Introduction Approximately 10-15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2-receptor antagonists. Areas covered This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post-hoc because of several previously published meta-analyses and commentaries on this medication. Expert opinion The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: (1) selection of appropriate study population; (2) ascertainment of antihistamine exposures; and (3) ascertainment of birth defects outcomes. Selected antihistamines have been very well-studied (e.g. loratadine); others, especially H2- receptor antagonists, require additional study before an assessment of safety with respect to birth defects risk could be made.