Introduction

In resource-limited settings, where child mortality due to diarrhoea, pneumonia and malnutrition is common, the dilemma of how HIV-infected mothers should feed their infants has to a large extent been resolved by the effectiveness of antiretroviral drugs (ARVs) to reduce the risk of postnatal transmission through breastfeeding[1-3]. In such settings, the World Health Organization (WHO) recommends that HIV-infected mothers receive ARVs and exclusively breastfeed (EBF) for six months and continue breastfeeding until at least twelve months while introducing complementary feeds from six months onwards[4].

Yet there remain challenges to scale-up access to these interventions and the support that would make them feasible. Programmatic questions related to the added value and feasibility of promoting and supporting EBF in the context of HIV are common. It is also questioned whether HIV-infected mothers receiving lifelong ARV treatment (ART) need to stop breastfeeding at 12 months. These questions highlight the uncertainty among health professionals and policy makers regarding the effectiveness of EBF and continued breastfeeding to improve survival of HIV-exposed infants, independent of any consideration of HIV infection.

As part of a study examining the effect of infant feeding practices on vertical transmission of HIV, we investigated the effect of exclusive breastfeeding by HIV-infected and HIV uninfected mothers on infant morbidity and mortality. Here we report diarrhoea prevalence and all-cause mortality over the first 12 months of life according to infant feeding practices in the first 6 months of life, among all infants born in a largely rural community in South Africa with high HIV prevalence.

Methods

The protocol for this trial and supporting TREND checklist are available as supporting information; see Checklist S1 and Protocol S1.

Results

Between October 2001 to April 2005, 2,789 women gave birth to 2,832 infants. Characteristics and availability of infants for analysis are summarised in table 1 and Figure 1 respectively. Feeding data to 6 months of age were available for 1,155 singleton infants of HIV-uninfected mothers and 1,082 singleton infants of HIV-infected mothers and were therefore included in the analyses. Vital status was available for 2,502 infants and were included in the mortality analysis.

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Figure 1. Cohort profile.

https://doi.org/10.1371/journal.pone.0081307.g001

Among 2,097 infants who started EBF, the median time to cessation of all breastfeeding was 171 days (interquartile range: 82-180). Overall, 203 infants started RF of whom 47 were born to HIV uninfected mothers. Among HIV-infected and uninfected mothers, 81.4% and 92.9% were exclusively breastfeeding at 6-8 weeks of age and 61.8% and 72.6% at 3-4 months respectively; 3.4% and 2.3% were partial breastfeeding at 6-8 weeks of age and 14.1% and 15.8% at 3-4 months respectively; 15.2% and 4.8% were replacement feeding at 6-8 weeks and 24.1% and 11.6% at 3-4 months respectively.

Mortality by 12 months of age by feeding practice and infant HIV exposure/infection status

In an adjusted cox regression analysis, the risk of death among all infants by 12 months of age was significantly greater in those who were never breastfed (aHR 3.5, p<0.001) or mixed fed (aHR 2.65, p<0.001). (Table 3) Postnatal HIV infection through breastfeeding was associated with higher mortality compared to HIV non-exposed infants, while the risk of death associated with perinatal HIV infection was even higher at 13 times greater risk of death. Maternal education was associated with reduced infant mortality (AHR 0.52 [95% CI 0.32-0.85. p=0.01]) but other maternal characteristics such as age, parity were not associated with a reduced risk.

	Events/ child-years	Unadjusted HR (95% CI)	P	Adjusted HR (95% CI)	P
Infant feeding practice
Exclusive breastfeeding	78/1449	1.00		1.00
Predominant breastfeeding†	-	-	-	-	-
Partial breastfeeding	31/431	3.05	<0.001	2.65	<0.001
		(1.79-5.18)		(1.85-3.79)
Never breastfed	60/366	21.62	<0.001	3.53	<0.001
		(13.52-34.58)		(2.44-5.12)
Infant HIV status
HIV non-exposed	58/2067	1.00		1.00
Perinatal infection or	83/111	30.77	<0.001	13.16	<0.001
unknown timing		(18.01-52.61)		(9.00-19.22)
Postnatal infection	14/27	7.99	<0.001	6.43	<0.001
		(3.47-18.38)		(3.46-11.96)
HIV exposed, uninfected	2/8	1.30	0.453	0.77	0.253
		(0.65-2.58)		(0.49-1.21)
Unknown status	12/115			6.11	<0.001
				(3.53-10.55)
Sex
Male	85/1164	1.00		1.00
Female	84/1164	0.96	0.776	0.97	0.926
		(0.73-1.27)		(0.75-1.31)
Water Source
Non-Piped	56/711	1.00		1.00
Piped	108/1575	1.06	0.705	1.19	0.285
		(0.78-1.45)		(0.86-1.65)
Unknown	5/42	9.09	<0.001	5.87	<0.001
		(5.39-15.33)		(3.11-11.06)
Maternal HIV
HIV uninfected	29/1187	1.00		-
HIV-infected	140/1138	3.07	<0.001	-
		(2.24-4.21)
Enrolment clinic
Rural/Peri urban	152/1966	1.00		1.00
Urban	17/362	0.64	0.052	0.66	0.081
		(0.41-1.00)		(0.42-1.05)

Table 3. Risk factors associated with mortality in the first 12 months of life.

