Natural rectal progesterone was administered vs placebo to twin pregnancies following IVF/ICSI.
This is a double-blind, placebo controlled, single center, randomized clinical trial performed during the period from January 2014 to July 2017.
Participants
All pregnant women, with dichorionic twins, who had not undergone cerclage, following an IVF/ICSI trial performed at the Egyptian IVF Center, Maadi, Cairo ,Egypt, were counseled to participate in this study after performing the first trimester scan.
Inclusion Criteria:
1) Non-Smokers, 2) Normal Fetal anatomy, 3) No Uterine anomalies, 4) Only Dichorionic twins, 5) No previous history of preterm birth, 6) Healthy pregnant women not suffering from medical disorders e.g. diabetes and hypertension, 7) No known allergy to progesterone.
To ensure eligibility of participants, all women enrolled in the study had a first trimester scan for risk assessment of Down’s Syndrome in addition to an anomaly scan at 11-14 weeks of pregnancy. Dating was performed by calculation from date of embryo transfer.
After the supervising Obstetrician explained the protocol and its aim and design, women who agreed to join the study signed a consent form and were randomized and began the suppositories immediately.
Participants received 100mg daily IM Progesterone injections (IBSA Egypt) for luteal phase support starting on the day of oocyte retrieval until the first viability ultrasound was performed at 7 weeks. Once fetal heart beats were confirmed they were advised to stop intake of progesterone. This was based on a previous study by our group which shows no significant difference in miscarriage rates in patients who stopped progesterone early as compared to those who continued till 10 weeks gestations (15)
Participants in both study and control groups received our routine antimicrobial agents given to twin pregnancy, for prophylactic & curative treatment of vaginitis and urinary tract infections. They received Clindamycin vaginal cream (2%) for 7 days each month and oral Amoxicillin as a single dose of 3gm once every month (16,17, 18). In addition, Preterm premature rupture of membranes is the cause of approximately one third of preterm deliveries. Its higher risk includes those who have lower socioeconomic status (19), which applies to our group of patients.
All women were followed up according to the routine antenatal care protocol of our institution. Every visit we confirmed adequate intake of the suppositories and took note of any reported side effects or adverse outcomes. Collection of data was done following delivery by direct contact with the patient’s obstetrician and neonatologist in addition to phone calls to the patient to confirm compliance to the use of the suppositories. This included gestational age at delivery, neonatal condition, and reporting of neonatal intensive care unit (NICU) admission, birth weight and congenital anomalies undetected during pregnancy.
Randomization
Randomization was done into either the Progesterone group or the placebo group. Women were randomized after performing the first trimester scan at 11-14 weeks by opening a numbered, sealed, opaque envelope, with either progesterone or the placebo at a ratio of 1: 1 ratio (hand generated using the Microsoft excel Software), which was executed by a third party not involved in the trial (a nurse). Progesterone and placebo suppositories were provided by the manufacturer (IBSA Egypt) in indistinguishable packings, labeled with the patient’s code, the study name. The manufacturer was not involved in the writing of the protocol or study design or writing of the paper or its submission. Suppositories were provided to the patient by the supervising nurse in sealed packages given once a month to cover the period till her next antenatal visit.
Intervention
The study group received natural progesterone suppositories of 400mg, while the Placebo was composed of 126mg hard fat, 36mg Gelucire pellets, 0.2 mg Sorbic acid, 300 mg cocoa butter, 195mg purified water (Supplied by IBSA Egypt), they both appeared exactly similar. All suppositories were administered rectally twice daily starting from the randomization process at 11-14 weeks until 37 weeks or delivery. Rectal administration was chosen as social and cultural background of our women showed that they have great fear from repeated vaginal administration, in addition we chose this route to minimize possible risks of vaginal infections from repeated prolonged periods of twice daily administration of vaginal suppositories
Participants, supervising doctors and nurses were unaware of the randomization and allocation of the women. Only an independent secretary had the key code but had no access to the data nor to the women. The blinding code was not broken until all data was collected from all participants which took place a few weeks following delivery of the last patient. Long term follow up of the infants was not performed in this study.
Study outcomes
Primary outcome measures: Spontaneous preterm birth before 37 weeks’ gestation.
Secondary outcome measures: Preterm births <34, <32 and <28 weeks
Neonatal outcome; including: NICU admission, neonatal death.
Relevant Definitions
- Early fetal loss: fetal death between 11 and 22weeks of gestational age [20]
- Late fetal loss: fetal death between 22 and 28 weeks of gestational age [20]
- Stillbirth: Fetal death after 28 weeks gestational age [20]
- NICU admission; neonatal admission to Intensive care for any reason other than neonatal jaundice
- Neonatal death; death up to 30 days after delivery
Sample size estimation
Sample size calculation was based on a 20% reduction of the previously reported 65% preterm birth rate in twin pregnancies before 37 weeks of gestation [7]. Calculation was done based on comparing 2 proportions from independent samples using Chi-square test wherein the α-error level was fixed at 0.05 and the power was set at 80%. Accordingly, the sample size was calculated to be 96 cases in each arm. Sample size calculation was done using PS Power and Sample Size Calculations software, version 3.0.11 for MS Windows (William D. Dupont and Walton D. Vanderbilt, USA).
Ethics approval and consent to participate
All women read and signed an informed consent after full explanation of the study design and procedure. The study protocol was designed according to the CONSORT statement. Ethical approval was obtained on 15/11/2013 by our local Ethical Committee “Ethics and research Committee of the Egyptian IVF center” headed by Professor Ibrahim Fahmy, ([email protected]) and received an IRB number of 3/2013. The trial was registered on 31 January 2014 at www.ISRCTN.com, number 69810120.
Statistical methods:
Data was statistically described in terms of mean ± standard deviation (± SD), or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables was done using Student t test for independent samples. Chi-square test was used to compare categorical data between groups. A two-tailed P value <0.05 was considered statistically significant. All statistical calculations were done using computer program SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) release 20 for Microsoft Windows (2006).