Reference Study name Country Study design Follow‐up Funding	Original cohort (N total) Exclusion criteria Population sampled Study population	Ascertainment of outcome	Exposure groups n/ person‐years Exposure assessment method	Incident cases	Model covariates	Results
Shrim et al. (2006) NR Canada PC ~ 32 weeks NR	N = 192 Population sampled: General population B6 intake G1: Pregnant women: > 50 mg/day) G2: Pregnant women: 0 mg Exclusion criteria: NA % lost to follow up: 0 n = 192 G1: 96 G2: 96 Sex (% women): 100 Age (y, mean ± SD): G1: 32.5 ± 4.4 G2: 33.1 ± 4.2 Heterogeneity: Smoking status, n: G1: 1 G2: 12 p = 0.002 Parity (mean) : G1: 1.04 G2: 0.73 p = 0.03	Self‐reported birth weight Gestational age Malformation Live birth Twins	Vit B6 intake (mg, mean ± SD): G1: 132.3 ± 74 G2: 0 Duration: Vit B6 intake: 9 ± 4.2 weeks Method: Self‐report via telephone interview	Birth weight (g, mean ± SD): G1: 3,542 ± 512 G2: 3,321 ± 562 Malformation, n: G1: 1 G2: 0 Live birth, n: G1: 91 G2: 92 Twins, n: G1: 1 G2: 2	NA	Birth weight p = 0.01 Malformation p = 0.3 Live birth p = 0.7 Twins NA
Chang (1999) NR Taiwan CS During pregnancy Public	N = 209 Population sampled: General population, healthy pregnant women Exclusion criteria: Diseases such as, diabetes, chronic hypertension, or kidney disease. Use of oral contraceptives or drugs known to interfere with B6 metabolism within 1 year of pregnancy n = 209 G1: 83 G2: 63 G3: 43 G4: 20 Sex (% women): 100 Age (y, mean ± SD): G1: 28.3 ± 4.1 G2: 30.2 ± 3.4 G3: 30.3 ± 1.8 G4: 29.4 ± 3.1 Heterogeneity: BMI (kg/m 2 , mean ± SD): G1: 19.3 ± 3.6 G2: 20.3 ± 2.0 G3: 20.3 ± 1.0 G4: 19.8 ± 1.1 Parity, n (mean ± SD): G1: 1.9 ± 0.8 G2: 1.7 ± 0.8 G3: 1.5 ± 0.5 G4: 1.3 ± 0.4	Measurement of birth weight	Dose of pyridoxine*HCL supplement (mg/day): G1: 0 G2: 1 G3: 2 G4: 3 Intake of B6: ~ 1.0 mg/day for all groups Method: Blood samples (10 mL cord blood) at time of delivery used for determining PLP, PL, B6 aldehyde in cord plasma B6 intake estimated with Food frequency table	NA	NA	Maternal measurements Cord plasma concentrations of PLP (nM/L, mean ± SD): G1: 29 ± 6 G2: 40 ± 8 G3: 78 ± 2 G4: 90 ± 7 Cord plasma concentrations of PL (nM/L, mean ± SD): G1: 15 ± 8 G2: 14 ± 4 G3: 14 ± 2 G4: 16 ± 6 Cord plasma concentrations of B6 aldehyde (nM/L, mean ± SD): G1: 44 ± 11 G2: 55 ± 9 G3: 91 ± 2 G4: 106 ± 6 Correlations between supplementation and – Cord plasma PLP: 0.78 p < 0.0001 – Cord plasma PL: −0.14 p = NS – Cord total B6 aldehyde: 0.61 p < 0.0002 Neonate measurements: Birth weight with various conc. of PLP (nM/L) in cord blood (kg, mean ± SD): < 40: 3.0 ± 0.3 40–50: 3.3 ± 0.4 > 50: 3.4 ± 0.3 significantly different between < 40 and > 50
Goodman et al. (2019) NR USA CC 22 months Public	N = 106 Population samples: G1 (case): Pregnant women diagnosed with fetal gastroschisis G2 (control): Maternal age and race/ethnicity matched pregnant women Exclusion criteria: Multiple pregnancies. Fetus known to have lethal anomalies, and/or chromosome abnormalities % lost to follow up: 0 n = 106 G1: 30 G2: 76 Sex (% women): 100 Age (y, mean ± SD): G1: 20.9 ± 4.5 G2: 22.7 ± 4.5 Heterogeneity: Parity, n (%): G1: Nulliparous: 18 (60.0) Parous: 12 (40.0) G2: Nulliparous: 28 (36.8) Parous: 48 (63.2) Conception BMI (kg/m 2 ), n (%): G1: < 19: 3 (10) 19–24: 12 (40) 25–29: 11 (37) > 30: 4 (130) G2: < 19: 3 (4)) 19–24: 32 (42) 25–29: 17 (22) ≥ 30: 24 (32)	Mid‐pregnancy ultrasound was performed at < 24 wk gestation. The diagnosis of gastroschisis was confirmed by a Maternal‐Fetal Medicine physician	Vit B6 supplementation n, (%): Prior to conception: G1: 2 (6.7) G2: 9 (11.8) After positive pregnancy test: G1: 12 (40.0) G2: 29 (38.2) After 6 weeks of gestation: G1: 15 (50.0) G2: 26 (34.2) None: G1: 1 (3.3) G2: 11 (14.5) Missing: G1: 0 (0.0) G2: 1 (1.3) Vit B6 concentration (ug/L), n (%): G1: Q1 (< 5): 2 (6.7) Q2 (≥ 5): 24 (80.0) Missing: 4 (11.3) G2: Q1 (< 5): 6 (7.9) Q2 (≥ 5): 60 (79.0) Missing: 10 (13.2) Method: 25 cc maternal blood sample (complete blood count of Vit B6)	Fetal gastroschisis, n: G1: 30 G2: 0	Model 1: Unadjusted Model 2: Adjusted for insurance, education, BMI, and nulliparity	Model 1: OR (95% CI) for gastroschisis: Q1: 0.81 (0.07–5.53) Q2: ref Model 2: OR (95% CI) for gastroschisis: Q1: 1.81 (0.11–22.32) Q2: ref
Salcedo‐Bellido et al. (2017) NR Spain CC NR	N = 1,066 Population sampled: General population, women who gave birth to a singleton baby Inclusion criteria: G1 (cases): Small for gestational age (SGA) infants without congenital malformations G2 (controls): non‐SGA infants without congenital malformations. Age matched to cases Excluded: G1: 15 G2: 15 Sex (% women): 100 n = 1,036 G1: 518 G2: 518 Sex (% women): 100 Smoking during pregnancy, n: G1: 149 G2: 80 p < 0,001 Previous preterm/LBW infant, n: G1: 64 G2: 26 p < 0,001 Preeclampsia, n: G1: 46 G2: 11 p < 0,001 Intrauterine growth retardation, n: G1: 141 G2: 8 p < 0.001 Pre‐pregnancy BMI (kg/m2, mean ± SD): G1: 23.1 ± 4.5 G2: 23.9 ± 4.1 p < 0.001	Birth weight was measured in the delivery room (data obtained from the clinical charts)	G1: Vit B6 intake level (mg/day), n per quintile: Q1 (< 1.949): 134 Q2 (1.950–2.257): 116 Q3 (2.258–2.508): 80 Q4 (2.509–2.858): 105 Q5 (> 2.858): 83 G2: Vit B6 intake level (mg/day), n per quintile: Q1 (< 1.949): 104 Q2 (1.950–2.257): 104 Q3 (2.258–2.508): 103 Q4 (2.509–2.858): 104 Q5 (> 2.858): 103 Method: Semi‐quantitative FFQ. Nutrient scores were computed using computer software	SGA, n: G1: 518 G2: 0	Model 1: No adjustments Model 2: Adjusted for energy intake, preeclampsia, education level, pre‐pregnancy body mass index, smoking, weight gain per week during pregnancy, and previous preterm/LBW newborn	Model 1: OR (95% CI) for SGA: Q1: 1 (ref) Q2: 0.85 (0.58–1.23) Q3: 0.62* (0.42–0.91) Q4: 0.76 (0.52–1.12) Q5: 0.62* (0.42–0.93) * = significant association Model 2: OR (95% CI) for SGA: Q1: 1 (ref) Q2: 0.80 (0.52–1.22) Q3: 0.62* (0.40–0.96) Q4: 0.70 (0.45–1.08) Q5: 0.69 (0.43–1.08) * = significant association
Hobbs et al. (2005) NR USA CC NR	Sex (% women): 100 Population sampled: General population G1 (cases): Women with pregnancies affected by congenital heart defects (CHD) G2 (controls): Women with pregnancies not affected by CHDs Inclusion criteria: G1: Live‐born infant, stillborn infant or elective termination. Diagnosis of a nonsyndromic septal, cono‐truncal, or right‐ or left‐sided obstructive heart defect, confirmed by prenatal or postnatal echocardiogram, surgery, or autopsy report or all 3. Only non‐syndromic CHDs. G2: No birth