. 2020 Jan 29;49(6):1972–1995. doi: 10.1093/ije/dyz272

Table 2.

Quasi-experimental studies examining the effects of prenatal alcohol exposure (PAE) on pregnancy and childhood outcomes. *3 Denotes rare allele found in sub-Saharan African populations; *2 denotes rare allele found in European ancestry populations; *1 denotes common allele found worldwide

Study (year)	Country	Sample size		Exposure definition (proxy for PAE)	Exposure categories	Age at outcome assessment (child)	Outcomes	Summary of results & conclusions as presented in the paper
Mendelian randomization studies
Viljoen et al. (2001)²¹	South Africa	56 Mother–child pairs 178 Controls Khoisan–Caucasian mixed ancestry	MR	Gene: ADH1B SNP-rs number: rs1229984	11 Slow metabolizers (ref. category) 2 Fast metabolizers 3 Intermediate metabolizers	5–9 years	Fetal alcohol syndrome (FAS)	Fetal genotype: 3 vs 11 OR 0.85 (95% CI: 0.·26, 2.72) 2 vs 11 OR 0.31 (95% CI: 0·10, 0·90) Maternal genotype: 3 vs 11 OR 0.85 (95% CI: 0.26, 2.72) 2 vs 11 OR 0.31 (95% CI: 0.10, 0.90)
Stoler et al. (2002)²²	USA	173 White women 85 Black women	MR	Gene: ADH1B SNP-rs number: rs1229984	11 Slow metabolizers (ref. category) 31 Intermediate metabolizers	At birth	Blinded physician assessment of a composite trait including: growth restriction, microcephaly or 4 of 6 predefined facial features typical of FAS	Maternal genotype (White women): OR 31 vs 11: 6.68 (95%CI: 0.89, 49.90) Maternal genotype (Black women): OR 31 vs 11: 2.62 (95%CI: 0.97, 7.04) Fetal genotype (White children): OR 31 vs 11: 4.75 (95%CI: 0.35, 64.74) Fetal genotype (Black children): OR 31 vs 11: 3.75 (95%CI: 1.00, 14.02)
Arfsten et al. (2004)²³	USA	305 African American infants	MR	Gene: ADH1B SNP-rs number: rs1229984	11 Slow metabolizers (ref. category) 3 Intermediate metabolizers	At birth	Birth weight (g) GA (weeks) LBW (<2500g) SGA	Fetal genotype: 3 vs 11 3211 vs 3196, P=0.83 3 vs 11 39.6 vs 39.4, P=0.37 3 vs 11 OR 0.85 (95%CI: 0.30, 2.39) 3 vs 11 OR 0.27 (95%CI: 0.06, 1.20)
Chevrier et al. (2005)²⁴	France	205 Case children + parents (195 fathers and 211 mothers) 115 Control children and 54 mothers	MR	Gene: ADH1C SNPs-rs numbers: rs169342 rs698	Biallelic (2 haplotypes) 11 Faster metabolizers (ref. category) 2 Slower metabolizers	−--	Non-syndromic oral clefts	Maternal genotype: 21 vs 11 OR 0.93 (95% CI: 0.50, 1.90) 22 vs 11 OR 0.20 (95% CI: 0.10, 0.50) Fetal genotype: 21 vs 11 OR 1.37 (95% CI: 0.80, 2.40) 22 vs 11 OR 0.41 (95% CI: 0.20, 0.80)
Boyles et al. (2010)²⁵	Norway	Mother–child pairs (483 cases 503 controls)	MR	Gene: ADH1C SNP-rs number: rs169342 rs698	Biallelic (2 haplotypes) 11 Faster metabolizers (ref. category) 2 Slower metabolizers	At birth	Oral cleft	Maternal genotype: 21 vs 11 OR 0.93 (95%CI: 0.70, 1.24) 22 vs 11 OR 0.95 (95%CI: 0.67, 1.36) Fetal genotype: 21 vs 11 OR 1.05 (95%CI: 0.78, 1.41) 22 vs 11 OR 0.81 (95%CI: 0.56, 1.17)
Lewis et al. (2012)²⁶	UK	4 167 Mother–child pairs	MR	Gene: ADH7 SNP-rs number: rs284779 Gene: ADH1B SNP-rs number: rs4147536 Gene: ADH1A SNP-rs number: rs975833 SNP-rs number: rs2866151	Allele score composed of 4 SNPs (unweighted) No information on how it affects metabolic rates	8 years	IQ: Wechsler Intelligence Scale for Children (WISC-III)	Fetal allele score^a Beta −1.20 (95% CI: −1.89, −0.52)
