In a recent study published in JAMA Network Open, researchers determined the relationship between infertility and its treatments on autism spectrum disorder (ASD) development risk and the mediating effects of adverse pregnancy outcomes on the relationship.

Study: Infertility and Risk of Autism Spectrum Disorder in Children. Image Credit: Chinnapong/Shutterstock.com

Background

ASD, a disease characterized by abnormal brain development, can appear within 18 months of life. Hereditary and environmental factors impact ASD development.

Infertility, maternal metabolic and inflammatory variables, and offspring epigenetic alterations are prenatal risk factors.

Children born following intrauterine insemination (IUI), ovulation induction (OI), intracytoplasmic sperm injections (ICSI), or in vitro fertilization (IVF) have a minimal risk of ASD; however, subfertility may be at a greater risk. Previous research did not take infertility or mediating effects into consideration.

About the study

In the present population-based, retrospective cohort study, researchers explored the impact of infertility as well as fertility treatments on ASD risk, considering the mediating effects of pregnancy outcomes.

The study was conducted in Ontario using administrative healthcare data, including individuals aged 18 to 55 with single and multiple children born at ≥24 weeks of gestation between 1 April 2006 and 31 March 2018.

Pregnancy-related data, including conception modes, were retrieved from the Better Outcomes Registry and Network (BORN) database of Ontario and linked datasets. Additional databases included hospitalization, outpatient visits, and emergency department visit data.

The exposure for the study was conception mode, i.e., (i) unaided conception, (ii) infertility but no fertility treatment (i.e., subfertility), (iii) IUI or OI, or (iv) ICSI or IVF. The outcome measure was an ASD diagnosis in children at ≥18 months of age.

Multivariable Cox regression modeling was performed to determine the adjusted hazard ratios (aHRs), adjusting for covariates such as maternal age, income, parity, rurality, smoking, immigration status, alcohol use, illicit substance usage, obesity, pre-pregnancy chronic hypertension or diabetes, history of psychiatric disorders in two years before conception and ≤19 months post-delivery, a history of maternal ASD, and infant gender at birth.

Causal mediation analyses were performed to assess the mediating effects of preeclampsia, cesarean birth, multifetal pregnancies, severe neonatal morbidities, and preterm birth before 37 weeks of gestation.

Data analysis was performed between October 2022 and October 2023. Subfertility was diagnosed based on the history of physician consultations for infertility within two years before conception and the lack of fertility treatment using the Ontario Health Insurance Plan (OHIP) and the International Classification of Diseases, Ninth Revision (ICD-9) codes.

The team excluded surrogate pregnancies, pregnancies ending in induced abortions, the death of a child before 18 months of age, and those with missing data. ASD diagnosis was based on at least two outpatient diagnoses using OHIP codes by pediatricians or psychiatrists and at least one diagnosis during hospitalization using ICD-10 codes.

Results

In total, the study included 1,370,152 infants [51% (n=703,407) were male]: 87% (n=1,185,024) with unaided conception, 10% (n=141,180) with sub-fertile parents, 1.5% (n=20,429) following IUI or OI, and 1.7% (n=23,519) following ICSI or IVF.

Sub-fertile individuals and those who received fertility treatment lived in high-income regions and were older; the mean participant ages in the unaided conception group, subfertility group, IUI or OI group, and ICSI or IVF group were 30 years, 33 years, 33 years, and 36 years, respectively.

In total, 1.6% (n=22,409) of children were diagnosed with ASD at a mean age of four years; 2,858 (two percent) with ASD were born to sub-fertile individuals (3.6 years); 404 (two percent) with ASD were born to parents treated with IUI or OI (3.4 years); and 458 (two percent) with ASD were born to individuals who received ICSI or IVF treatment (3.4 years).

ASD incidence was 1.9 per 1,000 individual years in children born to the unaided conception group. The aHR value for autism spectrum disorders was 1.2 in the sub-fertile group, 1.2 following IUI or OI, and 1.2 after ICSI or IVF.

The neonatal and obstetrical factors seemed to mediate the association between conception mode and ASD development risk. For those following ICSI or IVF, the mediation effects of cesarean birth, multifetal pregnancies, preterm births, and severe neonatal morbidities were

29%, 78%, 50%, and 25%, respectively.

Restricting the analysis to infertile individuals relative to sub-fertile individuals, the aHR value for autism spectrum disorders was 1.0 following IUI or OI and 0.9 after ICSI or IVF. Including only 23,519 live births, in comparison to IVF, the aHR value for ASD among children born to ICSI recipients was 1.1.

Limiting the analysis to singleton pregnancies, relative to unaided conception, and mothers aged below 45 years, adjusting for the calendar year, yielded similar aHRs. Multiple pregnancies had a 78% mediation effect on ASD risk.

The mediating impact of preeclampsia was below seven percent for all conception modes; however, after ICSI or IVF, the mediation effects from planned cesarean delivery and severe neonatal morbidities were 57% and 88%, respectively.

Conclusion

Overall, the study findings showed a marginally higher ASD risk among children birthed to infertile individuals, regardless of fertility treatment. Adverse pregnancy outcomes, such as cesarean birth, multiple pregnancies, preterm birth, and severe neonatal morbidities, are associated with ASD risk, especially after ICSI or IVF.

The findings indicate that underlying infertility might be the driver between parental infertility and ASD in the child, not fertility treatments themselves.

Efforts to decrease multifetal pregnancy following OI, IUI, and IVF should continue, along with the development of focused care pregnancy plans for sub-fertile individuals and those receiving fertility treatment.