Endometrial PreparationMethods and Obstetric Risks After Frozen Embryo Transfer in Endometriosis

Nationwide analysis identifies protocol-dependent obstetric vulnerabilities in endometriosis patients undergoing frozen embryo transfer

Key Points

Highlights:

• Artificial-cycle frozen embryo transfer (AC-FET) is linked to significantly higher obstetric risks in women with endometriosis.
• Natural-cycle FET appears to be safer for patients with endometriosis, especially those vulnerable to early pregnancy complications.

Importance:

• Selecting the appropriate FET protocol is clinically important for women with endometriosis, as protocol-related risks may compound pre-existing pregnancy vulnerabilities.

What’s done here?

• Data from the Korean National Health Insurance Service (NHIS) database, spanning 2017 to 2021, were analyzed.
• The study included 44,118 singletonin vitro fertilization (IVF) pregnancies, stratified by presence or absence of an endometriosis diagnosis.
• FET cycles were categorized into Artificial Cycle (AC-FET) and Natural Cycle (NC-FET) protocols.
• Multivariable logistic regression models were used to estimate adjusted odds ratios for obstetric and pregnancy outcomes, controlling for maternal characteristics and medical history.

Key results:

• In endometriosis patients, AC-FET resulted in a significantly higher risk for threatened abortion, Hypertensive Disorders of Pregnancy (HDP) and placenta previa, all compared to NC-FET.
• The interaction analysis confirmed a significantly stronger association between AC-FET and threatened abortion in women with endometriosis.
• The Absolute risk of threatened abortion in endometriosis group was 35.1% with AC-FET compared to 21.0% with NC-FET.
• In women without endometriosis, AC-FET was associated with higher miscarriage risk and lower term birth rates.
• For pregnancy outcomes (miscarriage, preterm birth, term birth), no significant differences were seen between AC-FET and NC-FET within the endometriosis group.

Strenghts and Limitations

• Large, nationally representative cohort with protocol-based subgroup comparison, enabling robust estimates and reducing selection bias ia the strength of the study.
• Limitations are the lack of critical clinical details (endometriosis stage, embryo quality, BMI, prior treatment history) in administrative data, which may leave residual confounding.

From the Editor-in-Chief – EndoNews

"This national cohort reinforces a critical point: for women with endometriosis, the choice of FET protocol carries real obstetric consequences. Artificial-cycle FET, although convenient and widely used, eliminates the physiological contributions of the corpus luteum and replaces natural endocrine dynamics with supraphysiologic hormonal exposure. In a uterus already shaped by chronic inflammation, impaired decidualization, and disturbed vascular remodeling, this shift may create an even more vulnerable environment for early placentation.

The markedly higher rates of threatened abortion, hypertensive disorders of pregnancy, and placenta previa observed after AC-FET highlight the need for a more individualized ART strategy in endometriosis. When feasible, natural-cycle FET appears to better preserve physiologic hormonal signaling and may provide a safer reproductive pathway for this population.

Looking ahead, prospective studies integrating lesion phenotype, disease stage, endocrine profiles, and placental biomarkers will be important to refine practice further. Nevertheless, the evidence presented here already makes a compelling case: for women with endometriosis, FET protocol selection should be regarded not as a logistical choice, but as a meaningful component of obstetric risk mitigation."

Lay Summary

Endometriosis is a common condition and is present in 30–50% of women who experience difficulty conceiving. Because it can cause pelvic adhesions, hormonal disturbances, and chronic inflammation, many women with endometriosis require assisted reproductive technologies such as IVF and frozen embryo transfer (FET) to achieve pregnancy. Beyond infertility, endometriosis is also associated with higher risks of obstetric complications, including early pregnancy bleeding, hypertensive disorders, and placental abnormalities.

Frozen embryo transfer (FET) is a common part of fertility treatment, and women with endometriosis often rely on it to . Before an embryo is transferred, the uterus must be prepared either through an artificial cycle using prescribed hormones or through a natural cycle, which follows the woman’s own hormonal pattern. Until recently, it has been unclear whether the choice of preparation method influences pregnancy safety for women with endometriosis.

In this large national cohort study from South Korea by Yu et al.,published in BMC Pregnancy and Childbirth, the researchers examined whether the methoduterine preparation affects pregnancy complications in women with and without endometriosis. They compared two approaches:artificial-cycle FET (AC-FET), in which the endometrium is prepared using external hormones, with natural-cycle FET (NC-FET), which relies on endogenous hormonal rhythms.

The findings show that for women with endometriosis, AC-FET was associated with notably higher rates of several early and obstetric complications, including threatened abortion, hypertensive disorders of pregnancy, and placenta previa. Early pregnancy bleeding occurred in 35% of endometriosis patients undergoing AC-FET, compared with 21% using NC-FET, indicating that the natural hormonal environment may better support implantation and early placental development in a uterus already affected by inflammation. These differences were not explained by age or other medical factors. Among women without endometriosis, AC-FET increased miscarriage risk but did not elevate other major complications to the same degree.

Overall, these results highlight that for women with endometriosis, the choice of FET protocol is not a routine technical decision but one that may significantly influence pregnancy safety. Selecting a protocol that aligns with the patient’s underlying biology may help reduce preventable obstetric risks.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41063059/