Zuccolo et al. (2013)²⁷	UK	6268 Mother–child pairs for KS2 analysis 4061 pairs for WISC analysis	MR	Gene: ADH1B SNP-rs number: rs1229984	Biallelic SNP 11 Slow metabolizers (ref. category) 2 Fast metabolizers	8 years	Total IQ: Wechsler Intelligence Scale for Children (WISC)	Maternal genotype:2 vs 11 MD −0.01 (95% CI: -2·8, 2·7)
Zuccolo et al. (2013)²⁷	UK		MR	Gene: ADH1B SNP-rs number: rs1229984		11 years	Academic achievement: Key Stage 2 scores	Maternal genotype: 2 vs 11 MD 1.7 (95% CI: 0.4, 3.0) Fetal genotype: 2 vs 11 MD 0.68 (95% CI: −0.24, 1.60)
von Hinke Kessler Scholder et al. (2014)²⁸	UK	Mother–child pairs KS1: 3255 KS2: 3067 KS3: 2812 KS4: 3138	MR	Gene: ADH1B SNP-rs number: rs1229984	Biallelic SNP 11 Slow metabolizers (ref. category) 2 Fast metabolisers	7–16 years	Academic achievement: Key Stage 1 scores (age 7) Key Stage 2 scores (age 11) Key Stage 3 scores (age 14) Key Stage 4 scores (age 16)	Maternal genotype: 2 vs 11 MD 0.198 (95% CI: 0.05, 0.35) Fetal genotype: 2 vs 11 MD −0.082 (95% CI: -0.24, 0.07) Maternal genotype: 2 vs 11 MD 0.239 (95% CI: 0.08, 0.40) Fetal genotype: 2 vs 11 MD −0.122 (95% CI: −0.30, 0.06) Maternal genotype: 2 vs 11 MD 0.192 (95% CI: 0.03, 0.36) Fetal genotype: 2 vs 11 MD −0.103 (95% CI: −0.28, 0.07) Maternal genotype: 2 vs 11 MD 0.25 (95% CI: 0.10, 0.40) Fetal genotype: 2 vs 11 MD −0.075 (95% CI: −0.22, 0.07)
Murray et al. (2016)²⁹	UK	Maternal genotype analysis: 3114 mother–child pairs	MR	Gene: ADH1B SNP-rs number: rs1229984	11 Slow metabolizers (ref. category) 2 Fast metabolizers	4–13 years	Child’s conduct problem trajectories aged 4–13 based on Strengths and Difficulties Questionnaire (SDQ), categorized as: low-risk (ref) early-onset-persistent	Maternal genotype: OR 1.20 (0.60, 2.44) for early-onset-persistent conduct problems vs low-risk^b
Sibling control studies
D’Onofrio et al. (2007)³⁰	USA	8621	Sibling comparison	Siblings discordant for PAE	Moderate alcohol exposure vs none	4–11 years	Conduct problems Attention/impulsivity problems	Moderate vs no alcohol intake: MD 0.05 SE: 0.02 Moderate vs no alcohol intake: MD 0.03 SE: 0.02
Eilertsen et al. (2017)³¹	Norway	34 283	Sibling comparison	Siblings discordant for PAE	Not available	5 years	Attention-deficit hyperactivity disorder (ADHD) Scales: the revised Conner’s Parent Rating Scale (CPRS-R) Child Behaviour Checklist (CBCL)	(β= 0.017, 95% CI: 0.005, 0.030) (β= 0.011, 95% CI: -0.002, 0.024)
Parental control studies
Alati et al. (2008)³²	UK	4332	Maternal–paternal comparison	Mother and partner alcohol intake	First trimester (regular use): never <1 drinks /week 1–6 drinks/week 7+ drinks/week Binge drinking: 1–4 drinks/occasion 5–10 drinks/occasion 10+ drinks/occasion	8 years	IQ: Wechsler Intelligence Scale for Children (WISC)	1st trimester regular alcohol use (pdiff = 0·43) MD per increase in maternal category: 0.03 (−0.58, 0.65) MD per increase in paternal category: 0.40 (−0.01, 0.82) Binge drinking; (Pdiff =0.38) MD per increase in maternal category: −0.45 (−1.32, 0.43) MD per increase in paternal category: 0.10 (−0.36, 0.56)
