per culture and sensitivity. Empirical antibiotics include Ampicillin + Gentamicin + Clindamycin

INFECTIVE ENDOCARDITIS (IE)

•

Infective endocarditis in pregnancy has a low incidence (0.006%).

•

The altered cardiovascular physiology of pregnancy and diminished febrile response can delay diagnosis. Any pregnant patient with unexplained fever and a cardiac murmur or pre existing heart disease should be carefully assessed for IE.

•

Risk factors: Pre-existing cardiac lesion (rheumatic heart disease or congenital heart disease), IV drug abuse

•

Complications: Heart failure and embolic events; maternal and fetal mortality is upto 33% and 29% respectively

•

Treatment: Antibiotics as per culture and sensitivity. These include crystalline penicillin, ceftriaxone, gentamicin, vancomycin, ampicillinsulbactum. Surgical treatment is delayed till infection has been eliminated with antibiotics.

Cardiac surgery is not recommended during the first two trimesters. Elective delivery by caesarean section may be performed before cardiopulmonary bypass to minimize maternal and foetal risks.

ACUTE BACTERIAL MENINGITIS (ABM)

•

Pregnancy does not predisposition for ABM

have

an

increased

•

Etiology: Streptococcus pneumonia, Neisseria meningitides, group B streptococci, Listeria monocytogenes, Haemophilus influenza type b

•

Listeriosis has increased incidence and severity in

REFERENCES

1.

Sappenfield E, Jamieson DJ, Kourtis AP. Pregnancy and Susceptibility to Infectious Diseases. Infect Dis Obstet Gynecol 2013; 2013:752852.

2.

World Health Organisation. Guidelines for the treatment of malaria, 3rd edition [Internet]. Geneva: World Health Organisation; 2015 Apr. [cited 2016 Aug 30] Available from: http://www.who.int/malaria/publications/ atoz/9789241549127/en/

3.

World Health Organisation. Leptospirosis factsheet [Internet]. [cited 2016 Aug 29] Available from: http://www. searo.who.int/about/administration_structure/cds/CDS_ leptospirosis-Fact_Sheet.pdf

4.

Puliyath G, Singh S. Leptospirosis in Pregnancy. Eur J Clin Microbiol Infect Dis 2012; 31: 2491-6.

5.

World Health Organisation. Handbook for clinical management of dengue [Internet]. 2012. [cited 2016 Aug 28] Available from: http://www.wpro.who.int/mvp/ documents/handbook_for_clinical_management_of_ dengue.pdf

6.

Navaneethan U, Al Mohajer M, Shata MT. Hepatitis E and pregnancy: understanding the pathogenesis. Liver Int 2008; 28:1190–1199.

7.

Mirazo S, Ramos N, Mainardi V, Gerona S, Arbiza J. Transmission, diagnosis, and management of hepatitis E: an update. Hepat Med 2014; 6: 45–59.

8.

National Centre for Disease Control (IN). Pandemic Influenza (H1N1) 2009. [Internet] [cited 2016 Aug 28] 2009 Aug- Sept. Available from: http://www.ncdc.gov.in/ writereaddata/linkimages/Aug-Sep_092813460594.pdf

9.

Centre for Disease Control and Prevention (US).

Recommendations for Obstetric Health Care Providers Related to Use of Antiviral Medications in the Treatment and Prevention of Influenza [Internet]. [cited 2016 Aug 28] Available from: http://www.cdc.gov/flu/professionals/ antivirals/avrec_ob.htm Updated May 26, 2016.

10. Carlson A, Thung SF, Norwitz ER. H1N1 Influenza in

CHAPTER 107

•

-

507

508

Pregnancy: What All Obstetric Care Providers Ought to Know. Rev Obstet Gynecol 2009; 2:139–145.

11. Mateus T, Silva J, Maia RL, Teixeira P. Listeriosis during Pregnancy: A Public Health Concern. ISRN Obstet Gynecol 2013; 2013:851712.

PREGNANCY

12. Society of Obstetricians and Gynaecologists of Canada.

SOGC Clinical Practice Guidelines. [Internet]. [Cited 2016 Aug 29] Available from: http://sogc.org/clinical-practiceguidelines.html 13. Costello A, Dua T, Duran P, Gülmezoglu M, Oladapo OT, Perea W et al. Defining the syndrome associated with congenital Zika virus infection. Bulletin of the World Health Organization 2016; 94:406-406A.

14. Habib G, Lancellotti P, Antunes M J, Bongiorni MG, Casalta JP, Zotti FD et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC)Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36:3075–3128.

15. Parry AJ, Westaby S. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 1996; 61:1865-9.

16. Schnarr J, Smaill F. Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy. Eur J Clin Investig 2008; 38:50–57.

Jaundice in Pregnancy

C H A P T E R

108 Abnormal liver function tests occur in 3%-5% of pregnancies. Pregnancy encompasses a wide variety of physiological changes with increased, decreased or unchanged parameters. Liver function abnormality can represent a physiological change, but elevations of transaminase, bilirubin, and prothrombin time almost always indicate a pathologic state. The major physiologic changes in pregnancy, that peak in second trimester and plateau at delivery, relating to liver functions are summarised in Table 1. Histology of the liver remains essentially normal during pregnancy. Lack of understanding of these changes can be misinterpreted as pathologic and can alter the criteria for diagnosis and therapy. The presenting clinical features of liver disease in pregnancy are often nonspecific and consist of jaundice, nausea, vomiting and abdominal pain. All liver diseases occurring during pregnancy can lead to increased maternal and foetal morbidity and mortality.

Causes of Liver Disease and Jaundice in Pregnancy

The jaundice can be classified in pregnancy on the basis of jaundice in existing liver disease, co-incidental liver disease and specific to pregnancy (Table 2).

Table 1: Physiological changes in pregnancy pertaining to liver Increases • Alkaline phosphatase levels rise three- to fourfold because of placental production • Clotting factors I, II, V, VII, VIII, X, and XII • Ceruloplasmin level • Transferrin level Decreases • Gallbladder contractility • Albumin and total protein levels • Antithrombin III and protein S level

Saurabh Srivastava, Payal Jain

JAUNDICE IN PRE-EXISTING LIVER DISEASE AND PREGNANCY

Although it is difficult to conceive with the an existing chronic illness like liver disease, a prompt diagnosis and treatment of a liver disorder before conception, will help in preventing foetal loss and exacerbations leading to liver failure.

Cirrhosis and Portal Hypertension

The prevalence of cirrhosis in women of reproductive-age group is approximates 0.45 cases per 1000. As the disease is pre-existing the aetiology is same as in non pregnant state. The most common cause being viral hepatitis B and C, autoimmune, alcohol induced or idiopathic.

Cirrhosis can affect ovulation, due to hypothalamicpituitary dysfunction and cause infertility. However, if their liver function is well compensated, and treatment is

Table 2: Causes of Jaundice in Pregnancy Preexisting Liver Disease • Cirrhosis and portal hypertension • Autoimmune hepatitis • Primary biliary cirrhosis, primary sclerosing cholangitis • Wilson’s disease • Chronic viral hepatitis B and C • Chronic liver Disease Liver Disease Coincidental with Pregnancy • Budd-Chiari syndrome • Hepatitis

Viral hepatitis E

Herpes simplex virus hepatitis

Acute hepatitis A, B, and C

Cytomegalovirus hepatitis

No Changes

• Alcohol and pregnancy

• Liver transaminase levels (aspartate aminotransferase, alanine aminotransferase)

• Gallstone disease Liver Disease Unique to Pregnancy

• γ-Glutamyl transferase (GGT) level

• Acute fatty liver of pregnancy

• Bilirubin level

• Preeclampsia, Eclampsia

• Prothrombin time

• HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count) • Intrahepatic cholestasis of pregnancy • Hyperemesis gravidarum

510

maintained during pregnancy, women might still become pregnant and outcome can be good. However there is an increased risk of premature delivery. Oesophageal varices should be screened in second trimester and can be treated with banding or octreotide, beta-blockers can also be given. Diuretics and spironolactone, are not advisable during pregnancy or lactation. It is recommended to have caesarean section to avoid increased straining.

PREGNANCY

Autoimmune Hepatitis

Autoimmune hepatitis is common in women of all ages. The disease activity is usually attenuated during pregnancy due to immune tolerance induced by the pregnancy. There is an increased risk of prematurity, lowbirth-weight infants, and fetal loss. Immunosuppressive therapy in the form of prednisone and azathioprine can be given with reduced doses.

Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Primary biliary cirrhosis and primary sclerosing cholangitis are autoimmune diseases that can overlap with autoimmune hepatitis. Pregnancy carries a high risk of prematurity, stillbirths, and liver failure. Serum bilirubin increase depends on the type of disease and presence of antinuclear, smooth muscle, liver-kidney microsomal antibodies or antibodies to soluble liver antigen/liver pancreas antibodies. Diagnosis is not different from that in the non pregnant woman. Ursodeoxycholic acid (UDCA) can be continued safely.

Wilsonâ&#x20AC;&#x2122;s disease

Wilsonâ&#x20AC;&#x2122;s disease is an inherited autosomal recessive disorder of copper transport. The disease is associated with amenorrhea and infertility; however fertility can improve with therapy. Treatment initiated before conception, should not be interrupted during pregnancy because of the risk of haemolysis, fulminant liver failure and death due to sudden copper release. The treatment of choice is zinc sulfate because of its efficacy and safety for the foetus. D-penicillamine or trientine treatment requires a dose reduction by 25% to 50% of that in the pre-pregnancy state especially during the last trimester.

Chronic viral hepatitis B and C

The prevalence chronic hepatitis B and C is quite high in India. Usual presentation is elevation of liver transaminases and bilirubin levels and diagnosis is similar to a non-pregnant woman. Mothers who are hepatitis B e antigen (HBeAg) positive have higher rates of perinatal transmission than do mothers with negative HBeAg. Without treatment 90% of infants born to HBeAg positive mothers and 10% of infant born to HBeAg negative mothers develop hepatitis B virus infection. The infants should receive hepatits B immunoglobulin at birth and also hepatitis B vaccine during the first day of life and at ages 1 and 6 months. Women with chronic hepatitis B are not treated with interferon during pregnancy however therapy with the nucleoside analogue, lamivudine is probably safe and has been reported to reduce the incidence of neonatal vaccination failure.

The risk for vertical or perinatal transmission of HCV is about 5%-10% and is associated with the presence of HCV

RNA in maternal blood at the time of birth. HIV coinfection in pregnant women increases the risk of perinatal HCV transmission by 2-fold. Combination antiviral therapy is not recommended in pregnancy.

Chronic Liver Disease

Aetiology of chronic liver disease in pregnant state is same as in non-pregnant state as the disease is pre existent. The treatment depends on the aetiology of the disease and drugs that can be used in pregnancy. The pregnancy in chronic liver disease is associated with increased foetal loss.

JAUNDICE IN LIVER DISEASES COINCIDENTAL WITH PREGNANCY

Budd-Chiari Syndrome

It is an occlusive syndrome of the hepatic veins that leads to sinusoidal congestion and necrosis of hepatocytes around the central vein. Most cases occur during the postpartum period. Underlying predisposing condition, such as factor V Leiden, antithrombin III, protein C or S deficiency, or the presence of antiphospholipid antibodies are present in 25% cases if seen during pregnancy.

Complete anticoagulation throughout pregnancy and the puerperium is required.

Viral Hepatitis

Acute viral hepatitis is the most common cause of jaundice in pregnancy, with an incidence of approximately 1 to 2 per 1000. The outcome is usually benign, except in viral hepatitis E and herpes simplex virus (HSV) hepatitis.

Viral Hepatitis E

Acute viral hepatitis E is transmitted via the fecaloral route and is associated with high morbidity and a maternal mortality rate of 30%. Vertical transmission occurs in 50% of cases if the mother is viremic at the time of delivery. Treatment is supportive.

Herpes Simplex Hepatitis

HSV hepatitis is a rare condition but is associated with a 40% risk for fulminant liver failure and death. Treatment of choice is intravenous acyclovir. Transmission to the foetus is high (â&#x2030;¤50%) when maternal acquisition occurs near the time of delivery. Caesarean section is strongly advisable if lesions are present at delivery.

Acute Viral Hepatitis A (HAV)

HAV infection is usually self-limited but transmission to the newborn can occur when delivery takes place during the incubation period because of viral shedding and contamination during vaginal delivery. Treatment is supportive.

Viral Hepatitis B and C (HBV, HCV)

Acute HBV and HCV infections during pregnancy do not seem to affect the course of pregnancy but are associated with an increased risk of transmission to the newborn as discussed in previous section.

Cytomegalovirus Hepatitis

The overall prevalence in women of childbearing age is 50% to 80%. The risk of transmission to the foetus is high, occurring at a rate of 30% to 40% when the infection is

511

Table 3: Pregnancy specific causes of Jaundice Disease

Symptoms

Lab values

Jaundice

Trimester

Treatment

Outcome

Prevalence

ICP

Pruritus

ALT/AST <1000

1-4 week after pruritus

2nd

UDCA

Gall stones

<1%

and

Recurrence

Delivery

Foetal distress

Multi-foetal gestation

Delivery

Maternal mortality <20%

Bilirubin <6mg/dl,

20-60%

PT normal AFLP

ALT/AST >300,

Common

3rd

Bilirubin increased

Foetal mortality up to 45%

PT elevated DIC

Eclampsia

High blood Preeclampsia pressure Oedema Seizures Renal failure Pulmonary edema

Uric acid elevated

HELLP syndrome

Abdominal pain Seizures Renal failure Pulmonary edema Liver hematoma and rupture

Platelets <100,000/mm3 Hemolysis High LDH AST/ ALT 70-6000 IU/L DIC

Late 5-14%

Nausea

AST/ALT <1000 IU/L

Mild

HG

Vomiting Pruritus

Late 25%

ALT <500

2nd and 3rd

Beta blocker

Beyond 20 wks

Methyldopa

Magnesium Recurrence sulphate

Proteinuria

Delivery

DIC - 7%

Maternal mortality 1-15 %

Primiparous Multi-foetal <0.01%

5% Multiparous

Multifetal Prematurity gestations and fetal death 5%-30%

Beyond 22 wk and after delivery

Prompt delivery

20% progress from severe eclampsia

ALT >AST

acquired before 22 weeks of gestation. There is no effective and safe therapy during pregnancy.

Alcohol and Pregnancy

Mothers who consume alcohol during pregnancy can have premature babies, stillbirths, babies with neonatal alcohol withdrawal (characterized by jitteriness, irritability, and poor feeding in the first 12 hours of life), and infants with foetal alcohol syndrome.

Gallstone Disease

Pregnancy promotes lithogenesis due to biliary cholesterol saturation and inhibition of the hepatic synthesis of chenodeoxycholic acid. In addition, prepregnancy obesity, low activity level, low serum leptin levels, and a history of gallbladder disease are risk factors for gallbladder disease. Approximately 10% of pregnant women may have gallstones by the third trimester, compared with 5% at the beginning. Gallstones regress in the postpartum period.

Laparoscopic cholecystectomy for symptomatic cholelithiasis is particularly safe when performed during

Hepatic rupture, with 60% maternal mortality; fetal death, 1%-30%

First trimester

IV fluids Benign for Thiamine mother and Pyridoxine child resolves Promethazine after 20 wk

0.5% Multiparous

<2% Primiparous

the second trimester.

JAUNDICE IN LIVER DISEASES UNIQUE TO PREGNANCY (TABLE 3)

Acute Fatty Liver of Pregnancy (AFLP)

AFLP is a rare disorder of the third trimester, affecting less than 0.01% of pregnant women. It is most common in primiparous women older than 30 years, with multiple gestations and male foetus. Free fatty acids (FFAs) increase in pregnancy because of the effects of hormonesensitive lipase and gestational insulin. Defects in the genes encoding for the transport and oxidation pathways are inherited as autosomal recessive traits and are known as fatty acid oxidation disorders. The most common disorder in AFLP is a deficiency of long-chain 3-hydroxylacyl-CoA dehydrogenase (LCHAD). During the last trimester when the metabolic demands of the foetus increase, mothers heterozygous for a fatty acid oxidation disorder and having homozygous foetus can develop AFLP because of their inability to metabolize fatty acids for energy production and foetal growth. Fatty acids then deposit in the liver. The foetal complications include failure to

CHAPTER 108

Nausea, Vomiting, Fulminant hepatic failure

PREGNANCY

512

thrive, hepatic failure, cardiomyopathy, microvesicular steatosis, hypoglycemia, and death

been implicated in premature labour, chronic placental insufficiency, meconium staining and sudden death.

Liver biopsy may be necessary for diagnosis. AFLP is characterized by microvesicular fat deposition in centrilobular hepatocytes. Delivery of the foetus leads to rapid recovery without sequel of chronic liver disease.

UDCA is the treatment of choice for reducing pruritus.

Other medications, such as cholestyramine and S-adenosyl-L-methionine, can be used but studies have found UCDA to be superior.

Preeclampsia and Eclampsia

Hyperemesis Gravidarum (HG)

Preeclampsia and eclampsia affect 5% of pregnancies and are more common in primiparous women with multifetal gestations. Other risk factors include preeclampsia in a previous pregnancy, chronic hypertension, pregestational diabetes, nephropathy, obesity, and antiphospholipid syndrome. Symptoms include hypertension of 140/90 mm Hg or higher and proteinuria higher than 0.3 g in 24 hours. Eclampsia is defined by the additional occurrence of new-onset seizures. Liver test abnormalities are present in 25% of cases. Overlap with the HELLP syndrome occurs in 20% of cases. In a woman with a prior history of eclampsia, the recurrence rate is 20% to 30% for preeclampsia and 2% to 6% for eclampsia.

Liver histology is distinct from that of AFLP. It indicates fibrin deposition in sinusoids, periportal hemorrhage, and liver cell necrosis. Hypertensive crisis, abruptio placentae, and liver failure can occur. Maternal mortality is noted in 1% to 15% of cases. Fetal mortality rates range from 5% to 30%. Labetolol and methyldopa are the drugs of choice for hypertension. Magnesium sulfate is the drug of choice for preventing and treating seizures.

HELLP (haemolytic anaemia, elevated liver enzyme and low platelet) Syndrome

The HELLP syndrome complicates 0.5% of pregnancies and the recurrence rate is as high as 20%. It is characterized by microangiopathic hemolysis with burr cells and schistocytes; elevated liver enzyme levels; and a platelet count lower than 100,000/mm.

It is more common in multiparous women and can manifest in 30% after delivery. Abdominal pain, disseminated intravascular coagulation, renal failure, subcapsular liver hematoma, and hepatic rupture are described. Maternal mortality is about 1% but reaches 60% in cases of hepatic rupture. Pathophysiology involves alterations in platelet activation, increases in proinflammatory cytokines, and segmental vasospasm with vascular endothelial damage.