defects G1 + G2: participation in the National Birth Defects Prevention Study Exclusion criteria: G1 + G2: Single gene disorder, chromosomal abnormality or syndrome. Pregnancy at the time of blood samples. Folate antagonist medication n = 456 G1: 331 G2: 125 Sex (% women): 100 Age, n: G1: < 30: 211 > 30: 120 G2: < 30: 74 > 30: 51 Heterogeneity: Smoking status, n: G1: 93 G2: 23 p = 0.0401	CHD knowledge was ascertained through the Arkansas Reproductive Health Monitoring System	G1: B6 concentrations (nmol/L), n: Q1 (< 31.86 (30th)): 161 Q2 (< 27.90 (20th)): 111 Q3 (< 24.52 (10th)): 67 G2: B6 concentrations (nmol/L), n: Q1 (< 31.86 (30th)): 37 Q2 (< 27.90 (20th)): 24 Q3 (< 24.52 (10th)): 12 Method: Plasma concentration of pyridoxal‐5′‐phosphate measured in blood samples using an HPLC method	CHD, n: G1: 331 G2: 0	Model 1: No adjustments Model 2: Adjusted for age, race, education, number of cigarettes smoked per day, alcohol consumption, vitamin intake, caffeine intake, breastfeeding status, and the interval between the end of pregnancy and study participation (multivariate linear regression)	Model 1: B6 plasma concentration (nmol/L, mean ± SD): G1: 34.22 ± 11.40 r2: 37.23 ± 12.00 p = 0.0066 OR (95% CI) for CHD: Q1: 2.25 (1.45–3.50) Q2: 2.12 (1.29–3.50) Q3: 2.39 (1.24–4.59) Model 2: B6 plasma concentration (nmol/L, mean ± SD): G1: 34.22 ± 11.40 G2: 37.23 ± 12.00 p = 0.0023 OR (95% CI) for CHD: Q1: 2.52 (1.54–4.11) Q2: 2.63 (1.49–4.64) Q3: 2.86 (1.38–5.93)
Zang et al. (2019) NR China CC NR	N = 2000 Population sampled: General population, G1 (Cases): Women who gave birth to a child with CHD G2 (controls): Women who gave birth to a child without CHD Exclusion criteria: NR n = 2000 G1: 500 G2: 1500 Sex (% women): 100 Age: NR	NR	Vitamin B6 intake: G1: NR G2: NR (G1 had higher intake of B6 than G2) Method: Semi‐quantitative FFQ	CHD, n: G1: 500 G2: 0	NA	OR (95% CI) for CHD: Highest tertile vs lowest tertile: 0.44 (0.28–0.70)
Furness et al. (2013) NR Australia PC Start: 18–20 weeks gestation End: after delivery Public	N = 143 Population sampled: General population, pregnant women G1: Low risk for adverse pregnancy outcome G2: High risk for adverse pregnancy outcome Inclusion criteria: 6–20 weeks gestation Exclusion criteria: Condition requiring termination of pregnancy. Major fetal anomaly or fetal demise. Twins. Disorders requiring systemic steroids. Pre‐existing maternal renal disease % loss to follow up/excluded: 4.2% (n = 6) n = 137 G1: 46 G2: 91 Sex (%women): 100 Age (y, mean (95% CI)): G1: 31.1 (29.5–32.4) G2: 34.0 (32.4–35.6) p = 0.020 BMI (kg/m2, mean (95% CI)): G1: 26.5 (25.4–27.8) G2: 29.5 (28.1–31.1) p = 0.010 Smokers, n (%): G1: 3 (6.5%) G2: 18 (19.8%) p = 0.042	Risks of adverse pregnancy outcome were obtained from clinical records by senior obstetricians High risk: Obstetric risk factors, including a history of one or more of pre‐eclampsia/ eclampsia, early‐onset IUGR (< 34 weeks gestation and birthweight < 10th centile), placental abruption, preterm birth < 34 weeks gestation, recurrent pregnancy loss (three or more miscarriages) and previous fetal demise Low risk: No known pre‐existing medical (including chronic hypertension and diabetes mellitus) or obstetric disorders, and had had a previous normal pregnancy (birth > 37 weeks gestation, customised birthweight > 10th centile, with no gestational hypertension)	Red blood cell (RBC) B6 concentration (nmol/L, mean (95% CI)): Total cohort: 41.9 (39.1–44.7) B6 supplementation, n: G1: 21 (45.7%) G2: 44 (48.4%) B6 supplementation dosage (ug, mean (95% CI)): G1: 1031 (653–1426) G2: 1301 (898–1703) Method: RCB B6 concentration: Blood samples Supplements: Dietary questionnaire data (type, dosage)	Adverse pregnancy outcomes, n: G1: 7 G2: 67	NA	RBC B6 concentration in different pregnancy outcomes (nmol/L, mean (95% CI)): Normal pregnancy: 41.9 (38–46) Pre‐eclampsia: 41.5 (29–54) IUGR: 50.0 (45–55) Other: 38.0 (33–44) p = 0.062
Carmichael et al. (2010) National Birth Defects Prevention Study USA CC 8–13 months from delivery until study interview Public	N = 3181 Population sampled: General population G1 (cases): Women who gave birth to an infant with hypospadias G2 (controls): Women who gave birth to a male nonmalformed infant Inclusion criteria: Only second and third‐degree hypospadias Exclusion criteria: Infants with recognised single gene disorders or chromosomal abnormalities. Each case received a final review by 1 clinical geneticist to ensure that cases from each study centre met standard eligibility criteria n = 3111 G1: 893 G2: 2218 (those with data on dietary intake) Sex (% women): 100 Age, n (%) G1: < 25: 217 (22.7) 25–29: 209 (21.8) 30–34: 324 (33.8) > 35: 208 (21.7) G2: < 25: 852 (33.6) 25–29: 617 (24.4) 30–34: 664 (26.2) > 35: 345 (13.6)	Medical record information (including operative reports when available) was reviewed by a clinical geneticist, who decided whether to include the case in the National Birth Defects Prevention Study database	Dietary intake of B6 (mg) for those that did not take folate supplements, n: G1: Q1 (< 1.36): 20 Q2 (1.36–1.80): 15 Q3 (1.81–2.54): 19 Q4 (>2.55): 22 G2: Q1 (< 1.36): 75 Q2 (1.36–1.80): 58 Q3 (1.81–2.54): 84 Q4 (>2.55): 87 Dietary intake of B6 (mg) for those that did take folate supplements, n: G1: Q1 (< 1.36): 226 Q2 (1.36–1.80): 231 Q3 (1.81–2.54): 212 Q4 (>2.55): 148 G2: Q1 (< 1.36): 483 Q2 (1.36–1.80): 509 Q3 (1.81–2.54): 470 Q4 (>2.55): 452 Method: FFQ ‐ intake of food the last year FFQ ‐ intake the last 3 months before pregnancy	Hypospadias, n: G1: 893 G2: 0	Model 1: Adjusted for energy intake, maternal race/ethnicity, education, age, number of previous live births, body mass index, plurality, fertility treatments or procedures and study site	Model 1: No folate supplement: OR (95% CI) for hypospadias Q1: ref Q2: 1.0 (0.4–2.4) Q3: 1.0 (0.4–2.4) Q4: 1.5 (0.5–4.8) Folate supplement: OR (95% CI) for hypospadias Q1: ref Q2: 1.0 (0.8–1.3) Q3: 1.2 (0.9–1.6) Q4: 0.9 (0.6–1.3)
McCullough et al. (2016) NR USA PC 3 years NR	N = 496 Population sampled: An ethnically diverse population of women Exclusion criteria: No intend of using one of the participating obstetric facilities for delivery. Planned to relinquish custody of the child. Move from the area in the subsequent 3 years. HIV infection. Infant death before, during or soon after delivery % loss to follow up: 45 n = 496 (at delivery) n = 273 (after 3 years) Sex (% women): 100 Age (at delivery), n (%): 18‐ < 20: 22 (4) 20–29: 278 (56) 30–35: 147 (30) > 36: 50 (10)	Extraction