In 2014, a systematic review and meta-analysis of observational cohorts reported birth outcomes among women exposed to efavirenz during the first trimester [57]. The primary endpoint was a birth defect of any kind with secondary outcomes

including rates of spontaneous abortions, termination of pregnancy, stillbirths and preterm delivery. Twenty-three studies met the inclusion criteria. The analysis found no increased risk of overall birth defects among 2026 women exposed to efavirenz during EPZ015666 molecular weight first trimester (n = 44, 1.63% 95% CI 0.78–2.48%) compared with exposure to other antiretroviral drugs. Only one neural tube defect was observed with first-trimester efavirenz exposure, giving a prevalence of 0.05% (95% CI < 0.01–0.28%). Furthermore, the prevalence of overall birth defects with first-trimester efavirenz exposure was similar to the ranges reported in the general population. This meta-analysis includes published data up to 30th June 2013 including data from the APR and the

IeDEA and ANRS databases [57]. Two publications have reported higher rates of congenital birth defects associated with efavirenz, Sirolimus mouse Brogly et al. (15.6%) [58] and Knapp et al. (12.8%) [59]. The Writing Group considers these rates to be inflated. Recruitment occurred prenatally but also up to 12 months of age, which could confer recruitment bias. Although the overall study numbers were large, the number of efavirenz exposures used as the denominator in the final analyses Adenylyl cyclase of first-trimester exposure was small, 32 and 47, respectively. There was no difference in the anomaly rate found with no exposure versus any exposure in T1/T2/T3. In addition, no pattern of anomalies specific to efavirenz was described by these studies: patent foramen ovale (n = 1); gastroschisis (n = 1); polydactyly

(n = 1); spina bifida cystica (n = 1); plagiocephaly (n = 1); Arnold Chiari malformation (n = 1) and talipes (n = 1). The reporting of two cases of congenital malformation was duplicated in the two studies. The paper by the NISDI Perinatal Study Group [60], which was used as a comparator by Knapp et al. to support their findings, reported similar overall congenital anomaly rates of 6.16% and also accepted reports up to 6 months of age. Adjustment of the congenital anomaly rate by the authors to those noted within 7 days, as reported by the APR (2.7%) and the non-HIV background rate (2.8%), gives a similar rate of 2.4% and is consistent with reported rates in the UK (3.1% for first trimester and 2.75% for second/third trimester-only ARV exposure) [61]. Thus, it remains the recommendation of the Writing Group, based on current evidence, that efavirenz can be used in pregnancy without additional precautions and considerations over and above those of other antiretroviral therapies.