An association with a defect in LCHAD has also been described, suggesting a possible overlap of HELLP syndrome and acute fatty liver of pregnancy. Immediate delivery is the definitive treatment for HELLP syndrome.

HG occurs in less than 2% of pregnancies, starting in the first trimester and resolving by week 20 of gestation. It is characterized by severe nausea and vomiting, and electrolyte disturbances. Weight loss exceeds 5% of pre-pregnancy body weight. HG is more common in primiparous women and may be associated with mild elevation of transaminase levels. The predisposing factors include female gender of the foetus. Vomiting may cause esophageal rupture, vascular depletion, and renal damage.

Prematurity and low birth weight is rare. Treatment is primarily supportive. Patients should avoid triggers and eat small, frequent, low fat meals. Intravenous fluids, thiamine and folate supplementation, and antiemetic therapy may be administered. Promethazine is a first-line agent, but other medications such as metoclopramide, ondansetron, and steroids have also been used.

CONCLUSION

Jaundice in pregnancy can manifest as a benign disease with abnormal elevation of liver enzyme levels and a good outcome, or it can manifest as a serious entity affecting hepatobiliary function and resulting in liver failure and death of the mother and foetus. The overall mortality attributed to liver disorders in pregnancy has dramatically decreased in the past few years because of clinicians’ understanding of the physiologic changes that occur during pregnancy, their ability to identify and treat preconception liver disorders, and their vigilance in recognizing clinical and laboratory abnormalities in a timely manner.

REFERENCES

1.

2.

3.

4.

5.

Intrahepatic Cholestasis of Pregnancy (ICP)

ICP affects less than 1% of all pregnancies in the second half of pregnancy. It is more common in multiparous women with twin gestations, advanced maternal age, and history of cholestasis with oral contraceptive use. It resolves after delivery and usually recurs in subsequent pregnancies. Mutations in the phospholipid translocator known as the ATP cassette transporter B4 (ABCB4) or multidrug resistant protein-3 (MDR3) are associated with the development of ICP. High levels of bile acids have

6.

7.

8.

Hepburn IS, Schade RR. Pregnancy -associated liver disorders. Dig Dis Sci 2008; 53:2334-2358.

Hay JE. Liver disease in pregnancy. Hepatology 2008; 47:1067-1076.

Mitra AK, Patki PS, Mitra SK. Liver disorders during pregnancy and their management. The Antiseptic 2008; 105:193-6.

Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J Gastroenterol 2006; 12:7397-404.

Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancycurrent achievements and unsolved problems.

World J Gastroenterol 2008; 14:5781-578.

P Kar, Shilpa Arora. Jaundice in pregnancy. In: Upadhyay R, Ed. Medicine update. India: 2015: 835-39.

Lata I. Hepatobiliary diseases during pregnancy and their management: An update. Int J Crit Illn Inj Sci 2013; 3 (3):17582.

Goel A, Jamwal KD, Ramachandran A, et al. Pregnancyrelated liver disorders. J Clin Exp Hepatol 2014; 4:151-62.

C H A P T E R

109 INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting young individuals of child bearing age.

Pregnancy is associated with an increased risk of lupus flares in 60% of the cases.1 Pregnancy in SLE is categorized as high risk due to increased risk of spontaneous abortions, preeclampsia, intrauterine growth restriction (IUGR), intrauterine fetal death and preterm birth.1 With the improvement in SLE survival rates due to medical advances, pregnancy outcomes have improved.2 Management of pregnancy in lupus poses a challenge, both for patients and physicians.

PATHOGENESIS OF PREGNANCY COMPLICATIONS

Underlying chronic inflammation with associated autoantibodies and hormonal disturbances can affect pregnancy outcomes in SLE.3 The increased incidence of miscarriages, IUGR, preterm birth and preeclampsia is the result of placental insufficiency with poor vascularisation and endothelial dysfunction. There will be an imbalance in production of angiogenic and antiangiogenic factors in maternal circulation tilting the balance towards antiangiogenic state. Excess use of glucocorticoids may increase vascular resistance in placental circulation by potentiating vasoconstriction.3 The increased rate of preterm birth in lupus can be due to stress, activating maternal or fetal hypothalamic pituitary axis. Stress will trigger labour by increased production of cortical and prostaglandins. The disease flare can induce preterm labour by increased production of cytokines, production and complement activation. Though oral prednisolone can reduce underlying inflammation, it is

Table 1: Contraindications to pregnancy 1. Severe pulmonary hypertension 2. Advanced cardiac failure 3. Severe restrictive lung disease 4. Moderate or severe chronic kidney disease (creatinine > 2.8 mg/dL) 5. Active lupus nephritis (proteinuria > 0.5g/day) 6. CNS disease in the past 6 months 7. Recent major thrombosis (< 2 years) 8. Current use of drugs like cyclophosphamide, mycophenolate mofetil, methotrexate, leflunomide, statins and angiotensin converting enzyme inhibitors

SLE and Pregnancy Sirisha K, Narasimulu G

associated independently with preterm birth.3

SLE DISEASE ACTIVITY IN PREGNANCY

Pregnancy probably increases the disease activity by 2-3 folds.4 Mild to moderate flares are common. Severe flares are observed in 15-30 % of the cases. Cutaneous disease, arthritis and hematologic are the common forms of disease flare.4 Lupus flares are observed throughout pregnancy and in post partum period. Lower rates of flares are observed in 3rd trimester due to lower estrogen levels and blunting of IL-6 levels.5 The main risk factor for increased disease activity is presence of active disease 6 months prior to conception. Others include multiple flares in years before conception and discontinuation of hydroxychloroquine.4 Lupus patients have higher rate of comorbidities and complications than healthy women like hypertension, pre-gestational diabetes, renal impairment, pulmonary hypertension, major infections, thrombotic events, anaemia, antepartum haemorrhage, postpartum haemorrhage and thrombocytopenia.6 There is 20 fold increased in the risk of maternal mortality.6 Patients with evidence of irreversible organ damage prior to pregnancy are more likely to prone for medical and obstetric complication including worsening of previous organ damage. Patients with active lupus nephritis are associated with maternal hypertension, preeclampsia and preterm births. Hence it is advisable to plan pregnancy 6 months following renal remission and if possible to 12-18 months. Interstitial pulmonary disease may get worsened during pregnancy due thoracic compression by the growing uterus. Women with cardiac disease are at risk of cardiac failure due to volume overload.1 The following table 1 summarises contraindications to pregnancy in SLE.1

IMPACT OF LUPUS ON PREGNANCY OUTCOMES

Women with SLE are at increased risk of miscarriages.

The risk factors identified for miscarriages include hypertension, proteinuria > 500mg/day, thrombocytopenia and secondary antiphospholipid antibody syndrome (APS). Lupus patients have increased risk of preeclampsia by 3 to 4 fold. It is very difficult to differentiate preeclampsia from a flare of lupus due to common overlapping features like hypertension, raising proteinuria, oedema, renal function impairment and thrombocytopenia. Some of the features to differentiate preeclampsia from lupus flare are summarised in Table

PREGNANCY

514

Table 2: Distinguishing lupus disease activity from Preeclampsia Pre-eclampsia

Lupus flare

Hypertension

Usually present

May be present

24 hour urine protein

Does not differentiate

Does not differentiate

Onset of proteinuria

Abrupt, after 20 weeks

Abrupt or gradual, anytime

Casts in urine

Absent

Present in lupus nephritis

RBCs in urine

Absent

Present in lupus nephritis

Symptoms of active SLE, eg: Skin and joint involvement

Absent

Present

Seizures

Present in eclampsia

Present if there is neurological involvement

Uric acid

Elevated

Not elevated unless CKD

Urine calcium

low

Normal

Serum albumin

Low

Very low if nephritic syndrome

Liver function tests

May be affected (in HELLP syndrome)

Rarely affected in a flare of SLE

Complements (C3 and C4)

Unchanged from baseline in early pregnancy

Low (or lower from the baseline; complement levels increase in pregnancy)

Anti-dsDNA

Unchanged

Elevated

Abbreviations: CKD-chronic kidney disease, HELLP- hemolysis, elevated liver enzymes, and low platelets, SLE-systemic lupus erythematosus, RBC-red blood cell

Table 3: Factors associated with adverse maternal and fetal outcomes Clinical factors

1. Active disease within 6 months prior to conception and during pregnancy 2. Active lupus nephritis or chronic kidney disease (creatinine > 2.8 mg/dL) 3. Maternal hypertension 4. Previous fetal loss

Serological factors

1. Antiphospholipid antibodies 2. Anti-dsDNA antibodies

Biochemical factors

1. Low complements 2. Proteinuria 3. Thrombocytopenia

2.6,7

Neonatal lupus syndromes (NNLS)

It refers to spectrum of clinical manifestations like cutaneous, cardiac, liver and systemic abnormalities observed in newborn infants born to mothers with Ro/ SS-A and La/SS-B antibodies. Cutaneous neonatal lupus is the most common form of NNLS followed by cardiac and liver forms. Rarely hematologic, neurologic and splenic abnormalities are also noted. However these syndromes are usually benign and self limited within 6 months, once the maternal antibodies get cleared from babyâ&#x20AC;&#x2122;s circulation.1,6,7 Congenital heart block (CHB) is the most severe form of NNLS occurring in 2% of babies born to lupus mothers with positive anti-Ro/SS-A and anti-La/

SS-B antibodies. The risk gets increased to 15-20% if the mother has already a child with CHB.8 It is the end result of fibrosis of fetal atriovententricular node and myocardium due to transfer of anti-Ro/SS-A and anti-La/SS-B antibodies triggering immune mediated inflammation. Less frequent cardiac manifestations include cardiomyopathy and endomyocardial fibroelastosis.6 Several risk factors associated with adverse maternal and fetal outcomes were identified in multiple studies with varied population and are shown in Table 3.

