Comparison of Perinatal Outcomes of Letrozole-Induced Ovulation and Hormone Replacement Therapy Protocols in Patients With Abnormal Ovulation Undergoing Frozen-Thawed Embryo Transfer: A Propensity Score Matching Analysis

Abstract

BackgroundWith the increasing use of frozen embryo transfer (FET), the best endometrial preparation protocol is continuously being discussed. The hormone replacement therapy (HRT) cycle and letrozole-induced ovulation (L-OI) cycle are available protocols for patients with abnormal ovulation. Previous comparisons of the two protocols have focused on pregnancy outcomes, with less attention to perinatal outcomes, and population heterogeneity was large; thus, convincing conclusions about which protocol is more appropriate could not be drawn.MethodsWe performed a retrospective cohort study using propensity score matching (PSM) analysis for a population of patients undergoing FET cycles in the reproductive center of the Third Affiliated Hospital of Zhengzhou University from January 2016 to September 2020. The main outcome measures were clinical pregnancy rate, live birth rate, very preterm delivery (VPTD), preterm delivery (PTD), low birth weight (LBW), macrosomia, small for gestational age (SGA), large for gestational age (LGA), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), premature rupture of membranes (PROM), placenta previa, and congenital abnormality.ResultsA total of 8010 women were enrolled. Due to the large heterogeneity among the patients, we conducted 1:1 PSM, and 1461 women matched in each group. Compared with the HRT group, the L-OI group had a smaller proportion of thin endometrium (27.38% vs. 41.07%) and thicker endometrium on the day of embryo transfer (9.63 ± 1.82 vs. 8.91 ± 1.38). There were no significant differences in clinical pregnancy rate, early abortion rate or live birth rate between the groups. There was no significant difference in perinatal outcomes of singleton live birth, including VPTD, PTD, postterm delivery, LBW, macrosomia, SGA, LGA, GDM, HDP, placenta previa, and congenital malformation.ConclusionFor women with abnormal ovulation, the pregnancy and perinatal outcomes of HRT and L-OI protocols are reassuring. It seems that both protocols are safe and effective for endometrial preparation in frozen-thawed embryo transfer in the clinic.

The future of frozen-thawed embryo transfer in hormone replacement therapy cycles

“…The largest study used propensity score matching (PSM) with 1461 women in both the letrozole ± hMG and HRT FET group and reported similar LBR in crude as well as in adjusted analysis [aOR 0.95 (95% CI 0.81–1.12)] [7]. Both Day 3 embryo and blastocyst transfers as well as single and double embryo transfers were included, but neither type nor number of embryos transferred were included in the PSM [7]. In the most recent paper from the centre, only single blastocyst transfers were included with 502 in the letrozole ± hMG group and 2280 in the HRT FET group with a significantly higher LBR (aOR 1.30 (95% CI 1.06–1.58)) and a lower MR [aOR 0.63 (95% CI 0.44–0.90)] in letrozole ± hMG compared to HRT FET [11].…”

“…None of the studies reported a poorer live birth rate (LBR) in letrozole FET compared to HRT FET. Three papers including the only RCT reported similar live birth rate (LBR) [6,7] or ongoing pregnancy rate (OPR) [8], whereas seven retrospective studies reported improved LBR in letrozole FET compared to HRT FET [9–15].…”

“…Such study design introduces critical selection bias due to exclusion of letrozole nonresponders in the letrozole FET group, who would not have been excluded in an HRT FET cycle as letrozole responders and nonresponders cannot be discriminated during HRT FET. The two largest studies included a letrozole ± hMG FET protocol where hMG was allowed if needed based on follicular response to letrozole [7,11]. The two studies originate from the same centre and the data are drawn from approximately the same period; however, the conclusions are different.…”

“…The two studies originate from the same centre and the data are drawn from approximately the same period; however, the conclusions are different. The largest study used propensity score matching (PSM) with 1461 women in both the letrozole ± hMG and HRT FET group and reported similar LBR in crude as well as in adjusted analysis [aOR 0.95 (95% CI 0.81–1.12)] [7]. Both Day 3 embryo and blastocyst transfers as well as single and double embryo transfers were included, but neither type nor number of embryos transferred were included in the PSM [7].…”

Letrozole Supplementation and the Increased Risk of Elevated Progesterone Levels on Trigger Day

“…Using LE during in vitro fertilisation and intracytoplasmic sperm injection (IVF/ICSI) treatment has many advantages. First, LE is used to prepare the endometrium in the frozen embryo transfer (FET) cycle, and no negative effect on endometrial receptivity has yet been reported (5)(6)(7)(8). Some studies revealed that clinical pregnancy rates and live birth rates in the LE group are significantly higher, and the rate of miscarriage is significantly lower compared to those in the natural and hormone replacement cycle groups (9,10).…”