Alati (2013)³³	UK	7062	Maternal–paternal comparison	Mother and partner alcohol intake	First trimester (regular use): never <1 drinks/week 1–6 drinks/week 7+ drinks/week Binge drinking: 1–4 drinks/occasion 5–10 drinks /occasion 10+ drinks/occasion	11 years	Academic achievement: Key Stage 2 scores (standardized)	1st trimester regular Alcohol use (Pdiff = 0·406) MD per increase in maternal alcohol category: Adjusted^c MD: 0.10 (-0.17, 0·37) MD per increase in paternal alcohol category: 0.25 (0.07, 0·43), (pdiff 0.41) Binge drinking; (Pdiff <0.0001) MD per increase in maternal category: −0.68 (−1.03, −0.33) MD per increase in paternal category: 0.27 (0.07, 0.46)
Zuccolo et al. (2016)³⁴	Norway	46 178	Maternal–paternal comparison	Mother and partner alcohol intake	Non-drinker (ref) <1 unit/week 1–2 units/week 3–4 units/week 5+ units/week	At birth and at 3 months post-partum	Head circumference Microcephaly	At birth- Fully and mutually adjusted model^c <1unit- Mother: mean difference (SD) 0.00 (95% CI: −0.02, 0·02) Father: mean difference (SD) −0.00 (95% CI: −0.05, 0.04) 1–2 units- Mother: mean difference (SD) −0.02 (95% CI: −0.05, 0.01) Father: mean difference (SD) 0.01 (95% CI: -0.03, 0·05) 3–4 units- Mother: mean difference (SD) 0.06 (95% CI: 0.02, 0.11) Father: mean difference (SD) 0.01 (95% CI: −0.03, 0.05) 5+ units- Mother: mean difference (SD) 0.01 (95% CI: −0.04, 0.06) Father: mean difference (SD) −0.01 (95% CI: −0.04, 0.03) At 3 months post-partum: fully and mutually adjusted model^d < 1unit- Mother: mean difference (SD) 0.02 (95% CI: −0.00, 0.05) Father: mean difference (SD) -0.02 (95% CI: -0.08, 0.04) 1–2 units- Mother: mean difference (SD) −0.02 (95% CI: −0.05, 0.02) Father: mean difference (SD) −0.03 (95% CI: −0.08, 0.02) 3–4 units- Mother: mean difference (SD) 0.04 (95% CI: −0.02, 0.10) Father: mean difference (SD) −0.04 (95% CI: −0.09, 0.01) 5+ units- Mother: mean difference (SD) 0.05 (95% CI: −0.02, 0.12) Father: mean difference (SD) −0.05 (95% CI: −0.10, 0.00) At birth: fully and mutually adjusted model^e <1 unit- Mother: OR 0.68 (95% CI: 0.50, 0.94) Father: OR 1.00 (95% CI: 0.53, 1.88) 1–2 units- Mother: OR 1.13 (95% CI: 0.81, 1.59) Father: OR 1.11 (95% CI: 0.66, 1.87) 3–4 units- Mother: OR 0.97 (95% CI: 0.57, 1.68) Father: OR 1.21 (95% CI: 0.72, 2·06) 5+ units- Mother: OR 1.22 (95% CI: 0.68, 2.20) Father: OR 1.36 (95% CI: 0.81, 2.28) At 3 months post-partum: fully and mutually adjusted model^f <1 unit- Mother: OR 0.82 (95% CI: 0.66, 1.02) Father: OR 1.25 (95% CI: 0.79, 1.95) 1–2 units- Mother: OR 0.82 (95% CI: 0.62, 1.09) Father: OR 1.16 (95% CI: 0.79, 1.71) 3–4 units- Mother: OR 1.08 (95% CI: 0.73, 1.59) Father: OR 1.38 (95% CI: 0.94, 2.03) 5+ units- Mother: OR 0.82 (95% CI: 0.49, 1.39) Father: OR 1.33 (95% CI: 0.90, 1.95)
McCormack et al. (2018)³⁵	Australia	2030	Maternal–paternal comparison	Mother and partner alcohol intake	First 6 weeks: Abstinent Low Moderate Binge Heavy Second 6 weeks Abstinence Low Trimester 2: Abstinence Low Trimester 3 Abstinence Low	12 months	Infant cognitive development (Bayley Scales for Infant Development, third edition)	Maternal alcohol use (compared with abstinence): Trimester 1: first 6 weeks Low: (β −0.45, SE 0.86) Moderate: (β 1.·35, SE 1.61) Binge: (β −0.90, SE 0.96) Heavy: (β −0.13, SE 1.02) Trimester 1: second 6 weeks Low: (β 0.54, SE 0.86) Trimester 2 Low: (β 2.11, SE 0.77) Trimester 3 Low: (β 1·60, SE 0.77) Partners alcohol use (compared with abstinence): Low: (β 2.42, SE 1.55) Moderate: (β 0.67, S.E 1.81) Heavy: (β 2.19, SE 1.98) Binge: (β 2.00, SE 1.58)
