Natural ovulation offers a safer path to IVF success

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Feb 4 2026

A landmark randomized trial shows that preparing the uterus using natural ovulation delivers the same chance of a healthy baby as hormone therapy, while sharply lowering the risk of dangerous pregnancy complications for mothers. 

Study: Natural ovulation versus programmed regimens before frozen embryo transfer in ovulatory women: multicentre, randomised clinical trial. Image Credit: Vectorium / Shutterstock.com

In a recent study published in the British Medical Journal, researchers compared the effectiveness of natural ovulation and external hormone replacement regimens for preparing the uterus before frozen embryo transfer in achieving a healthy live birth and reducing maternal pregnancy complications.  

How the uterus is prepared for frozen embryo transfer outcomes

Frozen embryo transfer is an assisted reproductive technology (ART) procedure that involves transferring and implanting a previously frozen blastocyst into the uterus. Comparatively, fresh embryo transfer is an in vitro fertilization (IVF) procedure that transfers and implants a fertilized embryo into the uterus during the same ovarian stimulation cycle. Frozen embryo transfer is becoming increasingly popular due to the widespread use of freeze-all strategies, reduced risk of ovarian hyperstimulation, and the opportunity for pre-implantation genetic testing.

The frozen embryo transfer procedure requires preparing the endometrium for embryo implantation, with the two most commonly used regimens being a natural, non-medicated regimen or a programmed regimen. Whereas the natural regimen relies on spontaneous follicular development or ovulation triggered by human chorionic gonadotropin, the programmed regimen involves sequential administration of exogenous hormones, including estrogen and progesterone.

Trial design

In the current multicenter, randomized clinical trial, researchers compare the success rate of delivering a healthy infant and the risks of maternal and infant health complications between natural ovulation and programmed regimens before a single blastocyst frozen embryo transfer.

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

In the natural regimen group, endometrial preparation and frozen embryo transfer timing were determined by monitoring natural follicle development and measuring serum levels of luteinizing hormone, estradiol, and progesterone, with ovulation triggered in some participants at the discretion of clinicians. In the programmed regimen, endometrial preparation involved sequential administration of estrogen and progesterone.

Key findings

Similar effectiveness in achieving healthy live births was observed with both natural ovulation and programmed regimens at 41 % and 40 %, respectively. However, as compared to study participants in the natural ovulation regimen group, those who completed the programmed regimen for endometrial preparation were more likely to be diagnosed with pre-eclampsia, particularly among those who achieved a clinical pregnancy.

Significantly lower risks of early pregnancy loss, vaginal bleeding, hypertensive disorders of pregnancy, placenta accreta spectrum, which is defined as the abnormal attachment of the placenta to the uterine wall, caesarean delivery, and postpartum hemorrhage were observed in the natural ovulation regimen group as compared to the programed regimen group, while neonatal outcomes such as birth weight and serious neonatal complications were similar between groups.    

Study significance

The natural ovulation regimen for endometrial preparation is as effective as a programmed regimen in achieving a healthy infant after frozen embryo transfer. However, women who complete a natural ovulation regimen are at a reduced risk of pregnancy-related complications than those undergoing a programmed regimen, despite a higher rate of cycle cancellation during the first transfer attempt.

Specifically, the programmed regimen was associated with a higher risk of pre-eclampsia, particularly late-onset pre-eclampsia without severe features, which may still carry long-term cardiovascular risks for both the mother and infant. Unlike early-onset pre-eclampsia, which is associated with placental dysfunction, late-onset pre-eclampsia is largely associated with maternal systematic dysfunction.

The observed risk of pre-eclampsia in women who completed the programmed regimen may be due to the absence of corpus luteum, which secretes relaxin, as well as other vasoactive and angiogenic factors, for maternal cardiovascular adaptation to pregnancy; however, these factors were not directly measured in the trial, and this explanation remains hypothetical. Future studies should consider measuring these factors and evaluating maternal-fetal interactions to gain more insights into the mechanisms.

In addition to pre-eclampsia, the programmed regimen was also associated with several late-pregnancy maternal complications that are potentially related to the placenta, which may result from hormonal therapy at the time of implantation and early pregnancy. These findings suggest that initiating an intervention started before conception can reduce maternal morbidity later in pregnancy.

Taken together, the natural ovulation regimen is preferred for endometrial preparation based on its safety profile, especially for women who are at higher risk of hypertensive disorders of pregnancy, such as women aged 38 years or older and those with obesity. The relative reduction of approximately 40 % in the risk of pre-eclampsia 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, especially in high-income countries where the prevalence of cardiometabolic complications and risk of pre-eclampsia is higher than low- and middle-income countries.