of parturition data from medical records by trained personnel	Vit B6 concentration (nM/L, range): PLP: Q1: (ref) ≤ 3.76 Q2: 3.77–7.47 Q3: 7.48–12.05 Q4: > 12.05 PA: Q1: (ref) ≤ 2.06 Q2: 2.07–3.21 Q3: 3.22–5.93 Q4: > 5.93 Method: Maternal serum concentrations of pyridoxal phosphate (PLP) and 4‐pyridoxic acid (PA)	Birth weight (g, mean ± SD): 3294 ± 541 g	Model 1: Adjusted for gestational age at delivery, gestational age at blood draw, maternal pre‐pregnancy BMI, maternal race/ethnicity, parity, household income, maternal smoking	Model 1: Regression coefficients: Values: beta coefficient, standard error, p‐value Birth weight: PLP Q1: (ref) Q2: −72.75, 71.50, 0.31 Q3: −45.61, 73.22, 0.53 Q4: 39.81, 75.75, 0.60 PA: Q1: (ref) Q2: −13.80, 70.48, 0.84 Q3: −35.02, 70.51, 0.62 Q4: 9.95, 72.43, 0.89
Chen et al. (2015) Growing Up in Singapore Towards Healthy Outcomes (GUSTO) Singapore PC Study: ≈ week 26–39 Public	N = 1247 Population sampled: General population, pregnant women Exclusion criteria: Mothers or fathers whose parents were of the different ethnicity. Serious health conditions such as psychosis and type 1 diabetes. In vitro fertilisation % lost to follow up: 1 (n = 15) n = 986 Sex (% women): 100 Age (y): 30.6 ± 5.2	Information on birth weight, gestational age, infant sex, and birth order was retrieved from birth delivery reports	Vit B6 concentration (nmol/L, median (IQRs)): Q1: 15.4 (12.4–18.8) Q5: 152 (135–177) Method: Maternal fasting blood sample at 26th‐28th week of pregnancy	Birth weight (g, mean ± SD): 3101 ± 449	Model 1: Unadjusted Model 2: Adjusted for infant sex, ethnicity, maternal age, gravidity, maternal height, prepregnancy BMI, weight gain up until 26 wk, educational level, and gestational diabetes mellitus	Model 1: Birth weight: β per 1 SD of log vitamin B6 concentration (95% CI): 5.8 (−22.1–33.7) p = 0.69 Small for gestational age: OR (95% CI): 0.95 (0.77–1.17) p = 0.62 Model 2: Birth weight: β per 1 SD of log vitamin B6 concentration (95% CI): −3.9 (−30.7–22.9) p = 0.78 Small for gestational age: OR (95% CI): 0.98 (0.79–1.22) p = 0.87
Robitaille et al. (2009) National Birth Defects Prevention Study (NBDPS) 1997–2003 USA CC NA Public	N = 5,464 Population sampled: General population G1a + b (cases): Women who gave birth to an infant with trans limb deficiency (TLD) or longitudinal limb deficiency (LLD) G2 (controls): Women who gave birth to nonmalformed infants Exclusion criteria: G1a + b: Identified single‐gene mutations or clinical histories suggestive of a mendelian disorder. Evidence of amnion rupture sequence or central axis deficiencies (split hand/split foot). Maternal diabetes pre pregnancy % loss to follow up: (did not answer maternal interview) G1a: 16 G1b: 21 G2: 20 n = 4366 G1a (TLD): 272 G1b (LLD): 125 G2: 3969 Age, n (%): G1a: < 24: 119 (36.7) 25–34: 168 (51.9) > 35: 37 (11.4) G1b: < 24: 84 (40.4) 25–34: 100 (48.1) > 35: 24 (11.5) G2: < 24: 1665 (33.4) 25–34: 26336 (52.9) > 35: 684 (13.7) Race/ethnicity, n (%): Non‐Hispanic white: G1a: 180 (55.7) G1b: 116 (55.8) G2: 2993 (60.2) Non‐Hispanic black or African American black: G1a: 27(8.4) G1b: 27 (13.0) G2: 583 (11.72) Hispanic: G1a: 100 (31.0) G1b: 54 (26.0) G2: 1119 (22.5) > 8% higher in Gr1a compared to Gr2: Other: G1a: 16 (5.0) G1b: 