Reference Study name Country Study design Follow‐up Funding	Original cohort (N total) Exclusion criteria Study population	Ascertainment of outcome	Exposure groups n/person‐years Exposure assessment method	Incident cases	Model covariates	Results
Michikawa et al. (2019) The Japan Environment and Children's Study Japan PC Follow‐up from first trimester to birth Funding: public	N  = 103,099 pregnancies Population sampled: General population of pregnant women Exclusion criteria: residing outside of study areas, restricting to first pregnancy per woman, and excluding twins and triplets, miscarriages and stillbirths, did not respond to FFQ in first trimester, reported extreme energy intake (lower and upper percentile), and missing information of maternal age at delivery % lost to follow up: NR n  = 89,658 Age at delivery, mean (SD): 31.2 (5.0) Infant sex (% females): 48.7	Outcome Identification of congenital diaphragmatic hernia (CDH) cases was made from medical records (ICD‐10 code Q79.0) CDH reported either at delivery or at the end of the first month	Total vitamin A (retinol + provitamin A carotenoids – from diet only) Median (IQR), μg RAE/day: Q1 (ref): 230 (185, 264) Q2: 346 (320, 373) Q3: 468 (433, 509) Q4: 738 (631, 940) N per quartile of vitamin A: Q1 (ref): 22,414 Q2: 22,415 Q3: 22,414 Q4: 22,415 Total vitamin A intake, Median, μg RAE/day (N): Q1 (ref): 230 (22,414) Q2‐Q4: 468 (67,244) Preformed vitamin A intake – from the diet only Median, μg/day: Q1 (ref): 81 Q2–Q4: 185 Exposure assessment method: 2 × FFQ: first trimester FFQ used as main exposure (median fill‐in week of gestation = 15), and second/third trimester FFQ used in sensitivity analyses (median fill‐in week 27 of gestation). Total vitamin A reported as μg RAE (retinol + provitamin A carotenoids), conversion factors NR	Cases of CDH per quartiles of total vitamin A intake (N cases per 10,000 live births): Q1 (ref): 14 (6.2) Q2: 8 (3.6) Q3: 9 (4) Q4: 9 (4) Q1 (ref): 14 Q2–Q4: 26 By preformed vitamin A intake: Q1 (ref): 10 Q2–Q4: 30 In women with BMI 18.5–25 kg/m 2 Total vitamin A Q1 (ref): 12 Q2–Q4: 18 Preformed vitamin A: Q1 (ref): 7 Q2–Q4: 23	Model 1: adjusted for maternal age at delivery Model 2: Adjusted for maternal age at delivery, smoking habits, alcohol consumption, pre‐pregnancy BMI, current history of diabetes or gestational diabetes and infertility treatment Many sensitivity analyses with similar results (adjusting for socio‐economic factors, excluding supplement users, excluding mothers with morning sickness, only isolated cases of CDH, adjusted for dietary folate and vitamin C, adjusting for vitamin A intake in mid/late pregnancy)	Total vitamin A intake and CDH, OR (95% CI) Model 1 Q1: ref Q2‐Q4: 0.6 (0.3–1.2) Model 2 (N = 89,481) Q1: ref Q2‐Q4: 0.6 (0.3–1.2) Retinol intake and CDH, OR (95% CI) Model 1 Q1: ref Q2‐Q4: 1.0 (0.5–2.1) Model 2 (N = 89,481) Q1: ref Q2‐Q4: 1.0 (0.5–2.0) Total vitamin A intake and CDH in women with BMI 18.5–25 kg/m 2 , OR (95% CI) Model 1 Q1: ref Q2‐Q4: 0.5 (0.2–1.0) Model 2 (N = 65,568) Q1: ref Q2‐Q4: 0.5 (0.2–1.0) Retinol intake and CDH in women with BMI 18.5–25 kg/m 2 , OR (95% CI) Model 1 Q1: ref Q2‐Q4: 1.1 (0.5–2.5) Model 2 (N = 65,568) Q1: ref Q2‐Q4: 1.0 (0.4–2.4)
