Abstract
Background: Early feeding patterns may affect the growth of HIV-exposed children and thus their subsequent health and cognition.
Objective: We assessed the association of infant feeding (IF) mode with length-for-age z score (LAZ) and stunting from age 2 d to 18 mo in HIV-exposed African children within a controlled randomized trial, which evaluated triple antiretrovirals initiated during pregnancy and continued for 6 mo postpartum to prevent HIV transmission.
Methods: HIV-infected pregnant women with CD4+ counts of 200–500 cells/mm3 from Burkina Faso, Kenya, and South Africa were advised to exclusively breastfeed for up to 6 mo or to formula-feed from birth. Factors associated with LAZ were investigated in all uninfected children by using mixed-effects linear models; those associated with stunting (LAZ <−2) at 6 or 12 mo were assessed in multiple logistic regression after exclusion of children stunted at age 2 d. Independent variables were IF mode: formula feeding (FF), exclusive breastfeeding (EBF) <3 mo, or EBF ≥3 mo (reference); sex; trial arm; maternal characteristics; and site.
Results: Among 728 children, FF was associated with a greater increase in LAZ from 2 d to 6 mo (+0.07 z score/mo, P < 0.001). Between 6 and 18 mo, FF and EBF <3 mo were both associated with greater mean LAZ than was EBF ≥3 mo (+0.52 z scores and +0.43 z scores, respectively, P < 0.001). Among children not stunted at 2 d, FF was independently associated with a reduced risk of stunting at 6 mo (OR: 0.24; 95% CI: 0.07, 0.81; P = 0.021), whereas EBF <3 mo was not (OR: 0.49; 95% CI: 0.22, 1.10; P = 0.09).
Conclusions: In this observational study of HIV-exposed uninfected infants, growth in length in the first 6 mo of life was faster in formula-fed infants than in exclusively breastfed infants. The plausibility of residual confounding and reverse causality is discussed. This trial was registered at www.controlled-trials.com as ISRCTN71468401.
Keywords: Africa, breastfeeding, HIV infection, infant growth, stunting
Introduction
Infant growth and nutritional status are strongly associated with later health and cognitive development. Stunting and wasting are associated with an increased risk of disease and mortality. Stunting also has been associated with school failure and impaired adult socioeconomic status and reproductive health (1, 2). Lack of breastfeeding is associated with increased risks of infectious morbidity and mortality in infancy and in some studies with lower cognitive development and adult income (3–8).
Studies of the relation between feeding mode and growth in uninfected HIV-exposed infants have yielded contradictory results. In Pune, India, breastfed infants were significantly less stunted at age 12 mo than their never-breastfed counterparts (9). In Zambia breastfeeding was associated with greater weight-for-age z score from 5 to 15 mo of age in adjusted analyses with no difference in height-for-age z score (10). Breastfed South African infants had greater weight-for-age z score and marginally greater length-for-age z score (LAZ)11 than formula-feeding (FF) infants at age 3 mo but no longer at 6 or 9 mo (11). Conversely, in a Kenyan randomized controlled trial (RCT), infants FF from birth had faster growth in length than their breastfed counterparts (12).
We aimed to quantify the association between infant feeding (IF) modality and LAZ and the risk of stunting in the first 18 mo of life in HIV-exposed uninfected children in an observational cohort study conducted within a randomized HIV-prevention trial. We hypothesized that exclusively breastfed children would grow faster and have better nutritional status than their never-breastfed counterparts.
Methods
Design.
The Kesho Bora RCT was designed to test the efficacy of an intervention to reduce mother-to-child transmission (MTCT) of HIV and to increase infant and maternal survival (13). The intervention group received a combination of 3 antiretroviral drugs from 28 to 36 wk of gestation until 6 mo postpartum (or breastfeeding cessation, if earlier). The control group received a standard short-course MTCT-preventive antiretroviral regimen (13). Women were recommended to either breastfeed exclusively up to 6 mo postpartum or formula-feed from delivery, in accordance with WHO recommendations and national guidelines at the time (14, 15).
Subjects.
All live-born singletons or first-born twins of enrolled women were included in the present analysis if they had ≥1 length measurement, were HIV-uninfected at the end of follow-up, and had no missing data for potentially confounding factors (i.e., study site, RCT arm, sex, wealth indicator, maternal education, height, and BMI).
Study procedures.
The study was conducted in Bobo-Dioulasso, Burkina Faso; Nairobi and Mombasa, Kenya; and Durban and a rural area of KwaZulu-Natal, South Africa. Enrollment started in January 2005 in the 3 former sites and in February and September 2007 in Durban and in Somkhele, rural KwaZulu-Natal, respectively. Enrollment was completed in August 2008 and follow-up in December 2010, respectively (13).
Ethical clearance was given by the ethical and regulatory committees in Burkina Faso, Kenya, and South Africa, and at the WHO and CDC. The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983, and all women provided written, informed consent.
Pregnant, HIV-infected women at <32 wk of gestation who did not participate in any other study and who had a WHO clinical stage 1, 2, or 3 disease and a CD4+ count of 200–500 cells/mm3 were eligible for enrollment. The triple-antiretroviral group received a combination of 3 antiretrovirals (zidovudine, lamivudine, lopinavir/ritonavir) from 28 to 36 wk of pregnancy up to 6.5 mo postpartum (or breastfeeding cessation, if earlier). Those in the short-course arm received standard prophylaxis, i.e., zidovudine and a single dose of nevirapine. All infants received a dose of nevirapine, preferably within 72 h of birth. The study was not blinded.
Infant feeding counseling was conducted antenatally and after delivery until complete cessation of breastfeeding, following WHO guidelines. Demonstrations of formula preparations were performed and free formula was provided for infants from birth until 6 mo of age, as appropriate. All medical care was provided free of charge.
Data collection.
Maternal background data were collected at enrollment (i.e., during pregnancy). Gestational age estimation was based on self-reported last menstrual period or symphysis-fundal height. Birth weight was measured routinely in maternity wards by hospital staff to the nearest 100 g; it was unavailable for home deliveries. Length measurements were not taken at birth.
Early neonatal recumbent length was measured, preferably within 48 h and at most 7 d after delivery. Subsequent length measurements were taken in study clinics at ages 4 and 8 wk and 4, 6, 9, 12, 15, and 18 mo. All measurements were read to the nearest millimeter by trained teams using infant measuring boards and standard procedures (16). Two readings were made for each measurement, and the mean was used in the analysis. If the difference between the 2 readings exceeded 5 mm, a third reading was made and the outlier was discarded. Weight was recorded to the nearest 10 g by using electronic infant scales.
IF data were collected during postnatal visits at study clinics at ages 2, 4, 6, and 8 wk and 3, 4, 5, and 6 mo, including all items fed to the infant since the preceding visit (since birth for the 2-wk visit). Continued breastfeeding was recorded at all clinic visits, including at ages 9, 12, 15, and 18 mo. In case of breastfeeding cessation since the preceding visit, the precise date of cessation was recorded.
Blood samples for diagnosis of child HIV infection status were taken at birth, ages 2 and 6 wk, and 3, 6, 9, 12, and 18 mo (17). The HIV infection status of all children was assessed by quantitative RNA PCR tests at ages 6 wk and 12 mo (18). Samples taken at other ages were used for HIV diagnosis in those who died or were lost to follow-up before age 12 mo. All children reaching age 18 mo had their HIV infection status confirmed through HIV serology.
The original protocol included follow-up until age 24 mo, but financial constraints reduced this to ages 12–18 mo during the course of the RCT. As a result, scheduled child follow-up changed over time; during the last year of the trial, child follow-up in the South African sites (i.e., Somkhele and Durban) was at age 12 mo only.
Variables.
Length-for-age and weight-for-length were expressed in z scores relative to the WHO growth standards by using the Anthro software (19). Unreliable length values (i.e., LAZ >3 or LAZ <−6) were excluded. Stunting was defined as LAZ <−2 and wasting as weight-for-length z score (WLZ) <−2.
IF was divided into 3 groups: never breastfed (i.e., exclusively formula-fed from birth), duration of exclusive breastfeeding (EBF) <3 mo, or EBF ≥3 mo (6, 7). Breastfed children who died or were lost to follow-up before 3 mo were classified as EBF <3 mo, as were those who were breastfed but not exclusively. Maternal education was divided into 3 groups (none, some primary, and some secondary), and maternal height was divided into 4 arbitrarily defined categories (Table 1). Maternal postpartum BMI was computed by using the weight measurement taken at 4 wk postpartum or, if missing, at 6 or 8 wk. BMI (in kg/m2) was divided into mild underweight, lower-normal range, upper-normal range, and overweight-obese (<20, 20–22.4, 22.5–25, and >25, respectively), because the prevalence of true underweight (i.e., BMI <18.5) was very low (20). Maternal CD4+ cell count at inclusion was divided into 2 groups, i.e., 200–349 and 350–500 cells/mm3. Selected household possessions (refrigerator, radio, television, cell phone) and characteristics of housing (access to gas or electricity for cooking, clean drinking water, electricity, flush toilets, and sharing of toilets with persons from outside the household) were used to compute a summary economic score by multiple correspondence analysis. All children had complete data for these variables. Site-specific tertiles were used in the analysis (6).
TABLE 1.
Characteristics of women and children in the Kesho Bora RCT by IF modality1
| Variable | Never breastfeeding (n = 166) | EBF <3 mo (n = 336) | EBF ≥3 mo (n = 226) | P2 | P (adjusted for study site)3 | All (n = 728) |
| RCT arm | 0.88 | 0.82 | ||||
| Triple antiretroviral | 86 (51.8) | 167 (49.7) | 116 (51.3) | 369 (50.7) | ||
| Short course | 80 (48.2) | 169 (50.3) | 110 (48.7) | 359 (49.3) | ||
| Study site | <0.001 | — | ||||
| Bobo Dioulasso | 15 (9.0) | 116 (34.5) | 86 (38.1) | 217 (29.8) | ||
| Mombasa | 48 (28.9) | 128 (38.1) | 41 (18.1) | 217 (29.8) | ||
| Nairobi | 9 (5.4) | 22 (6.7) | 6 (2.7) | 37 (5.1) | ||
| Somkhele | 18 (10.8) | 31 (9.2) | 37 (16.4) | 86 (11.8) | ||
| Durban | 76 (45.8) | 39 (11.6) | 56 (24.8) | 171 (23.5) | ||
| Child sex | 0.004 | 0.010 | ||||
| Male | 86 (51.8) | 181 (53.9) | 90 (39.8) | 357 (49.0) | ||
| Female | 80 (48.2) | 155 (46.1) | 136 (60.2) | 371 (51.0) | ||
| Maternal height, cm | 0.39 | 0.23 | ||||
| <155 | 40 (24.1) | 85 (25.3) | 58 (25.7) | 183 (25.1) | ||
| 155–159.9 | 53 (31.9) | 110 (32.7) | 54 (23.9) | 217 (29.8) | ||
| 160–164.9 | 40 (24.1) | 79 (23.5) | 65 (28.8) | 184 (25.3) | ||
| ≥165 | 33 (19.9) | 62 (18.5) | 49 (21.7) | 144 (19.8) | ||
| Maternal BMI,4 kg/m2 | 0.007 | 0.75 | ||||
| <20 | 12 (7.2) | 33 (9.8) | 25 (11.1) | 70 (9.6) | ||
| 20–22.49 | 34 (20.5) | 90 (26.8) | 48 (21.2) | 172 (23.6) | ||
| 22.5–25 | 36 (21.7) | 165 (31.3) | 66 (29.2) | 207 (28.4) | ||
| >25 | 84 (50.6) | 108 (32.1) | 87 (38.5) | 279 (38.3) | ||
| Maternal education | <0.001 | 0.001 | ||||
| None | 6 (3.6) | 56 (16.7) | 44 (19.5) | 106 (14.6) | ||
| Primary | 41 (24.7) | 130 (38.7) | 77 (34.1) | 248 (34.1) | ||
| Secondary | 119 (71.7) | 150 (44.6) | 105 (46.5) | 374 (51.4) | ||
| Maternal CD4+ cell count/mm3 | 0.004 | 0.26 | ||||
| 200–349 | 107 (64.5) | 165 (49.1) | 402 (57.5) | 402 (55.2) | ||
| 350–500 | 59 (35.5) | 171 (50.9) | 96 (42.5) | 326 (44.8) | ||
