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Increasing Incidence of Craniosynostosis in the United States: Is Folic Acid Supplementation Responsible?

Mabes, Erika Simmerman DO; Chishom, Taylor BS; Moraczewski, Jason BS; Dymanus, Kyle BS; Linder, Daniel PPhD; Yu, Jack C. MD, DMD

Plastic and Reconstructive Surgery - Global Open: August 2019 - Volume 7 - Issue 8S-1 - p 40-41
doi: 10.1097/01.GOX.0000584424.74207.04
Craniofacial Abstracts

Medical College of Georgia, Augusta University, Augusta, GA

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PURPOSE: Craniosynostosis, the premature fusion of cranial sutures, has increased in both prevalence and incidence as reported by international studies.1,2 To our knowledge, no recent studies have evaluated increasing incidence in the United States; therefore, we sought to evaluate if there was a significant increase in our national incidence of craniosynostosis. Methotrexate, a folic acid antagonist, has been associated with an increase in craniosynostosis.3 There has been a decrease in the incidence of cleft anomalies following the implementation of the folic acid supplementation program in 1998 within the United States. Both of these anomalies seem affected by folate. We hypothesize that there is a reciprocal relationship between cleft and craniosynostosis and seek to investigate the theory that as folate supplementation penetrates the population, we see a gradual increase in the incidence of craniosynostosis.

METHODS AND MATERIALS: The National Inpatient Sample Database was consulted to identify infants born with craniosynostosis between 2004 and 2013. Data were collected from the US Center for Disease Control and Prevention, including incidence of influenza virus infection according to year and month. Using multivariable logistic regression, we examined the relationship between craniosynostosis and the independent variables month and year. We then utilized mixed-effects logistic regression to estimate the odds ratio of occurrence of craniosynostosis in relation to previous months’ flu incidence. E values were calculated to evaluate for unmeasured confounders.

RESULTS: In 2004, there were 4,110 infants born with craniosynostosis, which increased to 6,155 infants in 2013. A statistically significant increase in the incidence of craniosynostosis within the United States was found (odds ratio of 1.57 in 2013; P < 0.001). Mixed-effects logistic regression revealed a lower incidence of craniosynostosis associated with an increased incidence of influenza infection. E values for national incidence of craniosynostosis and association with influenza incidence were 2.51 and 11.6, respectively.

CONCLUSIONS: To our knowledge, this is the first study demonstrating a significant increase in the national incidence of craniosynostosis in the United States, which we believe may be a result of folic acid supplementation penetrating the population. We also report for the first time a decreased incidence of craniosynostosis in association with influenza incidence, which support our hypothesis of a possible inverse relationship with cleft, as maternal influenza during pregnancy demonstrates increased incidence of cleft anomalies.4 We are further investigating the relationship between cleft and craniosynostosis at this time to uncover a mechanism that might explain this relationship.


1. Cornelissen M, Ottelander B, Rizopoulos D, et al. Increase of prevalence of craniosynostosis. J Craniomaxillofac Surg. 2016;44:1273–1279.

2. Morris JK, Springett AL, Greenlees R, et al. Trends in congenital anomalies in Europe from 1980 to 2012. PLoS One. 2018;13:e0194986.

3. Zarella CS, Albino FP, Oh AK, et al. Craniosynostosis following fetal methotrexate exposure. J Craniofac Surg. 2016;27:450–452.

4. Waller DK, Hashmi SS, Hoy AT, et al. Maternal report of fever from cold or flu during early pregnancy and the risk for noncardiac birth defects, National Birth Defects Prevention Study, 1997–2011. Birth Defects Res. 2018;110:342–351.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons. All rights reserved.