Condition category
Pregnancy and Childbirth
Date applied
21/11/2018
Date assigned
11/01/2019
Last edited
11/01/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Progesterone is an essential hormone for creating a suitable endometrial (womb) environment for embryo implantation, pregnancy maintenance and delivery at term. Presently, progesterone is used as the first-line drug for luteal phase support (LPS) in IVF treatment. On the other hand, dydrogesterone, an orally active progestogen, is well-tolerated and has a higher patient satisfaction rate than micronized vaginal progesterone. However, a few clinicians have expressed concern about the associated risk of birth defects in newborn infants born to women treated with oral dydrogesterone during early pregnancy. Therefore, it is important to ensure that there is no increased indication of birth defects in children owing to maternal use of dydrogesterone during pregnancy. This motivates us to compare congenital birth defects in children born to women receiving dydrogesterone or micronized progesterone following ovulation induction (OI), intrauterine insemination (IUI) or IVF. A third group of women conceiving spontaneously during investigation are also included for comparison purposes. The aim of this study is to assess and compare the incidence of birth defects among children of infertile couples who conceived either spontaneously during investigation, or with micronized progesterone or dydrogesterone for luteal phase support.

Who can participate?
Women aged 21- 45 with infertility

What does the study involve?
Participants unable to conceive spontaneously are randomly allocated to be treated with either oral micronized progesterone or oral dydrogesterone. Following successful conception, all women are followed up regularly. Fetal viability scan and detailed anatomy scans are performed at 6-7 weeks and 20-22 weeks of gestation, respectively. Fetal echocardiography is performed at around 22 weeks of gestational age to exclude congenital cardiac defects. The women are routinely examined by the obstetrician and the babies are thoroughly examined by a pediatrician during their postnatal visit. Electronic records are maintained for all women until their postnatal checkup. Demographic characteristics, pregnancy rate, miscarriage rate, congenital anomalies and fetal outcome are recorded. Information related to growth, learning abilities, and psychological functioning are recorded by a trained child psychologist and trained nurses. The functional abnormalities in children are closely monitored. These follow-up reports are collected using various methods such as analysis of birth records, regular health check-up of children by the pediatricians and pediatric-psychologist during annual baby get-together, and parents’ feedback.

What are the possible benefits and risks of participating?
This study is the first of its kind where congenital abnormalities in children born to women receiving oral dydryogesterone following IVF are investigated. The result will shed some light on a new treatment method for infertile women. There is no risk for patients.

Where is the study run from?
Institute of Reproductive Medicine (India)

When is the study starting and how long is it expected to run for?
January 2002 to June 2017

Who is funding the study?
Investigator initiated and funded

Who is the main contact?
1. Prof. Baidyanath Chakravarty
dtushar30@gmail.com
2. Prof. Koel Chaudhury
koel@smst.iitkgp.ernet.in

Trial website

Contact information

Type

Scientific

Primary contact

Prof Baidyanath Chakravarty

ORCID ID

Contact details

Institute of Reproductive Medicine
HB-36/A/3
Salt Lake City
Sector-III
Kolkata
700106
India
+91 (0)33-23215125
dtushar30@gmail.com

Type

Scientific

Additional contact

Prof Koel Chaudhury

ORCID ID

Contact details

School of Medical Science & Technology
Indian Institute of Technology Kharagpur
Kharagpur
721302
India
+91 (0)3222 283572
koel@smst.iitkgp.ernet.in

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

IRM/IEC/BNC-IHP-50

Study information

Scientific title

Congenital anomalies in children following maternal use of dydrogesterone or micronized progesterone as luteal phase support in infertile women: a randomized comparative study

Acronym

Study hypothesis

Oral dydrogesterone may be a promising drug for luteal phase support in infertility treatment.

Ethics approval

Institute of Reproductive Medicine Ethics Committee, 07/01/2002, ref: IRM/IEC/BNC-IHP-50

Study design

Prospective comparative randomized clinical study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a participant information sheet.

Condition

Infertility, luteal phase support

Intervention

A total number of 6537 women reporting for infertility treatment were screened for the present study. A total of 239 women with adenomyosis, congenital uterine anomalies and uterine synechiae, baseline FSH >12 IU, donor oocyte recipients and gestational surrogates were excluded from the study. Out of the remaining 6298 women, 2003 conceived spontaneously during investigation (Group A), while the remaining infertile women (n=4295) were randomly allocated for ovulation induction (OI), intrauterine insemination (IUI) or in vitro fertilization (IVF) treatment. Randomized allocation was such that 2103 women received oral micronized progesterone (Group B) as luteal phase support (LPS) and 2192 women received oral dydrogesterone (Group C) as LPS, while Group A did not require the necessary support (control group).

Patients in group B and group C undergoing OI/IUI received clomiphene citrate (50 mg) twice daily from days 3-7 of their menstrual cycle. Intramuscular 75 IU gonatropin was administered to patients undergoing OI on day 3, and was administered to patients undergoing IUI on day 3 and day 8. OI cases were advised of timed intercourse during the fertile window for conception. From day 10 onwards, IUI patients were monitored for ovarian follicular development and their endometrial thickness was monitored by transvaginal ultrasound. Ovulation was triggered with 5000 IU urinary hCG subcutaneously as a single dose when the leading follicle was ≥18 mm and endometrial thickness was ≥7 mm. Insemination was performed with ≥5 × 106/ml motile spermatozoa 36 hours post hCG injection following confirmation of ovulation.

