To address reverse causality, we reviewed data (i.e. routinely collected maternal recall of any infant feeding modification due to the illness leading to death) from the SAE form reporting the death of the child to determine whether the mother reported that she changed the way she fed her child as a result of health events. We also applied marginal structural models to estimate the effect of breastfeeding cessation on children's deaths by appropriate control for the effects of time-dependent confounders (i.e. the child's or the mother's health events) [31,32]. Three time-dependent covariates corresponding to the occurrence of an SAE for the child (excluding deaths) or for the mother and occurrence of a health event (diarrhea, vomiting or fever) for the child were considered. First, logistic regression models were fitted to predict patient-specific and time-specific probabilities of weaning as a function of baseline variables (as listed in Table 1) and health event variables as defined above. These predicted probabilities were then used to derive inverse probability weights (IPWs) for weaning. Second, these IPWs were used in a weighted pooled logistic model, which included baseline confounders and breastfeeding cessation variable, to estimate the parameters of a proportional hazards marginal structural model. The assumption of positivity was assessed by checking that all categories of exposure (weaned or not) were observed for the most important confounders. We also checked that stabilized weights satisfied the condition of small variability.
SAS (version 9.2; Cary, North Carolina, USA) and Stata (version 10.1; Stata Corp, College Station, Texas, USA) statistical software were used to conduct these analyses.
Size and characteristics of the study population
Of 824 HIV-infected women enrolled in the Kesho Bora RCT, 805 delivered live born infants between June 2005 and August 2008. Of these 805 infants, six died before feeding initiation, two were lost to follow-up before recording information on the first feeding, and two died without a PCR test to determine HIV-infection status. Therefore, the study population for this analysis comprised 795 mother-infant pairs. Of these, 177 (22.3%) mothers never breastfed, whereas 618 (77.7%) initiated breastfeeding (Table 1). Compared with mothers who initiated breastfeeding, mothers who chose replacement feeding had a higher level of education and were more likely to have access to a protected source of water. They were also more likely to have a CD4+cell countless than 350 cells/μl and to have had a Caesarean delivery. Cumulative follow-up rates at the 18-month visit (excluding deaths) were similar in formula fed and ever-breastfed children (89.3 versus 87.1%; P = 0.43).
Mortality among ever and never breastfed infants
A total of 63 children died within 18 months. The estimated overall mortality rate was 4.5% by 6 months, 7.4% by 12 months, and 8.3% by 18 months of age. The estimated cumulative mortality rate by 18 months was 10.5% in the never breastfed group compared with 7.7% among ever breastfed children, but the difference was not statistically significant (P-value for log-rank test = 0.20).
In univariate or multivariate analyses, study site, maternal age, maternal education, source of water, socioeconomic score, treatment allocation, maternal HIV-related characteristics at delivery (CD4 cell count and viral load), mode of delivery, infant characteristics (sex, birth weight) and cotrimoxazole prophylaxis were not associated with mortality. Period of enrollment showed a weak association with mortality in univariate analysis (see table, supplemental digital content 1, http://links.lww.com/QAD/A294). The risk of death tended to be higher for never-breastfed children compared with ever-breastfed children (Table 2, Model 1). HIV infection status of the child was strongly associated with the probability of death (aHR, 8.0; CI, 4.5;14.2; P < 0.001).
Mortality and infant feeding practices over time
The median duration of breastfeeding was 4.9 months (interquartile range, 2.8;6.0). A total of 161 (26.1%) mothers stopped breastfeeding before their child reached 3 months of age, 162 (26.2%) mothers continued to breastfeed at 6 months of age. Weaned and never-breastfed children were at greater risk of death compared with still-breastfed children with similar adjusted HRs (Table 2, Model 2 and Fig. 1).
