This analysis of a well-defined cohort of HIV-infected children in Zambia supports earlier work13
indicating that timing of MTCT has a large effect on early childhood mortality. In this cohort, children likely infected in the intrauterine or intrapartum period had substantially increased mortality compared with children infected in the postpartum period, even when limiting the analysis to children who survived at least 40 days to account for the increased mortality in this period. Thus, although children are at constant risk of infection throughout the breast-feeding period,8
children infected by means of this route seem to have decreased mortality compared with those infected earlier. In addition, we found that breast-feeding was strongly protective against mortality among HIV-infected children. Even after adjusting for the timing of infection and maternal death, we found that children who were not breast-fed were 3 times as likely to die over the first year after infection compared with children who were breast-fed. This suggests that increasing the duration of breast-feeding among HIV-infected children could prolong life.
The reasons for decreased mortality among the PP group are not known but may be explained in part by infection at a more mature immunologic stage in the child. Some of the differences may be attributable to inherent differences in age (ie, children infected later are, by definition, older and have survived a period of high mortality); however, we continued to find strong differences even after conditioning on surviving the first 40 days of life. Additionally, because postpartum transmission through breast milk occurs by a different route, the actual dose of virus that a child receives is likely to be different and may lead to different long-term patterns of mortality for children infected through different routes.
This finding of reduced mortality among those infected postpartum is consistent with previous studies that found relative associations of 0.1010
comparing mortality among late versus early infection, depending on the definition of time of infection and variables adjusted for in the analysis. Direct comparisons between our study and previous work are difficult, because the definitions of time of transmission groups used differ slightly. Our results are similar to but more pronounced than findings from the pooled analysis,13
which found later infection (at or after 4 weeks) to be associated with a 26% decrease in mortality (HR = 0.74, 95% CI: 0.55 to 0.99) compared with early infection (before 4 weeks) but found no difference between in utero and intrapartum infections. Their analysis was somewhat different in that they required a negative HIV test result at 4 weeks to be included in the late transmission group, whereas we used categorization based on the midpoint between the last negative and first positive test results. Our results are similar to a recent finding in a cohort of children in Zimbabwe that found similar mortality rates in children infected in utero compared with those infected intrapartum but a strongly reduced risk of mortality in children infected postpartum compared with those infected in utero.14
In our analysis, approximately 20% of children infected before 40 days of life died by 100 days after infection; those infected after 40 days had only reached approximately 10% mortality by that time, leaving more time to intervene. Because this analysis was conducted in a population in which half of the mothers were counseled to wean their children abruptly at 4 months, this study demonstrates that earlier findings of increased mortality associated with intrauterine transmission also hold true in the context of a breast-feeding intervention to prevent MTCT and further demonstrates the need for early detection of HIV so as to intervene as soon as possible.
Unlike our analysis, previous studies on the topic have not examined or have had insufficient variability to examine associations between breast-feeding and mortality in HIV-infected children. Because this analysis was conducted within a population of children involved in a trial of a breast-feeding intervention, detailed data were kept on mothers’ breast-feeding practices. Because HIV transmission can occur after birth through breast milk, children who are breast-fed longer are at increased risk of later HIV infection throughout the lactation period simply because of the prolonged exposure.8
Children who are breast-fed longer have reduced mortality compared with children who are breast-fed for a shorter period, however, making this a potentially strong confounder.
In the pooled analysis13
in which breast-feeding behavior was adjusted for, the authors found no difference in mortality between breast-fed and non–breast-fed children (HR = 1.1, 95% CI: 0.70 to 1.7). There may be residual confounding, however, because their analysis only compares children ever breast-fed with children never breast-fed; 80% of the women had some breast-feeding, which would tend to bias the association of breast-feeding and child death toward the null. Others, however, using time-dependent measures of breast-feeding as we have, have found a protective effect of breast-feeding duration among children born to HIV-infected mothers, even when the child is also infected.24
We found a strong increased risk of death associated with cessation of breast-feeding even after adjustment for maternal mortality, maternal disease stage, and low birth weight; further, addition of breast-feeding cessation to our multivariable model increased the effect of postpartum versus in utero transmission on child mortality, demonstrating the confounding effects of breast-feeding. Having detailed data on breast-feeding allowed us to adjust for changes in breast-feeding over time.
As with some9,13,14
but not all11,12
of the previous studies on this topic that attempted to separate intrapartum or early postpartum transmission from intrauterine transmission, we did not find important or robust differences between children likely infected in utero and children infected in the intrapartum or early postpartum period, even among children who survived to 40 days. This suggests that patterns of mortality in children infected near birth may require similar intervention strategies as those in children infected before birth.
Our study has several limitations that should be considered when interpreting the results. First, following a cohort of children is difficult and LTFs are inevitable. Among the HIV-infected subjects, the risk of LTF was 16% (30 of 187 subjects); LTF was highest among the earliest transmission group (24% in IU group, 13% in IP/EPP group, and 12% in PP group). We consider it unlikely that children in one of the time of transmission groups who were lost to follow-up would be more likely to have been lost because they were closer to death compared with any other group. If those who were lost were more likely to have died compared with others in their group, overall estimates of mortality would likely be underestimated and differences between the groups might be larger than what we observed.
Second, it is possible that some selection bias occurred through children who were excluded because they had no HIV data or because they were lost to follow-up at birth. It is possible that these children were excluded because they were more likely to be HIV infected at birth and that they had higher mortality than those children who were HIV infected in utero and were included in the study. Omitting these children would likely underestimate the effect of later versus early transmission on mortality, and perhaps obscure differences between intrauterine and intrapartum or early postpartum transmission.
In conclusion, this study demonstrates a clear survival benefit among children infected postpartum through breast-feeding transmission compared with children infected in utero or intrapartum, whereas no differences were detected between children infected intrapartum versus those infected in utero. Those who acquire infection at a younger age are at increased risk for mortality. Thus, the window for intervention in children infected earlier may be shorter. Testing children for HIV early in life (ie, at 4 to 6 weeks), as is recommended by current HIV diagnosis algorithms, provides a means for identifying those children most at risk of rapidly succumbing to their HIV infection risk.