Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis.
BACKGROUND
Primate studies and some observational human data have raised concern regarding an association of first-trimester efavirenz exposure with central nervous system congenital anomalies. The objective of this review is to update evidence on efavirenz safety in HIV-infected pregnant women to inform revision of the 2013 WHO guidelines for antiretroviral therapy in low and middle-income countries.


METHODS
A systematic review and meta-analysis.


METHODS
We searched for studies reporting birth outcomes among women exposed to efavirenz during the first trimester of pregnancy up to 10 January 2014. Relative risks of congenital anomalies comparing women exposed to efavirenz and nonefavirenz-based antiretroviral regimens were pooled using random effects meta-analysis.


RESULTS
Twenty-three studies were included in this review, among which 21 reported the birth outcomes of 2026 live births among women exposed to efavirenz during the first trimester of pregnancy. Forty-four congenital anomalies were reported, giving a pooled proportion of 1.63% [95% confidence interval (95% CI) 0.78-2.48], with only one neural tube defect. Twelve studies reported birth outcomes of women exposed to efavirenz or nonefavirenz-containing regimens during the first trimester of pregnancy. Pooled analysis found no differences in overall risks congenital anomalies between these two groups (relative risk 0.78, 95% CI 0.56-1.08). The incidence of neural tube defects was low, 0.05% (95% CI <0.01-0.28), and similar to incidence in the general population.


CONCLUSIONS
This updated analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz, similar to previous systematic reviews. This review contributed to the evidence base for the revised 2013 WHO guidelines on antiretroviral therapy, which recommend that efavirenz can be included as part of first-line therapy in adults regardless of sex, and that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted.
aHIV Department, World Health Organization, Geneva, Switzerland bEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA cDepartment of Infectious Disease Epidemiology, Imperial College London, London, UK dHIV/AIDS Unit, Infectious Disease Service, Geneva University Hospital eMédecins Sans Frontières, Geneva, Switzerland.
Nathan
N
Ford
Lynne
L
Mofenson
Zara
Z
Shubber
Alexandra
A
Calmy
Isabelle
I
Andrieux-Meyer
Marco
M
Vitoria
Nathan
N
Shaffer
Françoise
F
Renaud
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000480:Alkynes; D048588:Benzoxazines / Q000009:adverse effects*; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000151:congenital; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D011261:Pregnancy Trimester, First; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D016896:Treatment Outcome
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz