Risk of Congenital Malformations Associated with Exposure to Beta-blockers Early in Pregnancy: A Systematic Review and Meta-analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANGXin-kuan ,  YOUTao , LIUXing-guang , HOUXiao-dong , DINGFan , YIKang

Department of Cardiovascular Surgery, Gansu Provincial Hospital, Lanzhou 730000, P. R. China;

Corresponding author：

YOUTao, Email: syxzwk@126.com

Keywords：

Beta-blockers; Pregnancy; Congenital anomalies; Heart defects; Cleft lip/palate; Neural tube defects

DOI：

10.7507/1007-4848.20150173

Video：

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Objective To determine teratogenicity of beta-blockers in early pregnancy. Methods We searched PubMed, EMbase, Cochrane Clinical Trials, clinicaltrials.gov, CBM, Wanfang database, and CNKI from establishment of each database to December 2014. We evaluated the quality of included literature. Statistical analysis was conducted in RevMan5.3 software. Results Fifteen population-based case-control or cohort studies were identified. The score of included studies changed from 5-7 points. Based on meta-analysis, first trimester oral beta-blocker use showed no increased odds of all or major congenital anomalies. While in analysis examining organ-specific malformations, statistically increased odds of cardiovascular (CV) defects with OR 2.21 and 95% CI 1.63 to 3.01, cleft lip/palate (CL/P) with OR 3.11 and 95% CI 1.78 to 9.89, and neural tube (NT) defects with OR 3.56 and 95% CI 1.19 to 10.67 were observed. Conclusion Causality is difficult to interpret given small number of heterogeneous studies and possibility of biases. Given the frequency of this exposure in pregnancy, further research is needed.

Citation： WANGXin-kuan, YOUTao, LIUXing-guang, HOUXiao-dong, DINGFan, YIKang. Risk of Congenital Malformations Associated with Exposure to Beta-blockers Early in Pregnancy: A Systematic Review and Meta-analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2015, 22(7): 678-684. doi: 10.7507/1007-4848.20150173 Copy

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2.	Khairy P, Ouyang DW, Fernandes SM, et al. Pregnancy outcomes in women with congenital heart disease. Circulation, 2006, 113(4):517-524.
3.	Puho EH, Szunyogh M, Metneki J, et al. Drug treatment during pregnancy and isolated orofacial clefts in hungary. Cleft Palate Craniofac J, 2007, 44(2):194-202.
4.	Medveczky E, Puho E, Czeizel EA. The use of drugs in mothers of offspring with neural-tube defects. Pharmacoepidemiol Drug Saf, 2004, 13(7):443-455.
5.	Banhidy F, Cs N, Puho EH, et al. Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring:A population-based study. Hypertens Res, 2011, 34(2):257-263.
6.	Caton AR, Bell EM, Druschel CM, et al. Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations. Hypertension, 2009, 54(1):63-70.
7.	Caton AR, Bell EM, Druschel CM, et al. Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias. Birth Defects Res A Clin Mol Teratol, 2008, 82(1):34-40.
8.	Cedergren MI, Selbing AJ, Kallen BA. Risk factors for cardiovascular malformation——a study based on prospectively collected data. Scand J Work Environ Health, 2002, 28(1):12-17.
9.	Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Pharmacoepidemiology and Drug Safety (PDS), 2009, 18:S76.
10.	Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Research Part A-Clinical and Molecular Teratology, 2009, 85:416.
11.	Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Res B Dev Reprod Toxicol, 2010, 89(2):147-154.
12.	Queisser-Luft A, Eggers I, Stolz G, et al. Serial examination of 20, 248 newborn fetuses and infants:Correlations between drug exposure and major malformations. Am J Med Genet, 1996, 63(1):268-276.
13.	李冬梅. 妊娠期高血压疾病50例临床疗效分析. 中国社区医师, 2014, 21:58-59.
14.	Ersbøll AS, Hedegaard M, Søndergaard L, et al. Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction. BJOG, 2014, 121(5):618-626.
15.	Davis RL, Eastman D, McPhillips H, et al. Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiol Drug Saf, 2011, 20(2):138-145.
16.	Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol, 2003, 17(3):255-261.
17.	Lennestal R, Otterblad Olausson P, Kallen B. Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. Eur J Clin Pharmacol, 2009, 65(6):615-625.
18.	Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev, 2001, 61(2):85-95.
19.	Jensen DM, Damm P, Moelsted-Pedersen L, et al.Outcomes in type 1 diabetic pregnancies:A nationwide, population-based study. Diabetes Care, 2004, 27(12):2819-2823.
20.	Kitzmiller JL, Wallerstein R, Correa A, et al. Preconception care for women with diabetes and prevention of major congenital malformations. Birth Defects Res A Clin Mol Teratol, 2010, 88(10):791-803.
21.	Ray JG, O'Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus:A Meta-analysis. QJM, 2001, 94(8):435-444.
22.	Yang J, Cummings EA, O'Connell C, et al. Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol, 2006, 108(3 Pt 1):644-650.
23.	Levit RD, Reynolds HR, Hochman JS. Cardiovascular disease in young women:A population at risk. Cardiol Rev, 2011, 19(2):60-65.
24.	Li DK, Yang C, Andrade S, Tavares V, et al. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring:A retrospective cohort study. BMJ, 2011, 343:d5931.

