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. Author manuscript; available in PMC: 2014 Nov 13.
Published in final edited form as: AIDS. 2013 Nov 13;27(17):2809–2815. doi: 10.1097/01.aids.0000432540.59786.6d

Breastfeeding is associated with decreased pneumonia incidence among HIV-exposed, uninfected Kenyan infants

Kristjana H ÁSBJÖRNSDÓTTIR 1, Jennifer A SLYKER 2, Noel S WEISS 1, Dorothy MBORI-NGACHA 4, Elizabeth MALECHE-OBIMBO 4, Dalton WAMALWA 4, Grace JOHN-STEWART 1,2,3,5
PMCID: PMC4084504  NIHMSID: NIHMS577511  PMID: 23921609

Abstract

Objective

HIV-exposed uninfected infants (HEU) have higher infectious disease morbidity and mortality than unexposed infants. We determined the incidence and risk factors for pneumonia, a leading cause of infant mortality worldwide, in a cohort of HEU infants. Identifying predictors of pneumonia among HEU infants may enable early identification of those at highest risk.

Design

A retrospective cohort of HEU participating in a Kenyan perinatal HIV study, enrolled between 1999-2002.

Methods

Infants were followed monthly from birth to 12 months. Incidence of pneumonia diagnosed at monthly study visits, sick-child visits or by means of a verbal autopsy, was estimated with a 14-day window for new episodes. Cox proportional hazards regression was used to identify predictors of first pneumonia occurrence.

Results

Among 388 HEU infants with 328 person-years of follow-up, the incidence of pneumonia was 900/1,000 child-years (95% CI: 800-1,000). Maternal HIV viral load at 32 weeks gestation [HR=1.2 (1.0-1.5) per log10 difference] and being underweight (weight-for-age Z-score <-2) at the previous visit [HR=1.8 (1.1-2.8)] were associated with increased risk of pneumonia. Breastfed infants had a 47% lower risk of pneumonia than those never breastfed [HR=0.53 (0.39-0.73)], independent of infant growth, maternal viral load and maternal CD4%. Breastfeeding was also associated with a 74% lower risk of pneumonia-related hospitalization (HR=0.26 (0.13-0.53)).

Conclusions

The incidence of pneumonia in this cohort of HEU infants was high. Our observations suggest that maternal viral suppression and breastfeeding may reduce the burden of pneumonia among HEU.

Keywords: HIV-exposed uninfected, infants, morbidity, breastfeeding, pneumonia

INTRODUCTION

As increasingly effective measures to prevent infant HIV infection are implemented, the population of HIV-exposed uninfected infants (HEU) is growing. HEU have higher mortality and morbidity than unexposed infants [1, 2]; this may be due to increased exposure to infectious pathogens, impaired maternal caregiving, reduced breastfeeding, or compromised immune development [3].

Pneumonia is a leading cause of child mortality [4]. Annual incidence of pneumonia in the developing world among children under 5 is estimated at 29/100 [4, 5], with about 10% requiring hospitalization [4]. Approximately 50% of childhood pneumonias are caused by Haemophilus influenzae or Streptococcus pneumoniae [4]. Viral and mixed viral-bacterial infections are also common etiologies of childhood pneumonia in developing countries. [6, 7] HIV-infected children are at particularly high risk for pneumonia [6, 8]; in a perinatal HIV cohort in Kenya, we previously found pneumonia to be the leading cause of mortality among both HEU [9] and HIV-infected infants[10].

Elucidation of cofactors for pneumonia in HEU may inform interventions to prevent pneumonia or identification of mother-infant pairs at highest risk. In this study, we describe the incidence and predictors for pneumonia in a cohort of Kenyan HEU.

METHODS

Subject selection

Mother-infant pairs were enrolled in a study of HIV transmission in Nairobi, Kenya between 1999-2002, details of which have been described elsewhere[9, 11]. HEU were followed until 12 months of age. Singletons and first-born twins were eligible for this analysis if they were confirmed HIV-uninfected at birth. Infants were excluded if they died or were lost to follow-up (LTFU) without completing a study visit, or if they were HIV-infected in utero or during delivery.

