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Table 1 Summary of meta-analyses of environmental risk factors for autism spectrum disorders

From: Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses

Risk factor [ref], year No. of studies Study design Estimates Precision Consistency Directness Publication bias
Advanced parental age [23], 2017        
• 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        
• 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        
• 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        
• 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        
• 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        
• Postterm 14 NA +/− − − + Absent
• Preterm 17 NA +/− − − + Absent
• >4 weeks preterm 2 NA +/− − + + Absent
Birth weight [25], 2011        
• 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        
• 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        
• 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        
• 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        
• 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        
• 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        
• 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        
• 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        
• 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
  1. +/−, positive but statistically non-significant effect estimates; +/, marginally positive; −/+, negative but statistically non-significant effect estimates; +, positive statistically significant effect estimates (number of + corresponds to the strengths of the association); −, negative statistically significant effect estimates (number of − corresponds to the strengths of the association)
  2. aOnly direct −/+
  3. bBegg’s test was not significant; Egger’s test was significant
  4. cAdjusted for bias +
  5. dAdjusted for bias −/+
  6. NA not available, NC not calculated
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Molecular Autism

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