All patients undergoing IVF received subcutaneous injection of 1 mg (40 IU) daily of a GnRH agonist (leuprolide acetate) starting from the mid-luteal phase of the previous cycle which continued for a period of 14 days, or until the onset of the next menstruation (whichever was earlier). The dose of leuprolide acetate was reduced to 0.2 mg (8 IU) from 1 mg when the patient was down-regulated. Recombinant FSH was administered 150–300 IU with adjustment of the dose wherever necessary. Ovarian follicular development was monitored from day 6 of stimulation using transvaginal ultrasonography. Human chorionic gonadotropin injection was administered intramuscularly when the average diameter of the leading follicle (s) reached ≥18 mm. This occurred approximately between days 9 and 13 of stimulation. Serum peak E2 was assessed on the day of hCG administration. Oocytes were retrieved transvaginally under ultrasound guidance 34–36 hours post hCG injection. Subsequently, conventional IVF was performed when the semen sample of the male partner was normal. Intracytoplasmic sperm injection (ICSI) was the treatment option in case of azoospermia or severe oligoasthenozoospermia. An average of three embryos was transferred between 40 and 44 hours post insemination at the 4–8 cell stage.
LPS was initiated on day 16 and continued for 10 days, from the day after insemination and from day of embryo transfer of OI, IUI and IVF respectively.

Group B received oral micronized progesterone 200 mg three times daily and Group C received oral dydrogesterone 10 mg three times daily. While Group B and C received LPS up to 12 weeks of gestation, Group A did not require this support. Serum β-hCG level was estimated 13 days after OI/IUI/ET to confirm pregnancy. If the test was positive, LPS was continued up to 12 weeks of pregnancy.

Following successful conception, all participants were followed up regularly. Fetal viability scan and detailed anatomy scans were performed at 6-7 weeks and 20-22 weeks of gestation, respectively. Fetal echocardiography was performed at around 22 weeks of gestational age to exclude congenital cardiac defects. The women were routinely examined by the obstetrician and the babies thoroughly examined by a pediatrician during their postnatal visit. Electronic records till their postnatal checkup were maintained for all women. Demographic characteristics, pregnancy rate, miscarriage rate, congenital anomalies and fetal outcome were recorded. Information related to growth, learning abilities, psychological function were recorded by a trained child psychologist and trained nurses. The functional abnormalities in children were closely monitored.

Intervention type

Supplement

Phase

Drug names

Primary outcome measure

1. Congenital anomalies detected during pregnancy or following birth
2. Functional abnormality

Secondary outcome measures

1. Pregnancy rate
2. Miscarriage rate
3. Intrauterine fetal outcome (including gestational age)
4. Intrauterine growth restriction (IUGR)
5. Intrauterine fetal death (IUFD)
6. Neonatal characteristics including number of live births, body weight, APGAR score, neonatal intensive care unit (NICU) admission, respiratory distress syndrome (RDS), neonatal jaundice, hypoglycaemia and hypocalcaemia.

Overall trial start date

08/01/2002

Overall trial end date

30/06/2017

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Female
2. Aged 21- 45 years
3. Primary and secondary infertility (e.g. ovulatory and hormonal disorders, fallopian tube obstruction, endometriosis and having partners with male factor infertility)

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

6298

Participant exclusion criteria

1. Adenomyosis
2. Congenital uterine anomalies
3. Uterine synechiae
4. Baseline FSH >12 IU
5. Donor oocyte recipients
6. Gestational surrogates

Recruitment start date

08/01/2002

Recruitment end date

30/06/2017

Locations

Countries of recruitment

India

Trial participating centre

Institute of Reproductive Medicine
HB-36/A/3, Salt Lake City, Sector-III
Kolkata
700106
India

Sponsor information

Organisation

Institute of Reproductive Medicine

Sponsor details

HB-36/A/3
Salt Lake City
Sector-III
Kolkata
700106
India
+91 (0)3323215127
bncirm@gmail.com

Sponsor type

Hospital/treatment centre

Website

http://www.irm-bnc.org/contactus.php

Funders

Funder type

Other

Funder name

Investigator initiated and funded

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

A manuscript will be published in a peer reviewed scientific journal. Additional documents such as study protocol and statistical analysis plan are available upon request from the principal investigator, Dr. B.N. Chakravarty.

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Baidyanath Chakravarty (irmbnc@gmail.com).
Type of data: Demographic data and baseline characteristics of women, fetal and neonatal outcome of women and congenital, functional and chromosomal anomalies in infants born to women with spontaneous conception during infertility investigation and those receiving luteal progesterone following OI/IUI/IVF.
Time duration for data: Data will be available after publication
Criteria for access data: any scientist or doctor

Intention to publish date

15/12/2018

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes