Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks' gestation

Abstract

Background: No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.

Objective: We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.

Study design: This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).

Results: In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).

Conclusion: Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.

Keywords: autism; cervical-vaginal infection; extremely preterm delivery; fetal growth restriction; intellectual disability.

Figure 1. Percent of women who had selected demographic characteristics whose children were classified at age 10 years as ASD+/ID−, ASD+/ID+, ASD−/ID+ or ASD−/ID−

[Women who identified as Black, did not graduate from high school, and/or were eligible for government-provided healthcare (public) insurance gave birth to children who later had ASD−/ID+ or ASD+/ID+ more frequently than other women. *Infants may be in more than one category]

Figure 2. Percent of women who had selected pregnancy characteristics or exposures whose children were classified at age 10 years as ASD+/ID−, ASD+/ID+, ASD−/ID+ or ASD−/ID−

[Children whose mother reported a vaginal/cervical infection, and/or a periodontal infection during this pregnancy, had ASD+/ID+ more frequently than children of other women. By contrast, children of women who consumed antibiotics less frequently received a diagnosis of ASD+/ID− compared to the children of other women, whereas ASD−/ID+ occurred more frequently among children born to women who reported fever during this pregnancy than in children of other women.]

Figure 3. Percent of women who had selected pregnancy complications whose children were classified at age 10 years as ASD+/ID−, ASD+/ID+, ASD−/ID+ or ASD−/ID−

[Irrespective of their IQ, children whose mother had preeclampsia and/or received magnesium sulfate for seizure prophylaxis developed ASD more frequently than children of other mothers. Children born to women who had placental abruption, and those whose mother had fever within 48 hours before or after delivery, more frequently developed ASD unaccompanied by ID (ASD+/ID−) than children of other mothers.]

Figure 4. Percent of newborns with selected characteristics who were classified at age 10 years as ASD+/ID−, ASD+/ID+, ASD−/ID+ or ASD−/ID−

[Boys had ASD+/ID+ and ASD+/ID− twice as frequently as girls. The prevalence of ASD increased with decreasing gestational age and, to a lesser extent, with decreasing birth weight, regardless of IQ. Children who had birth head circumference Z-score < −2 also received ASD diagnoses more frequently than other children, irrespective of IQ. Children with the most severe fetal growth restriction (i.e., birth weight Z-score < −2) had the highest percent of ASD+/ID− diagnoses. Antecedents of ID unaccompanied by ASD (ASD−/ID+) included male sex, low gestational age, and fetal growth restriction (including microcephaly).]