A case control study to examine the pharmacological factors underlying ventricular septal defects in the North of England

Abstract

Background: Amphetamine exposure is associated with congenital cardiac abnormalities in animals. We previously reported an association between recreational use of 2,4-methylenedioxymethamphetamine (ecstasy, MDMA) and ventricular septal defect in babies born to users. We have carried out a case control study to investigate risks in the occurrence of ventricular septal defect in a cohort of babies born in the North East of England. Methods: Cases were identified from paediatric cardiology units in Newcastle upon Tyne and Leeds, and controls were recruited from the mothers of babies born in the same hospital as the index case. Research nurses carried out interviews using a structured questionnaire. Results: A total of 296 case control pairs were studied. There was insufficient exposure to ecstasy to test the primary hypothesis. Increased risk of ventricular septal defect was found to be associated with consumption of cough and cold remedies [pre-conception OR 2.2, 95% CI 1.41, 3.51; pregnancy OR 5.1, 95% CI 2.56, 11.27; exposure in either OR 2.83, 95% CI 1.85, 4.45; P<0.005] and in the case of non-steroidals for exposures in pregnancy (OR 4.2, 95% CI 1.54, 14.26; P<0.005). Conclusions: These findings suggest that ventricular septal defect is associated with consuming the medications identified. They are also compatible with the hypothesis that sympathomimetics (pseudoephedrine, phenylephrine and phenylpropanolamine) present in cough mixtures cause the increased risk, and with our original hypothesis that sympathomimetics and amphetamines are potentially cardiotoxic in utero.

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

References

  1. 1.

    Schaefer C, Peters P (2001) Diuretics. Drugs during pregnancy and lactation: handbook of prescription drugs and comparative risk assessment. Elsevier, Amsterdam, pp 113–115

    Google Scholar 

  2. 2.

    Shepard TH (2002) Annual commentary on human teratogens. Teratology 66:275–277

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Rost van Tonningen, van Driel MM, Garbis Berkvens JM, Reuvers Lodewijks WB (1999) Zwangerschapsuitkomst na ecstacygebruik; 43 gevallen gevolgd door de Teratologie Informatie Service van het RIVM. Ned Tijdschr Geneeskd 143:27–31

    PubMed  Google Scholar 

  4. 4.

    Ho E, Karimi-Tabesh L, Koren G (2001) Characteristics of pregnant women who use Ecstasy (3,4-methylenedioxymethamphetamine). Neurotoxicol Teratol 23:561–567

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    McElhatton PR, Bateman DN, Evans C, Pughe KR, Thomas SHL (1999) Congenital anomalies after prenatal ecstasy exposure. Lancet 354:1441–1442

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Little BB, Toosje T, VanBeveren TT, Gilstrap LC (1998) Amphetamine abuse during pregnancy, Chap 27. In: Gilstrap LC, Little BB (eds) Drugs and pregnancy, 2nd edn. Chapman and Hall, London

  7. 7.

    Schardein JL (2000) CNS stimulants and anorectic agents, Chap 8. In: Chemically induced birth defects, 3rd edn. Marcel Dekker, New York

  8. 8.

    Sands AJ, Casey FA, Craig BG, Dornan JC, Rogers J, Mulholland HC (1999) Incidence and risk factors for ventricular septal defect in ‘low risk’ neonates. Arch Dis Child Fetal Neonatal Ed 81:F61–F63

    CAS  PubMed  Google Scholar 

  9. 9.

    Loffredo CA (2000) Epidemiology of cardiovascular malformations: prevalence and risk factors. Am J Med Gen (Semin Med Genet) 97:319–325

    Article  CAS  Google Scholar 

  10. 10.

    Webb E, Ashton CH, Kelly P, Kamali F (1996) Alcohol and drug use in UK university students. Lancet 348:922–925

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Christophersen AS (2000) Amphetamine designer drugs—an overview and epidemiology. Toxicol Lett Mar 15:127–131

    Article  Google Scholar 

  12. 12.