Interaction terms combining study arm, HIV infection status of the child or cotrimoxazole use with infant feeding modality were not statistically significant (P > 0.20) and HR estimates in adjusted analyses were similar across the different subgroups. The aHR of weaned versus still breastfed was 8.7 (CI: 2.7–28.5; P < 0.001) and aHR of never breastfed versus still breastfed was 7.8 (CI: 2.3–26.7; P = 0.001) among uninfected children. In infected children aHR of weaned versus still breastfed was equal to 4.8 (CI: 1.1–20.3; P = 0.03) and aHR of never breastfed versus still breastfed was 5.5 (CI: 0.9–31.6; P = 0.06). The excess of mortality among weaned or never-breastfed children compared with still breastfed was also observed in the ZDV/sdNVP arm [aHR (weaned): 8.9; CI: 2.7;29.8; P < 0.001; aHR(never breastfed): 8.7; CI: 2.4;31.1; P < 0.001] and to a lesser extent in the triple ARV arm [aHR (weaned): 4.4; CI: 1.1;17.8; P = 0.04; aHR (never breastfed): 3.7; CI: 0.8;16.4; P = 0.09]. Results were less homogeneous when stratifying by cotrimoxazole prophylaxis. An excess of mortality among weaned or never breastfed children compared with still breastfed children was found in those who received cotrimoxazole prophylaxis until 12 months [aHR (weaned): 6.2; CI: 2.2;17.3; P < 0.001; aHR(never breastfed): 5.7; CI: 1.7;18.9; P < 0.01] but not among children who did not receive the prophylaxis throughout infancy [aHR (weaned): 0.8; CI: 0.1;8.5; P = 0.83; aHR (never breastfed): 1.3; CI: 0.2;9.3; P = 0.76].
Gastroenteritis and pneumonia accounted for 71% of all causes of death in weaned and formula fed children, whereas gastroenteritis was never reported as a cause of death in children who were still breastfed at the time of death (Table 3).
To investigate whether the association between weaning and mortality varied with age, we assessed the effect of weaning before 3 months and between 3 and 4.9 months by introducing two time-varying covariates for these two periods in comparison with weaning from 5 months of age. Among ever breastfed children, weaning before 3 months was associated with a 3.5-fold increase in mortality (CI: 1.7;7.3; P < 0.001), whereas weaning at 3 to 4.9 months was associated with a 2.2-fold increase (CI: 0.9–5.4; P = 0.08) compared with weaning after 5 months.
Reverse causality and time-varying confounders
Breastfeeding cessation as a consequence of a serious illness that led to death was reported in one case. Overall, the median period of time between breastfeeding cessation and death was 2.4 months [interquartile range (IQR): 1.4–5.4] and only one child died within 15 days after breastfeeding cessation.
Marginal structural models were used to account for time-dependent confounding. For ever-breastfed children, the unweighted model (i.e. without controlling for health event confounding) indicated that weaned children had a higher risk of mortality compared with still breastfed with an adjusted HR of 5.0 (CI: 1.8–13.6). The aHR obtained from the full weighted-model was slightly attenuated [4.4 (CI: 1.6–11.9)]. Similar HR attenuation was observed in uninfected and infected children (data not shown).
Mortality and mode of breastfeeding over time
Of 618 women, who initiated breastfeeding, 246 (39.8%) and 137 (22.2%) were still exclusively breastfeeding at 3 and 5 months, respectively. One hundred and four (16.8%) practiced partial breastfeeding for more than 1 month, in the first 6 months. When disaggregated by breastfeeding type, there was no statistical difference in the risk of death within the first 6 months between children who were exclusively, predominantly or partially breastfed (Table 2, Model 3). Weaned and never-breastfed children were at a substantially higher risk of mortality in comparison with exclusively breastfed children.
The relationship between infant feeding practices and mortality was investigated in 795 children born to HIV-infected mothers in three countries of sub-Saharan Africa. No evidence of difference in mortality risks was found when comparing never breastfed to ever-breastfed children. If mode of feeding was taken into account using time-dependent variables, weaned or never-breastfed children were at about a seven-fold higher risk of dying compared with children who were still breastfed. Additional results indicated that the adverse effect associated with breastfeeding cessation decreased with increasing age of infant between birth and 6 months of age. Moreover, although evaluating associations in sub-samples like infection status or trial arm may have been limited by the small number of events, breastfeeding appears to remain protective for HIV-infected infants as for HIV-uninfected ones, and whether or not the mother receives antiretroviral prophylaxis during breastfeeding.
