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Children of parents with infertility had a slightly higher rate of autism spectrum disorder, a population-based cohort study of over 1.3 million children found.

Compared with children born from unassisted conception, parents who experienced subfertility but didn't undergo fertility treatment had children with a 20% higher risk of autism (adjusted HR 1.20, 95% CI 1.15-1.25), Maria Velez, MD, PhD, of Queen's University in Ontario, Canada, and colleagues reported.

Children conceived via ovulation induction (OI) or intrauterine insemination (IUI) had a 21% (95% CI 1.09-1.34) higher risk of autism than those born without assisted conception. Likewise, children conceived by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) had a 16% (95% CI 1.04-1.28) higher risk, they wrote in .

However, children born via assisted conception did not have any higher risk for autism compared with those born to an individual with subfertility, the researchers noted.

"Our results suggest that there is a slightly increased risk of autism spectrum disorder in children born to patients previously diagnosed with infertility, independent of whether they received fertility treatment," Velez told 名媛直播. This link likely arises from a mix of genetic and environmental factors, she said.

Previous research about the risk of childhood autism spectrum disorders after fertility treatment did not account for infertility itself or the mediating effect of obstetrical and neonatal factors, the researchers observed. "In the pathogenesis of autism spectrum disorder, maternal metabolic and inflammatory factors, as well as offspring epigenetic changes, have each been implicated," they noted.

Most pregnancies included in the study involved unassisted conception (86.5%). Parents with subfertility made up 10.3% of the study population; IVF or ICSI cases were 1.7%, and OI or IUI cases were 1.5%. Individuals with subfertility or who underwent fertility treatments tended to be older and had higher rates of pre-pregnancy diabetes and chronic hypertension.

All pregnancies were singleton or multiple live births in Canada with at least 24 weeks gestation from 2006 to 2018. Children from these pregnancies were followed for a median of 8.1 years, starting at age 18 months.

Overall, 1.6% (22,409 children) were diagnosed with autism at a mean age of 3.9. Autism was diagnosed in 1.9% to 2.0% of kids born from fertility treatments or to parents with subfertility, compared with 1.6% of kids born with unassisted conception. A diagnosis of autism was based on at least two outpatient diagnoses by a pediatrician or psychiatrist, or one diagnosis during a hospitalization.

Velez's group found the link between infertility and autism was at least partly mediated by a few adverse pregnancy factors. In the mediation analysis for babies born from IVF or ICSI, the proportion of autism cases mediated by cesarean birth was 29%, by multifetal pregnancy was 78%, by preterm birth was 50%, and by severe neonatal morbidity was 25%.

Following OI or IUI, the proportion mediated by cesarean birth was 11%, by multifetal pregnancy was 36%, by preterm birth was 26%, and by severe neonatal morbidity was 14%.

Preeclampsia wasn't a significant mediating factor among babies born from any of these fertility treatments.

Study limitations included the possibility of exposure misclassification or incorrect estimations of autism diagnoses. The mediation analysis method allowed the researchers to examine each factor in isolation only, even though multiple mediators can co-occur in the same pregnancy.

"To improve child neurodevelopment outcomes, efforts to decrease adverse pregnancy outcomes -- like multifetal pregnancy, preterm birth, elective cesarean section -- following fertility treatments should continue to be reinforced," Velez recommended.

"Further studies are needed to understand some of the mechanisms by which a parental diagnosis of infertility, independent of fertility treatment, is associated with the slightly higher risk of autism spectrum disorder in the child," she added. "For example, we need more granular details about paternal factors and whether the oocyte or sperm are from the parent or a donor, among other factors."

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