Prenatal Primary Prevention of Mental Illness by Micronutrient Supplements in Pregnancy
Abstract
The Developmental Context of Prenatal Prevention
Possible Strategies for Prenatal Prevention and their Investigation
Method
Type of Trial | Subjects | Region or Country | Dose or Level and First Timing During Gestation | Effect | Limitations |
---|---|---|---|---|---|
Folic acid | |||||
Prospective, randomized (25) | 311 women | Europe | 400 μg of 5-methyltetrahydrofolate compared with placebo at 20 weeks | Decreased reaction time with distractor at 8.5 years (d′=0.32) | 130 of 311 children studied; no clinical ratings |
Prospective, observational (26, 27) | 3,210 women | Netherlands | ≥400 μg of folic acid within first 10 weeks’ gestation compared with no or later use | CBCL problems at 18 and 36 months; top 17th percentile (odds ratio=1.45, 95% CI=1.14–1.84) | Groups differ in sociodemographics; folic acid neonates 200 g heavier |
Prospective, observational (14) | 573 infants with facial clefts, 763 controls | Norway | ≥400 μg of folic acid within 9 weeks | Decreased facial clefts (odds ratio=0.61, 95% CI=0.39–0.96) | Not effective in cleft palate without cleft lip |
Prospective, randomized (15) | 1,817 women, prior neural tube defect | U.K., Europe, Israel, Australia, Canada, U.S.S.R. | 4 mg of folic acid at preconception until 12 weeks | Decreased neural tube defects (odds ratio=0.28, 95% CI=0.12–0.71) | No follow-up of other developmental traits |
Retrospective, observational (28) | 104,428 women | United States | 400 μg of folic acid at first trimester | Increased asthma at 4.5–6 years (odds ratio=1.2, 95% CI=1.1–1.3) | Data only from Medicaid claims |
Phosphatidylcholine | |||||
Prospective, randomized (29, 30) | 100 women | United States | 6,300 mg of phosphatidylcholine at 15 weeks | Increased 1-month EEG sensory gating; decreased 3.5-year CBCL attention (d′=0.59) and social (d′=0.79) problems | 50% attrition; parental CBCL reports only |
Prospective, observational (31) | 154 women | Canada | Plasma choline at 16 weeks’ gestation | Increased Bayley cognition score at 18 months (β=6.054, SE=2.283) | Healthy women in uncontrolled study |
Prospective, randomized (32) | 24 women | Canada | 550 mg compared with 100 mg of choline supplements in third trimester | Lower placental sFLT1, angiogenic factor in preeclampsia (d′=0.2) | Small study with no clinical outcome |
Prospective, observational (33) | 817 adults 33–55 years old | United States | Plasma trimethyl amine oxide, a choline bacterial metabolite | No increase in cardiac disease (odds ratio=1.03, 95% CI=0.71–1.52) | Patients were not supplemented |
Omega-3 fatty acids | |||||
Retrospective, observational (34) | 57 adult cases and 95 controls | United States | DHA acid >1.45% of fatty acids in second or third trimester | Increased schizophrenia spectrum (odds ratio=2.38, 95% CI=1.19–4.76) | Mercury from high fish diet not tested |
Prospective, randomized (24) | 543 women | Australia | 800 mg of fish oil at 20 weeks | Increased 7-year Conners ADHD score (d′=0.1) | Small effect in large sample |
Prospective, randomized (23) | 736 women and children | Denmark | 2.4 g of fish oil at 24–26 weeks | Decreased wheezing at 3–5 years (odds ratio=0.69, 95% CI=0.49–0.97) | Trend suggests vitamin D equally effective |
Prospective, randomized (35) | 2,399 women | Australia | 800 mg of fish oil at 20 weeks | Fewer gestations at <34 weeks (odds ratio=0.49, 95% CI=0.25–0.94) | More DHA induction (odds ratio=1.28, 95% CI=1.06–1.54) |
Vitamins A and D | |||||
Retrospective, observational (36) | 430 adult cases, 430 controls | Denmark | 25(OH)D3 <19.7 nM compared with >51 nM, low versus high quintiles | Increased schizophrenia (odds ratio=2.1, 95% CI=1.3–3.5) | Confounded with summer birth in high quintile |
Retrospective, observational (37) | 51 male adult cases, 4,616 in cohort | Finland | 2,000 IU of vitamin D in first year of life | Decreased schizophrenia (odds ratio=0.23, 95% CI=0.06–0.95) | Effects only in males |
Prospective, observational (38) | 68 cases in birth cohort of 4,334 | Netherlands | <25 nmol/L of vitamin D at 20 weeks | Increased autism spectrum at 6–9 years (odds ratio=2.42, 95% CI=1.09–5.07) | Small number of cases |
