Published online May 1, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. 941-946 (doi:10.1542/peds.2006-0780)
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ARTICLE

Maternal Antibodies in Breast Milk Protect the Child From Enterovirus Infections

Karita Sadeharju, MD, PhDa, Mikael Knip, MD, PhDb,c, Suvi M. Virtanen, MD, PhDd, Erkki Savilahti, MD, PhDb, Sisko Tauriainen, PhDa, Pentti Koskela, MD, PhDe, Hans K. Åkerblom, MD, PhDb, Heikki Hyöty, MD, PhDa and and the Finnish TRIGR Study Group

a Department of Virology, University of Tampere and Tampere University Hospital, Tampere, Finland
b Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
c Department of Pediatrics, Tampere University Hospital, Tampere, Finland
d Department of Epidemiology and Health Promotion, National Institute of Public Health, Helsinki, and School of Public Health, University of Tampere, Tampere, Finland
e National Institute of Public Health, Oulu, Finland


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Enterovirus infections are frequent in infants and may cause severe complications. We set out to assess whether breastfeeding can protect against these infections and whether such an effect is related to maternal antibodies in breast milk or in the peripheral circulation of the infant.

METHODS. One hundred fifty infants who were prospectively followed up from birth were monitored for enterovirus infections. The duration of breastfeeding was recorded, and maternal breast milk and blood samples were regularly taken at 3-month intervals for the detection of enterovirus antibodies and RNA. Maternal serum was available from early pregnancy, delivery, and 3 months postpartum.

RESULTS. Enterovirus infections were frequent and were diagnosed in 43% of infants before the age of 1 year and in 15% of the mothers during pregnancy. Infants exclusively breastfed for >2 weeks had fewer enterovirus infections by the age of 1 year compared with those exclusively breastfed for ≤2 weeks (0.38 vs 0.59 infections per child). High maternal antibody levels in serum and in breast milk were associated with a reduced frequency of infections. This effect was seen only in those infants breastfed >2 weeks, indicating that breast milk antibodies mediate this effect. Enterovirus RNA was not found in any of the breast milk samples.

CONCLUSIONS. These results suggest that breastfeeding has a protective effect against enterovirus infections in infancy. This effect seems to be mediated primarily by maternal antibodies in breast milk.

Key Words: enterovirus infections • maternal antibodies • autoantibodies • breastfeeding

Abbreviations: RT-PCR—reverse transcriptase polymerase chain reaction • IgG—immunoglobulin G • IgA—immunoglobulin A • CBV4—coxsackievirus B4 • EV11—echovirus 11 • EIA—enzyme immunoassay • EIU—enzyme immunoassay unit

Earlier studies have suggested that breastfeeding may protect the infant against infections. Breast milk contains several compounds that may have antimicrobial effects. Maternal antibodies in breast milk were proposed to play a major role, but other factors such as lactoferrin may also be important.1,2 In addition to antibodies in breast milk, systemic transplacentally transported antibodies contribute to the protection of the child.

Enterovirus infections are frequent in childhood. Most infections are mild or even asymptomatic, but complications are also quite common including meningitis, myocarditis, otitis media, and severe systemic infections in newborn infants. In addition, enteroviruses were suspected of playing a role in certain chronic diseases, such as type 1 diabetes and cardiomyopathies.3 Altogether, because of their frequent occurrence and relatively severe complications, enterovirus infections have considerable clinical relevance.

In our study, we wanted to assess whether breastfeeding can protect infants against nonpolio enterovirus infections. Although this question is of unequivocal clinical importance, only 1 study has so far been published.4 That study found an epidemiologic association between lack of breastfeeding and frequent enterovirus infections in young infants (<1 month of age), but it did not specifically assess the role of breast milk antibodies in this phenomenon. Accordingly, the possible protection conferred by breastfeeding needs to be confirmed. In addition, it is not known whether the protection is mediated by maternal antibodies in breast milk, other breast milk compounds, or transplacentally transferred antibodies. It is also not known how common is the transmission of enteroviruses from the mother to the child through breast milk, because only 1 study was published on this subject on the basis of a small series of children.5 The transmission through breast milk of some viruses like HIV and cytomegaloviruses was demonstrated.6

