INTRODUCTION: Data on efavirenz safety in first trimester pregnancy are conflicting. We conducted a systematic review and meta-analysis of the available evidence from observational cohorts. METHODS: We ran duplicate searches of databases (up to 02 January, 2010) and searchable websites of major HIV conferences (up to February, 2010) to identify observational cohorts reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy. Our primary endpoint was birth defects of any kind; secondary outcomes were spontaneous abortions, termination of pregnancy, stillbirths, and preterm delivery. RESULTS: Sixteen studies met our inclusion criteria, comprising 11 prospective cohorts and five retrospective reviews. Nine prospective studies reported on rates for birth defects both among women exposed to efavirenz-containing regimens (1132 live births) and non-efavirenz-containing regimens (7163 live births) during first trimester, giving a pooled, nonsignificant relative risk of 0.87 [95% confidence interval (CI) 0.61-1.24%, P = 0.45]. Low heterogeneity was observed between studies (I = 0, 95% CI 0-56.3%, P = 0.85). Across all studies (1256 live births), one neural tube defect (meningomyelocele) was observed with first trimester efavirenz exposure, giving a prevalence of 0.08% (95% CI 0.002-0.44%). CONCLUSION: We found no increased risk of overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs. Prevalence of overall birth defects with first trimester efavirenz exposure was similar to the ranges reported in the general population. However, the limited sample size for detection of rare outcomes such as neural tube defects prevents a definitive conclusion.