Study procedures

This study was approved by the Institutional Review Board at the University of Washington and the Ethics and Research Committee at Kenyatta National Hospital. Sociodemographic information was collected at enrollment, and maternal CD4 and HIV viral load were measured at 32 weeks gestation. Mothers received antenatal short-course zidovudine for PMTCT, but no ART during breastfeeding, per contemporary Kenyan guidelines. Study visits occurred at birth, 2 weeks post-delivery and monthly thereafter.

Clinical data collection

At scheduled visits, infants underwent detailed clinical examination by a physician. Symptoms, diagnoses, history of illness and hospitalization since the last visit and current feeding practices were collected on a standardized form. At sick-child visits, examination and history were limited to features related to the infant's reporting complaint. For infants who died outside hospital, verbal autopsy was conducted to determine most likely cause of death.

Outcome

Pneumonia was diagnosed according to Integrated Management of Childhood Illness (IMCI) guidelines. Diagnoses made at study visits, sick-child visits or recorded as cause of death were included in this analysis. To rule out data entry error, diagnoses recorded at study visits were checked for the presence of IMCI pneumonia symptoms. To avoid double-counting an unresolved episode, new diagnoses were not counted for 14 days following each diagnosis.

Statistical analysis

Analyses were conducted using Stata 11.2 (StataCorp, College Station, Texas). Infant growth was assessed using the WHO Child Growth Standards Stata igrowup package.

Incidence of all pneumonia, in the whole cohort and within strata of predictors, was calculated with censoring at non-pneumonia death, LTFU, last negative HIV-DNA before first HIV-DNA detection in HIV-infected infants, or study exit at 12 months. Infants did not contribute person-time for 14 days following a pneumonia diagnosis. Incidence of pneumonia-related hospitalization (allowing for repeat hospitalizations) and pneumonia-related mortality was calculated the same way.

Predictors of first pneumonia diagnosis were identified using Cox proportional hazards regression with censoring as above. All exposures were assessed at baseline except maternal viral load, CD4%, breastfeeding and weight-for-age Z-score (WAZ). Viral load and CD4% were measured at 32 weeks gestation; breastfeeding (ever/never, current) and WAZ were assessed at each study visit and analyzed as time-varying covariates.

In order to address whether associations with breastfeeding were mediated through infant growth, breastfeeding and lagged WAZ were included in the same model. Other models of the association between breastfeeding and pneumonia were adjusted for maternal viral load or CD4% to assess confounding by advanced maternal disease.

RESULTS

Study population

388 infants were included in this analysis; 365 remained uninfected while 23 acquired HIV, at a median of 33 days (IQR 29-180). Eighty-five infants were LTFU at a median of 243 days (IQR 105-320). Mothers were mostly young (median 25 years, IQR 22-28), married (90%), lived in one-room houses (78%) and lacked an independent income (70%). At 32 weeks gestation, mothers' median CD4 count was 438 cells/mm3 (IQR 310-611), median CD4% was 24 (IQR 18-30) and median viral load was 4.7log10 copies/ml (IQR 4.1-5.2). Seventy-six percent of mothers breastfed for a median of 273 days (IQR 123-364).

Pneumonia burden

Infants completed 328 person-years of follow-up. 177 infants were diagnosed with pneumonia (Figure 1A) and experienced a total of 296 episodes. Pneumonia incidence was 900/1,000 infant-years (95% CI: 800-1,000) and did not differ significantly between three-month intervals of age. Median age at first pneumonia was 127 days (IQR 60-211). Thirty-three infants were hospitalized a total of 41 times for pneumonia, corresponding to 110 hospitalizations/1,000 infant-years (95% CI 80-160). Median age at first hospitalization was 150 days (IQR 63-227). Ten infants died with pneumonia at a median age of 116 days (IQR 70-149), for a total pneumonia-related mortality rate of 30/1,000 infant-years (95% CI 16-57).

Fig. 1.

Fig. 1

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(a) Kaplan–Meier curve showing time to first physician-diagnosed pneumonia. Infants were censored at loss to follow-up or non-pneumonia mortality, and infants who acquired HIV were censored at their last negative HIV-DNA before first HIV-DNA detection. (b) Kaplan–Meier curves showing time to first pneumonia diagnosis, comparing ever-breastfed infants (breastfed at one or more visits by maternal report) to never-breastfed infants. (c) Kaplan–Meier curves showing time to first pneumonia-related hospitalization, comparing ever-breastfed infants to never-breastfed infants. (d) Kaplan–Meier curves showing pneumonia-related mortality, comparing ever-breastfed infants to never-breastfed infants. In (b)–(d), solid lines represent infants whose mothers reported breastfeeding at one or more visits; dashed lines represent infants who were never breastfed. P-values refer to comparisons of the curves using the log-rank test.

Predictors of first pneumonia

Infant pneumonia was not associated with maternal age, socioeconomic indicators, or maternal CD4% (Table 1). Each log10 difference in maternal viral load at 32 weeks gestation was associated with 20% increased pneumonia risk [HR=1.2 (1.0-1.5)]. Low birth weight and prematurity were not associated with risk of pneumonia, however being moderately to severely underweight (WAZ<-2) at a study visit was associated with increased risk of pneumonia at the following visit [HR=1.8 (1.1-2.8)]. Higher continuous lagged WAZ was associated with decreased risk of pneumonia [HR=0.86 (0.76-0.99)].

Table 1.

Predictors of first pneumonia diagnosis identified using Cox proportional hazards regression.

BASELINE FACTORS n1 Pneumonia (ever)2 Hazard Ratio (95% CI) p-value Incidence/1,000 i-yrs (95% CI)3
Sociodemographic factors
    Maternal age (per year) 388 177 1.0 (0.97-1.0) 0.9 900 (800-1,000)
    Maternal education < primary school 224 98 1.0 Ref. 930 (800-1,100)
    Maternal education >primary school 159 79 1.1 (0.84-1.5) 0.4 890 (740-1,100)
    >One room house 86 39 1.0 Ref. 880 (690-1,100)
    One room house 302 138 1.1 (0.74-1.5) 0.8 910 (800-1,000)
    ≥3 people/room of house 300 133 1.0 Ref. 860 (760-980)
    >3 people/room of house 85 43 1.4 (0.97-1.9) 0.08 1,100 (860-1,400)
Maternal characteristics
    CD4% at 32 weeks' gestation (cont.) 378 170 1.0 (0.98-1.0) 0.9 890 (790-1,000)
    CD4%≥20 at 32 weeks' gestation 257 115 1.0 Ref 870 (760-1,000)
    CD4%<20 at 32 weeks' gestation 122 55 1.1 (0.78-1.5) 0.6 910 (740-1,100)
    HIV viral load at 32 weeks gestation (per log10) 348 150 1.2 (1.0-1.5) 0.04 870 (770-980)
Infant characteristics
    Birth weight ≥2500 g 358 164 1.0 Ref. 900 (800-1,000)
    Birth weight <2500 g 21 10 1.0 (0.55-2.0) 0.9 990 (610-1,600)
    Infant born at term 324 153 1.0 Ref. 930 (820-1,100)
    Infant born pre-term 21 9 1.2 (0.60-2.3) 0.7 1,100 (690-1,800)
Never breastfed     93 58 1.0 Ref. 1,300 (1,100-1,600)
    Ever breastfed 294 118 0.54 (0.39-0.74) <0.001 770 (670-890)
TIME-VARYING COVARIATES Infant- years4 Pneumonia (ever) Hazard Ratio 95% CI p-value Incidence/1,000 i-yrs (95% CI)
    Not currently breastfeeding 144 98 1.0 Ref. 660 (550-800)
    Currently breastfeeding 173 77 0.46 (0.34-0.63) <0.001 1,200 (990-1,300)
    WAZ -score at previous visit (continuous) 301 174 0.86 (0.76-0.99) 0.03 930 (830-1,000)
    Not underweight (WAZ≥-2) at previous visit 281 155 1.0 Ref. 870 (770-990)
    Underweight (WAZ <-2) at previous visit 20 19 1.8 (1.1-2.8) 0.02 1,800 (1,300-2,400)
MULTIVARIATE PREDICTORS n Pneumonia (ever) Adjusted Hazard Ratio (95% CI) p-value
Model 1:
    Ever breastfed 374 173 0.53 (0.39-0.73) <0.001
    WAZ-score at previous visit (continuous) 0.88 (0.77-1.0) 0.04
Model 2:
    Ever breastfed 348 150 0.51 (0.36-0.72) <0.001
    Mother's HIV VL at 32 weeks gestation (per log10) 1.2 (0.98-1.5) 0.08
Model 3:
    Ever breastfed 379 170 0.52(0.38-0.72) <0.001
    Mother's CD4% at 32 weeks gestation (cont.) 1.0 (0.99-1.0) 0.5
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1