ANTIPHOSPHOLIPID ANTIBODIES IN PREGNANCY

Antiphospholipid antibodies are identified in 20-55% of SLE cases. One quarter of the patients fulfil criteria for APS. The presence of antiphospholipid antibodies and APS is associated with increased risk of pregnancy losses and preeclampsia. Anticoagulation and antiplatelets forms the main stay of treatment.9 Other newer options include intravenous immunoglobulins (IVIG), plasmapheresis and B cell depletion therapy.10

MEDICATIONS DURING PREGNANCY AND BREAST FEEDING

As a part of pre-pregnancy counselling, each lupus patient needs to be discussed about the use of appropriate drugs during pregnancy and breast feeding. Retrospective case series and isolated case reports form the basis for the use of medications during pregnancy and lactation.

Table 4 summarizes the list of drugs commonly used in rheumatology practice and their impact on pregnancy and breast feeding.1,7,2

515

Table 4: Drugs commonly used in lupus patients and their effect on pregnancy and breast feeding Drug

Recommendation for pregnancy planning

Effect on fetus

FDA classification

Recommendations for use in pregnancy

Breast feeding

NSAIDS

Avoided

Premature closure of ductus arteriosus, renal impairment, oligohydromnios

B in 1st and 2nd trimester

Avoid in 3rd trimester

Allowed

D in third trimester

Try to minimise the dose

Cleft lip, low birth weight, premature birth

B

Use lowest doses possible

Allowed (if > 40 mg wait for 3 hours)

Hydoxychloroquine

Continue to prevent lupus flares

None

C

Continue to prevent lupus flares

Allowed

Azathioprine

Need not be stopped

None

D

Used for lupus flares as an immunosuppressant and steroid sparing Allowed agent

Methotrexate

Stop 3-6 months prior to conception

Aminopterin syndrome

X

No use in pregnancy Not allowed

Leflunomide

Stop 2 years prior to conception

Malformations of X head, vertebral column and limb defects

No use in pregnancy Not allowed

Cyclophosphamide

Stop > 6 months

CY Clophosphamide embyopathy

D

Use only if no other Not allowed options in case of life threatening maternal disease after 1st trimester

Mycophenolate mofetil

Stop 3 months prior to conception

Congenital anomalies especially ear

D

Use only if no other options

Not allowed

Rituximab

-

None

C

Attempt to discontinue 2 months prior to delivery if possible to prevent neonatal B cell depression

Allowed

IV IG

-

None

C

Used as needed

Allowed

Cyclosporine and tacrolimus

-

None

C

Can be continued

Probably safe

Aspirin

-

None

B/C

Used in obstetric APS

Allowed

Warfarin

Stop at conception Warfarin embyopathy

X

Avoided especially in 1st trimester

Allowed

Heparin

-

C

LMWH is preferred due to ease of administration, high antithrombotic to anticoagulant ratio and predictable bioavailability

allowed

None

FDA-Food AND Drug Administration, LMWH- low molecular weight heparin, IV IG-intravenous immunoglobulins

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Prednisone and Prednisolone

516

Table 5: Baseline evaluation and monitoring of lupus patients at pregnancy Pre-pregnancy

Every 6-8 weeks

1. Complete blood count 1. Complete blood count

PREGNANCY

2. Prothrombin time and 2. Urine analysismicroscopy, spot Partial thromboplastin protein/creatinine time ratio 3. Urine analysis-

3. Anti-dsDNA microscopy, 24 hour urine protein and 4. Complements- C3, C4 creatinine clearance, spot protein/creatinine 5. Uric acid, AST, ALT, creatinine, blood ratio glucose 4. Lupus anticoagulant, anticardiolipin antibodies IgG and IgM, anti-β2 glycoprotein 1 IgG and IgM 5. Anti-Ro/SS-A, anti-La/ SS-B, anti-dsDNA 6. Complements-C3,C4 7. Uric acid, AST,ALT, creatinine, blood glucose

CONTRACEPTION IN SLE

Every lupus patient need to be counselled on contraceptive practices as planned pregnancy is associated with good maternal and obstetric outcomes. The main contraceptive methods available to lupus patients include barrier methods, progesterone only pills and intrauterine devices (IUD). Barrier methods are highly unreliable. Though estrogen containing contraceptives are commonly used by general female populations, with the main concern about increased flares and thrombotic tendency, they are better avoided in cases of unstable lupus and those with APS. IUD either copper containing or progesterone IUD are safe and effective.7,11

MANAGEMENT

Management of SLE in a pregnancy requires multidisciplinary effort by rheumatologists, obstetricians and nephrologists when necessary. Obstetrician visits are scheduled every monthly till 20 weeks, then fortnightly till 28 weeks and thereafter every weekly. Rheumatologist visits are scheduled every 4-6 weeks and the frequency of visits can be increased in case of active disease.2 Baseline evaluation is performed by history, physical examination and laboratory evaluation. The lists of investigations advised at baseline are summarized in table 5. Ultrasound and Colour Doppler aid in evaluation of fetal growth and amniotic fluid are carried out every monthly after 24 weeks. Fetal surveillance tests including the nonstress test (NST), the biophysical profile (BPP), and fetal umbilical artery Doppler velocimetry help in monitoring of IUGR. The testing begins usually at 26 weeks and there after every weekly until birth. Uterine artery evaluation is planned at

24 weeks and helps as a screening tool for preeclampsia.7 Screening for CHB should start from 16 weeks and carried out every weekly. Fetal M mode echocardiography as a screening test helps in early diagnosis of CHB.12 SLE should be well controlled with low risk medications at lowest possible doses. Hydoxychloroquine should be continued throughout pregnancy as it decreases the number of flares, hypertensive disorders, preterm delivery rates and IUGR.13 Hydoxychloroquine may also be helpful in prevention of CHB. Currently there is no definite treatment for established CHB. Fluorinated steroids (betamethasone and dexamethasone) may improve fetal survival in cases with myocarditis, hydrops or incomplete heart block. IVIG was studied in two open label interventional studies and it did not prevent or reduce the recurrence rate of CHB.14 Lupus flare during pregnancy can be managed by nonfluorinated corticosteroids like prednisone and prednisolone. The dose of steroids is guided by the severity and organ involvement. Usually lowest possible doses are recommended. Fluorinated glucocorticoids are recommended for fetal treatment (fetal lung maturation, prevention of CHB etc). There is no role for prophylactic steroids for prevention of disease flare.1 For management of arthritis or serositis, NSAIDS can be used in lower doses for shorter time. NSAIDS are discontinued in 3rd trimester. Azathioprine and calcineurine inhibitors can be used when required as an immunosupressants and steroid sparing agents. IVIG and plasmapheresis are alternative options for uncontrolled flare.2

LUPUS NEPHRITIS

Management of lupus nephritis requires coordination of rheumatologist and nephrologist. Prednisolone forms the backbone of management. Hydoxychloroquine needs to be continued. Azathioprine is the preferred immunosuppressant. Cyclophosphamide can be used especially after 1st trimester in refractory cases. Emergency hemodialysis should be considered in case of rapidly deteriorating renal function.12

SUMMARY

Planning of pregnancy is optimal for key success in lupus with pregnancy. Lupus with pregnancy is a high risk condition with flares of the disease and poor pregnancy outcomes. It is challenging for rheumatologist and obstetrician to differentiate flare from preeclampsia. The SLE disease should be quiescent for at least 6 months for prevention of flares during pregnancy. With better maternal and fetal surveillance morbidity and mortality associated with lupus pregnancy has reduced.

REFERENCES

1.

De Jesus GR, Mendoza-Pinto C, de Jesus NR et al.

Understanding and Managing Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015:943490.

2.

Lateef A, Petri M. Managing lupus patients during pregnancy. Best Pract Res Clin Rheumatol 2013; 27:435-47.

3.

Ostensen M, Clowse M. Pathogenesis of pregnancy

10. Lockshin MD. Pregnancy and antiphospholipid syndrome.

Am J Reprod Immunol 2013; 69:585-7.

4.

Clowse ME. Lupus activity in pregnancy. Rheum Dis Clin North Am 2007; 33:237-52.

11. Ă&#x2DC;stensen M. Contraception and pregnancy counselling in rheumatoid arthritis. Curr Opin Rheumatol 2014; 26:302-7.

5.

Doria A, Tincani A, Lockshin M. Challenges of lupus pregnancies. Rheumatology (Oxford) 2008; 47 Suppl 3:iii9-12.

12. Witter FR. Management of the high-risk lupus pregnant patient. Rheum Dis Clin North Am 2007; 33:253-6.

6.

Ateka-Barrutia O, Khamashta MA. The challenge of pregnancy for patients with SLE. Lupus 2013; 22:1295-308.

7.

Sammaritano LR. Management of Systemic Lupus Erythematosus during Pregnancy. Annu Rev Med 2016.

8.

Soh MC, Nelson-Piercy C. High-risk pregnancy and the rheumatologist. Rheumatology (Oxford) 2015; 54:2293.

13. Leroux M, Desveaux C, Parcevaux M et al. Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus 2015; 24:1384-91.

9.

