Progesterone Intramuscularly or Vaginally Administration May Not Change Live Birth Rate or Neonatal Outcomes in Artificial Frozen-Thawed Embryo Transfer Cycles.

Yuan Liu,Yu Wu

doi:10.3389/fendo.2020.539427

Abstract

BackgroundsPrevious studies suggested that singletons from frozen-thawed embryo transfer (FET) were associated with higher risk of large, post-date babies and adverse obstetrical outcomes compared to fresh transfer and natural pregnancy. No data available revealed whether the adverse perinatal outcomes were associated with aberrantly high progesterone level from different endometrium preparations in HRT-FET cycle. This study aimed to compare the impact of progesterone intramuscularly and vaginally regimens on neonatal outcomes in HRT-FET cycles.MethodsA total of 856 HRT-FET cycles from a fertility center from 2015 to 2018 were retrospectively analyzed. All patients had their first FET with two cleavage-staged embryos transferred. Endometrial preparation was performed with sequential administration of estrogen followed by progesterone intramuscularly 60 mg per day or vaginal gel Crinone 90 mg per day. Pregnancy outcomes including live birth rate, singleton birthweight, large for gestational age (LGA) rate, small for gestational age (SGA) rate, and preterm delivery rate were analyzed. Student’s t test, Mann-Whitney U-test, Chi square analysis, and multivariable logistic regression were used where appropriate. Differences were considered significant if p < 0.05.ResultsNo significant difference of live birth rate was found between different progesterone regimens (Adjusted OR 1.128, 95% CI 0.842, 1.511, p = 0.420). Neonatal outcomes like singleton birthweight (p = 0.744), preterm delivery rate (Adjusted OR 1.920, 95% CI 0.603, 6.11, p = 0.269), SGA (Adjusted OR 0.227, 95% CI 0.027, 1.934, p = 0.175), and LGA rate (Adjusted OR 0.862, 95% CI 0.425, 1.749, p=0.681) were not different between two progesterone regimens. Serum P level >41.82 pmol/L at 14 day post-FET was associated with higher live birth rate than serum P level ≤41.82 pmol/L in HRT-FET cycles when progesterone was intramuscularly delivered (Adjusted OR 1.690, 95% CI 1.002, 2.849, p = 0.049). But singleton birthweight, preterm delivery rate, SGA and LGA rate were not different between these two groups.ConclusionsRelatively higher serum progesterone level induced by intramuscular regimen did not change live birth rate or neonatal outcomes compared to vaginal regimen. Monitoring serum progesterone level and optimizing progesterone dose of intramuscular progesterone as needed in HRT-FET cycles has a role in improving live birth rate without impact on neonatal outcomes.

Highlights

As cryopreservation has been an efficient and reliable laboratory procedure, freeze-all policy and elective embryo cryopreservation have been increasingly prevalent with a variety of clinic indications like preventing OHSS, implantation of PGT-A, fertility preservation, etc [1]
There is little agreement on the ideal route and dose of Abbreviations: HRT, hormone replacement therapy; FET, frozen-thawed embryo transfer; COS, controlled ovarian stimulation; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; LGA, large for gestational age; SGA, small for gestational age; EVT, extravillous trophoblast; 95% CI, 95% confidence intervals; OR, odds ratios; BMI, body mass index
Controlling for maternal age, BMI, the route of estrogen administration, whether estradiol duration was longer than 21 days, whether there was at least one good quality embryo transferred, progesterone administered regimen did not modify the odds of achieving live birth (Adjusted OR 1.128, 95% CI 0.842, 1.511, p = 0.420) or clinical pregnancy (Adjusted OR 1.144, 95% CI 0.863, 1.518, p = 0.349) (Table 2)

Summary

Introduction

As cryopreservation has been an efficient and reliable laboratory procedure, freeze-all policy and elective embryo cryopreservation have been increasingly prevalent with a variety of clinic indications like preventing OHSS, implantation of PGT-A, fertility preservation, etc [1]. There is a growing number of FET cycles applied due to the endometrial synchrony and relative steady endocrine environment compared to supraphysiologic estrogen milieu generated by controlled ovarian stimulation (COS) in fresh IVF cycles. We must recognize the adverse perinatal outcomes of FET, like higher risk of macrosomia, perinatal mortality, and pregnancy complications [2,3,4,5]. Reports suggested that singletons from FET were associated with higher risk of large and post-date babies, placenta accrete, pre-eclampsia compared to fresh transfer and natural pregnancy [6,7,8,9]. Some reports suggested embryo cryopreservation altered epigenetics regulation and induced abnormal placentation and fetal growth [7]. Scarce literature has been focused on the supraphysiologic progesterone exposure to the deep placentation

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