We were able to address these issues in a unique prospective series of infants who were observed sequentially starting from birth. Details about breastfeeding were recorded by questionnaires during the follow-up, and serial blood samples were taken from the infant to diagnose enterovirus infections by using a wide panel of assays (reverse transcriptase polymerase chain reaction [RT-PCR] and antibody measurements). In addition, cord blood and breast milk samples were available for the measurement of maternal enterovirus antibodies and direct detection of viral RNA.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
The study population was comprised of 150 infants and their mothers from families with at least 1 member affected by type 1 diabetes. These infants carried increased HLA-conferred susceptibility to type 1 diabetes (HLA-DQB1 *0302 and/or *02 but no protective allele). The families took part in the second pilot study of the TRIGR (Trial to Reduce Insulin-Dependent Diabetes Mellitus in the Genetically at Risk) Project in Finland.7 This randomized, double-blind trial was intended to evaluate the feasibility of a nutritional intervention trial in infancy and to observe the possible effect of weaning to a highly hydrolyzed formula on the emergence of diabetes-associated autoantibodies. The pilot protocol was previously described in detail.7

The infants were born between March 1995 and December 1996 in 15 hospitals around Finland. In addition to the cord blood sample, blood samples were obtained from children at follow-up visits at the ages of 3, 6, 9, 12, 18, 24, and 36 months. Clinical symptoms were not recorded, but the children were healthy at the visits. More than 80% of the children (n = 125; 83%) were observed until the age of 24 months and 51% (n = 77) until the age of 36 months (average observation period: 27.6 months; range: 3–36 months). Eighteen children (12%) developed signs of ß-cell autoimmunity (≥1 type 1 diabetes-associated autoantibodies), and 8 had progressed to clinical type 1 diabetes by the age of 36 months.7

Maternal blood samples were obtained at the end of the first trimester of pregnancy, at the time of delivery, and at 3 months after delivery. Breast milk samples were taken after delivery (mean: 2 days' postpartum; range: 0–3 days) and 3 months later (range: 1.9–4.0 months). Only 1 breast milk sample was available from 66 mothers, and both samples were available from 84 (56%) mothers.

All samples were stored at –20°C until analyzed. Written informed consent was obtained from the mothers before enrollment. The study was approved by the Joint Ethics Committees of the participating hospitals.

Virus Analyses
Enterovirus Antibodies
Immunoglobulin G and immunoglobulin A (IgG and IgA) class antibodies were measured against purified coxsackievirus B4 (CBV4), purified echovirus 11 (EV11), and a synthetic enterovirus peptide antigen (sequence KEVPALTAVETGAT-C derived from an immunodominant region of capsid protein VP1, which is a common epitope for several enteroviruses8) by using enzyme immunoassay (EIA) as described earlier.9–13

The sensitivity and specificity of these antibody assays were validated in earlier studies by analyzing virus-isolation of neutralizing antibody-confirmed infections, indicating that these assays can detect 50% to 70% of enterovirus infections with close to 100% specificity. The purified CBV4 and EV11 were incubated at 56°C for 15 minutes to expose antigenic determinants common for various enterovirus serotypes. Serum and breast milk samples were analyzed at 1/100 (IgA), 1/500 (EV11-IgG), and 1/2000 (other IgG assays) dilutions in phosphate-buffered saline supplemented with 1% bovine serum albumin and 0.05% Tween 20. The results of antibody measurements (OD490) were expressed in enzyme immune units (EIUs), showing the relative antibody reactivity of the sample in relation to the positive and negative reference sera included in each assay.

Enterovirus RNA
RNA was extracted by a QIAamp viral RNA kit (Qiagen, Hilden, Germany) from 140 µL of serum or breast milk that was not previously thawed, according to the manufacturer's protocol. Enterovirus RNA was detected by RT-PCR and a subsequent hybridization, which detects practically all enterovirus serotypes, as previously described.14 All positive samples were confirmed by repeated RT-PCR.

Diagnostic Criteria for an Enterovirus Infection
A twofold or greater increase in the antibody level against an antigen observed between 2 consecutive serum samples from infants or mothers and exceeding the cutoff level of seropositivity (15 EIUs) was considered an infection according to the criteria validated in earlier studies.9–13 Because the sera were analyzed by using a single dilution (and not end-point titration), a twofold increase represented quite a noticeable change in antibody levels. The presence of enterovirus RNA in serum was taken as a marker of a current infection.