Stanhope TJ, White WM, Moder KG et al. Obstetric nephrology: lupus and lupus nephritis in pregnancy. Clin J Am Soc Nephrol 2012; 7:2089-99

14. Peart E, Clowse ME. Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Opin Rheumatol 2014; 26:118-23.

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complications in systemic lupus erythematosus. Curr Opin Rheumatol 2013; 25:591-6.

C H A P T E R

110

Rational Use of DMARDS During Pregnancy and Lactation

ABSTRACT

Pregnancy in patients with connective tissue diseses specially SLE and RA is a challenge to the physician.

RA usually improves during pregnancy, to flare up immediate post partum where as SLE usually flares up during pregnancy.The general principles to be followed are: pregnancy to be planned when the disease is quiescent for six to twelve months; minimum amount of medication should be applied to balance the risk and benefit ratio; potentially teratogenic drugs like methotrexate and leflunomide to be stopped three to six months prior to conception. Leflunomide if taken within two years is to be washed by cholestyramine. Sulfasalazine, hydroxychloroquine and azathioprine are safe during pregnancy. Corticosteroid can be used in low doses~ 10 mg /day. NSAIDs to be avoided in third trimester. Biologics have no proven teratogenic potentials but there is paucity of safety data. As such it is recommended that Abatacept, Rituximab and Tocilizumab to be withheld prior to pregnancy; however TNF inhibitors may be continued until conception. During lactation NSAIDs if required should be short acting Ibuprofen just after feeding. Low dose corticosteroids, sulfasalazine, hydroxychloroquine, and azathioprine are safe in lactation. Anti TNF agents can also be given during lactation.

KEY WORDS

Biologics, DMARDs, lactation, pregnancy, rheumatoid arthritis, SLE

RN Sarkar, Chandan Kumar Das

exacerbate during pregnancy. Whereas,Th1 mediated autoimmune diseases like RA, psoriasis, and multiple sclerosis improve during pregnancy.2,3 Most studies suggest that, chance of SLE flare during pregnancy and post partum is minimal if the patient has controlled or inactive disease at the time of conception.

Women with SLE in remission have approximately 80% chance of having a live birth. However, patients should be counselled about the adverse fetal outcome; like preterm birth and pregnancy loss. As such, women with SLE and RA, do not have decreased fertility. In the meta-analysis of SLE Pregnancies, there is a higher rate of miscarriage, stillbirth (pregnancy loss before 20 weeks) and neonatal death.4 Main causes of these are increased SLE activity at the time of conception, hypertension, prior or ongoing lupus nephritis and anti-phospholipid syndrome. All these increase the risk of pregnancy loss by 2 to 4 times than general population.5 Main issue is the continuation or discontinuation of DMARDs. The principles should be, 1.

Avoid potentially teratogenic drugs, like leflunomide, in women with child bearing age and to discontinue methotrexate, 3 months prior to planned pregnancy.

2.

Plan the pregnancy when the disease is quiescent for 6-12 months.

3.

Minimum amount of medication should be applied to balance harmful effects of the drug on pregnancy and risk of under treatment.

4.

Co-morbid conditions like hypertension, hyperglycemia should be controlled before conception.

INTRODUCTION

Majority of women with autoimmune diseases desiring pregnancy usually have safe and relatively uncomplicated pregnancy. Major complications of DMARDs therapy during pregnancy are pregnancy loss, congenital anomalies and intra uterine growth restriction. Risk of preterm birth before 37 weeks is around 33% in case of systemic lupus erythematosus (SLE) compared to 5 to 10 % in the general population. Regarding RA, about 75 % of patients experience reduction of disease activity by the end of first trimester and about 20 – 30 % of pregnant rheumatoid arthritis (RA) patients will need medications to control disease activity.

There are major modulation of the innate and humoral immune system of the mother during pregnancy possibly induced by increasing level of progesteron.1 In pregnancy, there is a shift of helper T cells towards Th2 dominant state possibly by increasing levels of progesterone. SLE being a Th2 predominant state, usually

CHOICE OF THERAPY

Use of medications must always balance the risk and benefit to both mother and fetus. Serious systemic rheumatological diseases which needs to be considered in this chapter, consists of mainly those in the child bearing age, like SLE, RA, Psoriatic arthritis, Polymyositis /Dermatomyositis, and vasculitides. US Food and Drug Administration (US FDA) rates each medications on the basis of its potential risk to the fetus. (Table 1)6

NON STEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS)

They are FDA category C drugs with possible risk in the first and second trimester, but’ D’ in the third trimester.

Taking these drugs in first trimester has 1.8 fold increased

Table 1: FDA drug classification with respect to teratogenicity • Category A: Controlled studies in women fail to demonstrate a fetal risk in the first trimester (and there is no evidence of risk in later trimester), and the possibility of fatal harm appears remote.

• Category C: Either studies in animals have revealed adverse fetal effect and there are no controlled studies in human being or studies in women and animals are not available. Drugs in this category should only be given if safer alternatives are not available and if the potential benefit justifies the known fetal risk or risks.

• Category D: Positive evidence of human fetal risk exists, but benefits for pregnant women may be acceptable despite the risks, as if life threatening or serious disease for which safer drugs cannot be used or are ineffective. An appropriate statement must appear in the “Warnings” section of the labelling of drug in this category.

• Category X: Either studies in animal and human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience (or both) and the risk of using the drug in pregnant woman clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. An appropriate statement must appear in the “contraindications” section of the labelling of drugs in this category. risk of miscarriage. This increases to 5.6 fold if taken in the first week of conception and to an 8.1 fold risk if taken daily.7 Suppression of prostaglandins by NSAIDs may lead to poor implantation or decreased placental perfusion, both of which may lead to miscarriage. Several studies have found a possible link between NSAIDs use and congenital heart defect.8 NSAIDs in second and third trimester may decrease fetal renal perfusion leading to oligohydramnios which is reversible on cessation of the drug.9 NSAIDs should not be used in the third trimester due to premature closure of the fetal ductus arteriosus, which has been reported mainly after 27 weeks of gestation.10 As around 80-90% patients of RA, may have flare in post partum period and may need NSAIDs due to restrictions in use of DMARDs. In that case Ibuprofen is the preferred NSAID due to its relatively short half life and low penetration in the breast milk. The ideal time of intake of ibuprofen should be just after breast feeding, so that the blood level falls in time of next feed.11

GLUCOCORTICOIDS

It is FDA category C drug with possible increased risk of cleft palate with doses more than 20 mg per day. Non fluorinated corticosteroids (prednisolone) are metabolised in the placenta by 11 beta hydroxysteroid dehydrogenase

In lactating mothers taking corticosteroids, level in the milk is less than 0.1% of the total prednsolone dose ingested. So mothers taking low dose prednisolone (less than 10 mg per day), the blood level is less than 10% of infant’s endogenous cortisol production, which is of little clinical significance. However exposure may be minimised if nursing is done 3-4 hours after a dose is taken, because the peak level in the breast milk occur about two hours after a dose is taken and declines rapidly.16

HYDROXYCHLOROQUINE (HCQ)

It is a FDA category C drug. This drug is relatively safe during pregnancy and need not be discontinued during pregnancy, particularly in patients with SLE and SLE with Anti Phospholipid Syndrome. There are some isolated reports of ocular toxicity in infants born to mothers receiving these group of drugs, particularly chloroquine.17,18 A study of cardiac conduction in exposed infants found no abnormalities.17 Several larger studies have found no increase in fetal abnormalities among infants exposed to daily HCQ.19 In SLE patients, discontinuation of HCQ early in pregnancy is associated with flare and decreased gestational age.

In nursing mothers, HCQ is quite safe as it is secreted in very low quantity in breast milk. With a maternal dosing of 6 mg/kg/day, a fully breast fed infant would ingest around 0.2 mg/kg/day of HCQ.18 The American academy of paediatrics has designated HCQ as compatible with breast feeding with only minimal risk to the infants.

SULFASALAZINE(SSZ)

It is a FDA category B drug and is among the most preferred drugs during pregnancy requiring ongoing disease modifying drugs. Though it can lead to reduced fertility in men due to oligospermia and reduced sperm motility, it has no effect on fertility in women.20 Most of the data of safety of SSZ in pregnancy comes from studies in inflammatory bowel disease. It can cause folate deficiency as it inhibits the enzyme dehydro folate reductase. So the

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• Category B: Either animal reproduction studies have not demonstrated a fetal risk and there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than decreased fertility) that was not confirmed in controlled studies on women in the first trimester (and there is no evidence of a risk in later trimesters).

to inactive forms, leaving less than 10% of the active drug to reach the fetus.12 Thus, it is the ideal glucocorticoid when treating the mother. On the contrary, fluorinated corticosteroids like betamethasone and dexamethasone will cross the placenta with direct effects on the fetus.13 This is the ideal drug to prevent congenital lupus when the mother is positive for anti Ro/ La antibodies. Recent reports suggest, betamethasone may be preferred over dexamethasone because it may offer better long term neuro-developmental outcomes for the fetus.14 Corticosteroids whenever required should be used in lowest possible dose, preferably less than 10mg per day, as they carry risk of steroid induced hyperglycemia and even frank gestational diabetes as well as osteopenia osteoporosis, and hypertension in the mother. In a metaanalysis looking at birth defects after maternal exposure to corticosteroids, incidence of cleft palate was found to be 3 fold higher than in normal population. There are also isolated reports of neonatal cataract and adrenal suppression which may be dose dependent.15

520

usual folic acid requirement during pregnancy should be doubled from 800 micro gram daily to prevent neural tube defect in fetus. Another important issue is the toxicity of its active metabolite sulfapyridine, which can cross the placenta and can displace bilirubin from albumin and can cause neonatal jaundice.21 In nursing mothers, it is advisable to consider restriction in the use of SSZ in preterm or jaundiced baby for 1-2 months. In usual cases it can be used safely in pregnancy.

PREGNANCY

AZATHIOPRINE(AZA)

It is a FDA category D drug, but still considered one of the safest immunosuppressive drug during pregnancy.

Several studies in patients of SLE, inflammatory bowel disease(IBD) or solid organ transplants have documented no risk of congenital anomalies; however there are reports of preterm birth and growth retardations. Though AZA crosses the placenta, drug levels are low in the infants and prospective studies have not reported increased neonatal infection. Benefits of disease suppression far outweigh the potential risk of hazard.

Regarding breast feeding while on AZA, WHO working group on drugs and human lactation discourages its use though the level in breast milk is insignificant.22,23

METHOTREXATE(MTX)

It is a class ‘X’ FDA drug and a known teratogen leading to dysmorphic facial features, skull and limb abnormalities and growth retardation known as ‘aminopterin syndrome’.

Main toxicity is in the first 8 weeks of gestation. In women contemplating pregnancy MTX should be stopped atleast 3 months before conception and folic acid supplementation throughout pregnancy is recommended.24,25 A study published in 2014 described an increased risk of major birth defects and spontaneous abortion in women exposed to MTX, at dosages typically used in rheumatic patients, only in the postconception period, while no abnormalities were noted in women exposed before conception.22 For its potential embryotoxicity and teratogenicity in animals and human pregnancy, methotrexate discontinuation is suggested 3–6 months before conception.

As regards breast feeding, there are no well documented reports and It is contraindicated in lactation.

LEFLUNOMIDE

It is also FDA category ‘X’ drug and is not recommended in pregnancy and lactation and should not be prescribed in women of child bearing age. It has been associated with fetal abnormalities in rats. In women treated with leflunomide wanting to conceive, medication should be stopped immediately and cholestyramine wash out to be given at doses of 8 gm thrice daily for 11 days. These should be followed by checking the blood level, which should be less than 0.02 mg/L, which is usually safe. Based on its long halflife, cholestyramine washout is needed in any women upto two years after stopping the medication, as recommended by a panel of experts.26 As data regarding effects of leflunomide in infants is not

available, it is not recommended and is considered unsafe during lactation.

MYCOPHENOLATE MOFETIL (MMF)

It is FDA category C drug. MMF is reversible inhibitor of inosine monophosphate dehydrogenase. It is now being increasingly used for the treatment of autoimmune diseases, particularly lupus nephritis, vasculitis, scleroderma lung syndrome.

In addition to reports of teratogenicity in experimental animals, there are case reports and registry studies of teratogenicity in human.27 MMF readily crosses the placenta and there are reports of increased rate of spontaneous abortion and around 25% rate of congenital malformation.26 There is a classical syndrome of MMF embryopathy consisting of tetrad “EMFO” E – ear – microtia and auditory canal arrest.

M – mouth – cleft lip and palate.

F – fingers – brachydactyly of 5th finger and hypoplastic toe nails.

O – organs – cardiac, renal, CNS, diaphragmatic, ocular US FDA has recently issued a blackbox warning based on this data.28 Use of reliable contraception is necessary in women of child bearing potential. This drug should be discontinued 6 weeks prior to conception. If immunosuppression is required during pregnancy, AZA is a safer alternative.

Regarding lactation this drug is contraindicated as data on excretion into breast milk and effect of ingestion in infants is lacking.

CYCLOPHOSPHAMIDE (CYC)

It is FDA category ‘ D’ drug with known risk to fetus.

First trimester exposure to CYC carries a high risk like congenital anomalies of palate, limbs, and eyes as well as miscarriage.29 In second and third trimester risk of congenital abnormalities are far lower. In life threatening flare of rheumatological diseases in 2nd and 3rd trimester, it can be used with consent from the patient because of the significant risk of pregnancy loss with or without CYC therapy.

In lactating mothers, there are reports of cytopenias in the infants in mothers taking CYC.30

BIOLOGIC DMARDS TNF Inhibitors

They belong to FDA category B drug, meaning thereby, no adverse effects were observed during exposure in pregnancy and lactation. Limited data on women exposed to TNF inhibitors suggest that, there is not an increase in fetal anomalies, pregnancy loss, pre-term birth.31 However there is a remote chance of VACTERL associations as one report of FDA database hypothesised. These consists of Vertebral anomalies, Anal atresia, Cardiac abnormalities, Trachea-Oesophageal fistula and/or Esophageal atresia, Renal agenesis and dysplasia, and Limb abnormalities.32

521

Table 2: Summary of drug compatibility in pregnancy and lactation (BSR & NICE guideline) Compatible peri-conception

Compatible with first trimester

Compatible with second/ third trimester

Compatible with breastfeeding

Compatible with paternal exposure

Prednisolone

Yes

Yes

Yes

Yes

Yes

Methylprednisolone

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yesa

Stop 3 months in advance

No

No

No

Yesa

Yes

Yes

Yes

Yesb

Yesc

Cholestyramine washout, no

No

No

No data

Yesa

AZA <2 mg/kg/day

Yes

Yes

Yes

Yes

Yes

CSA

Yes

Yes

Yes

a

Yes

Yesa

Tacrolimus

Yes

Yesd

Yesd

Yesa

Yesa

CYC

No

Noe

Noe

No

No

MMF

Stop 6 weeks in advance

No

No

NO

Yesa

IVIG

Yes

Yes

Yes

Yes

Yesa

Infliximab

Yes

Yes

Stop at 16 weeks

Yesa

Yesa

Etanercept

Yes

Yes

Second but not third

Yesa

Yesa

Adalimumab

Yes

Yes

Second but not third

Yesa

Yesa

Certolizumab

Yes

Yes

Yesa

Yesa

No data

No data

No data

No data

No data

No data

Rituximab

Stop 6 months in advance

Nof

No

No data

Yesa

Tocilizumab

Stop 3 months in advance

Nof

No

No data

No datag

Anakinra

No

Nof

No

No data

No datag

Abatacept

No

Nof

No

No data

No datag

Belimumab

No

Nof

No

No data

No datag

Corticosteroids

Antimalarials HCQ MTX <20 mg/week SSZ (with 5 mg folic acid) LEF

d

d

Anti-TNF

Golimumab Other biologics

There are fallacies in the relative risk of the drug as the cause of the anomalies because, the reported cardiac and urogenital anomalies are also the most common seen in general population.

TNF inhibitors do not cross the placenta before 16 weeks of gestation, but after that, there is linear level of progressive increase of placental transfer. The rate of transfer is more, in case of infliximab than etanercept, adalimumab and golimumab. At immediate and 6 weeks post partum, the level of maternal and fetal infliximab are equal compared to 4% of maternal serum level in fetus, in case of etanercept. 33 As per BSR and NICE recommendation,34

infliximab may be continued until 16 weeks and etanercept and adalimumab may be continued until end of second trimester. Etanercept and adalimumab should be avoided in 3rd trimester and stopped at 26 weeks. Certolizumab is compatible in periconception, throughout pregnancy.

Golimumab has no data in periconception and throughout pregnancy.

There is minimal or no transfer of anti TNFs in breast milk and they can be safely allowed in lactation.

Rituximab

It is a FDA category â&#x20AC;&#x2DC;Câ&#x20AC;&#x2122; drug. This drug crosses the

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522

placenta as the pregnancy advances beyond 12 weeks of gestation. Several case reports of rituximab use during 2nd and 3 rd trimester of pregnancy for acute life threatening maternal disease have not found association between ante- natal and post conception exposure to rituximab and adverse pregnancy outcome or congenital malformations.

33,35 Neonatal cytopenias only have been reported. BSR and NICE guidelines recommend stoppage of rituximab 6 months prior to conception.34

PREGNANCY

As per safety during lactation, no data are available regarding concentration in breast milk.

Tocilizumab

This is also a category ‘C’ drug, but its teratogenic potential is not definitely known. In the trials for FDA approval, the drug was found to increase risk of miscarriage. As per BSR and NICE34 recommendations, the drug should be stopped 3 months before conception. Unintentional exposure in the 1st trimester is unlikely to be harmful.35 There is no data to recommend tocilizumab during breast feeding.

Abatacept

It is FDA category ‘C’ drug. It crosses placenta in animal studies but did not produce any congenital malformations.

There is limited human pregnancy experience. The manufactuerer advises against pregnancy during therapy and recommends contraception for atleast 10 weeks after stopping the drug. The elimination half life of abatacept is 25 days. However Pham et al recommends 18 weeks taking into consideration 5 times the half life of abatacept.36 Regarding lactation, no data are available for excretion of abatacept in human breast milk. So, breast feeding can not be advised during breastfeeding.

Cyclosporin,Tacrolimus

They are category ‘C’ drugs. Both cyclosporine and tacrolimus are compatible throughout pregnancy in lowest effective dose. However there are reports of increase in premature delivery and low birth weight.37 Mothers on cyclosporine and tacrolimus should not be discouraged from breast feeding. It is suggested to monitor blood pressure, renal function strictly during treatment period.40

I.V. Gammaglobulin

This is used as a life saving therapy in cases of SLE flare, catastrophic APS and life threatening Vasculitic syndrome during pregnancy.

IVIG is compatible with pregnancy and breastfeeding.