11 (5.3) G2: 275 (5.5)	NBDPS records of limb deficiencies were reviewed independently by a clinical geneticist (R.S.O.) Clinical geneticists reviewed abstracted records of physical examinations, radiographs, laboratory investigations, autopsies, surgical reports, and other relevant medical information	Dietary vitamin B6 intake (mg) for those that did not take folate supplements, n, per quartile: G1a: Q1 (< 1.35): 16 Q2 (1.35–1.84): 16 Q3 (1.84–2.60): 12 Q4 (> 2.60): 19 G1b: Q1 (< 1.35): 14 Q2 (1.35–1.84): 3 Q3 (1.84–2.60): 11 Q4 (> 2.60): 11 G2: Q1 (< 1.35): 215 Q2 (1.35–1.84): 212 Q3 (1.84–2.60): 226 Q4 (> 2.60): 311 Dietary intake of B6 (mg) for those that did take folate supplements, n: G1a: Q1 (< 1.35): 58 Q2 (1.35–1.84): 57 Q3 (1.84–2.60): 52 Q4 (>2.60): 42 G1b: Q1 (< 1.35): 24 Q2 (1.35–1.84): 27 Q3 (1.84–2.60): 26 Q4 (> 2.60): 16 G2: Q1 (< 1.35): 788 Q2 (1.35–1.84): 790 Q3 (1.84–2.60): 758 Q4 (> 2.60): 669	TLD, n: G1a: 272 G1b: 0 G2: 0 LLD, n: G1a: 0 G1b: 125 G2: 0	Model 1: Adjustment for maternal age, maternal race or ethnicity, maternal education, smoking tobacco during the periconceptional period and drinking alcohol during the periconceptional period, energy intake (kcal), and body mass index	Model 1: B6 with No folate supplement: OR (95% CI) for TLD: Q1: 1.53 (0.52–4.50) Q2: 1.44 (0.54–3.85) Q3: 0.95 (0.36–2.47) Q4: 1.0 OR (95% CI) for LLD: Q1: 4.36 (0.93–20.48) Q2: 1.47 (0.28–7.57) Q3: 4.39 (1.19–16.12) Q4: 1.0 B6 with Folate supplement: OR (95% CI) for TLD: Q1: 1.30 (0.73–2.31) Q2: 1.19 (0.71–2.00) Q3: 1.11 (0.69–1.80) Q4: 1.0 OR (95% CI) for LLD: Q1: 1.15 (0.49–2.73) Q2: 1.32 (0.61–2.83) Q3: 1.39 (0.69–2.78) Q4: 1.0
de Weerd et al. (2003) NR Netherlands PC From preconce‐ption to 6 wk and 10‐wk amenorrhea Public	N = 253 Population sampled: General population, pregnant women Exclusion criteria: Treatment for infectious, endocrine, metabolic or malignant diseases. Twin‐pregnancy. Low birth weight (< 2.3 percentile). Preterm delivery (< 37 wk). Post term birth (> 42 wk). Intra‐uterine fetal death Controls: No first degree relative with known genetic disorder known to cause major congenital malformations n = 240 G1 (Normal birth): 194 G2 (miscarriages): 46 (119 women were diagnosed with epilepsy (99 were treated for it). 15 women with previous birth of a child with NTD. 106 healthy women) Age (y, mean ± SD) G1: 30 ± 3.5 G2: 30 ± 4.2	Birth weight was ascertained from the medical records Early pregnancy loss was defined as spontaneous abortion ending before or at 16 weeks amenorrhea	Vit B6 concentration (nmol/L, median (25–75 quartiles)): Preconceptional G1 (n = 96): 49 (43–59) G2 (n = 20): 47 (41–54) 6 weeks: G1 (n = 188): 47 (40–56) G2 (n = 41): 43 (37–51) 10 weeks: G1 (n = 174): 48 (41–57) G2 (n = 13): 44 (34–56)	Miscarriages, n: G1: 0 G2: 46	NA	Birth weight and Early pregnancy loss: Periconceptional and first trimester B6 levels were unrelated to low birth weight and early loss of pregnancy (no significant differences in B6 levels at the different time points)
