Investigation of Some Modifiable Risk Factors That Lead to Congenital Anomalies: A Review Article

Document Type : Scientific Review


1 Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Department of Emergency Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran


 Congenital anomalies are inborn errors of development. Genetic and environmental factors are known causes of congenital anomalies. Environmental factors are modifiable risk factors.
This review focuses on modifiable risk factors for birth defects. There is a strong link between alcohol use and an increased risk of congenital anomalies. Marijuana can be expected to cause fetal growth restriction; smoking before conception, even with cessation in the first trimester, may also pose a risk for gastroschisis. Benzodiazepines during the first trimester were associated with Dandy–Walker malformation , anophthalmia or microphthalmia  and esophageal atresia. While oral retinoids are absolutely contraindicated, topical retinoids, should conservatively be avoided during pregnancy but  if  were used by accident, the existing data can reduce the anxiety of happening adverse pregnancy outcomes. Antihypertensives such as labetalol, methyldopa and extended release nifedipine are relatively safe choices. Antiemetics  such as doxylamine-pyridoxine and metoclopramide may have potential teratogenicity in first trimester. Ondansetron use was not significantly associated with major congenital anomalies but recent meta-analysis suggested more concern.  An antiepileptic such as   valproate poses the highest risk among antiepileptic drugs, whereas the prevalence of congenital anomalies is the lowest with lamotrigine, levetiracetam, and oxcarbazepine.
Education and counseling to women who are planning to become pregnant can reduce the risk of congenital anolamies.                         


