Subfecundity, Infertility Treatment, and Child Neurodevelopment

Kahn LG; Hipwell AE; Stanford JB; Galai N; Zhao H; Alshawabkeh AN; Aschner JL; Barrett ES; Bertolla RP; Cajachagua Torres KN; Camargo CA Jr; Cordero JF; Croen LA; Deoni SC; Gogcu S; Herbstman JB; Karagas MR; LeWinn KZ; Lyall K; McEvoy CT; McKay K; O'Connor TG; Pilsner JR; Schantz SL; Schmidt RJ; Smith AK; Wilkening GN; Zhang E; Zhu Y; Ghassabian A; ECHO Cohort Consortium

doi:10.1001/jamanetworkopen.2026.17324

Subfecundity, Infertility Treatment, and Child Neurodevelopment

Kahn LG, Hipwell AE, Stanford JB, Galai N, Zhao H, Alshawabkeh AN, Aschner JL, Barrett ES, Bertolla RP, Cajachagua Torres KN, Camargo CA Jr, Cordero JF, Croen LA, Deoni SC, Gogcu S, Herbstman JB, Karagas MR, LeWinn KZ, Lyall K, McEvoy CT, McKay K, O'Connor TG, Pilsner JR, Schantz SL, Schmidt RJ, Smith AK, Wilkening GN, Zhang E, Zhu Y, Ghassabian A, ECHO Cohort Consortium

Published June 2026 JAMA Network Open

DOI 10.1001/jamanetworkopen.2026.17324 PMID 42258210 PMC PMC13247815

RRM Academy Synopsis

Subfecundity is linked to higher autism odds and behavior scores

Children of parents with subfecundity had higher odds of autism spectrum disorder, even when conceived naturally, in a US study of 15 382 mother-infant dyads. Non-IVF treatment went with higher odds of ADHD in a subsample. IVF showed no significant associations.

Key Findings

Autism spectrum disorder (ASD) odds were higher for children of parents with subfecundity: odds ratio (OR), 1.27 (95% CI, 1.03-1.57) overall; OR, 1.31 (95% CI, 1.04-1.64) in natural conceptions.
Across all pregnancies, subfecundity went with higher externalizing problem scores (b = 0.47 [95% CI, 0.14-0.81]) and higher Social Responsiveness Scale (SRS) scores (b = 1.08 [95% CI, 0.01-2.14]).
Among natural conceptions, externalizing problems were b = 0.45 (95% CI, 0.07-0.83) and SRS score was b = 1.12 (95% CI, −0.09 to 2.34). The SRS interval includes zero.
Children conceived with non-IVF treatment had ADHD odds of OR, 1.54 (95% CI, 1.05-2.25) against natural conception without subfecundity, and OR, 1.77 (95% CI, 1.16-2.68) against natural conception with it.
The full sample included 3 autism-enriched cohorts. In it, 876 offspring (7.6%) had an ASD diagnosis and 819 offspring (7.1%) had an ADHD diagnosis. There were no significant associations for IVF treatment.

Interpretation

This cohort study followed 15 382 mother-infant pairs, including three cohorts chosen for high autism rates, to look at subfecundity and child development. Subfecundity meant a history of infertility, two or more prior miscarriages, or 12 months of unprotected sex without pregnancy. The authors say the score differences are small and may not matter day to day. The findings call for larger studies of what causes subfecundity.

RRM Context

The authors say their results back a growing view: risk in treated children comes from the condition itself. They call for more study of the specific causes of subfecundity. RRM shares that view. Infertility points to a condition that can be diagnosed. Unexplained infertility means undiagnosed. Among 5197 pregnancies with PCOS data, 49% of the non-IVF treatment pregnancies were in people with PCOS.

Our editorial summary of this paper, not the article's abstract.

Abstract

Importance

Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment.

Objective

To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity.

Design, Setting, and Participants

This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026.

Exposure

Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment.

Main Outcomes and Measures

Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD).

Results

Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment.

Conclusions and Relevance

In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.

Topics

Assisted Reproduction Safety and Risks Long Term Child Outcomes

Assisted Reproduction › Safety and Risks › Long Term Child Outcomes

Linda G Kahn, Alison E Hipwell, Joseph B Stanford, Noya Galai, Haozuo Zhao, Judy L Aschner, Carlos A Camargo, Lisa A Croen, Semsa Gogcu, Margaret R Karagas, Kaja Z. LeWinn, Kristen Lyall, Cynthia T McEvoy, J Richard Pilsner, Susan L Schantz, Rebecca J Schmidt

L Kahn, A Hipwell, Joe Stanford, Joey Stanford, J Stanford, N Galai, H Zhao, J Aschner, C Camargo, L Croen, S Gogcu, Maggie Karagas, Peggy Karagas, M Karagas, K LeWinn, K Lyall, C McEvoy, Sue Schantz, S Schantz, Becky Schmidt, R Schmidt

PMID 42258210 42258210 DOI 10.1001/jamanetworkopen.2026.17324 10.1001/jamanetworkopen.2026.17324 Kahn et al. 2026, Kahn 2026

Subfecundity, Infertility Treatment, and Child Neurodevelopment

Subfecundity is linked to higher autism odds and behavior scores

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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