| Electricity | 0.018 | 0.42 | ||||
| Yes | 125 (75.3) | 211 (62.8) | 154 (68.1) | 490 (67.3) | ||
| No | 41 (24.7) | 125 (37.2) | 72 (31.9) | 238 (32.7) | ||
| Refrigerator | <0.001 | 0.13 | ||||
| Yes | 71 (42.8) | 86 (25.6) | 70 (31.0) | 227 (31.2) | ||
| No | 95 (57.2) | 250 (74.4) | 156 (69.0) | 501 (68.8) | ||
| Fuel | <0.001 | 0.21 | ||||
| Gas or electricity | 132 (79.5) | 183 (54.5) | 120 (53.1) | 435 (59.8) | ||
| Wood or charcoal | 34 (20.5) | 153 (45.5) | 106 (46.9) | 293 (40.2) | ||
| Toilet | <0.001 | 0.38 | ||||
| Flush | 84 (50.6) | 76 (22.6) | 68 (30.1) | 228 (31.3) | ||
| Latrines | 82 (49.4) | 260 (77.4) | 158 (69.9) | 500 (68.7) | ||
| Tap water | 0.007 | 0.16 | ||||
| Yes | 106 (63.9) | 174 (51.8) | 109 (48.2) | 389 (53.4) | ||
| No | 60 (36.1) | 162 (48.2) | 117 (51.8) | 339 (46.6) | ||
| Wealth tertile5 | 0.20 | 0.011 | ||||
| Lower | 49 (29.5) | 108 (32.1) | 89 (39.4) | 246 (33.8) | ||
| Middle | 55 (33.1) | 111 (33.0) | 73 (32.3) | 239 (32.8) | ||
| Upper | 62 (37.4) | 117 (34.8) | 64 (28.3) | 243 (33.4) |
Values are n (%). EBF, exclusive breastfeeding; IF, infant feeding; RCT, randomized controlled trial.
Distributions of variables across IF categories were compared by using chi-square tests.
Distributions of variables across IF categories were compared with adjustment for study site by using Cochran-Mantel-Haenszel tests.
Maternal weight measurements were taken during the first 2 mo postpartum.
Wealth tertiles were site specific.
Low birth weight was defined as birth weight <2500 g. Gestational age at delivery was defined as gestational age at enrollment plus the number of weeks of follow-up before delivery. Because of a high rate of unreliable values (e.g., ≥44 wk), this variable was not used in the analysis.
Statistical analysis.
Maternal and child characteristics were compared across IF modalities and study sites by using chi-square or Fisher’s exact tests. Adjustment for study site in the analysis of IF modalities was carried out by using Cochran-Mantel-Haenszel tests. Chi-square tests and Cochran-Mantel-Haenszel tests were used to compare children with a length measurement at age 18 mo and those who stopped follow-up between 12 and 18 mo.
Factors potentially associated with the hazards of becoming stunted at 6 or 12 mo for children not stunted at age 2 d were assessed in multiple logistic regression analysis. The main explanatory variable was IF, and the analysis was adjusted for the RCT arm, sex, and study site and maternal height, BMI, and wealth index (all categorical). Children already stunted at age 2 d were excluded from this analysis because early neonatal stunting cannot be attributed to IF. The existence of effect modification by study site was tested through the introduction of an interaction term between site and IF in a separate logistic regression model.
Mixed-effects linear models (MLMs) with an autoregressive covariance structure were used to examine the associations between IF modality and LAZ. These analyses included all children, irrespective of stunting status at age 2 d. Models included random intercepts for each participant. Linearity was determined graphically. Potential confounding factors were RCT arm, study site, and infant sex and maternal height, postpartum BMI, level of education, CD4+ cell count at inclusion, and wealth index. The age intervals of 2 d to 6 mo and 6–18 mo were considered separately per protocol. Again, effect modification by study site was tested by the introduction of an interaction term between study site and IF in separate models.
For each independent variable, MLMs provide 2 coefficients, β0 and β1. The former estimates the difference between a given category and its reference category at the start of the interval, whereas the latter assesses whether this difference is constant over time through an interaction term with age. If significant, the latter indicates that the slope of the category under study differs from that of the reference category. The estimated difference of a category with the reference at time 1 thus equals (β0 + β1 × time 1).
In sensitivity analyses of logistic regression and MLM, IF was used as a binary variable (never- compared with ever-breastfed children). Analyses were performed by using SAS (version 9.3) and Stata (version 14, Stata Corp) statistical software, and differences were considered significant at P < 0.05. All tests were 2-sided. Distributions of continuous variables are provided as means ± SDs, and proportions as P (95% CIs).
Results
Eight hundred five infants were born alive to women included in the RCT; 794 had ≥1 length measurement between ages 2 d and 18 mo. Sixty-two were HIV-infected by the end of follow-up, and 4 had missing data for maternal BMI. Thus, 728 uninfected children (719 singletons and 9 first-born twins) were included in the analysis and contributed with ≥1 length and weight measurement (Figure 1). Length and weight measurements were available for 674, 621, 610, and 488 children at ages 2, 6, 12, and 18 mo, respectively. One LAZ value (at age 2 mo) was >3; LAZ and WLZ at this age were excluded from the analysis for this child. The duration of follow-up was 16.2 ± 4.3 mo for a total duration of follow-up of 11,786 child-months.
FIGURE 1.
Flow diagram of HIV-exposed uninfected children included in the observational cohort study of infant and young child growth within the Kesho Bora randomized clinical trial. FU, follow-up.
