Drug Safety

, Volume 31, Issue 9, pp 775–788 | Cite as

Risk of Hypospadias in Offspring of Women Using Loratadine during Pregnancy

A Systematic Review and Meta-Analysis
  • Eleanor B. Schwarz
  • Myla E. Moretti
  • Smita Nayak
  • Gideon Koren
Original Research Article


Background: Loratadine, a second-generation antihistamine, is commonly used to treat seasonal allergies. Some studies have suggested that use of loratadine by pregnant women increases the risk of hypospadias in male offspring.

Objective: This meta-analysis was designed to assess the strength of the association between loratadine and hypospadias.

Methods: To locate pertinent articles published in any language from January 1989 until August 2007, we searched electronic databases (MEDLINE, OVID, EMBASE, SCOPUS, TOXLINE Special, ReproTox, TERIS, CINAHL and others), conference proceedings and bibliographies. Studies were eligible for this analysis if they were cohort, case-control or case series studies that reported the incidence of hypospadias in the offspring of women who were or were not exposed to loratadine during pregnancy. Two authors independently extracted information on study design, participant characteristics, measures of outcome, control for potential confounding factors and risk estimates using a standardized data collection form. The Newcastle-Ottawa Scale was then used to assess the quality of each study. We used a random-effects meta-analysis model to combine the risk data.

Results: In 1402 potentially relevant titles, we found three case-control studies and seven cohort studies that reported the incidence of hypospadias or other congenital malformations in offspring of women who did or did not use loratadine during pregnancy. Together the studies in our meta-analysis provided information about 453 053 male births in Brazil, Canada, Denmark, Israel, Italy, Sweden, the UK and the US.



This study was funded by grant K23 HD051585-01 from the National Institute of Child Health and Human Development (NICHD). The NICHD was not involved in study design; the collection, analysis and interpretation of data; or the writing of this report. We thank reference librarian Melissa Ratajeski for her guidance. No authors have any conflicts of interest to report.


