Ajog oct dec 2014 by IJCP

Volume 1, Number 3

FOGSI Special Issue

Happy New Year 2015

Asian Journal of

Online Submission

Volume 1, Number 3

An IJCP Group Publication Corporate Panel Dr Sanjiv Chopra Prof. of Medicine and Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

CONTENTS FROM THE ISSUE EDITOR Dr Alka Kriplani

FROM THE DESK OF GROUP EDITOR-IN-CHIEF

Winter Asthma

Dr (Mrs) Prabha Arora (Delhi) Dr Hema Divakar (Bangalore) Dr Kamini A Rao (Bangalore) Dr Deepti Goswami (Delhi) Dr Neerja Bhatla (Delhi) Dr Bhawna Malhotra (Delhi) Dr Biswas Nicholas (Australia) Dr Sudhaa Sharma (Jammu) Dr Jaibhagwan Sharma (Delhi) Dr Veena Mathur (Agra) Dr Garima Kachhawa

Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma Dr Kamala Selvaraj

ENT Dr Jasveer Singh

Cardiology Dr Praveen Chandra Dr SK Parashar

Gastroenterology Dr Ajay Kumar

Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses Dr Sidhartha Das Dr A Ramachandran Dr Samith A Shetty

Dentistry Dr KMK Masthan Dr Rajesh Chandna

Dermatology Dr Hasmukh J Shroff Neurology Dr V Nagarajan Journal of Applied Medicine and Surgery Dr SM Rajendran Dr Jayakar Thomas

Anand Gopal Bhatnagar Editorial Anchor Advisory Body Heart Care Foundation of India Non-Resident Indians Chamber of Commerce and Industry World Fellowship of Religions

Dr KK Aggarwal

AJOG Specialty Panel

Dr Alka Kriplani Editor Consultant Editor Dr Urmil Sharma Assistant Editors Dr Nutan Agarwal (Delhi) Dr Neera Aggarwal (Delhi) Dr A Biswas (Singapore) Dr CS Dawn (Kolkata) Dr Gauri (Delhi) Dr Suneeta Mittal (Delhi) Dr S Mehra (Delhi) Dr Prashant Mangeshikar (Mumbai) Dr Prakash Trivedi (Mumbai) Dr Gita Ganguly Mukherjee (Kolkata)

ORIGINAL ARTICLE

Serum Anti Mullerian Hormone Levels: A Predictor of Ovarian Response to Controlled Ovarian Hyperstimulation in Assisted Reproductive Technology 9 Radha Vembu, Sanjeeva Reddy Nellepalli, Anjalaksi Chandrashekar, Nalini Ganesan

CLINICAL STUDY

Cord Blood Nucleated RBCâ&#x20AC;&#x201C;NRBC

N.Hephzibah Kirubamani

Fertility Preservation

PM Gopinath

Vaginal Administration Of Isosorbide Mononitrate ( SR 60 Mg Nitric Oxide Donor) for Pre-Induction Cervical Ripening 22 Amulya L, Dhanalakshmi MG

Matching Medical Horoscope - A Look Into Future! 27 Rajapriya Ayyappan

CASE REPORT

Obstetrics Is Bloody Business Palaniappan N, Sathyapriya, Radha Vembu, Sivasundari

Asian Journal of Volume 1, Number 3

CONTENTS

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

REVIEW ARTICLE

Periodontal Infections And Adverse Pregnancy Outcomes 31

Printed at Crystal Offset, Chennai

Anupama Dave

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JOURNAL SCAN

Research Review

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FROM THE ISSUE EDITOR

Women die more than men in hospital from severe heart attack

Dr Alka Kriplani Professor and Head of Unit II Dept. of Obstetrics and Gynecology AIIMS, New Delhi E-mail: kriplanialka@gmail.com

Winter months are heart attack months Men and women have about the same adjusted in-hospital death rate for heart attack â&#x20AC;&#x201D; but women are more likely to die if hospitalized for a more severe type of heart attack. According to a report in Circulation: Journal of the American Heart Association: zz Women are twice as likely as men to die if hospitalized for a type of heart attack known as ST-elevation myocardial infarction (STEMI). zz Women are also less likely to receive appropriate and timely treatment for heart attack. zz Women with STEMI have a 12 percent higher relative risk for in-hospital death compared to men. zz Compared to men, women are 14 percent less likely to receive early aspirin; 10 percent less likely to receive beta blockers; 25 percent less likely to receive reperfusion therapy (to restore blood flow); 22 percent less likely to receive reperfusion therapy within 30 minutes of hospital arrival; and 13 percent less likely to receive angioplasty within 90 minutes of hospital arrival. zz Women admitted with a STEMI are about twice as likely to die in the first 24 hours of hospitalization as men.

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Winter Asthma

Dr KK Aggarwal

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee Sr. Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Senior Vice President, IMA Member, Ethics Committee, MCI Chairman, Ethics Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

Any breathlessness after the age of 40, appearing for the first time in winter, is cardiac asthma unless proved otherwise. Such patients should immediately have their blood pressure check-up done and if high needs immediate medical attention. First-onset breathlessness can also be an indication of angina or heart attack. However, the more common is winter asthma or acute exacerbation of winter COPD (chronic bronchitis). Asthma is reversible airway obstruction and COPD is irreversible airway obstruction. Sudden exposure to cold, humidity, pollution at lower levels in atmosphere can precipitate asthma in susceptible individuals. Winter is the time to increase the dose of asthma medicines. If a person can speak a full sentence, the asthma attack is mild; if a person speaks broken sentences the asthma attack is moderate and if the person is able to speak only words then the asthma attack is severe. Severe attack of asthma needs immediate hospitalization. An attack of asthma is due to inflammation, narrowing and collection of fluid in the wind pipe and needs medicines to widen the wind pipe and reduce the inflammation. The need of asthma medicines can be intermittent and/or permanent. The ‘Formula of ‘2’t becomes handy in such situations. A person who consumes more than two canisters of inhalers in a year or consumes asthma medicines more than twice in the night time in a month or more than twice in a day in a week, then he or she needs continuous asthma and anti inflammatory medicines. Inhalers are the best choices.

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

Participation At Medical Conferences ---- my perception *A Jaishree Gajaraj

Medical conferences, Symposia, CME programs are meant to educate and update students, Post Graduates and practicing Clinicians. Obstetricians and Gynaecologists convinced they are working 24/7, 365 days in a year feel compelled to attend these meetings.for varied reasons. Most of us have participated in these conferences in various capacities – as a delegate, as a session coordinator, as a speaker be it capsule or a talk, as a panelist or as a chairperson.I too have gone through these stages as it were What is or was my perception ? As a delegate…… Carefree, get to choose which session and which conference to attend, Can scoot sessions, go shopping, see the city and the sights. I loved it !! As a session coordinator …… As a post graduate I felt thrilled. My seniors have actually noticed me. Get a new saree, try to look pretty. Get all bio datas well ahead of time. I am all set but I must walk up and down the hall to get noticed Oops !! I cant recognize some of the speakers. Am sure someone will help. Delivering a capsule …. I have been asked to speak for 5 minutes on a current topic .I must gather all the information I can from the net – but how do I present this in 5 minutes. A challenge indeed – I need help. A talk for 15/20 minutes ….. A phone call. From a well wisher ” I have recommended your name for a talk on …., at the State / National conference at ….. city. Very encouraging. I must do a good job of this. I make an outline, run it by close friends – friends who will take the liberty to tell me its good or its not. I must get the timing right, I must finish a minute ahead. Interaction ? Questions ? Don’t know if I can handle that. I guess I’ll have to try. Hope some kind

soul will come to my rescue. A smile may help !! As aModerator ….. I have graduated. No shaking legs or that tell tale break in the voice. I have been asked to lead an expert panel of senior and experienced gynaecologists – take them through a topic of clinical relevance or a set of case discussions My panelists are more experienced than myself. I must conduct this panel – get the right messages to the audience. I cannot afford to offend anyone. Can I do it ? I have to try. As a panelist ….. A panelist ???? I have moderated several panels – some quite successfully – atleast I thought so. There must be a mistake. In fact I was very upset. Here I would like to recall my Dad’s advice. He sat me down and said “ A panelist is a senior experienced doctor, who can participate in discussions, who can draw upon years of experience and be able to give the right solution to common clinical dilemmas”.These are words I will always remember. As a Chairperson …. Have I lost it ? What does a chairperson do ? Keep time, ring the bell, introduce speakers, give momentos, we even get one for ourselves. Sit pretty on the stage straining your neck to look at that screen behind you or peeping over the head table to look at the LCD screen down below. Most certainly not. Chairing a session is an honour, it is a recognition of academic maturity, it is a call from the organizing committee to steer the proceedings down intended pathways – Pathways to clinical effectiveness. This is my humble perception of the various roles I have had to play over the last 30 years. I have no regrets I have enjoyed every moment. I can recall happiness, recall disappointment, recall exhilaration. Ever so often a gentle hand on the shoulder, a smile. A smile that told it all. “ Some are born great, some achieve greatness, and some have greatness thrust upon them ” Shakespeare, Twelth Night.

Address for correspondence Dr A Jaishree Gajaraj MD DGO FRCOG(UK) FRCS(Ed) Sr Con ObGyn Apollo Hospitals Fortis Hospitals MANGAI- Women’s Health Exclusive Chennai *

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

ORIGINAL ARTICLE

Serum Anti Mullerian Hormone Levels: A Predictor of Ovarian Response to Controlled Ovarian Hyperstimulation in Assisted Reproductive Technology *Radha Vembu, †Sanjeeva Reddy Nellepalli, ‡Anjalaksi Chandrashekar, #Nalini Ganesan

ABSTRACT Aim: To determine whether serum Anti Mullerian Hormone (AMH) is a predictor of ovarian response in patients undergoing Controlled Ovarian Hyper stimulation (COH). Objective: To determine the cut off value of AMH for predicting poor response to Controlled Ovarian Hyperstimulation. Materials & Methods: 246 women enrolled for ICSI fulfilling the selection criteria were recruited. On day 3 of cycle, serum AMH, FSH, LH, Estradiol, Antral Follicle count (AFC) was measured. Within 3 months they were subjected to COH and Intra Cytoplasmic Sperm Injection (ICSI). The data on age, BMI, basal AMH, AFC, FSH, number of days of stimulation, total dose of gonadotropins, number of oocytes retrieved, Mature oocytes(MII) and pregnancy rate were analysed. The study participants were divided into three groups based on the number of oocytes retrieved into poor, normal and hyper responders. The correlation between AMH, FSH, AFC and COH outcomes and cut off values of AMH for predicting the poor response were determined. Results: All 246 patients enrolled were analysed. The mean age was 30.8 ± 4.5years, mean BMI was 26.5 ± 4.7 kg/m2. Poor responders were 34 (13.8%), 153 (62.2%) were normal and 59 (24%) were hyper responders. Among the poor responders 9 patients did not undergo ICSI in view of poor follicle development, so stimulation outcome was determined for 25 patients in poor responders group. There was a statistically significant difference in the mean age, AMH, AFC, FSH, dose of gonadotropins, oocytes retrieved among the three groups. (P =0.001) There were no significant difference in mean BMI, number of follicles and pregnancy rate among the three groups. There was statistically significant correlation of AMH, AFC with the number of oocytes retrieved than FSH(r = 0.76, 0.73 & - 0.31 respectively). The AUC for AMH, AFC and FSH for predicting poor response were .978, .888 and .753 respectively (P = .0001). The cut off value of AMH for poor response were 1.25ng/ml (sensitivity & specificity of 91.2% & 94.1%). Conclusion: AMH is a better predictor of ovarian response and the cut off value of 1.25ng/ml has a good sensitivity and specificity to predict poor response Key words: Controlled Ovarian Hyper stimulation, Anti Mullerian Hormone, Ovarian response.

INTRODUCTION

he success of an Assisted Reproductive Technology (ART) cycle depends on the number and quality of oocytes retrieved after Controlled Ovarian Stimulation (COH). Recently AMH has been suggested as an ovarian reserve marker and predictor of ovarian response to COH in ART cycles.1,2 The major issues of

*Associate Professor Department of Reproductive Medicine, Sri Ramachandra University †

Professor & Head Department of Reproductive Medicine, Sri Ramachandra University

‡

Resident Department of Obstetrics & Gynecology, SRM University

#Professor

Professor, Department of Biochemistry, Sri Ramachandra University, Address for correspondence Dr V. Radha Associate professor E-2 SMART, Department of Reproductive Medicine Sri Ramachandra University Porur, Chennai – 600116 E mail: ganesh_radha@yahoo.in

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

ART cycles namely extremes of ovarian response, cycle cancellation demanding treatment burden predominate in many patients undergoing COH. So a programme designed to treat based upon their capacity of ovarian response is essential in the present era to achieve optimal clinical safety and pregnancy potential. This requires an accurate means to predict ovarian response and appropriate strategic approach to COH. A wide variety of indices have been proposed to define the extremes of ovarian response. Various studies have shown the ability of AMH to predict the type of extreme ovarian response, suggesting that it is an ideal marker for predicting ovarian response.3 This prior assessment facilitates appropriate pre treatment counselling and modification of treatment protocols to maximise their potential response. Chronological age is of limited value as women of same age can be at different stages of follicular depletion. Basal FSH is still used by many centres, but it has to be measured in early follicular phase and shows inter cycle variability with moderate predictive value to predict poor response.

ORIGINAL ARTICLE Antral Follicle Count (AFC) is a useful marker of ovarian reserve, 4 but is subjective and requires high resolution machine and a trained personale. Anti Mullerian Hormone (AMH) levels are stable across the menstrual cycle,5, 6 removing the constraint of early follicular blood sampling and ultrasound scans. Further it needs to determine the cut off levels of AMH to predict ovarian response in our Indian population. Based on the number of oocytes retrieved, poor response is considered if the cycle is cancelled due to inadequate response or ≤ 3 oocytes were retrieved.7 Hyper response is considered if ≥ 19 oocytes were retrieved.8 This study was undertaken to determine • If AMH could predict ovarian response better than FSH and AFC. • To establish the cut off values of AMH to predict poor response.

