Hungarian Prenatal Vitamin Trial

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Czeizel AE and Dudas I. "Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation". The New England Journal of Medicine. 1992. 327(26):1832-1835.
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Clinical Question

Among women planning to become pregnant, does administration of a periconceptual multivitamin reduce neural tube defects when compared a trace-element supplement?

Bottom Line

Among women planning on becoming pregnant, administration of a periconceptual multivitamin reduces neural tube defects when compared to administration of a trace-element supplement.

Major Points

The 1991 MRC Vitamin Study[1] demonstrated that folic acid was effective in secondary prevention in women with prior pregnancy complicated with a neural tube defect (spinal bifida, anencephaly, and encephalocele)[2] when compared to supplementation with vitamins A, D, B1, B2, B6, C, and nicotinamide. Whether a folic acid-containing multivitamin could be used as primary prevention for neural tube defects was unknown.

Published in 1992, this study by Czeizel and colleagues randomized women planning on becoming pregnant to supplementation with a multivitamin including folic acid (folate) 0.8 mg or a trace elements supplement. 4,704 pregnancies occurred in this trial. The group assigned to the multivitamin had no neural tube defects while the trace-element group had 6 births with neural tube defects (2.6/1,000 pregnancies). This reduction was statistically significance. There was also a significant reduction in all congenital malformations (13.3 vs. 22.9/1,000 pregnancies), though this was primarily driven by reduction in neural tube defects.

A 2010 Cochrane analysis[2] found that folic acid (with or without vitamins and minerals) prevents neural-tube defects without side effects. There was not enough evidence to assess the role of folic acid in preventing other birth defects.

Guidelines

USPSTF Prenatal folic acid to prevent neural tube defects (Adapted, 2009)[3]

  • All women planning or able to be pregnant take a supplement with folic acid 0.4-0.8 mg PO qday (grade A)

Design

  • Double blind, randomized controlled trial at an unclear amount of centers
  • N=4,704 pregnancies
    • Multivitamin (n=2,394 pregnancies)
    • Trace-element (n=2,310 pregnancies)
  • Setting: Not explicitly stated but presumably centers in Hungary
  • Enrollment: 1984-1991
  • Mean follow-up: Through delivery
  • Analysis: Intention-to-treat except women who conceived bore the end of the first month who were considered to have no receipt of the supplement
  • Primary outcome: Neural tube defects

Population

Inclusion Criteria

  • Women voluntarily participating in the Hungarian Family Planning Program trial
  • In the first four years of the trial only:
    • Age <35 years
    • No previous unwanted pregnancy, not including abortions

Exclusion Criteria

  • Delayed conception or infertility
  • Pregnancy

Baseline Characteristics

From the multivitamin group.

  • Demographics: Age 27 years
  • Pregnancy data: First pregnancy 95%

Interventions

  • Eligible women had a "checkup of reproductive health" by a nurse then were randomized to a group:
    • Multivitamin - Elevit Pronatal brand tablet PO qday for at least one month before planned conception
      • Contained:
        • Vitamin A (6,000 units until 1989 then 4,000 units)
        • Vitamin B1 (thiamine) 1.6 mg
        • Vitamin B2 (riboflavin) 1.8 mg
        • Nicotinamide 19 mg
        • Vitamin B6 (pyridoxine) 2.6 mg
        • Vitamin B12 (cobalamin) 4 ug
        • Vitamin C 100 mg
        • Vitamin D 500 units
        • Vitamin E 15 mg
        • Calcium pantothenate 10 mg
        • Biotin 0.2 mg
        • Folic acid (folate, vitamin B9) 0.8 mg
        • Magnesium 100 mg
        • Iron 60 mg
        • Copper 1 mg
        • Manganese 1 mg
        • Zinc 7.5 mg.
    • Trace element - One tablet PO qday for at least one month before planned conception
      • Contained:
        • Copper 1 mg
        • Manganese 1 mg
        • Zinc 7.5 mg
        • Vitamin C 7.5 mg
  • All participants had "protection of very early pregnancy" followed by prenatal care
  • Both groups were asked to stop taking other vitamins during the study
  • Groups were followed q3months, pregnancies were confirmed with ultrasound and serum pregnancy test
  • Groups continued their tablets until the third month of gestation

Outcomes

Presented as multivitamin vs. trace element.

Primary Outcome

Neural tube defect
0 vs. 6 occurrences (P=0.029)
Rate: 0 vs. 2.6/1000 pregnancies

Secondary Outcomes

Congenital malformation
13.3 vs. 22.9/1,000 pregnancies (P=0.02)
Type of congenital malformation
Neural tube defect: 0 vs. 6 occurrences (P=0.029)
Congenital hydrocephalus: 0 vs. 2 occurrences
CV malformations: 6 vs. 9 occurrences
Cleft palate: 0 vs. 2 occurrences
Cleft lip: 4 vs. 3 occurrences
Hypospadias: 1 vs. 1 occurrences
Urinary obstruction: 1 vs. 2 occurrences
Postural abnormality: 2 vs. 0 occurrences
Limb reduction: 2 vs. 0 occurrences
Foramina parietale permagna: 0 vs. 2 occurrences
Exomphalos and gastroschisis: 1 vs. 1 occurrence
Facial hemangioma: 3 vs. 1 occurrence
Down's syndrome: 3 vs. 3 occurrences
Other: 4 vs. 7 occurrences

Additional Analyses

Pregnancy outcome determined
99% of all women who became pregnant
"Uninformative pregnancy"
First trimester termination: 4 vs. 4 pregnancies
Early or intermediate fetal death: 286 vs. 254 pregnancies
Including miscarriages and ectopic pregnancies.

Criticisms

  • Calcium pantothenate/pantothenic acid (which was included in the multivitamin) may have played a role in reduction of neural tube defects as well[4]
  • Use of the antifolate TMP-SMX was not reported[4]
  • Incomplete reporting of baseline characteristics

Funding

  • Not explicitly stated
  • Author's disclosures not reported

Further Reading

  1. MRC Vitamin Study group. "Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study." The Lancet. 1991;338(8760):131-137.
  2. 2.0 2.1 De-Regil LM, et al. "Effects and safety of periconceptional folate supplementation for preventing birth defects." Cochrane Database of Systematic Reviews. 2002;6(10):CD007950.
  3. USPSTF writers. "Folic acid to prevent neural tube defects." Uspreventitiveservicestaskforce.org. Published 2009-05. Accessed 2014-09-08.
  4. 4.0 4.1 Multiple authors. "Correspondence: Vitamins to prevent neural-tube defects." The New England Journal of Medicine. 1993;328:1641-1642.