Human Reproduction, 2025
Abstract
Abstract
Study question What are the obstetric and neonatal clinical implications of large-for-gestational age (LGA) babies conceived after a frozen-thawed embryo transfer (FET)?
Summary answer Besides a lower risk of neonatal hypoglycaemia, obstetric and neonatal risks for FET LGA babies were comparable to those conceived spontaneously or after fresh ET.
What is known already It has been shown that conception after a FET is an independent risk factor for LGA babies. The underlying physiologic mechanism is still unclear but is likely different to the mechanisms that lead to LGA after fresh embryo transfers or spontaneous conception. As the freeze-all strategy and FETs are becoming increasingly popular, an important clinical question revolves around the significance of this complication both for the mother and the baby and whether the obstetric and neonatal risks differ between LGA babies conceived following FET compared to those conceived after fresh embryo transfer (Fresh) and spontaneously conceived babies (SC).
Study design, size, duration This population-based cohort study is based on the Medically Assisted Reproduction data linkage which is a bespoke data linkage of the Australian ART registry to nine population health datasets including births, hospital admissions, medical services, medications, and deaths. All singleton LGA babies in New South Wales (2009-2017) and the Australian Capital Territory (2009-2016) (N = 81,075) conceived either spontaneously or after fresh or frozen-thawed embryo ART were included.
Participants/materials, setting, methods The LGA births were divided into those conceived a) spontaneously without history of subfertility (SC) (n = 73,321), b) spontaneously with history of subfertility (SC-SubFert) (n = 4,516), c) after fresh ET (Fresh) (n = 1,461) d) after FET (n = 1,777). Relevant obstetric and neonatal outcome data were compared between LGA deliveries following FET and those following Fresh, SC and SC-SubFert while adjusting for important confounders including preexisting comorbidities (diabetes mellitus) and stratified by mode of delivery (vaginal birth-VB vs. cesarean section-CS).
Main results and the role of chance The caesarean section rate was similar between FET (58.2%) and Fresh LGA babies (57.9%) but significantly higher compared to the SC (39.1%) and SC-SubFert (49.9%) cohorts (p < 0.001). The use of forceps was also significantly (p < 0.001) higher in FET (4.6%) and Fresh (4.7%) LGA babies compared to the SC (3.5%) and SC-SubFert (2.1%) cohorts. Mean APGAR Scores at 1min (range: 8.3-8.4) and 5min (8.9 for all groups) after birth were similar between the four groups (p > 0.05). In VB, the adjusted risk ratios (aRR) for perineal tear, shoulder dystocia and postpartum haemorrhage, neonatal resuscitation, respiratory distress, transient tachypnea, admission to the NICU, perinatal death and hospitalization in the first 2 years of life were not significantly different between the four groups. The risk of neonatal hypoglycaemia was significantly elevated in the Fresh (aRR: 1.87, 95% CI: 1.16-3.01), SC-SubFert (aRR: 1.55, 95% CI: 1.03-2.34) and SC (aRR: 1.63, 95% CI: 1.11-2.40) compared to the FET LGA babies. In CS births, no significant differences were detected between the groups compared regarding all outcomes evaluated, apart from neonatal hypoglycaemia where SC LGA babies had significantly elevated risk compared to FET LGA babies (aRR: 1.22, 95% CI: 1.02-1.45).
Limitations, reasons for caution As data were sourced from population health registries, some risk of misclassification might be present, although this is unlikely to be systematically different between groups compared. Despite controlling for important confounders, including maternal age at delivery, nulliparity, history of diabetes mellitus and socioeconomic variables, residual bias may still be present.
Wider implications of the findings This is the first study evaluating the clinical implications of FET LGA babies, suggesting largely similar risks to other LGA babies. However, the difference in risk of hypoglycemia supports a different pathophysiological mechanism for LGA after FET compared to the one of LGA babies conceived spontaneously and following fresh ET.
Trial registration number No