Hand, foot and mouth disease (HFMD) is a common acute pediatric infectious disease characterized by benign febrile exanthema and typical vesicular rashes on the palms, soles, buttocks or in the mouth.1 Usually, HFMD is mild and self-limiting, resolving in fewer than 7 days. In rare cases, however, it becomes severe and leads to critical complications, such as encephalomyelitis, brainstem encephalitis, aseptic meningitis, acute pulmonary edema and circulatory failure.2 Because no vaccine is yet available against the virological agents linked to HFMD,3 controlling HFMD occurrence and progression is essential, in particular by identifying patients more likely to develop critical complications. Breastfeeding seems to protect against gastroenteritis, respiratory infection, sudden infant death syndrome and other problems later in life,4–7 as well as against infection by HFMD-associated enteroviruses during infancy.8 Our initial research suggested that breastfeeding may also reduce the severity of HFMD later in childhood.9 Here, we expanded on that work using a substantially larger sample and assessing risk based on breastfeeding duration.
This study was approved by the Medical Ethics Committee of the Second Affiliated Hospital of the Medical College of Xi’an Jiaotong University, Xi’an, China. Between April 2011 and October 2014, clinical samples were randomly collected from all children with HFMD admitted to the Second Affiliated Hospital or to Xi’an Children’s Hospital, also in Xi’an, China. Children were excluded from the study (n = 120) if their medical records did not indicate duration of breastfeeding. In the end, 1639 pediatric in-patients were retrospectively enrolled, comprising 603 with severe HFMD and 1036 with mild HFMD. Of the 1639 patients, 318 were analyzed in previous work from our group.9
HFMD was diagnosed based on criteria in the Hand, Foot and Mouth Disease Clinical Guide (2010 edition) issued by the Ministry of Health of the People’s Republic of China.10 Signs and symptoms in most diagnosed cases occurred during epidemics in preschool children, and they included typical exanthema on the hands, feet, mouth and/or buttocks, with or without fever. HFMD diagnosis was usually confirmed based on one of the following: (1) a positive test for RNA from Coxsackievirus A16 (CoxA16), Enterovirus 71 (EV71) or other enteroviruses; (2) isolation and identification of CoxA16, EV71 or other enteroviruses linked to HFMD or (3) a >4-fold increase in serum titer of antibodies against CoxA16, EV71 or other enteroviruses linked to HFMD, based on sampling during the acute and convalescent stages of the disease.10
Two authors (L.Y. and D.H.) used standardized forms to extract data independently from medical records. Demographic data were collected on the child’s gender, age, birth weight, residence, number of children in the family, feeding history, breastfeeding duration, delivery mode, gestational age and birth season.
Data on clinical manifestations of HFMD were collected to classify the patient as having mild or severe disease. Additional laboratory data included white blood cell count, fasting glucose level and virus infection.
Patients were classified as having mild or severe HFMD using the criteria described in our previous work.9 Children with severe HFMD were treated as “cases,” whereas those with mild disease served as “controls” and were used as the reference group when calculating odds ratios (ORs) describing the association of different characteristics with severe disease.
Patients were also classified according to breastfeeding duration as (1) never breastfed or breastfed for (2) ≤6 months, (3) 6–12 months or (4) >12 months. Children who had never been breastfed served as the reference group when calculating ORs of severe HFMD associated with different breastfeeding durations.
Data for continuous variables were summarized as mean ± standard deviation or median (range), and intergroup differences were assessed for significance using Student’s t test or the Wilcoxon rank-sum test. Data for categorical variables were summarized as numbers and percentages, and the χ2 test was used to assess differences between patients with mild and severe HFMD. Univariate and multivariate logistic regressions were used to identify risk factors associated with severe HFMD based on ORs. All variables with a univariate P value <0.20 along with those deemed to be clinically significant were considered for inclusion in multivariate models. All statistical analyses were performed using SPSS 13.0 (IBM, Chicago, IL). The threshold of significance for all statistical tests was P < 0.05.
Comparison of Demographic and Clinical Characteristics Between Patients with Mild and Severe HFMD
Demographic and clinical characteristics of the 1639 children with HFMD are compared in Table, Supplemental Digital Content 1, http://links.lww.com/INF/C342. Patients with mild or severe HFMD differed significantly in birth weight, residence, feeding history, duration of breastfeeding and type of delivery. Patients with severe disease were significantly worse than those with mild disease in terms of presence and duration of fever, peak temperature, cough, expectoration, central nervous system symptoms, white blood cell count, fasting glucose level, current EV71 infection, concomitant infection with Epstein–Barr virus, respiratory adenovirus, influenza virus and mycoplasma (data not shown).
Association Between Breastfeeding Duration and HFMD Severity
Univariate analysis identified 3 ranges of breastfeeding duration as significantly associated with reduced risk of severe HFMD: ≤6 months [OR: 0.743; 95% confidence interval (CI): 0.567–0.972], 6–12 months (OR: 0.678; 95% CI: 0.528–0.872) and >12 months (OR: 0.482; 95% CI: 0.330–0.703).
Multivariate logistic regression, which was carried out after controlling for age, gender, birth weight, number of children, delivery method and residence, showed that breastfeeding for ≤6 months was not associated with risk of severe HFMD (OR: 0.914; 95% CI: 0.793–1.053). In contrast, breastfeeding for 6–12 months remained independently associated with risk of severe HFMD (OR: 0.701; 95% CI: 0.539–0.913), as did breastfeeding for >12 months (OR: 0.504; 95% CI: 0.341–0.746; both P < 0.01). Figure 1 summarizes the trend in risk of severe HFMD for different durations of breastfeeding.