Mastroiacovo et al. (1999) 13 European Teratology Information Services (TIS) Follow‐up: from first trimester to 3–6 weeks after expected delivery (by mail or phone) Funding: NR	Original cohort N  = 423 pregnancies exposed to ‘high’ dose of vitamin A (10 000 IU per day [3000 μg/day] or 50,000 IU per week [15,000 μg/week]) for at least one week during first 9 weeks of gestation Women contacted TIS either directly or through their doctor Control groups were mothers who consulted a TIS in the same period as the study subjects Control group 1: all infants exposed to ‘high’ vitamin A doses after 9 weeks of gestation Control group 2: all infants exposed to a documented nonteratogenic agent Exclusion: chromosomal or genetic diseases, as well as deformations (e.g. clubfoot), minor anomalies (e.g. preauricular tag), birth marks (e.g. nevus or angiomas), functional problems (e.g. pyloric stenosis, gastroesophageal reflux), and mild findings (e.g. hydronephrosis identified by prenatal sonography and not demanding treatment during the neonatal period), were excluded from the analysis N with complete follow‐up (study group) = 394 N for analysis Study group = 311 Control group 1 = 116 Control group 2 = 679	Outcome Prevalence rate of major malformations, defined as a structural abnormality that has an adverse effect on either the functional or the social acceptability of the individual, and which called for medical or surgical treatment Ascertainment of the outcome was done by mail or telephone interviews from doctors or mothers	Preformed vitamin A, μg RE/day (from supplements) Cases Median = 15,000 IQR = 7500–18,000 Min‐max = 3000–90,000 N above 15,000 μg/day = 120 N above 30,000 μg/day = 32 Main reasons for high exposures were various dermatologic conditions and breast fibrocystic disease Dietary assessment method: NR. Preformed vitamin A expressed as IU/day, here converted to μg RE/day by a factor of 0.3	Cases of major malformations Study group: 3 Control group 1: 4 Control group 2: 13	Model 1: No covariates Model 2: Stratified by potential confounding factors (age, education, race, family history of birth defects) (NR) Model 3: Regression models adjusted for age, education, race, family history of birth defects, use of folate supplements during early pregnancy, diabetes, alcohol consumption, genital herpes infection, fever, use of antiseizure medication, retinoids or exogenous hormones (NR) Model 2 and 3 were similar to model 1, and therefore NR	Birth prevalence, % (95% CI) Study group: 0.96 (0.25–2.60) Control group 1: 3.45 (1.11–8.11) Control group 2: 1.91 (1.07–3.17) Rate ratio (95% CI) Study group vs. control group 1: 0.28 (0.06–1.23) Study group vs. control group 2: 0.50 (0.14–1.76)
Rothman et al. (1995) USA PC Funding: Mixed	N  = 22,755 Pregnant women undergoing screening were recruited around gestational week 15–20 (1984–1987) Exclusion: missing information on more than half of retinol‐containing foods N for analysis = 22,748 N Any birth defect = 339 Of which cranial neural crest defects = 121	The outcome of pregnancy was obtained from a questionnaire mailed to the obstetrician around expected time of delivery (76.5% responded); if the physician did not respond, the questionnaire was mailed to the mother (all remaining responded: 23.5%) Outcome Outcome was any birth defect, cranial neural‐crest defects, neural tube defects (NTDs), musculoskeletal or urogenital defects, or other defects	Preformed vitamin A, μg RE/day Total intake (from diet   +  supplements) C1: 0–1500 C2: 1501–3000 C3: 3001‐4500 C4: > 4500 Total pregnancies (n per category) C1: 6410 C2: 12688 C3: 3150 C4: 500 From supplements only C1: 0–1500 C2: 1501‐2400 C3: 2401–3000 C4: > 3000 Total pregnancies C1: 11083 C2: 10585 C3: 763 C4: 317 Dietary assessment method: Assessment of diet (incl. 50 food items containing retinol) and supplement use (incl. vitamin A) conduced by telephone, focusing on the last 3 months before conception and first 8 weeks of pregnancy. Preformed vitamin A expressed as IU/day, here converted to μg/day by a factor of 0.3	Total intake (from diet + supplements) Total defects C1: 86 (1.3) C2: 196 (1.5) C3: 42 (1.3) C4: 15 (3.0) Cranial neural‐crest defects C1: 33 (0.51) C2: 59 (0.47) C3: 