Natural experiments
Fertig and Watson (2009)³⁶	USA	All women 16 165 747 Native White women 11 426 203 Native Black women 3 032 108		Changes in minimum legal drinking age (MLDA)	Lower (18 years) vs higher (19–21 years) MLDA	At birth	Low birth weight (<2500g) Preterm birth (<37 weeks) Congenital anomalies	MLDA of 18 main effect; -0.17% (SE 0·07)^g MLDA of 18 x mother ≤17 years of age interaction; 0.50% (SE 0.18)^g MLDA of 18 x mother 18–20 years of age interaction; 0.26% (SE 0.10)^g MLDA of 18 main effect; −0.35% (SE 0.09)^g MLDA of 18 x mother ≤17 years of age interaction; 0.86% (SE 0.28)^g MLDA of 18 x mother 18–20 years of age interaction; 0.26% (SE 0.12)^g MLDA of 18 main effect; -0.18% (SE 0.12)^g MLDA of 18 x mother ≤17 years of age interaction; −0.04% (SE 0.05)^g MLDA of 18 x mother 18–20 years of age interaction; −0.03% (SE 0.02)^g
Zhang (2010)³⁷	USA	Infants with birthweight 71 501 237 Infants with APGAR scores 55 054 916		Raising alcohol taxes	Higher vs lower alcohol tax	At birth	Birthweight (g) Low birthweight (<2 500 g) Extremely low birthweight (<1 500 g) Low APGAR scores (<7)	Beer tax (β 0.931, SE 0.003) Wine tax (β 0.340, SE 0.006) Liquor tax (β 0·072, SE 0.027) Beer tax (β -0.023, SE 0.001) Wine tax (β -0·006, SE 0.0004) Liquor tax (β -0.001, SE 0·0001) Beer tax (β −0·002, SE 0·0004) Wine tax (β −0·002, SE 0·001) Liquor tax (β −0·001, SE 0·001) Beer tax (β -0·0002, SE 0·000001) Wine tax (β 0·0002, SE 0·0002) Liquor tax (β −0·0001, SE 0·0000)
Zhang and Caine (2011)³⁸	USA	All women (<21 years) 26 743 White women (<21 years) 16 596 Black women (<21 yrs) 11 147		State-specific MLDA when woman is 14 years as proxy of alcohol availability	Effects of different MLDA (18–2121 years), when woman is 14 (e.g. proxying for different alcohol availability)	At Birth	Low birthweight (<2 500 g) Low APGAR scores (<7) Preterm birth (<37 weeks)	MLDA of 18 (vs higher); 0·14% (P< 0·0001)^h MLDA of 19 (vs 18); −0·16% (P=0.002)^h MLDA of 20 (vs 18); −0·05% (P=0·217)^h MLDA of 21 (vs 18); −0·24% (P<0·0001)^h MLDA of 18 (vs higher); 1·12% (P< 0·0001)^h MLDA of 19 (vs 18); −1.80% (P<0·0001)^h MLDA of 20 (vs 18); −1.03% (P<0·0001)^h MLDA of 21 (vs 18); −1.82% (P<0·0001)^h MLDA of 18 (vs higher); 0·02% (P = 0.051)ⁱ MLDA of 19 (vs 18); −0.02% (P =0·051)ⁱ MLDA of 20 (vs 18); 0.01% (P =0·215)ⁱ MLDA of 21 (vs 18); −0.04% (P=0·0002)ⁱ
Barreca and Page (2015)³⁹	USA	14–17 years at conception 3 314 000 18–20 years at conception 6 287 000 21–24 years at conception 10 178 000		Differences in MLDA	Lower (18 years) vs higher (19–21) MLDA	At birth	Low birthweight (<2500 g) Preterm birth (<37 weeks) Low Apgar score (<7) Congenital anomaly Female	MLDA of 18 main effect; -0.19% (SE 0.08)^j MLDA of 18 x mother 14–17 years of age interaction; −0.02% (SE 0.07)^j MLDA of 18 x mother 18–20 years of age interaction; 0.10% (SE 0.05)^j Mean of outcome: 7.5 MLDA of 18 main effect; −0.04% (SE 0.10)^j MLDA of 18 x mother 14–17 years of age interaction; 0.05% (SE 0.12)^j MLDA of 18 x mother 18–20 years of age interaction; 