Table 1 Summary of meta-analyses of environmental risk factors for autism spectrum disorders
Risk factor [ref], year | No. of studies | Study design | Estimates | Precision | Consistency | Directness | Publication bias |
|---|---|---|---|---|---|---|---|
Advanced parental age [23], 2017 | Â | Â | Â | Â | Â | Â | Â |
• Highest paternal age category | 20 | 4 cohort; 16 case-control | + | + | − | + | Absent |
• Highest maternal age category | 19 | 4 cohort; 15 case-control | + | + | − | + | Absent |
Labor [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Prolonged labor | 9 | NA | +/− | − | − | + | Absent |
• Induced or augmented labor | 8 | NA | +/− | − | − | + | Absent |
• Precipitous labor | 5 | NA | +/− | − | − | + | Absent |
• Premature rupture of membranes | 7 | NA | +/− | − | + | + | Absent |
Delivery options [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Cesarean section [29], 2015 | 21 | 6 Cohort; 15 case-control | + | + | − | + | Absent |
• Emergency cesarean | 4 | NA | +/− | − | − | + | Absent |
• Elective cesarean | 2 | NA | +/− | − | − | + | Absent |
• Delivery anesthesia | 7 | NA | +/− | − | + | + | Absent |
• General anesthesia | 3 | NA | +/− | − | + | + | Absent |
• Assisted vaginal delivery | 14 | NA | +/− | + | + | + | Absent |
• Forceps | 7 | NA | +/− | − | + | + | Absent |
• Vacuum extraction | 2 | NA | −/+ | − | − | + | Absent |
Conditions at birth [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Abnormal presentation | 15 | NA | + | − | − | + | Absent |
• Breech presentation | 4 | NA | + | − | + | + | Absent |
• Cord complications | 14 | NA | + | − | + | + | Absent |
• Fetal distress | 4 | NA | + | − | + | + | Absent |
• Birth injury or trauma | 6 | NA | ++ | − | + | + | Absent |
• Twins or multiple birth | 10 | NA | + | − | − | + | Absent |
Maternal hemorrhage [25], 2011 | 4 | NA | ++ | − | + | + | Absent |
Timing of birth [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• January through March | 4 | NA | +/− | + | + | + | Absent |
• April through June | 4 | NA | +/− | − | − | + | Absent |
• July through September | 4 | NA | +/− | + | + | + | Absent |
• October through December | 4 | NA | −/+ | − | − | + | Absentb |
• Fall | 3 | NA | −/+ | − | − | + | Absent |
• Winter | 3 | NA | −/+ | − | − | + | Absent |
• Spring | 3 | NA | −/+ | − | − | + | Absent |
• Summer | 3 | NA | + | + | + | + | Absent |
Birth spacing (ref ≥36 m) [30], 2016 | 7 | 3 cohort; 3 cross-sectional; 1 case-control |  |  |  |  |  |
• <12 months | 5 | NA | + | − | − | + | NC |
• 12–23 months | 5 | NA | +/− | − | − | + | NC |
• 24–35 months | 5 | NA | −/+ | − | − | + | NC |
Birth spacing (ref 24–59 m) [30], 2016 |  |  |  |  |  |  |  |
• <12 months | 4 | NA | + | − | − | − | NC |
• 12–23 months | 4 | NA | + | − | − | − | NC |
• >60 months | 4 | NA | + | − | − | − | NC |
Gestational age [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Postterm | 14 | NA | +/− | − | − | + | Absent |
• Preterm | 17 | NA | +/− | − | − | + | Absent |
• >4 weeks preterm | 2 | NA | +/− | − | + | + | Absent |
Birth weight [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Birth weight <2500 g | 15 | NA | + | − | − | + | Absent |
• Birth weight <2000 g | 2 | NA | +/− | − | − | + | Absent |
• Birth weight <1500 g | 3 | NA | ++ | − | + | + | Absent |
• Birth weight >4000 g | 6 | NA | +/− | − | + | + | Absentb |
Neonatal clinical and medical conditions [25], 2011 | Â | Â | Â | Â | Â | Â | Â |
• Meconium aspirated | 3 | NA | +++ | − | + | + | Absentb |
• Neonatal infection | 2 | NA | −/+ | − | + | + | Absent |
• Elevated temperature | 2 | NA | +/− | − | − | + | Absent |
• ABO or Rh incompatible | 5 | NA | ++ | − | + | + | Absent |
• Hyperbilirubinemia or jaundice | 14 | NA | +/− | − | − | + | Absent |
• Jaundice | 4 | NA | +/− | − | + | + | Absent |
• Hyperbilirubinemia | 6 | NA | + | − | − | + | Absent |
• Phototherapy | 2 | NA | +/− | − | − | + | Absent |
• Medical intervention in the first month | 7 | NA | +/− | − | − | + | Absent |
Impaired gas exchange [28], 2016 | Â | Â | Â | Â | Â | Â | Â |
• Acidosis at birth | 2 | 2 population-based | + | + | + | + | Absent |
• Apgar at 1 min <6 | 3 | 3 population-based | ++ | − | + | + | Absent |
• Apgar at 1 min <7 | 3 | 3 population-based | + | + | + | + | Absent |
• Apgar at 5 min <7 | 6 | 6 population-based | + | − | + | + | Absent |
• Apgar at 5 min <8 | 3 | 2 population-based; 1 clinic-based | ++ | − | + | + | Absent |
• Apgar at 5 min <9 | 2 | 1 population-based; 1 clinic-based | +/− | − | + | + | Absent |
• Apnea/delayed crying | 5 | 3 population-based; 2 clinic-based | ++ | − | − | + | Absent |
• Respiratory distress | 12 | 6 population-based; 6 clinic-based | + | + | + | + | Absent |
• Ventilation/O2 treatment | 9 | 4 population-based; 5 clinic-based | ++ | − | + | + | Presentc |
• Undefined hypoxia/asphyxia | 9 | 2 population-based; 7 clinic-based | ++ | − | − | + | Absent |
Mother born in another country [24], 2009 | 5 | NA | +/− | − | − | + | Absent |
Previous fetal loss [24], 2009 | 13 | NA | +/− | − | + | + | Absent |
Birth order/parity [24], 2009 | Â | Â | Â | Â | Â | Â | Â |
• 1 pregnancy increase | 8 | NA | −/+ | + | − | + | Absent |
• 1st vs. not 1st | 11 | NA | +/− | + | − | + | Absent |
• 1st vs. 2nd | 4 | NA | +/− | − | − | + | Absent |
• 1st vs. 2nd or 3rd | 6 | NA | +/− | − | − | + | Absent |
• 1st vs. 3rd+ | 4 | NA | + | + | + | + | Absent |
• 1st vs. 4th+ | 6 | NA | −/+ | − | − | + | Absent |
• 1st or 4th vs. 2nd or 3rd | 5 | NA | +/− | − | − | + | Absent |
• 4th vs. 2nd or 3rd | 5 | NA | +/− | − | + | + | Absent |
Maternal illness/conditions [24], 2009 | Â | Â | Â | Â | Â | Â | Â |
• Maternal proteinuria | 3 | NA | −/+ | − | + | + | Absent |
• Toxemia/preeclampsia, hypertension, swelling | 25 | NA | +/− | − | − | + | Absent |
• Maternal diabetes [31], 2014 | 12 | 3 cohort | + | + | + | + | Absent |
9 case-control | + | − | + | + | Absent | ||
• Maternal infection [33], 2016 | 15 | 2 cohort; 13 case-control | + | + | − | + | Absent |
• Bacterial infection [33], 2016 | 4 | NA | + | + | − | + | Absent |
• Viral infection [33], 2016 | 4 | NA | +/− | − | − | + | Absent |
• Influenza [33], 2016 | 3 | NA | +/ | + | − | + | Absent |
• Genitourinary infection [33], 2016 | 8 | NA | + | + | + | + | Absent |
• Skin infection [33], 2016 | 3 | NA | + | − | + | + | Absent |
• Gastrointestinal infection [33], 2016 | 3 | NA | +/− | − | + | + | Absent |
• Respiratory infection [33], 2016 | 7 | NA | +/− | + | + | + | Absent |
• Family history of autoimmune disease [35], 2015 | 11 | 3 cohort; 6 case-control; 2 cross-sectional | + | + | − | + | Presentc |
• Maternal autoimmune disease [34], 2016 | 10 | 9 case-control; 1 cohort | + | + | + | + | Absent |
• Rubella | 3 | NA | +/− | − | + | + | Absent |
• Fever | 4 | NA | +/− | − | + | + | Absent |
• Nausea vomiting | 6 | NA | +/− | − | − | + | Absent |