Lagiou et al., 2005 NR USA PC 27th gestational wk until birth (~ 11–13 wks) Public	N = 325 Population sampled: General population, pregnant women. Inclusion criteria: Caucasian < 40 years old Exclusion criteria: Parity > 2. Hormonal medication during index pregnancy. Diabetes or thyroid diseases. Known major fetus abnormalities. Spontaneous or planned abortion. Twins. Pregnancy lasted less than 37 or more than 42 weeks. Preeclampsia % loss to follow up: 32 (n = 103) n = 222 Sex (% women): 100 Age, n: 18–24: 5 25–29: 60 30–34: 138 ≥ 35: 19 Heterogeneity: Pre‐pregnancy BMI (kg/m 2 ), n: < 18.9: 26 19–21.9: 107 22–24.9: 59 ≥ 25: 30 Smoking in pregnancy, n: Yes: 11 No: 211 Parity, n: 1: 136 2: 86	Birth weight, birth length and head circumference measured at delivery by study collaborators	B6 dietary intake (mg, mean ± SD and median (1th‐3th quartile)): 5.6 ± 7.7 4.1 (2.6–5.9) Method: Semi quantitative FFQ including vitamin supplements	NA	Model 1: No adjustments Model 2: Adjusted for age, education, parity, height, pre‐pregnancy BMI, oral contraceptives prior to index pregnancy, smoking, gender of offspring, exact gestational age at delivery and total energy intake	Model 1: Birth weight (g, mean change (95% CI)): + 6.8 (−57.5 to +71.2) p = 0.84 Birth length (cm, mean change (95% CI)): − 0.02 (−0.33 to +0.30) p = 0.92 Head circumference (cm, mean change (95% CI)): + 0.01 (−0.22 to +0.24) p = 0.94 Model 2: Birth weight (g, mean change (95% CI)): + 2.7 (−54.4 to +59.7) p = 0.93 Birth length (cm, mean change (95% CI)): – 0.04 (−0.32 to +0.25) p = 0.79 Head circumference (cm, mean change (95% CI)): − 0.02 (−0.23 to +0.19) p = 0.87
Shaw et al., 2014 NR USA CC B6 measured: 15th‐18th wk of pregnancy End: after delivery Public	N = 420 Population sampled: General population G1 (cases): Pregnant women with infants with cono‐truncal heart defects (d‐transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF)) G2 (controls): Pregnant women with nonmalformed infants Exclusion criteria: Single gene disorders or chromosomal aneusomies % loss to follow up: 1.4% (n = 6) n = 414 G1: 137 G2: 177 Sex (as % women): 100 Age, n (%): G1: < 25: 41 (29.3) 25–29: 37 (26.4) 30–34: 40 (28.6) > 34: 22 (15.7) G2: < 25: 105 (37.5) 25–29: 72 (25.7) 30–34: 73 (26.1) > 34: 30 (10.7) Heterogeneity: Race/ethnicity, n (%): G1: Hispanic: 67 (48.9) White non‐Hispanic: 45 (33.0) Asian: 12 (8.8) Black: 8 (5.8) Other: 5 (3.7) G2: Hispanic: 160 (57.8) White non‐Hispanic: 63 (22.7) Asian: 26 (9.4) Black: 13 (4.7) Other: 15 (5.4)	Case information was abstracted from multiple hospital reports and medical record	Pyridoxal‐5‐phosphate concentration (nmol/L, mean ± SD): G1: 65.40 ± 52.36 G2: 69.38 ± 72.38 G1, n per quartile (nmol/L) Q1 (< 31.16): 26 Q2 (31.16–80.00): 78 Q3 (≥ 80.01): 33 G2, n per quartile (nmol/L) Q1 (< 31.16): 69 Q2 (31.16–80.00): 139 Q3 (≥ 80.01): 69 Pyridoxal (nmol/L, mean ± SD): G1: 51.45 ± 79.23 G2: 75.07 ± 208.62 G1, n per quartile (nmol/L) Q1 (< 16.86): 26 Q2 (16.86–49.56): 71 Q3 (≥49.57): 40 G2, n per quartile (nmol/L) Q1 (< 16.86): 70 Q2 (16.86–49.56): 137 Q3 (≥ 49.57): 70 Pyridoxic acid (nmol/L, mean ± SD): G1: 50.57 ± 87.25 G2: 67.08 ± 167.10 G1, n per quartile (nmol/L) Q1 (< 14.37): 22 Q2 (14.37–47.42): 77 Q3 (≥ 47.43): 38 G2, n per quartile (nmol/L): Q1 (< 14.37): 68 Q2 (14.37–47.42): 139 Q3 (≥ 47.43): 70 Pyridoxine (nmol/L, mean ± SD): G1: 0.03 ± 0.19 G2: 3.63 ± 30.76 Method: Serum samples were taken using BDTM Vacutainer 3.5 mL serum separator tubes with no anticoagulants or preservatives and centrifuged within 30 min	Cono‐truncal heart defects, n: G1: 140 G2: 0	Model 1: Adjusted for maternal race and age	Model 1: Pyridoxal‐5‐phosphate: OR (95% CI): Q1: 0.7 (0.4–1.2) Q2: Ref Q3: 0.7 (0.4–1.3) Linear trend: p = 0.93 Pyridoxal: OR (95% CI): Q1: 0.7 (0.4–1.3) Q2: Ref Q3: 1.0 (0.6–1.7) Linear trend: p = 0.28 Pyridoxic acid: OR (95% CI): Q1: 0.6 (0.3–1.1) Q2: Ref Q3: 0.9 (0.5–1.5) Linear trend: p = 0.29
