Background
Methods
Results
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 |
Risk factors | Design | Summary of findings | Comments |
---|---|---|---|
Maternal immigration [53], 2015 | 10 population-based | The adjusted results showed higher rates of ASD if children had migrant mothers (2.69%) compared with children of non-migrant mothers (0.91%). Six out of ten studies found that giving birth postmaternal migration significantly raised risks of ASD, with the exception of children born to Hispanic migrant mothers who had lower rates of ASD (compared to all other migrant groups) | A meta-analysis by another group supports these findings |
Preconceptional chemical exposure [49], 2014 | 3 case-control | All studies showed an increased rate of ASD in children whose parents were exposed to chemicals | The studies were limited by retrospective design and small sample sizes |
Pesticide exposure during pregnancy [49], 2014 | 1 retrospective case-control; 3 prospective cohort | All showed an increased rate of ASD in children with gestational exposure to chemicals including two prospective studies of organophosphates | The studies provide enough evidence to justify larger studies of pesticide exposure in ASD |
Pesticide exposure during childhood [49], 2014 | 1 retrospective cross-sectional; 1 prospective cohort; 1 computer model | One study showed an association between organophosphate exposure; one between DDE exposure and ASD, and one between phosphine exposure and ASD | |
Air pollution during prenatal period [49], 2014 | 6 retrospective | All studies showed an increased rate of ASD associated with air pollution (with particulate matter in three studies and with NO2 in two studies) | A meta-analysis of four prospective European cohorts showed no association between air pollution and ASD |
Air pollution during childhood [49], 2014 | 3 retrospective case-control | All studies showed some association between air pollution and ASD (association with NO2 is replicated in two studies) | |
Exposure to other chemicals [49], 2014 | 2 prospective cohort; 4 retrospective case-control | No effect in prospective studies; retrospective studies found some effects for solvents and other toxicants | Retrospective studies used questionnaires |
Toxic waste sites [49], 2014 | 2 case series, ecological | Association of Superfund site with ASD in both studies | |
Water pollutant [49], 2014 | 2 ecological | No association between water chlorination and ASD in either studies | |
Heavy metals [49], 2014 | 8 ecological | 7 studies showed association between Hg and ASD, one showed no association | Ecological studies are limited by indirect measures of exposure |
In-house flooring [49], 2014 | 1 cohort | Polyvinyl chloride vs. wood floor increases the risk of ASD | |
Mercury levels [49], 2014 | 29 case-control | 12 studies with elevation in at least one tissue in patients with ASD | Studies measuring levels of heavy metals were limited by cross-sectional design and small sample size. Furthermore, it is unclear how much cross-sectional measurements of metals in the body reflect the causal effect of such exposures on ASD risk. |
Lead levels [49], 2014 | 25 case-control | 11 studies with elevation in at least one tissue in patients with ASD | |
Cadmium levels [49], 2014 | 14 case-control | 5 studies with elevation in at least one tissue in patients with ASD | |
Aluminum levels [49], 2014 | 11 case-control | 3 studies with elevation in at least one tissue in patients with ASD | |
Arsenic [49], 2014 | 8 case-control | 5 studies with elevation in at least one tissue in patients with ASD | |
Nickel [49], 2014 | 3 case-control | 2 studies with elevation in at least one tissue in patients with ASD | |
Uranium levels [49], 2014 | 2 case-control | 1 studies with elevation in at least one tissue in patients with ASD | |
Tin levels [49], 2014 | 1 case-control | 1 studies with elevation in at least one tissue in patients with ASD | |
Heavy metals and severity [49], 2014 | 7 correlational studies | All studies showed some correlation between ASD severity and heavy metal levels (particularly Hg and Pb) | These studies suggest a dose-response relationship between metal exposure and ASD. |
Heavy metals and chelation [49], 2014 | 12 uncontrolled studies | All showed improvement in symptoms of ASD following chelation treatment | The studies are limited by lack of the control group |
Urine porphyrin studies [49], 2014 | 4 case-series; 7 case-control | All studies showed some association with severity, prediction, or oxidative stress | The studies are limited by retrospective nature |
Solvents, pesticides, and PCB [49], 2014 | 2 case series; 2 case-control | Case series showed levels above normal adult range for children with ASD; case-control studies showed no association between PCB and ASD | The studies were limited by either lack of proper control group or small sample size |
Phthalate [51], 2016 | 2 cohort; 3 case-control | Three studies showed association between phthalate exposure and ASD; two studies showed no association | |
PBDE [49], 2014 | 1 case-control | PBDE resulted in higher activation of immune response in patients with ASD | |
Valproate [37], 2014 | 1 population-based prospective; 2 prospective case series; 1 retrospective | All studies found significant and strong association between prenatal valproate exposure and ASD | The association between valproate and ASD is likely to be causal given the strength of association and evidence for biological plausibility |
Folic acid [44], 2016 | 11 studies | The findings were inconsistent; some studies provide support for the beneficial effect of folic acid on risk of ASD, whereas others show the opposite effect | Observational studies were limited by self-report, whereas RCTs were limited by use of multivitamin |
Camel milk [115], 2016 | 2 small short-term RCTs | Results showed beneficial effects on ASD symptoms | It is unclear whether this benefit is clinical and whether it extends to longer period of treatment |
Casein and gluten-free diet [116], 2014 | 16 studies | Findings are inconsistent | Studies with positive findings were mostly of low quality |
Omega-3 [43], 2011 | 2 RCTs | Studies found no evidence for beneficial effects of omega-3 on ASD symptoms | |
Assisted reproductive technologies [36], 2013 | 2 cohort; 5 case-control | 3 studies showed positive association between ART and ASD, 3 studies showed no association, and 1 study showed a negative association between ART and ASD. The authors concluded that at present, no evidence supports the association between ART and ASD | There are several sources of heterogeneity such as study design, exposure definition, data source, and confounders. |