Total number of mother-infant pairs on whom data were available (continuous exposures) or number of mother-infant pairs per category (categorical exposures).

2

Number of infants on whom information was available and who experienced one or more episodes of pneumonia.

3

Incidence of pneumonia, allowing for repeat episodes and with a 14-day window for new episodes.

4

Infant-years of observation, stratified by category of the predictor.

Breastfed infants had a 47% lower risk of pneumonia than never-breastfed infants [Figure 1B, HR=0.53 (0.39-0.73)]. When analyzed as a time-varying covariate, current breastfeeding was associated with a 54% reduced risk of pneumonia [HR=0.46 (0.34-0.63)]. The association between ever-breastfeeding and pneumonia was unaffected by adjustment for lagged WAZ [aHR=0.50 (0.37-0.70)] and by adjustment for maternal log10 viral load [aHR=0.51 (0.36-0.72)] or CD4% [aHR=0.52 (0.38-0.72)].

Breastfed infants had a 74% lower risk of pneumonia-related hospitalization [Figure 1C, HR=0.26 (0.13-0.53)] and a trend for lower risk of pneumonia-related mortality [Figure 1D, HR=0.32 (0.09-1.1)] compared to never-breastfed infants.

An alternative analysis using a composite endpoint of first pneumonia or all-cause infant mortality revealed similar relationships and estimates (data not shown).

DISCUSSION

In this study, almost half of HEU infants (46%) experienced an episode of pneumonia during the first year of life. The overall incidence of pneumonia (90/100 infant-years) was substantially higher than the estimated worldwide under-five incidence of 29/100 child-years [4, 5]. Similarly, incidence of hospitalization (110/1,000 child-years) was higher than that reported in population-based studies in rural Kenya, which observed hospitalization rates of 48/1,000 person-years among infants [7] and 7/1,000 person-years among children under five [12]. Pneumonia-related mortality rate in our study was 30/1,000 child-years, which is also high compared to previous reports from Kenya [13]. These differences may be partly explained by the age of our cohort – rates of pneumonia are higher in the first year of life [7] – and by increased detection, access to clinical care and referrals for hospitalization. However, it is likely that there are true differences between our cohort and the general population of Kenyan infants due to maternal HIV infection; high rates of infant hospitalization have been observed in previous HEU cohorts [14]. Many factors related to maternal HIV may increase infant susceptibility to pneumonia, including compromised immunity or increased household respiratory infections; in our cohort, breastfeeding avoidance was likely a key factor.

