Obstetrical, perinatal, and children’s health outcomes following fresh embryo transfer after extended embryo culture

Abstract STUDY QUESTION Does extended embryo culture (EEC) associate with an increased risk of obstetrical, perinatal, or children’s health complications? SUMMARY ANSWER After thorough adjustment, EEC was not associated with widespread increased risks, although a moderate excess risk persisted for a few specific outcomes, notably cardiac anomalies, whereas reduced risks were observed for gestational diabetes, small birthweight, and musculoskeletal-limb anomalies. WHAT IS KNOWN ALREADY EEC is increasingly used in IVF cycles. While blastocyst transfer (day-5/6) often improves birth rates, concerns remain about its impact on maternal and child health. STUDY DESIGN, SIZE, DURATION In this nationwide longitudinal cohort study, all live-born singletons conceived through IVF—with or without sperm microinjection—and following fresh embryo transfer between 2014 and 2019 in France were included and followed for up to 8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Data were obtained from the French National Health System and the National Biomedicine Agency registries. A comparative study was conducted between singletons conceived at either day-2/3 (cleavage-stage embryos group) or day-5/6 (EEC group). Data from both registries were cross-linked to identify obstetrical, perinatal, and health outcomes, including major congenital malformations, hospitalizations, and surgical interventions. Multivariable logistic and survival models were used to adjust for maternal, paternal, and treatment-related factors. MAIN RESULTS AND THE ROLE OF CHANCE A total of 41 315 singletons were included (25 816 and 15 499 from day-2/3 and day-5/6 groups, respectively). Most outcomes were similar between groups, notably the incidence of global major congenital malformations. However, EEC was associated with increased risks of placenta praevia (aOR, 1.16; 95% CI, 1.02–1.30), admission in neonatal intensive care unit (aOR, 1.16; 95% CI, 1.05–1.29), and cardiac anomalies at age 3 years (aHR, 1.78; 95% CI, 1.21–2.60). Conversely, the risk of gestational diabetes (aOR, 0.94; 95% CI, 0.88–1.00; P = 0.041) and small birthweight (aOR, 0.94; 95% CI, 0.88–1.00, P = 0.039) was lower, as was the risk of musculoskeletal-limb anomalies (aHR, 0.63; 95% CI, 0.42–0.97)—a finding that persisted up to age 7. Other health outcomes were largely comparable. LIMITATIONS, REASONS FOR CAUTION One limitation of this study is that the data refer to live-born singletons, with stillbirths and medical terminations excluded from the analyses. Despite extensive adjustments, residual confounding cannot be excluded. Findings for specific pathologies/malformations should be interpreted with caution because the number of cases was small in some sub-groups. WIDER IMPLICATIONS OF THE FINDINGS In this large and unique study, after adjusting for multiple maternal, paternal, and cycle-related variables, our findings provide some reassurance regarding the safety of prolonged in vitro embryo culture. A moderate risk remained for a few maternal and child health conditions following EEC—warranting further investigation—whereas the risk was notably lower compared to short embryo culture, particularly for musculoskeletal-limb anomalies. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the AOI of University Hospital of Dijon. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.