Programmed frozen embryo transfer cycle increased risk of hypertensive disorders of pregnancy: a multicenter cohort study in ovulatory women

BACKGROUND Although live birth rates were comparable between programmed and natural frozen-thawed embryo transfer cycles, recent data showed that pregnancies after programmed cycle were associated with an increased risk of adverse perinatal outcomes, such as hypertensive disorders of pregnancy. Such a difference might be attributed to selection bias because patients with ovulation disorders are more likely to receive programmed endometrial preparation protocol than natural cycle. OBJECTIVE This study aimed to analyze whether programmed endometrial preparation protocol is associated with an increased risk of adverse perinatal outcomes compared with natural cycle during frozen embryo transfer in ovulatory women. STUDY DESIGN This regional multicenter retrospective cohort study was conducted in 5 reproductive medical centers in Southeast China. Patients with regular cycles (21–35 days), who underwent either programmed or natural cycle blastocyst frozen embryo transfer and delivered singleton live birth babies after 28 weeks of gestation between 2016 and 2019 were analyzed. Each patient only contributed 1 cycle per cohort. The patients’ frozen embryo transfer treatment cycles were linked to their obstetrical medication record, and a comprehensive medical record review was conducted to compare the maternal and neonatal outcomes between natural cycle and programmed cycle. Crude and adjusted odds ratios with 95% confidence intervals were calculated, and adjustment was made for relevant confounders. RESULTS Study samples included 499 natural cycle frozen embryo transfer cases and 900 programmed frozen embryo transfer cases. Pregnancies after programmed cycle were associated with increased odds of hypertensive disorders of pregnancy (adjusted odds ratio, 2.71; 95% confidence interval, 1.59–4.91) and preeclampsia (adjusted odds ratio, 2.71; 95% confidence interval, 1.17–6.23) compared with pregnancies after natural cycle. No significant difference was detected regarding other adverse perinatal outcomes between the 2 endometrial protocols. In subgroup analysis, both the subgroups of hormone replacement therapy and hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment had increased odds of developing hypertensive disorders of pregnancy than the natural cycle group. The risk of developing preeclampsia was higher in the hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment subgroup than in the other 2 groups (adjusted odds ratio, 4.99; 95% confidence interval, 1.94–12.82) (aOR, 2.47; 95% CI, 1.17–5.18). CONCLUSION Pregnancies after programmed frozen embryo transfer were associated with higher risks of hypertensive disorders of pregnancy in ovulatory women. The hormone replacement therapy with gonadotrophin-releasing hormone analogue pretreatment cycle led to the highest risk of preeclampsia among the 3 protocols.