We conducted a sensitivity analysis in which the pooled prevalence was assessed after dropping each study in turn to determine the degree of influence of any single study on the overall pooled prevalence estimate of congenital anomalies. In this analysis, the pooled prevalence was reduced from 3.5% (95% CI: 1.8% to 5.1%) to 2.6% (95% CI: 1.2% to 4.0%) when one study34 was dropped from the analysis (see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A531). This study differed from the other studies in 2 notable ways: first, fetal anomalies were diagnosed in utero; second, around half of the cohort were Bedouins in Israel, a community in which there is increased consanguinity.46 Incidence of birth defects was reported to be higher among the Bedouin community during the reporting period of this study.47 These factors may have led to both a higher ascertainment of congenital anomalies and a higher background prevalence of anomalies in this cohort.
Risk of bias was considered to be moderate to high. Seven studies did not directly ascertain cotrimoxazole use, 15 studies did not assess the potential influence of confounders, 14 studies used retrospective designs, 9 studies did not disaggregate outcomes by trimester of exposure, 17 studies did not report on folate use, and 7 studies were at risk of confounding by indication for secondary outcomes (see Table S4, Supplemental Digital Content,http://links.lww.com/QAI/A531). The risk of publication bias was considered to be high, considering that cohorts among whom adverse outcomes occurred are more likely to be documented and published. This was not formally assessed because of the small number of identified studies. Overall, the GRADE assessment determined that the quality of the evidence contributing to the assessment of prevalence and odds of congenital anomalies was very low. This information is summarized in Tables S5 and S6 (see Supplemental Digital Content,http://links.lww.com/QAI/A531).
This review highlights several areas for future research. First, improved surveillance is critical to gather data on cotrimoxazole exposure during pregnancy, as is the case for a number of drugs commonly used in the management of HIV/AIDS, notably efavirenz. This review found few reports from high HIV-burden resource-limited settings, where cotrimoxazole prophylaxis is likely to be of most benefit. The lack of screening for congenital abnormalities and the high rate of unattended deliveries in these settings may change the programmatic implications of the results reported by this review. It will be critical for pregnancy outcome surveillance to include an evaluation of exposure to cotrimoxazole and antiretroviral drugs. Pregnancy outcome surveillance is being reinforced in several countries with the support of WHO and major donors, and the findings from this work will help inform future guidance. More data are needed for all important maternal and infant outcomes when using cotrimoxazole for prophylaxis in HIV-infected pregnant women, in particular in settings of high malaria prevalence, with outcomes disaggregated by trimester and duration of cotrimoxazole exposure, and, where possible, reporting of relevant concomitant exposures (eg, smoking, folate and other nutritional supplementation, use of other drugs). Finally, cotrimoxazole inhibits folic acid synthesis, and 2 studies included in this review suggested that periconceptional daily folic acid supplementation may reduce cotrimoxazole's potential teratogenic effect.29,42 However, concomitant folate use may reduce the antibacterial effect of cotrimoxazole, which warrants further study.
In conclusion, the findings of this review support continued recommendations to provide cotrimoxazole prophylaxis to HIV-infected pregnant women. As with the use of any drug in pregnancy, the benefits of the drug need to be weighed against its potential risks. It is crucial that data collection on maternal and infant outcomes is improved to better assess the safety of cotrimoxazole use during pregnancy. Because of the substantial mortality reduction benefits associated with cotrimoxazole use in HIV-infected individuals with low immunity1,2 and the particular vulnerability of HIV-infected pregnant women to diseases potentially preventable by cotrimoxazole, such as malaria, continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women are warranted.
The authors would like to thank Marco Vitoria for comment on an earlier draft.
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