Study Highlights

• The researchers used causal inference methods to analyze observational data in a way that emulates a target randomized controlled trial.
• The study cohort comprised statewide linked maternal and childhood administrative data for 585,659 singleton infants conceived spontaneously or via IVF, born in Victoria, Australia, between 2005 and 2014, and who had school-age developmental and educational outcomes assessment.
• Investigators assessed childhood developmental vulnerability at school entry (age 4-6 years) in 173,200 children using AEDC and defined it as < 10th percentile in ≥ 2 of 5 developmental domains (physical health and well-being, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge).
• They used NAPLAN (n = 342,311) to determine educational outcome at age 7 to 9 years using overall z scores across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy).
• Researchers estimated population average causal effects using inverse probability weighting, with regression adjustment for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education.
• Across the 2 outcome cohorts, there were 412,713 children, with linked records available for 4697 IVF-conceived cases and 168,503 control participants for AEDC, and 8976 cases and 333,335 control participants for NAPLAN.
• Compared with spontaneously conceived children, children conceived via IVF had older, more highly educated parents, mothers with lower parity, and residence in areas with higher socioeconomic ranking and were less likely to be from non-English speaking backgrounds.
• IVF-conception had no causal effect on risk for developmental vulnerability at school-entry (AEDC) compared with spontaneously conceived children (13.6% vs 13.9%), with adjusted risk difference of −0.3% (95% CI: −3.7%, 3.1%) and adjusted relative risk of 0.97 (95% CI: 0.77, 1.25).
• There were no differences between IVF-conceived and spontaneously conceived children in adjusted risk difference for any of the individual AEDC domains.
• At age 7 to 9 years, IVF conception had no causal effect on NAPLAN overall z score between IVF-conceived and spontaneously conceived children (adjusted mean difference 0.03 [95% CI: −0.018, 0.077]).
• IVF-conceived children performed better, on average, in measures of writing than spontaneously conceived children (z score mean difference 0.068 [95% CI: 0.004, 0.132]), but this is unlikely to be clinically important.
• In 4 of 5 domains (numeracy, reading, spelling, and writing), IVF-conceived children were less likely to be below the national minimum standard than spontaneously conceived children.
• The investigators concluded that under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children.
• The causal effect of IVF conception on overall AEDC and NAPLAN z score was indistinguishable from zero.
• These findings offer important reassurance for current and prospective parents and for clinicians and may be useful in providing informed consent and education to persons considering IVF and persons with children conceived via IVF.
• Since the first successful IVF birth in 1978, > 8 million babies globally have been born after IVF conception.
• In Australia, ~ 1 in 20 babies are born after IVF conception, more than double since the year 2000, when 2% of births resulted from IVF.
• The relatively recent birth cohort may explain lower risks in this study compared with previous studies, as IVF practices have evolved over time, and now include blastocyst culture, vitrification, and single-embryo transfer.
• The findings are therefore more generalizable to contemporary fertility practice than those of previous studies, and use of updated epidemiological and statistical methods ensures a causal interpretation of estimated effects.
• Given differences in IVF techniques and procedures, future research should address the same school-aged outcomes after specific IVF-associated techniques.
• Study limitations include use of observational data, potential unmeasured confounding, presence of missing data, and inclusion only of children attending school, limiting analysis to outcomes for liveborn children.