^† There were no events among infants that were predominantly breastfed

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In multivariable analysis adjusted for infant HIV status and gender, parity, water source, enrolment clinic, maternal education and age, infants who were never breastfed had consistently higher mortality risk in all time intervals than infants who were exclusively breastfed. (Table 4) Infants who were mixed fed also incurred higher mortality. In a separate multivariable analysis, infants who were EBF for shorter durations had an increased risk of death compared to those EBF for 5-6 months [aHR 2.17 (95% CI, 1.58-2.98); p<0.001 for EBF 2-4 months and aHR 2.18 (95% CI, 1.56-3.01); p<0.001) for EBF under 2 months]. Children who had EBF up to 6 months had the lowest mortality rate compared to the other categories (Table 4). Figures 2 a-e shows Kaplan Meier analyses of the effect of infant feeding practices on mortality in the first 12 months of life according to cumulative infant feeding practice in the first 6 months.

	Mortality in first 3 months				Mortality between 3-6 months				Mortality between 0-12 months
	HR	p	AHR	p	HR	p	AHR	p	HR	p	AHR	p
	(95% CI)		(95% CI)		(95% CI)		(95% CI)		(95% CI)		(95% CI)
Exclusive breastfeeding	1.0		1.0		1.0		1.0		1.0		1.0
Predominant breastfeeding†	-		-		-		-		-		-
Partial	6.4	<0.001	2.8	0.008	1.9	0.113	2.6	0.113	3.9	<0.001	2.6	<0.001
breastfeeding	(3.5-11.7)		(1.3-6.1)		(0.9-4.1)		(0.8-8.4)		(2.9-5.4)		(1.9-3.8)
Never	3.2	<0.001	3.4	<0.001	2.6	0.003	2.9	0.007	4.5	<0.001	3.6	<0.001
breastfed	(1.7-5.8)		(1.7-6.8)		(1.4-4.8)		(1.3-6.5)		(3.2-6.4)		(2.5-5.2)

Table 4. Multivariate analysis of breastfeeding practices and infant mortality in the first year of life *

^* Adjusted for infant HIV status and gender, parity, water source, enrolment clinic, maternal education and age

^† There were no events among infants that were predominantly breastfed

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Figures 2. Survival by infant HIV exposure/infection status according to feeding practices in the first 6 months.

a. All infants. 2b. Infants infected perinatally or timing unknown. 2c. Infants infected postnatally.

2d. HIV-exposed uninfected infants. 2e. HIV unexposed infants.

https://doi.org/10.1371/journal.pone.0081307.g002

There was no significant difference in mortality by feeding practice (continued breastfeeding or no breastfeeding) following EBF cessation.

Discussion

We present detailed infant diarrhoeal morbidity and all-cause mortality data from a high HIV prevalent rural and peri-urban setting in South Africa that highlight the major protection that exclusive breastfeeding provides to both HIV-exposed and non-exposed infants. In this study, both HIV-infected and uninfected mothers were supported to exclusively breastfeed and, with this support that included periodic home visits, the vast majority of mothers successfully did so. In settings such as South Africa where diarrhoea and pneumonia are still significant causes of under-5 mortality, and even where HIV is highly prevalent, promoting and supporting EBF at population level would reduce infant mortality in the entire population. The impact of improving EBF rates would be especially significant if ARV interventions that prevent postnatal HIV transmission are effectively scaled-up and provided to HIV-infected mothers who want to breastfeed.

The frequency of diarrhoeal events and burden of diarrhoeal days were significantly fewer among those infants who EBF compared to those who were never breastfed; this was true for both HIV exposed and non-exposed infants. EBF was also more effective at reducing diarrhoeal morbidity compared with either predominant or partial breastfeeding. The longer the duration of EBF, the greater was the protection. These reductions in diarrhoeal morbidity mirrored significantly lower mortality among EBF infants, both in the first months of life and also at 12 months of age. The increased mortality risk among infants who were never breastfed or only partially breastfed compared to those who EBF remained significant even when adjusted for HIV exposure and infection status. Environmental conditions such as water supply and rural setting were significant risk factors for diarrhoeal morbidity but not for infant mortality. Study population characteristics including maternal age, parity and education appeared to have no influence on diarrhoeal outcomes. However, higher level of maternal education was associated with a 48% reduction in infant mortality risk at 12 months.

Mothers were counselled to stop all breastfeeding around 6 months of age according to global recommendations at that time[9]. This involved explaining the risk of HIV transmission through continued breastfeeding and providing practical suggestions regarding transitioning from breastfeeding to an alternative milk source. No specific milk supplements were provided. Among HIV-exposed infants there was increased diarrhoeal morbidity in those infants whose mothers stopped all breastfeeding compared to those infants who continued to receive some breastmilk in addition to complementary feeds. While increased morbidity, growth faltering and mortality have been reported in other southern Africa settings where HIV-infected mothers stopped breastfeeding prematurely [17,18], there was no difference in mortality among HIV-exposed infants who stopped breastfeeding at 6 months compared to those who continued breastfeeding. However, this was most likely due to the limited number of events among infants followed-up.

