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.

Keywords: blastocyst; child; congenital malformation; extended embryo culture; health; infertility; obstetrical outcomes; perinatal outcomes; singletons.