We identify an overlooked population of children at high risk for mortality and morbidity. Early infant mortality and severe morbidity among uninfected infants born to HIV-infected mothers were more than double when maternal CD4+ T cell counts were low. The increase was not explained by maternal mortality, separation due to maternal hospitalization, lower birth weight, or any other factors we investigated. Infant growth was slower when the maternal HIV load was higher.
The magnitude of the population-attributable fraction of this association is not trivial. The HIV seroprevalence among pregnant women remains high in sub-Saharan Africa and has reversed decades of improvement in child survival rates in the world’s poorest countries [15
]. Good population coverage of programs to prevent mother-to-child HIV transmission should be able to offset some of this HIV-related child mortality. However, our data suggest that even complete eradication of vertical transmission will not be able to counteract the full negative impact of HIV infection in reproducing women on the health of their children.
Antiretroviral treatment programs are being implemented in low-resource settings, including the communities where our study was based. Ideally, drug treatment should be reaching mothers with low CD4+
T cell counts whose uninfected children we identified as having poor outcomes. Effective drug treatment typically results in rapid decrease in viral load, gradual increase in CD4+
T count to normal level, and partial correction of many other HIV-related immune dysfunctions [16
]. Initiation of treatment during pregnancy may be too late to protect offspring from all the consequences of advanced HIV disease, but this hypothesis should be empirically tested. If effective, HIV treatment will not only improve maternal health and reduce HIV transmission but may also allow HIV-infected women to have healthier HIV-uninfected children.
We can only speculate on mechanisms underlying the association. Maternal coinfections with opportunistic pathogens, such as cytomegalovirus, Mycobacterium tuberculosis,
hepatitis C virus, and human herpesvirus 8, may be important [17
]. Increased shedding and higher pathogen loads related to immunosuppression may cause increasing numbers of virulent congenital or maternally acquired neonatal infections. Passive immunity may be deficient among infants born to HIV-infected immunocompromised mothers, because reduced transplacental transfer of IgG antibodies to common infections has been observed [24
]. Increased risk of early measles attributable to lower cord blood antibody titers among infants born to HIV-infected mothers has also been observed [25
]. Immunological deficiencies in breast milk may play a role, because immunoglobulins and other components of breast milk are important in protecting infants against infections [26
]. Viral exposure in utero and/or HIV-induced failure of the maternal immune system to adequately support development of competent infant immune capacity may result in diminished capacity of the infant to control common infections [27
]. These vulnerabilities would not have been noticed in US and European cohorts, in which the background coinfection burden is considerably lower. Of concern in cases in which HIV exposure has compromised fetal immune development is that vaccines given in early childhood may not be immunogenic. A study from The Gambia found decreased bacille Calmette-Guérin scar formation among uninfected children born to HIV-infected mothers [29
]. Nutritional or micronutrient deficiencies in breast milk [30
] may be related to poor outcome in infants. Finally, social and psychological factors may also play a role. A physically or emotionally impaired mother may be less able to care for her newborn as well as a vigorous, healthy mother can.
It will be important to investigate whether the association persists in older children as the morbidity profile shifts to diarrheal diseases with the introduction of weaning foods and whether the association is only observed among breastfed infants. Too few infants were not breastfed in these early months to examine nonbreastfeeding infants separately. Another limitation is that markers of advanced maternal disease were measured at a single point during pregnancy. Given the strong predictive power of this measurement, we assume that maternal HIV disease status during pregnancy is most relevant but do not have postnatal maternal data to confirm the assumption. Inclusion of a sufficiently large and identically followed cohort of infants born to HIV-negative mothers would be informative to address whether HIV infection has adverse consequences in the absence of immunosuppression, but it is unlikely that such a cohort would to have offered much additional insight into the association described here.
We cannot entirely rule out that unidentified HIV infection in the child is responsible for the association. The major constraint is the frequency of blood sampling among children. It does not seem reasonable to impose a protocol of blood sampling any more intensive than our own protocol; thus, some uncertainty about the HIV infection status of a deceased child is inevitable. If HIV transmission occurred during the interval between tests, it would also have to result in rapid disease progression. The relatively short lag between the last negative test result and the child’s death (median interval, 12 days) suggests that this is an unlikely explanation. HIV RNA load may be more sensitive than HIV DNA load (our preferred method) for pediatric diagnosis, but differences in sensitivity between these 2 methods are small [31
Maternal mortality and low birth weight were associated with infant mortality and morbidity, as shown elsewhere [4
]. Morbidity risks attributable to lack of breastfeeding are also consistent with expectations [36
]. These risks are the principal reason why avoidance of breastfeeding cannot simply be recommended for all HIV-infected women. Women who stopped breastfeeding early did so of their own volition. All had intended to breastfeed for at least 4 months when initially enrolled. Formula was provided because this commodity is otherwise unaffordable. Stopping breastfeeding was associated with severity of maternal disease, but the association persisted even after adjusting for this variable.
Similar associations have been noted elsewhere [4
]. We expand on these observations to demonstrate that the association between the severity of maternal HIV disease is robust across morbidity, mortality, and growth of HIV-exposed, HIV-uninfected children and remains strong even after adjustment for plausible confounders. Our results are also consistent with associations observed between maternal disease stage and the rapidity of disease progression among HIV-infected children [11
In conclusion, we identify a group of children at high risk of mortality and morbidity who may not necessarily benefit from the HIV treatment and prevention interventions that are currently being implemented. Earlier recognition of immunosuppression in women before they become pregnant may be needed. Understanding of the biological and/or social bases of this association may help develop interventions that could complement programs to prevent mother-to-child HIV transmission and adult HIV treatment services to address the needs of this population of children.