Relationships among common illness symptoms and the protective effect of breastfeeding in early childhood in MAL-ED: An eight-country cohort study

Children in low-income countries experience multiple illness symptoms in early childhood. Breastfeeding is protective against diarrhea and respiratory infections, and these illnesses are thought to be risk factors of one another, but these relationships have not been explored simultaneously. In the eight-site MAL-ED study, 1,731 infants were enrolled near birth and followed for 2 years. We collected symptoms and diet information through twice-weekly household visits. Poisson regression was used to determine if recent illness history was associated with incidence of diarrhea or acute lower respiratory infections (ALRI), accounting for exclusive breastfeeding. Recent diarrhea was associated with higher risk of incident diarrhea after the first 6 months of life (relative risk [RR] 1.10, 95% confidence interval [CI] 1.04, 1.16) and with higher risk of incident ALRI in the 3- to 5-month period (RR 1.23,95%CI 1.03, 1.47). Fever was a consistent risk factor for both diarrhea and ALRI. Exclusive breastfeeding 0-6 months was protective against diarrhea (0-2 months: RR 0.39, 95% CI 0.32, 0.49; 3-5 months: RR 0.83, 95% CI 0.75, 0.93) and ALRI (3-5 months: RR 0.81, 95% CI 0.68, 0.98). Children with recent illness who were exclusively breastfed were half as likely as those not exclusively breastfed to experience diarrhea in the first 3 months of life. Recent illness was associated with greater risk of new illness, causing illnesses to cluster within children, indicating that specific illness-prevention programs may have benefits for preventing other childhood illnesses. The results also underscore the importance of exclusive breastfeeding in the first 6 months of life for disease prevention. The MAL-ED study was conducted at eight different sites from November 2009 to February 2014: Bangladesh (Dhaka: BGD), India (Vellore: INV), Nepal (Bhaktapur: NEB), Pakistan (Naushehro Feroze: PKN), Brazil (Fortaleza: BRF), Peru (Loreto: PEL), South Africa (Venda: SAV), and Tanzania (Haydom: TZH).15 Children were enrolled within 17 days of birth and visited twice a week by well-trained fieldworkers who collected daily information about symptoms using harmonized and standardized data collection forms.16 Field workers asked caregivers if the child was ill or had any symptoms for each day since the last visit. On average, caregivers were visited in their homes 99 times per year (means at the sites ranged from 92 to 101 visits per year) to inquire about the last 3 days. Symptom prevalence per child was calculated as the sum of days with a symptom divided by the days followed in the study, multiplied by 100. The MAL-ED protocol defined diarrhea as three or more loose stools in 24 hours, or at least one loose stool with blood.17 Diarrhea episodes were separated by two diarrhea-free days.18 The study definition of ALRI was met when a child had 1) cough or shortness of breath (on the day of the visit or the previous day) and 2) a rapid respiratory rate on the day of the visit (average of two measurements taken by the field worker).19 A rapid respiratory rate was defined according to the age of the child using World Health Organization (WHO) guidelines (< 60 days old: ≥ 60 breaths/minute; 60–364 days: ≥ 50 breaths/minute; and ≥ 365 days of age: ≥ 40 breaths/minute).20 ALRI episodes were separated by 14 ALRI-free days. The daily number of symptoms was calculated by adding together symptoms reported on each day. Fieldworkers also recorded instances of hospitalization. Breastfeeding and other basic feeding characteristics were recorded for the day before the fieldworker visit.21 In this cohort, < 60% of children were exclusively breastfed (EBF) beyond 1 month of age,22 although often mothers reported giving non-breast milk foods to their children and then returning to exclusive breastfeeding.23 Because of this, to evaluate the role of exclusive breastfeeding on disease risk, for each day of follow-up, we calculated the percentage of days with exclusive breastfeeding during the past 30 days and then categorized feeding based on whether they were exclusively breastfed less than, or more than or equal to 50% of the previous month. Weight was measured at baseline and at each month of age. Weight-for-age z-scores (WAZ) were calculated using the WHO program for Stata version 12.1 (StataCorp, College Station, TX). The MAL-ED project generated a socioeconomic status (SES) composite indicator variable that could be compared across study sites. The SES construct combines access to improved Water and sanitation, Assets, Maternal education, and average monthly household Income into a score (WAMI) that ranges between 0 and 1.24 The SES variables were collected at 6, 12, and 18 months, and given the low temporal variability, the WAMI values were averaged for each child. We also collected information on the mother’s age and the number of children the mother had at the time of her infant’s enrollment into the cohort. To determine if the symptoms were distributed evenly throughout the cohorts or if they clustered in vulnerable children, we produced cumulative distribution plots to visually compare the percent of children in each site with the percent of days with illness that each child contributed. Separate plots were produced for any major symptom (any day with ALRI, diarrhea, cough, fever, or vomiting), diarrhea, and ALRI. Because more common symptoms are found more frequently in combination with other symptoms by chance alone, we assessed the likelihood of comorbidity pairs using bivariate probit regression (Stata version 14.2; StataCorp). Bivariate probit regression involves two binary dependent variables (e.g., diarrhea and ALRI) and assesses the likelihood that the two dependent variables occur simultaneously, controlling for site as a fixed effect and clustering within children (as a random effect).25 Each bivariate probit model was run, with pairs of symptoms as the outcome variables, after which we compared the correlation between the model residuals. A statistically significant (P < 0.05) correlation coefficient suggests that the two symptoms were found together more frequently than would be expected by chance alone. A Poisson regression model (Proc GLIMMIX, SAS 9.3, SAS Institute, Cary, NC) was used to estimate the risk of incident ALRI and diarrhea as a function of having had diarrhea or fever in the past 30 days (and in the case of the diarrhea outcome, history of ALRI, as well), adjusting for other risk factors and accounting for repeated measures within the same child with a child-level random intercept. The outcomes of interest for the Poisson models were daily incidence of diarrhea or ALRI because of their importance in the global burden of morbidity and mortality as well as their reported interrelationship.2,4,5 The model controlled for changing age patterns of illness with the inclusion of a linear spline with seven evenly spaced knots. Seasonality was considered for inclusion but was not found to be necessary in the model. The model controlled for WAZ at the most recent visit as an indicator of recent nutritional status. The mean WAMI (multiplied by 10 for model inclusion) was included to account for household-level factors that relate to environmental enteropathogen exposures26; similarly whether a child was first-born was included to address within-household transmission between siblings.27 Maternal age (in 5-year increments) was included to control for maternal experience in recognizing and reporting symptoms.26 Maternal education was not independently included given that it is a component of the WAMI construct. Child’s sex was included based on sex differences in the risk of illness that have been reported in the literature.28–32 The sites were included as fixed effects to adjust for local disease prevalence, and history of hospitalizations was included to adjust for access to health care, as well as to ascertain any short-term morbidity risks associated with recent hospitalization. Whether the child was mostly exclusively breastfed (> 50% of the past month during the first 3 months of life) was also included because of the long-standing evidence that exclusive breastfeeding is associated with lower rates of illness.13,14,33 Reported diarrhea, ALRI, and fever in the 30 days before each day of follow-up were included as independent variables in the models. Illness risk factors were evaluated separately for the 0–2, 3–5, and ≥ 6 month age periods. An interaction between morbidities and breastfeeding in the first 3 months of life was included because of observed improvement in Quasi-likelihood under the independence model criterion. The figures in this article were produced using R 3.3.2 (Foundation for Statistical Computing, Vienna, Austria).