Retrospective, observational (39) | 186 cases in cohort of 1,194 | New Zealand | Vitamin D intake >724 IU (highest quartile) | Decreased recurrent wheeze at 3 years (odds ratio=0.39, 95% CI=0.25–0.62) | Infection-related wheeze, not new incident asthma |
Retrospective, observational (40) | 55 cases, 106 controls | United States | <30 μg/dL of vitamin A at second trimester | Increased schizophrenia (odds ratio=3.05, 95% CI=1.06–8.79) | Higher levels in more educated women |
Supplement | Effect | Model Mechanism |
---|---|---|
Folic acid | Increased neuronal development | Deficiency lowers Stat3, allowing increased neurite outgrowth (41) |
Imprinting of maternal genes | Biochemical role in one-carbon metabolism and methylation of DNA (42) | |
Phosphatidylcholine | Development of inhibitory neurotransmission | Activation of α7-nicotinic receptors induces the chloride transporter NKCC1, establishing a chloride gradient for GABA inhibition (43); effects blocked in CHRNA7 null mice (43, 44) |
Omega-3 fatty acids | Antiseizure effect in ketogenic diet but could also affect synapse formation in development | Accelerates inactivation and retards recovery of sodium and calcium channels in vitro, which decreases neuronal excitation (45) |
Reduces preterm birth | Reduces prostaglandin E2 and F2α in uterine decidual cells (46) | |
Vitamin D | Neuronal development | Interacts with Nurr1 to support development of dopamine neurons (47); activates low voltage (l-type) calcium channels to increase neurofilament phosphorylation (48) |
Results
Folic Acid and the Baby’s Risk for Mental Illness
Omega-3 Fatty Acids (Fish Oil)
Phosphatidylcholine
Vitamins D and A
Discussion
Intervention | Current Recommended Daily Allowance | Study Dose, Timing | Major Developmental Finding | Other Conditions | Known Adverse Effects |
---|---|---|---|---|---|
Folic acid | 400–800 μgb plus 200 μg from diet | 400 μg at preconception to 10 weeks’ gestation (27) | Decreased emotional problems (child) | Decrease in cleft lip, spina bifida | Infant wheezing increased |
Phosphatidylcholine | 3,150 mg (450 mg of choline) from diet | 6,300 mg at preconception to 16 weeks’ gestation (30) | Decreased social and attention problems (child) | Possible decrease in preeclampsia | Trimethylamine N-oxide cardiotoxicity (in men with cardiac disease) |
Omega-3 fatty acids (fish oil) | Up to 300 g of low mercury–containing fish per week | 2.4 g of fish oil daily at 24–26 weeks’ gestation for wheeze (23) | Increased risk for schizophrenia spectrum (adult) | Premature birth and infant wheezing decreased | Increased ADHD symptoms at 7 years |
Vitamins A and D | Supplement of 2,567 IUb of vitamin A and 600 IUb of vitamin D, plus amounts from diet and sunlight | 1,000 IU of vitamin D3 for infants up to 1 year of age, 2,000 IU in northern countries (37) | Decreased schizophrenia (adult) with both vitamins A and D | Infant wheezing decreased | Teratogenicity with vitamin A intake >8,000 IU (diet plus supplement) |
Principal Investigator, Country | Title | Type of Trial, Dose, Timing | Principal Outcome | Registry and Date |
---|---|---|---|---|
C. Grant, Australia | Randomized placebo-controlled study of vitamin D during pregnancy and infancy | Randomized; mothers receive 2,000 IU of vitamin D and infants receive 800 IU, compared with 1,000 IU and 400 IU for each | Infant 25(OH) vitamin D >75 nM at 6 months | Australian New Zealand Clinical Trials Registry, ACTRN12610000483055; 2010 |
M.C. Hoffman, United States | Choline supplementation during pregnancy: impact on attention and social withdrawal | Randomized; 9 g of phosphatidylcholine at 15 weeks | Child Behavior Checklist rating at 3.5 years | ClinicalTrials.gov, NCT03028857; 2017 |
J. Zhu, China | Effects of genomic and metabolomic variations of choline on risk of preterm birth and clinical outcomes in preterms | Prospective, observational; effects of plasma choline level during gestation | Preterm birth incidence | ClinicalTrials.gov, NCT02841813; 2016 |
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