CONCLUSION

Motherhood is a sacred and divine fulfilment of womanhood and no woman can be denied this divine gift. As a physician our aim will be to help her achieve this by modifying immuno-modulatory therapy and timing of conception. Both the pregnant woman and her partner should be educated about appropriate contraception and avoiding unplanned pregnancy. Pregnancy should be planned when the disease is in remission.

In some cases like SLE, Vasculitis, and other connective tissue diseases in pregnancy it is absolutely necessary to continue medications for best pregnancy outcome with respect to both mother and infant. It is the responsibility of the physician, and maternal- fetal medicine expert (high risk obstetrician) to use the most suitable DMARDs in accordance with the patient’s desire during pregnancy, and initiating appropriate therapy post-partum to prevent severe flares taking into account the desire for breast feeding. For a comprehensive information regarding safety of drugs used in pregnancy and lactation EULAR guideline41 and BSR/NICE guidelines34 are given in Table 2.

The Organisation of Teratology Information Services (OTIS) is a useful resource to women (http:# WWW:otis pregnancy).

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1.

Whitacre CC, Reingold SC, O’Looney PA: A gender gap in autoimmunity, Science 1999; 283:1277-1278

2.

Mor G, Cardenas I : The immune system in pregnancy. A unique complexity : Am J Reprod Immunol 2010; 63:425-433

3.

Saito S, Nakashima A, Shima T, Ito M: TH1/TH2/TH17 And Regulatory T Cell Paradigm in pregnancy : AM J Reprod Immunol 2010; 63:601-610

4.

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Petri M, Albritton J; Fetal outcome of lupus pregnancy: a retrospective case control study of the Hopkins lupus cohort, J Rheumatol 1993; 20:650-656.

6.

www.fda.gov/fda/features/2001/301.preg.html#categories

7.

Li DK, Lin L, Odonli R et al: Exposure to Nonsteroidal Anti Inflammatory Drugs during pregnancy and risk of miscarriage; population based cohort study, BMJ 2003; 327:368.

8.

Ofori B, Oraichi D, Blais L et al, Risk of congenital anomalies in pregnant users of NSAIDs, a nested case control study, Birth defects Res. B. Dev. Reprod Toxicol 2006; 77:268-279

38

Belimumab

There is insufficient data to recommend belimumab during pregnancy. Accidental exposure in 1st trimester is unlikely to be harmful. There is no data on belimumab use in breastfeeding.

Tofacitinib

in august 2016 though approved by FDA in 2012 for RA. Tofacitinib is a category C drug,but data regarding safety in pregnancy and lactation is still inadequate.. In a recent review with over 1800 patients, no increase in incidence of pregnancy loss or congenital malformation than in general population was found.39 However, according to EULAR recommendation, Current evidence is insufficient and in a planned pregnancy, treatment with tofacitinib should be stopped 2 months before conception.

It is FDA category’ C’ drug. Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced in Indian market

9.

Ericson A, Kalley BA, Nonsteroidal and immunosuppressive drugs in eary pregnancy, Reprod Toxicol 2001; 15:371-375

10. Ostensen M, Khamashta M, Lockshin M, et al : Antiinflammatory and immunosuppressive drugs and reproduction, Arthritis Res Ther 2006; 8:209 11. Townsend RJ, Benedetti TJ, Erickson SH, et al : excretion of ibuprofen into breast milk; Am J Obstet Gynaecol 1984; 149:184-186.

12. Benediktsson R, Calder A A, Edwards CRW, Seckl JR; Placental 11 beta hydroxysteroid dehydrogenase : a key regulator of fetal glucocorticoid exposure : Clin Endocrinol 1997; 46:161-166

14. Lee BH, Stoll BJ, McDonald SA, et al : Neurodevelopmental outcomes of extremely low birth weight infants exposed pre natally to dexamethasone versus betamethasone, 2008 15. Ostensen M, Khamashta M, Lockshin M, et al; Anti inflammatory and immunosuppressive drugs and reproduction, Arthritis Res Ther 2006; 8:209 16. Ost L, Wettnell G, Bjorkham P, et al; Prednisolone excretion in human milk : J Pediatr 1985; 106:1008-1011 17. Motta M, Tincani A, Faden D, et al : Followup of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation, J Perinatol 2005; 25:86-89 18. Sperber K, Hom C, Chao CP, et al : Systemic review of hydroxychloroquine use in pregnant patients with autoimmune diseases, Pediatr Rheumatol 2009; 7:9 19. Costedoat-Chalumeau N, Amoura Z, Sebbough D, Piette JC; Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast feeding. Arthritis Rheum 2004; 50:3057-3058 20. O’Morain C, Smethurst P, Dora CJ, Levi AJ; Reversible male infertility due to sulfasalazine : studies in man and rat, Gut 1984; 25:1078-1084 21. Jarnerot G, Anderson S, Esbjorner E, Sandstrom B : Albumin reserve for binding of bilirubin in maternal and cord serum under treatment of sulfasalazine, Scand J Gastroenterol 1981; 16:1049-1055 22. Norgard B, Pedersen L, Christensen L, and Sorensen H; Theraputic drug use in women with chrons disease and birth outcomes : A Danish nation wide cohort study. Am J Gastroenterol 2007; 102:1406-1413 23. Weber-schoendorfer C, Chembers C et al. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicentric cohort study. Arthritis Rheumatol 2014; 66:110110 24. Hazes J M, conlie PG, Geenen V, et al. Rheumatoid arthritis and pregnancy evolution of disease activity and pathophysiological consideration for drug use.

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31. Vinet E, Pineau C, Gordon C et al : Anti TNF therapy and pregnancy outcome in women with inflammatory arthritis, Expert Rev Clin Immunol 2009; 5:27-34 32. Carter JD, Ladhani A, Ricca LR, et al : A safety assessment of TNF antagonists during pregnancy : a review of food and drug administration database, J Rheumatol 2009;36:635641 33. Chakravarty EF, Murray ER, Kelman A, Farmer P : Pregnancy outcomes after maternal exposure to rituximab, Blood 2011; 117:1499-1506 34. Flint J, Panchal S, Hurrell A et al : BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding : Rheumatology (Oxford) : march 2016 35. Rubbert-Roth A, Goupille P, Moosavi S, Hou A : First experiences with pregnancies in RA patients receiving tocilizumab therapy, Arthritis Rheum 2010;62:384 36. Pham T, Clandespierre, Constantin A, et al. Abatacept therapy and safety management. Joint Bone Spine 2009; 76:s3-55 37. Ostensen M, Forger F : How safe are anti rheumatic drugs during pregnancy ? Curr Opin In Pharmacol 2013; 13:470475 38. Perricone R, De Carolis C, Kroegler B, et al; intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology (Oxford) 2008; 47:646-651 39. Clowse MEB, Feldman SR, Isaacs JD, et al : Drug Safety 2016; 39:755 40. Bar Oz, B Hackman,R einarson, T. & Koren, G.Pregnancy outcome after CsA therapy during pregnancy: a meta‑analysis. Transplantation 2001; 71:1051–1055.

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Drugs in Pregnancy

C H A P T E R

111 Many physicians, family doctors, and most pregnant women are under the misconception that most drugs are harmful in pregnancy. Many obstetricians also remain very cautious about the use of drugs in pregnancy. This caution stems from the tragic fetal malformations which occurred following the use of thalidomide for nausea, vomiting and hyperemesis in early pregnancy in the late 1950’s and early 1960’s Thalidomide use resulted in a number of fetal malformations, specifically phocomelia where limbs either do not develop at all, or are shortened and malformed. The drug was eventually banned from use in pregnant women in 1962.

The consequences of thalidomide were that drug companies did not license drugs for use in pregnancy unless they have been specifically studied and found to be safe. However, drug companies rarely do trials in pregnancy and hence most data on safety in pregnancy comes from case series, exposure registries and clinical trials. When a new drug is introduced to the market, in due course a number of women who take the medication will fall pregnant. There will be a proportion of these women who continue taking the new drug in pregnancy and this allows for review of any harmful sequelae of drug use. Various databases and exposure registries have been set up across the world including the UK Teratology Information Service which is updated regularly and provides important information on harmful effects of drugs used in pregnancy. There are valid concerns about the safety profile of a number of medications, but most commonly used drugs have good safety data and can continue to be taken in pregnancy.

There are several principles that it is wise to follow when prescribing drugs in pregnancy: •

No drug should be used in pregnancy without a reasonable indication

•

The indication for using the drug in pregnancy and the benefit to the mother of its use should be balanced against any known harm to the fetus

•

Use the smallest effective dose of any drug

•

Switch agents if there is a similar drug with a better safety profile

•

The first trimester is a period that warrants special consideration

•

Known teratogens: there are a number of drugs known to have a risk of teratogenicity, however, the consequences of discontinuing them may be worse

Mandish K Dhanjal

than the effects of taking it, justifying continuation of therapy (e.g. anti-epileptic drugs).

•

Try to avoid using newly introduced medications many important drug toxicities in pregnancy have only been picked up in post marketing surveillance.

It is preferable to prescribe drugs which have been used for a number of years in pregnancy which appear to be safe

•

Absence of information about a drug does not imply safety

Many women stop taking medications as soon as they realise they are pregnant. This risks a flare of their medical disease, which may cause harm to them and their babies.

Interestingly they freely use herbal and homeopathy treatments with unknown side effects as they consider them to be natural and hence “safe”. Women with medical diseases on drug treatment should have a discussion regarding the safety profile of the medications in pregnancy, ideally prior to conception.

