What is the appropriate folic acid supplementation regimen for pregnant women in the third trimester, including dosage for low‑risk and high‑risk patients?

Folic Acid in the Third Trimester

For low-risk women, continue 400 μg (0.4 mg) folic acid daily throughout the third trimester and postpartum period, especially during breastfeeding; for high-risk women who took 4-5 mg daily before conception through 12 weeks gestation, reduce to 400 μg (0.4 mg) daily for the remainder of pregnancy after 12 weeks. 1

Low-Risk Women: Standard Third Trimester Dosing

• Continue 400 μg (0.4 mg) folic acid daily from 12 weeks gestation through the entire third trimester to meet ongoing fetal growth and developmental needs, even though this dose is no longer required specifically for neural tube defect prevention (which is only relevant through 12 weeks). 1

• Maintain this 400 μg daily dose through 4-6 weeks postpartum or as long as breastfeeding continues, as nutritional demands remain elevated during lactation. 2, 3

• This recommendation applies to all women without specific risk factors for neural tube defects, including those with no prior affected pregnancies, no personal or family history of neural tube defects, no diabetes, and not taking high-risk medications. 1

Evidence Supporting Continued Supplementation

• Continued folic acid supplementation in the second and third trimesters prevents the physiologic decline in maternal folate status and rise in homocysteine that otherwise occurs in late pregnancy. 4

• A randomized controlled trial demonstrated that women who continued 400 μg folic acid daily from 14-36 weeks gestation maintained stable serum folate (45.7 nmol/L at 14 weeks vs. stable levels at 36 weeks), while unsupplemented women experienced a significant decline (45.7 to 19.5 nmol/L; P < 0.001). 4

• The same trial showed that continued supplementation prevented the increase in plasma homocysteine that occurred in unsupplemented women (6.6 to 7.6 μmol/L; P < 0.001), with homocysteine remaining lower in supplemented women throughout the third trimester (5.45 vs 7.40 μmol/L; P < 0.05). 5

• Cord blood folate concentrations are significantly higher when mothers continue folic acid supplementation (red blood cell folate 1993 vs 1418 nmol/L; P = 0.001), suggesting improved fetal folate status. 4

High-Risk Women: Critical Dose Reduction After First Trimester

• Women who took 4-5 mg daily before conception and through 12 weeks gestation must reduce to 400 μg (0.4 mg) daily starting at 13 weeks and continue this lower dose throughout the second and third trimesters. 1, 6

• This dose reduction after 12 weeks is crucial to minimize potential adverse effects of long-term high-dose folic acid, particularly the risk of masking vitamin B12 deficiency-related neurological symptoms that could lead to irreversible neurologic damage. 1, 6

• High-risk women include those with: 1, 2

  • Prior pregnancy affected by neural tube defect
  • Personal history of neural tube defect
  • First-degree relative with neural tube defect
  • Type 1 diabetes mellitus
  • Obesity (BMI ≥ 30 kg/m²)
  • Taking antiepileptic medications (valproic acid, carbamazepine)

Rationale for Dose Reduction

• The 4-5 mg dose is only necessary during the critical period of neural tube closure (first 28 days after conception through 12 weeks gestation), when major organ development occurs. 1, 6

• After 12 weeks, the neural tube is fully closed and organogenesis is complete, so the high dose provides no additional benefit and only increases risk. 1

• Continuing high-dose folic acid beyond 12 weeks does not prevent any additional birth defects and may increase the risk of masking B12 deficiency. 1

Special Populations in Third Trimester

Women with Obesity or Diabetes

• Women with BMI > 30 kg/m² or diabetes who took 4-5 mg daily through 12 weeks should reduce to 400 μg daily for the remainder of pregnancy, but may continue higher doses (4-5 mg daily) postpartum if still obese or diabetic. 3

Women with History of Miscarriage

• Homocysteine concentrations are significantly higher in the third trimester in women with a history of miscarriage compared to those without (8.15 vs 6.38 μmol/L; P < 0.01), suggesting that continued folic acid supplementation may be particularly important in this population. 5

Critical Safety Considerations

• Total daily folate consumption should not exceed 1,000 μg (1 mg) unless prescribed by a physician, specifically to avoid masking vitamin B12 deficiency. 1

• Removing folic acid supplementation after 12-16 weeks gestation significantly reduces serum unmetabolized folic acid (UMFA) concentrations at 36 weeks (0.6 vs 1.4 nmol/L; P = 0.03), which may be beneficial given concerns about excessive folic acid intake. 7

• Do not prescribe or continue 4-5 mg doses to any woman beyond 12 weeks gestation—this provides no additional benefit and increases risks. 1

Common Pitfalls to Avoid

• Do not stop all folic acid supplementation after 12 weeks in low-risk women—continue 400 μg daily throughout pregnancy for fetal growth needs and to prevent the physiologic decline in folate status. 1, 4

• Do not continue 4-5 mg beyond 12 weeks gestation in high-risk women—reduce to 400 μg to minimize long-term high-dose risks. 1, 6

• Do not discontinue supplementation immediately postpartum—continue 400 μg daily for 4-6 weeks postpartum or as long as breastfeeding continues, as nutritional demands remain elevated. 2, 3

• Do not prescribe multiple prenatal vitamins to achieve higher folic acid doses—use single folic acid tablets in addition to one multivitamin to reach the desired dose. 2