Materials and Methods This was a prospective observational study conducted in the department of Reproductive Medicine, Sri Ramachandra University from January 2011 to August 2013. A total of 246 women enrolled for ICSI were recruited for the study. Women in the age group of 20 - 45 years, with bilateral ovaries were included in the study. Women more than 45 years, hypo gonadotropic hypogonadism were excluded. Informed consent was taken from all the participants and IEC approval (IEC - NI/10/June/17/17) was obtained to conduct the study. A detailed history and physical examination were performed. On day 3 of cycle, serum FSH, LH, Estradiol were assayed by Immune enzymometric assay. On the same day, serum sample for AMH assay was separated within one hour of vene puncture and was stored in aliquots at - 20ºC. The samples were later assayed in batches by AMH Generation II assay, the analytical sensitivity was 0.14ng/ml, intra assay and inter assay CVS were < 12.3 and < 14.2 % respectively. These patients underwent Controlled Ovarian Hyperstimulation (COH) within 3 months as per the unit protocol.9 Statistical Analysis The data obtained were analysed with SPSS 16.0 version. To describe about the data, descriptive statistics frequency analysis, percentage analysis, means and standard deviation were used. To find significance difference in the multivariate analysis, the one way ANOVA with Tukey’s Post - Hoc test was used, and to assess the relationship between the variables Pearson’s correlation was used. To 10

find the significance in the categorical data, Chi square test was used. In all the statistical tools, the probability value of P < 0.05 is considered as significant value. Table 1. Baseline characteristics of the participants. Characteristics

Values

Mean Age (years)

30.8 ± 4.5

Type of Infertility Primary Secondary

179 (72.8%) 67 (27.2%)

Duration of Infertility (years)

7.8 ± 3.9

Indication for ICSI Female Male Both Unexplained Donor

79 (32.1%) 60 (24.4%) 53 (21.5%) 34 (13.8%) 20 (8.1%)

BMI(kg/m2)

26.5 ± 4.7

Results All 246 women enrolled for the study were analysed. Table 1 shows the baseline characteristics of the participants. There was a statistically significant correlation (P= .0001) of AMH, AFC with the number of oocytes retrieved than Table 2. Comparison of clinical and hormonal profile among the poor, normal and hyper responders. Parameters

Response N=246

P value

Poor (N=34)

Normal (N=153)

Hyper (N=59)

Age (years)

33.8 ± 5.3

30.8 ± 4.4

29.0 ± 3.0

.0001

FSH (IU/L)

9.2 ± 2.8

6.7 ± 3.8

6.3 ± 1.4

.0001

AMH (ng/ml)

0.8 ± 0.5

3.4 ± 2.4

8.1 ± 3.0

.0001

AFC

6.1 ± 3.5

11.8 ± 4.8

19.1 ± 4.2

.0001

Significant at P value <0.05

FSH (r = 0.76, 0.73 & - 0.31 respectively). Among the participants, 34 (13.8%) were poor responders, 153 (62.2%) were normal responders and 59 (24%) were hyper responders based on the number of oocytes retrieved during ICSI. The clinical and the Table 3. Stimulation outcome among the poor, normal and hyper responders. Parameters

Number of days of stimulation

Response N=237 Poor (N=25)

Normal (N=153)

Hyper (N=59)

12 ± 2.4

12.1 ± 1.9

12.5 ± 1.8

P value .279

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

ORIGINAL ARTICLE Dose of gonadotropins (IU)

4905 ± 1656.1

3826.8 ± 1406.3

3595.2± 908.5

.0001

Number of follicles

6.7 ± 2.7

14 ± 5.3

25 ± 4.7

.164

Oocytes retrieved

2.6 ± 0.6

11.0 ± 4.5

25.5 ± 5.9 .0001

M II

2.2 ± 0.8

9.1 ± 4.0

20.8 ± 5.7 .0001

Oocytes fertilized

2.4 ± 1.2

7.2 ± 3.4

16.8 ± 5.4 .0001

Pregnancy rate (75)

5(6.6%)

47 (62.7%)

23 (30.7%)

.164

Significant at P value <0.05

hormonal profile among the poor, normal and hyper responders were compared as shown in Table 2. Among the poor responders, 5 patients had cycles cancelled due to less number of follicles on stimulation and 4 cycles were converted to Intra Uterine Insemination (IUI) and Table 4. Comparison of clinical and hormonal profile among the poor, normal and hyper responders. Parameters

Response Poor AUC

p value

AMH (ng /ml)

.912

.0001

AFC

.888

.0001

FSH (mIU/ml)

.753

.0001

Significant at P value <0 .05

hence 25 patients had oocytes retrieval. Stimulation outcome among the three groups were compared as shown in Table 3 ROC Curve

1.0

0.8

0.6

0.4

0.2

0.0 0.0

0.2

0.4

0.6

1 - Specificity

0.8

Figure 1. ROC curve for AMH to predict the Poor response

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

1.0

There was a statistically significant difference in the dose of gonadotropins, number of oocytes retrieved, MII oocytes and oocytes fertilized. To determine if AMH could predict poor response better than AFC and FSH, AUC were obtained (table 4). The cut off value of AMH for poor response of 1.25ng/ ml showed a sensitivity and specificity of 91.2% & 94.1 % respectively

Discussion AMH is a dimeric glycoprotein that belongs to Transforming Growth Factor (TGF) β super family. It is secreted by the pre antral and the small antral follicles. To determine the type of ovarian response prior to ART enrolment is very essential. Yates etal in their study found AMH guided COH improved the positive clinical outcomes and reduced the incidence of the complications.10 Another study by Gnoth etal found AMH is a predictor of Ovarian response and suitable for screening.11 In the present study, the authors investigated the value of serum AMH levels for predicting the ovarian response in patients undergoing COH for ART. The ovarian reserve markers FSH, AMH, AFC are correlated with the number of oocytes retrieved to predict the ovarian response. We observed a significant correlation of AMH with ovarian response when compared to AFC and FSH. (r =0.76, 0.73 and -0.31 respectively). This significant correlation implies that AMH is a promising marker for ovarian reserve. It has been observed that women of comparable age show wide variation in ovarian reserve. Various studies have shown varying cut off values of serum AMH to predict poor response. This may be due to different criteria for poor response, different study population and different sampling assays. In our study, the cut off value of serum AMH of 1.25ng/ml has shown a sensitivity of 91.2% and specificity of 94.1%. Singh Neeta et al 7 have shown a cut off value of 1.4ng/ml with a sensitivity and specificity of 80% respectively. Ruma Satwik et al 8 observed a cut off value of 2 pmol/l for poor response with sensitivity and specificity of 20% and 98%respectively. But they had a huge overlap between average and poor responders in the AMH range of 2-10pmol/L. Jae Eun Lee et al12 9 showed a cut off value of 1.08ng/ml with a sensitivity and specificity of 85.8% and 78.6% respectively. Gnoth etal 11 in their study found levels of AMH ≤ 1.26 ng/ ml are highly predictive of reduced ovarian reserve and should be confirmed by a second line AFC. This variation

ORIGINAL ARTICLE in the cut off values among different studies may be due to different methods of AMH assay being used. In our study AMH generation II assay was used. There are no limitations of the study.

Conclusion AMH is a better predictor of ovarian response and the cut off value of 1.25ng/ml seem to be discriminatory for poor response with good sensitivity and specificity of 91.2% and 94.1% respectively Acknowledgements • Sri Ramachandra University - for GATE Project Funding and for study population • Mr S.Venkatesan - for statistics work.

Competing Interests Nil Bibliography 1. Seifer DB, Mac Raughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum Mullerian- Inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles; Fertil Steril 2002; vol 77, Issue 3: 468-71. 2. Hazout A, Bouchard P, Seifer DB, Aussage P, Junea AM, Cohen Bacrie P. Serum Anti Mullerian Hormone / Mullerian Inhibiting Substance appears to be a more discriminatory marker of Assisted Reproductive Technology outcome than Follicle Stimulating Hormone, Inhibin B or Estradiol. Fertil Steril 2004; vol 82: Issue 5, 1323-9. 3. A.La Marca1, S.Giulini, A.Tirelli, E.Bertucci, T.Marsella, S.Xella and A.Volpe . Anti-Müllerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Human Reproduction 2007; Vol 22, N0 3 pp 766 -771. 4. Kwee J, Elting ME, Schatts R, Mc Donnell J, Lambalk CB. Ovarian volume and Antral Follicle Count for the prediction of low and hyper responders with In Vitro Fertilization; Reproduc Bio Endocrinol, 2007; 15: 9.

5. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum Anti Mullerian Hormone throughout the human menstrual cycle. Hum Reprod 2006; vol 21: issue 12; 3103 -3107. 6. Sleeuti I, Fraisse T, Pillet C, Ibecheole V, Bischof P, de Ziegler D. Serum Anti Mullerian Hormone levels remain stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids. Fertil Steril 2008; 90:395-400. 7. Singh N, Malik Ekta, Banerjee Ayan, Chosdol Kunzang, Sreenivas, Mittal Suneeta . Anti Mullerian Hormone: for Ovarian Response in Controlled Ovarian Stimulation for IVF Patients”: A first pilot study in the Indian Population. J of Obstet Gynecol 2013; 63(4):268 -272 8. Ruma Satwik, Mohinder Kochhar, Shweta M Gupta, Abha Majumdar. Anti Mullerian Hormone cut off values for predicting poor ovarian response to exogenous ovarian stimulation in In Vitro Fertilization. J Hum Reprod Sci 2012 May- Aug, 5(2): 206-212. 9. Renato Fanchin, Luca Maria Schonauer, Claudia Righini, Nelly Frydman, Rene Frydman, Joelle Taieb. Serum anti mullerian hormone dynamics during controlled ovarian hyperstimulation. Hum Rep, Vol 18, No.2 pp. 328 - 332, 2003. 10. A.P Yates, O. Rustamov, S.A. Roberts, H.Y.N. Lim, P.W. Pemberton, A. Smith, L.G. Nardo. Anti Mullerian Hormone- tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF; Hum Reprod, Vol 26, No 9 pp. 2353 -2362. 2011. 11. C.Gnoth, A.N. Schuring, K.Friol.J, Tigges, P. Mallmann, E. Godehardt. Relevance of Anti Mullerian Hormone measeurement in a routine IVF programme; Hum Reprod Vol 23, No 6, pp1359 -1365, 2008. 12. Jae Eun Lee, Jung Ryeol Lee, Byung Chul Jee, Chang Suk Suh, Ki Chul Kim, Won Don Lee, Seok Hyun Kim. Clinical application of Anti Mullerian Hormone as a predictor of Controlled Ovarian Hyperstimulation outcome; Clin Exp Reprod Med 2012; 39(4): 176 -181.

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY

Cord Blood Nucleated RBC–NRBC *N.Hephzibah Kirubamani

Introduction

ucleated RBC (NRBC) are rarely found circulating in older children but they are commonly seen in the cord blood at birth in varying counts. They are primarily produced in the fetal bone morrow in response to erythropoietin and are stored in the marrow as precursors to reticulocytes and mature erythrocytes. Many acute and chronic stimuli cause increases in the number of cord blood NRBCS from either increased erythropoietic activity or asudden release from the marrow storage pools. They can be used to predict the severity of birth asphyxia. It is cost effective and widely available in comparison with Ph estimation. This test can be used at low resource setting where cord blood Ph estimation is not possible. Infants with meconium aspiration syndrome with respiratory symptomatology had higher absolute nucleated RBC counts than infants with asymptomatic meconium aspiration and controls. Similar elevation of NRBC was documented in situations in which compensatory increases in erythropoiesis resulted from chronic fetal Hypoxia , such as maternal Diabetes, Preeclampsia, IUGR

Materials & Methods: Pilot study was done at ST. Thomas Hospital for one year .The control contains 26 Normal non asphyxiated newborns. The study group contains 24 newborns in the form of thin MSAF ,thick MSAF ,Nonreactive CTG, low APGAR at birth ..Cord blood was collected immediately after clamping and cutting the cord.Smears were prepared from these blood samples and stained with Leishman’s stain .These smears were studied in Neubauer chamber under the microscope and total number of nucleated RBCs ( NRBC ) in 100 WBCs were calculated. The counts were correlated with APGAR scores and need for NICU admission. New bon with NRBC of >14/100 WBCs had APGAR scores of less than 4 Results : Table 1 - Shows category of patients:New born recruited in the study were 24 Normal Newborn ,thin MSAF6(12%) ,thick MSAF –6(12%) Nonreactive CTG-6 (12%) low APGAR at birth -6 (12%) Table 1. Category of Patients Category

No of Patients

Normal New born

26(52%)

Thin MSAF

6(12%)

ThickMSAF

6(12%)

• To determine the cord blood nucleated RBCs in normal non asphyxiated Newborns

Non reactive CTG

6(12%)

Low Apgar

6(12%)

• To evaluate whether any difference in the count exists between these conditions and Normal Newborn.

Table one shows distribution of Newborn recruited for study. 52% of Newborn were Normal.12%had thinmMSAF,12% had thick MSAF, another 12% had Non reactive CTG and 12% had low APGAR

Objectives:

• To determine NRBC count in thin ,thick MSAF, Nonreactive CTG and in lowAPGAR states and correlate it with birth Asphyxia

*Prof.N.Hephzibah Kirubamani. Consultant.St.Thomus Hospital & Prof. Saveetha Medical College Saveetha Nager,Thandalam

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

S.NO 1

Table 2 – Shows NRBCs results in various Categories: Number of NRBCS results in various categories were, less than 10 with a mean of 4.76 in Normal Newborn, in Thin MSAF –it was between 4-12 with a mean of 6. In Thick MSAF it was between 8-20 with a mean of 16.6.In Low APGAR it was between 8-18 with a mean of 11.1,. In Nonreactive CTG it was between 2-13 with a mean of 5

CLINICAL STUDY Table 2. NRBC results in the various categories S.No

Category

Mean NRBCs,100WBCs

APGAR scores

Normal New born

8-9

Thin MSAF

Thick MSAF

>15

Low APGAR

4-5

Non reactive CTG

Four Neonates who had NRBC 15/100 WBCs required NICU admission and intensive monitoring.

Table 3 â&#x20AC;&#x201C; shows correlation of the count with APGAR scores: In Normal New born APGAR was 8-9, In thin MSAF, Apgar was 8, in Thick MSAF APGAR was <4, in low APGAR Newborn APGAR was <4 ,In Non reactive CTG APGAR was 6.

Discussion: In our study Newborn with cord blood nucleated RBC/100WBC > 15 had low APGAR scores < 4 correlates with Adhikari et al study. In our study Normal Newborn had NRBC less than 5 which is similar to Green et al study. In Beard RW et al study Newborn with lowAPGAR had NRBCS 13-15 correlating with our study Conclusion: Cord blood Nucleated RBC â&#x20AC;&#x201C;NRBCs gives a clue towards the severity of birth asphyxia and thus can be efficiently used to identify Newborn who require intense Neonatal monitoring, where cord blood Ph cannot be done in low resource setting. NRBCs counts increases with progressive increase in cord acidosis and results in progressive decrease in APGAR score. It very simple and inexpensive method. Acknowledgement: I thank Superintendent of St. Thomas hospital Dr. Rexilenefor permitting to do the study. Reference: 1. Adhikari M, GouwsE, VelaphiSC,Gwamanda.P Meconium aspiration syndrome Importance of the monitoring of Labour .JPerinatol 1998:18:55-60 2. Green DW ,MimouniF.Nucleatederythrocytes in healthy infants of Diabetic mothers.J.Pediatr 1990:116:129-31 3. Beard RW ,P.JSteer,Eigbe.e ,T.J Lissauer Nucleated red blood cells in Meconium aspiration syndrome.Libra.msra. cn Academic Publication

Oral zinc augmentation with vitamins A and D increases plasma zinc concentration: implications for burden of disease. Metab Brain Dis. 2006; 21(2-3):139-47 (ISSN: 0885-7490) Potocnik FC; van Rensburg SJ; Hon D; Emsley RA; Moodie IM; Erasmus RT Department of Psychiatry, Tygerberg Hospital and Stellenbosch University, Stellenbosch, South Africa.

A study evaluating zinc supplementation in patients with Alzheimer's disease yielded variable zinc plasma levels in spite of positive cognitive and physiological results. In an attempt to raise and sustain plasma zinc levels, a single patient was given 15 mg zinc/day with various combinations of vitamins. A sustained raise in plasma zinc concentration (and therefore its potential bioavailability) was obtained only when the zinc was augmented with both vitamins A and D (in RDA concentrations). In order to verify these results, a follow-up study was conducted in 70 volunteers. Seven groups of 10 healthy subjects received various combinations of zinc and the two vitamins A and D, namely: zinc, vitamin A, vitamin D, zinc plus vitamin A, zinc plus vitamin D, vitamins A and D, and zinc plus vitamins A and D. Plasma zinc levels were determined at baseline, 3 weeks and 6 weeks. Plasma zinc levels increased significantly (p < 0.02) from 11.82 (+/-2.60) to 13.32 (+/-3.04) mum/L only in the group receiving the combination of zinc and vitamins A and D. This novel method of increasing plasma zinc levels by the augmentation of vitamins A and D may have implications for the reduction of burden of disease.

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CLINICAL STUDY

Fertility Preservation *P.M.Gopinath

ABSTRACT Cancer survivors are living longer lives in ever greater numbers, due to significant improvements in cancer therapy and changes in population age structures. Cancer survivors may wish to become parents, if they have lost their reproductive function, by using previously stored gametes or gonadal tissue. There should be no ethical objections to offer these services since they are offered with the scope of preserving future fertility. Chemotherapy and radiation can both significantly decrease fertility potential. Radiation therapy impairs normal function of both the ovaries and the uterus. As cancer treatment and curses improve, assisted reproductive technology strives to keep pace. Oocyte cryopreservation, in vitro maturation, ovarian tissue cryopreservation, and uterus and ovary transplantation are all evolving to treat secondary infertility in cancer patients. Because of the rapidly changing field, it has become of paramount importance to educate both the parents and the patient with pediatric malignancy as to the impact their treatment may have on fertility and pregnancy outcome. Twenty-one percent of gynecologic cancers affect women in the reproductive age group. Since an increasing number of women are delaying childbearing and overall survival of many gynecologic malignancies has improved, fertility preservation is an important issue for these young patients. Sperm banking has become a widely accepted compendium of infertility treatment and in recent times mooted as having a new role as fertility insurance Following treatment for cancer, parents have many concerns about the effects on the developing embryo and future cancer risks to offspring and to maternal health during pregnancy. With close monitoring of maternal status during pregnancy, female cancer survivors can achieve a successful pregnancy.

The Epidemiology Of Fertility Preservation

ancer survivors are living longer lives in ever greater numbers, due to significant improvements in cancer therapy and changes in population age structures. Thus, the focus from merely living to living well has highlighted the need for fertility preserving methods during cancer treatment. Pregnancy for women with a previous diagnosis of cancer is safe, with no evidence of increased risk of recurrence. However, offspring of such women may be susceptible to preterm delivery, low birth weight and other perinatal morbidities. Both patients and providers alike may have poor knowledge about fertility preservation during cancer, which highlights the need for increased education in this area. Ethical Discussions In Approaching Fertility Preservation Cancer survivors may wish to become parents, if they have lost their reproductive function, by using previously stored gametes or gonadal tissue. Fertility preservation serves *Dr.P.M.Gopinath MD DGO FMMC FICS FICOG MBA Director & Senior Consultant in Obs & Gyne and IVF SRM Instituted for Medical Science, Vadapalani, Chennai

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

such a wide range of medico-social circumstances, some quite unique, that patient care requires an individualized and multidisciplinary approach. In particular, fertility specialists offering fertility preservation options to cancer patients should be properly trained and knowledgeable to discuss patientâ&#x20AC;&#x2122;s treatment plan, prognosis, as well as unusual health risks for future offspring and the potential harmful effects of pregnancy. Overall, there should be no ethical objections to offer these services since they are offered with the scope of preserving future fertility. However, in practice, there are objections: many options are still experimental; posthumous use of stored tissue or gametes carries some legal issues; concerns exist about the welfare of offspring resulting from an expected shortened life span of the parent; concerns exist about the welfare of children born using gametes frozen after chemotherapy already started; and reseeding of cancer is possible after transplanting cryopreserved tissue.

Ovarian Follicle Development And Fertility Preservation There are strong incentives to better understand the basic physiology of the mammalian ovary. Functioning ovaries have an enormous impact on the health and 15

CLINICAL STUDY well-being of women beyond their role in conception. Further, survivorship after treatment for cancer and other life-threatening illness is increasing. Maintaining ovarian function during and after treatment is therefore critical, given the health benefits of functional ovaries and the potential desire to conceive. Basic research efforts have resulted in increased access to human ovary tissue, and a number of key technologies moving into widespread clinical use in less than a decade. In this chapter, we review the basic biology of the ovary and ovarian follicle, including recent data on stem cell support of the organ, and clarify the difference between oocyte and follicle maturation in vivo with the clinical goal of â&#x20AC;&#x153;oocyte maturationâ&#x20AC;?. Breakthroughs will continue to result from the interplay among infertility treatment, efforts to preserve fertility, and advances in our understanding of basic ovarian biology.

Impact Of Chemotherapy And Radiotherapy On The Ovary Chemotherapy and radiation can both significantly decrease fertility potential. For chemotherapy, factors such as dose, age of patient, type of cancer, and type of drug being used are the most significant prognostic factors in determining future reproductive potential. As the dose and age of a patient increases, the chance of pregnancy decreases. Alkylating agents are the biggest culprits of decreased fertility. Some cancers that are more associated with decreased fertility potential are Hodgkinâ&#x20AC;&#x2122;s lymphoma and breast cancer. For radiotherapy, the most significant factors for future reproductive potential are dose and location. Radiotherapy to the ovaries is the most significant risk factor for acute ovarian failure. There is a direct inverse relationship between radiation dose and fertility potential. Considering the high cure rate of childhood cancers and the deleterious long-term effects of chemotherapy and radiation, it is important to be familiar with both the treatment options for cancer and future fertility. Impact Of Chemotherapy And Radiotherapy On The Uterus Survivorship issues surrounding conception and gestational outcome have gained recognition as the management and outcome of childhood malignancies has become increasingly successful. Issues surrounding future fertility are likely multifactorial including both direct and indirect effects of therapy on the pituitary system as well as the end organs. Radiation therapy impairs normal function of both the ovaries and the uterus. The magnitude of risk is related to the age and menarche status at the time of 16

treatment. Although all treatment for malignant disease is a balance between successful therapeutic outcome and minimized toxicity, it appears that the threshold for radiation is considerably lower than initially perceived. As cancer treatment and curses improve, assisted reproductive technology strives to keep pace. Oocyte cryopreservation, in vitro maturation, ovarian tissue cryopreservation, and uterus and ovary transplantation are all evolving to treat secondary infertility in cancer patients. Because of the rapidly changing field, it has become of paramount importance to educate both the parents and the patient with pediatric malignancy as to the impact their treatment may have on fertility and pregnancy outcome.

Ovarian Transplantation Preservation of ovarian function is a critical concern in premenopausal cancer patients whose treatment include radiation therapy to pelvic structures and incorporate the ovaries in the radiated field. Ovarian transposition is a surgical maneuver used to protect ovarian function prior to delivery of gonadocidal doses of radiation therapy. Embryo Cryopreservation And Alternative Controlled Ovarian Hyperstimulation Strategies For Fertility Preservation Fertility preservation with embryo cryopreservation is a safe and effective option in women with cancer and other disorders requiring gonadotoxic treatment. Most patients presenting have surgically treated breast cancer, who are about to undergo chemotherapy. Other less commonly encountered indications include hematological malignancies and autoimmune diseases such as severe SLE with organ involvement and ITP. Women who are undergoing surgery for endometriosis as well as women with genetic disorders such as Turner syndrome and fragile-X permutation who face similar risks further contribute to the population of women who need fertility preservation procedures. In women with an established partner, fertility preservation entails ovarian stimulation, egg collection, fertilization and embryo cryopreservation. Several concerns have been voiced over ovarian stimulation and resulting hyperestrogenism in women with surgically treated breast cancer. Alternative ovarian stimulation protocols using aromatase inhibitors combined with gonadotropins have been developed with the aim to obviate some of the potential adverse effects. Collection of immature oocytes followed by in vitro maturation and subsequent fertilization appears to be a viable and effective method that may prevent most of the drawbacks of classical ovarian stimulation. Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY Oocyte Cryopreservation Since the 1940s, the cryopreservation field has been deeply studied in order to increase the number of options available for human reproductive technologies. Initially, sperm cells were the only type to be preserved due to their size and high number available; these characteristics made the task relatively easy. Later on, with the advances made in the laboratories, embryo freezing became an available option in in vitro fertilization (IVF) clinics. In 1983, the first pregnancy was obtained from a cryopreserved embryo and provided an important new option, influencing daily practice in the field of reproductive medicine. Consequently, the number of multiple pregnancies was significantly reduced and in the event that pregnancy was not achieved with a fresh cycle, cryopreserved embryos could be used in subsequent cycles without the need to undergo a new stimulation cycle. The overall efficiency was definitely improved. This new success pushed the clinicians further and the investigation on oocyte cryopreservation started. Initially, outcomes were not very encouraging, mainly because of the particular features of the oocyte compared to sperm or embryos. The oocyte, especially in the human, has unique composition in term of water content, membrane stability and intracellular structures. All of these characteristics made it very difficult to cryopreserve oocytes and for many years clinical applications have not been routinely adopted. The low survival rates and objectionable developmental competence of oocytes initially obtained after cryopreservation suggest that this technique could not be safely applied to patients. Moreover, the good results obtained with embryo cryopreservation were satisfying enough to limit research in the area of oocyte freezing for many years. Ovarian Tissue Cryopreservation And Autotransplantation This focuses on an approach to protecting ovarian tissue: the surgical removal and cryopreservation of ovarian tissue (ovarian cortical fragments or the intact ovary) prior to cancer therapy, followed by later auto transplantation. The obvious advantage of this currently experimental approach is that ovarian tissue is completely protected from the deleterious effects of chemotherapeutic agents or irradiation. Challenges of this approach include those related to the surgical techniques, limiting ovarian damage from both cryopreservation and hypoxia, and adapting in vitro fertilization / embryo transfer (IVF/ET) techniques when required. Despite these challenges, this approach has been demonstrated to be feasible and shows great Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

promise for preservation of ovarian function and fertility in women treated for malignancy.

Oocyte In Vitro Maturation: Formidable Obstacles On The Road To Fertility Preservation Oocyte maturation is a complex process that is initiated in the ovarian follicle during pre-antral development and culminates with the release of the mature ovum at the time of ovulation. As fertility preservation strategies emerge, it has become increasingly apparent that supporting oocyte maturation in as physiological a context as is possible is an important goal. This chapter summarizes a body of evidence consistent with the view that enabling and sustaining the metabolic interplay between the oocyte and cumulus cells will be essential to realizing a mature state for the ovum capable of producing viable embryos. Two key parameters are addressed: (1) the changing demands and regulatory mechanisms that distinguish communication between oocyte and granulosa during the growth and maturative phases of oogenesis and (2) the introduction of a paradigm for dissecting periovulatory maturation into several components that extend beyond the traditional nuclear and cytoplasmic properties that have been previously adopted. This framework provides a novel range of attributes in the cumulus-oocyte complex that could be assayed as biomarkers of oocyte quality. Whole Ovary Cryopreservation Surgical, technological, and medical advances in cancer treatment have improved the life expectancy, making quality of life issues in cancer survivors more important than ever before. Within this context, fertility loss due to the side effects of the chemotherapeutic agents or involvement of the gonads has become an active area of investigation. Many patients demand restoration of their fertility after a successful struggle with cancer and ask to discuss fertility preservation options. Currently, the most recommended procedure is to discuss fertility preservation options with the patient prior to the cancer therapy and as a multidisciplinary team. Whole ovary cryopreservation, although still controversial, may soon become an integral part of this discussion. Fertility Preservation In Gynecologic MALIGNANCIES Twenty-one percent of gynecologic cancers affect women in the reproductive age group. Since an increasing number of women are delaying childbearing and overall survival of many gynecologic malignancies has improved, fertility preservation is an important issue for these young 17

CLINICAL STUDY patients. The standard treatment of gynecologic cancers often includes the removal of the ovaries and/or the uterus. Conservative surgery consists of the preservation of at least the uterine corpus and part of one ovary in order to maintain the reproductive potential. While fertility-preserving options are promising, the majority of these procedures are not considered standard of care. The selection of appropriate patients and counseling of interested patients are challenging. Close collaborations between the gynecologic oncologists, reproductive endocrinologists, geneticists and maternal-fetal medicine specialists are necessary. This chapter presents the current standard of care for each type of gynecologic malignancy and discusses the options of fertility preservation for each type of cancer, focusing on the indications, techniques and reproductive and oncological outcomes of fertilitypreserving surgery.

Third-Party Reproduction And Adoption After Cancer: Practical And Emotional Considerations Young women are increasingly treated successfully for cancer. When the treatment or the cancer itself leaves them with limited or no reproductive capacity, but not without the desire for children, they increasingly seek motherhood through third-party reproduction, such as oocyte donation or gestational surrogacy or through adoption. Fortunately, there are a number of resources available for guidance and support in making the transition to parenthood through third-party reproduction or adoption. Pregnancy And Cancer Treatment Following treatment for cancer, parents have many concerns about the effects on the developing embryo and future cancer risks to offspring and to maternal health during pregnancy. With close monitoring of maternal status during pregnancy, female cancer survivors can achieve a successful pregnancy. Fertility Preservation Strategies in Healthy Women Reproductive endocrinologists are faced with the challenge of using various technological and laboratory advances in the field to help healthy women preserve fertility for a number of years until conception is desired. Cryopreservation of oocytes has the advantage that it surmounts the possible ethical, religious and legal limitations of the cryopreservation of embryos. Further improvements in laboratory technologies, like vitrification and in vitro maturation of oocytes or ovarian 18

tissue, are likely to replace embryo cryopreservation as the main strategy for fertility preservation in the near future.

Approach To Fertility Preservation In Adult And Prepubertal Females Fertility preservation is recognized as an issue of great importance to patients diagnosed with cancer. Infertility is emotionally painful for many patients and female patients may see infertility as a loss of their femininity. The available evidence suggests that infertility resulting from cancer treatment may be still more devastating and is often associated with psychosocial distress. In western countries, women are delaying initiation of childbearing to later in life. Since the incidence of most cancers increases with age, delayed childbearing results in more female cancer survivors interested in fertility preservation. Fertility preservation is often possible in adult female patients before starting their gonadotoxic treatments. Embryos, oocytes, or ovarian tissue can be cryopreserved and stored until the time when the patients are diseasefree and wish to start a family. In prepubertal girls, the only options are still experimental and most challenging. Because of differences in clinical presentation of the main disease, expected treatment, age of the patient, existence of a partner and the time available before the onset of cancer treatment, each case is unique and therefore requires individual consideration with regard to the options for fertility preservation. Spermatogenesis And Testicular Function Spermatogenesis is characterized by three specific phases: proliferation and differentiation, meiosis and morphogenesis of haploid germ cells which takes approximately 1 month in mice and 2 months in humans. Sex determination occurs in the fetal gonads during development. Germ cells enter meiosis and thus commit to the oogenic pathway, or stay away from meiosis, enter a state of quiescence and commit to the spermatogenic pathway. The main clinical consequence of defects in testicular differentiation during fetal periods is likely to be infertility. Another outcome of this condition in humans is increased susceptibility to testicular germ cell tumors, which have been proposed to originate from impaired or delayed germ cell differentiation during fetal testis development. Chemotherapy and radiotherapy, even in low doses, may have a detrimental effect on the seminiferous epithelium and disrupt spermatogenesis in both children and adults. The extent of damage to germ cells depends on the class of chemotherapeutic agent, dosage, spermatogenic stage targeted as well as the Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY original pretreatment fertility potential of the patient. Cytotoxic therapy influences spermatogenesis at least temporarily and in some cases permanently. Germ cells are also very sensitive to irradiation while the Leydig cells are more resistant owing to their slower rate of turnover. Radiotherapy affects sperm concentration; moreover, irradiation increases sperm DNA damage.

Impact of Radiotherapy and Chemotherapy on The Testis Nowadays, anticancer treatments involving either chemotherapy or radiotherapy have become increasingly successful and the survival rates have dramatically improved in the last 30 years from less than 20% to nearly 80%. However, according to the doses used and the duration of the treatment, 10-100% of surviving cancer patients will show reduced semen parameters and overall 15-30% will remain sterile on the long term. Inter individual variability exists in the spermatogenetic recovery after any gonadotoxic treatment making any individual fertility prognosis virtually impossible. Furthermore, while the initial treatment is known when starting cancer therapy, eventually the treatment regimen may be changed making any assessment of the risk for sterility even more difficult. Therefore, sperm cryopreservation should be offered routinely to all male patients exposed to gonadotoxic treatments. Age must not be a discriminative parameter since different methods to obtained semen sample are available to obtain sperm from post pubertal patients. When patients have been cured, assisted reproduction, eg., intra cytoplasmic sperm injection can be used to offer patients the best chances to father their genetically own children. In pre pubertal boys, testicular stem cell banking may be offered. Update on Sperm Banking Sperm banking has become a widely accepted compendium of infertility treatment and in recent times mooted as having a new role as fertility insurance. Once looked upon with improbability, this practice has established time and time again to be a successful technique of keeping the anticipation of a family alive for countless families. The motives for storage are as diverse as humans themselves. So far, no limit has been established for how long human semen can be frozen when maintained and stored in appropriate liquid nitrogen storage. Scientific literature shows, conclusively, that the sperm motility, vitality and morphology are not affected by proper longterm cryopreservation. Cryo thaw semen pregnancies have been reported after 2-3 decades of semen banking, Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

till standard guidelines are available. However, the current recommendations being followed for sperm banking are guidelines by the British Andrology Society and the Practice Committee of the American Society for Reproductive Medicine.

Preservation of Sperm Isolates or Testicular Biopsy Samples Retrieval and cryopreservation of testicular sperm has become a cornerstone of infertility treatment in azoospermic men. In obstructive azoospermia, sperm may be retrieved from testis in almost 100% patients and can be frozen in multiple aliquots to avoid repeated surgeries. In approximately 50% of patients with nonobstructive azoospermia, enough sperm may be retrieved for IVFintra cytoplasmic sperm injection (ICSI). Any excess sperm remaining after ICSI can be frozen for future IVF attempts. Frozen testicular sperm are as effective in achieving successful pregnancies as freshly isolated testicular or ejaculated sperm. Treatment with motility â&#x20AC;&#x201C;enhancing agents, such as pentoxifylline, induces motility in frozen-thawed testicular sperm and facilitates selection of viable sperm for ICSI. Special techniques, such as cryopreservation of single sperm within evacuated hamster zona or on a cryoloop, allow storage of extremely poor sperm samples. In USA, at this time, there is no legislative directive with respect to the posthumous procurement of sperm. Germ Cell Transplantation and Neospermatogenesis Germ cells isolated from testicular tissue or derived from embryonic stem cells represent a possible treatment option for children who have survived cancer and for azoospermic men. Self-renewal of spermatogenesis is occurring throughout life. In recent years, spermatogonia transplantation in mammals has been successfully carried out and, more recently, the appearance of germ cell lines derived from embryonic stem cells has rendered the treatment or prevention of azoospermia conceivable. In our laboratory, we have identified and labeled human spermatogenic cells at various steps of differentiation and carried out their xenogeneic transplantation into recipient gonads. In addition, by appropriately modifying culture conditions, we have been able to propagate mouse SSCs in vitro. Testicular Tissue Transplantation for Fertility Preservation Spermatogenesis is a complex process of cell proliferation and differentiation, sustained by a pool of stem cells in 19

CLINICAL STUDY the testis. While our knowledge of spermatogenesis and the biology of spermatogonial stem cells is constantly increasing, it is still far from being complete, especially in the primate testis. Ectopic xeno grafting of testis tissue from larger animals into immune deficient mice results in donor spermatogenesis, with production of fertilizationcompetent sperm. Since its first report in 2002, testis tissue xeno grafting has been evaluated in many mammalian species, including primates. This technique represents a powerful tool to study testis development and spermatogenesis of diverse species in a mouse host. The current chapter focuses on transplantation of testis tissue as a potential alternative for fertility preservation in pre pubertal boys that are subjected to potentially sterilizing cytotoxic cancer treatment. The chapter provides a review of recent developments in testis tissue xeno grafting in primates, including humans. Second, we focus on the cryopreservation of testis tissue as an essential pre requisite to make testis xeno grafting a feasible and practical approach under clinical settings. Finally, we provide a detailed description of the methodology involved in cryopreservation and xeno transplantation of testis tissue.

Stem Cells and Fertility Preservation in Males Recent advances in stem cell biology related to fertility preservation have contributed to improve our knowledge about the etiologies of male infertility and its potential reversion. Several factors related with low fertility in males have been described, such as the effect of different drugs, several types of cancers, aging, hormonal treatments, and the increase in sexually transmitted diseases. Given these increasing hazards, different alternatives for the preservation of male fertility are currently suggested, for instance, cryopreservation of testicular tissue for patients with spermatogenesis activity. However, the number of pre pubertal patients increases yearly due to more cancer cases and associated anomalies. Chemotherapy and radiotherapy treatments block or destroy spermatogenesis. Thus, the search for suitable sources of germ stem cells, unique thanks to their self-renewal and differentiation characteristics, is increasingly necessary. Recent studies have demonstrated the presence of stem cells in adult testes and have described the methodology to isolate and culture these germ stem cells. Here we describe the state of the art in the field and the work underway in male fertility preservation relating to stem cells.

Approach to Fertility Preservation in Adult and Pre-Pubertal Males Recent advances in medicine have led to ever increasing number of pre pubertal and adult males surviving cancer treatment. This has increased the need to improve the existing technology for cryopreservation of gametes and search for new fertility preservation options. As of today, only sperm cryopreservation is considered accepted standard clinical practices. Fertility preservation options in pre pubertal males are still experimental. Cryopreservation of testicular tissue and spermatogonial stem cell transplantation should only be offered within IRB-approved clinical protocol after thorough counseling of patients and their family members as there are still many unresolved issues related to these technologies. Conclusion The cancer patients were considered only with oncological management. The survival was poor in the yester years. In the current years there is lot of improvements in the early diagnosis and tremendous advancements in the surgical, radiotherapy and chemotherapy. This has resulted in dramatic improvements in the survival rates. Now there is an increase in awareness of fertility and there is awareness about this new arena among both the patients and treating oncological team. The new approach is to discuss various options of fertility preservation with relevance to the time available and the availability of the partners and the severity of the malignant conditions at the initial stages of consultation well before the definitive treatment can be initiated. There is lot of ethical and legal issues to be considered before the fertility preservation. The new division of ONCOFERTILITY is a team approach comprising of surgical oncologist, medical oncologist, radiation oncologist and the ART specialist trained in fertility preservation. Preserving the fertility of patients who are minors further complicates the situation. After the acute phase of diagnosis and treatment, patients must adjust to living their lives as cancer survivors. If treatment brings cure or remission, they may consider having children. The decision will depend on the patientâ&#x20AC;&#x2122;s medical status and prognosis, their partner status, their age, whether reproduction can safely occur for patients and offspring, and reproductive options. If cancer survivors are not able to reproduce coitally, they may seek medical assistance, including the use of stored gametes or tissue. They also may consider donor gametes, gestational surrogacy, adoption, or not having children

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY References: 1. Fertility preservation and reproduction in patients facing gonad toxic therapies: A committee opinion, The Ethics committee of the American Society for Reproductive Medicine, Birmingham, Alabama. Received August 21.2013; accepted August 22, 2013; published online October 2, 2013. 2. Fertility Preservation , Emerging Technologies and Clinical Applications Seli & Agarwal, 2012 Springer science + Business Media, LLC First Indian Reprint 2014 3. Preserving options in patients with gynecologic malignancies Ramez.N , Eskander; etal WWW.AJOG August 2011, American Journals of Obstetrics & Gynecology 4. Robertson JA. Cancer and fertility: ethical and legal challenges. JNCI Monograph 2005; 34:104-5 5. U.S. National Institutes of Health, National Cancer Institute, Division of cancer Control and Population Sciences. Surveillance, Epidemiology and End Results Program, 1975-2000. Available at: http://WWW.seer. cancer.gov Last accessed August 30, 2013. 6. Bahadur G, Chatterjee R, Ralph D. Testicular tissue cryopreservation in boys. Ethical and legal issues: case report. Hum Reprod 2000; 15: 1416-20. 7. Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus- review of the effects of treatment of childhood cancer. Hum Fertil(Camb) 2002;5:61-6. 8. Visser JA, de Jong FH, Laven JS, Themmen AP. Anti Mullerian hormone: a new marker for ovarian function. 466 Reproduction 2006;131:1-9 9. Plante M. Fertility preservation in the management of gynecologic cancers. Curr Opin Oncol 2000; 12:497-507. 10. Blumenfeld Z. Gynecologic concerns for young women exposed to gonad toxic chemotherapy. Curr Opin Obstet Gynecol 2003; 15:359-70. 11. Badawy A, Elnashar M, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy- induced ovarian damage prospective randomized study. Fertil Steril 2009;91:694-7. 12. Donnez J, Squifflet J, Pirard C, Demylle D, Delbaere A, Armenio L, et al. Live birth after allografting of ovarian cortex between genetically non-identical sisters. Hum Reprod 2011;26:1384-8. 13. The practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Matyre oocyte cryopreservation: a guideline. Fertil Steril 2013; 99:37-43.

MCQ Q1.