Statistical Analyses
The ages at the time of infection, frequency of infections, and enterovirus antibody levels were compared by using the Mann-Whitney U test. Correlations were analyzed by using the nonparametric Spearman's correlation test. P values <.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Frequency of Enterovirus Infections
An enterovirus infection was diagnosed during pregnancy in 23 mothers (15%) and during the first 3 months after delivery in 8 mothers (5%). A total of 149 separate enterovirus infections were diagnosed in the children. Seventy-three children (49%) had 1 infection, whereas 35 children (23%) had 2, and 2 children (1%) had 3 infections. Forty-three percent (64 of 150) of the infants had at least 1 infection before the age of 1 year. Twelve percent (18 of 150) of all children were enterovirus RNA-positive in serum, and 3 of them had >1 RNA-positive sample. A rise in enterovirus antibody levels coincided with the detection of viral RNA in serum on 8 occasions (44%), and 5 additional RNA-positive samples (28%) were taken before or at the age of 6 months, when maternal antibodies are able to mask antibody rises. As an example, Fig 1 shows results from the virus analyses of 1 child and his/her mother.


Figure 1
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  		FIGURE 1 Results from enterovirus analyses in 1 study child and his or her mother. PCR results are shown at the bottom of the chart as samples positive (+) or negative (–) for viral RNA. Antibody levels are shown both in maternal serum samples (filled squares, CBV4-IgG) and in the child: CBV4-IgG (filled circles), CBV4-IgA (filled triangles), enterovirus peptide IgG (X), and enterovirus peptide IgA (filled diamonds). This child had an infection at 6 months indicated by the detection of enterovirus RNA in serum and a concomitant rise in CBV4-IgG. Antibody levels of the mother fell in the sample taken at delivery but increased again at 3 months' postpartum. This increase is not a sign of an infection but a normal phenomenon during pregnancy (see Fig 2).

 
Breastfeeding and Enterovirus Infections
Infants were exclusively breastfed for an average of 2.6 months (range: 0–6 months), and 18% of the children were exclusively breastfed for > 4 months. The average duration of the whole breastfeeding period (exclusive and nonexclusive) was 8.1 months (range: 0.15–23 months). Seventy percent of the children had breast milk for >6 months and 12% for >1 year.

The children exclusively breastfed for 2 weeks or less (N = 38) tended to have more enterovirus infections compared with the children with a longer duration of exclusive breastfeeding (N = 112). This difference was seen in infections diagnosed before the age of 1 year (0.59 vs 0.38 infections per child; P = .04) but not in infections diagnosed at an older age (0.54 vs 0.49 infections per child, not significant). The average duration of exclusive breastfeeding was shorter in those infants who experienced at least 1 enterovirus infection before the age of 1 year compared with the infants who had no infections during their first year (median: 2.1 vs 2.9 months, respectively; P = .05). However, the duration of the total breastfeeding period did not differ between the 2 groups (median: 7.6 vs 8.5 months, not significant). The infants who had enterovirus RNA detectable in their serum before the age of 1 year (N = 18) also had a shorter exclusive breastfeeding period than the other infants (median duration: 1.0 vs 3.0 months; P = .04).

Maternal Antibodies and Enterovirus Infections
Maternal IgG class enterovirus antibody levels were lower in serum at delivery compared with early pregnancy or 3 months after delivery (Fig 2). A strong correlation was seen between IgG enterovirus antibody levels in cord blood and in maternal serum (CBV4-IgG: r = 0.94; enterovirus peptide IgG: r = 0.90; EV11-IgG: r = 0.86). The offspring of mothers who had particularly high CBV4 antibody levels (exceeding the 75th percentile) at delivery had fewer enterovirus infections before the age of 1 year compared with the offspring of mothers with lower antibody levels (0.32 vs 0.56 infections per child; P = .01, Fig 3). The same phenomenon was observed when antibodies against the common enterovirus peptide antigen were used as an indicator of enterovirus immunity (0.38 vs 0.60 infections per child, respectively; P = .001).


Figure 2
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  		FIGURE 2 Maternal enterovirus antibody levels in serum at the end of first trimester (pregnancy), at delivery, and 3 months after delivery. Enterovirus antibody levels in cord blood are shown for comparison. The columns represent the 25th and 75th percentiles, and the horizontal line represents the median of the antibody levels.

 

Figure 3
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  		FIGURE 3 The protective effect of maternal serum (CBV4-IgG) and breast milk (IgA) antibodies against enterovirus infections in children during the first year of life. Lower frequencies of enterovirus infections were seen in children whose mothers had higher antibody levels in breast milk or serum.

