TABLE 2.
Pregnancy and birth health outcomes associated with FA intake1
| Outcomes, specific outcomes | Study type | FA dose | Timing of FA supplementation | Direction of effect | Ref. |
|---|---|---|---|---|---|
| Birth outcomes | |||||
| BW, LBW, SGA, preterm | Cochrane review | • No FA• FA supplements (with or without other micronutrients) | • During pregnancy (studies with periconceptional FA supplementation excluded) | No association of FA supplementation with BW or with risk of preterm birth, stillbirths/neonatal deaths, or LBW | (63) |
| SGA | Meta-analysis, systematic review | • No FA (15% of women)• FA taken (85%) in dosages of either: 400 µg/d (95.5%), 5000 µg/d (3.5%), or other dosage (1%) | • Preconceptional (25.5%)• Postconceptional (74.5%) | Reduced risk of SGA if supplemented preconceptionallySGA <10th centile (adjusted OR: 0.80; 95% CI: 0.71, 0.90; P < 0.01)SGA <5th centile (adjusted OR: 0.78; 95% CI: 0.66, 0.91; P < 0.01). | (64) |
| LBW (BW <5th centile) | Meta-analysis, systematic review | • No FA (15% of women)• FA taken (85%) in dosages of either: 400 µg/d (95.5%), 5000 µg/d (3.5%), or other dosage (1%) | • Preconceptional (25.5%)• Postconceptional (74.5%) | Preconception low-dose FA supplement:LBW adjusted OR: 0.75; 95% CI: 0.61, 0.92; P = 0.006Postconception: not significant | (64) |
| SGA for height, SGA for weight | Population-based multicenter cohort study | • No FA use• FA use ≤1000 µg/d• FA use >1000 µg/d | • Periconceptional (≥1 mo of FA use between 3-mo preconception and end of first trimester) | Increased risk of SGA for height for women with FA use >1000 μg/d | (65) |
| Embryonic growth | Prospective cohort study | • No FA use• FA use 400 µg/d | • Periconceptional• Postconceptional | No or postconceptional FA use negatively associated with crown-rump-length and embryonic volume | (66) |
| LBW, SGA | Prospective cohort study | • No FA use• FA use 400 µg/d | • Periconceptional• Preconceptional• Postconceptional | Periconceptional FA intake (until end of first trimester) associated with 20% lower risk of LBW and 10% lower SGA risk | (67) |
| SGA, LGA | Prospective cohort study | 400 µg/d | • Periconceptional only• Periconceptional + second trimester• Periconceptional + third trimester• Periconceptional + second + third trimesters | FA supplement use beyond first trimester (group of periconceptional + second + third trimester FA use) associated with increased risk of LGA compared with FA supplement in periconceptional time only; RR: 1.87; 95% CI: 1.21, 2.87 | (68) |
| Childhood disease outcomes—asthma and allergic diseases | |||||
| Asthma | Meta-analysis, systematic review | • No FA use• FA use | • Periconceptional or first trimester• Second + third trimesters• Any trimester/throughout pregnancy | No association between first trimester FA use and risk of asthma; conflicting results for second and third trimester FA use and asthma | (69) |
| Asthma and allergic disease | Review including 10 prospective cohort studies | Different doses | • Periconceptional• Preconceptional• Postconceptional | Majority of studies support no association of maternal FA intake and development of childhood asthma and allergy; limited evidence on dose-response relation between FA and risk of asthma or allergic diseases | (70) |
| Asthma, wheezing, dermatitis—allergic diseases | Prospective cohort study | Median (ranges) of FA:• early pregnancy 700 µg/d (43–5500 µg/d)• late pregnancy 300 µg/d (27–5895 µg/d) | • Early pregnancy (<16 weeks of gestation)• Late pregnancy (30–34 weeks of gestation) | FA use in late pregnancy associated with 26% increased risk of asthma at 3.5 y of age, but not at 5.5 y of age; pre- and periconceptional FA use not associated with asthma risk | (71) |
