New Study Compares Uterine Preparation Methods for Frozen Embryo Transfer

A recent multicenter, randomized clinical trial, published in the British Medical Journal, has shed new light on optimal uterine preparation methods for frozen embryo transfer (FET). The study specifically investigated two distinct approaches: a natural ovulation regimen and a programmed hormone regimen, comparing their effectiveness in achieving healthy live births and their impact on maternal pregnancy complications.

Understanding Frozen Embryo Transfer (FET)

Frozen embryo transfer (FET) is a crucial assisted reproductive technology (ART) procedure. It involves the implantation of a previously frozen blastocyst into the uterus. This method has gained increasing popularity due to the adoption of freeze-all strategies, a reduced risk of ovarian hyperstimulation, and expanded opportunities for pre-implantation genetic testing.

For endometrial preparation prior to FET, two primary methods are typically employed. The natural regimen relies on the body's spontaneous follicular development, sometimes supplemented with ovulation triggered by human chorionic gonadotropin. In contrast, the programmed regimen involves the sequential administration of exogenous hormones, specifically estrogen and progesterone.

Trial Design and Participants

The trial encompassed 4,376 ovulatory women, recruited from 24 academic fertility centers across China. Participants were randomly assigned to either the natural ovulation or the programmed regimen for endometrial preparation before their first single blastocyst FET attempt.

In the natural regimen group, endometrial preparation and transfer timing were meticulously determined by monitoring natural follicle development and measuring serum hormone levels. Ovulation was triggered in some participants based on clinical judgment. The programmed regimen, as described, involved the sequential administration of estrogen and progesterone.

Key Findings: Effectiveness and Complications

The study revealed that both regimens demonstrated similar effectiveness in achieving healthy live births.

Both regimens demonstrated similar effectiveness in achieving healthy live births, with rates of 41% for the natural ovulation regimen and 40% for the programmed regimen.

However, significant differences were observed concerning maternal complications:

• Participants in the programmed regimen group faced an increased likelihood of being diagnosed with pre-eclampsia, a serious condition, particularly among those who achieved a clinical pregnancy.
• The natural ovulation regimen group exhibited notably lower risks of several adverse outcomes, including early pregnancy loss, vaginal bleeding, hypertensive disorders of pregnancy, placenta accreta spectrum (abnormal attachment of the placenta), caesarean delivery, and postpartum hemorrhage.
• Crucially, neonatal outcomes, such as birth weight and serious neonatal complications, were found to be similar between both groups.

Significance and Public Health Impact

The findings unequivocally indicate that the natural ovulation regimen for endometrial preparation is as effective as the programmed regimen for achieving a healthy infant after FET. Moreover, women undergoing the natural ovulation regimen experienced a reduced risk of pregnancy-related complications. While the natural regimen did present a higher rate of cycle cancellation during the initial transfer attempt, its overall safety profile is considered superior.

The findings indicate that the natural ovulation regimen for endometrial preparation is as effective as the programmed regimen for achieving a healthy infant after FET.

The association between the programmed regimen and a higher risk of pre-eclampsia, particularly late-onset pre-eclampsia without severe features, raises concerns about potential long-term cardiovascular risks for both mothers and infants. Researchers hypothesize that this may be linked to the absence of the corpus luteum, which typically secretes factors vital for maternal cardiovascular adaptation during pregnancy. This specific hypothesis, however, was not directly measured in the study.

The study suggests that interventions initiated before conception can reduce maternal morbidity later in pregnancy.

This research strongly suggests that interventions initiated even before conception can significantly reduce maternal morbidity later in pregnancy. Consequently, the natural ovulation regimen is now considered preferable, especially for women at higher risk of hypertensive disorders, such as those aged 38 or older or with obesity. The observed approximately 40% relative reduction in pre-eclampsia risk in the natural ovulation regimen—corresponding to an absolute risk difference of about two percentage points—is expected to have a meaningful public health impact, particularly in high-income countries.