Previous studies documenting an association between feeding modality and mortality among HIV-exposed children have shown that, at best, replacement feeding results in no benefit in survival [7,33–37] and, at worse, results in a six-fold increase in mortality by 12 months of age compared with breastfeeding [3,5]. Heterogeneity of findings between these reported studies can be explained by different socioeconomic and cultural settings. The definition of infant-feeding modality (fixed or time-dependent variable) used in studies might also have led to the different magnitude of effect; however the direction of effect was consistent in the various studies.
In agreement with observations made by Kuhn and colleagues , our results indicated a continuous adverse effect of receiving replacement feeding after cessation of breastfeeding, rather than a temporary deleterious effect of the event of weaning. First, deaths in weaned children were not concentrated in the period immediately following weaning but were homogeneously distributed in the whole period of replacement and complementary feeding. Second, HRs were similar in weaned and never breastfed children. The median time period between breastfeeding cessation and death was 2.4 months, which is longer than in a study in rural Uganda (i.e. 1.5 months) despite similar duration of follow-up, maybe because the level of schooling and hygiene were lower in the latter .
No evidence of difference between exclusive and predominant breastfeeding was found, and partial breastfeeding was associated with an intermediate risk between exclusive/predominant and replacement feeding. However, the number of events was limited in the partial category and the study was not powered to examine this question. Several studies have documented the relationship between breastfeeding mode and HIV transmission or HIV-free survival in HIV-exposed children [38–42] whereas others focused specifically on morbidity or mortality of children [3,9,39,43]. Overall, these studies indicated that exclusive breastfeeding is associated with the lowest risks of transmission, morbidity and mortality, and partial breastfeeding with the highest, but the difference between these two categories was reduced for mortality risk.
An important strength of this study lies in the effort made to control for confounding, notably of time-dependent variables. Indeed, the study of infant-feeding modality and mortality may be affected by a time-dependent confounding, which cannot be handled by traditional statistical means. Few studies have addressed this issue of reverse causality [11,44,45]. Some investigators tried to account for situations in which breastfeeding cessation and death both caused by a serious illness occurred within a short time, about 1 week. In this analysis, we addressed the issue of reverse causality by using marginal structural models. It allowed us to account for potential reverse causality situations wherein an illness episode, breastfeeding cessation, and death could occur over a long period. Although the child's and the mother's morbidity were determinants of weaning (results not shown), the amount of confounding was low. Marginal structural models are appropriate tools to explore causal relationships. However, estimation of the causal effect relies on several assumptions including the assumption of exchangeability, that is, all confounders are measured and appropriately taken into account in the models. Although we cannot exclude the possibility of unmeasured confounding, the great amount of information collected during the Kesho Bora trial allowed us to include all major potential confounders in the analysis.
It should be pointed out that breastfeeding durations were limited to approximately 6 months. Women were strongly encouraged to wean by that age in agreement with international and national recommendations at the time of the study. Our results cannot necessarily be generalized to longer periods of breastfeeding. However, it seems reasonable to hypothesize that the decrease in the protective effect of breastfeeding with increasing child age demonstrated within the 0–6-month age interval continues beyond the age of 6 months.
Four out of five of the Kesho Bora study sites were in urban African settings. Our results cannot be generalized to rural areas. However, it is likely that the detrimental effect of non or short-duration breastfeeding would be even larger in more remote rural areas.
In conclusion, the data presented here confirm the benefits of breastfeeding for survival of HIV-exposed children for the first 6 months in a context in which extensive counseling, support and other interventions were provided to reduce risks. Additionally, they confirm the potential risks of replacement feeding, independent of the event of weaning. In resource-constrained settings, it has long been recognized that promotion of breastfeeding is a key intervention for reducing the mortality among HIV-exposed and nonexposed children. In the context of antiretroviral drugs being available to reduce postnatal transmission through breastmilk, interventions to support HIV-infected mothers to exclusively breastfeed should be prioritized to promote HIV-free survival of HIV-exposed children.
We thank all participants enrolled in the study. We acknowledge Pierre de Beaudrap for statistical advice.
Author contribution: J.S.R., A.C., I.D.V., K.B. conceived the analysis. A.C. performed the analysis with the contribution of P.G., C.C. and K.B. for infant feeding definitions implementation. A.C., J.S.R., K.B., I.D.V. wrote the article. All authors read, commented and approved the final version of the article.
The Kesho Bora Study Group and the study sites: Bobo Dioulasso, Burkina Faso (Centre Muraz): Nicolas Meda (Principal Investigator), Paulin Fao, Odette Ky-Zerbo, Clarisse Gouem (Study coordinators), Paulin Somda, Hervé Hien, Patrice Elysée Ouedraogo, Dramane Kania, Armande Sanou, Ida Ayassou Kossiwavi, Bintou Sanogo, Moussa Ouedraogo, Issa Siribie (Investigators), Diane Valéa (Laboratory Coordinator), Sayouba Ouedraogo & Roseline Somé (Data Managers), François Rouet (Inter-Site Laboratory Coordination); Durban, South Africa (University of KwaZulu Natal): Nigel Rollins (Principal Investigator), Lynne McFetridge, Kevi Naidu (Study Coordinators); Mombasa, Kenya (International Centre for Reproductive Health): Stanley Luchters, Marcel Reyners (Principal Investigators), Eunice Irungu (Study Coordinator), Christine Katingima, Mary Mwaura and Gina Ouattara (Investigators), Kishor Mandaliya, Sammy Wambua (Laboratory Coordinators), Mary Thiongo (Data Manager); Nairobi, Kenya (Network for AIDS Researchers in East and Southern Africa): Ruth Nduati (Principal Investigator), Judith Kose (Study Coordinator), Ephantus Njagi (Laboratory Coordinator), Peter Mwaura (Data Manager). Somkhele, South Africa (Africa Centre for Health and Population Studies, University of KwaZulu Natal): Marie-Louise Newell (Principal Investigator), Stephen Mepham (Study Coordinator), Johannes Viljoen (Laboratory Coordinator), Ruth Bland (Investigator), Londiwe Mthethwa (Data Manager).
Supporting institutions: Agence Nationale de Recherches sur le SIDA et les hépatites virales, France: Brigitte Bazin and Claire Rekacewicz (Sponsor Representatives); Centers for Disease Control and Prevention, USA: Allan Taylor (Sponsor Representative and Co-Investigator), Nicole Flowers, Michael Thigpen, Mary Glenn Fowler, Denise Jamieson (Co-Investigators); Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA: Lynne M. Mofenson (Sponsor Representative), Jennifer S. Read (Co-Investigator); Institut de Recherche pour le Développement (IRD), Montpellier, France: Kirsten Bork, Cécile Cames and Amandine Cournil (Nutrition Coordination); International Centre for Reproductive Health (ICRH), Ghent University, Ghent, Belgium: Patricia Claeys, Marleen Temmerman, Stanley Luchters (Sponsor Representatives); Université Montpellier 1, EA 4205 ‘Transmission, Pathogenèse et Prévention de l’infection par le VIH’ ; and CHU Montpellier, Laboratoire de Bactériologie-Virologie, Montpellier, France: Philippe Van de Perre, Pierre Becquart (until December 2006), Vincent Foulongne, Michel Segondy (Laboratory Coordination).
Study coordination: World Health Organization, Geneva, Switzerland: Isabelle de Vincenzi (Study Coordinator), Philippe Gaillard (Site Coordinator), Tim Farley (Project Manager), Ndema Habib (Study Statistician), Sihem Landoulsi (Study Analyst).
Financial support was provided by Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS), Department for International Development (DFID), European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation, GlaxoSmithKline Foundation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, UNDP/UNFPA/UNICEF/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction and the Victorian Operational Infrastructure Support Program.
Funding: The Bobo-Dioulasso site was funded by l’Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP).
The Mombasa site was funded by ANRS, WHO/HRP, European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation.
The Nairobi site was funded by the Centers for Disease Control and Prevention (CDC) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) through a cooperative agreement.
The South-African sites were funded by the Department for International Development (DFID), EDCTP, UNICEF and WHO/HRP.
The Nutrition and laboratory coordination were funded by ANRS.
The overall coordination and external monitoring was funded by WHO/HRP.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the World Health Organization, of the Centers for Disease Control and Prevention or of the National Institutes of Health
Conflicts of interest
The authors have no conflict of interest to disclose.
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