| Wheeze, asthma, atopic dermatitis, eczema, allergic sensitization | Prospective cohort study | • No FA use• FA use | • Periconceptional/first trimester• Throughout pregnancy• Others (e.g., third trimester only) | No association between FA use during pregnancy and increased risk of developing eczema, atopic dermatitis, allergic sensitization, wheeze, or asthma | (72) |
| Childhood disease outcomes—autism | |||||
| Autism/ASD/neurodevelopment | Systematic review (22 studies) | Different doses | • Periconceptional• Preconceptional• Postconceptional | Fifteen studies showed beneficial effect, 6 studies reported no significant findings, 1 prospective cohort study reported increased risk of delayed psychomotor development in 7-y-old children of mothers who took >5000 µg/d FA during pregnancy | (73) |
| ASD | Case-control study | • FA use (400 µg/d)• Multivitamin use• FA and/or multivitamin use (with FA 400 µg/d) | • Before pregnancy (i.e., 540–271 d before birth)• During pregnancy (i.e., 270 d before birth up to date of childbirth) | Lower risk of ASD in children of mothers exposed to FA and/or multivitamin supplements before and/or during pregnancy (adjusted RR: 0.27–0.56); no significant risk reduction in offspring of parents with psychiatric condition; no risk reduction if women took vitamin supplements before pregnancy for treatment of vitamin deficiency | (74) |
| ASD | Case-control study | • No FA (28% of women)• FA 400 µg/d (72%) | • Periconceptional (4 wk before to 8 wk after conception) | Reduced risk of ASD (adjusted OR: 0.61; 95% CI: 0.41, 0.90) in children (mean age 6.4 y) of mothers with periconceptional FA | (75) |
| ASD | Case-control study | Total FA intake summed based on data including dose, brand, frequency of supplement, and fortified food intake | • 3 mo before pregnancy and throughout each month of pregnancy | Lower risk (OR: 0.62; 95% CI: 0.42, 0.92) of ASD in children of women who took ≥600 µg/d compared with <600 µg/d in first month of pregnancy; decreasing OR with increasing FA intake (0, ≤500, 500–<800, 800–1000, >1000 µg/d) | (76) |
| Childhood disease outcomes—metabolism, insulin resistance, and obesity | |||||
| Obesity/insulin resistance (HOMA-IR) | Systematic review (5 human and 9 animal studies) | In human studies/RCTs:• No FA use• FA 400 µg/dFolate status in observational studies | During pregnancy | Inconsistent findings; animal studies showed overall protective effect of FA on obesity + insulin resistance; human studies reported decreased risk of metabolic syndrome, and higher HOMA-IR with FA supplementation, and no or a positive association between late-pregnancy maternal folate status and HOMA-IR | (77) |
| HOMA-IR | Cluster RCT | • No FA• FA 400 µg/d• FA 400 µg/d + iron• FA 400 µg/d + iron + zinc• FA 400 µg/d in multimicronutrient supplement | Start of supplementation in early pregnancy | No association between maternal plasma folate concentration and HOMA-IR in 6- to 8-y-old children | (78) |
| HOMA-IR | Prospective cohort study | 500 µg/d | Start of supplementation at 18 weeks of gestation | Higher maternal folate status predicted higher adiposity (fat mass and body fat percentage) and insulin resistance (HOMA-IR) in 6-y-old children; highest HOMA-IR if mothers had high folate and low vitamin B-12 status | (79) |
| Body composition | Population-based birth cohort study | • No FA use• FA use | During pregnancy: 18 and 32 weeks of gestation | No association between maternal FA supplementation during pregnancy and body composition in 9-y-old children | (80) |
1ASD, autism spectrum disorder; BW, birthweight; FA, folic acid; LBW, low birthweight; LGA, large-for-gestational-age; RCT, randomized controlled trial; Ref., reference; SGA, small-for-gestational-age.