Skip to main content
SpringerLink
Log in

Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis

  • Original Article
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Maternal hypertension is common during pregnancy, and multiple studies have reported on an association between maternal hypertension and congenital heart defects (CHDs) in offspring; however, there is variability in the quality of these studies. A systematic review and meta-analysis was conducted on the associations between untreated and treated maternal hypertension and the risk of CHDs, evaluating CHDs overall as well as specific CHD subtypes. A systematic search of peer-reviewed articles published before August 2013 identified 16 studies evaluating the associations between untreated and treated maternal hypertension and CHDs. Summary relative risk (RR) estimates were calculated using fixed-effects models and random-effects models. Significant associations were observed between maternal hypertension and overall CHDs, for both treated [RR 2.0; 95 % confidence interval (CI) 1.5, 2.7] and untreated (RR 1.4; 95 % CI 1.2, 1.7) hypertension, as well as for overall hypertension regardless of treatment status (RR 1.8; 95 % CI 1.5, 2.2). The magnitude of effect was similar for the majority of CHD subtypes evaluated. The effects were also similar among women with hypertension who used one of multiple specific hypertension medications. There was no evidence of publication bias, and our results were robust to several factors considered in sensitivity analyses (e.g., source of exposure data, adjustment for potential confounders, and study design). Maternal hypertension was associated with CHDs. By understanding the specific mechanisms involved, appropriate strategies may be developed to reduce this risk, in order to prevent CHDs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Al Khaja KA, Sequeira RP, Alkhaja AK, Damanhori AH (2014) Drug treatment of hypertension in pregnancy: a critical review of adult guideline recommendations. J Hypertens 32(3):454–463. doi:10.1097/HJH.0000000000000069

    Article  CAS  PubMed  Google Scholar 

  2. Alwan S, Polifka JE, Friedman JM (2005) Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A 73(2):123–130. doi:10.1002/bdra.20102

    Article  CAS  Google Scholar 

  3. Ananth CV, Peedicayil A, Savitz DA (1995) Effect of hypertensive diseases in pregnancy on birthweight, gestational duration, and small-for-gestational-age births. Epidemiology 6(4):391–395

    Article  CAS  PubMed  Google Scholar 

  4. Banhidy F, Acs N, Puho EH, Czeizel AE (2011) Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population-based study. Hypertens Res 34(2):257–263. doi:10.1038/hr.2010.227

    Article  PubMed  Google Scholar 

  5. Bateman BT, Huybrechts KF, Fischer MA, Seely EW, Ecker JL, Oberg AS, Franklin JM, Mogun H, Hernandez-Diaz S (2014) Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study. Am J Obstet Gynecol. doi:10.1016/j.ajog.2014.09.031

    PubMed Central  Google Scholar 

  6. Botto LD, Correa A, Erickson JD (2001) Racial and temporal variations in the prevalence of heart defects. Pediatrics 107(3):E32

    Article  CAS  PubMed  Google Scholar 

  7. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, National Birth Defects Prevention Study (2007) Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A 79(10):714–727. doi:10.1002/bdra.20403

    Article  CAS  Google Scholar 

  8. Caton AR, Bell EM, Druschel CM, Werler MM, Lin AE, Browne ML, McNutt LA, Romitti PA, Mitchell AA, Olney RS, Correa A, National Birth Defects Prevention Study (2009) Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations. Hypertension 54(1):63–70. doi:10.1161/HYPERTENSIONAHA.109.129098

    Article  CAS  PubMed  Google Scholar 

  9. CDC (1997) Postmarketing surveillance for angiotensin-converting enzyme inhibitor use during the first trimester of pregnancy—United States, Canada and Isreal, 1987–1995. MMWR Morb Mortal Wkly Rep 46:2

    Google Scholar 

  10. Clark EB (1986) Mechanisms in the pathogenesis of congenital cardiac malformations. In: Pierpont ME, Moller JH (eds) The genetics of cardiovascular disease. Martinus Nijhoff Publishing, Boston, MA, p 8

    Google Scholar 

  11. Clark EB (1996) Pathogenetic mechanisms of congenital cardiovascular malformations revisited. Semin Perinatol 20(6):465–472

    Article  CAS  PubMed  Google Scholar 

  12. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA (2006) Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 354(23):2443–2451. doi:10.1056/NEJMoa055202

    Article  CAS  PubMed  Google Scholar 

  13. Czeizel AE, Banhidy F (2011) Chronic hypertension in pregnancy. Curr Opin Obstet Gynecol 23(2):76–81. doi:10.1097/GCO.0b013e328342b7a9

    Article  PubMed  Google Scholar 

  14. Davis RL, Eastman D, McPhillips H, Raebel MA, Andrade SE, Smith D, Yood MU, Dublin S, Platt R (2011) Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiol Drug Saf 20(2):138–145. doi:10.1002/pds.2068

    Article  PubMed Central  PubMed  Google Scholar 

  15. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  16. Excellence NIfHaC (2010) Hypertension in pregnancy: the management of hypertensive disorders during pregnancy. NICE Guidelines. Accessed June 9, 2014

  17. Fang J, Madhavan S, Alderman MH (1999) The influence of maternal hypertension on low birth weight: differences among ethnic populations. Ethn Dis 9(3):369–376

    CAS  PubMed  Google Scholar 

  18. Ferencz C, Rubin J, Loffredo C, Magee C (1993) Epidemiology of Congenital Heart Disease: the Baltimore Washington Infant Study 1981–89. Futura Publishing Company, Mount Kisco