As expected from changes in scheduled duration of follow-up, children who discontinued follow-up after the age of 12 mo, by either design or dropout, were significantly more likely to be from the South African sites than those who continued until age 18 mo (P < 0.001). They were also more likely to be enrolled in the study later, adjusted for study site (P < 0.001). In univariate analyses, IF was not significantly associated with discontinuation (P = 0.09), but when adjusted for study site, IF became significantly associated with risk of early discontinuation: never-breastfed children were more likely to have been followed up until 18 mo than children with short or longer periods of EBF (P = 0.018). Indeed, IF modality changed over time in South African sites: the proportion of never-breastfed infants decreased from 43% to 30% and that of infants exclusively breastfed for ≥3 mo increased from 26% to 47% between the first and second half of the inclusion period (P < 0.001, adjusted for study site). Duration of follow-up was not associated with the RCT arm; sex; maternal education, height, or BMI; family wealth; or neonatal LAZ (P > 0.20 for all).
Of 728 children, 116 (22.8%) were never breastfed, 336 were exclusively breastfed for <3 mo, and 226 were exclusively breastfed for ≥3. The breastfeeding duration was 3.50 ± 2.31 mo and 5.95 ± 2.28 mo for the 2 latter groups, respectively, and their EBF duration was 0.93 ± 0.89 mo and 5.03 ± 0.99 mo, respectively (P < 0.001 for both). Thirty-five children were still breastfeeding at 7 mo (11 and 24, respectively, among those exclusively breastfed <3 mo and exclusively breastfed ≥3 mo), among whom 25 lived in Bobo Dioulasso. Ten were still breastfeeding at 10 mo and 5 at 18 mo (i.e., 2.0% and 1.3%, respectively, of ever-breastfed children still in follow-up).
Children included in the analysis differed across IF categories in terms of study site, sex, maternal BMI and education, and housing characteristics (Table 1). Women in Bobo Dioulasso had the lowest and women in Durban the highest proportion of never-breastfed children. Girls were more likely to be exclusively breastfed for ≥3 mo than boys were. Women with a higher level of education and those living in households with access to a refrigerator, modern fuel for cooking, and flush toilets were more likely to avoid breastfeeding than those with lower socioeconomic status (P < 0.001 for all).
However, IF and most background characteristics (i.e., maternal height, BMI, education, CD4+ cell count, and access to electricity, a refrigerator, modern fuel for cooking, flush toilets, and tap water) differed widely across study sites (P < 0.001, Supplemental Table 1). In analyses adjusting for study site, only sex, maternal education, and the wealth indicator differed significantly by IF mode (Table 1).
The prevalence (95% CI) of stunting was 15.4% (12.8%, 18.1%), 11.7% (9.3%, 14.1%), 13.7% (11.0%, 16.3%), and 21.6% (18.1%, 25.1%) at age 2 d and 6, 12, and 18 mo respectively. The prevalence (95% CI) of wasting was 9.4% (7.2%, 11.6%), 2.6% (1.3%, 3.7%), 4.0% (2.5%, 5.5%), and 2.7% (1.3%, 4.1%), respectively, at the same ages.
Factors associated with stunting at 6 and 12 mo of age.
At age 6 mo, 621 children had a length measurement. Of them, 90 were stunted at age 2 d, leaving 531 children for the analysis. The prevalence of stunting was 6.8% (36 of 531), i.e., 4 of 117, 16 of 247, and 16 of 167 for children never breastfed, exclusively breastfed <3 mo, and exclusively breastfed ≥3 mo, respectively (P = 0.12). Crude excess risks of stunting were OR: 0.33 (95% CI: 0.11, 1.03; P = 0.056) and OR: 0.65 (95% CI: 0.32, 1.35; P = 0.25), respectively, for never-breastfed children and those exclusively breastfed <3 mo. In logistic regression analysis allowing for the RCT arm, sex, study site, maternal height, maternal BMI, and wealth tertile, never-breastfed children had lower risk of becoming stunted between birth and age 6 mo than children exclusively breastfed ≥3 mo [adjusted OR (aOR): 0.24; 95% CI: 0.07, 0.81; P = 0.021]. The risk of stunting did not differ significantly between children exclusively breastfed <3 mo and those exclusively breastfed ≥3 mo (Table 2). There was no interaction between study site and IF (P > 0.20, results not shown). When IF was classified as a binary variable, never-breastfed children did not have significantly lower risks than their ever-breastfed counterparts (aOR: 0.35; 95% CI: 0.11, 1.10; P = 0.07).
TABLE 2.
