Reproductive Health · 1992
Czeizel & Dudas: Folic Acid Prevents First-Occurrence Neural Tube Defects
After the MRC Vitamin Study reported in 1991 that periconceptional folic acid reduced recurrence of neural tube defects in women with a previously affected pregnancy, a gap remained. Recurrence was rare enough that secondary prevention addressed only a small fraction of all NTD cases. Most were first occurrences, in women who had no warning from a prior pregnancy and no specific reason to take supplementary folate. Whether folic acid could prevent these first-occurrence defects had never been tested in a properly controlled trial.
Andrew Czeizel, a Hungarian geneticist working in Budapest, and his co-investigator Istvan Dudas designed a randomized trial specifically for this group. Women planning a first pregnancy were enrolled through family planning clinics across Hungary and assigned to receive either a folic acid-containing multivitamin supplement or a trace-element preparation without folate. Periconceptional use meant women began supplementation before conception and continued through the first weeks of pregnancy, covering the critical window of neural tube closure.
Zero neural tube defects occurred among the infants of women in the folic acid group. Six cases of spina bifida or anencephaly occurred in the control group. The difference was large enough, and the biological rationale strong enough, that the trial was stopped early. No sample size gives a zero, and the result attracted immediate attention from reproductive epidemiologists and public health officials who had been watching for exactly this evidence.
The Czeizel and Dudas paper appeared in the New England Journal of Medicine in December 1992. Together with the MRC recurrence trial, it gave regulators the two-sided evidence base they needed: folic acid prevented NTDs both in women at elevated recurrence risk and in the general population of women entering their first pregnancy. The mechanism, impaired folate-dependent methionine and thymidylate synthesis during neural tube closure around days 21 to 28 post-conception, was already understood; what had been missing was the clinical proof.
Following recommendations from the CDC and the US Public Health Service that dated to 1992, the United States mandated folic acid fortification of enriched grain products in 1998. Surveillance data in the years after fortification showed the prevalence of spina bifida and anencephaly in the US fell by roughly a third. Several dozen countries adopted similar fortification programs over the following two decades, making it one of the more consistently replicated successes in micronutrient public health policy.
Key People
- Andrew Czeizel — Hungarian geneticist who led the randomized primary-prevention trial
- Istvan Dudas — Co-investigator on the Budapest folic acid trial
- Nicholas Wald — Led the 1991 MRC recurrence trial that set the stage for Czeizel's work
N Engl J Med. 1992;327(26):1832-1835
Related landmarks
- 1991 · MRC Vitamin Study: Folic Acid Prevents Neural Tube Defect Recurrence (Reproductive Health)
- 1995 · Collaborative Eclampsia Trial: Magnesium Sulfate for Eclampsia (Reproductive Health)
- 1997 · Dolly the Cloned Sheep (Reproductive Health)
- 2002 · Magpie Trial: Magnesium Sulfate for Pre-eclampsia (Reproductive Health)