In this randomized clinical trial, we found no significant difference in 2-year mortality rates between infants randomly assigned to be formula fed or to be breastfed. Because HIV-1 infections occurred with higher frequency in the breastfeeding arm, we considered the possibility that excess formula-associated deaths might be masked by excess HIV-1–related deaths in the breast-feeding arm. However, even when we performed analyses that adjusted for or stratified by HIV-1 infection status, there was no significant difference in 2-year mortality rates between the 2 trial arms. The major causes of death in the study were infections, and there was no difference in cause-specific infection mortality between the 2 study arms except for an increased frequency of sepsis as a contributing cause of death in the formula arm. Thus, in this study population, formula feeding and breastfeeding were associated with similar mortality risks during the first 2 years of life.
At first glance, our results may seem paradoxical. Breastfeeding was associated with higher rates of HIV-1 transmission; HIV-1 infection in infants was associated with higher mortality; formula resulted in no increased mortality. One might have predicted that we would have seen significantly higher mortality risk in the breastfeeding arm. However, our trial terminated with only 2years of follow-up, by which time many deaths had occurred among infants infected in utero, peripartum, or through early breastfeeding, but relatively few among infants with later acquisition of HIV-1 through breast milk. Of children infected after 2 months of age, only 9% had died by 2 years but most of the remaining children would be expected to die sometime during childhood. At study end, there were 19 HIV-1 infected children who were alive at their last visit in the formula arm and 35 in the breast-feeding arm. The 2 years of follow-up was sufficient to capture any potential adverse consequences of formula feeding but not all of the adverse consequences of breast-feeding with respect to HIV-1 related mortality. Because of this, HIV-1–free survival (the percentage of children who remained alive and HIV-1 uninfected) best captures the combined risks of feeding modality and HIV-1 infection. In this trial, HIV-1–free survival at 2 years was significantly higher in the formula arm.
The mortality risk among the children in this study was high, largely because of infant HIV-1 infection which was associated with a 9.0-fold increased risk of dying during the first 2 years of life. Among children who remained HIV-1 uninfected, the 12 month infant mortality rate (7.0%; 95% CI, 3.9%–10.0%) was not significantly different than the infant mortality rate of 4.1% reported for Nairobi or 7.4% reported for Kenya as a whole12
although it is higher than what might have been predicted given the level of medical care available in the research context. This suggests that infants of HIV-1–infected mothers may have a somewhat elevated mortality risk, even if they them-selves escape HIV-1 infection.
There have been concerns that the use of formula by women infected with HIV-1 inresource-poor settings would result in increases in diarrheal morbidity and mortality.13,14
We found no significant difference in diarrheal incidence in the 2 study groups of the trial over the 2 year follow-up period. This was true for the group of infants as a whole and after stratifying by HIV-1 infection status. We did find an increased incidence of current diarrhea (at the time of a visit) and dehydration in the formula feeding arm during the first 3 months of life. This coincides with the period during which most breastfed infants were fed exclusively by breast milk (the median age of introduction of supplemental feeds was 3.8 months) and were thus at low risk of exposure to diarrheal pathogens from food sources. Our results are consistent with previously published observational studies in which breast milk has been most protective against diarrheal disease in the first 3 months of life,3,4,5
a finding that underscores the necessity of careful follow-up of formula fed infants during early infancy.
In the cohort overall, we did not observe increased risk of any major childhood morbidities, including pneumonia, sepsis, malaria, or otitis media, associated with formula feeding. Among HIV-1–infected formula feeders, there was an increased risk of sepsis during the 2 years of follow-up and an increased risk of hospitalization toward the end of the first year of age. Although our study suggests that formula feeding by HIV-1–infected mothers does not increase the risk of most childhood morbidities, there may be some increased risk among HIV-1–infected infants.
Infants in the breastfeeding arm had better nutritional status than those in the formula feeding arm, particularly during the first 6 months of life, consistent with observational studies.15
We observed a fairly high prevalence of malnutrition during the second year of life, consistent with patterns of malnutrition seen in sub-Saharan Africa, due in part to repeated infections and introduction of poor weaning diets. However, there was no difference in the prevalence of malnutrition in the 2 study groups. Thus, with adequate supplies of formula and nutrition counseling, the mothers in this trial were able to administer formula feeds without seriously compromising the nutritional status of their infants. However, the better growth in breastfed infants, particularly during the first 6 months, highlights the importance of nutritional counseling for mothers of formula feeding infants.
The major strength of our study was its randomized clinical trial design. Choice of infant feeding modality may be influenced by factors that affect infant health outcomes and not all observational studies have controlled for important confounding factors such as educational level, socioeconomic status, and low birth weight. Nor have most studies addressed the possibility of reverse causality, eg, that changes in infant feeding modality (and in particular a switch from breast milk to formula) may be influenced by childhood illnesses. Our randomized clinical trial design allows us to present data regarding morbidity and mortality associated with formula that are not potentially confounded.
There are several limitations of our trial that warrant discussion. First, compliance with feeding modality in the formula feeding arm was imperfect, and 30% of such infants had some exposure to breast milk. In our intent-to-treat analyses, this could potentially result in underestimates of risk associated with formula feeding. However, when we repeated our mortality analyses using true feeding modality rather than randomization group, we found similar results. Two-year mortality was 18.8% among true formula feeders and 22.0% among true breastfeeders (P=.39). Among HIV-1–uninfected children, the 2-year mortality was 8.7% among true formula feeders and 7.3% among true breastfeeders (P=.74). Second, we relied on maternal histories to capture childhood illnesses that occurred between clinic visits, so our estimates of morbidity may be underestimates. In addition, our study was not designed to determine causes of death and these data are imprecise because of limited availability of diagnostic testing and reliance on verbal autopsies. Finally, the number of visits to the clinic was lower for breastfeeding than formula feeding children. Although this would not affect our mortality rates, it could influence our estimates of the incidence of diarrheal disease and other morbidities. We corrected for this in our analyses by adjusting all relative risks for the various infant morbidities of interest by the number of clinic visits made.
Our estimates of morbidity and mortality risk are not generalizable to all women in developing countries. Our results represent the best-case scenario. All women participating in the trial had access to potable water, extensive health education regarding safe preparation of formula, a reliable supply of formula, and access to medical care for their infants. The magnitude of risks associated with formula feeding will vary in different settings depending on differences in these important variables. Because of these differences, we would advocate context-specific counseling for HIV-1–infected expectant mothers so that each woman can select the feeding method that maximizes benefits and minimizes risks given her individual situation, as is recommended by the World Health Organization.16
In addition, our trial was conducted among HIV-1–infected mothers and the results may not be generalizable to uninfected women. It is possible that the breast milk of HIV-1–infected women lacks factors that confer protection from death, diarrheal disease, and pneumonia.
We previously reported that the use of formula could prevent 44% of HIV-1 infections in infants of HIV-1–seropositive mothers.1
Our current results demonstrate that in a developing country setting, it is possible for this gain to be realized without increased morbidity or mortality during the first 2 years of life. In our trial, formula-fed infants clearly had a better outcome than breastfed infants because they were more likely to be alive and HIV-1 uninfected at the age of 2 years.1
Formula feeding conferred a 28% protective effect from an adverse outcome (HIV-1 infection or death). In addition, mothers who used formula were more likely to be alive 2 years after delivery than mothers who breastfed.11
Thus, formula provided advantages for both mother and child. Our current analyses show that the use of formula to prevent HIV-1 transmission can be a safe and viable option even in resource poor settings, if maternal education, clean water, a supply of formula, and access to health care are available.