Parental subfecundity may be associated with poorer neurodevelopmental outcomes in offspring, including a higher likelihood of autism spectrum disorder (ASD) and greater behavioral difficulties.
Investigators analyzed data from 15,382 mother-child dyads participating in the National Institutes of Health ECHO Cohort. They included pregnancies conceived between 1998 and 2022 and focused on distinguishing the potential effects of infertility treatments from those of underlying subfecundity, which they defined as a history of infertility diagnosis, infertility consultation or treatment, at least two prior miscarriages, or at least 12 months of unprotected heterosexual intercourse without conception.
Neurodevelopmental outcomes were assessed in children aged 2 to 10 years using caregiver-reported measures of externalizing and internalizing behavioral problems and autism-related traits. The researchers also evaluated physician-diagnosed autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).
Among all pregnancies, children born to parents with subfecundity had higher externalizing behavior scores and 1.27 times the odds of having ASD compared with children whose parents had no history of subfecundity. Similar findings were observed when the analyses were restricted to naturally conceived pregnancies, with subfecundity associated with 1.31 times the odds of ASD and higher externalizing behavior scores.
The researchers also observed higher scores on the Social Responsiveness Scale, a measure of autism-related traits, among the children of parents with subfecundity. However, they noted that the differences in symptom scores were small.
When infertility treatments were examined separately, in vitro fertilization (IVF) was not associated with statistically significant differences in behavioral outcomes, autism-related traits, ASD, or ADHD.
By contrast, children conceived using non-IVF infertility treatments had higher odds of ADHD compared with children conceived naturally. Non-IVF treatment was associated with 1.54 times the odds of ADHD compared with natural conception among parents without subfecundity and 1.77 times the odds compared with natural conception among parents with subfecundity.
Sensitivity analyses generally supported the primary findings, although some associations involving autism-related outcomes were attenuated in restricted analyses. Mediation analyses suggested that gestational age at birth contributed to associations between subfecundity and certain behavioral outcomes but was not on the causal pathway between subfecundity and ASD.
The researchers said the findings supported growing evidence that fertility-related factors may be more closely associated with offspring neurodevelopment than infertility treatment itself. They also noted that the association between non-IVF treatment and ADHD may have reflected underlying conditions leading to treatment. Nearly half of the patients who received non-IVF infertility treatment had polycystic ovarian syndrome compared with just 11% of the patients with subfecundity who conceived naturally and 3% of those without subfecundity who conceived naturally.
The study has several limitations. Its observational design could not establish causality, and residual confounding may have remained despite adjustment for demographic, socioeconomic, and clinical factors. The researchers also noted that differences in access to infertility diagnosis and treatment could have influenced the findings. In addition, the cohort included autism-enriched populations, which may limit generalizability.
“[S]ubfecundity was associated with offspring behavior problems and ASD regardless of infertility treatment, and non-IVF infertility treatment was associated with child ADHD,” wrote lead study author Linda G. Kahn, PhD, of New York University Grossman School of Medicine, and colleagues.
The study was funded by the ECHO Program. Full disclosures of the study authors can be found in the study.
Source: JAMA Network Open