When stratifying studies according to completion of participant enrollment in relation to the implementation of PMTCT in public sector (pre-2002 vs. 2002 or after), the relative risk of all-cause mortality was higher amongst HEU vs. HUU children before the implementation of PMTCT (pre-2002 risk ratio: 1.73; 95% CI: 1.22–2.46). This increased risk remained even after the widespread availability of PMTCT services, as shown when restricting the analysis to studies that completed study enrollment in 2002 or after (risk ratio: 1.46; 95% CI: 1.14–1.87) (Fig. 4), suggesting that PMTCT does not fully eliminate the risk of increased mortality. This finding was robust even when the cutoff was shifted to 2004 (pre-2004 risk ratio: 1.78; 95% CI: 1.30–2.44 vs. 2004 or after risk ratio: 1.37; 95% CI: 1.05–1.79), a time selected to account for delayed implementation of PMTCT in addition to potentially increased access to triple therapy for PMTCT in some situations. In meta-regression analyses, when regressing the log(risk ratio) against time as a continuous variable, there was a slight trend toward declining mortality among the HEU children vs. HIV-unexposed children, but this difference was not statistically significant (Supplementary Fig. 1, http://links.lww.com/QAD/A956).
When stratified by region within Africa, excluding Central Africa that had only one study, we found that estimates were comparable between southern (risk ratio: 1.55; 95% CI: 1.13–2.13) and western (risk ratio: 1.40; 95% CI: 0.93–2.10) regions of the continent. Although NS and strongly influenced by three studies with the largest effect sizes [24,26,36], summary estimate for Eastern Africa were substantially higher (risk ratio: 5.21; 95% CI: 0.71–38.5) (Supplementary Fig. 2, http://links.lww.com/QAD/A956).
To our knowledge, this is one of the first meta-analyses of the literature showing an increased risk of mortality in HEU children compared with HUU children in LMICs, spanning different contexts and eras of maternal antiretroviral therapy and PMTCT. The increased risks of mortality for perinatally HIV-infected infants and children has been well described compared with uninfected infants and children , but in the current era of worldwide Option B+ for PMTCT, HEU children are a critical population. Our results show that, overall, HEU children compared with HUU children had a 70% increase in the risk of mortality.
The impact of PMTCT programs over the last 14 years is a major public health success, and it is essential that the expansion of antiretroviral prevention and treatment programs remain a global health priority . However, our results show that HEU children are at higher risk of death at least within the first 2 years of life, compared with HUU children. The precise reason for this difference in mortality is unknown, but is likely multifactorial, and may include unrecognized coinfections (e.g. pneumonia, diarrhea or malaria) in the HEU children, impact of HIV on maternal health status (e.g. high viral load, poor transplacental maternal IgG antibody transfer or other immunological phenomena) during pregnancy, increased risk of preterm and or low birth weight outcomes for HIV-positive women [41,42], poorer maternal health or maternal death postnatally impacting the quality of infant care, or corresponding lower socioeconomic status for children born into households with an HIV-infected mother . Although decreased transplacental antibody transfer from HIV-infected mothers has been demonstrated , the fact that the increased risk of mortality for HEU children persists to 2 years postnatally suggests that this cannot be the sole explanation for the mortality difference observed, though it may contribute to a higher mortality risk for exposed uninfected infants in the first 6 months of life. In addition, a number of immunological effects in the children of HIV-infected mothers have been noted, including increased immune activation factors in infants associated with high maternal viral load [45–48]. Few studies describe immunological changes in HIV-exposed infected and HEU children demonstrating HIV-specific immune responses in setting of maternal HIV, though the number of these studies is small [49,50]. It remains to be shown whether HIV-specific immune responses are persistent in HEU infants in this current era of complete maternal viral suppression with combination antiretroviral therapy for PMTCT . In addition, decreased adaptive immunity, in the form of decreased antibody response to standard childhood immunizations, has been found in HEU children, which may account for some differences in mortality [51,52]. The decreased vaccine responses in HEU children is consistent with possible persistent immunological effects that may differentially impact or skew immune responses in the long term for HEU children as result of in-utero HIV exposure [51,52].