The vast majority of infants breastfed for some period of time irrespective of whether they were HIV-exposed or not. Infants who were HIV-exposed but uninfected were neither at increased risk of diarrhoeal morbidity or death compared to infants born to HIV uninfected mothers. This suggests that these infants were either at no immunological disadvantage by virtue of their HIV exposure or that breastfeeding ameliorated any adverse consequence of being born to an HIV-infected mother. In contrast, infants who became HIV-infected during pregnancy or delivery were thirteen times more likely to die by 12 months of age compared to infants who were not exposed to HIV infection. However, infants who became HIV-infected postnatally were only about six times more likely to die in the first year suggesting that these infants managed to acquire some immunocompetency before becoming HIV-infected, and they had already survived the greatest risk period for infant mortality. While similar findings have been reported in recent meta-analyses [19], our data provide robust confirmation of this finding but from an infant population exposed to the same set of environmental conditions and risks.

The findings reported above are based on daily infant feeding and morbidity data that were collected weekly from HIV-infected and uninfected mothers at their homes in rural and periurban settings. Comparable datasets are not available elsewhere and the dataset permits valuable comparative analyses. Rigorous definitions of cumulative exclusive breastfeeding were strictly applied. HIV-infected mothers self-selected their infant feeding practice as it was deemed unethical and impractical to allocate practices by randomisation. Inherent differences among participating HIV-infected mothers that may influence morbidity and mortality outcomes have been previously reported in detail[20]. Mothers who chose to breastfeed tended to have poorer water supplies and sanitation, less income and less access to electricity. Despite these less favourable environmental circumstances, breastfeeding conferred a survival benefit on breastfed children. Diarrhoeal morbidity was inferred from maternal history and was only confirmed by the research team if the infant had loose stools at the time of home visit. Associations with lower respiratory infections were not examined in the analysis. For while data on cough and fast breathing were also collected, it is more difficult to apply and interpret clinical algorithms to estimate the prevalence of severe pneumonia and infer cause-specific deaths.

In countries where national authorities promote and support breastfeeding while providing ARVs to HIV-infected mothers, WHO recommends that HIV-infected mothers exclusively breastfeed for the first 6 months and continue to breastfeed for at least the first 12 months while introducing complementary feeds around 6 months. While exclusive breastfeeding is reported to reduce the risk of postnatal HIV transmission compared to mixed feeding [5,21], in the context of ARVs that reduce the risk of HIV transmission exclusive breastfeeding makes a different and more significant contribution, namely to prevent other causes of infant mortality. Our findings support current WHO recommendations for improving HIV free survival of HIV exposed infants. WHO still recommends mothers who are HIV-uninfected to EBF until 6 months and continue breastfeeding until their infants are 24 months of age. Our findings confirm that infant mortality could be reduced by two or threefold if all infants were exclusively breastfed for 6 months[22].

Despite compelling evidence that EBF would make a significant contribution to reducing infant mortality in high HIV prevalence settings, and the consequences of not breastfeeding having been quantified in terms of mortality [22] and DALYs [23], national and district health authorities infrequently invest and aggressively promote exclusive breastfeeding among either HIV-infected or uninfected mothers. Health workers lack of confidence in their own ability to support exclusive breastfeeding and mothers doubt the merits and feasibility of EBF and continued breastfeeding. However a range of interventions including health policies [24], political leadership [25], systems interventions [26,27], simplified health facility [28] and community-based support [29,30], community engagement [31,32] and peer support [33] have reported improved exclusive breastfeeding rates under programmatic conditions.

The findings provide strong and further rationale for financial and human resource investment for promoting, supporting and protecting exclusive breastfeeding. In HIV prevalent settings such as South Africa, the evidence endorses a public health approach that actively invests in improving EBF rates while providing ARVs to HIV-infected mothers as linked child survival interventions – a direction that South Africa has moved towards through updated clinical protocols, introduction of legislation on the Code of marketing of Breastmilk Substitutes and new workplace regulations under consideration. The availability of simple ARV interventions to prevent postnatal transmission to infants, whether it be prophylaxis or lifelong treatment for breastfeeding HIV-infected mothers, creates the opportunity to harmonize and enhance interventions to improve infant feeding practices in the entire population. In this context, appropriate investments are essential to improve access and adherence to these regimens to ensure that benefits of breastfeeding for child survival are not undermined by inadequate ARV prophylaxis. The return on such financial investment, whether from HIV-designated funds or not, will not only increase the likelihood of HIV-free survival of HIV-exposed infants but also improve the health, development and survival of all children.

Supporting Information

Acknowledgments

We are especially grateful to the women and children who participated in the study, the clinic staff and district health management team who accommodated the study teams within their facilities, and the general support of the community that enabled the study to be implemented. We wish to acknowledge the commitment of the field research team and data management staff of the Africa Centre throughout the duration of the study.