Medication Exposure During Pregnancy And The Risk Of Orofacial Clefts: A Scoping Review
Abstract
Orofacial clefts (OFCs), including cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP), are among the most common congenital malformations worldwide, affecting approximately 1 in 500 to 550 live births. Such malformations occur due to a failure in the fusion of the embryonic facial processes, a process that generally occurs between the 4th and 12th weeks of gestation. OFCs have a substantial impact on quality of life and can cause lifelong issues, including feeding problems, speech abnormalities, hearing loss, dental abnormalities, and psychosocial challenges; therefore, there is a need for studies to explore possible solutions to these issues. There are studies examining the use of medications in the periconceptional period; however, the findings from these studies are largely inconsistent. This review strives to find answers to possible contributing factors to increased risks of OFCs by evaluating the association of maternal medication use during pregnancy and the increased risk of OFCs. In conducting this review, we searched the PubMed and Dimensions databases for published literature relevant to the study's focus. We further selected the studies included in our review based on the inclusion criteria we had developed before the study. We included a total of five studies in this review — three case-control studies and one cohort study — most of which were conducted by researchers in European countries and the USA. The five articles included in this study featured research data from congenital disability registries, hospital medical records, and information obtained through interviews with mothers. The medications evaluated in the studies included in this review include corticosteroids administered via various routes, antiepileptics (such as lamotrigine), and bronchodilators commonly used in the treatment of asthma. The exposure period considered in the studies was mainly four weeks before pregnancy and the end of the first trimester. Ultimately, the findings from this study showed that there is an association between medication use during pregnancy and the incidence of orofacial clefts in newborns. However, this association is dependent on the types or classes of medications. There are varying results from epidemiologic studies on the association between the maternal use of corticosteroids and the risk of orofacial clefts. However, administration during pregnancy should be done with caution. However, antiepileptic drugs were found to be associated with an increased incidence of orofacial clefts, and maternal bronchodilators used in asthma management were linked to an increased risk of cleft lip only and cleft lip with cleft palate.
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1. Shaye, D., Liu, C. C., & Tollefson, T. T. (2015). Cleft lip and palate. Facial Plastic Surgery Clinics of North America, 23(3), 357–372. doi: 10.1016/j.fsc.2015.04.008
2. Kulesa-Mrowiecka, M., Lipowicz, A., Marszałek-Kruk, B. A., Kania, D., Wolański, W., Myśliwiec, A., & Dowgierd, K. (2024). Characteristics of factors influencing the occurrence of cleft lip and/or palate: a case analysis and literature review. Children, 11(4), 399. doi: 10.3390/children11040399
3. Babai, A., & Irving, M. (2023). Orofacial clefts: Genetics of cleft lip and palate. Genes, 14(8), 1603. doi: 10.3390/genes14081603
4. El-Shazly, M., Helmy, Y., Abdelsalam, L., & Ali, T. (2022). Global incidence of Cleft palate. In Surgical Atlas of Cleft Palate and Palatal Fistulae (pp. 1–6). doi: 10.1007/978-981-15-3889-6_129-1
5. CDC. (2024). Cleft Lip/Cleft Palate. Retrieved from https://www.cdc.gov/birth-defects/about/cleft-lip-cleft-palate.html
6. Rodd, H. D., Marshman, Z., Porritt, J., Bradbury, J., & Baker, S. R. (2011). Oral health-related quality of life of children in relation to dental appearance and educational transition. BDJ, 211(2), E4. doi: 10.1038/sj.bdj.2011.574
7. Tolarova, M. M., & Elluru, R. G. (2024). Pediatric Cleft Lip and Palate. Medscape.
8. Sander, A. K., Grau, E., Kloss-Brandstätter, A., Zimmerer, R., Neuhaus, M., Bartella, A. K., & Lethaus, B. (2021). Continuous multidisciplinary care for patients with orofacial Clefts—Should the follow-up interval depend on the cleft entity? The Cleft Palate-Craniofacial Journal, 59(9), 1139–1144. doi: 10.1177/10556656211035253
9. Wehby, G., & Cassell, C. (2009). The Impact of Orofacial Clefts on Quality of Life, Healthcare Use, and Costs. Oral Diseases, 16(1), 3–10. doi: 10.1111/j.1601-0825.2009.01588.x
10. Amzat, J., Murererehe, J., Uwambaye, P., Yusuf, L., Olaopa, O., Salami, A., Harerimana, I. E., Ineza, M. C., Ntigura, E., Ober-Oluoch, J., Dusenge, M. A., Nishimwe, D. D., Abimana, V., Tuyishime, G., Milanes, D. Z., Adisa, A., Jayasinghe, R. D., & Kanmodi, K. K. (2025). The Burden and Care of Orofacial Clefts in Rwanda: A Scoping Review. BMC Oral Health, 25(1). doi: 10.1186/s12903-025-05900-y
11. Kini, U. (2023). Genetics and orofacial clefts: a clinical perspective. BDJ, 234(12), 947–952. doi: 10.1038/s41415-023-5994-3
12. Garland, M. A., Reynolds, K., & Zhou, C. J. (2020). Environmental mechanisms of orofacial clefts. Birth Defects Research, 112(19), 1660–1698. doi: 10.1002/bdr2.1830
13. Burg, M. L., Chai, Y., Yao, C. A., Magee, W., & Figueiredo, J. C. (2016). Epidemiology, Aetiology, and Treatment of Isolated Cleft Palate. Frontiers in Physiology, 7. doi: 10.3389/fphys.2016.00067
14. Shimizu, T., & Maeda, T. (2009). Prevalence and Genetic Basis of Tooth Agenesis. Japanese Dental Science Review, 45(1), 52–58. doi: 10.1016/j.jdsr.2008.12.001
15. Ács, M., Cavalcante, B. G. N., Bănărescu, M., Wenning, A. S., Hegyi, P., Szabó, B., Harnos, A., Gerber, G., & Varga, G. (2024). Maternal factors increase risk of orofacial cleft: a meta-analysis. Scientific Reports, 14(1). doi: 10.1038/s41598-024-79346-7
16. Little, J., Cardy, A., & Munger, R. G. (2004). Tobacco smoking and oral clefts: a meta-analysis. Bull World Health Organization, 82(3), 213–218.
17. Honein, M. A., Rasmussen, S. A., Reefhuis, J., Romitti, P. A., Lammer, E. J., Sun, L., & Correa, A. (2007). Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts. Epidemiology, 18(2), 226–233. doi: 10.1097/01.ede.0000254430.61294.c0
18. Correa, A., Gilboa, S. M., Besser, L. M., Botto, L. D., Moore, C. A., Hobbs, C. A., Cleves, M. A., Riehle-Colarusso, T. J., Waller, D. K., & Reece, E. A. (2008). Diabetes Mellitus and Birth Defects. American Journal of Obstetrics and Gynecology, 199(3), 237.e1-237.e9. doi: 10.1016/j.ajog.2008.06.028
19. Shaw, G., Wasserman, C., O'Malley, C., Tolarova, M., & Lammer, E. (1995). Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. The Lancet, 346(8972), 393–396. doi: 10.1016/s0140-6736(95)92778-6
20. Bille, C., Skytthe, A., Vach, W., Knudsen, L. B., Andersen, A. N., Murray, J. C., & Christensen, K. (2005). Parentʼs age and the risk of oral clefts. Epidemiology, 16(3), 311–316. doi: 10.1097/01.ede.0000158745.84019.c2
21. Rezaallah, B., Lewis, D. J., Zeilhofer, H., & Berg, B. (2018). Risk of cleft lip and/or palate associated with antiepileptic drugs: Postmarketing safety signal detection and evaluation of information presented to prescribers and patients. Therapeutic Innovation & Regulatory Science, 53(1), 110–119. doi: 10.1177/2168479018761638
22. Hernández-Díaz, S., & Levin, M. (2014). Alteration of bioelectrically controlled processes in the embryo: A teratogenic mechanism for anticonvulsants. Reproductive Toxicology, 47, 111–114. doi: 10.1016/j.reprotox.2014.04.008
23. MotherToBaby. (2023). Isotretinoin (Accutane®). Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK582775/
24. Atmadani, R. N., Nkoka, O., Yunita, S. L., & Chen, Y. (2020). Self-medication and knowledge among pregnant women attending primary healthcare services in Malang, Indonesia: a cross-sectional study. BMC Pregnancy and Childbirth, 20(1). doi: 10.1186/s12884-020-2736-2
25. Abduelkarem, A. R., & Mustafa, H. (2017b). Use of Over-the-counter Medication among Pregnant Women in Sharjah, United Arab Emirates. Journal of Pregnancy, 1–8. doi: 10.1155/2017/4503793