Breastfeeding was associated with lower risk of pneumonia among HEU infants in our cohort, and the association was neither mediated by infant growth nor confounded by maternal HIV disease severity. This observation is consistent with literature supporting the role of breastfeeding in the prevention of respiratory tract infections among children in general [15-17] and in reducing infectious morbidity among HEU children [14, 18-20]. Breastfed infants have a larger thymus at four months of age than those not breastfed, have higher titers of neutralizing antibodies post-vaccination, and may mount more effective immune responses [17]. IgA antibodies from breast milk have been suggested to protect against infection by neutralizing pathogens at mucosal surfaces [17, 21].

Underweight infants were at 80% increased risk of pneumonia at the following visit compared to normal-weight infants, consistent with previous studies [22, 23]. This may be due to increased susceptibility to infection due to malnutrition, or to increased risk of pneumonia following other acute illness [23], which is often accompanied by weight loss [23, 24].

Several HEU studies have noted an association between maternal CD4 and infant hospitalization, [1, 14] mortality [14, 25] and lower respiratory tract infection [26]. We observed an association between maternal HIV viral load and infant pneumonia, but not with CD4, consistent with a South African study [27]. Maternal viral load could affect infant immunity to respiratory pathogens; higher viral loads during pregnancy have been associated with decreased transplacental antibody transfer [28].

Strengths of our study included detailed standardized characterization of serial morbidity and exposure history. Limitations include a lack of systematic confirmatory diagnostic techniques such as chest X-rays; specificity of pneumonia diagnosis in African settings is as low as 15-40% [29, 30]. Our ability to identify predictors of pneumonia would be attenuated by misclassification of the outcome; therefore the associations we report may be underestimated. A second limitation is the potential for non-random loss to follow-up. Low birth weight [31] and prematurity [32] have been consistently found to be associated with risk of pneumonia among children in general, but we found no association. It is possible that these factors contributed to mortality before the first study visit and exclusion from this analysis. We do not have an HIV-unexposed comparison cohort and thus cannot estimate contribution of HIV exposure to incidence of pneumonia. Finally, the study was conducted prior to addition of Hib and pneumococcal vaccines to the Kenyan vaccination schedule. Although these would be expected to decrease incidence of pneumonia, ~50% of pneumonias are estimated to be caused by other pathogens [4, 7] and the cofactors we identified likely remain relevant to HEU.

As the population of HEU infants increases, understanding the increased vulnerability of this population will be critical for optimizing child health. WHO 2010 guidelines recommend that HIV-infected mothers breastfeed with either extended maternal ART or infant prophylaxis [33]. Our study suggests that in addition to enhanced prevention of infant HIV and improved maternal health resulting from maternal ART, these guidelines may lead to decreased pneumonia among HEU infants, both through reducing maternal viral load and by allowing safe extended breastfeeding.

Acknowledgements

GJ-S conceived and acquired funding for the primary cohort study. GJ-S, DM-N and EM-O developed the primary cohort and designed clinical protocols. EM-O and DW collected clinical data and interpreted clinical results. KHA, JAS, NSW and GJ-S participated in design and interpretation of the statistical analyses. The final manuscript was written by KHA with comments and input from all authors. The authors wish to thank the women and infants who participated in this study, the CTL study peer counselors and the data, clinical and laboratory teams at the University of Nairobi and Kenyatta National Hospital, without whom this study would not have been possible. We thank the University of Nairobi and Kenyatta National Hospital for providing administrative and physical infrastructure for the study. We thank Julie Overbaugh's team at the Fred Hutchinson Cancer Research Center for HIV viral assays and the Kizazi working group (UW Global Center for Integrated Health of Women, Adolescents and Children (Global WACh)), particularly Ken Tapia and Lisa Cranmer, for their comments on the analysis and support during the preparation of this article.

Support: US National Institute of Child Health and Human Development (grant R01 HD-23412). KHA was supported in part by NIH K24 HD054314-06 and by NIH Interdisciplinary Training in Cancer Research, T32 CA080416.

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