Our GRADE assessment rated the quality of studies as being low. The main limitations were that the majority of studies failed to consider potential threats to validity; five studies considered sources of bias and only three studies adjusted for potential confounders. Most studies were also limited by a small sample size and low event rate that resulted in low statistical confidence around the point estimate.
Our systematic review of the available evidence to date 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. The incidence of overall birth defects with first trimester efavirenz use (2.9%) was similar to the ranges reported in the general population; 2.7% in the United States , 2–5% in France , and 2.5–8% in South Africa . Only one case of a neural tube defect was reported across all cohorts reporting congenital birth defects among first-trimester exposed women (1256 women with live births), giving a point prevalence (0.08%) that is within the range reported among the general population in the United Kingdom (0.14%)  and South Africa (0.36%) . Although these data should provide reassurance to health providers confronted with women who become pregnant while on efavirenz, the low incidence of neural tube defects in the general population means that a larger sample size is still needed to be able to definitively rule out an increased risk of this specific defect. The range in prevalence of secondary outcomes is an effect of both variability in the sample size of individual studies and the diversity of settings included in the review, resulting in differing background rates of these outcomes in the general population. Pooled estimates are not provided for secondary outcomes for this reason.
Strengths of this review include a broad search strategy that identified a number of studies not yet published in the literature and the inclusion of updated data for several cohorts. In addition, our primary analysis was limited to data that were derived from prospective studies, which are less subject to reporting bias than retrospective reports. Nevertheless, there may be a publication bias towards reporting birth defects when a women is on efavirenz and but not reporting birth outcomes if no birth defects occur. Such a publication bias would be expected to lead to an overestimation of the risk of efavirenz compared with other antiretroviral drugs.
An important limitation is that few studies reported on risk of bias or attempted to control for potential confounders, and we were therefore not able to assess the potential effect of these in this review. In particular, women on efavirenz may differ from those not on efavirenz; the latter group may comprise more women who planned their pregnancies and so were more likely to be exposed to protective factors (such as folate supplementation) and reduced risk factors (such as smoking and poor diet). Consideration of confounding is all the more important given that it would not be ethically acceptable to conduct a randomized trial to assess risk. Nevertheless, such differences are unlikely to affect our results importantly, and moreover would be expected to result in an overestimation of the relative risk of birth defects in the efavirenz group.
The main limitation to this review is the limited sample size. Despite calls for more systematic recording of birth outcomes from women receiving antiretroviral drugs during pregnancy , such data remains persistently under-reported, and while there has been a rapid increase in women of childbearing age receiving efavirenz in Africa in recent years, we were only able to identify one registry report from Africa. The few prospective cohorts that do provide reports are inconsistent in reporting of birth outcomes beyond overall birth defects.
Our review provides several directions for research and practice. First, the establishment of prospective birth registries should be supported, particularly in African countries where the majority of first-trimester exposures occur. A number of treatment cohorts contacted during the conduct of this review stated that first-trimester efavirenz exposures were not uncommon, but that such data were not routinely captured. This represents an important missed opportunity. Second, there is a need to support the standardized collection of birth outcome data such that meaningful comparisons can be made with respect not only to rates of birth defects but also other important outcomes such as termination of pregnancy and spontaneous abortions, stillbirths, and preterm deliveries. Third, women in childbearing age represent a substantial proportion of the total number of people infected with HIV in developing countries , and healthcare providers will continue to be faced with women presenting with unintended pregnancies while taking efavirenz. The high rate of termination of pregnancy reported in some cohorts points to a need for improved counseling for women inadvertently exposed during pregnancy. Fourth, periconceptional provision of high-dose folates have proven efficacy in preventing neural tube defects among women with prior risk and could be considered for women of childbearing age who are receiving efavirenz and are likely to become pregnant in settings where folate supplementation is not provided . Finally, efforts must continue to support HIV-positive women to seek care early in their pregnancy.
We would like to thank Musaed Abrahams, Elaine Abrams, Emrahim Bera, Marco Floridia, Didier Ekouevi, Fatima Laher, Elizabeth Machado, Claire Townsend, Patrick A Coffie, and Xavier Anglaret for providing additional data, and Gary Maartens and D. Heather Watts for helpful comments on an earlier draft.
There are no conflicts of interest.
The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of their respective organizations.
N.F. and A.C. conceived the study. N.F., L.M. and K.K., undertook searches, extracted data, and conducted authors for additional data. N.F. performed the statistical analyses and wrote the first draft. All authors supported the interpretation of results, provided comments on subsequent drafts and approved the final version.
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