  1. 1.
    Mazzotta P, Loebstein R, Koren G. Treating allergic rhinitis in pregnancy: safety considerations. Drug Saf 1999; 20(4): 361–75PubMedCrossRefGoogle Scholar
  2. 2.
    Werler MM, Mitchell AA, Hernandez-Diaz S, et al. Use of overthe-counter medications during pregnancy. Am J Obstet Gynecol 2005; 193 (3 Pt 1): 771–7PubMedCrossRefGoogle Scholar
  3. 3.
    Glover DD, Amonkar M, Rybeck BF, et al. Prescription, overthe-counter, and herbal medicine use in a rural, obstetric population. Am J Obstet Gynecol 2003; 188(4): 1039–45PubMedCrossRefGoogle Scholar
  4. 4.
    Gilbert C, Mazzotta P, Loebstein R, et al. Fetal safety of drugs used in the treatment of allergic rhinitis: a critical review. Drug Saf 2005; 28(8): 707–19PubMedCrossRefGoogle Scholar
  5. 5.
    Kallen B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002; 11(3): 146–52PubMedCrossRefGoogle Scholar
  6. 6.
    Kallen B, Olausson PO. Monitoring of maternal drug use and infant congenital malformations: does loratadine cause hypospadias? Int J Risk Safety Med 2001; 14: 115–9Google Scholar
  7. 7.
    Gallentine ML, Morey AF, Thompson Jr IM. Hypospadias: a contemporary epidemiologic assessment. Urology 2001; 57(4): 788–90PubMedCrossRefGoogle Scholar
  8. 8.
    Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev 2001; 61(2): 85–95PubMedCrossRefGoogle Scholar
  9. 9.
    Fredell L, Kockum I, Hansson E, et al. Heredity of hypospadias and the significance of low birth weight. J Urol 2002; 167(3): 1423–7PubMedCrossRefGoogle Scholar
  10. 10.
    Wennerholm UB, Bergh C, Hamberger L, et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000; 15(4): 944–8PubMedCrossRefGoogle Scholar
  11. 11.
    Mclntyre BS, Vancutsem PM, Treinen KA, et al. Effects of perinatal loratadine exposure on male rat reproductive organ development. Reprod Toxicol 2003; 17(6): 691–7CrossRefGoogle Scholar
  12. 12.
    Willingham E, Agras K, Vilela M, et al. Loratadine exerts estrogen-like effects and disrupts penile development in the mouse. J Urol 2006; 175(2): 723–6PubMedCrossRefGoogle Scholar
  13. 13.
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283(15): 2008–12PubMedCrossRefGoogle Scholar
  14. 14.
    Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. 2006 [cited 2006 Nov 14]. OHRI [online]. Available from URL: http://www.ohri.ca/programs/clinical_epidemiology/nosgen.doc [Accessed 2006 Nov 14]
  15. 15.
    Werler M, McCloskey C, Edmonds L, et al. Evaluation of an association between loratadine and hypospadias: United States, 1997–2001. Arch Dermatol 2004; 140(7): 893–4CrossRefGoogle Scholar
  16. 16.
    Pedersen L, Norgaard M, Skriver MV, et al. Prenatal exposure to loratadine in children with hypospadias: a nested casecontrol study within the Danish National Birth Cohort. Am J Ther 2006; 13(4): 320–4PubMedCrossRefGoogle Scholar
  17. 17.
    Pedersen L, Skriver MV, Norgaard M, et al. Maternal use of loratadine during pregnancy and risk of hypospadias in offspring. Int J Med Sci 2006; 3(1): 21–5PubMedCrossRefGoogle Scholar
  18. 18.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3): 177–88PubMedCrossRefGoogle Scholar
  19. 19.
    Brown JE, Stern H, Leeds T. Loratadine and pregnancy: outcomes in 49 pregnancies. Allergy Asthma Proc 1999; 20(3): 199–200CrossRefGoogle Scholar
  20. 20.
    Werler M, McCloskey C, Edmonds L, et al. Evaluation of an association between loratadine and hypospadias: United States, 1997–2001. JAMA 2004; 291(15): 1828–30CrossRefGoogle Scholar
  21. 21.
    Werler M, McCloskey C, Edmonds L, et al. Evaluation of an association between loratadine and hypospadias: United States, 1997–2001. MMWR Morb Mortal Wkly Rep 2004; 53(10): 219–21Google Scholar
  22. 22.
    Diav-Citrin O, Shechtman S, Aharonovich A, et al. Pregnancy outcome after gestational exposure to loratadine or antihistamines: a prospective controlled cohort study. J Allergy Clin Immunol 2003; 111(6): 1239–43PubMedCrossRefGoogle Scholar
  23. 23.
    Kallen B, Olausson PO. No increased risk of infant hypospadias after maternal use of loratadine in early pregnancy. Int J Med Sci 2006; 3(3): 106–7PubMedCrossRefGoogle Scholar
  24. 24.
    Moretti ME, Caprara D, Coutinho CJ, et al. Fetal safety of loratadine use in the first trimester of pregnancy: a multicenter study. J Allergy Clin Immunol 2003; 111(3): 479–83PubMedCrossRefGoogle Scholar
  25. 25.
    Wilton LV, Pearce GL, Martin RM, et al. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998; 105(8): 882–9PubMedCrossRefGoogle Scholar
  26. 26.
    Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatal 1997; 14(3): 119–24CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Eleanor B. Schwarz
    • 1
  • Myla E. Moretti
    • 2
  • Smita Nayak
    • 1
  • Gideon Koren
    • 2
  1. 1.Division of General Internal Medicine, Department of Medicine, Center for Research on Health CareUniversity of PittsburghPittsburghUSA
  2. 2.Motherisk Program, Division of Clinical Pharmacology/ToxicologyHospital for Sick ChildrenTorontoCanada

Personalised recommendations