A landmark randomized trial showed that using natural ovulation to prepare the uterus may be as likely to deliver a healthy baby as hormone therapy, while significantly lowering the risk of dangerous pregnancy complications for the mother.

study: A programmed regimen before spontaneous ovulation and frozen embryo transfer in ovulating women: a multicenter randomized clinical trial. Image credit: Vectorium / Shutterstock.com

In a recent study published in british medical journal, Researchers compared the effectiveness of natural ovulation and external hormone replacement therapy to prepare the uterus before frozen embryo transfer to achieve a healthy birth and reduce maternal pregnancy complications.

How the uterus is prepared for the outcome of frozen embryo transfer

Frozen embryo transfer is an assisted reproductive technology (ART) procedure in which a previously frozen blastocyst is transferred to the uterus for implantation. In comparison, fresh embryo transfer in vitro An insemination (IVF) procedure in which embryos fertilized during the same ovarian stimulation cycle are transferred to the uterus for implantation. Frozen embryo transfer is becoming increasingly popular due to the widespread use of the all-freeze strategy, reduced risk of ovarian hyperstimulation, and opportunities for preimplantation genetic testing.

Frozen embryo transfer procedures involve preparing the endometrium for embryo transfer, and the two most commonly used regimens are natural, non-medicated regimens or programmed regimens. Natural therapies rely on spontaneous follicular development or ovulation induced by human chorionic gonadotropin, whereas programmed therapies require continuous administration of exogenous hormones such as estrogen and progesterone.

trial design

In the current multicentera randomized clinical trial, researchers are comparing the birth success rate of healthy infants and the risk of maternal and child health complications between natural ovulation and programmed therapy before single blastocyst frozen embryo transfer..

A total of 4,376 ovulating women from 24 academic fertility centers in China were recruited into this study. Study participants were randomly assigned to a programmed regimen for natural ovulation or endometrial preparation before attempting their first frozen embryo transfer.

In the naturopathic group, the timing of endometrial preparation and frozen embryo transfer was determined by monitoring natural follicular development and measuring serum levels of luteinizing hormone, estradiol, and progesterone., Ovulation will be triggered in some participants at the discretion of the clinician. In the programmed regimen, endometrial preparation included sequential administration of estrogen and progesterone.

Main findings

Similar efficacy in achieving a healthy birth was observed for both natural ovulation and programmed therapy at 41% and 40%, respectively. However, compared to study participants in the natural ovulation therapy group, participants who completed programmed therapy for endometrial preparation were more likely to be diagnosed with preeclampsia., This is especially true among those who have achieved clinical pregnancy.

Significantly lower risks of early miscarriage, vaginal bleeding, gestational hypertension, placenta accreta spectrum defined as abnormal attachment of the placenta to the uterine wall, caesarean section, and postpartum hemorrhage were observed in the natural ovulation therapy group compared to the programmed therapy group., Meanwhile, neonatal outcomes such as birth weight and severe neonatal complications were similar between groups.

Significance of research

A natural ovulation plan to prepare the endometrium is as effective as a programmed plan in delivering a healthy infant after frozen embryo transfer. However, women who complete natural ovulation therapy have a lower risk of pregnancy-related complications than women who undergo programmed ovulation therapy., Despite the high cycle cancellation rate during the first transfer attempt.

Specifically, programmed regimens are associated with an increased risk of preeclampsia, particularly late-onset preeclampsia without severe symptoms, which may still pose long-term cardiovascular risks for both mother and infant. Unlike early-onset preeclampsia, which is associated with placental insufficiency, late-onset preeclampsia is primarily associated with maternal systemic dysfunction.

The risk of preeclampsia observed in women completing the programmed regimen may be due to the lack of the corpus luteum secreting relaxin and other vasoactive and angiogenic factors necessary for maternal cardiovascular adaptation to pregnancy.; However, these factors were not directly measured in trials, and this explanation remains hypothetical. Future studies should consider measuring these factors and evaluating maternal-fetal interactions to gain further insight into the mechanisms.

In addition to pre-eclampsia, the programmed regimen is It is associated with several late pregnancy maternal complications that may be placenta-related and may result from hormone therapy at the time of implantation and early pregnancy. These findings suggest that maternal morbidity in late pregnancy can be reduced by starting interventions before pregnancy.

Taken together, natural ovulation therapy is preferable for endometrial preparation based on its safety profile, especially for women at high risk for gestational hypertension, such as women older than 38 years and those with obesity. of The approximately 40% relative reduction in the risk of preeclampsia with spontaneous ovulation therapy (equivalent to an absolute risk difference of approximately 2 percentage points) is expected to have significant public health implications, particularly in high-income countries where the prevalence of cardiometabolic complications and the risk of preeclampsia are higher than in low- and middle-income countries.