No studies have reported on nonbiological risk factors, such as social or environmental conditions, that might contribute to this difference in mortality. One possibility is that HIV-infected mothers may be sicker or more likely to be deceased (along with their male partner), than non-HIV infected mothers and therefore may be less able to provide care. None of the studies reported here provided such data. Such differences in maternal health status could also account for differences in breastfeeding practices between HIV-positive and HIV-negative mothers. As breastfeeding occurs after in-utero HIV exposure it is an effect modifier of the relationship between HIV exposure and all-cause mortality. Previous research has established that breastfeeding is protective against all-cause mortality for all children, and is the recommended feeding modality for all mothers, including those with HIV, in LMICs [51,52]. Breast-feeding can result in mother-to-child transmission of HIV and subsequent HIV-associated mortality, but a shorter duration of breast-feeding (or no breast-feeding at all) by HIV-infected mothers increases mortality from common childhood illnesses [5,6,14,52–57]. However, previous research has shown that when breastfeeding patterns are similar, mortality in HEU infants is still higher than infants born to HIV-uninfected mothers [5,6,14,52].
Given that this meta-analysis reflects over a 20-year time span (1994–2015), it is important to note that there has been a substantial overall decrease in global child mortality over the same time period . However, given the overall decrease in childhood mortality observed in the past 20 years, we would then expect to see an overall smaller effect size over time, with the assumption that childhood mortality would similarly decline in both HEU and HUU populations over the same time period.
Our results should be considered alongside their limitations. First, as with any systematic review, there is the possibility of incomplete retrieval or abstraction of data; due to either human error or those studies, primary outcome was not mortality. However, we used the most complete and comprehensive publically available literature in which most major and well conducted studies should be reported. We also used two independent reviewers for cross reference and error checking. Second, we did not obtain raw data from study investigators for pooled estimation of mortality; we used only those studies that reported appropriate simple proportions or included Kaplan–Meier curves in their data presentation. Third, there was also substantial heterogeneity among the studies. Despite this heterogeneity, we felt it was important to pool the existing data to estimate mortality probability as these data provide a more robust estimate than any single study alone. Fourth, given the smaller number of studies in the postantiretroviral therapy PMTCT era, it is not possible for us to know how much of this effect on child mortality is mediated by maternal antiretroviral therapy (and, subsequently, improved maternal or paternal health status). Fifth, the majority of studies included in our analysis were conducted in an era when antiretroviral therapy was not available for pregnant women. As such, our inability to account for differences in maternal health status and maternal mortality between HIV-positive and HIV-negative women could result in an overestimate of our results. Maternal health status, in relation to when HIV exposure in the infant occurs, could confound or modify the association, whereas maternal mortality is an effect modifier as it occurs after HIV exposure in the infant. Sixth, we were unable to account for breastfeeding practices as an effect modifier in our study. With the exception of Shapiro et al., whose entire study population for the analysis was the arm of The Mashi Study randomized to 6 months exclusive breastfeeding, and Rollins et al. who classified breastfeeding according to WHO definitions as exclusive, predominant, partial or never breastfed, no other study clearly defined breastfeeding practices. As such, our results could be overestimating the association between HIV-exposure and all-cause mortality. However, as the previous research has shown [5,6,14,52], even when controlling for breastfeeding HEU infants and children remain at higher risk of mortality compared with their HIV unexposed counterparts.
We show that there is a consistently observed increased risk of all-cause mortality for HEU infants and children compared with HUU infants and children. The mechanisms for this difference will require carefully conceived prospective cohorts to determine which of the several potential biological or environmental factors is partly or wholly responsible. With the great success of PMTCT, change in breastfeeding practices and HIV-infected adults living longer because of antiretroviral therapy, the population of HEU infants is increasing, highlighting the importance and need to understand the long-term health outcomes in this population. Understanding the causes of increased mortality in HIV-exposed, but uninfected, children will help countries strengthen the capacity to provide quality long-term services for this population. These efforts should ideally be complementary to national and international efforts to improve overall child survival as HEU children are still at risk from major childhood diseases such as pneumonia, diarrhea and malnutrition.
Source of support: Funding was provided by USAID under the terms of the Cooperative Agreement 674-A-00-08-0000-700 to Right to Care and INROADS USAID-674-A-12-00029. This study is made possible by the generous support of the American people through the United States Agency for International Development (USAID). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID, the United States government or the Right to Care Clinics.
There are no conflicts of interest.
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