Parents’ underlying difficulty conceiving may be linked to a slightly higher likelihood of autism diagnoses and behavior problems in children, according to a study published in JAMA Network Open.

The study also found that some non-in vitro fertilization (IVF) fertility treatments, such as ovulation-induction medications and intrauterine insemination, were associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) in offspring. But the researchers also posited that underlying reasons for difficulty conceiving may play a larger role in child neurodevelopment than fertility treatment itself.

Jennifer K. Blakemore, MD, a reproductive endocrinologist and infertility specialist at NYU Langone Health, who was not involved in the study, said the findings underscore the challenging nature of separating the effects of fertility treatment from conditions that lead people to need treatment, such as polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS).

“I don’t think there’s a one-size-fits-all answer when discussing potential risks with patients,” Blakemore said. “It probably is more multifactorial and in ways that we don’t understand or need more learning.”

Drawing from the National Institutes of Health’s Environmental Influences on Child Health Outcomes (ECHO) Cohort, researchers analyzed data from 15,382 mother-child pairs, some of whom had experienced subfecundity. The study tracked children conceived over a 24-year period starting in 1998, evaluating neurodevelopment between the ages of 2 and 10. 

Researchers defined subfecundity as people who had ever sought infertility evaluation or treatment, received an infertility diagnosis, experienced at least two miscarriages, or tried unsuccessfully to conceive for at least 1 year.

Children born to parents with a history of subfecundity had 27% higher odds of later receiving a diagnosis of autism spectrum disorder than children whose parents had no history of fertility problems (odds ratio [OR], 1.27; 95% CI, 1.03-1.57). The association remained nearly identical when researchers limited the analysis to children conceived naturally (OR, 1.31; 95% CI, 1.04-1.64).

Compared with children of parents without fertility issues, those born to parents with subfecundity also had slightly higher scores of caregiver-reported behavior problems and autism-like traits after adjusting for factors including maternal age, race and ethnicity, and psychiatric history.

Because subfecundity can arise from many different causes, the study may have captured a broad range of underlying reproductive and metabolic factors that could influence fertility and child neurodevelopment, said Linda G. Kahn, PhD, MPH, assistant professor in the Department of Pediatrics at the New York University Grossman School of Medicine in New York City, who led the study.

Conditions such as PMOS, for example, have been linked to fertility problems and neurodevelopmental and psychiatric conditions.

Kahn and colleagues found that children born to parents with fertility difficulties were more likely to have been born earlier in gestation.

A Deeper Dive

To better separate the effects of fertility treatment from those of infertility, Kahn examined a subset of ECHO participants for whom detailed treatment information was available. They compared children conceived through IVF (n = 345) or non-IVF treatments (n = 475) with children conceived naturally with and without a history of subfecundity (n = 2333 and n = 12,188, respectively).

Children conceived using non-IVF treatments had higher odds of developing ADHD (OR, 1.77; 95% CI, 1.16-2.68) than those conceived naturally after a history of subfecundity. Children conceived with one of the treatments had 54% higher odds of ADHD (OR, 1.54; 95% CI, 1.05-2.25) than those conceived naturally without subfecundity.

One possible explanation for the associations might be that nearly half of the children conceived using non-IVF treatments were among people with PMOS. Nearly one third of children conceived using IVF were born to people with PMOS, compared with 11% of naturally conceived pregnancies among parents with subfecundity and just 3% of naturally conceived pregnancies among parents without subfecundity.

“The women with PCOS are much more likely to be treated with non-IVF treatments than IVF,” Kahn said. “I think the signal that we’re probably picking up is not the treatment itself, but the indication for that particular type of treatment.”

Kahn and colleagues found no statistically significant association between IVF and any neurodevelopmental outcomes studied.

Previous reviews have similarly concluded that links between fertility treatments and neurodevelopmental problems are often explained by factors such as multiple births, preterm delivery, and parental characteristics.

Kahn said the results should reassure patients considering fertility treatments, and that future research should focus on conditions that lead people to seek treatment.

“We’ve been worried so much about the treatment,” she said. “We really have to be thinking about the indications for treatment.”

Kahn and Blakemore reported no relevant conflicts of interest.

Lara Salahi is a health journalist based in Boston.