Multiple logistic regression analysis of stunting at ages 6 and 12 mo among HIV-uninfected African children in the Kesho Bora RCT who were not stunted at age 2 d1
| Variable | Age 6 mo (n = 531) | P | Age 12 mo (n = 522) | P |
| Infant feeding | ||||
| Never breastfeeding | 0.24 (0.07, 0.81) | 0.021 | 0.26 (0.07, 1.00) | 0.049 |
| EBF <3 mo | 0.49 (0.22, 1.10) | 0.09 | 0.83 (0.40, 1.73) | 0.61 |
| EBF ≥3 mo | 1 | 1 | ||
| Child sex | 0.10 | 0.027 | ||
| Male | 1.84 (0.88, 3.85) | 2.19 (1.10, 4.38) | ||
| Female | 1 | 1 | ||
| RCT arm | 0.75 | 0.97 | ||
| Triple antiretroviral | 0.89 (0.43, 1.82) | 1.01 (0.52, 1.97) | ||
| Short course | 1 | 1 | ||
| Study site | ||||
| Bobo Dioulasso | 0.38 (0.11, 1.34) | 0.13 | 0.98 (0.33, 2.92) | 0.97 |
| Mombasa | 0.76 (0.26, 2.21) | 0.61 | 1.18 (0.42, 3.36) | 0.75 |
| Nairobi | 4.29 (0.90, 20.5) | 0.07 | 1.67 (0.33, 8.47) | 0.54 |
| Somkhele | 1.35 (0.40, 4.50) | 0.63 | 0.75 (0.18, 3.21) | 0.70 |
| Durban | 1 | 1 | ||
| Maternal BMI,2 kg/m2 | ||||
| <20 | 2.26 (0.49, 10.5) | 0.30 | 4.14 (1.31, 13.1) | 0.016 |
| 20–22.49 | 3.84 (1.44, 10.2) | 0.007 | 2.67 (1.07, 6.65) | 0.035 |
| 22.5–25 | 1.78 (0.66, 4.81) | 0.25 | 1.08 (0.41, 2.88) | 0.88 |
| >25 | 1 | 1 | ||
| Maternal height, cm | ||||
| <155 | 6.45 (1.53, 27.3) | 0.011 | 4.25 (1.22, 14.7) | 0.023 |
| 155–159.9 | 2.88 (0.69, 12.1) | 0.15 | 2.32 (0.67, 8.07) | 0.19 |
| 160–164.9 | 2.19 (0.49, 9.80) | 0.31 | 2.01 (0.56, 7.16) | 0.28 |
| ≥165 | 1 | 1 | ||
| Wealth tertile3 | ||||
| Lower | 1.06 (0.43, 2.64) | 0.90 | 2.40 (0.95, 6.11) | 0.07 |
| Middle | 1.28 (0.52, 3.15) | 0.59 | 2.40 (0.93, 6.21) | 0.07 |
| Upper | 1 | 1 |
Values are adjusted ORs (95% CIs). Ninety and 88 children stunted at age 2 d were excluded from the analysis at ages 6 and 12 mo, respectively. Stunting was defined as length-for-age z score <−2 of the WHO growth standards. EBF, exclusive breastfeeding; RCT, randomized controlled trial.
Maternal BMI was measured during the first 2 mo postpartum.
Wealth tertiles were site specific.
At 12 mo, 88 children were excluded because of stunting at age 2 d, leaving 522 children for the analysis. The prevalence of stunting was 8.1% (42 of 522), affecting 3 of 113, 23 of 248, and 16 of 161 of never-breastfed children, children exclusively breastfed <3 mo, and children exclusively breastfed ≥3 mo, respectively (P = 0.057). Crude ORs of stunting were 0.25 (95% CI: 0.07, 0.87; P = 0.029) and 0.93 (95% CI: 0.47, 1.81; P = 0.82) for never-breastfed children and those exclusively breastfed <3 mo, respectively.
In adjusted logistic regression models, never-breastfed children had significantly lower risks of being stunted at age 12 mo than did children exclusively breastfed ≥3 mo (aOR: 0.26; 95% CI: 0.07, 1.00; P = 0.049), whereas those exclusively breastfed <3 mo had odds similar to those of the reference group (Table 2). There was no significant difference between ever- and never-breastfed children overall (aOR: 0.29; 95% CI: 0.08, 1.10; P = 0.058, data not shown). There was no difference between triple-antiretroviral and short-course arms at either 6 or 12 mo (P > 0.20 for both), but boys were more likely to be stunted than girls at age 12 mo (aOR: 2.19; 95% CI: 1.10, 4.38; P = 0.027; Table 2). There was no interaction between study site and IF (P > 0.20, results not shown). Maternal education and CD4+ cell count were not included in adjusted logistic regression models because of P values >0.40 in preliminary models.
Because duration of follow-up beyond 12 mo was associated with IF modality, the association of IF with the risk of stunting at 18 mo could not be assessed.
Mean unadjusted LAZ by IF status from birth to 18 mo.
Mean unadjusted LAZ and WLZ of children from age 2 d to 18 mo are shown in Figure 2. Among children with an EBF duration ≥3 mo, mean LAZ increased slightly between age 2 d and 4–6 mo and decreased thereafter. Never-breastfed children had decreasing LAZ during the first month of life, followed by a steep increase and had the highest means of all groups from age 4 mo onward. Children with EBF duration <3 mo had intermediate patterns with a slight decrease in LAZ during the first month and increasing means from 1 to 9 mo. The mean LAZ was below the international standard in all IF groups at all times. The mean unadjusted WLZ increased steeply for all groups during the first 2 mo of life and remained above the international standard up to age 18 mo; never-breastfed children had the highest means from age 6 mo.
FIGURE 2.
LAZ (A) and WLZ (B) by infant feeding mode from birth to age 18 mo in HIV-exposed uninfected children in the Kesho Bora randomized clinical trial. Values are means and 95% CIs (n = 114–311). Seven hundred twenty-eight children had ≥1 length measurement. Short EBF: <3 mo; long EBF: ≥3 mo. BF, breastfeeding; EBF, exclusive breastfeeding; LAZ, length-for-age z score; WLZ, weight-for-length z score.
MLM analysis of change in LAZ from age 2 d to 6 mo.
In MLM analysis allowing for intervention arm, sex, study site, and maternal BMI, height, education, CD4+ cell count, and wealth indicator, IF mode was not associated with early neonatal LAZ (P = 0.73, Table 3), but it was closely associated with change in LAZ from age 2 d to 6 mo: never-breastfed children had greater slopes than those EBF ≥3 mo (β1 = 0.073 z scores/mo; P < 0.001), whereas those exclusively breastfed <3 mo did not differ from the reference. When IF was considered as a binary variable, there was no difference between never- and ever-breastfed children at age 2 d (β0: −0.07; P > 0.20), but the former again had a greater increase over time (β1: 0.067 z scores/mo; SE: 0.018; P < 0.001). There was no interaction between IF and study site (P > 0.20, results not shown).
TABLE 3.
