Fresh elective single versus double embryo transfer and healthy singleton birth in women aged 38–42 years: a target trial emulation using the UK HFEA registry

Women of advanced maternal age undergoing assisted reproductive technology face a difficult trade-off between maximizing live birth rates and minimizing the maternal and neonatal risks associated with multiple gestation. Although double embryo transfer (DET) is commonly used to compensate for age-related declines in implantation, elective single embryo transfer (eSET) may improve perinatal safety. We compared fresh eSET versus DET in women aged 38–42 years using a patient-centred “healthy singleton birth” outcome. We conducted a target trial emulation using the UK Human Fertilisation and Embryology Authority (HFEA) registry, including 61,371 fresh autologous IVF/ICSI cycles from women aged 38–42 years between 2011 and 2018. Cycles involving donor gametes, preimplantation genetic testing, frozen embryo transfer, no oocytes retrieved, or inconsistent records were excluded. The primary outcome was healthy singleton birth rate, defined as a term, normal birthweight singleton live birth without major congenital anomalies. Inverse probability of treatment weighting was used to balance measured baseline characteristics. Adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) were estimated. Interaction testing was performed by maternal age group and embryo developmental stage. E-values were calculated to assess sensitivity to unmeasured confounding. After weighting, the healthy singleton birth rate was not statistically different between eSET and DET (15.78% versus 14.99%; aRR 1.05; 95% CI 0.99–1.12). eSET was associated with a lower live birth rate per fresh transfer (aRR 0.84; 95% CI 0.80–0.88), but substantially lower risks of multiple birth (aRR 0.05; 95% CI 0.03–0.07) and ectopic pregnancy (aRR 0.55; 95% CI 0.37–0.84). Subgroup analyses suggested effect modification by maternal age and embryo stage. eSET was associated with higher healthy singleton birth rates among women aged 38–39 years (aRR 1.11; 95% CI 1.04–1.19), but not among women aged 40–42 years (aRR 0.94; 95% CI 0.84–1.05; P-interaction = 0.030). Similarly, eSET was associated with higher healthy singleton birth rates in blastocyst transfers (aRR 1.15; 95% CI 1.09–1.21), but not cleavage-stage transfers (aRR 0.92; 95% CI 0.80–1.05; P-interaction = 0.003). In women aged 38–42 years undergoing fresh IVF/ICSI transfer, eSET was associated with a healthy singleton birth rate that was not statistically different from DET, although the confidence interval does not exclude clinically meaningful differences. eSET was associated with lower multiple birth and ectopic pregnancy risks, but also with a lower live birth rate per fresh transfer.