Correspondence

Higher Rate of Multiple Births after Periconceptional Vitamin Supplementation

N Engl J Med 1994; 330:1687-1688June 9, 1994

Article

To the Editor:

Periconceptional supplementation with multivitamins including folic acid or with folic acid alone can reduce both the first occurrence and the recurrence of neural-tube defects1-3. We examined the effect of such supplementation on multiple births.

The Hungarian trial of periconceptional multivitamin supplementation was stopped in 1992, and the outcomes of the pregnancies were evaluated one year later1. The multivitamin supplement contained 12 vitamins, including 0.8 mg of folic acid, four minerals, and three trace elements; a control supplement contained three trace elements. Pregnancy was confirmed in 5502 women, and outcome could be evaluated in 5453. The rate of multiple births in the multivitamin group was higher than the rate in the trace-element group (Table 1Table 1Maternal Age, Parity, and Categories of Births in the Two Study Groups.). In the 1980s the rate of multiple births in Hungary as a whole was 2.2 percent. The multiple births were evaluated with respect to sex, placentation, anthropometric features, and genetic markers. The distribution of zygosity was comparable in the two study groups, and the demographic characteristics of the women in both groups were similar.

It is known that the use of ovulation-inducing drugs increases the rate of multiple births. Altogether, 180 of the 2421 women in the multivitamin group and 184 of the 2346 women in the trace-element group whose pregnancies ended in live births or stillbirths had been treated for infertility, mainly with clomiphene (7.4 percent vs. 7.8 percent, P = 0.60). The high rate of ovarian stimulation was explained by the diagnosis of anovulation or luteal insufficiency in the women who participated in the study4. Pregnancies resulting in multiple births were stratified according to whether or not the women had received clomiphene. Among the women who had not received clomiphene, 27 of 2261 women (1.2 percent) in the multivitamin group and 19 of 2190 (0.9 percent) in the trace-element group had multiple births, as compared with 19 of 160 women (11.9 percent) in the multivitamin group and 13 of 156 (8.3 percent) in the trace-element group among the women who had taken the drug. Thus, treatment with clomiphene does not explain the higher frequency of multiple births among the women in the multivitamin group.

Periconceptional multivitamin supplementation resulted in an absolute increase of 1.1 percent and a relative increase of 40.7 percent in multiple births. Multiple births, however, were not one of the outcomes related to the hypothesis that the trial was designed to test. Thus, this result, despite its statistical significance, may be due to chance.

Andrew E. Czeizel, M.D., D.Sc.
Julia Metneki, Ph.D.
Istvan Dudas, M.D.
National Institute of Hygiene, H-1966 Budapest, Hungary

4 References

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   Smithells RW, Sheppard S, Wild J, Schorah CJ. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 1989;2:498-499
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   Czeizel AE. Medical genetics in Hungary. J Med Genet 1988;25:2-8
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Citing Articles (21)

Citing Articles

1. 1

   Judith Lumley, Lyndsey Watson, Max Watson, Carol Bower, Judith Lumley. 2011. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. .
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2. 2

   Alice Rumbold, Philippa Middleton, Ning Pan, Caroline A Crowther, Alice Rumbold. 2011. Vitamin supplementation for preventing miscarriage. .
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3. 3

   Luz Maria De-Regil, Ana C Fernández-Gaxiola, Therese Dowswell, Juan Pablo Peña-Rosas, Luz Maria De-Regil. 2010. Effects and safety of periconceptional folate supplementation for preventing birth defects. .
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4. 4

   Tsunenobu Tamura, Mary Picciano, Michelle McGuire. 2009. Folate in Pregnancy and Lactation. , 111-131.
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5. 5

   2006. Folic acid, folinic acid, and calcium folinate. , 1432-1436.
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6. 6

   Alice Rumbold, Philippa Middleton, Caroline A Crowther, Alice Rumbold. 2005. Vitamin supplementation for preventing miscarriage. .
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7. 7

   Stein Emil Vollset, H??kon K. Gjessing, Anne Tandberg, Thorbj??rn R??nning, Lorentz M. Irgens, Valborg Baste, Roy M. Nilsen, Anne Kjersti Daltveit. (2005) Folate Supplementation and Twin Pregnancies. Epidemiology 16:2, 201-205
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8. 8

   Jean M. Lawrence, Margaret L. Watkins, Vicki Chiu, J. David Erickson, Diana B. Petitti. (2004) Food fortification with folic acid and rate of multiple births, 1994-2000. Birth Defects Research Part A: Clinical and Molecular Teratology 70:12, 948-952
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   Andrew E. Czeizel, Peter Vargha. (2004) Periconceptional folic acid/multivitamin supplementation and twin pregnancy. American Journal of Obstetrics and Gynecology 191:3, 790-794
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10. 10

    D. K. Waller, A. T. N. Tita, J. F. Annegers. (2003) Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998. Paediatric and Perinatal Epidemiology 17:4, 378-383
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    Judith G Hall. (2003) Twinning. The Lancet 362:9385, 735-743
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12. 12

    Gary M. Shaw, Suzan L. Carmichael, Verne Nelson, Steve Selvin, Donna M. Schaffer. (2003) Food fortification with folic acid and twinning among California infants. American Journal of Medical Genetics 119A:2, 137-140
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    Andrew E. Czeizel. (2001) Miscarriage and use of multivitamins or folic acid. American Journal of Medical Genetics 104:2, 179-180
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14. 14

    Judith Lumley, Lyndsey Watson, Max Watson, Carol Bower, Judith Lumley. 2001. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. .
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15. 15

    A Ericson, B Källén, A Åberg. (2001) Use of Multivitamins and Folic Acid in Early Pregnancy and Multiple Births in Sweden. Twin Research and Human Genetics 4:2, 63-66
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    Ernest B. Hook. (2000) Folic acid: Abortifacient or pseudoabortifacient?. American Journal of Medical Genetics 92:5, 301-302
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    Machelle M Seibel. (1999) The role of nutrition and nutritional supplements in women’s health. Fertility and Sterility 72:4, 579-591
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    Andrew E Czeizel. (1998) Terathanasia, folic acid, and birth defects. The Lancet 351:9100, 450
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19. 19

    Martha M. Werler, Janet D. Cragan, Cathy R. Wasserman, Gary M. Shaw, J. David Erickson, Allen A. Mitchell. (1997) Multivitamin supplementation and multiple births. American Journal of Medical Genetics 71:1, 93-96
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20. 20

    A. E. Czeizel, M. Rockenbauer, E. Susamky. (1996) No change in sexual activity during preconceptional multivitamin supplementation. BJOG: An International Journal of Obstetrics and Gynaecology 103:6, 569-573
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21. 21

    I. Duds, M. Rockenbauer, A. E. Czeizel. (1995) The effect of preconceptional multivitamin supplementation on the menstrual cycle. Archives of Gynecology and Obstetrics 256:3, 115-123
    CrossRef