1. Feldkamp ML, Carey JC, Byrne JLB, Krikov S, Botto LD. Etiology and clinical presentation of
birth defects: Population based study. BMJ 2017; 357: j2249.
2. Toobaie A, Yousef Y, Balvardi S, St-Louis E, Baird R, Guadagno E, et al. Incidence and prevalence of congenital anomalies in low- and middle-income countries: A systematic review. J Pediatr Surg 2019; 54(5): 1089-93.
3. Daliri S, Sayehmiri K, Asadollahi K, Rezaei N, Saroukhani D, Karimi A. Prevalence of congenital anomalies in Iran: A systematic review and meta-analysis. IJN 2018; 9(2): 21-32.
4. Turnpenny P, Ellard S. Emery's elements of medical genetics. 24th ed. Amsterdam, Netherlands: Elsevier; 2017.
5. Eberhart JK, Parnell SE. The genetics of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 2016; 40(6): 1154-65.
6. Roozen S, Black D, Peters GY, Kok G, Townend D, Nijhuis JG, et al. Fetal alcohol spectrum disorders (FASD): An approach to effective prevention. Curr Dev Disord Rep 2016; 3(4): 229-34.
7. Sulik KK. Prenatal alcohol exposure and abnormal brain development – Findings from basic research. In: Jonsson E, Clarren S, Binnie I, editors. Ethical and legal perspectives in fetal alcohol spectrum disorders (FASD). 2019. p. 37-48.
8. Del CM, Jones KL. A review of the physical features of the fetal alcohol spectrum disorders. Eur J Med Genet 2017; 60(1): 55-64.
9. Baptista FH, Rocha KBB, Martinelli JL, Silva de Avó LR, Ferreira RA, Germano CMR, et al. Prevalence and factors associated with alcohol consumption during pregnancy. Rev Bras Saude Mater Infant 2017; 17(2): 271-9.
10. Louis CS. Pregnant women turn to marijuana, perhaps harming infants [Online]. 2017 [cited 2017 Feb 02]; Available from: URL:
11. Gonzales SK, Krishna I. Marijuana use in pregnancy. Topics in Obstetrics & Gynecology 2017; 37(12): 1-5.
12. Harris BS, Bishop KC, Kemeny HR, Walker JS, Rhee E, Kuller JA. Risk Factors for Birth Defects. Obstet Gynecol Surv 2017; 72(2): 123-35.
13. Tinker SC, Reefhuis J, Bitsko RH, Gilboa SM, Mitchell AA, Tran EL, et al. Use of benzodiazepine medications during pregnancy and potential risk for birth defects, national
Congenital Anomalies & Modifiable Risks
78 World J Peri & Neonatol 2019; Vol. 2; No. 2
birth defects prevention study, 1997-2011. Birth Defects Res 2019; 111(10): 613-20.
14. Uguz F, Orsolini L. Perinatal psychopharmacology. 1st ed. Switzerland: Springer International Publishing; 2019. p. 1-376.
15. Kalaitzopoulos DR, Chatzistergiou K, Amylidi AL, Kokkinidis DG, Goulis DG. Effect of methamphetamine hydrochloride on pregnancy outcome: A systematic review and meta-analysis. J Addict Med 2018; 12(3): 220-6.
16. Jablonski SA, Williams MT, Vorhees CV. Mechanisms involved in the neurotoxic and cognitive effects of developmental methamphetamine exposure. Birth Defects Res C Embryo Today 2016; 108(2): 131-41.
17. Fraser A, Walker K, Green J. Maternal cocaine abuse – An evidence review. J Neonatal Nurs 2016; 22(2): 56-60.
18. Perry MF, Mulcahy H, DeFranco EA. Influence of periconception smoking behavior on birth defect risk. Am J Obstet Gynecol 2019; 220(6): 588.
19. Downing KF, Riehle-Colarusso T, Gilboa SM, Lin AE, Oster ME, Tinker SC, et al. Potential risk factors for Ebstein anomaly, national birth defects prevention study, 1997-2011. Cardiol Young 2019; 29(6): 819-27.
20. Khiali S, Gharekhani A, Entezari-Maleki T. Isotretinoin; A review on the utilization pattern in pregnancy. Adv Pharm Bull 2018; 8(3): 377-82.
21. Prevost N, English JC. Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol 2013; 26(5): 290-3.
22. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992; 26(4): 599-606.
23. Farhidnia N, Memarian A. Congenital anomalies following use of isotretinoin: Emphasis on its legal aspects. Med Leg J 2017; 85(1): 33-4.
24. Du H, Taylor HS. The Role of Hox Genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb Perspect Med 2015; 6(1): a023002.
25. Kaplan YC, Ozsarfati J, Etwel F, Nickel C, Nulman I, Koren G. Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis. Br J Dermatol 2015; 173(5): 1132-41.
26. MacDonald SC, Cohen JM, Panchaud A, McElrath TF, Huybrechts KF, Hernandez-Diaz S. Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance. Pharmacoepidemiol Drug Saf 2019; 28(9): 1211-21.
27. Albadr TA, Alruhaimi DK, Cahusac PMB, Rohra DK. Knowledge and use of isotretinoin in Saudi female college students: Cross -sectional study. J Dermatol Dermatol Surg 2019; 23(2): 76-80.
28. Alshammari SA, Alamri Y, Alanazi AM, Almuhanna SA, Pinjabi L, and Alsnaidi NA. Prevalence and associated risk factors of acne relapse among Saudi acne vulgaris patients using isotretinoin. Saudi Pharm J 2020; 28(3): 374-9.
29. Barbieri JS, Shin DB, Wang S, Margolis DJ, Takeshita J. The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time. J Am Acad Dermatol 2020; 82(1): 72-9.
30. Werner CA, Papic MJ, Ferris LK, Schwarz EB. Promoting safe use of isotretinoin by increasing contraceptive knowledge. JAMA Dermatol 2015; 151(4): 389-93.
31. Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US food and drug administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol 2019; 155(10).
32. Williams AL, Pace ND, DeSesso JM. Teratogen update: Topical use and third-generation retinoids. Birth Defects Res 2020; 112(15): 1105-14.
33. Fisher SC, Van Zutphen AR, Werler MM, Lin AE, Romitti PA, Druschel CM, et al. Maternal antihypertensive medication use and congenital heart defects: updated results from the national birth defects prevention study. Hypertension 2017; 69(5): 798-805.
34. Fisher SC, Van Zutphen AR, Romitti PA, Browne ML. Maternal hypertension, antihypertensive medication use, and small for gestational age births in the national birth defects prevention study, 1997-2011. Matern Child Health J 2018; 22(2): 237-46.
35. Fitton CA, Steiner MFC, Aucott L, Pell JP, Mackay DF, Fleming M, et al. In-utero exposure to antihypertensive medication and neonatal and
Abdi, et al.
World J Peri & Neonatol 2019; Vol. 2; No. 2 79
child health outcomes: a systematic review. J Hypertens 2017; 35(11): 2123-37.
36. Hoeltzenbein M, Fietz AK, Beck E, Wernicke J, Kayser A, Weber-Schoendorfer C, et al. OP 27 methyldopa during the first trimester and pregnancy outcome – A prospective observational cohort study. Pregnancy Hypertension 2017; 9: 21.
37. Al-Balas M, Bozzo P, Einarson A. Use of diuretics during pregnancy. Can Fam Physician 2009; 55(1): 44-5.
38. Koren G. Safety considerations surrounding use of treatment options for nausea and vomiting in pregnancy. Expert Opin Drug Saf 2017; 16(11): 1227-34.
39. Berard A, Sheehy O, Gorgui J, Zhao JP, Soares de MC, Bernatsky S. New evidence for concern over the risk of birth defects from medications for nausea and vomitting of pregnancy. J Clin Epidemiol 2019; 116: 39-48.
40. Parker SE, Van BC, Anderka M, Mitchell AA. Ondansetron for treatment of nausea and vomiting of pregnancy and the risk of specific birth defects. Obstet Gynecol 2018; 132(2): 385-94.
41. Picot C, Berard A, Grenet G, Ripoche E, Cucherat M, Cottin J. Risk of malformation
after ondansetron in pregnancy: An updated systematic review and meta-analysis. Birth Defects Res 2020; 112(13): 996-1013.
42. Heitmann K, Solheimsnes A, Havnen GC, Nordeng H, Holst L. Treatment of nausea and vomiting during pregnancy -a cross-sectional study among 712 Norwegian women. Eur J Clin Pharmacol 2016; 72(5): 593-604.
43. Tsamantioti ES, Hashmi MF. Teratogenic Medications. 2020.
44. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol 2018; 17(6): 530-8.
45. Tomson T, Battino D, Perucca E. Teratogenicity of antiepileptic drugs. Curr Opin Neurol 2019; 32(2): 246-52.
46. Lagana AS, Triolo O, D'Amico V, Cartella SM, Sofo V, Salmeri FM, et al. Management of women with epilepsy: from preconception to post-partum. Arch Gynecol Obstet 2016; 293(3): 493-503.