In this large prospective cohort study, we found no difference in 2-y rates of adverse health outcomes between early weaned breast-fed and formula-fed children born to HIV-infected mothers. Moreover, the 2-y probabilities of remaining free from severe events (hospitalization or death) and from morbidity validated by an independent committee were comparable in these two groups. However, compared to short-term breast-fed children and after adjustment for potential confounders, the formula-fed ones had a slightly increased risk of diarrhea or acute respiratory infections, but this difference materialized into neither differences in malnutrition rates nor hospitalization or death rates.
Another important issue was whether these two modified infant feeding practices were safe as opposed to the standard, more prolonged breast-feeding. For that purpose, we compared 18-mo mortality among these short-term breast-fed and formula-fed children with the mortality observed in long-term breast-fed children within a historical trial conducted in the same population. No excess in mortality was observed in children exposed to alternatives to prolonged breast-feeding when taking into account HIV status: an overall 18-mo probability of survival of 96% was observed among HIV-uninfected short-term and formula-fed children, which was similar to the 95% probability observed in the long-term breast-fed ones.
At first glance, a randomized clinical trial allocating infant feeding modalities at random would have been the ideal design for investigating adverse health outcomes. We, however, believe the way of feeding one's forthcoming child has to follow an informed and reasoned choice, and thus depends on individual situations. The choice of the infant feeding modality was thus left to the mother in a real-life situation in which alternatives to prolonged breast-feeding were available. The corollary of this nonrandomized design was that breast-feeding women of the Ditrame Plus study were different from those who did not breast-feed. The comparison between the feeding groups could have thus been biased by these differences. The breast-feeding group indeed had lower maternal education, lived in more crowded housing, and was less likely to have in-house access to tap water. All of these factors could be expected to be associated with greater morbidity and mortality in the breast-fed group, but all our analyses adjusted for these potential confounders to minimize this bias.
The Ditrame trial was used as a group of comparison because no alternatives to prolonged breast-feeding had been proposed within that study. The strength of this strategy was that the women had been recruited at the same sites, with the same criteria, and in the same population as the Ditrame Plus study, and both of these studies were coordinated by the same study group. Morbidity data had not been collected and validated as in the Ditrame Plus study, however, limiting our present analysis to mortality. Because the Ditrame trial and the Ditrame Plus study were performed in the same setting by the same team, we cannot exclude the possibility that the medical team was less knowledgeable about managing infants born to HIV-infected women in the earlier period of the research program. We also acknowledge that there may have been confounding factors that had not been taken into account by our design, but we consider that the most important ones were controlled for.
We had previously reported that the women included in the Ditrame Plus cohort were representative of the general population of pregnant women in Abidjan because they had been prenatally recruited among all attendees of community-run health facilities located in poor areas, with no other selection criteria than being HIV infected and at least 18 y old, and having accepted the study protocol [18
]. All the women included in the study had access to tap water. But because two-thirds of them lived in typical shared housing, the tap was mainly outside the home. It had been previously reported that the quality of municipal water in Abidjan was good, but that household water storage was a common practice that contributed to contaminated drinking water [14
]. Within our study, women were encouraged to avoid water storage, but one-third of them reported having given stored water to their child [26
]. Such a practice might have had adverse consequences on infant health.
Emphasis was made in the study protocol on the quality of follow-up of mother–infant pairs. Overall, 88% of the expected follow-up had been completed, and lost-to-follow-up children had participated in the study for a median of 1 y. The reasons for stopping follow-up earlier than expected was recorded for two-thirds of these women, which means that they had come to study sites to explain their intent or that they had been traced at home. In all cases, the vital status of the child was recorded at this last contact. Most of these women were unable to continue their study participation because they moved outside Abidjan to return to the north part of Côte d'Ivoire or to their birth country (mainly Mali or Burkina Faso), which might have been linked to the current political crisis in Côte d'Ivoire. As reported within another study, the follow-up was better among nonbreast-feeding mothers [12
]. This could be explained by the mother's sociodemographic characteristics or the health care workers' attitude toward this latter group, and could be a possible source of bias [27
Given the relatively high standard of care proposed within our study (closed clinical follow-up adapted to the child's age with free provision of care), our primary outcome was the occurrence of adverse health outcomes, defined as morbidity, hospitalization, or death. Emphasis was thus made on the collection and validation of morbidity. The same criteria were used for breast-fed and formula-fed children because the event validation committee was blinded to the exact child feeding practices. Because most of the women in our study were illiterate, we have extended the WHO definition of diarrhea to any diarrhea associated with dehydration or requiring at least a second consultation for the same reason. This may have contributed to a slightly overestimated incidence of diarrhea.
