Table 1.
Key characteristics of studies published through April 2020 examining maternal dietary factors in association with ASD or ASD-traits.
| Reference | Nutrient/Category | Sample size (n) | Study type, population, location† (PC=prospective cohort, RC= retrospective cohort, CC= case control) | Exposure assessment‡ (P= prospective, R= retrospective; SR=self-report, B= biomarker; M= medical/dispensation record/ registry, FFQ=food frequency questionnaire) | Outcome assessment information§ (Dx= ASD diagnosis; AT=autism-related traits) | Key finding(s) |
|---|---|---|---|---|---|---|
| Schmidt et al 2011 PMID: 21610500 | Prenatal Vitamins (PV) | 288 ASD, 141 DD controls, 278 TD controls | CC; CHARGE; Northern California, USA | PV use from 3 months preconception to breastfeeding according to R SR | Dx at age 2–5 yrs based on SCQ, ADOS-G, ADI-R (2–3 yrs)¶ | Periconceptional PV use ↓ ASD odds; Interaction with susceptible genes involved in one-carbon metabolism |
| Braun et al 2014 PMID: 24710813 | 209 mother-child pairs | PC; HOME; Ohio, USA | PV use at 14–39 wks according to P SR | AT at age 4–5 yrs using SRS Total T scores | PV use ↓ odds of clinically elevated SRS scores. | |
| Schmidt et al., 2019 PMID: 30810722 | 305 mothers 332 children (55 ASD) | PC; MARBLES; California, USA | PV use from preconception to after birth according to P SR | Dx at age 3 yrs based on DSM-IV, ADOS and MSEL†† | 1st month pregnancy PV intake ↓ ASD risk. | |
| Schmidt et al 2011 (See above in PV) | Multivitamin (MVS) | 288 ASD, 141 DD controls, 278 TD controls | CC; CHARGE; Northern California, USA | MVS use from 3 months preconception to breastfeeding according to R SR | Dx at age 2–5 yrs based on SCQ, ADOS-G, ADI-R (2–3 yrs) ¶ | No significant association overall |
| DeVilbiss et al., 2017 PMID: 28978695 | 27, 3107 mother-child pairs | PC; SYC; Sweden | MVS use at 1st trimester (interquartile range 9.0–12.7 weeks) according to P SR | Dx at age 4–15 yrs based on ICD-10 or DSM-IV from registry | MVS use during early pregnancy↓ odds of ASD with intellectual disability | |
| Raghavan et al, 2018 PMID: 28984369 | 1,257 mother-child pairs (86 ASD) | PC; Boston Birth Cohort, USA | MVS use at 1st trimester according to P SR & plasma folate concentration at 24–72 hrs post-delivery according to P B | Dx at mean age 6 yrs based on ICD-9 from EMR | U-shaped relationship between MVS frequency and ASD risk | |
| Levine et al., 2018 PMID: 29299606 | 45,300 children (572 ASD) | CC (nested); Israel | MVS use before and/or during pregnancy according to P M | Dx up until 12 yrs based on ICD-9 from registry | MVS use before and/or during pregnancy ↓ ASD risk | |
| Virk et al 2015 PMID: 26408631 | 35,059 mothers (552 ASD) | PC; DNBC; Denmark | MVS use during periconception period according to P SR | Dx at age 8.1–11.4 yrs based on ICD-10 from National Hospital Registry | No significant association overall | |
| Tan et al 2019 PMID: 31759952 | 416 ASD, 201 TD | CC; China | Micronutrient supplement use from last menstrual period to birth according to R SR | Dx at mean age 4.68 yrs based on DSM-5; AT using ABC, CARS, SRS§§§ | Micronutrient supplement during pregnancy ↓ ASD odds and severe AT symptoms | |
| Schmidt et al., 2019 (See above in PV) | Folic Acid (FA) | 305 mothers 332 children (55 ASD) | PC; MARBLES; California, USA | Calculated FA intake based on PV use from preconception to after birth according to P SR | Dx at age 3 yrs based on DSM-IV, ADOS and MSEL†† | Highest tertile of 1st month pregnancy FA intake and FA intake at or above 600 μg ↓ ASD risk. |
| Schmidt et al 2012 PMID: 22648721 | 429 ASD, 130 DD, 278 TD controls | CC; CHARGE; Northern California, USA | Calculated quantified FA intake from supplement and food from preconception to pregnancy according to R SR | Dx at age 2–5 yrs (see above- CHARGE criteria) | High periconceptional FA consumption of >=600 μg FA/day (relative to <600 μg) ↓ ASD risk | |