    St Omer VE, Ali SF, Holson RR, Duhart HM, Scalzo FM, Slikker W Jr (1990) Behavioural and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats. Neurotoxicol Teratol 13:13–20

    Article  Google Scholar 

  13. 13.

    Ferencz C, Rubin JD, Loffredo CA, Magee CA (1993) Epidemiology of congenital heart disease: the Baltimore-Washington Infant Study, 1981–1989. Futura Publishing Co., Mt. Kisko

    Google Scholar 

  14. 14.

    Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson D (2001) Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979–1997. Circulation 103:2376–2381

    CAS  PubMed  Google Scholar 

  15. 15.

    Pradat P, Francannet C, Harris JA et al (2003) The epidemiology of cardiovascular defects, Part I: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 24:195–221

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Tikkanen J, Heinonen OP (1991) Risk factors for ventricular septal defect in Finland. Public Health 105:99–112

    CAS  PubMed  Google Scholar 

  17. 17.

    Chambers CD and Jones KL (2002) Is genotype important in predicting the fetal alcohol syndrome? J Pediatr 141:1751–1752

    Google Scholar 

  18. 18.

    Day NL, Leech SL, Richardson GA et al (2002) Prenatal alcohol exposure predicts continued deficits in offspring size at 14 years of age. Alcohol Clin Exp Res 26:1584–1591

    CAS  PubMed  Google Scholar 

  19. 19.

    O’Callaghan FV, O’Callaghan M, Najman JM et al (2003) Maternal alcohol consumption during pregnancy and physical outcomes up to 5 years of age: a longitudinal study. Early Hum Dev 71:137–148

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Testa M, Quigley BM, das Eiden R (2003) The effects of prenatal alcohol exposure on infant mental development: a meta-analytical review. Alcohol Alcohol 38:295–304

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Källén K (2002) Maternal smoking and congenital malformations. Fetal Matern Med Rev 13:63–86

    Article  Google Scholar 

  22. 22.

    Källén K (1999) Maternal smoking and congenital heart defects. Eur J Epidemiol 15:731–737

    Article  PubMed  Google Scholar 

  23. 23.

    Torfs CP, Katz EA, Bateson TF et al (1996) Maternal medications and environmental exposures as risk factors for gastroschisis. Teratology 54:84–92

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Werler MM, Sheehan JE, Mitchell AA (2002) Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol 155:26–31

    Article  PubMed  Google Scholar 

  25. 25.

    Heinonen OP et al (1997) Birth defects and drugs in pregnancy. Publishing Sciences Group, Littleton, pp 345–356

    Google Scholar 

  26. 26.

    Ericson A, Källén BAJ (2001) Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 15:371–375

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Nielsen GL, Sørensen HT, Larsen H et al (2001) Risk of adverse birth outcome and miscarriage in pregnant users and non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 322:266–270

    Article  CAS  PubMed  Google Scholar 

  28. 28.

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

    Article  PubMed  Google Scholar 

  29. 29.

    Wasserman CR, Shaw GM, O’Malley CD, Tolarova MM, Lammer EJ (1996) Parental cigarette smoking and risk factor for congenital anomalies of the heart, neural tube, or limb. Teratology 53:261–267

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The British Heart Foundation supported this study, and we gratefully acknowledge their support (grant number BHF RES/0130/6595). We also acknowledge the hard work of our research nurses.

Author information

Affiliations

Authors

Corresponding author

Correspondence to D. N. Bateman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bateman, D.N., McElhatton, P.R., Dickinson, D. et al. A case control study to examine the pharmacological factors underlying ventricular septal defects in the North of England. Eur J Clin Pharmacol 60, 635–641 (2004). https://doi.org/10.1007/s00228-004-0829-x

Download citation

Keywords

  • Amphetamine
  • Cough
  • Ecstasy
  • Ventricular Septal Defect
  • Maternal Smoking