26. Sawicki, E., Stewart, K., Wong, S., Leung, L., Paul, E., & George, J. (2011). Medication use for chronic health conditions by pregnant women attending an Australian maternity hospital. Australian and New Zealand Journal of Obstetrics and Gynaecology, 51(4), 333–338. doi: 10.1111/j.1479-828x.2011.01312.x
27. Kim, J. H., & Scialli, A. R. (2011). Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease. Toxicological Sciences, 122(1), 1–6. doi: 10.1093/toxsci/kfr088
28. Charlton, R. A., & McGrogan, A. (2022). Drug safety in pregnancy: data, methods, and challenges. In Springer eBooks (pp. 1–11). doi: 10.1007/978-3-030-50247-8_27-1
29. Alwan, S., & Grant, K. S. (2024). Maternal Medication Use in Pregnancy: A Narrative Review on Assessing and Communicating the "Risk" of Birth Defects to the Patient. Pharmacoepidemiology, 3(4), 336–349. doi: 10.3390/pharma3040023
30. Gotlib, D., Perelstein, E., Kurlander, J., Zivin, K., Riba, M., & Muzik, M. (2016). Guideline Adherence for Mentally Ill Reproductive-Aged Women on Treatment with Valproic Acid. The Journal of Clinical Psychiatry, 77(04), 527–534. doi: 10.4088/jcp.15m10046
31. Skuladottir, H., Wilcox, A., McConnaughey, R., Vindenes, H., & Lie, R. T. (2014). First-trimester nonsystemic corticosteroid use and the risk of oral clefts in Norway. Annals of Epidemiology, 24(9), 635–640. doi: 10.1016/j.annepidem.2014.06.005
32. Kmet, L. M., Lee, R. C., & Cook, L. S. (2004). Standard Quality Assessment Criteria for Evaluating Primary Research Papers From a Variety of Fields. Alberta Heritage Foundation for Medical Research. doi: 10.7939/r37m04f16
33. Hviid, A., & Molgaard-Nielsen, D. (2011). Corticosteroid use during pregnancy and risk of orofacial clefts. Canadian Medical Association Journal, 183(7), 796–804. doi: 10.1503/cmaj.101063
34. Dolk, H., Wang, H., Loane, M., Morris, J., Garne, E., Addor, M., Arriola, L., Bakker, M., Barisic, I., Doray, B., Gatt, M., Kallen, K., Khoshnood, B., Klungsoyr, K., Lahesmaa-Korpinen, A., Latos-Bielenska, A., Mejnartowicz, J. P., Nelen, V., Neville, A., De Jong-Van Den Berg, L. T. (2016). Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology, 86(18), 1716–1725. doi: 10.1212/wnl.0000000000002540
35. Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., & Carmichael, S. L. (2014). Corticosteroid use and risk of orofacial clefts. Birth Defects Research, 100(6), 499–506. doi: 10.1002/bdra.23248
36. Munsie, J. W., Lin, S., Browne, M. L., Campbell, K. A., Caton, A. R., Bell, E. M., Rasmussen, S. A., Romitti, P. A., & Druschel, C. M. (2011). Maternal bronchodilator use and the risk of orofacial clefts. Human Reproduction, 26(11), 3147–3154. doi: 10.1093/humrep/der315
37. Cragan, J. D., Friedman, J. M., Holmes, L. B., Uhl, K., Green, N. S., & Riley, L. (2006). Ensuring the safe and effective use of medications during pregnancy: planning and prevention through preconception care. Maternal and Child Health Journal, 10(S1), 129–135. doi: 10.1007/s10995-006-0102-2
38. Dathe, K., & Schaefer, C. (2019). The use of medication in pregnancy. Deutsches Ärzteblatt International. doi: 10.3238/arztebl.2019.0783
39. Stock, S. J., & Norman, J. E. (2019). Medicines in pregnancy. F1000Research, 8, 911. doi: 10.12688/f1000research.17535.1
40. Gunatilake, R., Patil, A. S., & Goje, O. (2023). Drug safety in pregnancy. Retrieved from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/drug-safety-in-pregnancy/drug-safety-in-pregnancy
41. Xiao, W., Liu, X., Liu, Y., Zhang, D., & Xue, L. (2017). The relationship between maternal corticosteroid use and orofacial clefts-a meta-analysis. Reproductive Toxicology, 69, 99–105. doi: 10.1016/j.reprotox.2017.02.006
42. Peterka, M., Heringova, L. H., Sukop, A., & Peterkova, R. (2021). Anti-asthma drugs formoterol and budesonide (Symbicort) induce orofacial clefts, gastroschisis, and heart septum defects in an in vivo model. In Vivo, 35(3), 1451–1460. doi: 10.21873/invivo.12397
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