How can you protect ovarian function prior to delivery of Gonadocidal doses of radiation therapy? a) b) c) d) e)

Wedge resection Ovarian drilling Ovarian transposition Hormone therapy None of the above

Q 2. All are prognostic factors in determining future reproductive potential except. a) b) c) d)

Dose of chemo Age of patient Type of cancer Family history

Q 3. The malignancies associated with decreased fertility potential are a) Hodgskin lymphoma b) Breast cancer c) Leukemia d) None of the above Q 4. Indication for fertility preservation are all except. a) Breast malignancy b) Severe SLE with organ involvement c) ITP d) Sickle cell disease e) Social reasons Q 5. Ovarian stimulation protocol in women with surgically treated breast cancer. a) b) c) d)

Aromatase inhibitors + Gonadotropins Clomiphene + Gonadotropins GnRH antagonists All the above

Q 6. Embryo cryopreservation is the best choice of fertility preservation in a) b) c) d)

Adolescent boys before radiotherapy Where partners are available Prior to chemotherapy in adolescent girls All of the above

Q 7. The best person to deal with fertility preservation in cancer patents a) Surgical Oncologist b) Medical oncologist c) Radiotherapist d) ART specialist e) All of them as a team Ans. 1 c ,2 d, 3 d, 4 b, 5 a, 6 b, 7 e

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY

Vaginal Administration of Isosorbide Mononitrate (SR 60 mg Nitric Oxide Donor) for Pre-induction Cervical Ripening Amulya L*, Dhanalakshmi MG†

ABSTRACT Objective: To determine the effectiveness and safety of vaginal administration of 60 mg Isosorbide mononitrate (ISMN SR60 mg) for pre-induction cervical ripening. Study design: This study was a prospective interventional study. The study group consisted of 100 term nulliparous women between 19 and 30 years of age who required pre-induction cervical ripening based on Modified Bishop’s score. They received ISMN SR-60 mg vaginally, in the posterior fornix. After 48 hours Bishop score was reassessed. Results: The highest number of inductions in this study was for postdatism (61%). The majority of patients had a Pre-induction Bishop score of 3-4 (64%). After using ISMN SR-60, the mean Bishop’s score improved by 1-2 with a maximum increase of 4 (p value <0.001) which is statistically significant. It reduced doses of PGE2 gel needed for labour induction and shortened induction delivery interval. Maternal side effects were minimal and no significant fetal side-effects. None of the patients got into spontaneous labour. Conclusions: Vaginal administration of ISMN-SR 60 mg as a single dose is safe and effective in significantly improving the modified Bishop’s score. Since, it does not induce uterine contractions, it can be used as outpatient medication with minimal maternal and no fetal adverse effects. Key words: Pre-induction cervical ripening, isosorbide mononitrate, Bishop’s score

abor is one of the most exciting events for a pregnant woman. Most often the process follows a normal pattern and results in the delivery of a healthy child. Some of the patients who need induction of labour for various medical and obstetrical indications may have an unripe cervix as evidenced by a poor Bishop’s score. These patients tend to have a prolonged induction, requiring long hospital stay before delivery and failed induction which results in an operative delivery. An agent that ripens the cervix without stimulating uterine activity would be the ideal cervical ripening agent.1 This study is focused on the effectiveness and safety of vaginal administration of isosorbide mononitrate (60 mg ISMNSR), a nitric oxide donor (NO) for pre-induction cervical ripening for such patients with a poor pre-induction Bishop’s score.

Material and Methods One hundred pregnant women between 19 and 30 years of age who were nulliparous, term, who fulfilled the inclusion and exclusion criteria were asked to participate

in the study. The women so included in the study were informed about the purpose and nature of the study before giving their consent to participate. This study was a prospective interventional study done in between July 2011 to August 2013. The study was undertaken in the Dept. of Obstetrics and Gynecology in Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Chennai. Drug material used in this study is IMDUR-SR 60 mg (Isosorbide mononitrate) marketed in tablet formulation and is stable at room temperature. (This study was approved by the Institutional Human Ethics Committee REF: CSP/11/DEC/20/90). A detailed history of the pregnancy and other medical problems was taken. General and obstetric examination was done. Vaginal examination was done to assess the bony pelvis and to determine cervical score. Inducibility of cervix was predicted using the modified Bishop’s Table 1. Calde`s Modified Bishop`s Score Score

*Postgraduate Student (2011-2014), † Professor, Dept. of Obstetrics and Gynaecology Sri Ramachandra Medical College and Research Institute (Sri Ramachandra University)Porur, Chennai - 116. Tamil Naidu Address for correspondence Dr MG Dhanalakshmi #3 ,VOC colony Second Street, Aminjikarai, Chennai - 600 029 E-mail: mgdhana@yahoo.in

Dilatation of internal os (cm)

1-2

2-4

Length of cervix (cm)

2-4

1-2

Consistency of cervix

Firm

Average

Soft

Posterior

Mid,

-3

-2

-1,0

Position of cervix Station of head

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY scoring system (Table 1). Ultrasound examination was done whenever appropriate. Inclusion criteria

• • • •

Valid reason for induction of labor Modified Bishop’s Score ≤ 6 Singleton pregnancy Nulliparity

• Cephalic presentation • Intact membrane • 37 completed weeks of gestational age Exclusion criteria

• H/O headache

Observations and Results The age of the patients in this study ranged from 19 to 30 years with a mean of 24.26 (±2.86) years. All patients were nulliparous of which the majority were primigravidae (85%). The majority of patients had a gestational age of 40 weeks. The indications for induction for labor in this study population were gestational hypertension, gestational diabetes, postdatism, oligohydramnios, Rh-negative pregnancy and intrauterine growth restriction IUGR. The highest number of inductions in this study was for postdatism (61%)(Table 2). Table 2. Indication for Induction of Labour

• Intolerance to Isosorbide Mononitrate

Indication

n=100

% percentage

Post datism

• Previous uterine scar

Gestational Diabetes Mellitus

• Chorioamnionitis

Rh negative pregnancy

• Severe pre-eclampsia One hundred nulliparous women who required preinduction cervical ripening, who fulfilled the inclusion and exclusion criteria and who signed an informed consent form, received ISMN SR 60 mg vaginally, placed in the posterior fornix. After 48 hours Bishop score was reassessed. Maternal side effects were recorded. Cervix was defined as ripe, if Bishop’s score was 6. After assessment of Bishop score, subjects underwent further cervical ripening, if Bishop’s score <6 with prostaglandin E2 (PGE2) gel to a maximum of 3 doses. At the appropriate time, amniotomy was performed. Depending on the uterine contractions, frequency and duration, augmentation with oxytocin was done. Intrapartum monitoring was continued. Indications for operative deliveries were documented. Mode of delivery and neonatal outcome were recorded with respect to meconium stained liquor, APGAR score at 1 minute and 5 minutes, and neonatal Neonatal intensive care unit NICU admissions.

Gestational Hypertension

Oligohydramnios

IUGR

• The data is summarized as frequencies or percentages for categorical variables and as means and standard deviations and interquartile ranges for continuous variables, depending on the distribution. • Differences between the pre-drug and post, drug Bishop’s score were compared using the Chi-square test for categorical variables and a two-sample T-test for continuous variables. • A p value of 0.05 or less was used for statistical significance. Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

The distribution of Bishop’s score prior to ISMN-SR 60 mg score ranges between 0 to 4, mean is 2.77 (±0 .993)(Table 3). The Bishop’s score after administration of ISMN SR-60mg was 4.38 ± 1.052 with a range of 0 to 6. The Bishop’s score improved to 5-6 in the majority of patients (51%).(Table 4). Table 3. Bishop‘s Score Prior to ISMN-SR 60 mg Bishop’s score

Frequency (n=100)

Percentage (%)

0-2

3-4

Table 4. Distribution of Bishop’s Score After Administration of ISMN-SR 60mg Post-ISMN score

Frequency

Percentage (%)

0-2

3-4

5-6

Among patients with a pre-Bishop’s score of 0-2, postBishop’s score improved to 3-4 or 5-6 in 94.4% of patients. Among patients with a pre-Bishop’s score of 3-4, post-Bishop’s score improved to 5-6 in 64% of patients. After using ISMN-SR 60 mg, the mean Bishop’s score improved by 1-2 with a maximum increase of 4 (p value <0.001), which is a statistically significant. Thus, there

CLINICAL STUDY Table 5. Mean Change In Bishop’s Score With ISMNSR 60 mg (mean + SD) Bishop’s score

Mean

Standard deviation

Pre-Bishop’s score

2.77

0.993

Post-Bishop’s score

4.38

1.052

Statistically significant (p < 0.001).

was an increase in the proportion of women improving to a favorable Bishop’s score for induction of labor with PGE2 gel.(Table 5 and Table 6) Table 6. Comparison of Pre and Post-ISMN Bishop’s Score Bishop’s score Post-ISMN 0-2

3-4

5-6

0-2 (36%)

24%

10%

3-4 (64%)

23%

41%

Total (100)

47%

51%

Bishop’s score Pre-ISMN

Statistically significant p 0.001.

Up to 35% of patients reported no side effects. Forty-four percent of patients complained of nausea that did not require intervention (Table 7). Table 7. Maternal Side Effects of ISMN-SR 60 mg Maternal effects

n=100

Percentage (%)

Table 9. Post ISMN Bishop’s Score & Induction to Delivery Time Interval Post ISMN Bishop’s score

Delivery time interval (Hrs)

18.3

15.3

Table 10. Mode of Delivery Mode of delivery

n= 100

Percentage (%)

No side effects

Spontaneous vaginal delivery

Nausea

LSCS for fetal distress

Headache

Nausea and head ache

Vacuum assisted delivery for Maternal exhaustion

Vomiting

LSCS for meconium stained liquor

Vacuum assisted delivery for fetal distress

LSCS for arrest of dilatation

LSCS for failed induction

Tachysystole

Hyperstimulation

Table 8. Post Bishop’s Score in Relation with Number of PGE2 Gel Needed for Induction of Labor Post ISMN Bishop’s score

Number of PG E 2 gel used

Fifty-four percentage had spontaneous vaginal delivery, 14% had instrumental deliveries, and 32% had cesarean deliveries.(Table 10). Of the two patients who had cesarean section for failed induction, the Bishop’s score after ISMN 60 mg was 5. The number of PGE2 gel

1 dose

2 doses

3 doses

2 (2)

3 (22)

4 (24)

5 (37)

Table 11. Fetal and Neonatal Side Effects

6 (14)

Side effects

TOTAL

The higher the Bishop score achieved after administration of ISMN SR 60mg, the lesser were the number of doses

of PGE2 gel required for delivery. Forty-four percentage delivered only with two doses of PGE2 gel (Table 8). Among the 100 patients, 65 patients were augmented with oxytocin in the active phase of labor. Thirty patients went into second stage within 4-5 hours period, 35 patients took 6 hours to get into second stage. In 35 patients, oxytocin augmentation was not done, of which 6 patients had meconium stained liquour and 20 patients had fetal distress, so were taken up for low-segment cesarean section (LSCS). For the remaining 9 of patient progressed normally without oxytocin augmentation. Also the higher the Bishop’s score after administration of ISMN 60 mg SR, shorter was the time for induction to delivery (Table 9).

Number

Percentage (%)

MSL

Fetal distress

NICU admission

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY needed for induction was three in both cases and both had ARM, oxytocin augmentation as additional inducing methods. There were no significant neonatal side-effects reported within the 48 hours of observation after administration of ISMN 60 mg SR per vaginally (Table 11). All neonates were examined by a neonatologist and 1 min and 5 minutes APGAR score was assessed. Among the 100 neonates studied, 9 % of babies had an APGAR score ≤7 at 1 minute Among these 9 neonates, 3 were kept for observation for 6 hours in NICU and sent back to the mother’s side and 6 had meconium stained liquor (septic work up done and blood culture sent) observed for 8-12 hours and shifted to mother’s side. The mean APGAR score at 1 min was 6/10. The mean APGAR score at 5 mins was 8/10 (Table 12) Table 12. APGAR Score at 1 Minute and 5 Minutes APGAR 1 min, 5 min

Frequency

6/10, 8/10

7/10, 8/10

8/10, 9/10

DISCUSSION Nitric oxide, a free radical gas with a short half-life of 4 seconds, is thought to be a fundamental mediator of cervical ripening.2,3 The NO concentration in the cervix increases at the end of pregnancy and this may be the final pathway for stimulating cervical ripening by activation of metalloenzymes and increased expression of

cyclooxygenase.4,5 An ideal cervical ripening agent is one which induces cervical remodeling without stimulating uterine activity, No donor ISMN will be such an agent as it has no significant effect on the myometrium, while used for cervical ripening. Ripening of the cervix prior to the induction of labor in women (either pharmacologically or physiologically) is associated with a shorter latent and active phase of labour and a decreased rate of cesarean section.6,7 In this study an attempt has been made to examine NO donors in respect to Efficacy, Safety and Side effects of the agent. In the studies cited above, though various doses and time intervals had been used, the improvement in Bishop’s score ranged from 62% to 68% while the present study had 75% improvement. In the present study, no patients went into spontaneous labour, as in studies by Agarwal8 and Bollapragada9, although T.Shubamangala et al.10 & S.M.Habib et al11 studies had 26% and 19% getting into spontaneous labor. The cesarean rates ranged from a low of 14% in Shubamangala et al10 to a high of 36% in Bollapragada et al9. These rates often reflected the institutional rates and not the influence of the drug. In all the studies the maternal side-effect noted was headache (2-63%) which was manageable with simple analgesics. Nausea was observed in some ranging from 4% to 40%, which was manageable. Eventhough palpitations had been reported anywhere between 13-18% no adverse consequences were observed with most of them settling spontaneously.

