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The Journal of Obstetrics and Gynecology of India Volume 70 | Issue No. 1 | January - February 2020 | RNI NO. 6107/57 | Mumbai | Rs. 20

Vol. No. 70 Issue No. 1 : January - February 2010 TM

www.jogi.co.in



The Journal of Obstetrics and Gynecology of India (January - February 2020)
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The Journal of Obstetrics and Gynecology of India (January - February 2020)

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COPYRIGHTS RESERVED - INTELLECTUAL PROPERTY OF AECS

II

The Journal of Obstetrics and Gynecology of India

Official Publication of The Federation of Obstetric & Gynecological
Societies of India (FOGSI)
Peer Reviewed Journal Indexed Website: www.jogi.co.in

Founder Editor Editor-in-Chief Secretary & Manager

Late J. Jhirad Suvarna Khadilkar Ashwini Bhalerao Gandhi

Founder Secretary & Manager Associate Editor Assistant Secretary

Late G.N. Vazifdar Geetha Balsarkar Pradnya Changede

Past Editors Jt. Associate Editor Jt. Assistant Secretary

Late K.M. Masani Madhuri Patel Pradnya Supe
Late V.N. Purandare
Late R.D. Pandit Assistant Editor Consultant Biostatistician
Late C.V. Hegde
Sujata Dalvi Kailas Gandewar
Editors Emeritus
First Jt. Assistant Editor Indexed/Abstracted
Mahendra N. Parikh
Adi E. Dastur Arun Nayak PubMed (12 months embargo), PubMedCentral,
C.N. Purandare SCOPUS, EMBASE, Chemical Abstracts Service
Gautam N. Allahbadia Second Jt. Assistant Editor (CAS), Google Scholar, Emerging Sources
Citation Index, Indian Science Abstracts, MedInd,
Ex. Officio Members Anahita R. Chauhan OCLC, SCImago, Summon by ProQuest.

Nandita Palshetkar, President, FOGSI National Corresponding Editors 2017–2020 Disclaimer
Jaydeep Tank, Secretary General, FOGSI Sushil Chawla, Pune
Madhuri Patel, Dy. Secretary General, FOGSI Kavita Agarwal, Delhi The Editor disclaims any responsibility or
Suvarna Khadilkar, Treasurer, FOGSI Laxmi Shrikhande, Nagpur liability for statements made and opinions or
Parikshit Tank, Jt. Treasurer, FOGSI Jyoti Ramesh Chandran, Calicut views expressed by authors and contributors
Ameya Purandare, Joint Secretary, FOGSI Arup Kumar Majhi, Calcutta and claims made by advertisers.
Sreelakshmi K. N., Karnataka
International Advisory Board Sadhana Gupta, Gorakhpur Copyright Information
Sudhir Shah, Rajkot
Bala Bhagavath, USA Alka Pandey, Bihar No part of this Journal can be reproduced
Baris Ata, Turkey Hiralal Konar, Calcutta or transmitted in any form or by any means,
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Monika Chawla, UAE Meena Jain, Bhilai
Jorge Hennefrund, Germany Padma Rekha Jirge, Kolhapur Compliance with Ethical
Ertan Saridogan, UK Deepti Shrivastava, Wardha Requirements
Liza Chowdhury, Bangladesh Vidya A. Thobbi, Vijayapur
Rajesh Devassy, UAE The Journal of Obstetrics & Gynecology of
Ved Prakash Singh, New Zealand Journal Website India requests that all authors comply with
Steven Lindheim, USA Springer’s ethical policies. To view our ethics
Rudy Leon deWilde, Germany www.springer.com/13224 statements please visit the following:
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Printed and published by Dr. Anahita Rajesh Chauhan on Behalf of the Federation of Obstetrics & Gynaecological Societies of India, Printed at Spenta
Multimedia Pvt. Ltd. Plot No. 15, 16 & 21/1, Village-Chikhloli, Morivali Midc, Ambernath (West), Dist. Thane and Published from the Federation
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Editor- in-Chief: Dr. Suvarna S. Khadilkar

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Affiliated Societies of FOGSI

Adoor Bidar Gulbarga Katni Namakkal Shahjahanpur
Agartala Bijapur Guntur Khamam Nanded Shillong
Agra Bijnor Gurgaon Khora Makanpur Nashik Shimoga
Ahmedabad Bikaner Guwahati Kohima Navi Mumbai Silchar
Ahmednagar Bilaspur Gwalior Kolhapur Navsari Siliguri
Aizawl Bokaro Haldwani Kollam Nellore Singrauli
Ajmer Bulandshahr Hanumangarh Korba Nizamabad Sirsa
Akluj Buldana Haridwar Kota Noida Sitamarhi
Akola Burla Hassan Kottayam North Orisha (Balasore) Solapur
Aligarh Calicut Himatnagar Krishnagiri Northern India Southern India
Allahabad Cannanore Hingoli Kurnool Ongole Sri Ganganagar
Alleppey Chalisgaon Hisar Latur Orissa Srinagar
Alwar Chandrapur Hoshangabad London Chapter Osmanabad Surat
Ambala Chikamagalur Hubli - Dharwad Loni Palanpur Tezpur
Amravati Chitradurga Hyderabad Lucknow Palwal Thane
Amritsar Cochin Ichalkaranji Ludhiana Panaji Thanjavur
Anand Covai Imphal Madurai Pandharpur Theni
Anantpuramu Darbhanga Indore Magadh Parbhani Thrissur
Asansol Davangere Islampur Mahabubnagar Patiala Tirunelveli
Aurangabad Dehradun Jabalpur Malda Patna Tirupati
Azamgarh Delhi Jaipur Malegaon Perinthalmanna Tiruvannamalai
Bangalore Deoli sawangi Jalandhar Mancherial Pondicherry Trichy
Baramati Dhanbad Jalgaon Mandya Porbandar Trivandrum
Bardhaman Dhule Jalna Mangalore Pune Tumkur
Bareilly Dibrugarh Jammu Manipal Pusad Tuticorin
Baroda Dindigul Jamnagar Margoa Raichur Udaipur
Barpeta Durg Jamshedpur Mathura Raigad Udgir
Bathinda Durgapur Jaunpur Mau Raipur Ujjain
Beed Eluru Jhansi Meerut Rajahmundry Valsad
Belgaum Erode Jodhpur Mehsana Rajkot Vapi
Bellary Faizabad Jorhat Miraj Ranchi Varanasi
Bengal Faridabad Junagadh Mirzapur Ratlam Vellore
Berhampur Faridkot Kadapa Moradabad Rewa Vijayawada
Bagalkot Ferozepur Kakinada Mumbai Rewari Virudhunagar (west)
Bhagalpur Firozabad Kalyani Muzaffarnagar Rohtak Visakhapatnam
Bhandara Gadag Kancheepuram Muzaffarpur Roorkee Warangal
Bharatpur Gadhinglaj Kanpur Mysore Rourkela Yamunanagar
Bharuch Gandhinagar Karad Nabha Rudrapur Yavatmal
Bhavnagar Gangtok Karimnagar Nadiad Sagar
Bhilai Ghaziabad Karnal Nagaon Saharanpur
Bhiwani Godhra Karur Nagercoil Saharsa
Bhopal Gondia Kasaragod Nagpur Salem
Bhubaneshwar Gorakhpur Kashipur Nalbari Satara
Bhuj Greater Noida Katihar Nalgonda Sevagram – Wardha

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The Journal of Obstetrics and Gynecology of India (January - February 2020)

TM

WE FOR STREE - FOGSI’S MISSION FOR WOMENS HEALTH IN 2019-2020

My dear fellow FOGSians vaccum aspiration, to ensure safe abortions in low resource
setting areas.
I pen this with great sense of joy, satisfaction and fulfilment. As
FOGSI president 2019, I feel privileged to have shouldered this 7. Condemn and strongly oppose female fetocide.#BETI BACHAO
responsibility and contributed positively towards the improvement
of womens health in India. Hence, the theme for the my FOGSI year • FOGSI and FPAI participated in the Mumbai Marathon by
2019 has been “We for Stree – Safer, Stronger, Smarter”. I think it is creating a platform to bring about awareness of violence
prime responsibility of every citizen and organisation like FOGSI to against women and to condemn it. Besides this in the North
help make each woman of India safer, stronger and smarter. Zone Yuva FOGSI, there was an awareness walk “BETI
BACHAO BETA SAMJHAO”.
As President of FOGSI, we identified 10 key priorities regarding
womens health in India. 8. Propogate awareness and screening of genital cancers in women
#FIGHT AGAINST CANCER
1. To provide optimal antenatal care for best maternal and fetal
outcome. #DONTFORGETMOMS • FOGSI launched the WOW that is Wellness of Women in
February to help increase awareness regarding genital cancers.
• There was the initiation of Manyata Phase 3 which saw the There were also camps where over 5000 women were screened
expansion of the program into Karnataka and Rajasthan and and a walkathon to bring about awareness.
saw the number of accredited facilities increase from 300 to
800. • Besides this Breast cancer awareness and screening was
another major component which FOGSI wished to cover.
• There was the initiation of worlds first private and public Mass Screening programs were held all over India and over
Partnership for improvement of quality of care of women in 10000 women were not only screened but also taught self
Maharashtra through the LaQshya Manyata Program. examination

2. Reduce maternal mortality by detecting and treating high risk • Free Cervical cancer screening camps were also carried out
pregnancies. #SAFEMOTHERHOOD through out the country by FOGSI members which shows
their dedication towards womens health.
• Under this abhiyaan, FOGSI released over 15000 posters on
post-partum hemorrhage 9. Educate adolescent girls about health hygiene and nutrition in
order to get India’s girls healthy #HEALTHYGIRLS
• The Champions of Motherhood program was another
initiative which was launched this year where we were able • FOGSI and Run for Niine Foundation had an awareness
to treat women below the poverty line absolutely free of cost. program which was simultaneously carried out all over the
Over 200 women benefitted through this initiative. country on International womens day.

3. To make child birth a safe successful and satisfying experience is the • FOGSI also wanted to bring about awareness regarding
goal of reproductive maternal care. #RESPECTFULMATERNALCARE Fibroids and the enigma around it, so there was an awareness
walk “Freedom from Fibroids”.
• FOGSI has continued volunteering and promoting the
PMSMA program and over 2 crore women have benefitted • Anaemia testing was done all over the country and more than
from this initiative 2 lakh women were screened in over 130 cities.

• FOGSI played a major role in strategising and planning the • Adolescent health awareness and life skill development
curriculum for midwifery training in India. workshops for a public forum were carried out.

4. To encourage and promote breast feeding practices • FOGSI helped carried out health camps for CRPF and their
#MOMSMILKISBEST families to not only screen the women for cancers but their
overall health.
• During breast feeding awareness week, there were multiple
talks and programs carried out all over India to promote breast • FOGSI also tied up with the Indian Thyroid Society to launch
feeding practices and also increase the awareness regarding MITA (Making India Thyroid Aware)
the benefits of breast feeding.
• FOGSI also carried out adolescent even called Olympia where
• FOGSI along with Alive and Thrive foundation created a over 12000 adolescents participated in 5 days of sporting
document to bring about Breast feeding practice modules events
which would promote this abhiyaan. Besides this FOGSI along
with Indian association of Pediatrics came out with a position • Adolescent health camps (Health for Her) were held in rural
statement regarding breast feeding post LSCS. areas to screen adolescents for any health issues

5. Promote effective contraceptive methods to cause population 10. Diagnose and treat reproductive tract infections, promote safe sex
stabilisation. #POPULATIONSTABILISATION practices. #SAFESEX

• Population stabilisation is one of the key goals in India. • On 22nd may, Adult Immunisation was carried out.
FOGSI collaborated with the government and FPAI to carry
out various programs to bring about awareness regarding this • FOGSI and FPAI released guidelines on STI and RTI so as to
abhiyaan. help practioners get a quick and easy update on treatment
options
• FOGSI with the government and their stake holders met
in Delhi to create a position statement regarding injectable • Conferences on safe sex’s.
contraceptives which would soon be included in the
government contraceptive list. • FOGSI with Saathi, NACO, Plan India released guidelines on
EMTCT
• FOGSI and FPAI released a position statement to ensure
that both organisations achieved the goal of population This year, FOGSI was privileged and pleased to bridge new
stabilisation. collaborations and cement old ones with most importantly the Health
Ministry, NGO’s and public health stakeholders at the spectacular
6. Ensure abortion is safe and accessible #SAFEABORTION FOGSI Arogya Mahila Summit in New Delhi which was attended by
Dr. Harsh Vardhan (Minister of State and Welfare) and Mr. Ashwini
• FOGSI through awareness programs via media posters and Chaubey (minister of state). Various joint strategies, position
booklets ensured that the message reached to as many women statements, pledges and health awareness campaigns were launched
as possible. Besides this gynaecologists were trained in manual across the country which will ensure that the community is made
aware on the importance of health related issues and accessibility of

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The Journal of Obstetrics and Gynecology of India (January - February 2020)

health care. Quality during health care is a human right and FOGSI’s Contribution to Health Sector
Manyata initiative has amplified this philosophy not only across
India but beyond India’s borders as well. FOGSI’s Impact on People’s Lives
FOGSI Saves Lives
Technology has benefitted mankind beyond doubt and healthcare
is no exception. This year, FOGSI used technology to create web
based learning for FOGSIans, app for PG students, Narika - an
online information portal for patients. The successful E-elections
reinforced FOGSI’s policy of transparency, equity, accessibility and
good governance.

Being appreciated and acknowledged results in motivation to achieve
more. FOGSI’s “WE FOR STREE”, “PRIDE OF FOGSI”, “WONDER
FOGSIANS”, “YOUNG TURKS”, “CHAMPIONS” awards
acknowledged all those who have shown selfless commitment
towards the upliftment of womens health in India.

