Perinatal outcomes of progesterone in natural frozen-thawed embryo transfer pregnancies: insights from two randomized controlled trials.

Objective: To explore whether progesterone supplementation during luteal phase and early pregnancy following a natural frozen-thawed embryo transfer cycle (NC-FET) affects perinatal outcomes.

Design: A secondary data analysis study based on two randomized control trials taking place during 2008-2011 and 2013-2018 at two university hospitals in Sweden.

Subjects: A total of 923 women undergoing a natural FET cycle. The present study included all women who became pregnant after treatment and delivered a single liveborn infant (N=227).

Intervention: Study participants were randomized to receive luteal phase-vaginal progesterone supplementation until gestational week 8 (n=136) or to the standard of care that was no progesterone supplementation (n=91).

Main Outcome Measures: We assessed the incidence of obstetric and neonatal outcomes. Furthermore, we calculated the odds ratios (OR) with 95% CIs representing the likelihood of developing gestational hypertensive disorders. ORs were adjusted for participants' demographics (Model 1) or both demographic and IVF-treatment variables (Model 2).

Results: Apart from a slightly higher maternal age in the group receiving progesterone supplementation, the subjects in both groups were otherwise comparable in terms of infertility diagnosis, fertilization mode, embryo stage and number of embryos transferred. Our results revealed a higher proportion of infants delivered with birthweights in the normal range after progesterone supplementation (82.4% vs 70.3% respectively, p=0.033). Furthermore, pregnancies following progesterone supplementation in NC-FET cycles showed a numerically lower incidence of gestational hypertensive disorders; however, this difference did not reach statistical significance (4.4% vs 11.1, p=0.057). A similar pattern was noted in the logistic regression analyses performed. No differences were observed regarding other major adverse obstetric or neonatal outcomes.

Conclusion: Our study demonstrates the absence of harmful perinatal effects associated with the use of vaginal progesterone supplementation at the luteal phase and early pregnancy of a natural FET cycle. These findings have increased generalizability across other populations and are particularly significant given the growing utilization of cryopreservation and freeze-all practice in assisted reproduction. The associations noted between progesterone supplementation and certain perinatal outcomes warrant further investigation.