1. Meidahl Petersen K, Jimenez-Solem E, Andersen JT, et al. β-Blocker treatment during pregnancy and adverse pregnancy outcomes:a nationwide population-based cohort study. BMJ Open, 2012, 2(4):e001185.
2. Khairy P, Ouyang DW, Fernandes SM, et al. Pregnancy outcomes in women with congenital heart disease. Circulation, 2006, 113(4):517-524.
3. Puho EH, Szunyogh M, Metneki J, et al. Drug treatment during pregnancy and isolated orofacial clefts in hungary. Cleft Palate Craniofac J, 2007, 44(2):194-202.
4. Medveczky E, Puho E, Czeizel EA. The use of drugs in mothers of offspring with neural-tube defects. Pharmacoepidemiol Drug Saf, 2004, 13(7):443-455.
5. Banhidy F, Cs N, Puho EH, et al. Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring:A population-based study. Hypertens Res, 2011, 34(2):257-263.
6. Caton AR, Bell EM, Druschel CM, et al. Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations. Hypertension, 2009, 54(1):63-70.
7. Caton AR, Bell EM, Druschel CM, et al. Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias. Birth Defects Res A Clin Mol Teratol, 2008, 82(1):34-40.
8. Cedergren MI, Selbing AJ, Kallen BA. Risk factors for cardiovascular malformation——a study based on prospectively collected data. Scand J Work Environ Health, 2002, 28(1):12-17.
9. Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Pharmacoepidemiology and Drug Safety (PDS), 2009, 18:S76.
10. Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Research Part A-Clinical and Molecular Teratology, 2009, 85:416.
11. Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Res B Dev Reprod Toxicol, 2010, 89(2):147-154.
12. Queisser-Luft A, Eggers I, Stolz G, et al. Serial examination of 20, 248 newborn fetuses and infants:Correlations between drug exposure and major malformations. Am J Med Genet, 1996, 63(1):268-276.
13. 李冬梅. 妊娠期高血压疾病50例临床疗效分析. 中国社区医师, 2014, 21:58-59.
14. Ersbøll AS, Hedegaard M, Søndergaard L, et al. Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction. BJOG, 2014, 121(5):618-626.
15. Davis RL, Eastman D, McPhillips H, et al. Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiol Drug Saf, 2011, 20(2):138-145.
16. Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol, 2003, 17(3):255-261.
17. Lennestal R, Otterblad Olausson P, Kallen B. Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. Eur J Clin Pharmacol, 2009, 65(6):615-625.
18. Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev, 2001, 61(2):85-95.
19. Jensen DM, Damm P, Moelsted-Pedersen L, et al.Outcomes in type 1 diabetic pregnancies:A nationwide, population-based study. Diabetes Care, 2004, 27(12):2819-2823.
20. Kitzmiller JL, Wallerstein R, Correa A, et al. Preconception care for women with diabetes and prevention of major congenital malformations. Birth Defects Res A Clin Mol Teratol, 2010, 88(10):791-803.
21. Ray JG, O'Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus:A Meta-analysis. QJM, 2001, 94(8):435-444.
22. Yang J, Cummings EA, O'Connell C, et al. Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol, 2006, 108(3 Pt 1):644-650.
23. Levit RD, Reynolds HR, Hochman JS. Cardiovascular disease in young women:A population at risk. Cardiol Rev, 2011, 19(2):60-65.
24. Li DK, Yang C, Andrade S, Tavares V, et al. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring:A retrospective cohort study. BMJ, 2011, 343:d5931.

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Risk of Congenital Malformations Associated with Exposure to Beta-blockers Early in Pregnancy: A Systematic Review and Meta-analysis

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