0·04% (SE 0.09)^j Mean of outcome: 10.7 MLDA of 18 main effect; 0.39% (SE 0.32)^j MLDA of 18 x mother 14–17 years of age interaction; 0.46% (SE 0.53)^j MLDA of 18 x mother 18–20 years of age interaction; 0.19% (SE 0.26)^j Mean of outcome: 901.4 MLDA of 18 main effect; −0.28% (SE 0.20)^j MLDA of 18 x mother 14–17 years of age interaction; −0.002% (SE 0.06)^j MLDA of 18 x mother 18–20 years of age interaction; 0.04% (SE 0.03)^j Mean of outcome: 8.0 MLDA of 18 main effect; −0.01% (SE 0.12)^j MLDA of 18 x mother 14–17 years of age interaction; 0.01% (SE 0.10)^j MLDA of 18 x mother 18–20 years of age interaction; 0.18% (SE 0.07)^j Mean of outcome: 48.8
Evans et al. (2016)⁴⁰	USA	1 704 191 (Education sample) 985 118 (Obesity/height sample)		Effect of state alcohol prohibitions	States with alcohol prohibitions vs states without prohibitions	In utero, 8, and 10 years of exposure to state alcohol prohibitions	Adult education attainment Height	Exposure before 8 years of age 0·04 (SE 0·01) per year Exposure before 10 years of age 0.05 (SE 0.01) per year Exposure in utero 0.08 (SE 0.05) Exposure before 8 years of age 0.·0001 (SE 0.0001) per year Exposure before 10 years of age 0.0002 (SE 0.0001) per year Exposure in utero 0.0003 (SE 0·0005)
Cil (2017)⁴¹	USA	Birth weight: 60 914 264 Pre-term: 53 276 541 FAS: 28 371 025 APGAR: 48 291 613		Effect of point-of-sale warnings about risks of drinking during pregnancy	States with warnings vs states without warnings (including pre-/post-intervention within states)	At birth	Low birth weight (<2500 g) Very low birth weight (<1500 g) Pre-term (<37 weeks) Very pre-term (<32 weeks) FAS Low APGAR (<7)	−0.115% (SE 0.082) decreased odds of low birth weight (P > 0.1) −0.047% (SE 0.023) decreased odds of very low birth weight (P < 0.05) −0.065% (SE 0.14) decreased odds of pre-term birth (P > 0.1) −0.052% (SE 0.029) decreased odds of very pre-term birth (P >0.1) −0.003% (SE 0.002) decreased odds of FAS (P > 0.1) −0.014% (SE 0.047) decreased odds of low APGAR (P > 0.1)
Nilsson (2017)⁴²	Sweden	353 742		Relaxing the regulation of alcohol sales	Children born in counties with relaxed regulation on alcohol sales vs those born in counties with stronger regulation on alcohol sales (Exposed from first half of pregnancy)	Mean age 32 years	Earning, education and welfare dependency rate	Exposed children had: A reduction in years of schooling −0.31 (SE 0.09) years, males −0.52 (SE 0.17) years, females -0.21 (SE 0.12) Were less likely to complete high school −0.63 (0.02), males −0.1(SE 0.02), females -0.03 (SE 0.03) Had lower (log) earnings −0.24 (SE 0.09), males −0.24 (SE 0.11), females -0.17 (0.14) An increased risk of no labour income 0.07 (SE 0.03), males 0.08 (SE 0.02), females 0.06 (SE 0.04) A higher proportion were on welfare 0.04 (0.01), males 0.05 (SE 0.02), females 0.03 (SE 0.01)
Randomized controlled trial
Tzilos et al. (2011)⁴³	USA	Intervention group 27 Control group 23		Computer-delivered brief intervention for reduced prenatal alcohol use (33 days)	Children born to mothers receiving intervention on prenatal alcohol use vs to mothers receiving standard care	At birth	Birthweight	Intervention group: mean= 3189.6, SD=328.0 Control group: mean= 2965.3, SD= 387.7

LBW, low birth weight; ELBW, extremely low birthweight; GA, gestational age; APGAR, appearance, pulse, grimace, activity, respiration; MLDA, minimum legal drinking age; NICU, neonatal intensive care unit; OR, odds ratio; CI, onfidence interval; MD, mean difference; SD, standard deviation; SGA, small for gestational age; IQ: intelligence quotient; RR, relative risk.

unweighted allele score composed of the four fetal SNPs.

Adjustments: mother’s ancestry principle components from Genome wide association studies (GWAS) analysis.

Adjustments: sex, other parent’s alcohol consumption, maternal age, parity, socio-economic position, ethnicity, and, maternal and paternal education and smoking.

Test for trend maternal and paternal alcohol intake in full model: P = 0.267 and P = 0.201.

Test for trend maternal and paternal alcohol intake in full model: P = 0.390 and P = 0.124.

Test for trend maternal and paternal alcohol intake in full model: P = 0.545 and P = 0.056.

Test for trend maternal and paternal alcohol intake in full model: P= 0.178 and P = 0.090.

Adjustments: state fixed effects, year–month fixed effects, maternal age fixed effects, state-specific time trends and birth characteristic controls.

ⁱ

Adjustments: state fixed effects, year fixed effects, mother’s education, age, marital status, smoking during pregnancy, real income per capita and real beer taxes (federal plus state level).

Adjustments: state fixed effects, year-by-month fixed effects, age fixed effects, state-specific trends, age-by-year fixed effects, state-by-age fixed effects and state-by-year fixed effects.