Perinatal and Neonatal Risk Factors for Autism: A Comprehensive Meta-analysis
“Factors associated with autism risk in the meta-analysis were abnormal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubinemia. Factors not associated with autism risk included anesthesia, assisted vaginal delivery, postterm birth, high birth weight, and head circumference.
The meta-analysis identified several perinatal and neonatal factors that were associated with an increased risk for autism. These included abnormal presentation in general (RR: 1.44, P = .02), breech presentation (RR: 1.81, P = .004), umbilical-cord complications (eg, prolapsed cord, cord wrapped around the neck; RR: 1.50, P = .05), fetal distress (RR: 1.52, P = .01), birth injury or trauma (RR: 4.90, P = .01), multiple birth (RR: 1.77, P = .002), maternal hemorrhage (RR: 2.39, P = .003), summer birth (RR: 1.14, P = .02), low birth weight (<2500 g; RR: 1.63, P = .002), very low birth weight (<1500 g; RR: 3.00, P < .001), small for gestational age (RR: 1.35, P = .001), congenital malformations (RR: 1.80, P < .001), low 5-minute Apgar score (RR: 1.67, P = .001), meconium aspirated (RR: 7.34, P = .001), feeding difficulties (RR: 3.35, P = .01), neonatal anemia (RR: 7.87, P = .02), ABO or Rh incompatibility (RR: 3.70, P < .001), and hyperbilirubinemia (RR: 1.87, P = .05). Cesarean delivery was associated with a 26% increased risk of autism that did not reach statistical significance (P = .06).
Heterogeneity (P < .10) in effect estimates across studies was observed for many factors including prolonged labor, induced or augmented labor, precipitous labor, Cesarean delivery, abnormal presentation, amniotic fluid not clear or meconium staining, multiple births, season of birth, preterm birth, postterm birth, low birth weight, low 1-minute Apgar score, weak or no crying after birth, respiratory distress, elevated temperature, hyperbilirubinemia, medical intervention during the neonatal period, and oxygen treatment or resuscitation. Table 3 shows the results of the regression analyses that examined the potential between-study sources of heterogeneity for those risk factors that showed heterogeneity in effect estimates across studies (P < .10). Heterogeneity in effect estimates across studies for prolonged labor, Cesarean delivery, and multiple births could not be explained by between-study variability in any of the methodological characteristics examined.”
This study suggests that several perinatal and neonatal complications may be related to autism risk, either alone, in combination, or perhaps only in those who are genetically vulnerable. However, the correlated occurrence of many of these complications limits the ability to determine which factors, if any, are independently associated with autism. For example, Cesarean deliveries are more common in pregnancies with abnormal fetal presentation, fetal distress, and multiple birth.80,81 Congenital malformations, low birth weight, abnormal presentation, and low Apgar score also are interrelated.36 Most studies did not use multivariate analyses to simultaneously control for all obstetrical factors examined, and a different set of factors was examined in each study. It is possible that increasing rates of some obstetrical factors, such as Cesarean delivery, low birth weight, multiple birth, and neonatal resuscitation, may be contributing factors to the rising prevalence of autism.81
The obstetrical complications that have emerged as significant risk factors for autism in the current meta-analysis suggest a possible role of fetal and neonatal hypoxia. In particular, growth retardation, fetal distress, umbilical-cord wrapping around the neck, low Apgar score, respiratory distress, resuscitation, meconium aspiration, and Cesarean delivery are all potential risk factors that also may be associated with an increased risk of hypoxia.6,24,26,36,38,82 Although some brain abnormalities observed in individuals with autism may reflect a potential role of oxygen deprivation during development, this possibility requires additional examination. Hypoxia also has been shown to increase dopaminergic activity, and there is evidence for dopamine overactivation in autism.83″