Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles

Background Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown. Objective To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception. Study Design A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders. Results A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43–2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22–2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20–3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29–2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27–2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47–2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26–2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03–1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies. Conclusion No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes. Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown. To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception. A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders. A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43–2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22–2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20–3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29–2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27–2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47–2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26–2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03–1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies. No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes.