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 (ECHO) 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.
1. Endocrinology. 2014 May;155(5):1956-69. doi: 10.1210/en.2013-2081. Epub 2014
Mar 31. Use of a mouse in vitro fertilization model to understand the developmental
origins of health and disease hypothesis. Feuer SK(1), Liu X, Donjacour A, Lin W, Simbulan RK, Giritharan G, Piane LD,
Kolahi K, Ameri K, Maltepe E, Rinaudo PF. Author information:
(1)Department of Obstetrics, Gynecology and Reproductive Sciences (S.K.F., X.L.,
A.D., W.L., R.K.S., G.G., L.D.P., K.K., P.F.R.), and Department of Pediatrics
(K.A., E.M.), University of California San Francisco, San Francisco, California
94143; Nevada Center for Reproductive Medicine (G.G.), Reno, Nevada 89511;
Obstetric and Gynecology Department (L.D.P.), University of Turin, Turin, Italy;
and Oregon Health & Science University (K.K.), Portland, Oregon 97239. The Developmental Origins of Health and Disease hypothesis holds that
alterations to homeostasis during critical periods of development can predispose
individuals to adult-onset chronic diseases such as diabetes and metabolic
syndrome. It remains controversial whether preimplantation embryo manipulation,
clinically used to treat patients with infertility, disturbs homeostasis and
affects long-term growth and metabolism. To address this controversy, we have
assessed the effects of in vitro fertilization (IVF) on postnatal physiology in
mice. We demonstrate that IVF and embryo culture, even under conditions
considered optimal for mouse embryo culture, alter postnatal growth trajectory,
fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic
profiling in serum and microarray analysis of pancreatic islets and insulin
sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad
changes in metabolic homeostasis, characterized by systemic oxidative stress and
mitochondrial dysfunction. Adopting a candidate approach, we identify
thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating
cellular nutritional and oxidative states with metabolic response, as a marker
for preimplantation stress and demonstrate tissue-specific epigenetic and
transcriptional TXNIP misregulation in selected adult tissues. Importantly,
dysregulation of TXNIP expression is associated with enrichment for H4
acetylation at the Txnip promoter that persists from the blastocyst stage
through adulthood in adipose tissue. Our data support the vulnerability of
preimplantation embryos to environmental disturbance and demonstrate that
conception by IVF can reprogram metabolic homeostasis through metabolic,
transcriptional, and epigenetic mechanisms with lasting effects for adult growth
and fitness. This study has wide clinical relevance and underscores the
importance of continued follow-up of IVF-conceived offspring. 10.1210/en.2013-2081
PMC3990843
24684304 [Indexed for MEDLINE]
Stroke accounts for 7% of pregnancy-related deaths in the US. As the use of infertility treatment is increasing, many studies have sought to characterize the association of infertility treatment with the risk of stroke with mixed results. To evaluate the risk of hospitalization from hemorrhagic and ischemic strokes in patients who underwent infertility treatment. DESIGN, SETTING, This population-based, retrospective cohort study used data abstracted from the Nationwide Readmissions Database, which stores data from all-payer hospital inpatient stays from 28 states across the US, from 2010 and 2018. Eligible participants included individuals aged 15 to 54 who had a hospital delivery from January to November in a given calendar year, and any subsequent hospitalizations from January to December in the same calendar year of delivery during the study period. Statistical analysis was performed between November 2022 and April 2023. Hospital delivery after infertility treatment (ie, intrauterine insemination, assisted reproductive technology, fertility preservation procedures, or use of a gestational carrier) or after spontaneous conception. The primary outcome was hospitalization for nonfatal stroke (either ischemic or hemorrhagic stroke) within the first calendar year after delivery. Secondary outcomes included risk of stroke hospitalization at less than 30 days, less than 60 days, less than 90 days, and less than 180 days post partum. Cox proportional hazards regression models were used to estimate associations, which were expressed as hazard ratios (HRs), adjusted for confounders. Effect size estimates were corrected for biases due to exposure misclassification, selection, and unmeasured confounding through a probabilistic bias analysis. Of 31 339 991 patients, 287 813 (0.9%; median [IQR] age, 32.1 [28.5-35.8] years) underwent infertility treatment and 31 052 178 (99.1%; median [IQR] age, 27.7 [23.1-32.0] years) delivered after spontaneous conception. The rate of stroke hospitalization within 12 months of delivery was 37 hospitalizations per 100 000 people (105 patients) among those who received infertility treatment and 29 hospitalizations per 100 000 people (9027 patients) among those who delivered after spontaneous conception (rate difference, 8 hospitalizations per 100 000 people; 95% CI, -6 to 21 hospitalizations per 100 000 people; HR, 1.66; 95% CI, 1.17 to 2.35). The risk of hospitalization for hemorrhagic stroke (adjusted HR, 2.02; 95% CI, 1.13 to 3.61) was greater than that for ischemic stroke (adjusted HR, 1.55; 95% CI, 1.01 to 2.39). The risk of stroke hospitalization increased as the time between delivery and hospitalization for stroke increased, particularly for hemorrhagic strokes. In general, these associations became larger for hemorrhagic stroke and smaller for ischemic stroke following correction for biases. In this cohort study, infertility treatment was associated with an increased risk of stroke-related hospitalization within 12 months of delivery; this risk was evident as early as 30 days after delivery. Timely follow-up in the immediate days post partum and continued long-term follow-up should be considered to mitigate stroke risk.
restorative-reproductive-medicine/restorative-care-and-assisted-reproduction/outcome-comparisonsinfertility/evaluation/epidemiology-and-risk-factors
Open Access
Stanford JB et al., 2026·Frontiers in Reproductive Health
Background The total fertility rate (TFR) in most developed countries has been declining for decades. In the United States (U.S.), the total fertility rate has remained below replacement level since 2007. Subfertility affects at least 15% of women or couples over their reproductive lifespan and contributes to reduced TFR. Restorative reproductive medicine (RRM) is a medically based approach to subfertility care that can be delivered in primary care settings to increase live birth rates. Objective To estimate the theoretical impact of use of RRM among subfertile couples in the United States. Methods We conducted a simulation study. Model inputs included the number of women of reproductive age in the United States by 5-year age groups; current age-specific and total fertility rates; the proportion of women in each age group with subfertility; estimated spontaneous live birth rates among women with subfertility; and age-specific crude live birth rates with RRM treatment. We evaluated fifteen scenarios including sensitivity analyses: two different varying assumptions for spontaneous conception (25% vs. 50%), two levels of RRM utilization among subfertile women (20% vs. 50%), three different estimates of the number of subfertile women who would be potentially eligible for RRM treatment, and 4 different levels of effectiveness (live birth) from RRM treatment. Results The baseline TFR in the United States was 1.77 during 2015-2019, and 13.5% of women ages 20-44 were estimated to have subfertility. In a conservative scenario (50% spontaneous births; 20% RRM utilization; married women trying to conceive for at least 12 months, 20.7% RRM live births), the TFR increased to 1.79, representing a 1.0% relative increase (absolute +0.02). In an optimistic scenario (25% spontaneous births; 50% RRM utilization; all subfertile women), the TFR increased to 2.02, a 14.5% relative increase (absolute +0.26), approaching replacement-level fertility. Conclusion Simulation results suggest that expanding access to RRM within primary care settings could meaningfully increase the U.S. TFR, by reducing unresolved subfertility. Realizing this potential would require policy and health system changes to address workforce capacity, insurance coverage, and equitable access. These findings underscore the potential contribution of non-IVF fertility care pathways in addressing population-level fertility decline.
Parnell TA et al., 2026·Journal of Restorative Reproductive Medicine
This study examined public attitudes toward restorative reproductive medicine (RRM) and in vitro fertilization (IVF) using secondary analysis and comparative reporting of two independent surveys conducted in the United States. It also explored preferences among individuals with fertility issues and the general population’s views on treatment options. A secondary analysis was conducted using data from two nationally representative online surveys, designed and administered by organizations independent of the researchers, whose samples demographically reflected the U.S. adult population. The surveys—conducted by J.L. Partners (N=1002) and McLaughlin & Associates (N=1000)—assessed familiarity, acceptance, and attitudes toward IVF and RRM. The J.L. Partners survey focused on IVF, including medical risks, creation and use of embryos, preimplantation genetic testing, arguments for government oversight of IVF, and overall attitudes toward IVF. The McLaughlin survey focused on comparative descriptions of IVF and RRM. Pearson’s Chi-Square tests of independence were used to assess differences in response distributions across demographic subgroups and between survey items of interest. Findings: Overall, there was strong consistency of responses to items that were similar in the two surveys. Approximately 80% supported IVF initially, although both surveys found respondents to have limited knowledge about IVF procedures. In contrast, 33% supported RRM initially, with 43% having never heard of RRM. After learning more about the characteristics of RRM and IVF approaches, as presented within the surveys, preference shifted toward approaches consistent with RRM (e.g., 69% preference for an approach for natural fertilization in a woman’s body vs. 17% for fertilization in a lab). Respondents prioritized baby health (74%) over cost (13%) and time to conceive (6%). Many IVF patients were concerned about undiagnosed health issues and being rushed into IVF. Overall, 70% wanted treatments that addressed underlying causes; nearly half were unaware of any medical risks of IVF. Stated support for IVF declined by 10% overall after presentation of medical risks, questions about the creation and use of embryos and genetic testing, and arguments to support government oversight of IVF. Both surveys showed strong support for patient access to full information about treatments and treatment processes. While IVF is widely accepted, these national survey data suggest preferences for fertility treatments that prioritize diagnosis and restoration of natural reproductive health, which is the focus of restorative reproductive medicine. Comprehensive assessment, restoration of healthy function, transparency regarding treatment processes, and sensitivity to ethical concerns in patient care reflect important public values. Greater awareness and public education, improved consent, more research, and ongoing surveys are needed to inform public health strategies and meet patient needs in fertility care.