    Google Scholar 

  19. Hoffman JI (1990) Congenital heart disease: incidence and inheritance. Pediatr Clin North Am 37(1):25–43

    CAS  PubMed  Google Scholar 

  20. Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, Elixson M, Warnes CA, Webb CL, American Heart Association Council on Cardiovascular Disease in the Young (2007) Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115(23):2995–3014. doi:10.1161/CIRCULATIONAHA.106.183216

    Article  PubMed  Google Scholar 

  21. Johnson KC, Rouleau J (1997) Temporal trends in Canadian birth defects birth prevalences, 1979–1993. Can J Public Health 88(3):169–176

    CAS  PubMed  Google Scholar 

  22. Kallen BA, Otterblad Olausson P (2003) Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 17(3):255–261

    Article  CAS  PubMed  Google Scholar 

  23. Lawler J, Osman M, Shelton JA, Yeh J (2007) Population-based analysis of hypertensive disorders in pregnancy. Hypertens Pregnancy 26(1):67–76. doi:10.1080/10641950601147945

    Article  PubMed  Google Scholar 

  24. Lennestal R, Otterblad Olausson P, Kallen B (2009) 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 65(6):615–625. doi:10.1007/s00228-009-0620-0

    Article  CAS  PubMed  Google Scholar 

  25. Lennestal R, Olausson P, Kallen B (2009) Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in infants. Eur J Clin Phamacol 65:10

    Article  Google Scholar 

  26. Li DK, Yang C, Andrade S, Tavares V, Ferber JR (2011) Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 343:d5931. doi:10.1136/bmj.d5931

    Article  PubMed Central  PubMed  Google Scholar 

  27. Liu S, Joseph KS, Lisonkova S, Rouleau J, Van den Hof M, Sauve R, Kramer MS (2013) Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 128(6):583–589. doi:10.1161/CIRCULATIONAHA.112.001054

    Article  PubMed  Google Scholar 

  28. Malm H, Artama M, Gissler M, Klaukka T, Merilainen J, Nylander O, Padlan M, Palva E, Ritvannen A, Tyrkko K (2008) First trimester use of ACE-inhibitors and risk of major malformations. Reprod Toxicol 05:5

    Google Scholar 

  29. Mastrobattista JM (1997) Angiotensin converting enzyme inhibitors in pregnancy. Semin Perinatol 21(2):124–134

    Article  CAS  PubMed  Google Scholar 

  30. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012. doi:10.1016/j.jclinepi.2009.06.005

    Article  PubMed  Google Scholar 

  31. Moussa HN, Arian SE, Sibai BM (2014) Management of hypertensive disorders in pregnancy. Women’s Health 10(4):385–404. doi:10.2217/whe.14.32

    Article  CAS  PubMed  Google Scholar 

  32. Nakhai-Pour HR, Rey E, Berard A (2010) Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Res B 89(2):147–154. doi:10.1002/bdrb.20238

    CAS  Google Scholar 

  33. Roberts CL, Bell JC, Ford JB, Hadfield RM, Algert CS, Morris JM (2008) The accuracy of reporting of the hypertensive disorders of pregnancy in population health data. Hypertens Pregnancy 27(3):285–297. doi:10.1080/10641950701826695

    Article  PubMed Central  PubMed  Google Scholar 

  34. Roberts JMAP, Bakris G et al (2013) Hypertension in pregnancy report of the American College of Obstetricians and Gynecologists’ Task Force on hypertension in pregnancy. Obstet Gynecol 122(5):9

    Google Scholar 

  35. Schoendorfer C, Hannemann D, Meister R, Eléfant E, Maarschalkerweerd B, Arnon J, Vial T, Pinilla E, Clementi M, Gnansia E, Santis M, MalmH Dolivo A, Schaefer C (2008) The safety of calcium channel blockers during pregnancy: a prospective, multicenter, observational study. Reprod Toxicol 26:24

    Article  Google Scholar 

  36. Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J (2001) The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Obstet Gynecol Scand 80(5):397–401

    Article  CAS  PubMed  Google Scholar 

  37. Tikkanen J, Heinonen OP (1990) Risk factors for cardiovascular malformations in Finland. Eur J Epidemiol 6(4):348–356

    Article  CAS  PubMed  Google Scholar 

  38. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2013) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed Mar 24, 2015

  39. Vereczkey A, Kosa Z, Csaky-Szunyogh M, Gerencser B, Czeizel AE (2014) Birth outcomes of cases with conotruncal defects of heart—a population-based case–control study. J Maternal-Fetal Neonatal Med. doi:10.3109/14767058.2014.918598

    Google Scholar 

  40. Yang Q, Chen H, Correa A, Devine O, Mathews TJ, Honein MA (2006) Racial differences in infant mortality attributable to birth defects in the United States, 1989–2002. Birth Defects Res A 76(10):706–713. doi:10.1002/bdra.20308

    Article  CAS  Google Scholar 

  41. Zen TD, Rosa RF, Zen PR, Trevisan P, da Silva AP, Ricachinevsky CP, Paskulin GA (2011) Gestational and family risk factors for carriers of congenital heart defects in southern Brazil. Pediatr Int 53(4):551–557. doi:10.1111/j.1442-200X.2011.03341.x

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5P01HD070454). We thank Helena Vonville, MLS, MPH for assistance with the literature search.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, 1200 Herman Pressler, Houston, TX, USA

    Anushuya Ramakrishnan, Laura J. Lee, Laura E. Mitchell & A. J. Agopian

Authors
  1. Anushuya Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura J. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura E. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. J. Agopian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. J. Agopian.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramakrishnan, A., Lee, L.J., Mitchell, L.E. et al. Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis. Pediatr Cardiol 36, 1442–1451 (2015). https://doi.org/10.1007/s00246-015-1182-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-015-1182-9

Keywords

Search

Navigation