Table 12. Comparison of Various Studies Author Year

Dose

Improvement Spontaneous in Bishop’s onset of score labor

Mode of delivery

Maternal side effects

NICU admission

APGAR score of <7

Shubhamangala (2011)

60 mg 48 hours

62%

26%

Vaginal-86% Ceserean 14%

Headache (22%) Nausea (4%)

Agarwal (2012)

40 mg 24 hours

65%

Nil

Headache (63%) Palpitations (18%)

1% at 1 min

Bollapragada (2009)

40 mg 48,36,12 hours

68%

Nil

Vaginal 64% Ceserean 36%

Headache (2%) Nausea (17%)

10.2%

1.7% at 5 min

Habib (2007)

2or 3 doses Self administered

62%

19%

Vaginal-(70.59%) Ceserean29.41%

Headache (13.7%) Palpitations (13.7%) Tachysystole (1.1%)

Nil

1.96% at I min

Present study (2013)

60 mg 48 hours

75%

Nil

Vaginal-(68%) Caeserean -32%

Headache (11%) Nausea (40%)

Nil

3% at 5 min

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY Most of the NICU admissions were mainly done for observing babies who had meconium stained liquor or low APGAR Score at birth. APGAR Scores at either 1 minute or 5 minutes reflected peripartum events and do not seem to have been worsened by ISMN-SR-60 mg administration. Thus vaginal administration of 60 mg ISMN to pregnant women at term is safe with minimal documented side effects on maternal and fetal hemodynamics. Hence, No donors are suitable agents for preinduction cervical ripening at term, and can be used as outpatient method with no need for fetal monitoring, being a uterine relaxing agent. This study provides evidence on the efficacy of outpatient ISMN SR-60 mg for pre-induction cervical ripening at term. This drug (tablet) which is cheap and widely available is effective, acceptable to women, and cost-effective, it could be implemented into obstetric practice.

Conclusion Vaginal administration of ISMN-SR 60 mg as a single dose is effective in significantly improving the modified Bishop’s score. Since, it does not induce uterine contractions, it can be used as outpatient medication with minimal maternal and fetal adverse effects. References 1. Furchgott RF and Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 288, 373-376. 2. Väisänen-Tommiska M, Nuutila M, Aittomäki K, Hiilesmaa V, Ylikorkala O (2003) Nitric oxide metabolites in cervical fluid during pregnancy: further evidence for a role of cervical nitric oxide in cervical ripening. Am J Obstet Gynecol, 188, 779-785.

3. Chwalisz K and Garfield RE (1998) Role of nitric oxide in the uterus and cervix: implications for the management of labor. J Perinat Med, 26, 448-457. 4. Habib SM, Enam SS, Saber AS. Outpatient cervical ripening with nitric oxide donor isosorbide mononitrate prior to induction of labor. Int J Gynaecol Obstet 2008;101:57-61 5. Garfield RE, Saade G, Buhimschi C, Buhimschi I, Shi L, Shi SQ and Chwalisz K (1998). Control and assessment of the uterus and cervix during pregnancy and labor. Human Reproduction Update 4(5) 673-675. 6. Vahratian A, Zhang J, Troendle JF, Sciscione AC, Hoffman MK. Labor progression and risk of cesarean delivery in electively induced nulliparas. Obstet Gynecol 2005;105:698–704 7. Johnson DP, Davis NR, Brown AJ. Risk of cesarean delivery after induction at term in nulliparous women with an unfavorable cervix. Am J Obstet Gynecol 2003;188:1565–9 8. Kavita Agarwal , Aruna Batra, Achla Batra, Anjali Dabral, Abha Aggarwal.Evaluation of isosorbide mononitrate for cervical ripening prior to induction of labor for postdated pregnancy in an outpatient setting. International Journal of Gynecology and Obstetrics 118 (2012) 205–209. 9. Bollapragada S.S., Mackenzie F., Norrie J.D., Eddama O., Petrou S., Reid M. et al. ,2009. Randomised placebocontrolled trial of outpatient (at home) cervical ripening with isosorbede mononitrate (IMN) prior to induction of labourclinical trial with analyses of efficacy and acceptability. The IMOP study. BJOG; 116: 1185-95 10. T.Shubamangala, Ramalingappa C, Anfarantani. Out patient vaginal administration of isosorbide mononitrate for pre induction cervical ripening. Asian journal of Obs and Gynae practice ,vol 2,April-june 2011. 11. Habib SM, Enam SS, Saber AS. Outpatient cervical ripening with nitric oxide donor isosorbide mononitrate prior to induction of labor. Int J Gynaecol Obstet 2008;101:57-61

Knowledge and use of folic acid in women of reproductive age Folic acid reduces the risk of neural tube defects. As approximately 50% of pregnancies are unintended, women of reproductive age should be aware of the importance of folic acid. We reviewed the existing literature on these women's knowledge of folic acid and neural tube defects. Databases searched were PubMed, CINAHL, and Health Reference Center Academic. We used terms such as "folic acid knowledge" and "folic acid awareness" to search articles published from 1998 to 2010. Awareness of the benefits of folic acid before conception and during pregnancy was low, although knowledge levels were associated with education and household income. Women who were already knowledgeable about folic acid cited health care professionals, magazines and newspapers, and radio and television as common sources of information. Effective knowledge translation is needed to ensure that women are informed about the benefits of folic acid during the reproductive years. This knowledge will allow them to make informed decisions about folic acid consumption. Health care professionals play an influential role in promoting folic acid knowledge among women of childbearing age. Lower levels of knowledge among women with lower levels of education and/or household income must be addressed. Source: Can J Diet Pract Res. 2011

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CLINICAL STUDY

Matching Medical Horoscope - A Look Into Future ! Rajapriya Ayyappan

ndia is a country diverse in culture ,language ,religion and ways of life. Marriage is traditionally and proudly arranged by the parents based on what they think is right for the concerned couple. With changing times and more freedom for the younger generation to express their likes and dislikes ,it is getting difficult to make an arranged Marriage work long! IS Marriage STILL DIVINE ! With people becoming more career-oriented, casual and self-centred, marriage is gradually losing its status of a dignified institution. The sanctity attached to this institution is fading away. In metropolitan cities, the picture is even more disheartening. Divorce rates are skyrocketing. In India, the practice is still part of tradition–of alliances made on the basis of horoscopes, religious, cultural and/or financial backgrounds . Premarital counselling may soon have a regular role as part of marriage event manager’s agenda! It is time we start ascertaining the compatibility of a couple to make marriages work better – and, on more practical and realistic grounds by way of pre-marital counselling and certain pre-marriage medical check-ups. Q1. Why the need ? To make marriage work better,plan better. Is the goal of marriage, procreation, recreation or a successful partnership into eternity! To give knowledge from the medical perspective –sexual counselling,contraceptive advice,preconceptional folate use,address fertility potential of the concerned partners. To enlighten on healthy lifestyle to become ready to start a family ,to plan a baby,to postpone a pregnancy until financially stable,to avoid termination of pregnancy and the risk of pelvic infection and possible subfertility! To be able to handle new relations,adapt to a different homestyle ,sometimes a counsellor may be part of this process too! In many Christian weddings the church plays an active role by conducting premarital classes, afterall with marriage comes responsibility! SOON, An

Dr Rajapriya Ayyappan Ohm IVF And Research centre, Perambur

increasing number of would-be couples ,will be opting for the pre-marital medical tests and medical counselling sessions. A healthy trend to be welcomed! Q.2 What services are provided to couples through the premarital counseling program? a) Review of medical and family history for genetic diseases. b) Relevant blood tests,semen analysis c) Arranging for specialist consultation as needed. Heart problems or epilepsy or medical disease d) Providing the necessary vaccines such as Rubella and Hepatitis B to susceptible individuals. e) Providing health education and guidance on a healthy pregnancy. f ) Offering sex education,family planning advice g) Identify - chronic ailments, if any/any pelvic or genital surgery h) History of psychiatric disorder i) Gynecologist role to identify Sexually Transmitted Diseases, genetic disorders,previous pelvic surgery and possible subfertility in the male and female. Cousin couples or consanguineous marriages should also be scrutinized for genetic diseases. Apart from sexuallytransmitted-diseases, it is essential to know whether both partners are unknowingly carrying thalassaemia minor traits. This may manifest in the form of a thalassaemia major child,a dreaded blood disorder. It is essential to know about the physical wellbeing of both partners before they marry, particularly about one’s “reproductive ability”, and diseases that could be transmitted sexually. People are fast becoming aware of HIV testing before marriage; however, a majority still do not know about the “window period.” We strongly recommend two HIV tests with a gap of three months before marriage.A carrier of hepatitis-B appears healthy outwardly, but can transmit the deadly disease to the partner through sexual contact. VDRL test, or TPHA test, for syphilis is a must in all check-ups before marriage. If a test result proves positive for any genetic disorder or HIV in any of the prospective Cont'd on page 30...

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CASE REPORT

Obstetrics Is Bloody Business *Palaniappan N, †Sathyapriya, ‡Radha Vembu, ‡Sivasundari

ABSTRACT Subarachnoid hemorrhage is a rare obstetric complication, but associated with a high maternal mortality rate, requiring timely diagnosis and intervention (1,2). SAH most commonly occurs in the third trimester (4,5). We present a case report of a primigravida at 38 weeks gestation who was referred to our hospital with severe headache. A plain MRI revealed SAH in all the ventricles and a bilobed aneurysm in the left intracranial Internal Carotid Artery. A caesarean section was performed to deliver the baby, followed by Digital Subtraction Angiography and endovascular coiling by balloon remodelling technique.

INTRODUCTION Subarachnoid hemorrhage (SAH) following rupture of cerebral aneurysms in pregnancy, is a rare cause of morbidity and mortality, accounting for 5 to 12% of maternal deaths from non obstetric causes.1,2 The risk of aneurysmal rupture and bleed in pregnancy is thought to increase with gestational age.2 Hemodynamic and endocrine changes associated with pregnancy play a role in the growth and rupture of aneurysms.3 The risk of aneurysmal rupture during the first, second, third trimester, and postpartum is reported to be 6%, 31%, 55%, and 8% respectively.4,5 Because of its rare occurrence, SAH manifested by severe headache maybe confused with other conditions such as eclampsia, postdural puncture headache, venous sinus thrombosis hence rapid diagnosis and immediate treatment is beneficial in reducing the maternal mortality.

Figure 1. (A) MRI brain showing bilobed aneurysm in the left intracranial Internal Carotid Artery

CASE REPORT A primigravida at 38 weeks gestation was admitted with severe headache. She had been referred from an outside hospital where she had been scheduled for an emergency caesarean section. She developed sudden severe headache with neck stiffness following three bloody spinal taps. Prior to this she had had an uneventful antenatal period.

*Professor † Senior Resident ‡ Associate Professor Address for correspondence Sri Ramachandra Medical College Porur, Chennai-600116

Figure 1. (B) CT brain done after coiling demonstrates reveals coil in situ.

Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

CASE REPORT

On admission, neurologist opinion was obtained and a plain MRI brain carried out. The same revealed Sub Arachnoid Hemorrhage in all the ventricles and basal cisterns, mild dilatation of bilateral ventricles, and a bilobed aneurysm in the left intracranial Internal Carotid Artery just before the origin of the ophthalmic artery measuring 3.5 x 2.8 mm. After consultation with the attending neurologist, it was decided that the patient would undergo caesarean section. The same was performed under general anaesthesia, and a healthy girl baby was delivered. Intraoperatively she had mild atonic hemorrhage, which was managed with uterotonic agents, compression sutures and balloon tamponade. She was shifted to the intensive care unit and continued on elective ventilation. On postoperative day 1 the bakri balloon was removed. A decision was made to perform endovascular coiling of the aneurysm. On postoperative day 2, under general anaesthesia, using retrograde Seldinger’s technique, 4 vessel angiogram was done which revealed left ophthalmic segment of ICA aneurysm measuring 4.8 x 3.6 x 3.8 mm with neck dimension of 3mm. Rest of the intracranial vessels appeared normal. The aneurysm was accessed with ECHELON/ TRANSCEND microcatheter/ guidewire combination. The aneurysm was coiled by balloon remodelling technique, while taking care to avoid prolapse of coil or catheter into the parent artery. Post procedure angiogram revealed coiled aneurysm. Postoperatively she was monitored in the ICU, and extubated the following day. The postoperative period was uneventful and the patient was discharged on POD.9

DISCUSSION SAH is a very rare complication in pregnancy, the main causative factor being ruptured intracranial aneurysms (5180%), followed by hypertensive disease (10- 15%), and arteriovenous malformations (5-10%). Other rare causes are meningeal infections, tumours and blood dyscrasias.6,7 The diagnosis may be confirmed with neuroimaging (CT scan, MRI, cerebral angiography). Studies suggest that the hemodynamic changes associated with pregnancy are the cause of aneurysmal instability. 4,8,9,10 Cardiac output increases as much as 60% by the end of the second trimester. Progressive increases in blood volume and pressure reaches a maximum at term. Analysis suggests that surgical treatment after aneurysmal SAH is beneficial for both mother and fetus, with a significant reduction in maternal mortality in the operative group. A multidisciplinary approach must be made towards Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

the management of SAH from aneurysmal rupture in pregnancy and must involve the neurosurgeon, intensivist, neuroradiologist, obstetrician, neonatologist. Ruptured aneurysm in the pregnant patient requires immediate treatment, and the general consensus is that the treatment must be administered as in non pregnant patients.11,12 One of the main concerns involved with the endovascular treatment is the angiography involved with the procedure and the potential risk to the fetus resulting from radiation exposure. This risk was eliminated in our patient since a decision was taken to deliver the fetus by caesarean section before endovascular coiling of the ruptured aneurysm. Nevertheless the interventional radiologist has the responsibility to limit radiation exposure through abdominal shielding, limited fluoroscopy in proximity to the uterus, and minimizing procedure time. The safety, efficacy, and successful outcome of endovascular coiling in treating cerebral aneurysms has been highlighted through many studies.13,14 Despite the low incidence of Subarachnoid hemorrhage due to aneurysmal rupture in pregnancy, it is associated with a high mortality rate and therefore it is imperative that the obstetricians maintain a high index of suspicion when a patient presents with acute headache particularly if accompanied by neurological symptoms, and initiate treatment at the earliest possible. Obstetric haemorrhage whether from the uterus or elsewhere is definitely a bloody business

REFERENCES 1. de Swiet M. Maternal mortality: confidential enquiries into maternal deaths in the United Kingdom. Am J Obstet Gynecol 2000;182:760–6. 2. Kittner SJ, Stern BJ, Feeser BR, Hebel JR, Nagey DA, Buchholz DW, et al. Pregnancy and the risk of stroke. N Engl J Med 1996;335:768. 3. Marshman LAG. The implications of ISAT and ISUIA for the management of cerebral aneurysms during pregnancy. Neurosurg Rev 2007;30:177. 4. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery 1990;27:855– 65, discussion 865–56. 5. Stoodley MA, Macdonald RL, Weir BK. Pregnancy and intracranial aneurysms. Neurosurg Clin N Am 1998;9:549–56. 6. Young BJ, Seigerman MH, Hurst RW. Subarachnoid hemorrhage and aneurysms. Semin Ultrasound CT MR 1996; 17: 265-77. 7. Latchaw RE, Silva P, Falcone SF. The role of CT following aneurysmal rupture. Neuroimaging Clin N Am 1997; 7: 693-708.