Some of the key highlights of FOGSI 2019 are

• Launch of We For Stree - Safer, Stronger and Smarter Campaign

• Release of We For Stree Abhiyaans identifying key priorities for
Women’s Health in India

• Record Number of Academic activities conferences, CME’s,
YUVA FOGSI, Conclaves, PG Activities all across India

• FOGSI contributes as a prime influencer in key health policy
creation with Government of India, medical professional bodies
and international societies

• FOGSI goes beyond health care through various community
health initiatives impacting lakhs of Indian Women nationwide

• FOGSI goes Digital - FIRST TIME IN ITS HISTORY - successful
execution of e-Elections, e-Gurukul, e-Pathshala, online CME
courses & Narika (patient education platform)

• FOGSI and India become the first national body globally to launch
and expand quality of care and respectful maternal are during
pregnancy and childbirth via LaQshya-Manayata Program

• FOGSI honours through “We For Stree Awards” Government
officials, NGO’s, FOGSIans and eminent individuals for their
exemplary work in the upliftment of Women’s Health in India.

While FOGSI has made significant contributions to society, previously
there has been no comprehensive set of metrics to showcase the
scope of this work. FOGSI engaged Catalyst Management Services to
support an assessment of its contribution.

A survey was taken of FOGSI members to see how FOGSI impacted
its members, society and nation through its work. According to
FOGSI data, 679 CME’s, 307 CSR activities, 24 Conferences, 12
conclaves and 58 publications were done this year with FOGSI
reaching at least 99,300 people this year (although the real numbers
may even be higher)

FOGSI Cares for Mothers
FOGSI Provides Respectful Care to Women Across Life Cycles

Reach of FOGSI For all the mammoth and exceptional work done, FOGSI has been
VI awarded the CSR and CME Awards this year. Besides this FOGSI
has also been awarded the Best Professional Organisation by the
Association of Medical Consultants (AMC), National IMA and
Medscape India. These awards are a true reflection of each and every
FOGSIans unrelenting passion and commitment towards the growth
and development of India. I congratulate and feel truly proud of each
and every FOGSIan and I am sure each and everyone of you will
amplify your efforts in the future.

Wishing you and your family a very happy and healthy new year

Yours Truly

Dr. Nandita Palshetkar

President, FOGSI 2019-2020

INSTRUCTIONS FOR AUTHORS

Types of Papers
1. Original Article- word limit 2500 maximum 40 references not more than 5 years old, not more than 6 gures/tables.
2. Case Report - word limit 1200 maximum 4 references not more than 5 years old, not more than 2 gures
3. Instrumentation and Techniques - word limit 1200 maximum 5 references not more than 5 years old, not more than 3 gures/tables.
4. Short Commentary - word limit 800 maximum 7 references not more than 5 years old.

5. Correspondence (Letter to the Editor) - word limit 600 words maximum 5 references not more than 5 years old.

6. Pictorial Essay - Authors may send in their contribution of exclusive unique and exceptional clinical pictures which should be of academic and/
or practical interest to readers, it should be accompanied with a para with 100 words that summarizes succinctly the clinical information. Any
information that might identify the patient in the gure must be removed (including acquisition date). Authors must obtain and submit written
consent / permission from the patient before uploading article on EM.

7. Systematic Reviews/Meta-analysis - Word limit 3500 maximum 50 references not more than 7 years old, not more than 8 gures/tables. It should
discuss, review and enlighten readers about all the available literature on the subject (letter of Intent should be sent to the EIC at journalobgyn@
gmail.com for approval in prescribed format by clicking on (http://www.fogsi.org/wp-content/pdf/LetterofIntent.pdf). Authors should preferably
adhere to updated PRISMA guidelines.

8. Invited Review Article - word limit 3500, maximum 50 references not more than 7 years old, not more than 8 gures/tables
9. Invited Mini Review Article - word limit 2500, maximum 25 references not more than 7 years old, not more than 6 gures/tables.
10. Invited Book Review - word limit 700, maximum 5 references not more than 5 years old, image of the book cover, ISBN and Publisher details

required

11. Invited Debate –word limit 1500 per article. In this section a team of authors for and against a motion/statement, will be invited by EIC. Authors
should present differing views about a controversial issue of interest to readers.

* Important Note:
• Word limits of all articles are exclusive of the text in the title page, abstract, references, tables and gures.
• Letter of invitation should be uploaded along with the submission manuscript of the invited articles.
• Letter of intent in prescribed format (http://www.fogsi.org/wp-content/pdf/LetterofIntent.pdf) should be sent to EIC at journalobgyn@gmail.

com by authors volunteering to write articles types 7-11 before submission and approval letter should be uploaded along with the manuscript of
respective article.
• All submissions will be subjected to the review process of the journal.
• Letter of invitation, approval of letter of intent do not guarantee acceptance / publication.
• Please note that the commissioned/invited author will necessarily be the rst author.
Please note that any submission reporting on animal or human subjects must include ethical and patient consent statements.

Please refer to the COMPLIANCE WITH ETHICAL REQUIREMENTS section below.

MANUSCRIPT SUBMISSION (www.editorialmanager.com/jogi)
Manuscript Submission

Submission of a manuscript implies: that the work described has not been published before; that it is not under consideration for publication anywhere
else; that its publication has been approved by all co-authors, if any, as well as by the responsible authorities – tacitly or explicitly – at the institute
where the work has been carried out. The publisher will not be held legally responsible should there be any claims for compensation.

Permissions
Authors wishing to include gures, tables, or text passages that have already been published elsewhere are required to obtain permission from the
copyright owner(s) for both the print and online format and to include evidence that such permission has been granted when submitting their papers.
Any material received without such evidence will be assumed to originate from the authors.

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Authors should submit their manuscripts online. Electronic submission substantially reduces the editorial processing and reviewing times and shortens
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given on the screen.

Please note:

First time authors have to “register” themselves on the Editorial Manager. If you already are registered on Editorial Manager, please use your provided
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Copyright on all accepted manuscripts will be held by The Federation of Obstetrics and Gynaecological Societies of India (FOGSI). It is mandatory that the
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COMPLIANCE WITH ETHICAL STANDARDS
To ensure objectivity and transparency in research and to ensure that accepted principles of ethical and professional conduct have been followed,
authors should include information regarding sources of funding, potential conicts of interest (nancial or non-nancial), informed consent if the
research involved human participants, and a statement on welfare of animals if the research involved animals.

Authors should include the following statements (if applicable) in a separate section entitled “Compliance with Ethical Standards” before the
References when submitting a paper:
1. Disclosure of potential conicts of interest
2. Research involving Human Participants and/or Animal
3. Informed consent
Please note that standards could vary slightly per journal dependent on their peer review policies (i.e. double blind peer review) as well as per journal
subject discipline. Before submitting your article check the Instructions for Authors carefully.

The corresponding author should be prepared to collect documentation of compliance with ethical standards and send if requested during peer review
or after publication.

The Editors reserve the right to reject manuscripts that do not comply with the above-mentioned guidelines. The author will be held responsible for
false statements or failure to fulll the above-mentioned guidelines.

VIVII

Disclosure of potential conicts of interest

Authors must disclose all relationships or interests that could have direct or potential inuence or impart bias on the work. Although an author may
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Awareness of a real or perceived conicts of interest is a perspective to which the readers are entitled. This is not meant to imply that a nancial relationship
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Examples of potential conicts of interests that are directly or indirectly related to the research may include but are not limited to the following:

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The corresponding author will include a summary statement in the text of the manuscript in a separate section before the reference list, that reects what
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Topic Examples of disclosures

Funding Funding : This study was funded by X (grant number X)

Conict of Conict of Interest: Author A has received research grants from Company A.
Author B has received a speaker honorarium from Company X and owns stock in Company Y.

Author C is a member of committee Z.

If no conict exists, Conict of Interest: The authors declare that they have no conict of interest.
the authors should state

Research involving human participants and/or animals

1) Statement of Human Rights

When reporting studies that involve human participants, authors should include a statement that the studies have been approved by the appropriate
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The following statements should be included in the text before the References section:

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Ethical Approval Ethical approval: All procedures performed in studies involving human participants were in accordance with
the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki
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For retrospective Ethical approval: For this type of study formal consent is not required but ethical committee permission is
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The welfare of animals used for research must be respected. When reporting experiments on animals, authors should indicate whether the international,
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If applicable (where Ethical approval: All procedures performed in studies involving animals were in accordance with the ethical
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If articles do not contain studies with human participants or animals by any of the authors, please select one of the following statement:

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VVIIII

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Ibdah JA, Bennet MJ, Rinaldo P, Zhao Y, Gibson B, Sims HF, Strauss AW. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant
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Springer
http://www.springer.com[Journal/13224
The journal of Obst etrics and Gynecology of India
Edit or-in-Chief: Suvarna Khadilkar
ISSN: 0971-9202 (print version)
ISSN: 0975-643 4 (electronic version)
Journal No. 13 2 2 4

XXII

The Journal of Obstetrics and Gynecology of India (January - February 2020)

TM A F E T Y F I R S S T

FOGSI conferences-2020

D at e Place PROGRAM
29th Jan - 2nd Feb
28th Feb lucknow 63rd aIcOG-2020
29th Feb - 1st Mar
20th - 22nd Mar New Delhi Surakshit Naritva Women's Health & empowerment Summit-2020 ensure|enable|enhance
18th - 19th Apr
25th - 26th Apr New Delhi Women reproductive and Sexual health (Population stabilization):
30th - 31st May Vishakhapattanam ensure|enable|empower
12th - 14th June chandigarh
26th - 28th June South Zone Yuva FOGSI conference - Vishakhapattanam – ‘Redefine and Reinvent Skills’ in
17th - 19th July Obst-Gynaec
24th - 26th July
15th-16th Aug North Zone Yuva FOGSI - Chandigarh – Optimizing Perinatal Outcome (Preventing &
28th-30th Aug auditing Stillbirths)
11th-13th Sept
25th Sept Nagpur FOGSI managing committee meeting
26th-27th Sept
2nd-4th Oct chennai l2l: love to labour conclave
9th-11th Oct (Optimizing labour outcome & Safe delivery)
16th-18th Oct
30th-31st Oct 1st Nov Patna 7th Gestosis conference
20th-22nd Nov
4th-6th Dec ahmedabad Presidential conference –
19th-20th Dec International congress on critical care in Obstetrics

Friday, 31st Jan Goa FOGSI Friends conclave, Funference
Sunday, 8th Mar
Sunday, 10th May Pune Just Tumour – (Benign and Malignant)
Firday, 5th June
Sunday, 21st June australia Proposed FOGSI chapter launching
Wednesday, 1st July
Wednesday, 12th Aug Gurgoan empowering adolescents in Diversity and complexity
Wednesday, 25th Nov
Daman West zone Yuva FOGSI conference - Daman - technologies save lives

Mumbai Satellite conference- PCOS: Managing the eternal challenge / Webcast conference
Mumbai
Hyderabad FOGSI Managing committee meeting
Dubai
Siliguri 17th World congress of IFcPc 2020
Jaipur
Bangalore FOGSI-EMA-ACOG conference
East Zone Yuva FOGSI- Siliguri – Developing Strategy: Minimum intervention, yet better
outcome in Ob-Gyn
conquering infections in Obst - Gynaecology

Practicing Protocols and achieving SDG

Mumbai FOGSI- ICOG conference / Prevention, Prediction & Practices in NCDs in women
Youth and leadership summit/ Lifestyle management

CSR Activities, FOGSI -2020
 Launching of "Each Society adopts a PHC/CHC for Safe Pregnancy"
 Screening Camps: Ca Cx & Breast cancer- International women's Day
 Beti Bachao, Beti Vadhao, Beti Padhao- Mother’s day
 Save Pregnancy & Future Generation from Pollution & toxins - International earth day
 exercise & Yoga in Pregnancy - International Yoga Day
 Organ Donation: Pledge, share, care, donate - Doctors’ Day
 Preventable adolescent health Satellite education- International Youth Day

 Prevent Violence against Women-International Day for elimination of Violence against
Women

XIII

The JournTahleoJfoOurbnsatel torficOs basntdetGriycns eacnodloGgyynoefcoInlodgiay(oJafnInudariay (-MFaeyb-rJuuanrey 201290)
XVIVI

The Journal of Obstetrics and Gynecology of India January/February 2020

CONTENTS
Volume 70, No. 1, January/February 2020

EDITORIAL 1
6
Satish V Khadilkar Bias in Clinical Practice 12
Suvarna S Khadilkar 18
23
MINI REVIEW

K N Sreelakshmi Medical Genetics for Practicing Obstetrician

ORIGINAL ARTICLES

OBSTETRICS Down’s Syndrome Screening in the First Trimester with Additional
Serum Markers: Indian Parameters
Seshandri Suresh
Howard S Cuckle ART in Prevention of Mother-to-Child Transmission of HIV
Sujatha Jagadeesh
Kushagradhi Ghosh Pilot Interventional Study Comparing Fetomaternal Outcomes of
Gayathri Vemavarapu 150 mg Versus 75 mg Aspirin Starting Between 11 and 14 Weeks of
Pregnancy in Patients with High Risk of Preeclampsia: A Randomized
Tulika Taval Control Trial
Sudarshan Suresh

Abhilasha Gupta
Aruna Verma

Monika Kashyap
Priti Gautam

Namrata Kumar
Vinita Das

Anjoo Agarwal
Amita Pandey
Smriti Agrawal
Amrita Singh

Contributors must meticulously follow instructions tgoivaeunthinortshe Indian domestic edition

XV

The Journal of Obstetrics and Gynecology of India (January - February 2020)
XVI

The Journal of Obstetrics and Gynecology of India January/February 2020

CONTENTS
Volume 70, No. 1, January/February 2020

ORIGINAL ARTICLES

Sowmya Mahesh Spot Urinary Albumin-to-Creatinine Ratio: A Novel Marker for Detecting 30
Deepa Borgohain Fetomaternal Outcomes and Complications in Preeclamptic Women 36

Vidyashree Multimodality Screening for Lower Genital Tract Infections Between 44
Ganesh Poojari 18 and 24 Weeks of Pregnancy and its Efficacy in Predicting 50
Samantha Dawson Spontaneous Preterm Delivery 57
Akhila Vasudeva
Nivedita Hegde

Geetha Kaipa
Vandana Eshwara
Chaitanya Tellapragada

Pratap Kumar

GYNECOLOGY

Leena Wadhwa Impact of Vitamin D Supplementation on Semen Quality in
Srishti Priyadarshini Vitamin D-Deficient Infertile Males with Oligoasthenozoospermia

