Folic Acid Supplementation: What is New? Fetal, Obstetric, Long-Term Benefits and Risks

Figures & data

Figure 1.  Prevalence of neural tube defects (anencephaly and spina bifida) before and after mandatory folic acid fortification, by maternal race/ethnicity – 19 population-based birth defects surveillance programs, USA, 1995–2011.

Contributing programs are based in Arkansas, Arizona, California, Colorado, Georgia, Illinois, Iowa, Kentucky, Maryland, New Jersey, New York, North Carolina, Oklahoma, Puerto Rico, South Carolina, Texas, Utah, West Virginia and Wisconsin.

^†95% confidence interval.

NTD: Neural tube defect.

Taken from Center for Disease Control and Prevention [7].

Table 1.  International Guidelines for Preventive Folic Acid Dosage in Pregnancy American Congress of Obstetrics and Gynecology Recommendation.

Level of evidence	Low-risk women	400 μg/day
Level A^†	High-risk women/women who have had NTD in previous pregnancy	4 mg/day
	MSAF evaluation is an effective screening test for NTDs and should be offered to all pregnant women
Level B^‡	Women with elevated serum AFP	Should have a specialized ultrasound examination to further assess the risk of NTDs
	Fetus with an NTD	Should be delivered at a facility that has personnel capable of handling all aspects of neonatal complications
Level C^§	Women capable of becoming pregnant	400 μg/day
	The ideal dose of folic acid has not been appropriately evaluated in prospective clinical trials
	Route of delivery for the fetus with an NTD	Should be individualized due to the lack of data indicating that any one dosage provides a superior outcome

† Level A: The following recommendations are based on good, consistent scientific evidence.

‡ Level B: The following recommendations are based on limited or inconsistent scientific evidence.

§ Level C: The following recommendations are based primarily on consensus and expert opinion.

AFP: Alfa fetoprotein; MSAF: Maternal serum alfa fetoprotein; NTD: Neural tube defect.

Data taken from [14].

Table 2.  Royal College of Obstetrics and Gynecologists Recommendation.

All pregnant women	400 μg/day preconception until 12th week of pregnancy
High-risk pregnant women^†	5 mg/day

† High-risk women:

– History of neural tube defect in previous pregnancy

– History of neural tube defect in pregnant woman or in her partner

– Using certain epilepsy medications

– Diabetes or celiac disease

– BMI 30 or more

– Sickle cell anemia or thalassemia

Data taken from [15,16].

Table 3.  Society of Obstetricians and Gynecologists of Canada Recommendation.

Risk category	Recommendation
Low risk group^†	0.4 mg/day: beginning at least 2–3 months before conception, continuing throughout the pregnancy and for 4–6 weeks postpartum or as long as breastfeeding continues
Moderate risk group^‡	1.0 mg/day: beginning at least 3 months before conception, continuing until 12 weeks’ gestational age. From 12 weeks, throughout the pregnancy, and for 4-6 weeks postpartum or as long as breastfeeding continues, daily multivitamin supplementation with 0.4–1.0 folic acid is recommended
Increased/high risk group^§	4.0 mg/day: beginning at least 3 months before conception, continuing until 12 weeks’ gestational age. From 12 weeks’ gestational age, continuing throughout the pregnancy, and for 4-6 weeks postpartum or as long as breastfeeding continues, daily multivitamin supplementation with 0.4–1.0 folic acid is recommended

Personal positive or family history of other folate-sensitive congenital anomalies (limited to specific anomalies for cardiac, limb, cleft palate, urinary tract, congenital hydrocephaly).

Family history of NTD in a first or second-degree relative. Maternal diabetes (type I or II) with secondary fetal teratogenic risk. Measurement of red blood cell folate levels could be part of the preconception evaluation to determine the multivitamin and folic acid supplementation dose strategy (1.0 mg with RBC folate< 906 and 0.4 to 0.6 mg with RBC folate >906) with a multivitamin).

Teratogenic medications with secondary fetal teratogenic effects by folate inhibition via anticonvulsant medications (carbamazepine, valproic acid, phenytoin, primidone, phenobarbital), metformin, methotrexate, sulfasalazine, triamterene, trimethoprim (as in cotrimoxazole), and cholestyramine.

Maternal GI malabsorption conditions secondary to co-existing medical or surgical conditions that have been shown to result in decreased RBC folate levels (Crohn’s or active Celiac disease, gastric bypass surgery, advanced liver disease, kidney dialysis, alcohol overuse).

† LOW risk group: women or their male partners with no personal or family history of health risks for folic acid sensitive birth defects.

‡ MODERATE risk group: women with the following personal or co-morbidity scenarios (1–5) or their male partner with a personal scenario (1 and 2).

§ INCREASED/HIGH risk group: women or their male partners with a personal NTD history or a previous neural tube defect pregnancy.

Data taken from [17].

Table 4.  International Recommendations for Folic Acid in Pregnant Women with Epilepsy.

Society	Recommendation	Ref.
ACOG	4 mg/day	[26]
NICE	5 mg/day	[27]
SOGC	5 mg/day	[28]

Table 5.  Folic acid supplementation timing and pregnancy outcomes.

Outcome/time	Preconception	First trimester	Second trimester	Third trimester
NTD	^‡	^‡	^§	^§
Preeclampsia	^†	^†	^‡	^†
Anemia	^†	^†	^†	^†
FGR	^‡	^‡	^†	^†
Autism	^†	^†	^§	^§

† Beneficial.

‡ Significant benefit.

§ No benefit.

FGR: Fetal growth restriction; NTD: Neural tube defect.

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