Mixed-effects linear model of LAZ from age 0 to 6 mo in African HIV-exposed uninfected children in the Kesho Bora RCT1
| Fixed effects | β02 | P | β13 | P |
| Age, mo | 0.09 ± 0.03 | 0.003 | — | |
| Infant feeding | 0.73 | 0.001 | ||
| Never breastfeeding | −0.03 ± 0.11 | 0.79 | 0.073 ± 0.020 | <0.001 |
| EBF <3 mo | 0.05 ± 0.09 | 0.61 | 0.012 ± 0.017 | 0.45 |
| EBF ≥3 mo | 0 | 0 | ||
| RCT arm | 0.015 | 0.008 | ||
| Triple antiretroviral | −0.18 ± 0.08 | 0.015 | 0.037 ± 0.014 | 0.008 |
| Short course | 0 | 0 | ||
| Child sex | 0.60 | 0.047 | ||
| Male | −0.04 ± 0.08 | 0.60 | −0.028 ± 0.014 | 0.047 |
| Female | 0 | 0 | ||
| Study site | 0.005 | 0.008 | ||
| Bobo Dioulasso | 0.30 ± 0.12 | 0.012 | −0.028 ± 0.022 | 0.19 |
| Mombasa | 0.26 ± 0.11 | 0.018 | −0.042 ± 0.020 | 0.041 |
| Nairobi | −0.24 ± 0.20 | 0.22 | −0.123 ± 0.035 | <0.001 |
| Somkhele | 0.16 ± 0.14 | 0.26 | −0.011 ± 0.024 | 0.66 |
| Durban | 0 | 0 | ||
| Maternal BMI,4 kg/m2 | <0.001 | 0.08 | ||
| <20 | −0.42 ± 0.15 | 0.005 | 0.029 ± 0.028 | 0.29 |
| 20–22.49 | −0.47 ± 0.12 | <0.001 | 0.030 ± 0.021 | 0.16 |
| 22.5–25 | −0.06 ± 0.09 | 0.50 | −0.017 ± 0.17 | 0.30 |
| >25 | 0 | 0 | ||
| Maternal height, cm | <0.001 | 0.30 | ||
| <155 | −0.45 ± 0.12 | <0.001 | −0.031 ± 0.022 | 0.16 |
| 155–159.9 | −0.18 ± 0.11 | 0.11 | −0.017 ± 0.021 | 0.40 |
| 160–164.9 | −0.02 ± 0.11 | 0.88 | 0.002 ± 0.022 | 0.93 |
| ≥165 | 0 | 0 | ||
| Maternal education | 0.48 | 0.27 | ||
| None | 0.12 ± 0.14 | 0.38 | −0.017 ± 0.026 | 0.51 |
| Primary | 0.10 ± 0.09 | 0.27 | 0.019 ± 0.017 | 0.27 |
| Secondary | 0 | 0 | ||
| Maternal CD4+ cell count/mm3 | 0.77 | 0.09 | ||
| 200–349 | −0.02 ± 0.08 | 0.77 | −0.025 ± 0.014 | 0.09 |
| 350–500 | 0 | 0 | ||
| Wealth tertile5 | 0.20 | 0.042 | ||
| Lower | −0.16 ± 0.09 | 0.10 | −0.009 ± 0.017 | 0.59 |
| Middle | −0.13 ± 0.09 | 0.17 | 0.032 ± 0.017 | 0.06 |
| Upper | 0 | 0 |
Values are means ± SEs. n = 728. EBF, exclusive breastfeeding; LAZ, length-for-age z score; RCT, randomized controlled trial.
The β0 coefficient represents the estimated mean difference in LAZ at age 2 d.
The β1 coefficient represents the estimated mean change (slope) in LAZ/mo from age 2 d to 6 mo.
Maternal BMI was measured during the first 2 mo postpartum.
Wealth tertiles were site specific.
Children living in Nairobi had significantly slower linear growth than those in Durban in this age interval (P < 0.001, Table 3). At age 2 d, children in the triple-antiretroviral arm experienced lower mean LAZ than those in the short-course regimen arm (by 0.18 z scores; P = 0.015), but they had greater slopes in LAZ up to 6 mo (by 0.037 z scores/mo; P < 0.01, Table 3).
MLM analysis of change in LAZ between ages 6 and 18 mo.
Table 4 shows results of MLM analysis for the age interval from 6 to 18 mo. Never-breastfed children and those exclusively breastfed <3 mo had greater LAZ at age 6 mo than those exclusively breastfed ≥3 mo when allowing for intervention arm, sex, study site, and maternal BMI, height, education, CD4+ cell count, and wealth indicator (P < 0.001 for both). There was no difference in slopes of LAZ between never-breastfed children and those exclusively breastfed ≥3 mo (P > 0.20), but those exclusively breastfed <3 mo had slightly lower slopes than the reference (P = 0.034). When compared with all breastfed children, the mean LAZ of never-breastfed children at age 6 mo was greater (by 0.29 z scores, P = 0.024), with no difference between slopes between 6 and 18 mo (P = 0.98, results not shown).
TABLE 4.