 
Infants whose mothers had high enterovirus IgA levels (over the 75th percentile) in breast milk at delivery had fewer enterovirus infections by the age of 1 year (0.33 vs 0.67 infections per child; P = .001; Fig 3). As expected, breast milk samples taken a few days after delivery (colostrum) had higher IgA class enterovirus antibody levels than samples taken ~3 months later (median: 38 vs 12 EIUs; P = .0001; Fig 4). However, the antibody levels increased exceptionally by >50% in 5 mothers, which may reflect a recent enterovirus infection. In fact, an enterovirus infection was diagnosed during pregnancy in 2 of them. This phenomenon was seen when the mothers who had an enterovirus infection during pregnancy were compared with the other mothers: the former group had higher IgA class enterovirus antibody levels in breast milk (median IgA: 76 vs 38 EIUs; P = .005).


Figure 4
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  		FIGURE 4 Enterovirus antibody levels in breast milk at delivery and 3 months later measured against a synthetic enterovirus peptide antigen.

 
Because a clear correlation was seen between enterovirus antibody levels in breast milk and maternal serum, we wanted to analyze which maternal antibodies are more important for the protection of the offspring, those transferred by breast milk or those transplacentally transferred. We analyzed the effect of these antibodies in 2 groups. One group (N = 38) included infants who were exclusively breastfed for ≤2 weeks, which would not provide the child with significant protection by breast milk (discussed earlier in this article), whereas the other group (N = 112) included children who were breastfed for a longer period. In the group with a short duration of breastfeeding, the levels of enterovirus antibodies in the maternal serum and breast milk were not related to the frequency of enterovirus infections among these infants. However, in the group with a longer duration of breastfeeding, the mothers whose offspring experienced an enterovirus infection by the age of 1 year had lower maternal enterovirus antibody levels both in serum and in breast milk at delivery than the mothers whose offspring had no signs of an infection by that age (medians in serum CBV4 IgG: 30 vs 50 EIUs; P = .007 and in breast milk IgA: 29 vs 38 EIUs; P = .01).

Enterovirus RNA in Breast Milk
None of the breast milk samples (N = 234) was positive for enterovirus RNA. Eight mothers were enterovirus RNA positive in serum at the same time as the breast milk sample was taken.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Maternal immunity is transferred to the infant by antibodies. Both transplacentally transported maternal IgG, as well as breast milk IgA, can protect the child against infections by neutralizing the infectivity of microbes (Fig 3). In addition, breast milk contains other antimicrobial substances, which may also play a role. Breastfeeding decreases morbidity in gastroenteritis, septicemia, otitis media, celiac disease, and other diseases.15 Despite this evidence, surprisingly few studies are available with the effect of breastfeeding evaluated prospectively by using laboratory-confirmed microbial diagnosis. In addition, the relative significance of breast milk antibodies and transplacentally transferred antibodies remains unknown.

Enteroviruses are important pathogens, being one of the most frequent causes of infections in children. Despite their considerable clinical significance, there are no protective treatments available except for polioviruses, and, therefore, it is important to assess the possible beneficial effect of breastfeeding in this respect. Only 1 study has addressed this question.4 In that study, children were followed up for a much shorter period than in our study (from birth until the age of 1 month). Enterovirus infections were diagnosed by virus isolation from serial stool samples whereas serum samples were not analyzed. As in our study, these investigators found that the absence of breastfeeding was associated with an increased risk of enterovirus infections. We had a unique opportunity to assess the possible protective effect in relation to maternal antibody levels in serum and breast milk. The protection conferred by breastfeeding was related to the levels of IgA class enterovirus antibodies in breast milk, which seemed to be more important than transplacentally acquired antibodies. This is logical, because the primary replication of enteroviruses occurs in gut mucosa, where breast milk antibodies can directly neutralize the virus in the intestine and prevent its subsequent spread to the circulation. The protective effect was related to exclusive breastfeeding rather than total breastfeeding, suggesting that there may be a dose-effect related to the greater amount of breast milk ingested by exclusively breastfed infants. In addition, protection correlated with enterovirus IgA levels, supporting true biological effect rather than the influence of potential confounding factors, like family size or socioeconomic status. Eighteen children developed signs of ß-cell autoimmunity or clinical type 1 diabetes during the follow-up, but the protective effect of maternal antibodies was seen irrespective of the diabetes status. However, we observed previously that these children experienced more enterovirus infections compared with other children of this cohort,16 suggesting that enterovirus infections may increase the risk of ß-cell autoimmunity.

