Download PDF
Am J Perinatol 2014; 31(08): 701-710
DOI: 10.1055/s-0033-1358772
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Re-analysis of Safety Data Supporting Doxylamine Use for Nausea and Vomiting of Pregnancy

Jessica W. S. Chin
1   Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
,
Sarah Gregor
1   Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
,
Navindra Persaud
1   Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
2   Department of Family and Community Medicine, St Michael's Hospital, Toronto, Ontario, Canada
3   Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations
Further Information

Publication History

05 November 2012

23 August 2013

Publication Date:
09 December 2013 (online)

Also available at
    Permissions and Reprints

Abstract

Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded antihistamine use for NVP was safe as they had been studied in more than 200,000 participating women and the pooled odds ratio for congenital malformations was 0.76 (95% confidence interval [CI]: 0.60–0.94). Our analysis of this meta-analysis showed that 139,414 women were included in 22 original studies involving antihistamines, 129,108 of which were in studies involving doxylamine. In these studies, 23,485 women were exposed to antihistamines, 14,624 of which were exposed to doxylamine. The summary relative risk (cohort studies) and odds ratio (case–control studies) for congenital malformations from antihistamine exposure were 1.09 (95% CI: 1.01–1.18) and 1.04 (95% CI: 0.91–1.19), and for doxylamine exposure, the summary relative risk and odds ratio were 0.94 (95% CI: 0.80–1.10) and 1.07 (95% CI: 0.93–1.23), respectively. Although not a new systematic review, our re-analysis demonstrates that the safety data for antihistamines, and doxylamine in particular, are based on many fewer than 200,000 participating women and exposures, and that doxylamine use is not associated with a decreased risk of malformations as previously reported.

Keywords

congenital malformations - doxylamine - nausea and vomiting of pregnancy - drug safety
 