Ashish Fauzdar Retrospective Analysis of 32 Cases of Ovarian Granulosa Cell Tumours
Sanjana N Wadhwa
Is performing sacrospinous fixation with vaginal hysterectomy and
Sarika Arora McCall’s culdoplasty for advanced uterovaginal prolapse preferable
over McCall’s culdoplasty alone?
Amrita Makhija
Bijal M Patel

Mangirish A Kenkre
Ava D Desai

Shilpa M Patel
Meeta H Mankad
Chetana D Parekh

Deepa Rajan
Patsy Varghese

Mariam Roy
Kunjamma Roy

Alice David

Contributors must meticulously follow instructions tgoivaeunthinortshe Indian domestic edition

XVII

The Journal of Obstetrics and Gynecology of India (January - February 2020)
XVIII

The Journal of Obstetrics and Gynecology of India January/February 2020

CONTENTS
Volume 70, No. 1, January/February 2020

ORIGINAL ARTICLES

Edouard N’guessan Immediate Postpartum Intrauterine Device in HIV-Infected Women: 64
Franck Gbeli Experience from a Tertiary Care Center in Coˆte d’Ivoire 69
78
Jean-Marc Dia Laparoscopic In-Bag Morcellation Compared with Conventional
Privat Guie Morcellation of Myomas and Uterus with Myomas 81
Nguessan

Kouame Roseline

Prakash H Trivedi
Soumil Trivedi
Sandeep Patil

CASE REPORTS

OBSTETRICS Pregnancy in a Rare Case of Intracranial Rosai Dorfman Disease (RDD)

Shashikala Ksheerasagar
N Venkatesh
Niti Raizada

K M Prathima
Ravindra B Kamble

K Srinivas
M A Suzi Jacklin
B A Chandramouli

GYNECOLOGY

Amirmohsen Jalaeefar Granulosa Cell Tumor of the Ovary Accompanying with Ollier’s
Mohammad Shirkhoda Disease: First Case of Contralateral Presentations

Amirsina Sharifi
Mohsen Sfandbod

Contributors must meticulously follow instructions gtoivaeunthinortshe Indian domestic edition

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The Journal of Obstetrics and Gynecology of India (January - February 2020)
XX

The Journal of Obstetrics and Gynecology of India January/February 2020

CONTENTS
Volume 70, No. 1, January/February 2020

PICTORIAL ESSAY

Nitin Shah Hysteroscopic Management of Robert’s Uterus 86
Pradnya Changede 89

FOGSI PAGES & ADVERTISEMENTS

SHORT COMMENTARY

Hema Rajesh Enterobius vermicularis Infection of the Uterine Endometrium
Balu Kuppusamy in an Infertile Female
Chaitra Venkataswamy
Nidhya Ganesan

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XXI

The Journal of Obstetrics and Gynecology of India (January - February 2020)
XXII

The Journal of Obstetrics and Gynecology of India (January–February 2020) 70(1):1–5
https://doi.org/10.1007/s13224-019-01304-5

EDITORIAL

Bias in Clinical Practice

Satish V. Khadilkar1 · Suvarna S. Khadilkar2

Received: 30 December 2019 / Accepted: 30 December 2019 / Published online: 16 January 2020
© Federation of Obstetric & Gynecological Societies of India 2020

Abstract
Role of bias in errors of decision making is receiving increasing attention. It is turning out to be one of the main sources of
mistakes. Hence, it is important to be aware of biases and to design strategies toward an unbiased approach. Biases are of
various types, and the potential sources of bias can be related to the consultant, patients and factors related to working condi-
tions. Availability bias, base rate neglect, confirmation bias, conjunction rule, diagnostic momentum bias, framing effect and
confirmation bias are the common types, and these have been discussed in this manuscript using a scenario-based format.
Two types of human thinking, the rapid intuitive mode and the slow reflective mode, their pros and cons and their role in
biases are discussed. Strategies to enhance awareness of biases, tips to improve reasoning, promote freethinking, enhance
decision-making skills and resorting to checklists have been deliberated to achieve an unbiased approach.

Keywords Bias in practice · Conjunction rate · Availability bias · Diagnostic momentum · Framing effect · Confirmation
bias · Base rate neglect · Commission bias

‘The unexamined thought is not Medical interactions, such as consultations and proce-
worth thinking’- Socrates. dures, take place between two individuals, and hence each
one is unique and open to bias. As shown in Table 1, poten-
Introduction tial sources of bias are consultant related or patient related.
Some others can be situational and circumstantial. Clearly,
Bias in clinical medicine is an extremely important and every day and every decision are different, subject to vari-
under recognized area. It is believed that diagnostic errors ous factors. For example, if you have had a surgical mishap,
are associated with 6–17% of adverse events in hospitals and when you take the next patient up, the previous case will
28% of these are attributed to cognitive errors [1]. Cognitive linger on in your mind and may affect your judgment!
bias accounts for 70% of diagnostic errors, and knowledge
deficit contributes to a very minute proportion [2]. While unbiased decision making is based on intelligence,
experience, and objective assessment, in reality, biases and
Dr. Satish V. Khadilkar MD, DM, DNBE, FIAN, FICP, FAMS, prejudices often complicate and influence decision making.
FRCP (London) is presently the dean and professor and head at Bias arises from beliefs, and beliefs are linked to the scien-
the Department of Neurology at the Bombay Hospital Institute of tific, cultural and social inputs received by the individual
Medical Sciences, Mumbai. Prof. Suvarna Satish Khadilkar MD over his or her life and need not be accurate; moreover curi-
DGO FICOG, CIMP, Diploma in Endocrinology (UK), is editor- ously, it is often independent of intelligence [3].
in-chief of Journal of Obstetrics and Gynecology of India and
Treasurer, FOGSI. This manuscript will look at various biases which one
may encounter in clinical practice as obstetrician and
* Suvarna S. Khadilkar gynecologist.
[email protected];
[email protected] Scenario 1

1 110, New Wing, First Floor, Bombay Hospital, 12, New A practitioner attends a mortality meeting where death of
Marine Lines, Mumbai, India a patient due to massive intra-abdominal hemorrhage from
a misdiagnosed ectopic pregnancy is presented. We were
2 Bombay Hospital and Medical Research Centre, 12, New
Marine Line, Mumbai 400020, India

1 3Vol.:(0123456789)

2 S. V. Khadilkar et al.

Table 1 Potential sources of bias leukocytosis and I need to find the cause for it.” In the words
of Arthur Conan Doyle, “the temptation to form premature
Consultant related theories on insufficient data is the bane of our profession.”
We need to remember to get data before the theory and not
Overwork and mental fatigue to put data to suit our theory!
Availability of confounding information
Emotional involvement with the patients Scenario 3
Clouding judgment of the consultant
Patient related A patient is admitted for eclampsia and is being treated with
magnesium sulfate as anticonvulsant. During the course in
Multiple and complex medical or surgical ailments ICU, she develops complete anuria. Interpreting this as acute
Inability to express symptoms, interaction issues renal failure due to eclampsia, a battery of investigations is
Others done to prepare her for dialysis. It shows normal urea and
creatinine levels. Re-evaluation uncovers a blocked catheter,
Inadequacy of time, information, lack of available paradigms, etc. which is completely unrelated to eclampsia!

taught “To Think Ectopic” in older times. But in today’s This is the conjunction rule. A single unifying explana-
day and age, deaths due to ectopic pregnancy are very tion is statistically more probable than many unrelated events
rare, because of easy accessibility and availability of ultra- occurring in the same patient, the Occam’s razor. While this
sonography. The doctor returns to the consulting rooms and is generally true, Occam’s razor is a broad principle and
examines a young unmarried girl having pain in the left situations do exist where multiple unrelated events can be
iliac region. An ultrasound is available and is reported to be responsible for what is happening to the patient. Hence, as
within normal limits, and serum beta HCG test is negative. we discover plethora of parameters and investigative tools,
Doctor sends this patient for a CT scan to make sure that it is possible that Occam’s razor will need to be put to rigor-
there is no ectopic pregnancy. ous testing.

This is an example of the availability bias. What the mind Scenario 4
has seen recently is recalled easily and firmly, often with
undue importance. In this case, the chance of ectopic preg- Senior doctor makes a plan for the cesarean section of a
nancy was very little but still the patient was subjected to primigravida with breech presentation in antenatal outpa-
CT scan exposing her to radiation. This scenario teaches us, tient department. The patient, however, gets admitted with
“to think Ectopic….Unbiased.” There is another bias in this strong labor pains in emergency. The junior doctor on duty
example: the base rate neglect! Base rate is the incidence immediately plans to prepare her for cesarean section on
of the given condition. Ectopic pregnancy in an unmarried seeing the advice of the senior doctor on antenatal clinic
girl with normal ultrasound and negative beta HCG is excep- card, ignoring the fact that in the meantime patient is already
tional though not unknown. This was not kept in mind by fully dilated. He does not change the plan as the earlier plan
the doctor. The base rate neglect in a given situation leads was made by the senior colleague, so patient is shifted to the
to over-investigations. Further, if investigations have false- operation theater and patient delivers on the trolley.
positive or false-negative results, it compounds the issue.
This is the diagnostic momentum bias. So often on the
Another common example of availability bias is the oft- ward rounds, a plan made by a senior and respected mem-
noted transient increase in unscheduled cesarean deliveries ber of the fraternity remains operational without the doctor
following the occurrence of catastrophic cases of uterine on-site acting on the ongoing changes in the patient’s condi-
rupture or neonatal hypoxic ischemic encephalopathy in the tion. When asked about it, the younger doctor justifies that
obstetric wards. “management plan was made by a more senior colleague.”

Scenario 2 Scenario 5

A middle-aged woman presented with general feeling of A new drug is presented to the doctor as the most effective
tiredness and fatigue. Her routine investigations showed medicine till date. Studies from reputed journals depicting
leukocytosis of 11,000/mm3. The practitioner assumes that success rates of around 80% are shown: a huge positive.
she has an infection and prescribes antibiotics. Other molecules depict failure rates of 10–12%!! The doctor

This is the confirmation bias wherein the doctor pre-
sumes that there is an infection and seeks support of his
presumption from the elevated leukocyte count. This is the
situation of fitting the results in preconceived notions, rather
than the reverse. An unbiased analysis would be “there is

13

Bias in Clinical Practice 3

prefers to use the new drug, not paying attention to the fact for maximum benefit. This is a time-consuming and labor-
that 12% failure means 88% success rates!! intensive process but surely will lead to fewer misadventures
and give the doctor a chance to be unbiased. This method
This bias is called the framing effect. The way the infor- puts a lot of stress on the cognitive skills.
mation is put up confuses the mind into believing what is
presented. Most medical practitioners are not well versed It has been known that the human mind is in the rapid
with medical statistics and find it difficult to interpret studies mode of pattern recognition for most of the time, as it is a
in the correct light. While a rigorous peer-review process is low cognitive stress process. Mind can shift to the second
expected to eliminate this bias, at times, a “statistical truth” mode when directed, and this is usually achieved by actively
may be presented to the common medical practitioner, who slowing down. Asking yourself a question such as “Hey,
may take it at face value. what’s happening here?” will slow you down and make you
go in the second, more objective mode. When there is fail-
Scenario 6 ure to account for all the data and when red flags are seen,
we should reconsider and analyze the case once again in
A patient hears a story from her friend that she was advised the slow reflective mode [4]. The trick perhaps lies in the
hysterectomy for abnormal uterine bleeding, which she understanding as to when to employ which method, for best
refused and later she developed cancer. The patient gets balance of efficiency and accuracy which some astute clini-
scared and consults a doctor seeking a hysterectomy. Doc- cians possess.
tor complies with her request!
In the expert practice model [5], two types of experts have
This would be the commission bias. Human mind leans been identified; the routine expert and the adaptive expert.
toward activity than inertia. Hence, acts of commission are Routine expert appropriately uses preexisting knowledge to
more often seen than those of omission. Truthfully, both quickly solve routine, familiar or uncomplicated problems
have negative repercussions. (the rapid mode). The adaptive expert is able to employ a
deep conceptual understanding and engage in reflection to
What is the Explanation for Biased Thinking? create novel solutions for complicated or unfamiliar prob-
lems (the slow mode). Adaptive expertise builds with time,
In India, where work load is a major issue, doctors are a function of having participated in multiple problem-solv-
always looking for time-efficient paradigms. Hence, they ing exercises. Yee et al found that obstetricians who scored
resort to the oft-promoted method of pattern recognition. higher on reflective capacity tests had higher rates of suc-
cessful attempts of vaginal birth after cesarean section [5].
Pattern recognition is a method by which you identify a
set of symptoms or signs which represent a common disease What can be Done to Develop the Ability
condition. Pattern recognition is based on the rapid mental to Take Unbiased Decisions?
processing, taking cues from memory stores and intuition,
and is a low energy-consuming method. While effective for While the first step in this direction would appear to be
the routine cases, it basically looks at the broad diagnos- informing doctors of the various types of bias that exist and
tic label, ignoring nuances and the oddities. Moreover, the to suggest strategies to correct these, but there is currently
deep-rooted need for achieving a diagnosis prompts “pigeon little evidence that it works. Also, there are very interesting
holing,” which can take precedence over facts, and ill-fitting studies, which show that the doctors who believe that they
patterns also get slotted into diagnostic categories. Thus, the are unbiased in their decision making do not do well on tests
advantage of this method of medicine is time efficiency at given to them! So the issues are of non-recognition of one’s
the cost of bias and missing the unusual. own faults and not having very satisfactory teaching modules
to rectify them.
The second technique is of being methodical and thought-
ful, at every stage of the diagnostic process and therapy Actively slowing down has been shown to eliminate
options. As some teachers have stressed, take history in some of the biases, and it is easy to do [6]. Deliberating
entirety and keep it aside. Do a complete clinical examina- on the problem can make us think in a more unbiased way.
tion, not to just confirm the diagnosis offered by history but As we start thinking about a clinical problem, our mind
to check things on their own merit. Then, sit down with these originally directs us in a certain way, toward a certain
two independent parts of assessment and correlate them. diagnosis and the management approach. This initial pro-
Then, decide on which investigations you really need and cess is often “intuitive” and incorporates bias. Curiously,
how will your actions change if they are positive or nega- once these thoughts are formed, intelligence does its best
tive. Based on all this information, take a decision about to defend the original thoughts; however, irrational they
which procedure you will want to perform on the patient, may be! While the mind and intelligence are busy proving