Czeizel et al., 2004 Hungarian Case–Control Surveillance of Congenital Abnormalities Hungary CC 17 years Public	N = 70,074 Population sampled: General population G1 (cases): Women with newborns or foetuses with congenital abnormalities (CA) G2 (controls): Women with infants without CA Exclusion criteria: NR % loss to follow‐up: 13 (n = 9,080) n = 60,994 Gr1: 22,843 Gr2: 38,151 Sex (% women): 100 Age (y, means ± SD): Gr1: 25.5 ± 5.3 Gr2: 25.5 ± 4.9	Cases are selected from the Hungarian Congenital Abnormality Registry. It is mandatory for physicians to register CA in the registry	B6 supplement, n (%): G1: 2013 (8.8) G2: 4086 (10.7) General dose of B6 was 60 mg/day as treatment for nausea and vomiting during pregnancy Mean duration of treatment: G1: 2.5 months G2: 2.8 months Method: B6 data from antenatal care logbook and/or medical records. Or from questionnaire about supplementation use during pregnancy	CA, n: G1: 22,843 G2: 0	Model 1: Adjusted for birth order, maternal age and employment status, nausea/vomiting during the second and third months of pregnancy	Model 1: B6 supplementation the entire pregnancy G1: POR (95% CI) for total CA: 0.8 (0.7–0.9) G2: POR (95% CI) for total CA: Ref B6 supplementation the first month of pregnancy G1: POR (95% CI) for total CA: 0.7 (0.6–0.8) G2: POR (95% CI) for total CA: Ref B6 supplementation the second to third month of pregnancy G1: POR (95% CI) for total CA: 0.8 (0.7–0.9) G2: POR (95% CI) for total CA: Ref Medically B6 supplementation without folic acid G1 (n = 765): POR (95% CI) for total CA: 0.89 (0.80–0.98) G2 (n = 1645): POR (95% CI) for total CA: Ref
Baker et al. ( 1977 ) NR USA Matched CC 1 year Private	N = 100 Population sampled: General population, mothers of a child birthed at term Exclusion criteria: Supplemental vitamins, hard drugs, signs of malnutrition, C‐section n = 100 G1 (low birth weight (< 2500 g): 50 G2 (normal birth weight (> 2,500 g): 50 Sex (% women): 100 Age: (y, median): G1: 28 G2: 27	Birth weight measured at birth	Plasma B6 concentration (ng/mlL mean ± SD): Gr1: 22.3 ± 1.51 Gr2: 21.8 ± 1.50 Method: Blood samples from antecubital vein 30 min. post‐partum	Low birth weight, n: G1: 50 G2: 0	NA	No significant differences in Vit B6 concentration between G1 and G2

Mean ± SD, unless specified otherwise.

BMI: body mass index; CC: case–control; CI: confidence interval; CHD: congenital heart defects; CrSe: cross sectional; FFQ: food frequency questionnaire; Gx: group; LLD: longitudinal limb deficiency; TDL: trans limb deficiency; IUGR: intrauterine growth retardation; NA: not applicable; NR: not reported; OR: odds ratio; PA: pyridoxic acid PC: prospective cohort; POR: prevalence odds ratio; PLP: pyridoxal phosphate; PL: pyridoxal; Qx: quartile or quintile; SGA: small for gestational age; SD: standard deviation; y: year.