| Suren et al 2013 PMID: 23403681 | 85,176 children (270 ASD) | PC; MoBa; Norway | FA use at 18, 22 wks gestation according to P SR (FFQ) | Dx screen at age 3,5,7 yrs, referral, or registry; based on ADI-R, ADOS | Periconceptional FAS use ↓ ASD risk | |
| Bjork et al., 2018 PMID: 29279889 | 104,946 children | PC; MoBa; Norway | FA use and dose from preconception, periconception (−4 to 12 wks), to pregnancy according to P SR & plasma folate concentration at 17–19 wks gestation according to P B | AT based on screener scores (M-CHAT‡‡ at age 18 months, SCQ at age 3 yrs) | Periconceptional FAS use and dose and prenatal folate status ↓ ASD risk | |
| Levine et al., 2018 (See above in MVS) | 45,300 children (572 ASD) | CC (nested); Israel | FA use before and/or during pregnancy according to P M | Dx up until 12 yrs based on ICD-9 from registry | Maternal FAS use before and/or during pregnancy ↓ ASD risk | |
| Steenweg-de Graaff et al 2014 PMID: 25085472 | 3,893 children | PC; Generation R; Netherlands | FA use according to P SR & plasma folate concentration at 13 wks gestation according to P B | AT at age 6 yrs using SRS subset | Prenatal FAS use ↓ child autism-related traits; No association with plasma folate concentration. | |
| Virk et al 2015 (See above in MVS) | 35059 women (552 ASD) | PC; DNBC; Denmark | FA use during periconceptional and prenatal according to P SR (FFQ) | Dx at age 8.1–11.4 yrs (see above- DNBC criteria) | No significant association overall | |
| Strom et al., 2018 PMID:28946926 | 87210 mother-child pairs (1234 ASD) | PC; DNBC; Denmark | FA use during periconceptional and prenatal according to P SR (FFQ) | Dx at age 8.1–11.4 yrs (see above- DNBC criteria) | No significant association overall | |
| DeVilbiss et al., 2017 (See above in MVS) | 27,3107 mother-child pairs | PC; SYC; Sweden | FA use at first antenatal visit according to P SR | Dx at age 4–15 yrs (see above-SYC criteria) | No significant association overall | |
| Li et al., 2018 PMID: 30593205 | 374 ASD, 354 controls | CC; ACED; China | FA use during preconception, pregnancy, and breastfeeding according to R SR | Dx at age 3–6 based on DSM-IV-TR and total raw SRS T scores ≥ 56.5 | No significant association overall | |
| Sharman et al, 2019 PMID: 31376478 | 2009 ASD, 19,886 controls | CC (nested); Israel | FA use during pregnancy according to P M | Dx up until 6 yrs based on DSM§§ from registry | No significant association overall | |
| Braun et al 2014 (See above in PV) | 209 mother-child pairs | PC; HOME; Ohio, USA | WBF concentration at 11–21 wks gestation according to P B | AT at age 4–5 yrs (see above- HOME criteria) | No significant association with measured levels; | |
| Raghavan et al, 2018 (see above in MVS) | 1,257 mother-child pairs | PC; Boston Birth Cohort, USA | Plasma folate concentration at 24–72 hrs post-delivery according to P B | Dx at mean age 6 yrs based on ICD-9 from EMR | Low and extreme high plasma folate concentration levels ↑ ASD risk | |
| Egorova et al, 2020 PMID: 32131900 | 100 ASD, 100 TD controls | CC (matched); Sweden | Total folate concentration from stored pre-diagnostic blood samples at 14 wks gestation according to P B | Dx based on ICD-10, DSM-IV (born between 1996 and 2009) | Higher early plasma folate concentration ↑ offspring ASD odds | |
| Tan et al 2019 (See above in MVS) | 416 ASD, 201 TD | CC; China | FA use from 12 wks before (LMP) to 12 wks after LMP according to R SR | Dx at mean age 4.68 yrs; AT using ABC, CARS, SRS | FAS during pregnancy ↓ ASD odds and severe AT symptoms | |
| Whitehouse et al 2013 PMID: 23070790 | Vitamin D | 406 children | PC; Raine; Australia | Maternal serum 25(OH)D at 18 wks gestation according to P B | Dx at age 5,8,10,14,17 yrs based on DSM-IV; AT using total ASQ scores7 | Low 25(OH)D ↑ risk of higher scores on the Attention Switching subscale; No association with Dx |
| Chen et al., 2016 PMID: 27663117 | 68 ASD, 68 controls | CC (matched); China | Maternal 25(OH)D3 at first trimester pregnancy according to P B | Dx at age 3–7 yrs based on DSM-V, clinically confirmed | Lower 1st trimester 25(OH) D levels ↑ ASD risk | |
| Vinkhuyzen et al 2017 PMID: 28446959 | 4,334 children (68 ASD) | PC; Generation R; Netherlands | Maternal serum 25(OH)D at 18.1–24.9 wks gestation, and neonatal from cord blood at birth according to P B | Dx at age 6–9 yrs based on SRS, CBC, SCQ total score; | Mid-gestational, but not neonatal, vitamin D deficiency ↑ ASD risk | |
| Vinkhuyzen et al 2018 PMID: 27895322 | 4,229 children | PC; Generation R; Netherlands | Maternal 25(OH)D at 18.1–24.9 wks gestation, and neonatal from cord blood at birth according to P B | AT at mean age 6 yrs using 18-item SRS subset | Mid-gestational and neonatal 25OHD deficient ↑ SRS scores | |
| Fernell et al 2015 PMID: 25874075 | 58 sibling pairs | CC; Sweden | Neonatal 25(OH)D levels from stored dried blood spots at birth according to P B | Dx at preschool age based on clinical assessments | ASD cases ↓ 25OHD level at birth than siblings | |
| Lee et al., 2019 PMID: 31695167 | Maternal sample (449 ASD, 574 controls); neonatal sample (1399 ASD, 1607 controls)¶¶ | CC; SYC; Sweden | Maternal 25OHD level at 10.9 wks gestation and neonatal 25OHD from stored DBS at 3–5 days of age according to P B | Dx screened at age 0–5 yrs and diagnosed based on ICD-9, ICD-10, DSM-IV from registry | Neonatal, but not maternal, vitamin D deficiency ↑ ASD odds | |
| Windham et al., 2019 PMID: 30883046 | 563 ASD, 190 ID, 436 control | CC; EMA; Southern California | Neonatal 25(OH)D from stored DBS at birth according to P B | Dx at age 4.5–7 yrs based on DSM-IV-TR | No significant association overall | |
| Schmidt et al., 2019 PMID: 31094097 | 357 ASD, 134 DD, 234 TD controls | CC; CHARGE; Northern California, USA | Neonatal 25(OH)D from stored DBS at birth according to P B | Dx at age 2–5 yrs (see above- CHARGE criteria) | Higher neonatal 25(OH)D ↓ ASD odds only in females. | |
| Lopez-Vicente et al., 2019 PMID: 31616023 | 2,107 mother-child pairs | PC; INMA; Spain | Maternal 25(OH)D3 at 10–13 wks gestation according to P B | AT at age 5 yrs using CAST | No significant association overall | |
| Wu et al., 2017 31094097 | 310 ASD, 1240 controls | CC (matched); NBSIB; China | Neonatal 25(OH)D3 from stored DBS at birth according to P B | Dx at age 3 yrs based on DSM-5 | Higher neonatal vitamin D ↓ ASD risk | |
| Egorova et al, 2020 (See above in FA) | 100 ASD, 100 TD controls | CC (matched); Sweden | Maternal 25(OH)D3 from stored pre-diagnostic blood samples at 14 wks gestation according to P B | Dx based on ICD-10, DSM-IV (born between 1996 and 2009) | No significant association overall | |
| Lyall et al 2013 PMID: 23813699 | Fish and polyunsaturated fatty acid (PUFAs) ††† | 317 ASD, 17728 controls | PC; NHS II; USA | PUFA intake and fish oil supplement use during prenatal, pregnancy, postnatal according to P SR (FFQ) | Dx based on maternal report‡‡‡ | Higher PUFA intake ↓ ASD risk |
| Steenweg-de Graaff et al, 2016 PMID: 27052119 | 4,624 children | PC; Generation R; Netherlands | Fish intake at 10.8–21.4 wks in early pregnancy according to P SR (FFQ) & maternal plasma PUFA concentration and ω−3: ω−6 ratio at mid-pregnancy according to P B | AT at mean age 6.2yrs using SRS subset and the pervasive developmental problems subscale scores | Lower maternal ω−3: ω−6 ratio during pregnancy ↑ autism-related traits | |
| Julvez et al., 2016 PMID: 26740026 | 1,892 and 1589 mother-child pairs | PC; SCEP; Spain | Fish intake at 10–13wks, 28–32 of pregnancy, at child age14 months and 5 years according to P SR (FFQ) | AT at age 5 yrs using CAST scores | Maternal large fatty fish consumption ↓ CAST scores | |
| Gao et al., 2016 PMID: 28081749 | 108 ASD, 79 ID, 108 controls | CC (matched); China | Parental dietary habits from preconception to childbirth according to P SR | Dx at age 4–17 yrs based on DSM-IV, CARS ≥ 30 | Parental fish consumption ↓ odds of ASD with intellectual disability | |
| Suren et al 2013 (See above in FA) | 85,176 children (270 ASD) | PC; MoBa; Norway | Prenatal fish oil supplement according to P SR | Dx at age 3,5,7 yrs (see above – MoBa criteria) | No significant association overall | |
| Huang et al 2020 PMID:31958995 | 258 mother–child pairs (57 ASD, 62 non-TD, 139 TD) | PC; MARBLES; California, USA | Maternal PUFAs intake during pregnancy according to P SR (FFQ) & plasma PUFAs concentration at 3rd trimester according to P B | Dx at age 3 yrs (see above-MARBLES criteria) | Higher total omega-3 reported intake in 2nd half of pregnancy ↓ ASD risk; No significant associations with 3rd trimester plasma PUFA concentration | |
| Lyall et al, 2020, In press | 499 ASD cases, 501 controls | CC; California, USA | Maternal mid-pregnancy PUFA levels according to P B | Dx at (minimum age 5 yrs) from registry | No significant association overall; lower levels of PUFA ↑ ASD with ID | |
| Vecchione et al, 2020 PMID: 32519188 | 426 children | PC; EARLI & HOME; USA | Maternal fish intake across pregnancy according to P SR | AT at age 3 yrs using SRS | Higher overall fish intake ↑ autism-related traits; Higher salmon intake ↓ autism-related traits | |
| Raghavan et al, 2018 (See above in FA) | Other Nutrients: Vitamin B12 | 1,257 mother-child pairs (86 ASD) | PC; Boston Birth Cohort, USA | Vitamin B12 supplements use during prenatal according to P SR | Dx at mean age 6 yrs based on ICD-9 from EMR | Very high B12 levels ↑ASD risk; No association between B12 deficiency and ASD risk |
| Li et al., 2018 (See above in FA) | Other Nutrients: Calcium | 374 ASD, 354 controls | CC (matched); ACED; China | Maternal preference of calcium during preconception, pregnancy, and breastfeeding according to R SR | Dx at age 3–6 yrs (see above-ACED criteria) | Preconception calcium supplementation ↓ ASD risk |
| DeVilbiss et al., 2017 (See above in MVS, FA) | Other Nutrients: Iron | 27, 3107 mother-child pairs | PC; SYC; Sweden | Iron supplement at first antenatal visit according to P SR | Dx at age 4–15 yrs (see above-SYC criteria) | No significant association overall |
| Schmidt et al., 2014 PMID: 25249546 | 510 ASD, 341 TD controls | CC; CHARGE; Northern California, USA | Quantified mean maternal daily iron intake from supplements and cereals during 3 months preconception, pregnancy, and breastfeeding according to R SR | Dx at age 2–5 yrs (see above- CHARGE criteria) | Highest quintile of iron intake relative to lowest ↓ ASD risk, especially during breastfeeding. | |
| Wiegersma et al., 2019 PMID:31532497 | 532 232 children | PC; SYC; Sweden | Maternal anemia diagnosis during pregnancy (≤30 or >30 weeks) according to P M | Dx at age 4–15 yrs (see above-SYC criteria) | Maternal anemia diagnosed in early pregnancy ↑ ASD risk | |
| Schmidt et al., 2019 (See above in PV and FA) | 305 mothers 332 children (55 ASD) | PC; MARBLES; California, USA | Calculated iron intake from PV use in the 1st months of pregnancy according to P SR | Dx at age 3 yrs based on DSM-IV, ADOS and MSEL†† | The top two tertiles of 1st month pregnancy iron intake ↓ ASD risk. | |
| Bakian et al., 2018 PMID: 30246047 | Other Nutrients: Magnesium | 4855 children (112 ASD) | PC; Utah, USA | Neonatal magnesium level from serum at 24–48 hours after birth according to P B | Dx at age 4–12 yrs based on ICD-9 from registry | No significant association overall |
| Li et al., 2018 (See above in FA) | Dietary habit: balanced diet | 374 ASD, 354 controls | CC (matched); ACED; China | Maternal dietary habits during preconception, pregnancy, and breastfeeding according to R SR | Dx at age 3–6 (see above- ACED criteria) | Mostly meat or mostly vegetables (relative to balanced diet) ↑ ASD odds |
| House et al., 2018 PMID: 30246009 | Dietary habit: Mediterranean Diet | 325 mother-child pairs | PC; NEST; North Carolina, USA | Mediterranean diet adherence (MDA) scores during periconceptional/ early pregnancy according to P SR (FFQ) | AT at age 2 yrs using ITSEA (problem and competency portions) | Middle and high tertile of Mediterranean diet (relative to lowest tertile) ↓ ASD behaviors |
| Gao et al., 2016 (See above in PUFAs/fish) | Dietary habit: Fruit | 108 ASD, 79 ID, 108 controls. | CC (matched); China | Maternal dietary habits from preconception to birth according to R SR (FFQ) | Dx at age 4–17 yrs based on DSM-IV, CARS ≥ 30 | Low fruit intake during preconception and pregnancy relative to high intake ↑ ASD odds. |
†
Study names/acronyms are provided as relevant. SYC=Stockholm Youth Cohort; MoBa=Norwegian Mother and Child Cohort Study; NES=Newborn Epigenetics Study; CHARGE=Childhood Autism Risks from Genetics and the Environment; SCEP=Spanish Childhood and Environment Project; NHS II= Nurses’ Health Study II; Raine=The Western Australian Pregnancy Cohort Study; HOME=the Health Outcomes and Measures of the Environment Study; ACED=Autism Clinical and Environmental Database; DNBC=Danish National Birth Cohort; MARBLES=Markers of Autism Risk in Babies Learning Early Signs; NBSIB= the Expanded newborn screening in Beijing Study; EMA= the Early Markers for Autism Study; INMA= the INfancia y Medio Ambiente (Environment and Childhood) Project.
‡
Exposure acronyms are provided as relevant. MVS=Multivitamin supplement; PV=Prenatal Vitamins; FAS=Folic Acid supplement; WBF=maternal whole blood folate concentration; LMP=last menstrual period; DBS= Dried blood spots.
§
Outcome assessment/sources are provided as relevant. ICD=International Classification of Diseases; Diagnostic and Statistical Manual of Mental Disorders=DSM; EMR= Electronic medical records; SCQ= Social communication Questionnaire; ADOS= Autism Diagnostic Observation Schedule; ADOS-G= Autism Diagnostic Observation Schedule-Generic; ADI-R= Autism Diagnostic Interview-Revised; MSEL= Mullen Scales of Early Learning; M-CHAT= Modified Checklist for Autism in Toddlers; CARS= Childhood Autism Rating Scale; AQ= Autism Spectrum Quotient; SRS= Social Responsiveness Scale; ITSEA= Infant Toddler Social and Emotional Assessment; CAST=Childhood Asperger Syndrome Test; VABS= Vineland Adaptive Behavior Scale; ABC= the Autism Behaviour Checklist; Bayley=Bayley Scales of Infant Development Second Edition;
¶
To be defined as a case, children must have scored ≥ 15 (with >7 or more in the social domain) on SCQ; a score of 4 or more in the communication domain and a combined social-communication total of at least 12 (with scored 10 for the Social Interaction Domain, 8 for the Communication Domain for verbal children and 7 for nonverbal children, and 3 for the Restricted/repetitive Domain) on ADOS-G.
††
To be defined as a case, children must have scored below 70 for composite scores. (2 or more MSEL subscale scores more than 1.5 SD below the normative mean or at least 1 MSEL subscale score more than 2 SD below the normative mean).
‡‡
On M-CHAT, to be defined as case, children aged 16 to 30 months need to miss any 3 of 23 items or 2 of 6 critical items.
§§
DSM version was not specified
¶¶
The study included a total of four groups: maternal sample (449 ASD, 574 controls); neonatal sample (1399 ASD, 1607 controls), matched neonatal-sibling sample (357 ASD, 364 unaffected siblings), and paired maternal-neonatal sample (340 ASD, 426 controls)
†††
A few studies have also examined methylmercury in fish in association with ASD traits and diagnosis; these have generally not seen associations and are briefly summarized in the text.
‡‡‡
Maternal report of diagnosis was validated in a subset of participants using the ADI-R
§§§
Autism-related traits are measured as >=53 on the Autism Behaviour Checklist (ABC), >=30 on Childhood Autism Rating Scale (CARS), and > 65 on Social Responsiveness Scale (SRS).