Mixed-effects linear model of LAZ from age 6 to 18 mo in African HIV-exposed uninfected children in the Kesho Bora RCT1
| Fixed effects | β02 | P | β13 | P |
| Age, mo | −0.04 ± 0.01 | 0.006 | — | — |
| Infant feeding | <0.001 | 0.10 | ||
| Never breastfeeding | 0.52 ± 0.14 | <0.001 | −0.008 ± 0.009 | 0.37 |
| EBF <3 mo | 0.43 ± 0.12 | <0.001 | −0.015 ± 0.007 | 0.034 |
| EBF ≥3 mo | 0 | 0 | ||
| RCT arm | 0.43 | 0.26 | ||
| Triple antiretroviral | −0.08 ± 0.10 | 0.43 | 0.007 ± 0.006 | 0.26 |
| Short course | 0 | 0 | ||
| Child sex | 0.19 | 0.031 | ||
| Male | −0.13 ± 0.10 | 0.19 | −0.013 ± 0.006 | 0.031 |
| Female | 0 | 0 | ||
| Study site | <0.001 | 0.008 | ||
| Bobo Dioulasso | 0.04 ± 0.18 | 0.84 | −0.001 ± 0.011 | 0.91 |
| Mombasa | −0.25 ± 0.15 | 0.10 | −0.022 ± 0.009 | 0.016 |
| Nairobi | −1.17 ± 0.29 | <0.001 | 0.046 ± 0.020 | 0.021 |
| Somkhele | −0.01 ± 0.18 | 0.97 | 0.007 ± 0.011 | 0.56 |
| Durban | 0 | 0 | ||
| Maternal BMI,4 kg/m2 | 0.07 | 0.016 | ||
| <20 | −0.32 ± 0.20 | 0.11 | −0.018 ± 0.012 | 0.12 |
| 20–22.49 | −0.27 ± 0.15 | 0.07 | −0.022 ± 0.004 | 0.015 |
| 22.5–25 | −0.30 ± 0.12 | 0.014 | 0.004 ± 0.008 | 0.59 |
| >25 | 0 | 0 | ||
| Maternal height, cm | <0.001 | 0.15 | ||
| <155 | −0.93 ± 0.16 | <0.001 | 0.019 ± 0.010 | 0.06 |
| 155–159.9 | −0.61 ± 0.15 | <0.001 | 0.012 ± 0.009 | 0.17 |
| 160–164.9 | −0.14 ± 0.15 | 0.38 | 0.001 ± 0.009 | 0.87 |
| ≥165 | 0 | 0 | ||
| Maternal education | 0.39 | 0.06 | ||
| None | 0.04 ± 0.18 | 0.82 | −0.017 ± 0.011 | 0.12 |
| Primary | 0.16 ± 0.12 | 0.20 | −0.017 ± 0.007 | 0.026 |
| Secondary | 0 | 0 | ||
| Maternal CD4+ cell count/mm3 | 0.46 | 0.66 | ||
| 200–349 | −0.07 ± 0.10 | 0.46 | −0.003 ± 0.006 | 0.66 |
| 350–500 | 0 | 0 | ||
| Wealth tertile5 | 0.002 | 0.23 | ||
| Lower | −0.44 ± 0.13 | <0.001 | 0.012 ± 0.008 | 0.14 |
| Middle | −0.23 ± 0.12 | 0.07 | 0.000 ± 0.008 | 0.98 |
| Upper | 0 | 0 |
Values are means ± SEs. n = 672. Fifty-six children had died or were lost to follow-up between birth and age 6 mo. EBF, exclusive breastfeeding; LAZ, length-for-age z score; RCT, randomized controlled trial.
The β0 coefficient represents the estimated mean difference in LAZ at age 6 mo.
The β1 coefficient represents the estimated mean change (slope) in LAZ/mo from age 6 to 18 mo.
Maternal BMI was measured during the first 2 mo postpartum.
Wealth tertiles were site specific.
There was no difference by the RCT arm during this age interval, neither for LAZ at 6 mo nor for slopes up to 18 mo. Boys had a similar mean LAZ at 6 mo but a lower increase in LAZ from 6 to 18 mo than girls (P = 0.031, Table 4).
Discussion
This observational cohort study was nested within an RCT comparing 2 antiretroviral regimens for the prevention of MTCT of HIV during pregnancy and breastfeeding (17). It included 728 HIV-exposed, uninfected African children from 5 diverse settings in Burkina Faso, Kenya, and South Africa, of whom 513 were followed up to age 18 mo. In contrast to our research hypothesis, never-breastfed children had a greater increase in LAZ from age 2 d to 6 mo than those exclusively breastfed ≥3 and 0.52 z scores greater LAZ between age 6 and 18 mo in analyses adjusting for socioeconomic status. They also had reduced risk of being stunted at age 6 mo, if not stunted at age 2 d, than those exclusively breastfed for ≥3 mo.
This faster linear growth of formula-fed children is consistent with findings from an RCT in Nairobi, Kenya (12), but at odds with those from a study in South Africa in which breastfed children had a marginally greater LAZ at 3 mo (11). They also differ from those of a study in Zambia, in which breastfed children had similar growth in length and faster growth in weight than weaned children from age 5 to 15 mo (10). However, that analysis compared the growth of children by current breastfeeding mode, whereas virtually all children in the Kesho Bora study had ceased breastfeeding by 6 mo of age.
Higher linear growth rates associated with FF compared with EBF have been described in several healthy Western populations (21, 22). However, we did not expect such a pattern in low-income sub-Saharan populations of HIV-infected mothers. Indeed, we previously reported 6-fold increased risk of serious infectious morbidity and mortality among never-breastfed infants compared with those exclusively breastfed ≥3 mo in the Kesho Bora study (6, 7). We expected that such high excess risk of severe morbidity among never-breastfed infants would be reflected in less-favorable linear growth patterns, but this was not the case. Thus, never-breastfed infants might seem to thrive well as a group and still be exposed to a high risk of death.
Like all observational studies, the analysis presented here may suffer from methodological limitations precluding causal inference, including confounding and reverse causality (i.e., that maternal IF decisions are a result of child growth and nutritional status). Although a number of sociodemographic and maternal nutrition indicators were accounted for, we acknowledge that residual confounding by unmeasured factors cannot be ruled out.
With regard to the risk of reverse causality, we showed previously (23) that neonatal morbidity (fever, diarrhea, vomiting) was associated with a lower probability of remaining EBF by 3 mo of age (aOR: 0.54; 95% CI: 0.31, 0.93; P < 0.05). These observations are in accordance with evidence from the literature that mothers may cease EBF early in response to perceived hunger or failure of their infant to thrive (24–26). Thus, any reverse causality would lead to better nutritional status of children exclusively breastfed after the age of 3 mo compared with those weaned very early. The relation between LAZ and EBF presented here is in the opposite direction and cannot be explained by reverse causality. The persistence of significant differences in the LAZ when never- and ever-breastfed children were compared would also suggest that the association was not a consequence of reverse causality. Finally, never-breastfed infants did not differ significantly from those exclusively breastfed ≥3 in mean LAZ at age 2 d in MLM (i.e., −0.03 ± 0.11 z scores, P = 0.79), suggesting that early neonatal length was not a criterion for maternal IF decisions.