Enterovirus antibody levels were on average >2 times higher in breast milk samples taken a few days after delivery than 3 months later (Fig 4). This is in line with the fact that the initial breast milk, colostrum, has particularly high concentrations of antibodies, which then gradually decrease over the first 2 weeks' postpartum and remain fairly stable throughout subsequent lactation.17 Because of the high levels of neutralizing antibodies in colostrum, the first dose of oral poliovirus vaccine is not given just after birth, because these antibodies could decrease the efficacy of the live vaccine.18 After the age of 6 weeks, breastfeeding no longer has such an inhibitory effect on the oral poliovirus vaccine.19

Some viruses, such as HIV20 and cytomegalovirus,21 can be transmitted via breast milk. In our study, enterovirus RNA was not detected in any of the breast milk samples, although many mothers had an infection during lactation and some of them were even positive for enterovirus RNA in serum. Although we could not find enterovirus RNA in breast milk, it is possible that the virus may be excreted into breast milk during peak viremia for a short period of time. In fact, such a phenomenon was recently described in 2 mothers whose infants experienced an enterovirus infection immediately after birth.5 These infections were confirmed to be caused by the same virus on the basis of 100% nucleotide sequence identity between the viruses isolated from the mother and child.

Enterovirus infections are common in children. This was also confirmed in our study, where 43% of the subjects had their first infection by the age of 1 year and 73% by the age of 3 years. This is likely still an underestimation, because the large number of enterovirus serotypes makes it difficult to diagnose all infections, even with this kind of wide panel of tests. The current EIA methods are known to find ~50% to 70% of infections.10,11 Our polymerase chain reaction (RT-PCR) assay detects practically all enterovirus types,14 but viral RNA is present in serum for only a short time (usually <2 weeks). As shown in our earlier studies, the proportion of infections diagnosed can be increased by combining antibody analyses (EIA) and the detection of viral RNA (RT-PCR).16 Enterovirus infections were also common in adults, because an enterovirus infection was diagnosed in 15% of the mothers during pregnancy. Enterovirus antibody levels decreased during pregnancy (Fig 2), which may be because of hemodilution (the plasma volume increases by 30%-50% during pregnancy22) or to changes in the maternal immune system.23 After pregnancy, the antibody levels regained their earlier levels within 2 to 3 months.


   CONCLUSIONS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our study suggests that breastfeeding confers protection against enterovirus infections, and that breast milk antibodies mediate a significant proportion of this protective effect. Accordingly, breastfeeding seems to be a feasible way to decrease the risk of enterovirus infections in young infants, particularly if they are immunocompromized or otherwise susceptible to severe infections.


   ACKNOWLEDGMENTS
 
This research was supported by the European Commission DGXII, Contract BMH4-CT96-0233, the Sigrid Jusélius Foundation, the Juvenile Diabetes Foundation International (grants 192612 and 195003 to Dr Åkerblom and grants 197114 and 395019 to Dr Hyöty), the Academy of Finland, the Liv and Hälsa Foundation, the Novo Nordisk Foundation, the Pediatric Research Foundation in Finland, and the Finnish Diabetes Association.

The Finnish TRIGR Study Group is composed of the following members: H.K. Åkerblom (principal investigator); V. Eskola, H. Haavisto, C. Holm, A.-M. Hämäläinen, R. Jokisalo, U. Kaski, J. Komulainen, P. Korpela, M.-L. Käär, P. Lautala, K. Niemi, A. Nuuja, P. Rantanen, R. Renko, M. Renlund, M. Salo, T. Talvitie, T. Uotila, and G. Wetterstrand (local investigators); and H. Hyöty, J. Ilonen, P. Klemetti, M. Knip, P. Kulmala, J. Paronen, A. Reunanen, T. Saukkonen, E. Savilahti, K. Savola, K. Teramo, O. Vaarala, and S.M. Virtanen (special investigators).


   FOOTNOTES
 
Accepted Dec 22, 2006.

Address correspondence to Heikki Hyöty, MD, PhD, Department of Virology, Medical School, University of Tampere, Biokatu 10, 33520 Tampere, Finland. E-mail: heikki.hyoty{at}uta.fi

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 CONCLUSIONS
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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