CASE REPORT 8. Copeland EL, Mabon RF. Spontaneous intracranial bleeding in pregnancy. Obstet Gynecol 1967;20:373–378

12. Ng J, Kitchen N. Neurosurgery and pregnancy. J Neurol Neurosurg Psychiatry 2008;79:745.

9. Daane TA, Tandy RW. Rupture of congenital intracranial aneurysms in pregnancy. Obstet Gynecol 1960;15:305–314

13. Kassell NF, Torner JC. Size of intracranial aneurysms. Neurosurgery 1983;12:291-7.

10. Robinson JL, Hall CJ, Sedzimir CB. Subarachnoid hemorrhage in pregnancy. J Neurosurg 1972;36:27–33

14. MeyersPM, Halbach VV, Malek AM, et al. Endovascular treatment of cerebral artery aneurysms during pregnancy: report of three cases. AJNR Am J Neuroradiol 2000; 21(7): 1306–1311.

11. Sloan MA, Stern BJ. Cerebrovascular disease in pregnancy. Curr Treat Options Neurol 2003;5:391–407.

...Cont'd from page 27 partners, does any law have the power to prevent them from legally marrying? No, it would be an encroachment on the autonomy and the human rights of the individual. It would be completely unethical. An ethical question arises that the most important fundamental human right is to marry and reproduce, and the premarital medical examination undermines that right A simple semen examination of the groom-to-be and sonography examination of the uterus and ovaries of the bride-to-be are recommended as screening tests – to assess the reproductive ability of the couple. Sex education sessions need to include a frank discussion

on family planning and contraceptive measures to be used. Planned parenthood, which takes into account the feelings of both partners, is extremely important in order to have a pleasant feeling during pregnancy. This creates an agreeable, conducive environment to welcome a healthy child. A healthy understanding of their new relationship and teach them the art of enjoying their sexuality and freedom with responsibility . In an era of holistic health for man,its time for Holistic Matchmaking of Couples from routine horoscope to medical horoscope.

Effects of maternal zinc supplementation on pregnancy and lactation outcomes Observational studies in human populations suggest that maternal zinc deficiency during pregnancy may cause adverse pregnancy outcomes for the mother and fetus. Therefore, we reviewed the current evidence from studies of zinc supplementation, with or without other micronutrients, during pregnancy and lactation to assess its impact on maternal, fetal, and infant health. A meta-analysis of supplementation trials indicates a 14% reduction in premature delivery among zinc-supplemented women. Most studies found no significant impact of maternal zinc supplementation on infant birthweight, but a subset of studies conducted in underweight or zinc-deficient women suggests that there may be a positive effect of zinc supplementation in such women. However, the number of relevant studies is limited, and more information is needed to confirm these observations. The results for other pregnancy outcomes are inconsistent, and the number of available studies is small. Likewise, the impact of maternal zinc supplementation during pregnancy on infant postnatal growth and risk of infection is variable, and few studies are available. Thus, more research will be needed to allow definitive conclusions to be drawn, especially for the second half of infancy and later childhood. Studies found no adverse effects of maternal zinc supplementation on iron status during pregnancy. More information is required on other potential adverse effects, particularly with regard to a possible modifying effect of preexisting maternal zinc status. In view of the possible benefits of zinc supplementation for reducing the risk of premature delivery, the possible positive impact of zinc supplementation on infant birthweight among undernourished women, and the lack of reported adverse effects, zinc should be included in maternal supplements given during pregnancy in populations at risk for zinc deficiency.. Source: Food Nutr Bull. 200

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REVIEW ARTICLE

Periodontal Infections And Adverse Pregnancy Outcomes *Anupama Dave

ABSTRACT Focal infection, a concept widely popular in the 20th century went into oblivion later. However, it has a reawakening in the last two decades. Dental infections play a major in this concept. Inflamed gums and supporting structures of teeth called periodontal disease have gained increasing importance with reference to their ability to cause/contribute to various systemic diseases. Periodontal disease, a chronic inflammatory disease caused by Gram –ve bacteria and resulting in release of several inflammatory mediators has been associated with adverse pregnancy outcomes like preterm birth, low birth weight, threatened abortion, bacterial vaginosis, intrauterine growth restriction, small for-gestational babies. Treatment of periodontal infections in a pregnant patient appears to have beneficial outcomes. However, there is a controversy related both to association of periodontal disease and pregnancy outcomes, and also effect of dental treatment on beneficial outcomes. This review presents a balanced view of the Oral-Pregnancy association and aim at improving obstetrician’s awareness of the current status of the relationship between dental infections and pregnancy outcome. Controversy notwithstanding, proper oral hygiene and elimination of dental sepsis during pregnancy seems to be prudent.

ental infections causing systemic diseases in distant parts of the body has been known for decades. The concept called focal infection was very popular in the beginning of 20th century. It got an impetus after William Hunter’s forceful pleas against dental sepsis in 1910. The concept fell into oblivion due to thoughtless and unmindful sacrifice of teeth and tonsils for alleged role in causing systemic disease. In 1989 the concept got a fillip when a couple of Danish workers reported increasing incidence of coronary heart diseases in the presence of periodontal disease . From then on there is a surge of interest in dental infections causing systemic disease. From cardiocavascular disease , stroke, preterm babies, pulmonary disease, total mortality, Alzheimer’s disease, dementia, many other systemic conditions are directly or indirectly relayed to chronic periodontal infections. Galloway in 19311 reported focal infection in teeth and tonsils affected the fetus. His was probably the first interventional study when he resorted to extraction of abscessed teeth and observed no incidents of miscarriage

*Associate Professor Address for correspondence Associate Professor MGM MC Indore

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or still birth in such subjects. He suggested that all focus of infection should be removed or treated early in pregnancy to avoid later unwanted sequel. Periodontal diseases are a group of diseases which affect the supporting structures of teeth. The involved teeth are normal but it is the gums and alveolar bone which suffer most. Called Pyorrhea in earlier literature, it is prevalent universally and no continent or country is unaffected from this chronic ailment. Characterized by gum bleeding, discharge of pus and progressive mobility of teeth and their ultimate loss, the disease is chronic, painless and there is no compelling urge for seeking treatment in the absence of severe pain. Contrary to dental caries which involves few teeth, periodontal disease involves most teeth and is the most common cause of tooth loss (fig.1) During pregnancy the incidence of gingivitis and periodontitis is increased and many pregnant women suffer from bleeding spongy gums. The changing hormone levels during pregnancy coupled with lack of oral hygiene account for most of the gingival changes. 50-70 % of all pregnant women develop gingivitis called pregnancy gingivitis. Increase in progesterone and estrogen levels during pregnancy affect small blood vessels of gingiva leading to their increased permeability. The increase inflammatory nature of the gingiva favors pathogenic bacteria to take advantage of the situation and a frank disease results. The result is a host response to the microbial attack by increased proinflammatory cytokines like PG2, ILl alpha and tumor necrosis factor. Preterm birth and low birth weight are leading problems

REVIEW ARTICLE and cause considerable social, psychological and economic burden on the families affected. Important risk factors include intrauterus infections and bacterial vaginosis of the mother. Even distant infections may also produce preterm births. Periodontitis being chronic and often subclinical is also suspected for providing the inflammatory component to fetal life . It has been increasingly reported that pregnant women with periodontitis have more chances of associating with adverse pregnancy outcomes like preterm birth, lowbirth weight, preeclampsia, gestational diabetes, , delivery of small-for-gestational age infant and fetal loss. It al started 13 years ago when Offenbacher 1996 2 and workers at University of North Carolina studied whether the prevalence of maternal periodontal infection could be associated with preterm low birth weight (PLBW), controlling for known risk factors and potential covariates. Studying 124 pregnant women or postpartum mothers and assessing other known obstetric known risk factors, demonstrated that periodontal disease is a statistically significant risk factor for Preterm Low birth weight and concluded that periodontal diseases represent a previously unrecognized and significant risk facto for preterm low birth weight. From 1996, there has been a deluge of research papers dealing with the subject. There have been papers supporting the hypotheses and some which did not report any association and some reporting weak association. In another study the average weight of the newborns in the periodontitis group was less than in the control group, and it was concluded that localized periodontitis of the patient during pregnancy can be regarded as an important risk factor for PB. In an article published in Lancet, Pihlstrom and workers (2005)3 stated that periodontal disease have been associated with adverse pregnancy outcomes, cardiovascular disease, stroke, pulmonary disease, and diabetes but the causal relations have not been established. Controlling bacterial biofilm, arresting periodontal disease and restoring lost support has been suggested to improve pregnancy. A prospective study entitled Oral Conditions and Pregnancy (OCAP), Offenbacher (2006)4 reported incidence of preterm birth as 11.2% among periodontally healthy women, compared with 28.6% in women with moderate-severe periodontal disease and concluded that maternal periodontal disease increases relative risk for preterm or spontaneous preterm births. Xiong (2006)5 in a paper published in BJOG reviewed the status of periodontal disease and adverse pregnancy outcomes. Of twenty five studies, 18 suggested an

association between periodontitis and adverse pregnancy outcomes, 7 found no evidence of association. In three studies, prior scaling and periodontal treatment lead to an 57 % reduction in PLBW and a 50 % reduction in preterm births. Delivery of a small-for-gestational-age infant in mothers with moderate or severe periodontal disease early in pregnancy was reported by Boggess et al.6 Linking gingivitis to bacterial vaginosis Person(2009)7 reported that higher vaginal bacterial counts are possible in women with gingivitis in comparison to with bacterial vaginosis but no gingivitis. P. bivia and P. disiens may be specific in a relationship between vaginal and gingival infections. In a thorough review of literature on the subject, twenty-six epidemiological studies reported associations between periodontal disease and adverse pregnancy outcomes. However, most studies did not control for confounders, thus raising serious doubts about their conclusions. The conclusions drawn by various workers had methodological limitations and could not be relied upon to establish an association between periodontal disease and adverse pregnancy outcomes. In spite of conflicting risk factors and contradicting statements, most of the clinical studies indicate a positive correlation between periodontal disease and preterm birth. Microbiological and immunological findings strongly support the association. Placental-fetal exposure to periodontal infection and resulting fetal inflammatory response can lead to preterm delivery. To determine whether maternal periodontitis is associated with an increased risk of preeclampsia a case-control study in Brazil reported that maternal periodontitis was associated with increased risk of preeclampsia . In a study in Turkey, Tygor8 reported that maternal periodontal disease may be a risk factor for an adverse pregnancy outcome. Studying 1,305 Brazilians in a case-control study to determine the association between maternal periodontitis and preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR) In a prospective cohort study in Pakistan 1152 women were assessed for their dental status and followed up for pregnancy outcomes.9 Low birthweight was not related to measures of periodontal disease. Stillbirth and neonatal and perinatal deaths increased with the severity of periodontal disease. In a study of 1404 pregnant women in Spain reported a modest association was reported between periodontitis and preterm birth Lopez (2008).10 Though not all of the actual data support the periodontalâ&#x20AC;&#x201C;pregnancy connection, assessment of the periodontal status of pregnant women during an early pregnancy might be Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

REVIEW ARTICLE useful to minimize future obstetric complications.

A review of 31 published studies showed that 22 showed a positive association between premature birth and periodontal disease.11 Preterm low birth weight was reported to be related to periodontal infections that might influence the fetus-placenta complex. If periodontal inflammation is directly or indirectly responsible for adverse pregnancy outcomes, the natural corollary would be treatment or elimination of such inflammation would reflect in lesser occurrence of adverse events. There are contradictory reports in this regard. The strategy involves exposing the pregnant woman to good oral hygiene, oral prophylaxis and observing their post partum events and comparing with those who did not receive any dental treatment. The hypotheses would be tenable only if significant number of pregnant women show lesser adverse outcome events compared to controls. Few studies have examined the potential effects of periodontal treatment during pregnancy on pregnancy outcomes, periodontal status, and inflammatory biomarkers. In a pilot study in 2003, Jeffcoat 12 and workers did periodontal treatment during pregnancy and observed them for pregnancy outcomes. Performing scaling and root planing suggested a reduction of preterm birth in their group. Periodontal treatment resulted in a significant decrease in periodontopathic bacteria, serum IL-6, and gingival crevicular fluid IL-1beta. This particular research supports the view that periodontal treatment has beneficial value on pregnancy outcomes. A 3.8- fold decrease in the rate of preterm delivery with periodontal intervention is a welcome development.13 Gazolla et al ( 2007)14 tried to evaluate the efficacy of any periodontal treatment benefits on pregnancy outcomes. Mothers who had treatment for their periodontal conditions fared better than those who did not receive such interventions. Periodontal disease was related significantly to preterm delivery. Another study of particular relevance is an Indian one from Bangalore conducted by Fouzia Tarannum and Faizuddin15 who tested the efficacy of periodontal treatment during pregnancy and compared with controls for any adverse outcomes. Periodontal treatment during pregnancy included plaque control instructions, scaling and root planing. A Asian Journal of Obstetrics and Gynecology Practice, Vol. 1, No. 3

significant effect of periodontal treatment on birth outcomes was the reported observation. P gingivalis is a microorganism involved in periodontal disease and has been found in amniotic fluid of few pregnant women and some of them experienced threatened premature labour.16 Pregnant mice infected with p. gingivalis have elevated levels of maternal tumor necrosis factor alpha, suppresses maternal interleukin-10 and enhances fetal growth restriction. With reference to the awareness of periodontal health pregnancy outcomes among obstetricians and physicians, an interesting study in North Carolina reported that most answered correctly that periodontal disease is caused by bacteria and 84 % considered periodontal disease to be as important a risk factor to adverse pregnancy events. Medical fraternity was aware of periodontal disease and its implications on pregnancy outcomes. Such a dissemination of information about oral-systemic connection among the medical colleagues in India is the need of the hour. THE OTHER SIDE OF THE COIN: Not all the evidence supports the oralâ&#x20AC;&#x201C;pregnancy connection. In a study of 328 all Caucasian women, Heimonnen (2008)17 found no differences between the preterm and full-term mothers. As far as their periodontal status was concerned, Primiparity, low weight-gain, and antimicrobial drug use during pregnancy were the significant predictors for preterm birth. The study could not establish any linkage between periodontal parameters and pregnancy outcomes. Only established systemic risk factors explained the preterm birth. In a multicentered, randomized controlled clinical trial published in New England Journal of Medicine, Michalowicz (2006)18 and workers could not establish any association between treatment of periodontal disease during pregnancy and subsequent pregnancy outcomes. This has opened up an interesting debate and the topic continues to enliven the research circles to further probe the relationship. However, it has been pointed that single randomized trial cannot have finality and additional research and focus are needed in this important tissue. Wimmer (2008)19 is more categorical and forthright in highlighting the inadequacies of research in establishing the association. Definitions of what constitutes periodontal disease and inadequate control of confounding factors make the study of association between periodontal infections and adverse pregnancy outcomes. There is no 33