As mentioned above, never-breastfed and weaned children were 6 times more likely to die between birth and age 18 mo than those still breastfeeding in the Kesho Bora RCT (6). Thus, a survival bias might have affected our results. In the sample of 728 children above, 24 (3.3%) died before age 6 mo, i.e., 8, 12, and 4 among those never breastfed, exclusively breastfed <3 mo, and exclusively breastfed ≥3 mo, respectively. Differences in LAZs between surviving and dying children have not been investigated, but the latter might have suffered from slower growth in length. Finally, a small fraction of children, especially among those living in Bobo Dioulasso, were still breastfeeding after the age of 6 mo, and might have faltered because of insufficient complementary feeding. We were unable to test this hypothesis, because no data were collected on complementary feeding beyond that age. However, this would not have affected their growth rate during the first 6 mo of life.
The difference in LAZs at 6 mo between never-breastfed children and those exclusively breastfed ≥3 mo (i.e., 0.52 z scores) was far from trivial. Indeed, it was larger than the difference between children in the lowest compared with highest wealth tertile in adjusted MLM. It is important to emphasize, however, that these results should not be taken to change IF recommendations for HIV-exposed children. First, they might not be causal, and even then, the major benefits of breastfeeding for child health and survival are far more important for public health than any possible impact on growth.
We found a small negative association between the maternal triple antiretroviral used to prevent postnatal HIV transmission and neonatal LAZ (−0.18 z scores, P = 0.015). This result is consistent with previous observations on birth weight and length after antiretroviral exposure (17, 27–29). Unfortunately, we could not distinguish between preterm birth and small-for-gestational age at birth, because self-reported data on pregnancy duration were deemed not reliable. From age 2 d to 6 mo, infants with maternal triple-antiretroviral exposure grew faster (by 0.037 z scores/mo). From age 6 to 18 mo, once triple antiretroviral would have ceased, the mean LAZ did not differ significantly by intervention arm.
Overall, the nutritional status of these HIV-exposed uninfected children was better than expected. The LAZ increased slightly from age 1 to 6 mo in all IF groups and started decreasing during the second half of infancy, in contrast to many African populations whose mean LAZ starts decreasing already shortly after birth (30). In addition, mean WLZ remained above the growth standard from age 1 to 18 mo in all IF groups. Possible explanations for these relatively favorable growth patterns include the urban context of most sites, free health care and infant formula, intensive hygiene and nutrition counseling, and free food aid to breastfeeding women in Mombasa, Somkhele, and Durban (20) or to children from 6 to 12 mo in Bobo Dioulasso (31).
A limitation of this study is the relatively high rate of discontinuation between 12 and 18 mo, which did not occur at random in that never-breastfed children tended to be more likely to have length data at 18 mo than those exclusively breastfed ≥3 mo. This is explained by shorter follow-up of children during the last year of the study in South African sites, associated with changes in maternal IF choice over time in these sites. No such informative censoring occurred during infancy.
In conclusion, the data presented here show that never-breastfed, African, HIV-exposed, uninfected children had faster growth in length from age 2 d to 6 mo than those exclusively breastfed for ≥3 mo. These results contrast with the sharply increased risk of severe morbidity and mortality among never-breastfed children in this and other studies (6, 7, 32–35). Reverse causality is not likely to explain differences related to LAZ, but residual confounding cannot be ruled out.
Acknowledgments
The members of the Kesho Bora Study Group are as follows—1) Bobo Dioulasso, Burkina Faso (Centre Muraz): Nicolas Meda (Principal Investigator), Paulin Fao, Odette Ky-Zerbo, and Clarisse Gouem (Study Coordinators), Paulin Somda, Hervé Hien, Patrice Elysée Ouedraogo, Dramane Kania, Armande Sanou, Ida Ayassou Kossiwavi, Bintou Sanogo, Moussa Ouedraogo, and Issa Siribie (Investigators), Diane Valéa (Laboratory Coordinator), Sayouba Ouedraogo and Roseline Somé (Data Managers), and François Rouet (Inter-Site Laboratory Coordination); 2) Durban, South Africa (University of KwaZulu Natal): Nigel Rollins (Principal Investigator), Lynne McFetridge and Kevi Naidu (Study Coordinators); 3) Mombasa, Kenya (International Centre for Reproductive Health): Stanley Luchters and Marcel Reyners (Principal Investigators), Eunice Irungu (Study Coordinator), Christine Katingima, Mary Mwaura, and Gina Ouattara (Investigators), Kishor Mandaliya and Sammy Wambua (Laboratory Coordinators), Mary Thiongo (Data Manager); 4) 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); 5) 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—1) Agence Nationale de Recherches sur le SIDA et les hépatites virales, France: Brigitte Bazin and Claire Rekacewicz (Sponsor Representatives); 2) Centers for Disease Control and Prevention: Allan Taylor (Sponsor Representative and Co-Investigator), Nicole Flowers, Michael Thigpen, Mary Glenn Fowler, and Denise Jamieson (Co-Investigators); 3) Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH: Jennifer S Read (Co-Investigator); 4) Institut de Recherche pour le Développement (IRD), Montpellier, France: Kirsten Bork, Cécile Cames, and Amandine Cournil (Nutrition Coordination); 5) International Centre for Reproductive Health (ICRH), Ghent University, Ghent, Belgium: Patricia Claeys, Marleen Temmerman, and Stanley Luchters (Sponsor Representatives); 6) 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, and 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).
KAB, CC, and JSR designed the research; CC, M-LN, KA, FM, and GM conducted the research; AC provided input on the data; and KAB analyzed the data, wrote the first draft of the manuscript, and had primary responsibility for the final content. All authors commented on manuscript drafts and read and approved the final version.
Footnotes
Abbreviations used: aOR, adjusted OR; EBF, exclusive breastfeeding; FF, formula feeding; IF, infant feeding; LAZ, length-for-age z score; MLM, mixed-effects linear model; MTCT, mother-to-child transmission; RCT, randomized controlled trial; WLZ, weight-for-length z score.
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