13

4 S. V. Khadilkar et al.
Table 2 Steps to avoid bias
Increasing awareness of biases and providing facts
Departmental meetings
Mortality meetings
Case reviews with lessons
Sharing personal experience of complications
Helping improve reasoning, promote freethinking and enhance decision-making skills
Awareness and understanding of one’s own thought process (Meta cognition sessions)
Counterintuitive thinking “can this be explained in any other way?”
Developing systematic reasoning for accurate analysis
Simulated case scenarios for gaining experience
Response from peers about decisions taken
Making working conditions more conducive
Displaying protocols and checklists
Availability of colleagues to discuss decisions
Work hour regulations and avoiding fatigue

the initial thoughts, it may be a good idea for doctors to in working toward unbiased decision making and execu-
ask a counterintuitive question to themselves, e.g., “Why tion. Rapid mental processing works on intuitive elements
could it not be Y, why am thinking only of X,” to free and does not take into account counterarguments. Slowing
their thinking. Another question to oneself “how confident down, asking counterintuitive questions, delinking intel-
am I of this diagnosis?” can be used to begin thinking of ligence from beliefs and generating checklists can help
alternatives. In the words of Sherlock Holmes, “When you the decision-making process to be unbiased and objective.
have eliminated the impossible, what remains, however
improbable, must be the truth!” References

Checklists are often recommended in clinical practice 1. Balogh EP, Miller BT, Ball JR. Improving diagnosis in health
as they are known to result in a certain degree of de- care. Washington: National Academic Press; 2015.
biasing. As the doctor goes through the checklist, he is
forced to stop, think and act rationally at each point, which 2. Saber Tehrani AS, Lee H, Mathews SC, Shore A, Makary MA,
he may not do in his fast mode intuitive thinking. As an Pronovost PJ, Newman-Toker DE. Twenty five-year summary
obstetrician, a fast mode of action is required in many of US malpractice claims for diagnostic errors 1986–2010: an
life-threatening emergency situations such as peripartum analysis from the National Practitioner Data Bank. BMJ Qual
hemorrhage. Display of checklists and protocols in labor Saf. 2013;22(8):672–80. https://doi.org/10.1136/bmjqs-2012-
room will help in taking action rapidly with accuracy in 001550 (Epub 2013 Apr 22).
such situations [7].
3. Royce CS, Hayes MM, Schwartzstein RM. Teaching critical
Checklists are easy to create and personalize and hence thinking: a case for instruction in cognitive biases to reduce
a practical aid to de-biasing. These strategies are sum- diagnostic errors and improve patient safety. Acad Med.
marized in Table 2. 2019;94(2):187–94.

Conclusions 4. O’sulivan ED, Schofield SJ. Cognitive bias in clinical medicine.
J R Coll Phys Edinb. 2018;48:225–32.
Bias pervades daily professional life of medical practition-
ers and affects outcomes. Being aware of various biases 5. Mylopoulous M, Regeher G. Putting the expert together again.
that exist and understanding why they occur is important Med Educ. 2011;45:920–6.

6. Dobbler CC, Morrow AS, KAmath CC. Clinician’s cognitive
biases: a potential barrier to the implementation of evidence
based clinical practice. BMJ Evid Based Med. 2019;24(4):137–
40. https://doi.org/10.1136/bmjebm-2018-111074.

7. Khadilkar SS, Sood A, Ahire P. Quantification of peri-partum
blood loss: training module and clot conversion factor. J Obstet
Gynecol India. 2016;66:307–14. https://doi.org/10.1007/s1322
4-016-0888-9.

Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

13

Bias in Clinical Practice 5

About the Author Royal College of Physicians (London), National Academy of Medical
Sciences, Indian Academy of Neurology and Indian College of Physi-
cians. He has to his credit six books, 43 book chapters and over 150
publications in national and international peer-reviewed journals.

Dr. Satish V. Khadilkar is presently
the dean and professor and head
at the Department of Neurology
at the Bombay Hospital Institute
of Medical Sciences, Mumbai.
He is the immediate past presi-
dent of Indian Academy of Neu-
rology and the past president of
Maharashtra Association of Neu-
rology and Bombay Neurologi-
cal Association. He was previ-
ously editor-in chief of the
Annals of Indian Academy of
Neurology. He is the Fellow of

13

The Journal of Obstetrics and Gynecology of India (January–February 2020) 70(1):6–11
https://doi.org/10.1007/s13224-019-01257-9

MINI REVIEW

Medical Genetics for Practicing Obstetrician

K. N. Sreelakshmi1

Received: 5 March 2019 / Accepted: 27 July 2019 / Published online: 28 August 2019
© Federation of Obstetric & Gynecological Societies of India 2019

Abstract
Medical genetics has evolved over a decade, and hence, all investigations are available for clinical practice. Many diseases
are diagnosed accurately today because of new investigations. These advanced investigations are affordable, accessible and
available in day-to-day practice. Hence, there is a need and it is a time for us to understand these advanced technologies.
Karyotyping and rapid aneuploidy tests are basic tests, while chromosomal microarray and next-generation sequencing are
advanced technologies. It is time to update the knowledge and utilize them in day-to-day practice. These tests are utilized
both in prenatal diagnosis and in some clinical scenarios, which are elaborated in detail. Karyotyping is the basic tool to
detect both numerical and structural abnormalities. It is advantageous in that it is accurate with error of 0.001% but has a
resolution of up to 5 MB. Rapid aneuploidy detection tests are equally accurate and detect as good as 99%. They are FISH,
QF-PCR and MLPA. They have high sensitivity and specificity, and results are available within 3 days of time. Hence, these
tests are apt for Indian scenarios, where late detection of anomalies (18–20 weeks) is common. Chromosomal microarray
is the hybridization technique which detects aneuploidy of all chromosomes. This is useful for detection of deletion and
duplication in chromosomes. This is not available for prenatal diagnosis in India now, whereas this is available for prenatal
diagnosis in developed countries. Whole-exome sequencing and whole-genome sequencing are advanced techniques which
have been described and discussed at length.

Keywords Karyotyping · Rapid aneuploidy detection tests · Chromosomal microarray · Whole-exome sequencing ·
Whole-genome sequencing

Introduction Here, basic investigations, interpretation of these tests
and common clinical conditions needing genetic investiga-
There have been tremendous developments in the field of tions are discussed at length.
medical genetics in the past decade, especially in decipher-
ing the genome and identifying the phenotypic effects of Karyotyping in Clinical Practice
genomic variations. Diagnosis and management of genetic
disorders, namely monogenic and chromosomal disorders, As early as 1882, Walther Flemming, an Austrian cytolo-
are affected by genomic techniques like next-generation gist and professor of Anatomy, published the first illustra-
sequencing and microarray. tion of human chromosomes. In 1959, Lejeune described
extra chromosome in Down syndrome in each cell. The
Sreelakshmi K. N., MS, DNB, FICOG is an Associate Professor word chromosome is derived from the Greek word “colored
of KMC, Manipal, India. Professor and Head of Subbaiah Medical body.” Human cells contain 46 chromosomes comprising
College, Shimoga, Karnataka, India. Fellowship from SIAMG 22 pairs. The numbers are assigned in descending order of
(Society of Indian Academy of Medical Genetics), KMC, Manipal, length, size and centromere position of each chromosome
India. pair, with long arm as “q” and short arm as “p.” Karyo-
type is done by g banding technique with resolution of up to
* K. N. Sreelakshmi 350–550 MB [1, 2].
[email protected]
Chromosome abnormalities can be either numerical or
1 Malnad Hitech Diagnostic Center, Shivamogga, Karnataka, structural abnormality. Most common abnormalities are
India

1 3Vol:.(1234567890)

Medical Genetics for Practicing Obstetrician 7

aneuploidies, i.e., Down syndrome, Trisomy 21, Trisomy
18, Trisomy 13 and monosomy X (Figs. 1, 2).

Common clinical conditions to order karyotype are:

1. Suspected/known chromosomal abnormality like Down Fig. 2 Partial karyotype with translocation between chromosomes 7
syndrome, trisomy 18, turner syndrome and Klinefelter and 11
syndrome.
• Well-established cytogenetic technique which has been
2. Unexplained intellectual disability (developmental delay extensively used as a diagnostic tool for pregnant women
with dysmorphic features) (yield of 4–8%). Chromo- undergoing prenatal invasive procedures.
somal microarray increases the yield.
• Whole chromosome is analyzed.
3. Disorders of sex development: Individuals with ambig- • Karyotyping using amniotic fluid is considered the “gold
uous genitalia, delayed or incomplete pubertal devel-
opment need a karyotype. Often turner syndrome and standard” in fetal aneuploidy testing due to high sensitiv-
Klinefelter syndrome are diagnosed. ity and relatively low risks.

4. Pregnancy loss and infertility: Chromosomal structural Limitations/Disadvantages of Karyotyping
rearrangements can often lead to recurrent spontaneous
abortions (5.5% is the yield with three or more first tri- • Small submicroscopic alterations below 4–5 MB size are
mester losses). usually not picked up by routine karyotype.

5. Parents of the child with structural chromosomal abnor- • It is important to remember that most mendelian dis-
mality like balanced translocation in mother need karyo- orders have mutations involving only one or very few
typing. nucleotides and are not diagnosed by karyotype. It is also
worthwhile to note that commonly used genetic test with
Advantages of karyotyping are: fair diagnostic yield has limited resolution, which can

• Time-tested study with vast clinical experience.
• Widely available.
• Can be done in peripheral blood, abortal tissues, amniotic

fluid and in chorionic villous sampling.
• It is accurate with an error rate of 0.001% which is pri-

marily related to maternal cell contamination, sample
mix-up and typographical errors.

Fig. 1 Complete normal karyo-
type 46XY

13

8 K. N. Sreelakshmi

be explained by large size and complexity of the human FISH: Fluorescent In situ Hybridization
genome.
• Long culture days. It is usually performed on uncultured interphase cells with
• Possibility of culture failure. probes designed specifically for chromosomes 13, 18, 21, X
• Requires actively growing cells. and Y. The number of fluorescent signals per cell gives the
• Maternal cell contamination (0.1–0.2%). number of copies of the targeted chromosome. The tech-
• Inability to detect mosaicism (prevalence of 0.1–0.2%). nique is known to be almost 100% accurate with an added
advantage of ability to detect triploidy also. However, FISH
Prenatal Diagnosis and Genetics technique is non-automated and time-consuming and neces-
sitates a skilled technician.
The various indications for fetal cytogenetic testing include:
QF-PCR: Quantitative Fluorescent In situ Hybridization
1. Abnormal ultrasound scan.
2. Abnormal maternal serum biochemical results. This assay has been widely used for the past 2 decades,
3. Advanced maternal age (≥ 35  years of age at the which uses fluorescent-labeled primers to amplify specific
DNA markers which are polymorphic and unique for chro-
expected time of confinement). mosomes 13, 18, 21, X and Y. Detection of maternal cell
4. One of the parents, being a carrier of a chromosomal contamination, triploidy and mosaicism as low as 15% is an
important advantage of these techniques.
rearrangement.
5. History of previous offspring with chromosomal disor- MLPA: Multiplex Ligation-Dependent Probe Ampli cation

der. It is also a PCR-based method, which is cheaper and less
labor-intensive than FISH technique. The free ends of the
In India, many ultrasound abnormalities become apparent ligated probes are complementary to the primer which ena-
during 18–20 weeks of scan; hence, accurate rapid ane- bles the amplification of target sites. The technique has a
uploidy detection techniques are important. capacity to quantify up to 40–50 different target sequences in
one reaction. One of the major drawbacks of this technique is
Rapid aneuploidy detection methods the failure to detect triploidies, especially in a female fetus. It
is a completely automated method and is being increasingly
These are primarily targeted for the diagnosis of common used as a method for RAD, especially where large-scale test-
autosomal trisomies (13, 18, 21) and sex chromosomal ane- ing of samples is required. Table 1 summarises advantages
uploidies [3–5]. and disadvantages of RAD techniques.

Three methods of diagnostic techniques validated for pre-
natal diagnosis are:

1. FISH: Fluorescent in situ hybridization.
2. QF-PCR: Quantitative fluorescent in situ hybridization.
3. MLPA: Multiplex ligation-dependent probe amplifica-

tion.

Table 1 Advantages and disadvantages of rapid aneuploidy detection tests

S. no Technique Advantages Disadvantages

1 FISH Almost 100% accurate with an added advan- Non-automated
tage of ability to detect triploidy also Time-consuming
Does not require capillary electrophoresis Necessitates a skilled technician

2 QF-PCR Detection of maternal cell contamination, Only specific chromosomes are analyzed
triploidy and mosaicism as low as 15% Commercial kits increase cost
Reliable, automated Cannot detect structural chromosomal aberrations
Requires capillary electrophoresis

3 MLPA Cheap Failure to detect triploidies, especially in a female fetus
Less labor-intensive
Large scale of samples are tested

13

Medical Genetics for Practicing Obstetrician 9

New Methods of Genetic Testing for Prenatal Diagnosis: Premature ovarian aging/failure and genetics
Chromosomal Microarray
Genetic aberrations comprise one-third of women with pre-
This is based on the principle of hybridization, and the mature ovarian aging and also ovarian failure. When FSH is
strength of signals from these probes is interpreted in an elevated above the age-specific cutoffs, premature ovarian
automated manner to provide information regarding the aging is considered. A study by Gleicher et al. titled “Do the
number of copies of that region of the genome. In contrast to etiologies of POF and POA same?” concluded that presumed
the commonly used RAD techniques, chromosomal microar- underlying etiologies of POA follow a similar distribution
ray can detect aneuploidies of all 23 chromosomes as well pattern as reported for POF. They proved the hypotheses that
as submicroscopic copy number abnormalities in a genome- POA is a precursor stage of POF and hence requires similar
wide manner [6, 7]. evaluation [12–14].

