Premature truncation of the usual breastfeeding duration more than doubled the risk of death among uninfected children and the increase was more than 4-fold if mothers were not yet immunocompromised. Weaning at older ages continued to confer elevated mortality risks with 3- and 4-fold elevations with weaning between 6-11 months and 12-18 months, respectively, relative to breastfeeding for longer than 18 months. Mortality elevations were > 7-fold higher with weaning 6-11 months and 12-18 months if mothers had CD4 counts >350 cells/uL. These sobering results are consistent with prior studies which have observed among the general population that breastfeeding continues to protect against mortality even into the second year of life [5
There was some evidence that the study interventions to support early weaning were beneficial. These interventions included counseling, education about preparation of replacement feeds and hygiene, growth monitoring, including nutritional supplementation of children manifesting signs of failure to thrive, cotrimoxazole, and provision of a 3-month supply of nutritionally-replete replacement foods. Hazard ratios associated with weaning during the study-supported interval of 4-5 months were slightly lower than elevations observed at older ages. Despite these interventions, weaning was associated with a more than 2-fold higher risk of death than continued breastfeeding. It is unclear what more could be added to make weaning safer than what was done as part of our study. It is possible that we have reached a biological threshold. Moreover, adverse effects of early weaning were not confined to the acute period immediately after weaning, suggesting that it is the absence of breast milk, rather than some temporary difficulty of the child adjusting to change, that is responsible for elevated mortality. It is likely that death due to weaning will be greater in real-world program situations where the extent of education and nutritional support is less than provided by our trial. Higher mortality rates have been observed in program settings [13
We did not observe attenuation of the hazard ratios associated with weaning among women with more advantaged socioeconomic characteristics but numbers of women who met even crude indicators of advantage were small. Benefits of breastfeeding are demonstrated even in well-resourced settings e.g. in the United Kingdom, where breastfeeding was found to be associated with significantly reduced risks of severe diarrhea and pneumonia-related morbidity resulting in hospitalization [14
]. Our hazard ratios may be biased towards the null by the nature of clinical research which over-represents motivated and compliant participants and provides a health service safety net with easier access to medical care and medications.
It is intriguing that the benefits of breastfeeding were greatest among women with higher CD4 counts. Although some risks associated with weaning may be in part related to environmental factors, the effect modification by maternal immune status highlights the importance of immunologically-active components of breast milk [15
]. Our findings suggest that there may be some deficiencies in breast milk of immunocompromised women but these are yet to be identified [17
Our results pertaining to the effects of early weaning on uninfected child mortality should be viewed in the context of HIV-free survival. The only reason to encourage early weaning is to reduce HIV transmission. Guidelines for uninfected women are unambiguous in their support for breastfeeding to 24 months or longer.[18
] Our study was conducted largely prior to the availability of antiretroviral therapy for women. We have previously reported in both intent-to-treat analysis[8
] and in analyses based on actual behavior[19
] that early weaning resulted in no net benefit for HIV-free survival. Benefits for HIV reduction were off-set by elevations in uninfected child mortality. There are encouraging new data that antiretroviral drug regimens given as prophylaxis to the infant can reduce post-natal HIV transmission [20
]. Mothers receiving effective antiretroviral therapeutic regimens also appear to be at low risk of HIV transmission [22
]. When antiretroviral drugs are given, the risks for uninfected child mortality take on greater salience as even small elevations can counter-balance the now lessened HIV transmission risks. The balance also shifts among women who are at low risk of transmitting such as women with high CD4 counts. As we demonstrate here, women least likely to transmit HIV because of higher CD4 counts are also those for whom stopping breastfeeding confers the greatest dangers. As we have previously reported, even in the absence of antiretroviral therapy in women with higher CD4 counts, there is net benefit in terms of HIV-free survival with longer breastfeeding [19
There are limitations of our analysis. We aimed to reduce the risks of reverse causality by reviewing the clinical circumstances of each death to exclude deaths where underlying illness was the motivation for weaning but we acknowledge that we may not have had all necessary information in every case. Our observation that early weaning was associated with death in both the intervention and the control group, despite the vastly different reasons for early weaning in these two groups, strengthens our inference about the effects of early weaning on mortality. We also investigated possible confounding by several socioeconomic and clinical factors known to be associated infant and young child death and none of these factors accounted for the associations. Unmeasured confounders may play a role but, given the consistency of our results with biological plausibility and studies in uninfected populations, this is unlikely. One of the greatest strengths of our cohort is the degree of heterogeneity of feeding practice. Other studies among HIV-infected women tend to be more homogenous in their feeding practices limiting the comparisons possible. The fact that women in the intervention group were specifically encouraged to wean early also minimizes the usual reasons for early weaning making our associations less prone to the confounding factors that may dominate in other studies precluding sufficient variability for adequate statistical adjustment.
Support is needed for programs in low resource settings to incorporate antiretroviral therapy for pregnant women with low CD4 counts and other strategies addressing HIV transmission over the postnatal period so that breastfeeding for a normal duration can be unambiguously supported. Our data, consistent with prior data among uninfected children, demonstrate that survival of uninfected children born to HIV-infected mothers is compromised through the second year of life when breastfeeding is stopped early. Nutrition, education and counseling interventions may reduce, but do not eliminate, this excess mortality.