20 (0.63) C4: 9 (1.80) NTDs C1: 13 (0.20) C2: 29 (0.23) C3: 5 (0.16) C4: 1 (0.20) Musculoskeletal or urogenital defects C1: 24 (0.37) C2: 62 (0.49) C3: 10 (0.32) C4: 4 (0.80) Other defects C1: 16 (0.25) C2: 46 (0.36) C3: 7 (0.22) C4: 1 (0.20) From supplements Total defects C1: 148 (1.3) C2: 168 (1.6) C3: 13 (1.7) C4: 10 (3.2) Cranial neural‐crest defects C1: 51 (0.46) C2: 54 (0.51) C3: 9 (1.18) C4: 7 (2.21)	Model 1: No covariates Model 2: Stratified by potential confounding factors (age, education, race, family history of birth defects) (NR) Model 3: Regression models adjusted for age, education, race, family history of birth defects, use of folate supplements during early pregnancy, diabetes, alcohol consumption, genital herpes infection, fever, use of antiseizure medication, retinoids or exogenous hormones (NR)	Preformed vitamin A (from diet + supplements) Prevalence ratio (95% CI) Model 1: Cranial neural crest defects C4 vs. C1: 3.5 (1.7, 7.3) All birth defects C4 vs. C1: 2.2 (1.3, 3.8) Preformed vitamin A (from supplements only) Prevalence ratio (95% CI) All birth defects C4 vs. C1: 2.4 (1.3–4.4) Cranial neural crest defects C4 vs. C1: 4.8 (2.2–10.5) Models 2 and 3 were similar to model 1, and therefore NR Smoothed curves (unrestricted quadratic splines) indicated a threshold at ~ 3000 μg RE/day where the prevalence ratio increased (both total preformed vitamin A and preformed vitamin A from supplements only)
				NTDs C1: 21 (0.19) C2: 26 (0.25) C3: 1 (0.13) C4: 0 Musculoskeletal or urogenital defects C1: 44 (0.40) C2: 52 (0.49) C3: 2 (0.26) C4: 2 (0.63) Other defects C1: 32 (0.29) C2: 36 (0.34) C3: 1 (0.13) C4: 1 (0.32)
Bille et al. (2007) Denmark Danish National Birth Cohort Prospective case‐cohort study Funding: Public	N Total birth cohort ~100,000 Cases = 220 Controls = 880 Exclusion criteria: Twins were excluded and pregnancies not leading to births. Controls: Randomly selected from the birth cohort. % lost to follow up Cases: 8.2 Controls: 6 Periconceptional vitamin A supplement use (first weeks of pregnancy), %: Cases: 53 Controls: 58	Cases identified through maternally reported or a discharge diagnosis of oral clefts, including cleft lip with or without (±) cleft palate and isolated cleft palate cases, or an ICD code for reconstructive surgery on lips or palate.	Preformed vitamin A intake from supplements only (μg/day) Binary (yes/no) Cases: 102 /90 Control: 480/348 Categorical (μg/day, from suppl. only), C1: 0 C2: 0–400 C3: 400–800 C4: ≥ 800 n cases/controls per category of intake: C1: 90/348 C2: 40 /173 C3: 25/154 C4: 37/153 Exposure assessment method: Data on daily supplement use was obtained through a questionnaire at enrolment	Total cases = 192 Cleft lip ± cleft palate cases = 134 Cleft palate cases = 58 Controls = 828	Model 1: No covariates, NR Model 2: Adjusted for parental age and social class Results reported for binary, continuous (unit not reported, probably per 1 μg increment), and categorical (3 and 4 categories).	OR (95% CI) All oral clefts Binary: 0.82 (0.59–1.13) Continuous: 0.99 (0.99–1.00) Categorical analysis C1: ref C2: 0.93 (0.61–1.43) C3: 0.62 (0.38–1.02) C4: 0.90 (0.57–1.40) Cleft lip ± cleft palate Binary: 0.73 (0.50–1.06) Continuous: 0.99 (0.99–1) Categorical analysis C1: ref C2: 0.69 (0.41–1.18) C3: 0.51 (0.28–0.93) C4: 1.00 (0.61–1.63) Isolated cleft palate Binary: 1.06 (0.6–1.86) Continuous: 0.99 (0.99–1.00) Categorical analysis C1: ref C2: 1.60 (0.82–3.11) C3: 0.93 (0.41–2.10) C4: 0.60 (0.24–1.50)

Abbreviations: BMI, body mass index; CDH, congenital diaphragmatic hernia; FFQ, food frequency questionnaire; NR, not reported; NTD, Neural tube defects; OR, odds ratio; RAE, retinol activity equivalents; RE, retinol equivalents.