  • References

  • 1 Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43 (371) 245-248
    PubMedGoogle Scholar
  • 2 Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000; 182 (4) 931-937
    CrossrefPubMedGoogle Scholar
  • 3 Briggs G, Freeman RK, Yaffe SJ. Doxylamine. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risks. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011: 4527
    Google Scholar
  • 4 Public Health Agency of Canada. Statement on Pregnancy and Travel; 2010. Available at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-2/index-eng.php . Accessed May 17, 2012
    PubMedGoogle Scholar
  • 5 Arsenault MY, Lane CA, MacKinnon CJ , et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can 2002; 24 (10) 817-831 , quiz 832–833
    PubMedGoogle Scholar
  • 6 Einarson A, Maltepe C, Boskovic R, Koren G. Treatment of nausea and vomiting in pregnancy: an updated algorithm. Can Fam Physician 2007; 53 (12) 2109-2111
    PubMedGoogle Scholar
  • 7 Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997; 14 (3) 119-124
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Kar S, Krishnan A, Preetha K, Mohankar A. A review of antihistamines used during pregnancy. J Pharmacol Pharmacother 2012; 3 (2) 105-108
    PubMedGoogle Scholar
  • 9 So M, Bozzo P, Inoue M, Einarson A. Safety of antihistamines during pregnancy and lactation. Can Fam Physician 2010; 56 (5) 427-429
    PubMedGoogle Scholar
  • 10 Magee LA, Mazzotta P, Koren G. Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol 2002; 186 (5, Suppl Understanding ): S256-S261
    CrossrefPubMedGoogle Scholar
  • 11 Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and non-pharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000; 59: 781-800
    CrossrefPubMedGoogle Scholar
  • 12 Ayd Jr FJ. Haloperidol: fifteen years of clinical experience. Dis Nerv Syst 1972; 33 (7) 459-469
    PubMedGoogle Scholar
  • 13 Aselton PJ, Jick H. Additional follow-up of congenital limb disorders in relation to Bendectin use. JAMA 1983; 250 (1) 33-34
    CrossrefPubMedGoogle Scholar
  • 14 Gibson GT, Colley DP, McMichael AJ, Hartshorne JM. Congenital anomalies in relation to the use of doxylamine/dicyclomine and other antenatal factors: an ongoing prospective study. Med J Aust 1981; 1 (8) 410-414
    PubMedGoogle Scholar
  • 15 Bunde CA, Bowles DM. A technique for controlled survey of case records. Curr Ther Res Clin Exp 1963; 5: 245-248
    PubMedGoogle Scholar
  • 16 Kullander S, Källén B. A prospective study of drugs and pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976; 55 (2) 105-111
    CrossrefPubMedGoogle Scholar
  • 17 Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. First-trimester drug use and congenital disorders. JAMA 1981; 246 (4) 343-346
    CrossrefPubMedGoogle Scholar
  • 18 Golding J, Vivian S, Baldwin JA. Maternal anti-nauseants and clefts of lip and palate. Hum Toxicol 1983; 2 (1) 63-73
    CrossrefPubMedGoogle Scholar
  • 19 Greenberg G, Inman WHW, Weatherall JAC, Adelstein AM, Haskey JC. Maternal drug histories and congenital abnormalities. BMJ 1977; 2 (6091) 853-856
    CrossrefPubMedGoogle Scholar
  • 20 Newman NM, Correy JF, Dudgeon GI. A survey of congenital abnormalities and drugs in a private practice. Aust N Z J Gynaecol 1977; 17: 156-159
    PubMedGoogle Scholar
  • 21 General Practitioner Research Group. General Practitioner Clinical Trials: drugs in pregnancy survey . Practitioner 1963; 191: 775-780
    PubMedGoogle Scholar
  • 22 Smithells RW, Sheppard S. Teratogenicity testing in humans: a method demonstrating safety of bendectin. Teratology 1978; 17 (1) 31-35
    CrossrefPubMedGoogle Scholar
  • 23 Zierler S, Rothman KJ. Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med 1985; 313 (6) 347-352
    CrossrefPubMedGoogle Scholar
  • 24 Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton MA: PSG Publishing; 1977
    Google Scholar
  • 25 Mellin G, Katzenstein M. Meclozine and fetal abnormalities. Lancet 1963; 26: 222-223
    PubMedGoogle Scholar
  • 26 Milkovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976; 125 (2) 244-248
    PubMedGoogle Scholar
  • 27 Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. BMJ 1971; 1 (5748) 523-527
    CrossrefPubMedGoogle Scholar
  • 28 Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109 (4) 433-439
    PubMedGoogle Scholar
  • 29 Morelock S, Hingson R, Kayne H , et al. Bendectin and fetal development. A study of Boston City Hospital. Am J Obstet Gynecol 1982; 142 (2) 209-213
    PubMedGoogle Scholar
  • 30 McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994; 50 (1) 27-37
    CrossrefPubMedGoogle Scholar
  • 31 Michaelis J, Gluck E, Michaelis H , et al. Does Lenotan have teratogenic effects?. Dtsch Arzt 1980; 23: 1527-1529
    PubMedGoogle Scholar
  • 32 Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989; 40 (2) 151-155
    CrossrefPubMedGoogle Scholar
  • 33 Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985; 65 (4) 451-455
    PubMedGoogle Scholar
  • 34 Erickson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology 1991; 43 (1) 41-51
    CrossrefPubMedGoogle Scholar
  • 35 Fejzo MS, Ingles SA, Wilson M , et al. High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. Eur J Obstet Gynecol Reprod Biol 2008; 141 (1) 13-17
    CrossrefPubMedGoogle Scholar
  • 36 Matthews A, Dowswell T, Haas DM, Doyle M, O'Mathúna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010; (9, Issue 9) CD007575
    PubMedGoogle Scholar
  • 37 Seto A, Einarson T, Koren G. Evaluation of brompheniramine safety in pregnancy. Reprod Toxicol 1993; 7 (4) 393-395
    PubMedGoogle Scholar
  • 38 Nora JJ, Nora AH, Sommerville RJ, Hill RM, McNamara DG. Maternal exposure to potential teratogens. JAMA 1967; 202 (12) 1065-1069
    CrossrefPubMedGoogle Scholar
  • 39 Fleming DM, Knox JDE, Crombie DL. Debendox in early pregnancy and fetal malformation. Br Med J (Clin Res Ed) 1981; 283 (6284) 99-101
    CrossrefPubMedGoogle Scholar
  • 40 Michaelis J, Michaelis H, Glück E, Koller S. Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations. Teratology 1983; 27 (1) 57-64
    CrossrefPubMedGoogle Scholar
  • 41 Eskenazi B, Bracken MB. Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982; 144 (8) 919-924
    PubMedGoogle Scholar