• Physical injury accident | 5 | NA | +/− | − | + | + | Absent |
• Any illness | 4 | NA | +/− | − | + | + | Absent |
Maternal weight [32], 2016 | Â | Â | Â | Â | Â | Â | Â |
• Maternal underweight | 5 | All cohort | +/− | + | + | + | Absent |
• Maternal overweight | 5 | All cohort | + | + | + | + | Absent |
• Maternal obesity | 7 | 6 cohort; 1 case-control | + | − | − | + | Absent |
Prenatal visit [24], 2009 | 2 | NA | −/+ | − | − | + | Absent |
Bleeding [24], 2009 | 19 | NA | + | − | − | + | Absent |
• 1st trimester | 2 | NA | +/− | − | + | + | Absent |
• 2nd trimester | 2 | NA | −/+ | − | + | + | Absent |
• 3rd trimester | 2 | NA | −/+ | − | + | + | Absent |
Placental abnormalities [24], 2009 | 8 | NA | +/− | − | + | + | Absent |
• Placenta previa | 2 | NA | +/− | − | + | + | Absent |
• Placenta abruption | 2 | NA | −/+ | − | + | + | Absent |
• Placental infarcts | 2 | NA | +/− | − | + | + | Absent |
High maternal weight gain during pregnancy [24], 2009 | 5 | NA | −/+ | − | − | + | Absent |
Maternal smoking [39], 2015 | 15 | 4 cohort; 11 case-control | +/− | + | − | + | Absent |
• Prenatal | 8 | NA | +/− | + | − | + | NC |
• Neonatal | 2 | NA | − | + | + | + | NC |
• Postnatal | 5 | NA | + | − | − | + | NC |
Medication use during pregnancy [24], 2009 | 15 | NA | + | − | + | + |  |
• Anticonvulsants | 2 | NA | +/− | − | + | + | Absent |
• SSRIs [38], 2016 | 8 | 3 cohort; 5 case-control | + | − | + | + | Absent |
• Antidepressants [112], 2014 | 3 | All case-control | +/− | − | − | + | Absent |
Thimerosal [47], 2014 | 9 | 1 retrospective and 2 prospective cohort; 6 case-control | +/− | + | + | Mixeda | Presentd |
Inorganic mercury [47], 2014 | 3 | 3 case-control | + | − | + | + | NC |
Vaccination [52], 2014 | 10 | 5 cohort | −/+ | + | + | + | Absent |
5 case-control | − | + | − | + | Absent | ||
MMR vaccine [52], 2014 | 3 | All cohort | −/+ | + | + | + | Absent |
Metal exposure [48], 2014 | Â | Â | Â | Â | Â | Â | Â |
• Hg through vaccine [52], 2014 | 2 | Both retrospective cohort | +/− |  |  |  |  |
• Hair Hg | 7 | All case-control | +/− | − | NC | + | NC |
• Hair Cd | 4 | All case-control | −/+ | − | NC | + | NC |
• Hair Pb | 5 | All case-control | + | − | NC | + | NC |
• Hair Cu | 4 | All case-control | +/− | − | NC | + | NC |
• Hair Se | 3 | All case-control | −/+ | − | NC | + | NC |
• Hair Li | 3 | All case-control | −/+ | − | NC | + | NC |
• Zn/Cu [113], 2015 | 11 | All case-control | −/+ | − | − | + | Absent |
Nutritional intake [40], 2013 | Â | Â | Â | Â | Â | Â | Â |
• Zinc [41], 2016 | 12 | All case-control | − | + | − | + | Absent |
• Calcium | 8 | NA | −− | − | − | − | Absent |
• Carbohydrates | 7 | NA | −/+ | − | − | − | Absent |
• Energy | 6 | NA | −/+ | − | − | − | Absent |
• Fiber | 6 | NA | +/− | − | − | − | Absent |
• Iron | 7 | NA | +/− | − | − | − | Absent |
• Protein | 7 | NA | −− | − | − | − | Absent |
• Total fat | 6 | NA | +/− | − | − | − | Absent |
• Vitamin A | 6 | NA | −/+ | − | − | − | Absent |
• Vitamin C | 7 | NA | −/+ | − | − | − | Absent |
• Vitamin D [42], 2016 | 11 | All case-control | −−− | − | − | + | Possible |
• Vitamin E | 5 | NA | +/− | − | − | − | Absent |
Air pollution [46], 2016 | Â | Â | Â | Â | Â | Â | Â |
• PM10 (every 10 μg/m3) | 6 | 5 case-control; 1 cohort | + | + | − | − | NC |
• PM2.5 (every 10 μg/m3) | 3 | 3 case-control | + | + | − | − | NC |
• O3 (every 10 μg/m3) [114], 2014 | 2 | 2 case-control | + | + | + | − | NC |