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The last 15 years have seen dramatic progress globally in reducing mother-to-child transmission of HIV—from a rate of more than 25 percent to less than 5 percent.

But as one public health crisis has been addressed, another has emerged, according to a new study by School of Public Health researchers: children exposed to HIV, but not infected, have a 70 percent higher risk of dying, often within the first two years of life, than those of uninfected mothers.

The study in the journal AIDS raises concerns that a growing population of these children, born to HIV-infected mothers, but who escaped infection, are vulnerable to illness and death, for reasons not yet understood. The higher risk of death did not appear to change after 2002, when global implementation of antiretroviral therapy for all HIV-positive pregnant women became policy, the study found.

“We had thought that the children who were spared transmission might have dodged the bullet—but it seems instead that some portion of them are more susceptible to illness and death,” says study lead author Donald Thea, an SPH professor of global health. “We don’t really know why—and given the serious health outcomes, we need to find out. The more success we have in preventing mother-to-child transmission, the larger this group of children will become. This could easily become one of the most prevalent medical-induced causes of death among children in the world.”

The research team, led by Alana Brennan (SPH’08,’16), an SPH epidemiology instructor and a global health research scientist, conducted the first-ever meta-analysis of more than 20 studies that have been done over the last 15 years on mortality among HIV-exposed children, many of them in sub-Saharan Africa. Nearly all of the studies showed a higher risk of mortality among young children born to HIV-infected mothers than among those not exposed.

The researchers say that while the exact reasons for the elevated risk remain unknown, they may include a combination of biological and social factors such as immune dysfunction in the child because of an abnormality passed on by an HIV-infected mother; poorer maternal health that impacts the quality of infant care; unrecognized non-HIV infections passed from the mother; side effects of HIV medicines given to the mother; and increased preterm or low-birth-weight outcomes for HIV-positive women.

Although decreased antibody transfer from the placenta of HIV-infected mothers has been demonstrated, the researchers say, the fact that the increased risk of death for exposed children persists through the first two years of life “suggests that this cannot be the sole explanation” for the increased mortality risk.

The authors note that there have been no studies on nonbiological risk factors, such as social or environmental conditions.

“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” during the vulnerable infant period, the study says. “Such differences in maternal health status could also account for differences in breastfeeding practices between HIV-positive and HIV-negative mothers.” Breastfeeding is protective against all causes of mortality for all children and is recommended even for mothers with HIV.

The authors urge further studies to determine which biological or environmental factors might be fueling the higher risk.

“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,” they write. “These efforts should ideally be complementary to national and international efforts to improve overall child survival, as [HIV-exposed] children are still at risk from major childhood diseases such as pneumonia, diarrhea, and malnutrition.”

Funding for the study was provided by the US Agency for International Development.

Study coauthors included Matthew Fox, an SPH professor of global health and epidemiology, Christopher Gill, an SPH associate professor of global health, and Rachael Bonawitz, an SPH assistant professor of global health and a School of Medicine assistant professor of pediatrics. Also contributing was Lawrence Long, from the University of Witswatersrand in South Africa.

Lisa Chedekel can be reached at chedekel@bu.edu.