Overall, we believe follow-up quality was high enough and sufficiently unbiased so that estimates of the incidence of adverse health outcomes are adequately made with the same definitions in both groups.
When compared with the Ditrame trial in which no specific infant feeding counseling was made available, the provision of peripartum antiretroviral prophylaxis combined with the promotion of two alternatives to prolonged breast-feeding within Ditrame Plus considerably reduced the number of HIV-infected children: mother-to-child transmission of HIV was significantly reduced with a long-term benefit sustained until age 18-mo. For instance, 18-mo HIV transmission rates as low as 7% (95% CI, 4%–11%) and 6% (95% CI, 2%–10%) were obtained in short-term breast-fed and formula-fed children, respectively, whose mothers had received a peripartum short-course combination of zidovudine and 3TC in addition to single-dose nevirapine [28
]. In comparison, the HIV transmission rate was 22% (95% CI, 16%–30%) at age 18 mo among the long-term breast-fed children of the Ditrame trial. Moreover, the mortality among HIV-uninfected children exposed to short-term breast-feeding or formula feeding was similar to the mortality observed among long-term breast-fed uninfected children. Hence, the overall probability of survival was improved among early weaned and formula-fed children in comparison to the long-term breast-fed ones.
Given appropriate nutritional counseling and care, access to clean water, and an adequate supply of breast-milk substitutes, early weaning and formula feeding were not harmful for infant health among HIV-exposed children. Given these constraints, these alternatives to prolonged breast-feeding were not only safe, but socially acceptable and feasible within our population-based study. These results need to be balanced with the evaluation of other outcomes such as the assessment of child growth according to infant feeding practices and maternal perceptions of stigma given different infant feeding strategies.
These findings of the Ditrame Plus study are consistent with a previous clinical trial of randomly allocated infant feeding practices in Kenya, with the preliminary results of a cohort study in Uganda and with a large African pooled analysis [12
]. However, these findings differ from operational research suggesting that formula feeding was associated with higher mortality, morbidity, and stigma in field settings [31
]. More recently, a clinical trial conducted in Botswana allocated at random 6 mo of breast-feeding plus prophylactic infant zidovudine, or formula feeding plus 1 mo of zidovudine [33
]. In that trial, the probability of infant death by month 7 was significantly higher in the formula-fed group than in the breast-fed group (9.3% versus 4.9%; p
= 0.003), but this difference diminished beyond month 7, such that the time-to-mortality distributions through 18 mo of age were not significantly different (10.7% versus 8.5%; p
The access to care, support, and counseling, the provision of the breast-milk substitutes, and the clean water availability, as well as the good follow-up observed within the Ditrame Plus study, would all be expected to lead to more optimal outcomes for alternatives to prolonged breast-feeding in contrast to what was observed in less well-structured or well-supported programs. However, the clean water access, the education level of the mothers, and the economic status of the families included in our cohort appear representative of many urban settings in Africa and lead to a cautious but possible generalization of our results to contexts with appropriate political and structural supports.
In conclusion, we urge the operational implementation in urban African settings of programs aimed at the overall reduction of mother-to-child transmission of HIV. HIV-infected pregnant women could be offered several alternatives to prolonged and predominant breast-feeding so that they could find the one adapted to their individual situation: either complete avoidance of breast-feeding or exclusive breast-feeding with early cessation. The recent rollout in Africa of programs of access to care for people living with HIV could provide a unique opportunity to routinely implement these infant feeding strategies. Both women and children could be given appropriate nutritional counseling and care within these initiatives. Moreover, the clinical support available in such infrastructures could contribute to minimizing infant mortality. The place of heavily subsidized breast-milk substitutes within these programs should, however, be politically discussed. At the same time, more research is needed to improve on safe infant feeding options for resource-constrained settings.