REVIEW ARTICLE conclusive evidence that treatment of periodontal infection results in better birth outcome. While maternal treatment of periodontal disease will improve reducing signs of gum disease, it does not reduce the rate of preterm birth. Srinivas and workers from the Department of Obstetrics and Gynecology, University of Pennsylvania Health System very recently ( May 2009) in a multicenter prospective cohort study 20involving three hundred eleven patients with and 475 without periodontal disease could not establish any association between periodontal disease and composite outcome or PTB. They had the last word in this regard when they concluded that ‘despite the body of literature suggesting an association between PD and adverse pregnancy outcomes in urban populations, this large prospective study failed to demonstrate an association.’ Pre-term birth is a major cause of infant mortality and morbidity and has considerable social, medical, and economic impacts. The rate of pre-term birth appears to be increasing world-wide and efforts to prevent or reduce its prevalence have been largely unsuccessful. Adverse pregnancy outcomes have many risk factors and periodontal disease if recognized as a risk factor, the identification of such causal /contributory relationship would have far reaching and long-lasting effects on the society. Conceding that there is an ongoing debate, it has to be borne in mind that the reports showing a positive association also have emanated from world class researchers and published in peer reviewed journals. It pays to be prudent and not ignore shouts and whispers and continue to have our vigil on pregnancy and oral health.

REFERENCES 1. Galloway CE. Focal Infection. Am J Surg. 1931 ;14(3):643645. 2. Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, et al . Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67:1103-13. 3. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet.2005 19;366(9499):1809-20. 4. Offenbacher S, Boggess KA, Murtha AP, Jared HL, Lieff S, McKaig RG, Mauriello SM, Moss KL, Beck JD. Progressive periodontal disease and risk of very preterm delivery. Obstet Gynecol. 2006 ;107(1):29-36. 5. Xiong X, Buekens P, Fraser WD, Beck J, Offenbacher S. Periodontal disease and adverse pregnancy outcomes: a systematic review. BJOG. 2006 Feb;113(2):135-43. 6. Boggess KA, Beck JD, Murtha AP, Moss K, Offenbacher S. Maternal periodontal disease in early pregnancy and risk for a small-for-gestational-age infant. Am J Obstet

Gynecol.2006 May;194(5):1316-22. 7. Persson R, Hitti J, Verhelst R, Vaneechoutte M, Persson R, Hirschi R, Weibel M, et al. The vaginal microflora in relation to gingivitis. BMC Infect Dis. 2009 Jan 22;9:6. 8. Toygar HU, Seydaoglu G, Kurklu S, Guzeldemir E, Arpak N. Periodontal health and adverse pregnancy outcome in 3,576 Turkish women. J Periodontol. 2007 Nov;78(11):2081-94. 9. Mobeen N, Jehan I, Banday N, Moore J, McClure EM, Pasha O, Wright LL, Goldenberg RL. Periodontal disease and adverse birth outcomes: a study from Pakistan. Am J Obstet Gynecol. 2008 May;198(5):514.e1-8. 10. López R. Periodontal disease and adverse pregnancy outcomes. Evid Based Dent. 2008;9(2):48. 11. Clothier B, Stringer M, Jeffcoat MK. Periodontal disease and pregnancy outcomes: exposure, risk and intervention. Best Pract Res Clin Obstet Gynaecol. 2007 Jun;21(3):451-66. 12. Jeffcoat MK, Hauth JC, Geurs NC, Reddy MS, Cliver SP, Hodgkins PM, Goldenberg RL Periodontal disease and preterm birth: results of a pilot intervention study. J Periodontol. 2003 Aug;74(8):1214-8. 13. Offenbacher S, Lin D, Strauss R, McKaig R, Irving J, Barros SP, Moss K et al . Effects of periodontal therapy during pregnancy on periodontal status, biologic parameters, and pregnancy outcomes: a pilot study. J Periodontol. 2006 Dec;77(12):2011-24. 14. Gazolla CM, Ribeiro A, Moysés MR, Oliveira LA, Pereira LJ, Sallum AW. Evaluation of the incidence of preterm low birth weight in patients undergoing periodontal therapy. J Periodontol. 2007 May;78(5):842-8. 15. Fouzia Tarannum, Mohamed Faizuddin. Effect of Periodontal therapy on pregnancy outcome in women affected by periodontitis. Journal of Periodontology 2007, Vol. 78, No. 11, Pages 2095-2103. 16. León R, Silva N, Ovalle A, Chaparro A, Ahumada A, Gajardo M, Martinez M, Gamonal. Detection of Porphyromonas gingivalis in the amniotic fluid in pregnant women with a diagnosis of threatened premature labor . J Periodontol. 2007 Jul;78(7):1249-55. 17. Heimonen A, Rintamäki H, Furuholm J, Janket SJ, Kaaja R, Meurman JH.Postpartum oral health parameters in women with preterm birth.Acta Odontol Scand. 2008;66(6):334-41. 18. Bryan S. Michalowicz, , James S. Hodges, , Anthony J. DiAngelis, Virginia R. Lupo, M. John Novak, , James E. Ferguson et al .Treatment of periodontal disease and the risk of preterm birth. N Engl J Med . 19. Wimmer G, Pihlstrom BL. A critical assessment of adverse pregnancy outcome and periodontal disease. J Clin Periodontol. 2008 Sep;35(8 Suppl):380-97. 20. Srinivas SK, Sammel MD, Stamilio DM, Clothier B, Jeffcoat MK, Parry S, et al. Periodontal disease and adverse pregnancy outcomes: is there an association? Am J Obstet Gynecol. 2009 May;200(5):497.e1-8.

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JOURNAL SCAN

Effects of Resveratrol in Pregnancy Using Murine Models with Reduced Blood Supply to the Uterus Preeclampsia (PE) and fetal growth restriction (FGR) contribute significantly to fetal and maternal morbidity and mortality. Although the causes of PE and FGR are not fully understood, both conditions are known to be associated with impaired uterine artery blood flow. Resveratrol, a polyphenol found in a number of plants, has been shown to induce relaxation of uterine arteries in vitro as well as improve many pathological conditions associated with PE and FGR. We hypothesized that treatment of endothelial nitric oxide synthase knockout mice (eNOS−/−) and catechol-O-methyltransferase knockout mice (COMT−/−) with resveratrol during pregnancy would improve uterine artery blood flow and therefore ameliorate the PE-like phenotype and FGR in these murine models. Pregnant C57BL/6J, eNOS−/−and COMT−/−mice received either resveratrol supplemented diet (4 g/kg diet) or control diet between gestational day (GD) 0.5 and GD 18.5. Resveratrol supplementation significantly increased uterine artery blood flow velocity and fetal weight in COMT−/−but not in eNOS−/−mice. There were no effects of resveratrol on litter size and placental weight among the groups. In conclusion, resveratrol increased uterine artery blood flow velocity and fetal weight in COMT−/−mice, suggesting potential as a therapeutic strategy for PE and FGR. Advantages of the association of resveratrol with oral contraceptives for management of endometriosis-related pain Background: The effect of resveratrol on the management of endometriosis-related pain was investigated in 12 patients who failed to obtain pain relief during use of an oral contraceptive containing drospirenone + ethinylestradiol. Methods and results: The addition of 30 mg of resveratrol to the contraceptive regimen resulted in a significant reduction in pain scores, with 82% of patients reporting complete resolution of dysmenorrhea and pelvic pain after 2 months of use. In a separate experiment, aromatase and cyclo-oxygenase-2 expression were investigated in the endometrial tissue of 42 patients submitted to laparoscopy and hysteroscopy for the management of endometriosis. Sixteen of these patients were using oral contraceptives alone prior to hospital admission, while the remaining 26 were using them in combination with resveratrol. Inhibition of both aromatase and cyclo-oxygenase-2 expression was significantly greater in the eutopic endometrium of patients using combined drospirenone + resveratrol therapy compared with the endometrium of patients using oral contraceptives alone. Conclusion: These results suggest that resveratrol potentiates the effect of oral contraceptives in the management of endometriosis-associated dysmenorrhea by further decreasing aromatase and cyclo-oxygenase-2 expression in the endometrium. Source: International Journal of Women's Health October 2012

Resveratrol might be the most promising candidate for HRT and prevention of breast cancer. Menopause is a natural part of aging in women between the ages of 45 and 55. It is characterized by a drop in estrogen levels, with symptoms that include hot flashes, fatigue, and weight gain, and health risks that include osteoporosis (1). In an effort to counter menopause symptoms, many women try hormone replacement therapy. But studies in 2002 (2) and 2004 (3) found that hormone replacement therapy increases risks for both cancer and deep vein thrombosis. Women have then turned to alternative methods in the form of phytoestrogens, natural plant substances in plants that exert weak estrogen-like effects in the body. While there is “limited evidence” showing red clover’s benefit for menopause symptoms and breast cell health (4), more definitive evidence has been found for soybeans and soy products, due to 36

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their phytoestrogens daidzein, genistein and glycitein and their associations with reduced breast cancer risk in China (5), the Netherlands (6) and Japan (7). Now a new study (8) has found that resveratrol, an antioxidant found in red wine, may be beneficial for breast cell health. In the study, researchers found that exposing the human breast cancer cell line MCF-7 to resveratrol (0.00005 moles) produced two very important beneficial effects in breast cancer cells. The first was a “significantly enhanced” activity of an anti-tumor protein called p53. Specifically, p53 activity in the resveratrol-treated cells more than doubled, compared to cancer cells not treated with resveratrol. The second benefit regarded the activity of a protein called Bcl-2, whose increased activity has been implicated in cancer (9). Specifically, resveratrol reduced Bcl-2 activity by 23%. These results led the researchers to conclude that “resveratrol might be the most promising candidate for HRT and chemoprevention of breast cancer due to its estrogenic activity and high antitumor activity.” Suggested Reading 1. “Menopause” posted on www.nlm.nih.gov/medlineplus/ency/article/000894.htm 2. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama, 2002. 288(3): p. 321-33. 3. Cushman, M., et al., Estrogen plus progestin and risk of venous thrombosis. Jama, 2004. 292(13): p. 1573-80 4. N.L. Booth, C.E. Piersen, S. Banuvar, S.E. Geller, L.P. Shulman and N.R. Farnsworth, Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review, Menopause 13 (2006), pp. 251–264. 5. Q. Dai, A.A. Franke, F. Jin, X.O. Shu, J.R. Hebert and L.J. Custer et al., Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai, Cancer Epidemiol Biomarkers Prev 11 (2002), pp. 815–821 6. M. Verheus, C.H. van Gils, L. Keinan-Boker, P.B. Grace, S.A. Bingham and P.H.M. Peeters, Plasma phytoestrogens and subsequent breast cancer risk, J Clin Oncol 25 (2007), pp. 648–655 7. M. Iwasaki, M. Inoue, T. Otani, S. Sasazuki, N. Kurahashi and T. Miura et al., Plasma isoflavone level and subsequent risk of breast cancer among Japanese women: a nested case–control study from the Japan Public Health Center-based prospective study group, J Clin Oncol 26 (2008), pp. 1677–1683 8. Sakamoto T. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptorpositive breast cancer cells. Journal of Nutritional Biochemistry. Published online ahead of print: doi: 10.1016/j. jnutbio.2009.06.010 9. Marek L. Apoptotic Pathways as Targets for Novel Therapies in Cancer and Other

Prioritizing micronutrients for the purpose of reviewing their requirements: a protocol developed by EURRECA. The EURRECA (EURopean micronutrient RECommendations Aligned) Network of Excellence (http://www.eurreca. org) is working towards the development of aligned recommendations. A protocol was required to assign resources to those micronutrients for which recommendations are most in need of alignment. Three important 'a priori' criteria were the basis for ranking micronutrients: (A) the amount of new scientific evidence, particularly from randomized controlled trials; (B) the public health relevance of micronutrients; (C) variations in current micronutrient recommendations. A total of 28 micronutrients were included in the protocol, which was initially undertaken centrally by one person for each of the different population groups defined in EURRECA: infants, children and adolescents, adults, elderly, pregnant and lactating women, and low income and immigrant populations. The results were then reviewed and refined by EURRECA's population group experts. The rankings of the different population groups were combined to give an overall average ranking of micronutrients. The 10 highest ranked micronutrients were vitamin D, iron, folate, vitamin B12, zinc, calcium, vitamin C, selenium, iodine and copper. Micronutrient recommendations should be regularly updated to reflect new scientific nutrition and public health evidence. The strategy of priority setting described in this paper will be a helpful procedure for policy makers and scientific advisory bodies Source: Eur J Clin Nutr. 2010

CASE REPORT

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