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Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study

  • PERINATAL EPIDEMIOLOGY
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Abstract

Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0–12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95 % confidence interval 1.19–2.49), especially of cleft lip/alveolus (3.16, 1.69–5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects—mainly clefts of the lip/alveolus—with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.

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Acknowledgments

We thank Nicole Siemensma and Lies ter Beek from Eurocat for their contribution to the data verification and analysis in this study. We would also like to express our gratitude to the cleft palate teams of Friesland and Groningen, the parents involved in Eurocat, and the NVSCA, including its board. Without their efforts these systems would not have succeeded. The Eurocat registry is financed by the ministry of Public Health, Welfare, and Sports (VWS) of the Netherlands. The funding source had no role in the study design; the collection, analysis, and interpretation of data; in writing the report; and in the decision to submit the paper for publication.

Ethical statement

Eurocat data were collected with written informed consent of the parents and the NVSCA data were anonymously collected. Studies using data from these health registries do not require ethical approval in the Netherlands. The principles outlined in the declaration of Helsinki were followed.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, Room EE 1591, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Anna M. Rozendaal & Christl Vermeij-Keers

  2. Department of Orthodontics, Erasmus MC–Sophia Children’s Hospital, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Anna M. Rozendaal

  3. Department of Genetics, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands

    Anthonie J. van Essen & Gerard J. te Meerman

  4. Department of Genetics, Eurocat Registration Northern Netherlands, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands

    Marian K. Bakker & Hermien E. K. de Walle

  5. Department of Plastic Surgery, Cleft Palate Team Friesland, Medical Center Leeuwarden, P.O. Box 888, 8901 BR, Leeuwarden, The Netherlands

    Jan J. van der Biezen

  6. Department of Speech and Languages, Cleft Palate Team Groningen, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands

    Sieneke M. Goorhuis-Brouwer

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  1. Anna M. Rozendaal
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  8. Hermien E. K. de Walle
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Correspondence to Anna M. Rozendaal.

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Rozendaal, A.M., van Essen, A.J., te Meerman, G.J. et al. Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study. Eur J Epidemiol 28, 875–887 (2013). https://doi.org/10.1007/s10654-013-9849-0

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