Common Clinical Conditions and Application Genetic causes comprised approximately 16% of the total
of Genetic Testing in the study conducted by Gleicher et al. Both autosomes
and X chromosomal involvement are documented. They are
Recurrent pregnancy loss and genetics Turner mosaicism, partial X chromosome deletion, X chro-
mosome mosaicism, X chromosome inactivation and FMR
Recurrent pregnancy losses, also known as recurrent spon- 1 (fragile site mental retardation X gene). X chromosome
taneous abortions, are traditionally defined as 3 or more partial deletions are more common, while balanced X chro-
consecutive pregnancy losses of less than 20 weeks of ges- mosome to autosome translocation of Xq13–q26 is rare, but
tation. A total of 3–5% of couples experience RPL. The documented. Autosomes involved are at the following gene
cause of RPL is difficult to assess, and in fact, no cause can loci: 3q, 13q, 14q, 17q, 15q and 11p [15, 16]. We had a rare
be determined in half of the cases in spite of a battery of case of triple X syndrome of premature aging in our clinical
investigations. This suggests the presence of unidentified practice which is reported and Fig. 3 represents  karyotype
genetic causes. of the same.

In 3–5% of couples, with RPL, one partner is found to Primary amenorrhea and genetics
carry a balanced chromosomal rearrangement, 50% are
balanced reciprocal translocations, and 12% are sex chro- Clinical features with Turner syndrome like webbed neck,
mosomal mosaicism. Although carriers of balanced trans- short stature, cubitus valgus with absent menstruation
location are phenotypically normal, their pregnancies are and absent secondary sexual characteristics by the age of
at increased risk miscarriages or live births with congenital 15  years are definite indications for karyotyping. There
abnormalities or intellectual disability. The remainders are may be Y element in karyotype, and this is an indication for
chromosomal inversions and other sporadic abnormalities. gonadectomy to prevent gonadoblastoma.
In these couples, RPL occurs due to abnormal segregation
of gametes at the time of meiosis. In couples, with recur- Fig. 3 Complete karyotype premature ovarian aging with triple X
rent miscarriage, chromosomal abnormalities of the embryo syndrome
account for 30–57% of further miscarriages [8–10].

RCOG recommends karyotyping of products of con-
ception of third and subsequent miscarriages and parental
peripheral blood karyotyping in couples with unbalanced
structural abnormality [11].

Couples with balanced translocations have a low risk
(0.8%) of pregnancies with an unbalanced karyotype sur-
viving into second trimester, and chance of having healthy
child is 83%.

Preimplantation genetic diagnosis or fetal karyotyping by
amniocentesis is an option for these couples to select fetuses
with normal chromosomal content. Some chromosomal vari-
ations like pericentric inversion of 9, small or large hetero-
chromatin arm of Y chromosome and inversion Y are seen in
many normal individuals and are not known to be associated
with poor reproductive outcome.

13

10 K. N. Sreelakshmi

Recent Advances and Technologies in Medical Compliance with Ethical Standard
Genetics
Conflict of interest The author declares that there is no conflict of in-
Whole-exome sequencing (WES) and whole-genome terest.
sequencing (WGS) [17] are two important new technolo- Human and Animal Rights Not applicable.
gies which have become affordable, accessible and available Informed Consent Not applicable.
in India. This has enhanced the diagnostic yield in medical
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1. Variants of unknown significance (VUS) Since few 2. Seabright M. A rapid banding technique for human chromosomes.
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2. If these genetic data are not interpreted correctly, this tive validation of quantitative fluorescent polymerase chain reac-
may lead to misjudgement and hence may lead to deci- tion for rapid detection of common aneuploidies. Genet Med.
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the proteins called exons, which constitute about 1% of the 6. Van Opstal D, Boter M, de Daneille J, et al. Rapid aneuploidy
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second step is to sequence the exonic DNA using any high- a prospective study of 4000 amniotic fluid samples. Eur J Hum
throughput DNA sequencing technology. After sequencing, Genet. 2009;17:112–21.
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somal microarray for prenatal diagnosis using a prospective cohort
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rangements in couples with recurrent fetal wastage. Eur J Obstet
1. Children with intellectual disability. Gynecol Reprod Biol. 1998;81:171–6.
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Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

13

Medical Genetics for Practicing Obstetrician 11

About the Author

K. N. Sreelakshmi She is a con-
sultant fetal medicine in Malnad
Diagnostic centre, Shimoga,
Karnataka. She has done MBBS
from Bangalore Medical Col-
lege, Karnataka and MS (OBG)
from KMC Manipal in the year
2005. She was a former Associ-
ate Professor of KMC, Manipal
and was working as Professor
and Head of Subbaiah Medical
College, Shimoga, Karnataka
(2012–2018). Her areas of inter-
est are: prenatal diagnosis with
special interest in fetal cardiol-
ogy. Recently she was awarded
3 months (April–July 2018) fellowship from SIAMG (Society of Indian
Academy of Medical Genetics) which she has done from KMC,
Manipal.

13

The Journal of Obstetrics and Gynecology of India (January–February 2020) 70(1):12–17
https://doi.org/10.1007/s13224-018-1198-1

ORIGINAL ARTICLE

Down’s Syndrome Screening in the First Trimester
with Additional Serum Markers: Indian Parameters

Seshandri Suresh1 • Howard S. Cuckle2 • Sujatha Jagadeesh1 • Kushagradhi Ghosh3 • Gayathri Vemavarapu4 •
Tulika Taval4 • Sudarshan Suresh1

Received: 17 February 2018 / Accepted: 18 December 2018 / Published online: 11 February 2019
Ó Federation of Obstetric & Gynecological Societies of India 2019

About the Author

Dr. Seshandri Suresh is the director of Mediscan Systems, Chennai. With over 32 years’ experience in ultrasound, he has
established a comprehensive foetal medicine and therapy centre which is a referral centre for India and neighbouring
countries. He is a dedicated teacher, and he has trained a large number of doctors from India and abroad in ultrasound and
foetal medicine. He has been awarded the FRCOG (honoris causa) by the Royal College of Obstetricians and Gynaecologists,
London, and DSc (honoris causa) from the MGR Medical University, Chennai. He is a visiting professor in perinatology in
Sri Ramachandra University, Chennai. He has been nominated as ‘Ambassador to India’ by the ISUOG and also serves on
the Educational Task Force of ISUOG.

Seshandri Suresh is a Director of Mediscan Systems, Diagnostic Abstract
Ultrasound Research and Training Centre, Chennai, India; Hony Objective To derive a risk calculation algorithm suit-
Secy, Voluntary Health Services Hospital, Taramani, Chennai, India able for use in India when screening for Down’s syndrome
and Visiting Prof. in Perinatology , Sri Ramachandra University, using four first-trimester maternal serum markers either
Porur, Chennai, India. Howard S. Cuckle is currently working for alone or with ultrasound nuchal translucency (NT).
Department of Obstetrics and Gynecology, Columbia University Methods Stored maternal serum samples (- 20 °C) from
Medical Center New York, NY USA. Sujatha Jagadeesh is Head of 411 singleton unaffected pregnancies were retrieved and
the Department of Genetics and Dysmorphology, Mediscan Systems measured for pregnancy-associated plasma protein (PAPP-
and Fetal Care Research Foundation, Chennai, India. Kushagradhi A), free b-human chorionic gonadotropin (hCG), placental
Ghosh is Professor of Obstetrics and Gynecology, Vivekananda growth factor and a-fetoprotein. Samples were taken at
Institute of Medical Sciences (Kolkatta Health University), Kolkatta,
India. Gayathri Vemavarapu is Senior Consultant in OBGYN, 2 Department of Obstetrics and Gynecology, Columbia
Rainbow Children Hospital and Birth Right by Rainbow, Hyderabad. University Medical Center, 622 W 168th Street, New York,
Tulika Taval is Senior Consultant in OBGYN, Rainbow Children NY 10032-3725, USA
Hospital and Birth Right by Rainbow, Hyderabad. Sudarshan Suresh
is Consultant in Fetal Medicine, Mediscan Systems, Diagnostic 3 Fetal Care Center, 152 SP Mukherjee Road, Kolkata 700026,
Ultrasound Research and Training Centre, Chennai, India. India

& Seshandri Suresh 4 Rainbow Children Hospital & BirthRight by Rainbow, 22
[email protected] Road Number 4, Banjara Hills, Hyderabad 500034, India

1 Mediscan Systems & Fetal Care Research Foundation, 197
Dr Natesan Road, Mylapore, Chennai 600004, India

123

Down’s Syndrome Screening in the First Trimester 13

10–13 weeks’ gestation. Equations were derived to express even when there is no increase in detection. It provides
marker levels in multiples of the gestation-specific normal earlier reassurance, and if an affected pregnancy is diag-
median, adjusted for maternal weight. Gaussian model nosed, termination can be carried out with greater safety,
parameters were derived and compared with six published less psychological trauma and more discretion. Moreover,
non-Indian studies; NT parameters were derived from the four-marker serum-only test can be used in first-tri-
27,647 women screened in India. On the basis of the mester screening for preeclampsia as well as spina bifida.
maternal age distribution in 64,473 Indian women screened Maternal serum PAPP-A and PlGF can detect about two-
in 2016–2017, the model was used to predict test thirds of preeclampsia cases destined to present before
performance. 37 weeks’ gestation [5]. Maternal serum AFP and free b-
Results The model predicted a detection rate for a serum- hCG together with ultrasound biparietal diameter (BPD)
only protocol of 80% for a 5% false-positive rate. Using a 1 measurement can detect about two-thirds of open spina
in 250 at term Down’s syndrome risk cut-off, the predicted bifida [6].
detection rate was 78% and the false-positive rate was
4.1%. When NT was also included, the rates were 95% for Substantial numbers of pregnant women in India do not
5% and 90% for 1.4%, respectively. have access to quality NT. They would benefit from a first-
Conclusion First-trimester screening using four serum trimester four-marker serum-only test, but there are no
markers only can be carried out in India. Performance is published Down’s syndrome risk calculation algorithms
expected to be similar to the second-trimester Quad test suitable for this country. The minority for whom quality
and will also facilitate early screening for preeclampsia and NT is available would also benefit from the additional
open spina bifida. A protocol of NT plus the four serum serum markers. We have therefore carried out a study in
markers enhances the performance compared with NT, India to derive the information needed to calculate risk in
PAPP-A and free b-hCG. both circumstances.

Keywords First trimester Á Screening Á Down’s syndrome Á Methods
Prenatal diagnosis Á PlGF Á AFP
Stored maternal serum samples from singleton unaffected
Introduction pregnancies at 10–13 weeks’ gestation were retrieved from
storage and measured for the four markers. Equations were
The most widely used protocol for Down’s syndrome derived to express marker levels in multiples of the ges-
screening in the first trimester is the ‘Combined’ test, tation-specific normal median (MoM), adjusted for mater-
comprising maternal serum pregnancy-associated plasma nal weight. Gestational age was determined on the basis of
protein (PAPP)-A and free b-human chorionic gonado- first-trimester foetal biometry. Gaussian model parameters,
tropin (hCG) together with ultrasound nuchal translucency standard deviations and correlation coefficients were
(NT). One multivariate Gaussian statistical model predicts derived and compared with the literature. Parameters for
that at 11 weeks’ gestation it will yield a detection rate of Down’s syndrome pregnancies were derived by meta-
87% for a false-positive rate of 5%, with slightly lower analysis from the literature. On the basis of the maternal
performance at 12 and 13 weeks’ gestation [1]. By com- age distribution in India, the model was used to predict the
parison, the model predicted a detection rate for the sec- test performance.
ond-trimester serum-only ‘Quad’ test of just 71%.
Women participating in the Combined test screening
However, the performance of the Combined test is programmes at three centres, Mediscan Systems (Chennai),
critically dependent on the availability of quality NT which Rainbow Hospitals (Hyderabad) and Fetal Care Centre
accounts for 30% of the 87% detection rate. The model (Kolkata), were recruited to have blood samples taken for
predicted a detection rate for maternal serum PAPP-A and the project. Five millilitres of sample was collected into a
free b-hCG alone of 57%. Three studies have considered plain tube and refrigerated locally before being sent to the
the possibility of improving this by including two addi- laboratory of Perkin Elmer Health Sciences (Chennai), a
tional markers, placental growth factor (PlGF) and a-fe- facility of PerkinElmer Inc., where they were centrifuged,
toprotein (AFP) [2–4]. They derived, for the four-marker aliquoted and frozen at - 20 °C. Samples from Mediscan
serum-only test, a model that predicted detection rate of Systems arrived within 1–2 h, whilst others took
66–82% suggesting a performance comparable with the 1–1.5 days, and probes in the transport boxes indicated a
second-trimester Quad test. temperature of 20–25 °C. Recruitment continued sequen-
tially until 50 samples had been collected at each half week
Screening for Down’s syndrome in the first trimester has of gestation between 10 and 13 completed weeks of ges-
substantial advantages over second-trimester screening tation, based on ultrasound.

123

14 S. Suresh et al.

When a sufficient number of samples had been col- The maternal age distribution observed in 64,473
lected, they were retrieved from storage and tested for women maternal serum screening samples was tested at the
PAPP-A, free b-hCG, PlGF and AFP in Perkin Elmer Perkin Elmer Health Sciences laboratory between July
Health Sciences using Delfia XpressTM assays. 2016 and February 2017.

