First-trimester uterine artery pulsatility index and preeclampsia risk in pregnancies after artificial frozen embryo transfer: analysis of over 27,000 pregnancies.

Background: Accumulating evidence indicates that pregnancies after artificial cycle frozen embryo transfer are associated with an increased risk of preeclampsia. Uterine artery Doppler, along with maternal factors and serum biomarkers, is a crucial biomarker for first-trimester preeclampsia screening, aiding in identifying "high-risk" patients. Guidelines strongly recommend administering aspirin (150 mg/d) in these women, owing to robust evidence demonstrating a 62% reduction in the incidence of preeclampsia. Although previous studies suggested lower uterine artery pulsatility index after frozen embryo transfer, no previous studies explored the impact of the type of endometrial preparation in Uterine Artery Doppler or its influence on estimating first-trimester preeclampsia risk.

Objective: The study aims to evaluate the possible impact of endometrial preparation for frozen embryo transfer on the uterine artery pulsatility index during the first-trimester preeclampsia screening.

Study Design: This is a retrospective single-center study including 27,289 singleton pregnancies (naturally conceived or after assisted reproductive treatment) who underwent the first-trimester ultrasound screening at our University Hospital between January 2010 and May 2023. Overall, 27,289 pregnancies were included: 23,410 naturally conceived and 3879 following assisted reproductive technologies including 391 after ovulation induction and intrauterine insemination, 888 in vitro fertilization and fresh embryo transfer, and 2600 natural or artificial frozen embryo transfer cycles. An analysis of covariance was conducted to assess if there is an association between the uterine artery pulsatility index value and the mode of conception, adjusting for confounding factors (age, weight, smoking, and oocyte donation).

Results: Overall, pregnancies after artificial frozen embryo transfer demonstrated significantly lower first-trimester uterine artery pulsatility index as compared with all other modes of conception in a multivariable regression analysis adjusted for age, weight, smoking, and oocyte donation. The percent difference was 22.6 [confidence interval, CI 95%: 20.6; 24.5] compared to naturally conceived pregnancy, 24.5 [CI 95%: 20.7; 28.1] to ovulation induction or intrauterine insemination, 24.8 [CI 95%: 22.9; 27.6] to fresh embryo transfer and 21.7 [CI 95%: 17.6; 25.5] compared to natural cycle frozen embryo transfer. When calculating the risk for initiating preventive aspirin administration, the number of patients with increased risk (>1/100) who initiated prophylactic aspirin was significantly lower in the artificial cycle frozen embryo transfer group (7.8% vs 16.0% in natural cycle P<.001 vs 11.0% in Fresh embryo transfer P=.01 vs 10.5% in ovulation induction or intrauterine insemination P=.14 vs 9.3% in naturally conceived pregnancy P=.03). Surprisingly although significantly fewer patients were considered at high risk for preeclampsia in the artificial cycle frozen embryo transfer group, analysis of the actual incidence of preeclampsia demonstrated 3 times higher preeclampsia incidence in artificial cycle group 5.3% (122/2284) as compared with naturally conceived 1.4% (321/23,410), ovulation induction and intrauterine insemination 1.3% (5/391) or natural cycle pregnancies 1.6% (5/316) and more than 2 times higher when compared to fresh embryo transfer pregnancies 2.3% (20/888), P<.001.

Conclusion: Pregnancies following frozen embryo transfer in artificial cycle are associated with significantly lower uterine artery pulsatility index during first-trimester preeclampsia screening. This results in a significantly lower number of patients being classified as high-risk for developing preeclampsia, despite accumulating evidence that artificial cycles are linked to an increased risk of preeclampsia. Therefore, the first-trimester preeclampsia risk algorithm should be adjusted to accurately assess risk for those patients undergoing artificial cycle frozen embryo transfer, to prevent the undertreatment of patients who are at very high risk of developing preeclampsia and may benefit from prophylactic aspirin.