The value of oral micronized progesterone in the prevention of recurrent spontaneous preterm birth: a randomized controlled trial SHERIF ASHOUSH1, OSAMA EL-KADY1 , GEHAN AL-HAWWARY1 & AHMED OTHMAN2 1Department of Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University, Cairo, and 2Department of Obstetrics and Gynecology, Ghamra Military Hospital, Cairo, Egypt ACTA Obstetricia et Gynecologica Scandinavica Journal Club -Obstetrics- December 2017 Edited by Francesco D’Antonio

Introduction Spontaneous preterm delivery (SPD) represents the leading cause of neonatal mortality and long-term morbidity and a considerable financial burden.+ SPD is at least partly related to an untimely decline in the progesterone effect. A recent Cochrane systematic review showed that intramuscular 17-alpha-hydroxyprogesterone-caproate (17OHP-C) and the vaginally administered progesterone significantly reduced the rate of SPD, perinatal mortality, neonatal morbidity and low birthweight [relative risk (RR) 0.64, 0.55, 0.74 and 0.92, respectively] when compared with placebo. Vaginally administered progesterone has become the most widely effective alternative in preventing SPD. However, it is poorly accepted by some women and is frequently associated with an unpleasant vaginal discharge. On the other hand, 17OHP-C was only proven effective among women with singleton gestations and a history of SPD, while was shown to be ineffective in other high-risk groups such as women with an isolated short cervical length or those with multiple pregnancies

Aim of the study To assess the role of oral micronized progesterone in preventing SPD in women with past history of spontaneous preterm delivery and to ascertain whether it improves perinatal outcome

Material and Methods Study design: Single-center, prospective, double-blind, randomized placebo-controlled trial. Inclusion criteria: Singleton pregnancies at 14-18 weeks of gestation, and a past history of at least one SPD at <37 weeks. Exclusion criteria: Persistent uterine contractions, progesterone use in the current pregnancy, active liver disease, obstetric, medical or surgical complications indicating delivery, presence of fetal anomalies incompatible with life, and preterm premature rupture of membranes (PPROM). Randomization: The study randomized 212 patients, with a history of prior SPD, into a progesterone group (n = 106) receiving six-hourly 100 mg OMP capsules and a placebo group (n = 106) receiving identical oral capsules Outcomes observed: Primary outcome: Incidence of SPD (<37 weeks of gestation). Primary outcome: Neonatal birthweight, admission (and duration of stay) to neonatal intensive care units, neonatal mortality rate and mid-trimester miscarriages.

Material and Methods Statistical analysis: Categorical data (proportions) were expressed as frequency and percentage. They were compared using the Chi-square test or Fisher’s exact test for quantitative variables of small sample size. Numerical data were presented as mean and standard deviation. They were compared using Student t-test when comparing continuous variables with a normal distribution, or Mann–Whitney U-test for non-parametric data. Relative risk and number-needed-to-treat (NNT) were calculated, using the same software, based on the absolute risks of the treatment and control groups and the resulting absolute risk reduction.

Results 212 women (106 per group) were randomized and started the study, while the final outcome data were available for 96 women in the progesterone group and 91 women in the placebo group

Results The two groups matched well for baseline characteristics. Cervical lengths were statistically similar (p = 0.17) The two groups underwent cervical cerclage at similar rates, whether electively at the end of the first trimester or emergency/rescue procedures at ≥20 weeks. Progesterone levels were checked at 20 and 28 weeks and were higher in the progesterone group esepcially during the third trimester

Results Women in the progesterone group delivered at a significantly higher gestational age, and those who needed tocolysis had significantly longer tocolysis-to-delivery intervals. The progesterone group had a higher cumulative percentage of undelivered cases per gestational week. The RR of delivering preterm was 0.7, with a 95% CI of 0.54–0.92 (p = 0.01), and the NNT to prevent one case of preterm delivery was 5.28, with a 95% CI of 3.03–20.35. Rates of operative delivery or other maternal postpartum complications were statistically similar among the two groups. On the other hand, the placebo group had higher rates of neonatal complications (mainly low birthweight and respiratory distress syndrome), longer duration of admission to neonatal intensive care units (NICU) and higher neonatal mortality rates.

Limitations 75% of the study population underwent cervical cerclage Some women in the control group underwent other treatments. Part of the original population was lost to follow-up. Lack of stratification according to gestational age at birth (only SPD <37 weeks explored).

Conclusion Oral micronized progesterone is effective in preventing spontaneous preterm delivery. The additional advantages of oral administration, affordability, and high safety profile make it worth recommending, at least for further research.