For each serum marker, normal gestation-specific med- Results
ian curves were derived from the median concentration in
each half-week group against median gestation in days A total of 415 samples were measured, of which four were
weighted for the number in the group. The best-fitting excluded because the pregnancy was subsequently found to
curves were used to express results in MoMs. Maternal be twins. Table 1 shows the curves used to calculate MoMs
weight correction curves were derived by dividing the and, where appropriate, for calculating weight correction.
samples into eight weight groups and carrying out regres- The normal median data were best-fitted by log-linear
sion of median MoM on median weight, weighted by the equations except for PAPP-A which required a quadratic
numbers in each group. There were too few smokers (six) equation. There was no statistically significant effect of
and diabetics (two) to adjust for these potential co- maternal weight on PlGF; PAPP-A data were best-fitted by
variables. an inverse, free b-hCG by a log-linear and AFP by a
quadratic equation.
The standard deviations of log10 MoM were estimated
from the 90th–10th centile range divided by 2.563; the r- The parameters derived from the samples are shown in
values were estimated directly, after excluding outliers Table 2 and compared with parameters from the six pub-
exceeding three standard deviations from the median. lished studies which have also assessed the four-marker test
alone or in other combinations. There was no material
Multivariate log Gaussian modelling was used to predict difference in the standard deviations compared with the
test performance [1]. Numerical integration was used other studies. There were statistically significant correla-
whereby the theoretical range is divided into a number of tions between PAPP-A and both free b-hCG and PlGF
equal sections, thus forming a ‘grid’ in multidimensional which were also statistically significant in the other studies.
space. The Gaussian distributions are then used for calcu- There was a statistically significant correlation between
lating each section: the proportion of Down’s syndrome free b-hCG and PlGF, but this was not found consistently
and unaffected pregnancies in the section and the likeli- in the other studies. Smaller non-significant correlations
hood ratio. These values are then applied to the maternal were found between the other markers, and this was
age distribution to derive a distribution of Down’s syn- inconsistent across the studies. There were differences in
drome risk values. At each maternal age, the number of magnitude of the correlations for all combinations. How-
Down’s syndrome and unaffected pregnancies was esti- ever, this is to be expected as the confidence intervals on r-
mated from an age-specific risk curve [1]. The results were values are generally wide.
summed over the theoretical range to compute detection
rates for various fixed false-positive rates. Table 1 Median and weight correction equations

The serum marker distribution parameters for unaffected Type* A B C
pregnancies were derived from the analysed samples. The
corresponding values and the mean for Down’s syndrome Median
pregnancies were derived from a meta-analysis of the three
studies of the four-marker serum-only protocol together PAPP-A Quadratic 40,158.1 - 1091.22 7.60518
with three studies that investigated combinations of the 3.05575 - 0.01571 –
four markers and NT, ductus venosus or foetal heart rate Free b-hCG Log-linear 0.81799 0.01025 –
[7] or inhibin-A [8, 9]. The average of each parameter was - 0.45832 0.01827 –
calculated weighted for the number of cases. PlGF Log-linear
- 0.35250 84.1341 –
Performance was also predicted for an ‘Enhanced’ AFP Log-linear 0.41761 - 0.00703 –
Combined test whereby maternal serum PlGF and AFP are
added to the Combined test. Assuming that the four bio- Weight correction 4.49232 - 0.09793 0.000663
chemical markers are independent of NT, risk is calculated
by applying a likelihood ratio (LR) from the NT MoM to PAPP-A Inverse
the risk from the four serum marker MoMs and maternal
age. A log Gaussian model was used for LR based on a Free b-hCG Log-linear
published Down’s syndrome mean of 2.10 MoM at
12 weeks’ gestation [1] with standard deviation tailored to PlGF None
the standard deviation of log10 MoM in 27,647 results from
Mediscan Systems. AFP Quadratic

Log-linear = 10A?Bx; quadratic = A ? Bx ? Cx2; inverse = A ? B/
x; x = days or kg

123

Down’s Syndrome Screening in the First Trimester 15

Table 2 Unaffected serum parameters compared with six published studies [2–4, 9–11]

Parameter Current Donalson et al. Johnson et al. Wright et al. Huang et al. Palomaki et al. Carmichael et al.
study [2] [3] [7] [4] [8] [9]

SD (log10 MoM) 0.248 NK 0.262 0.235* 0.240 0.238 0.251
PAPP-A NK 0.252 0.256* 0.269 0.268 0.242
0.147 0.168 0.171 0.167 0.144 0.171
Free b-hCG 0.263 0.183 0.195 0.188 0.172 0.178 0.187

PlGF 0.147 0.216 0.043 NK 0.274 0.258 0.191

AFP 0.207 0.120 0.302 0.325 0.264 0.267 0.251
- 0.087 - 0.076 - 0.031 - 0.100 - 0.118 0.088
R-value 0.177h 0.070 0.130 0.090
0.312! - 0.010 0.085 0.007 0.086 0.209 - 0.024
PAPP-A & free b- - 0.087 - 0.021 - 0.102 - 0.051 - 0.071 - 0.045
hCG - 0.076 - 0.100 - 0.035

PAPP-A & PlGF

PAPP-A & AFP 0.030
Free b-hCG & PlGF 0.131?

Free b-hCG & AFP 0.039

PlGF & AFP - 0.028

*Calculated from the log inter-quartile range divided by 1.35
Current study only: ?P\0.01; hP \ 0.0005; !P \ 0.0001

The six published studies included a total of 603 Down’s standard deviation of NT MoM was 0.0878, and the tai-
syndrome cases although one study did not report the lored value for Down’s syndrome pregnancies was 0.2230.
means and standard deviation for PAPP-A and free b-hCG
and the correlation between them [2] and one study only Figure 1 shows the maternal age distribution in single
tested a subset for PlGF and AFP and also did not report years of age. The median age was 28, and 10% of women
the correlation between PAPP-A and free b-hCG [7]. were age of 35 or more.
Table 3 shows the Down’s syndrome parameters and the
number of cases used to derive each of them. The log10 Table 4 shows for the four-marker serum-only test the
model that predicted test detection rates for three fixed
Table 3 Down’s syndrome serum parameters: weighted average false-positive rates (3%, 5% and 7%) as well as the false-
from six studies [2–4, 9–11] positive rates for three fixed detection rates (65%, 75% and
85%). Using a fixed 1 in 250 term Down’s syndrome risk
Parameter Cases Value cut-off, the predicted detection rate was 78% and the false-
positive rate was 4.1%.
Mean (MoM) 603 0.503
PAPP-A 603 2.029 The Enhanced Combined test has a model that predicted
Free b-hCG 530 0.655 the detection rate of 95% for a 5% false-positive rate.
PlGF 457 0.776 Using a fixed 1 in 250 term risk cut-off, the predicted
AFP detection and false-positive rates were 90% and 1.4%,
603 0.278 respectively. By comparison, a standard Combined test has
SD (log10 MoM) 603 0.258 a predicted 91% detection rate for 5% false-positive rate,
PAPP-A 530 0.162 and using the 1 in 250 risk cut-off, the rates are 85% and
Free b-hCG 457 0.173 1.8%, respectively.
PlGF
AFP 300 0.123 Discussion
530 0.164
R-value 457 0.059 Our study provides all the information required for an
PAPP-A & free b-hCG 530 - 0.005 algorithm that can be used to interpret a first-trimester four-
PAPP-A & PlGF 457 - 0.087 marker serum-only protocol or an Enhanced Combined test
PAPP-A & AFP 457 - 0.044 in India. Using such an algorithm, modelling predicts that
Free b-hCG & PlGF the screening performance of the serum-only test is com-
parable with the second-trimester Quad test. And the
Free b-hCG & AFP Enhanced Combined test has a superior performance to a
PlGF & AFP standard Combined test. The same cut-off risk of 1 in 250

123

16 S. Suresh et al.

Fig. 1 Distribution of maternal ages predicted detection rate was 71, 69 and 66% at 11, 12 and
13 weeks’ gestation for a 5% false-positive rate. Two case–
Table 4 Model that predicted the performance: four-marker serum- control studies were carried out in Canada. Johnson et al.
only test [3] tested 90 cases and 1607 controls predicting a detection
rate of 74%, whilst Huang et al. [4] tested 137 cases and
Detection rate (%) False-positive rate 684 controls predicting a detection rate of 82%.

Fixed false-positive rate 74 3.0 Unlike the predicted second-trimester Quad test detec-
Fixed detection rate 80 5.0 tion rate of 71% for a 5% false-positive cited above [1], the
84 7.0 estimates for the first-trimester serum-only test in the three
65 1.5 case–control studies and the current analysis are somewhat
75 3.2 inflated by ‘viability’ bias since cases were identified from
85 7.4 prospective screening. The bias arises because of the high
intrauterine fatality rate for Down’s syndrome so that a
at term used by other screening protocols in India could be proportion of affected pregnancies which were detected
maintained for the new tests. and terminated would not have been viable. Nevertheless,
the magnitude of the bias is likely to be smaller enough to
The current restricted availability in India of quality conclude that performance is at least as good as the Quad
ultrasound NT could be overcome, to a great extent, by the test.
introduction of a first-trimester four-marker serum-only
test. For centres already carrying out a second-trimester For all Down’s syndrome screening protocols, both the
Quad test, this could be readily achieved. The cost of detection and false-positive rates are determined by the cut-
implementing a first-trimester four-marker serum-only test off risk. In a given protocol, the detection rate can be
will be no different to that of a second-trimester Quad test increased but only at the expense of an increased false-
and yields the benefits of early diagnosis and reassurance, positive rate. In general, when two protocols are being
as well as facilitating early screening for preeclampsia and compared, it is best to either fix the false-positive rate and
open spina bifida. Protocols involving the ultrasound compare detection rates or fix the detection rate and
measurement on NT are much more expensive; in a compare false-positive rates. Fixing the cut-off risk will, in
Canadian study, the unit cost of an NT scan was 4.4-fold general, mean that neither detection nor false-positive rates
greater than a four-marker serum test [3]. For those centres will remain the same. Nevertheless, in the current analysis
already carrying out a standard Combined test, the mea- using a fixed 1 in 250 term cut-off risk will result in pre-
surement of PlGF and AFP on the same automatic equip- dicted performance for the serum-only protocol similar to
ment used for PAPP-A and free b-hCG is unlikely to either fixing detection or false-positive rates to that
considerably increase costs. expected for the second-trimester Quad test.

For the serum-only test, the model predicted a Down’s All women included in our study had first-trimester
syndrome detection rate of 78% for a fixed 4.1% false- ultrasound biometry, and MoMs were calculated from
positive rate. In England, Donalson et al. [2] carried out a gestational ages calculated on the basis of these measure-
study based on stored serum samples from 92 Down’s ments. Therefore, to achieve in practice the performance
syndrome cases and 522 unaffected matched controls; the predicted here for the serum only test it will be necessary to
have reasonably accurate gestational dating. In localities
with insufficient resources to perform an early crown-rump
length measurement on all women, high performance can
still be achieved if only those with uncertain menstrual
dates are scanned. Alternatively, only women with positive
test results could have ultrasound dating and risk revision.

For the Enhanced Combined test, a model predicted a
Down’s syndrome detection rate of 90% for a 1.4% false-
positive rate, which was much better performance than the
Combined test where the rates were 85% and 1.8%,
respectively. A specialist centre that also routinely deter-
mines an additional ultrasound marker, say nasal bone,
would also benefit. Modelling shows that the rates for the
Enhanced Combined test would be 95% and 0.8% com-
pared with 92% and 1.1% for the Combined test. In addi-
tion to these advantages in performance, the additional

123

Down’s Syndrome Screening in the First Trimester 17

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9. Carmichael JB, Liu HP, Janik D, et al. Expanded conventional first
trimester screening. Prenat Diagn. 2017;37(8):802–7.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.

123

The Journal of Obstetrics and Gynecology of India (January–February 2020) 70(1):18–22
https://doi.org/10.1007/s13224-019-01263-x

ORIGINAL ARTICLE

ART in Prevention of Mother-to-Child Transmission of HIV

Abhilasha Gupta1 · Aruna Verma1 · Monika Kashyap1  · Priti Gautam1

Received: 22 January 2019 / Accepted: 9 August 2019 / Published online: 3 September 2019
© Federation of Obstetric & Gynecological Societies of India 2019

Abstract
Aim To evaluate the efficacy and safety of ART in prevention of mother-to-child transmission of HIV.
Methods All pregnant females who were tested and found positive for HIV from April 2015 to March 2017 were included
in this study and started on TLE regimen (Tenofovir 300 mg, Lamivudine 300 mg, Efavirenz 600 mg). After delivery these
newborns were given syrup Nevirapine 2 mg/kg for 6 weeks of life if mother was started on ART before 12 weeks of gesta-
tion and was continued upto 12 weeks if mother was started on ART later than 12 weeks of gestation. Infants were tested
with PCR and Rapid test for HIV was done at 6 weeks, 6 months, 12 months, and 18 months of life.
Result Out of 66 HIV-positive mothers (26 diagnosed in our institute and 40 referred patients), 53 delivered in our hospi-
tal. Out of these 53 deliveries, 3 were stillbirth, so 50 babies were registered. Out of 50 registered babies, 2 babies died in
follow-up (one at the age of 12 months due to malnutrition and other at the age of 4 months due to diarrhea). Five babies
were referred to nearby ART centers. So, we followed 43 babies out of which two were found to be positive for HIV (trans-
mission rate of HIV was 4.6%).
Conclusion The risk of transmission of HIV from mother-to-child had declined with the use of combination ART, and the
emergence of drug resistance was reduced. The ART used during pregnancy appears to be well tolerated and safe.

Keywords ART · PPTCT · TLE regimen · Nevirapine

Introduction of its 1.2 billion populations. Nearly 5% of infections are
attributable to parent-to-child transmission [1]. It is the sec-
According to WHO, there were approximately 35 million ond commonest mode of transmission of HIV [first being
people worldwide living with HIV/AIDS in 2013, of these sexual transmission].
3.2 million were children (less than 15 years old). Though
India has a low prevalence of HIV 0.27% in adults and Women account for around one million of people liv-
6.54% in children less than 15 years of age, yet in terms ing with HIV. In the absence of any intervention, an esti-
of individuals infected, India is home to the third largest mated cohort of 13,000 infected babies will be born annually
number of people living with HIV in the world by virtue (transmission rate 20–45%) [2].

Abhilasha Gupta is a Professor and Head in Department of So, to reduce the burden of the disease by cutting down
Obstetrics and Gynaecology at LLRM Medical College, Meerut, the transmission from parent to child in year 2015, WHO
U.P., India. Aruna Verma is an Associate Professor in Department recommended initiation of antiretroviral therapy for all HIV-
of Obstetrics and Gynaecology at LLRM Medical College, infected pregnant women regardless of CD4 cell count and
Meerut, U.P., India. Monika Kashyap is an Ex. Assistant Professor to continue ART lifelong [3]. Infants born to HIV-infected
in Department of Obstetrics and Gynaecology at LLRM Medical mothers should also receive post-exposure antiretroviral
College, Meerut, U.P., India. Priti Gautam is a Junior Resident prophylaxis.
in Department of Obstetrics and Gynaecology at LLRM Medical
College, Meerut, U.P., India. The recommended first-line ART regimen is TLE, i.e.,
Tenofovir 300 mg, Lamivudine 300 mg, Efavirenz 600 mg
* Monika Kashyap combination once daily in pregnant and breast-feeding
[email protected] women (it is same as recommended in non-pregnant adults).
TLE regimen is the first line because of less side effects
1 Department of Obstetrics and Gynaecology, LLRM Medical and once daily dosing schedule, thus increased chances of
College, Meerut, U.P., India

1 3Vol:.(1234567890)

ART in Prevention of Mother-to-Child Transmission of HIV 19

adherence to treatment and reduced risk of development of done. Referred HIV reactive cases from nearby centers were
resistance [4]. also included in this study.

Early testing of antenatal mothers, administration of ART, All patients were counseled in PPTCT in department of
lifelong continuation, institutional delivery, counseling on obstetrics and gynecology and started on TLE combination
infant feeding and ART to infant, effective family planning regimen by ART Center (HIV Department) in our hospital
and reproductive health services and linkage to long-term [Tenofovir 300 mg, Lamivudine 300 mg, Efavirenz 600 mg]
HIV care are critical for prevention of PTCT of HIV. By all on registration and continued throughout pregnancy, post-
these means, we can achieve the goal of HIV transmission partum and lifelong thereafter.
from parent to child to zero.
After delivery all infants were registered and serial
Aims and Objectives screening was done for newborns (by PCR and rapid test
for HIV at 6 weeks 6 months, 12 months and 18 months of
• To evaluate life) with post-exposure prophylaxis in form of syrup nevi-
rapine 2 mg/kg which was continued for 6 weeks if mother
• The efficacy of TLE regimen in prevention of PTCT. was started on ART within 12 weeks of gestation and was
• To assess the safety of TLE Regimen in mother and continued upto 12 weeks if mother had started ART after
12 weeks of gestation.
baby.
Mother was counseled and advised for choice of alterna-
Materials and Methods tive feed or breast-feed and contraceptive advice was given.

In this study, we have included all the HIV-positive pregnant Results
women who had delivered at LLRM Medical College and
SVBP Hospital, Meerut from April 2015 to March 2017. In our study, total 7836 antenatal low risk women were
tested for HIV in antenatal clinic from April 2015 to March
Study Design 2017. Out of these 7836 women, 26 were diagnosed as HIV
reactive (incidence in ANC was 0.33%), and 40 patients
Prospective observational study. were referred from other hospitals, so total 66 patients were
All pregnant women who came to our hospital for routine enrolled. Total 5768 patients delivered in our institute out of
these 53 were HIV positive. The incidence of HIV in deliv-
antenatal checkup were booked and thorough history with ered patients was 0.91% in our hospital because majority of
complete general, systemic and obstetrical examination was patients were referred from nearby hospitals and districts.
done. All routine ANC tests (hemoglobin, VDRL, urine rou-
tine and microscopy, OGTT with 75 g glucose, HIV, HbsAg, Following observations were made:
HCV) were advised and repeated accordingly with proper
antenatal care and follow-ups. Demographic Parameters of HIV-Positive Mothers
at the Time of Registration
The cases who were found to be HIV reactive were con-
firmed by rapid immunodot test (total three cards). Other The mean age of HIV reactive women in our study was
investigations like CD4 count, liver function tests were also 26 years with majority of women belonging to age group
24–28 years. In terms of parity out of 66 patients, 27 women
were primipara, 22 were nullipara, 15 were multipara and

Table 1 Demographic Demographic parameters (N-66)
parameters of HIV reactive
mothers at the time of Age (in years) 20–24 years 25–29 years 30–34 years 35–40 years
registration Parity 11 2
28 25 Multipara (≥ 2 Grand multipara

Nullipara (no prior Primipara (1 child birth) child birth) (≥ 4 child
child birth) birth)
15 2
Gestation at diag- 22 27 24–35 weeks > 36 weeks
nosis (in weeks) < 12 weeks 12–23 weeks 23 7
18 18

13

20 Gupta et al.

Table 2 CD4 count of HIV-positive mothers at the time of registra- In these 43 infants, 41 were negative for HIV and 2 tested
tion positive for HIV during follow-ups (transmission rate was
4.65% and efficacy of TLE 95.35%) (Table 4).
CD4 count > 500 351–500 251–350 < 250
N (53) 21 19 7 6

2 patients were grand multipara. In our study, 18 women Discussion
were diagnosed as HIV reactive and TLE was started before
12 weeks and 48 women were found to be HIV reactive after In 2011, WHO estimated that only 46% of HIV-infected
12 weeks of gestation and treatment was started. All women pregnant women in resource limited settings received
were compliant and took TLE regime regularly (Table 1). antiretroviral regimens for the prevention of PTCT. The
Joint United Nations program on HIV/AIDS reported that
CD4 Count of HIV-Positive Mothers at the Time coverage of antiretroviral programs for prevention of PTCT
of Registration increased from 36 to 80% in 2015 among their 21 priority
countries [5].
In our study, 40 patients had CD4 count > 350 and 13
patients had CD4 count < 350 (Table 2). According to HIV sentinel surveillance (HSS)
2014–2015, the overall prevalence among antenatal clinic
Birth Weight of Infants and Gestation at Delivery attendees, continue to be approximately 0.29% (90% CI
of HIV-Positive Mothers 0.28–0.31) in our country [6]. In our study, the incidence
was 0.33% in antenatal clinic.
The average weight of infants delivered was 2.6 kg, and the
mean age of gestation at delivery was 38 weeks (Table 3). As we discussed before that in absence of any antiretrovi-
ral therapy, the risk of vertical transmission is approximately
In total 53 deliveries, 35 (66%) were delivered by cesar- 15–45%. Use of single-dose nevirapine to mother and syrup
ean section and 18 (44%) by vaginal delivery. Cesarean sec- nevirapine to newborn has shown reduction in transmission
tion were done for obstetric indications only. Out of these to 10% or less. Combination ART followed by post-exposure
53 deliveries, 3 were stillbirth and 2 died in the infantile prophylaxis to the newborn as recommended by WHO in
period (one at the age of 12 months due to malnutrition 2013 has potential to further reduce transmission to less than
and other at the age of 4 months due to diarrhea). Since, 5% in breast-feeding population [2]. In our study, the trans-
these women hailed from various districts and shifted to mission rate is 4.65%.
their native places 5 babies were transferred to nearby ART
centers. So we followed 43 infants. Dr. S. Sumithra et al. followed 74 babies born to HIV
reactive mothers receiving TLE in their study. Out of these,
Out of these 43 infants, 28 babies were breast-fed and 15 5 tested positive for HIV and 69 were negative. The trans-
received alternate feeds (9 babies received formula feed and mission rate of HIV was 6.7% [7].
6 babies received animal milk).
According to the latest guidelines of ACOG given in 2018
stabilized and ongoing research has shown that treatment
of HIV-infected pregnant women with combined ART can
achieve a 1–2% or lower risk of mother-to-child transmission

Table 3 Birth weight of infants and gestation at delivery of HIV reactive mothers

Birth weight at delivery (in kg) 3–3.5 kg 2.5–3 kg 2–2.5 kg 1.5–2.0 kg 1.0–1.5 kg 40–42 weeks
N (53) 14 20 15 3 1 4
Gestation at the time of delivery (in weeks) 25–27.6 weeks 28–30.6 weeks 31–33.6 weeks 34–36.6 weeks 37–39.6 weeks
N (53) 1 1 1 3 43

Table 4 Characteristics of HIV-positive baby (N-2)

Parity Gestation at start of CD4 count Gestation at Mode of delivery Feeding practices Positive at age
TLE (weeks) delivery
Cesarean section Formula feeding 6 weeks
Nullipara 37 530 38 Cesarean section Breast-feeding 12 months
Primipara 8 371 40

13

ART in Prevention of Mother-to-Child Transmission of HIV 21

if maternal viral load of 1000 copies/ml or less can be sus- ART her viral load may have not reduced to sufficiently low
tained, independent of the route of delivery or duration of levels. This baby was formula fed and found reactive at very
ruptured membranes before delivery [8]. early age of 6 weeks.

NACO also do not recommend Cesarean sections for The mother of second baby was diagnosed and started
prevention of PTCT. Particularly, where women are taking ART at 8 weeks of gestation, she delivered at 38 weeks.
ART for their own health, C-section should be performed for Baby received nevirapine after delivery and was breast-
obstetric indications only [2]. In our study, we did cesarean fed. This baby was found reactive at 12 months of age. So
in these patients for obstetric indications only. even after receiving post-exposure prophylaxis, this baby
may become reactive through breast-feeding, as there is no
Combination ART is well tolerated except for few GI side method by which we can reduce the risk of transmission to
effects, hyperglycemia, elevated liver transaminases. In our zero percent till date by any treatment.
study, we did not encounter any major side effect in patients
for which discontinuation of the drugs was needed. So this Conclusion
regime is quiet convenient because of once daily dosing and
without much side effects. • New pediatric HIV infections from PTCT remain a sub-
stantial health burden in our country. With improved
Most studies from developing countries have suggested access to antiretroviral agents and improved care deliv-
an increased risk of preterm births, stillbirths, intrauterine ery systems, the goal of virtual elimination of HIV can
growth restriction and death of infants born with HIV-infected be achieved.
women with more advanced disease [9] which can only be
prevented by active interventions like antiretroviral drugs and • The tide of emerging drug resistance is reduced with
other measures. The use of antiretroviral drugs in pregnancy combination ART compared to single-dose nevirapine.
has generally been found to be safe in trials till date and the
benefits for preventing fatal illness in mothers and reduction in • Nevertheless, successful prevention programs must also
PTCT been judged to outweigh the potential adverse effects. include other measures like rapid HIV testing, monitor-
Currently, recommended regime TLE has been used exten- ing and support for antiretroviral adherence and toxicity,
sively during pregnancy and appear to be well tolerated and counseling on infant feeding, effective family planning
safe. However, further studies regarding potential risk of birth and reproductive health services and linkage to long-term
defects and end organ toxicities in women are necessary to HIV care.
assure short and long-term safety [10, 11].
Funding Antiretroviral treatment to the patients was provided by ART
The use of combination ART avoids the problem of low Center of our institute which is funded by UPSACS (U.P. state AIDS
efficacy and emergence of higher rates of viral resistance control society) as per NACO guidelines.
associated with the use of single-dose nevirapine and zido-
vudine [12]. Compliance with Ethical Standards

In year 2009, WHO released new recommendations on Conflict of interest The authors declare that they have no conflict of
infant feeding by HIV-positive mothers, according to which interest.
babies of HIV-positive mothers can have benefit of breast-
feeding with very little risk of becoming infected with HIV. Ethical Statement The authors that all procedures performed in this
Research had shown that exclusive breast-feeding in the first study involving human participants were in accordance with the ethi-
six months of an infant’s life is associated with a three- to cal standards of the institutional research committee and with the 1964
fourfold decreased risk of HIV transmission compared to Helsinki Declaration and its later amendments or comparable ethical
infants who were breast-fed [13]. standards.

In our study, we counseled parents for feeding methods Informed Consent An informed consent was obtained from all the
and their risks and we emphasized regarding avoidance individual participants in the study.
of any kind of mixed feeding at all. Out of 43 babies, 28
babies were breast-fed (65%) and 15 were on alternative References
feeds (35%) and no baby received mixed feeding.
1. UNICEF India. HIV/AIDS. Available from latest stories. http://
Previously it was considered that LSCS prevents the www.unicef.in/story/1123/HIV-AIDS. Accessed Dec 2017.
mother to child of HIV. In our study, we found that both
HIV-positive newborns were delivered by cesarean section.
So, mode of delivery does not change the transmission rate.

Out of the 2 infants who tested reactive for HIV, mother
of one baby was diagnosed HIV positive at 37 weeks of
gestation and she delivered at 38 weeks, so even by giving

13

22 Gupta et al.

2. NACO: Updated Guidelines for PPTCT of HIV using multidrug 12. Fowler MG, Qin M, Fiscus SA, et al. Benefits and risks of antiret-
antiretroviral regimen in India, December 2013. http://naco.gov. roviral therapy for perinatal HIV prevention. N Engl J Med.
in/upload/NACP%20%20IV/18022014%20BSD/National_guidl 2016;375:1726–37.
ines_for_PPTCT.pdf. Accessed Sept 2017.
13. WHO. Breast is always best even for HIV positive, Nov 2009.
3. World Health Organization. Guideline on when to start antiret- h t t p : / / w w w. w h o . i n t / b u l l e t i n / vo l u m e s / 8 8 / 1 / 1 0 - 0 3 0 1 1 0 . p d f .
roviral therapy and on pre-exposure prophylaxis for HIV, Sept Accessed July 2018.
2015. http://apps.who.int/iris/bitstream/10665/186275/1/97892
41509565_eng.pdf?ua=1. Accessed 30 Sept 2015. Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
4. WHO consolidated guidelines on the use of antiretroviral drugs
for treating and preventing HIV infection, recommendations for a About the Author
public health approach, June 2013. http://www.who.int/hiv/pub/
guidelines/arv2013/download/en/. Accessed Dec 2017. Dr. Abhilasha Gupta has done her
MBBS, MD, DGO, from King
5. World Health Organization. On the fast track to an AIDS-free George Medical College Luc-
generation. Geneva, Switzerland. 2016. http://emtct-iatt.org/wp- know. She has 35 years of teach-
content/uploads/2016/06/globalplan2016_en.pdf. Accessed 20 ing experience, heading the
June 2016. Department of Obstetrics and
Gynecology at LLRM Medical
6. NACO Annual Report 2016–17. http://naco.gov.in/documents/ College, Meerut for 11  years.
annual-reports.pdf. Accessed Aug 2018. She is member of editorial board
of journal of UPCOG. She has
7. Sumithra S, Manonmani R. Efficacy of TLE regimen in prevention published and presented many
of mother to child transmission of HIV. IOSR J Dent Med Sci. papers, lectures and orations in
2017;16(2):36–8. national and regional confer-
ences. She is member of editorial
8. Committee on Obstetric Practice; HIV Expert Work Group. board of journal of UPCOG and
ACOG committee opinion number-751: Labor and delivery also contributed chapters in
management of women with HIV virus infection. American many books. Her special interests are high risk pregnancy and
College of Obstetricians and Gynecologists. Obstet Gynaecol. infertility.
2018;132:e131–7.

9. James DK, Steer PJ, Weiner CP, Gonik B. High risk pregnancy,
management options. 4th ed. Amsterdam: Elsevier; 1994. p.
480–1.

10. Zash R, Souda S, Chen JY, et al. Reassuring birth outcomes with
Tenofovir/Emtricitabine/Efavirenz used for prevention of mother-
to-child transmission of HIV in Botswana. J Acquir Immune Defic
Syndr. 2016;71:428.

11. Malaba T, Phillips T, Petro G, et al. Timing of ART initiation
in pregnancy and birth outcomes in South African women. In:
Conference on retroviruses and opportunistic infection, 22–25 Feb
2016, Boston, MA. Abstract 799.

13

The Journal of Obstetrics and Gynecology of India (January–February 2020) 70(1):23–29
https://doi.org/10.1007/s13224-019-01277-5

ORIGINAL ARTICLE

Pilot Interventional Study Comparing Fetomaternal Outcomes
of 150 mg Versus 75 mg Aspirin Starting Between 11 and 14 Weeks
of Pregnancy in Patients with High Risk of Preeclampsia:
A Randomized Control Trial

Namrata Kumar1,3 · Vinita Das1 · Anjoo Agarwal1 · Amita Pandey1 · Smriti Agrawal1 · Amrita Singh2

Received: 2 April 2019 / Accepted: 9 September 2019 / Published online: 20 September 2019
© Federation of Obstetric & Gynecological Societies of India 2019

Abstract
Introduction Hypertensive disorders of pregnancies complicate around 5–10% of pregnancies worldwide, and together they
are a member of the deadly triad along with haemorrhage and infection that contribute to a significant amount of maternal
morbidity and mortality.
Aims and Objectives To compare differences in the fetomaternal outcomes with the use of 150 mg aspirin versus 75 mg
aspirin in pregnant women found to be at high risk of PE.
Methodology This was a two-armed double-blind parallel randomized control trial conducted in the Department of Obstetrics
and Gynaecology, King George’s Medical University, carried over a period of 1 year.
Results Preeclampsia occurred in 15 of 87 participants (17%) in the 75 mg aspirin group compared with 6 of 91 (6.5%) in
the 150 mg aspirin group. There were a significantly higher incidence of PE, its severity and lesser period of gestation at
delivery in the group given 75 mg dose compared to the group given 150 mg dose. There were significantly higher values of
mean arterial pressure and uterine artery PI in women who developed preeclampsia compared to those who do not in both
the groups. Foetal outcomes were observed in both the groups of women, and there was no statistically significant difference
between them.
Conclusion This randomized trial showed that among women with singleton pregnancies who were identified by means of
first-trimester screening as being at high risk of preterm preeclampsia, use of aspirin 150 mg per day started between 11
and 14 weeks till 36 weeks is a potent intervention to reduce the development of both early- and late-onset preeclampsia as
compared to a dose of 75 mg per day.

Keywords Preeclampsia · Aspirin · MAP · Uterine Doppler

Dr. Namrata Kumar is a Associate Professor, the Department of Introduction
Obstetrics and Gynaecology, King George’s Medical University,
Lucknow; Vinita Das is a Professor and Head, the Department of Hypertensive disorders of pregnancies including preec-
Obstetrics and Gynaecology, King George’s Medical University, lampsia (PE) and eclampsia complicate around 5–10% of
Lucknow; Anjoo Agarwal is a Professor, the Department of pregnancies worldwide, and together they are a member
Obstetrics and Gynaecology, King George’s Medical University, of the deadly triad, along with haemorrhage and infection,
Lucknow; Amita Pandey is a Professor, the Department of which contribute to a significant amount of maternal mor-
Obstetrics and Gynaecology, King George’s Medical University, bidity and mortality [1]. The possibility of complications is
Lucknow; Dr. Smriti Agrawal is a Additional Professor, the higher when the disease is severe and of early onset, requir-
Department of Obstetrics and Gynaecology, King George’s ing delivery before 37 weeks of gestation.
Medical University, Lucknow; Dr. Amrita Singh is a Assistant
Professor, the Department of Obstetrics and Gynaecology, Era In low-resource settings like the Indian subcontinent, it
Lucknow Medical College, Lucknow. is common to encounter patients with severe preeclamp-
sia and its complications like eclampsia, HELLP syn-
* Namrata Kumar drome, placental abruption, disseminated intravascular
[email protected]
1 3Vol.:(0123456789)
Extended author information available on the last page of the article

24 Kumar et al.

coagulation, intrauterine growth retardation and intrauter- Materials and Methods
ine death. The aetiology of preeclampsia and to an extent
foetal growth restriction are attributed to abnormal pla- The trial was a two-armed double-blind parallel ran-
centation. A combination of maternal demographic char- domized control trial conducted in the Department of
acteristics, including medical and obstetric history, serum Obstetrics and Gynaecology, King George’s Medical
markers, uterine artery pulsatility index (PI) and mean University. The pregnant women attending the outpatient
arterial pressure (MAP), at 11–13 weeks of gestation has department between 11 and 14 weeks of gestational age
been studied and reported to identify a high proportion of (at crown-rump length of 45–84 mm) and meeting the
pregnancies at high risk of preterm PE [2–6]. inclusion criteria were enrolled in the study after a writ-
ten informed consent. The study was carried out over a
Uterine artery PI is an indirect measure of uteroplacen- period of 1 year.
tal perfusion, and the postulated hypothesis is that high
PI implies impaired placentation with the consequent Inclusion criteria were women with high risk of preec-
increased risk of developing preeclampsia, foetal growth lampsia (diagnosed by FMF Eclampsia calculator which
restriction, abruption and stillbirth [7, 8]. involved history, body mass index, medical disorders,
mean arterial pressure and uterine artery PI). Exclusion
More than fifty trials and meta-analysis of these stud- criteria were active peptic ulcer disease, bleeding disorder,
ies reported that the administration of low-dose aspirin chronic kidney disease, thrombocytopenia (platelet count
in high-risk pregnancies is associated with a moderate < 1.5 lac), history of vaginal bleeding and foetus diag-
decrease in the rate of PE and its complication [9]. More nosed with malformations/anomaly/aneuploidy.
recent meta-analysis of randomized studies reported that
low-dose aspirin started at or before 16 weeks was associ- All women were asked for previous obstetric history,
ated with a 50% reduction in the overall risk of PE and a pre-pregnancy weight and past history of preeclampsia.
significant reduction in preterm PE [10, 11]. Still, early Weight and height were recorded. Mean arterial pressure
screening for PE and aspirin do not find a place in national was calculated for each arm in sitting position. Transvag-
guidelines. inal Ultrasound (Toshiba Xario) was done, and crown-
rump length and bilateral uterine artery PI were recorded
Moreover, majority of these studies have used relatively for all enrolled women between 11 and 14 weeks. After
lower doses of the drug (75–100 mg) and very few trials enrolment, these women were randomized according to
have actually used 150 mg since there could be a possibility computer-generated random number table into two groups:
of non-responders [12, 13]. Whether aspirin in relatively one receiving 150 mg aspirin and the other 75 mg aspi-
higher dosage, i.e. 150 mg, is better in outcome compared to rin per day at bed time. Allocation concealment was done
60–80 mg is less studied and evaluated, and there is a dearth by sequentially numbered opaque sealed envelopes. The
of evidence in the reported literature. principal investigator was blinded for allocation sequence.
Pharmacist distributed the sealed drug packets to the
First-trimester use of aspirin is not associated with the women of both groups without disclosing the content and
increased risk of foetal abnormalities and there is no evi- group to the patient. Health care providers were unaware
dence of any increase in maternal bleeding form any site of the intervention drug. Outcome analysis was done
or placental abruption [14]. Also, there is no association after decoding the allocation sequence. Every patient was
between low-dose aspirin during the third trimester and instructed to take one capsule at bed time starting from the
antenatal closure of the ductus arteriosus, intraventricular time of enrolment and continued until 36 weeks. Patients
haemorrhage or neonatal bleeding [10]. were followed till delivery and outcome was recorded. The
trial was registered in CTRI no: CTRI/2018/01/011155,
There is a paucity of data for the Indian population and ethical clearance was obtained from the Institutional
regarding their response to different dosages of aspirin. Ethical Committee of King George’s Medical University
There is growing concern that the dose of aspirin 75 mg (reg no ECR/262/Inst/UP/2013): 83rdECM IIB-IMR-F/P2.
per day used commonly in clinical settings has no benefit in
majority of pregnant women, and to our knowledge, there Results
are limited trials which have actually compared dosage of
150 mg with 75 mg. A total of 1090 women with singleton pregnancies were
screened for preeclampsia, and 200 (18.0%) were found to
The present study is planned to compare differences in be at high risk. However, 10 women (5%) were not fulfilling
the fetomaternal outcomes with the use of 150 mg aspirin
compared to another group given 75 mg aspirin which is the
usual recommended dose in majority of standard guidelines.
Primary outcome was the development of preeclampsia
before 37 weeks. Secondary outcomes were comparison of
severity of PE, foetal growth restriction, neonatal morbidity
and mortality.

13

Pilot Interventional Study Comparing Fetomaternal Outcomes 25

Number of women screened for Preeclampsia = 1090

200 ( 18.3 % ) were found to be at high risk ,
assessed for eligibility

Excluded = 10
1- thrombocytopenia = 2
2- pepƟc ulcer disease = 1
3- missed aborƟon = 3
4- fetal malformaƟon = 2
5- raised creaƟnine = 1
6- aneuploidy = 1

Eligible for inclusion = 190

RandomizaƟon

Group A 150 mg Aspirin Group B 75 mg Aspirin
n = 96 n = 94

Lost to follow up = 5 Lost to follow up
=7

Analysed and followed up Analysed and follow up
N = 91 N = 87

Fig. 1 Flow chart of randomization

the inclusion criteria and were excluded (Fig. 1). After ran- (150 mg aspirin) and 87 women in group B (75 mg aspirin).
domization of 190 women who participated in the trial, 12 After enrolment, five women in group A and seven women
were lost to follow-up. There were 91 women in group A in group B refused to participate in the study.

13

26 Kumar et al.

Data were analysed as mean standard deviation (SD), fre- and uterine artery PI in women who developed preeclampsia
quency and percentage whenever appropriate. Comparison compared to those who did not, in both the groups.
of the different variables between the study groups was done
using t test (for independent samples in case of continuous Foetal outcomes were observed in both the groups of
data) and χ2-test. For smaller values, Fisher’s exact test was women, and there was no statistically significant difference
used. between them as shown in Table 4.

There were no significant differences between the aspirin Discussion
group and the placebo group with regard to the characteris-
tics of the participants at baseline (Table 1). In this trial, we identified women at high risk of preeclamp-
sia by combined screening which included maternal factors,
Preeclampsia occurred in 15 of 87 participants (17%) in uterine artery pulsatility index and mean arterial pressure;
the 75 mg aspirin group compared with 6 of 91 (6.5%) in the however, placental growth factor and pregnancy-associated
150 mg aspirin group. There were a significant difference in plasma protein A were not incorporated due to financial con-
the incidence of PE, its severity and period of gestation at straints in a low-resource setting. Studies have shown that
delivery in the two groups as shown in Table 2. There was the detection rate of preeclampsia at less than 37 weeks by
no significant difference in the mode of delivery in both the maternal characteristics is 33% while it increases to 72% if
groups (p = 0.638). uterine artery PI and mean arterial pressure are added to it
[15]. Further addition of serum biomarkers improves the
Among various high-risk factors seen in women as shown detection rate to 77% [16].
in Table 3, on univariate analysis there was no significant
difference in medical diseases or prior history of PE. There
were significantly higher values of mean arterial pressure

Table 1 Characteristics of 150 mg aspirin 75 mg aspirin group p value
included women in the trial n = 91 n = 87 0.458
0.554
Gestational age (median) (crown-rump 62.2 63.3 0.478
length mm) 0.446
28.1 ± 4.9 27.7 ± 5.2
Age (mean ± SD) 24.5 ± 3.7 25 ± 4.2 0.762
Body mass index (mean ± SD)
Method of conception 86 (94.5%) 80 (92%) p value
 (a) Spontaneous 3 (3.2%) (2.3%) 0.046
 (b) OI 2 (2.2%) 5 (5.7%) 0.114
 (c) IVF 0.051
Obstetric history 67 (73.6%) 60 (68.9%) 0.637
 (a) Nullipara 7 (7.69%) (9.2%) 0.051
 (b) Multipara with PE 17 (18.68%) 19 (21.89%)
 (c) Multipara without PE 0.007

Table 2 Comparison of Outcomes 150 mg aspirin 75 mg aspirin
the development of PE, n = 91 n = 87
complication and mean period Development of preeclampsia
of gestation in both the groups Early-onset preeclampsia 6 (6.5%) 15 (17.2%)
Severe PE 1 (1%) 5 (5.7%)
Placental abruption 2 (2.1%) 9 (10.3%)
Severe PE 2 (2.1%) 4 (4.5%)
 (a) Thrombocytopenia 2 (2.1%) 9 (10.3%)
 (b) HELLP 0 1 (1.1%)
 (c) Pulmonary oedema 1 (1%) 2 (2.2%)
 (d) BP > 160/110 mm Hg 0 2 (2.2%)
Mean POG at the time of delivery 1 (1%) 4 (4.5%)
37.3 36.6

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