In this study with a relatively large sample stratified by duration of breastfeeding, we observed a significant positive association between duration and risk of severe HFMD: longer breastfeeding was associated with lower risk of severe disease. The results suggest that 6 months is the minimum duration that protects against severe disease. This provides support for the World Health Organization’s recommendation that mothers feed babies exclusively by breastfeeding during the first 6 months,11 but it suggests the need for even longer breastfeeding to ensure a protective effect against severe HFMD.
Our findings confirm previous reports of an association between duration of breastfeeding and aspects of HFMD onset and clinical manifestations. A recent prospective cohort study suggested that exclusively breastfeeding protects children against occurrence of HFMD during the first 28 months.12 Another retrospective study suggested that breastfeeding reduces the risk of fever in patients with HFMD.7
Our finding that breastfeeding for at least 6 months significantly reduces risk of severe HFMD adds to the demonstrated benefits of longer term breastfeeding against other diseases. A large randomized trial showed that breastfeeding for >6 months reduced risk of gastrointestinal infection.6 Lamberti et al4 showed that breastfeeding for 6–23 months reduced morbidity and mortality caused by diarrhea, whereas other work has reported that longer breastfeeding reduced risk of respiratory infection-related diseases13 and type 2 diabetes.14 Our finding that only breastfeeding for longer than 6 months exerted a protective effect may reflect the fact that infant immune function during the first 24 months relies heavily on factors from the mother, which do not persist for long in the baby’s circulation. Thus, continued breastfeeding is needed to replenish these immune factors until the infant’s own immune system begins to function effectively on its own. Given that maternity leave in China and several other countries is less than 6 months, at which point many mothers stop breastfeeding for various reasons, we advocate targeted campaigns to highlight the advantages of breastfeeding for more than 6 months.
How breastfeeding reduces risk of severe HFMD is unclear. It may be related to the ability of breastfeeding to provide immune protection against infection and reduce production of proinflammatory factors in infants.15
Because this study focused on severe HFMD, we compared children with severe disease with those with mild disease. This allowed us to generate risk estimates specifically reflecting the likelihood of severe disease, which is associated with potentially life-threatening complications, thereby minimizing confounding by factors associated only with mild HFMD, which is not linked to serious complications.
This study has several limitations. First, selection bias may be an issue because all participants were in-patients and we excluded those with incomplete medical records. Nevertheless, the fact that we selected our participants randomly may counterbalance these biases. Second, some data were based on parents’ recall, including the key variable of breastfeeding duration. This introduces the risk of recall bias, although the fact that we treated duration as a categorical rather than continuous variable likely minimized the impact of this bias. In addition, such bias would probably be comparable between the patient subgroups with mild or severe HFMD, because the researchers collecting the data and interviewing parents were unaware a priori of a link between breastfeeding duration and disease severity.
We thank the physicians in the infectious disease departments at the Second Affiliated Hospital of the Medical College of Xi’an Jiaotong University and at Xi’an Children’s Hospital for their dedicated assistance with data collection.
1. Richardson HB Jr, Leibovitz A. “Hand
, foot, and mouth disease” in children; an epidemic associated with coxsakie virus A-16. J Pediatr. 1965;67:6–12
2. Tan CW, Lai JK, Sam IC, et al. Recent developments in antiviral agents against enterovirus 71 infection. J Biomed Sci. 2014;21:14
3. Li L, Yin H, An Z, et al. Considerations for developing an immunization strategy with enterovirus 71 vaccine. Vaccine. 2015;33:1107–1112
4. Lamberti LM, Fischer Walker CL, Noiman A, et al. Breastfeeding
and the risk for diarrhea morbidity and mortality. BMC Public Health. 2011;11(suppl 3):S15
5. Vennemann MM, Bajanowski T, Brinkmann B, et al.GeSID Study Group. Does breastfeeding
reduce the risk of sudden infant death syndrome? Pediatrics. 2009;123:e406–e410
6. Kramer MS, Kakuma R. Optimal duration
of exclusive breastfeeding
. Cochrane Database Syst Rev. 2002:CD003517
7. Zhu Q, Li Y, Li N, et al. Prolonged exclusive breastfeeding
, autumn birth and increased gestational age are associated with lower risk of fever in children with hand
, foot, and mouth disease. Eur J Clin Microbiol Infect Dis. 2012;31:2197–2202
8. Sadeharju K, Knip M, Virtanen SM, et al.Finnish TRIGR Study Group. Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics. 2007;119:941–946
9. Li Y, Dang S, Deng H, et al. Breastfeeding
, previous Epstein–Barr virus infection, enterovirus 71 infection, and rural residence are associated with the severity
, foot, and mouth disease. Eur J Pediatr. 2013;172:661–666
12. Lin H, Sun L, Lin J, et al. Protective effect of exclusive breastfeeding
, foot and mouth disease
. BMC Infect Dis. 2014;14:645
13. Papenburg J, Hamelin MÈ, Ouhoummane N, et al. Comparison of risk factors for human metapneumovirus and respiratory syncytial virus disease severity
in young children. J Infect Dis. 2012;206:178–189
14. Jäger S, Jacobs S, Kröger J, et al. Breast-feeding and maternal risk of type 2 diabetes: a prospective study and meta-analysis. Diabetologia. 2014;57:1355–1365
15. Field CJ. The immunological components of human milk and their effect on immune development in infants. J Nutr. 2005;135:1–4