Drugs which are known to cause harm may only do so at specific periods in pregnancy. These drugs should be avoided at those times, but may be used at a different stage in pregnancy when they may have no effect on the fetus.

•

Pre-embryonic stage (0–14 days after conception): methotrexate, thalidomide, retinoids, misoprostol, mifepristone, can result in miscarriage. Misoprostol and mifepristone are both used as abortifactants, however, misoprostol is used in the third trimester to induce labour.

•

Organogenesis (generally regarded as first trimester, until 10 weeks gestation): a number of drugs are teratogenic i.e. they affect organogenesis and result in congenital malformation. These drugs include antiepileptic drugs, angiotensin enzyme converting (ACE) inhibitors, retinoids, and warfarin.

•

Growth and functional development (second and third trimester): some drugs can cause fetal growth restriction, affect functional development, neuropsychological behaviour (e.g. high-dose sodium valproate), have a toxic effect on fetal tissues (e.g. ACE inhibitors, tetracycline) or cause fetal bleeding (e.g. warfarin). The effects of some drugs are only apparent later on in life e.g. adenocarcinoma of the vagina after puberty in the

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Table 1: Drug safety in pregnancy Drugs that can be used in pregnancy

Drugs considered unsafe to use in pregnancy

Analgesics (paracetamol, codeine, NSAIDs <32 weeks gestation, opiates)

NSAIDs >32 weeks gestation

Antiemetics e.g. cyclizine, promethazine, metoclopramide, Thalidomide prochlorperazine, ondansetron Warfarin*

Most laxatives e.g. lactulose, fybogel, senna

Codanthramer, paraffin

Antihistamines including chlorpheniramine, cetirizine, loratidine

Statins

NSAIDs under 32 weeks gestation

Cyclophosphamide

Oral antiglycaemic drugs e.g. metformin glargine

Methotrexate

Calcium channel blockers e.g. nifedipine, amlodipine

Mycophenolate mofetil

Beta blockers e.g. labetolol, propranolol, sotalol, bisoprolol ACE inhibitors, angiotensin receptor blockers Alpha blockers e.g. prazocin, doxazocin

Alendronate

Methyldopa, nitrates

Leflunamide

Most antidepressants (tricyclic antidepressants, SSRIs except prazocin)

Paroxetine

Most antibiotics: Penicillins, cephalosporins, metronidazole, gentamicin, rifampicin, macroglides

Tetracycline, doxycycline

Beta agonists Steroids: inhaled, oral, intravenous Hormones e.g. insulin, thyroxine Low dose aspirin Low molecular weight heparins Ursodeoxycholic acid Hydroxychloroquine, azathioprine, cyclosporin Sulfasalazine, 5 ASAs Intravenous immunoglobulin (IVIG) Some biologics** (etanercept, infliximab, rituximab, adalimumab, certolizumab, golimumab) *used in some circumstances e.g. two metal heart valves where maternal benefit outweighs fetal risk; **usually stopped in late 2nd to early 3rd trimester to prevent neonatal immunosuppression (must not have live vaccines for 6 months postnatal)

female when exposed to diethylstilbestrol whilst in-utero.

Table 1 shows the safety profile of various categories of drugs in pregnancy.

SPECIFIC DRUGS

Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

Non steroidal anti-inflammatory drugs (NSAIDs) can be used in pregnancy until approximately 32 weeks gestation. Use is avoided following this gestation as they can cause premature closure of the fetal ductus arteriosus.

NSAID use may be required for women with migraines in pregnancy and for women with ankylosing spondilitis who do not respond well to other types of analgesia.

Beta Blockers

Beta blockers are commonly used in pregnancy for a variety of indications including hypertension (labetolol), migraine prophylaxis (propranolol), symptomatic control

of tachycardia in thyrotoxicosis (propranolol), and a variety of cardiac conditions including mitral stenosis, dilated aortic root, coarctation of the aorta and arrhythmias (metoprolol, bisoprolol, sotalol and atenolol). Beta blockers have been shown to be associated with smaller babies, but this is from studies in women with hypertension who are prone to have fetal growth restriction due to hypertension irrespective of the antihypertensive agent they are on.

Labetolol is recommended as the first line drug treatment for hypertension in pregnancy according to the National Institute for Heath and Care Excellence in the UK. Women on beta blockers are safe to breastfeed.

Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs)

ACE inhibitors and ARBs are avoided in pregnancy at all gestations. First trimester use is associated with a doubling in the background risk of congenital malformations and second and third trimester use is associated with a

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All antacids, H2 blockers and proton pump inhibitors

526

Table 2: Anti Xa levels for maintenance of effective anticoagulation with LMWH

PREGNANCY

Indication for therapeutic LMWH

Peak anti Xa level recommended (i.u./ml)

Venothromboembolism

0.6-0.9

Aortic metal valves

0.8-1.0

Mitral metal valves

1.0-1.2

reduction in development of nephrons leading to renal dysfunction and oligohydramnios and skull ossification defects. Pregnant women should be advised to stop ACE inhibitors and ARBs pre-conception. In some instances it is recommended to stop these treatments as soon as they fall pregnant so as not to spend an indefinite time off treatment whilst trying to conceive e.g. when they are used for the treatment of proteinuric nephropathy. ACE inhibitors can be used postnatally. The most studied drug is enalapril which is commonly used postpartum for the treatment of hypertension and cardiomyopathy.

Corticosteroids

Steroids in inhaled, oral and intravenous forms are commonly used for a variety of conditions in pregnancy.

Only minimal amounts of the small inhaled steroid doses are absorbed into the systemic circulation. Prednisolone is metabolised into an inactive form by the placenta and only 10% crosses to the fetus. There are no adverse fetal effects from oral steroids and meta-analyses have shown that initial concerns regarding orofacial clefts are unsubstantiated in humans. Oral steroids are associated with maternal gestational diabetes which needs to be controlled with metformin or insulin. Women on steroids are safe to breastfeed.

Antiepileptic Drugs (AEDs)

Most antiepileptic drugs (AEDs) are associated with major congenital malformations (MCMs). The background risk of MCMs is 2-3%. With most of the antiepileptic drugs, this risk is increased to 4-6%. Combinations of AEDs have higher risks of MCMs. Levetiracetam appears to have very low rates of MCM (reported as less than background), followed by lamotrigine. The risk of MCMs is much higher with sodium valproate and increases significantly with the doses at 600mg/day, with the largest risk in doses over 1000 mg/day with MCM rates of 20.3% at this level. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) prospective study showed that offspring of women taking Sodium Valproate at any stage in pregnancy had lower IQs aged 6 years compared to children exposed to other AEDs, with a difference in IQ of 8-11 points. This effect is also dose related with worse IQ outcomes in women receiving higher doses of valproate. It is therefore recommended that women considering pregnancy be changed to a less harmful AED pre-pregnancy, such as levetiracetam or lamotrigine.

Lamotrigine levels need to be checked regularly in pregnancy and the dose increased as metabolism can increase by 300% by the third trimester resulting in low blood levels. All women on AEDs should be prescribed

5mg folic acid to take preconception and for 3 months into the pregnancy to protect the fetus from neural tube defects. Women on AEDs are safe to breastfeed.

Anticoagulants

Indications for therapeutic anticoagulation in pregnancy include: •

Metal heart valves

•

Atrial fibrillation

•

Venothromboembolism (VTE) in pregnancy

•

Multiple previous VTE with a highly thrombogenic thrombophilia

Low molecular weight heparin (LMWH) has largely replaced warfarin for anticoagulation in pregnancy.

Warfarin is a teratogen causing chondrodysplasia punctate in 6% with exposure between 6-12 weeks gestation. It also crosses the placenta and anticoagulates the fetus which is therefore vulnerable to miscarriage, intracerebral bleeding and stillbirth. LMWH does not cross the placenta and is therefore safe to use for the fetus.

Dosing in pregnancy differs from outwith pregnancy and depends on the agent used e.g. enoxaparin dose is 1 mg/ kg bd antenatally changing to 1.5 mg/kg od postnatally.

Doses should be adjusted to maintain peak anti Xa levels (4 hours post dose and measured monthly) at the levels shown in Table 2.

LMWH it is not as good an anticoagulant as warfarin: there are more cases of metal valve thrombosis occurring with LMWH compared to warfarin. This is primarily due to suboptimal anticoagulation and non-adherence to the advised anti-Xa levels. Women with metal heart valves should also be on aspirin 75 mg daily. Those with two metal valves or a highly thrombogenic metal valve in the mitral position should remain on warfarin in pregnancy, converting to therapeutic LMWH or unfractionated heparin close to delivery. Warfarin should also be used in women who have had venothromboembolism despite treatment doses of low molecular weight heparin (LMWH). Women on LMWH and warfarin are safe to breastfeed.

REFERENCES

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Dhanjal MK. Pre-Conception Counselling. Edmonds DK (Ed). Dewhurst’s Textbook of Obstetrics and Gynaecology.

Oxford, UK. Wiley–Blackwell, Eighth edition 2012 p35-41.

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UK Teratology Information Service: www.uktis.org

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National Institute for Heath and Care Excellence.

Hypertension in pregnancy: diagnosis and management, Clinical guideline. Published: 25 August 2010 www.nice. org.uk/guidance/cg107

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Meador KJ, Baker GA, Browning N et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study.

Lancet Neurology 2013; 12:244-252.

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Adamson DL, Dhanjal MK, Nelson-Piercy C. Heart Disease in Pregnancy. Oxford Specialist Handbooks in Cardiology.

Oxford University Press. 2011.