Does folic acid before pregnancy prevent birth defects?

What the trials found

A 2015 Cochrane review pooled 5 trials with 7,391 women. Of them, 2,033 had had a pregnancy with a neural tube defect before, and 5,358 had not.^[1] Daily folic acid, alone or with other vitamins and minerals, lowered the risk of a neural tube defect: risk ratio 0.31, from 6,708 births. The review rated this evidence as high quality.^[1] For women who had had an affected pregnancy, the risk ratio for another one was 0.34, from 1,846 births.^[1]

Two large trials:

• In the British MRC Vitamin Study, 1,817 women who had had an affected pregnancy took folic acid, other vitamins, both or neither. Folic acid prevented 72% of neural tube defects (relative risk 0.28). The other vitamins had no clear effect.^[3]
• In a Hungarian trial, women who planned a pregnancy took a multivitamin with 0.8 mg of folic acid or a trace element tablet, from at least 1 month before conception. There were 6 neural tube defects in 2,052 pregnancies in the trace element group and none in 2,104 pregnancies in the vitamin group.^[4]

Dose and timing

In the Cochrane review, the effect did not differ between 400 µg a day and higher doses, or between folic acid alone and folic acid with other vitamins.^[1] In 2023, the US Preventive Services Task Force found high certainty of a substantial net benefit. It recommends 400 to 800 µg of folic acid a day for everyone who plans to or could become pregnant.^[2] WHO recommends 400 µg a day from the moment a woman starts trying to conceive until 12 weeks of pregnancy.^[5] The Task Force advises starting at least 1 month before conception and continuing for the first 2 to 3 months of pregnancy.^[6]

Timing matters because the neural tube closes 21 to 28 days after conception, and about half of pregnancies in the US are not planned.^[6] Red blood cell folate rises slowly: in a trial in young women, it was still rising after 24 weeks of 400 µg a day.^[7]

After an affected pregnancy

WHO says that women who have had a pregnancy with a neural tube defect should be told about the risk of another one. They should be offered 5 mg of folic acid a day.^[5] Other experts advise 4,000 to 5,000 µg a day from at least 1 to 3 months before conception until 2 and a half to 3 months after. These doses are above the upper limit and are taken only under medical care.^[6]

Why it may work

Folate is needed to make DNA, and the cells of an embryo divide fast. The exact way folic acid prevents neural tube defects is not known.^[6]

Food fortification

Since the US began adding folic acid to enriched grain in 1998, neural tube defects have fallen by 28%.^[6] A 2017 review for the Task Force found that studies done before fortification showed protection from folic acid supplements. Newer studies, done after 1998, did not show it consistently, but they may have errors in how women remembered what they took.^[8]

Other outcomes

The 2015 Cochrane review found no clear effect on cleft lip, cleft palate, heart defects or other birth defects, and no clear difference in miscarriages.^[1] A 2013 Cochrane review of 31 trials with 17,771 women looked at folic acid taken during pregnancy. It found no effect on preterm birth or stillbirth, a mean birthweight 136 g higher, and fewer cases of megaloblastic anemia (risk ratio 0.21).^[9]

Women with an MTHFR gene variant

Women with the MTHFR 677C>T variant make less of the active form of folate and may have a higher risk of neural tube defects. The US Centers for Disease Control and Prevention still recommends 400 µg of folic acid a day for them, not 5-MTHF. This dose helps prevent neural tube defects in them too.^[6] See Is methylfolate better than folic acid?

Who should ask first

Women who take medicines for epilepsy should ask their doctor, because these medicines lower folate and folate may lower their level.^[6] So should women who had an affected pregnancy, because the higher dose is above the upper limit.^[6]