Keywords
breastfeeding - exclusive breastfeeding - systemic lupus erythematous
Introduction
Breast milk is a rich source of infants' nutrition and also known to be a source of
immune enhancing molecules.[1] Breastfeeding has many benefits such as reducing the incidence and severity of diarrhea,
respiratory diseases, otitis media, bacterial meningitis, and necrotizing enterocolitis.[2]
[3]
[4]
[5] It has been shown that the breast milk is enriched with the immune activating molecules,
metabolites, and vitamins that provide protection against various types of infection
and improve the sufficiency of immune system.[6] Breastmilk is a rich source of antibodies and contributes to the infant's immune
system development. Also, it may play an important role in the establishment of the
normal gut flora. More than one pathway may play in the mechanism of several autoimmune
diseases but all of them are related to the implicit response of the immune system.[7] It is likely that the first months of life may have a long-term effect on the immune
system, and the role of breast milk can be noted.[8]
[9]
Several studies have examined the relationship between breast milk consumption and
autoimmune diseases. Studies have shown the relationship between breast milk consumption
and fewer autoimmune diseases, including type 1 diabetes, celiac disease, and inflammatory
bowel disease.[10]
[11]
[12]
[13] On the other hand, recent studies have shown that the mode of delivery has a remarkable
impact on immune regulation.[14]
[15] Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that can
affect various organs including the renal, cardiovascular, and nervous system, characterized
by the elevated levels of autoantibodies in the circulation.[16]
The purpose of this study is to investigate the relationship between the breast milk
consumption and mode of delivery with SLE incidence and onset in children under the
age of 16 years.
Materials and Methods
A total number of 118 patients with the diagnosis of SLE were referred to the Children's
Medical Center and Imam Khomeini Hospital Complex, Tehran, Iran, from 2011 to 2017, in which 39 patients were older than 16 years of age by the end
of 2017 and were excluded based on the study protocol. The remaining 79 patients were
enrolled and the age of diagnosis and involvement of vital organs have been studied.
The control group consisted of 301 children under the age of 16 who were referred
to the outpatient clinics of Children's Medical Center and schools of Tehran and Sari
cities, with no remarkable history of diseases. A full description of the study was
given to the parents via phone call and the informed consents were completed prior
to filling out the questionnaires by an expert physician.
The inclusion criterion was being under 16 years of age by the end of 2017, in both
the groups. SLE diagnosis was confirmed for those who completed at least 4 criteria
or more out of the 17 criteria of clinical and immunological criteria in the Systemic
Lupus International Collaborating Clinics (SLICC) classification system (at least
one clinical criterion and one immunologic criterion and/or lupus nephritis in the
presence of positive antinuclear antibody or anti-double-stranded DNA).[17] In the control group, inclusion criteria were: no history of SLE and no history
of severe medical conditions leading to hospitalization or frequent visits to the
outpatient clinics. Also, diagnosis of all patients was confirmed by a pediatric rheumatologist.
Lack of parents' cooperation during data gathering was considered as the exclusion
criteria in both groups.
Three major organ involvements, including renal, neurological, and cardiac, were considered
as main variables based on SLICC classification system.[17] Perinatal variables were mode of delivery, history of exclusive breastfeeding, duration
of breastfeeding, and birth weight.
Data Analysis
All of the data were analyzed using IBM SPSS 23.0 software (IBM, Armonk, New York, United States). To examine the relationship
between qualitative variables, “Pearson's chi-squared” test (χ2) was performed. To check the normal distribution of data, “Kolmogorov–Smirnov” and “Shapiro–Wilk” tests were used. Regarding the non-normal distribution of data in this study, the
nonparametric “Mann–Whitney” U test was performed.
Sample Size Calculation
In a study by Simard et al in 2008, the history of exclusive breastfeeding during
infancy up to 6 months of age was 5% among patients with established SLE; while in
an Iranian study in 2015, this prevalence was estimated up to 17%. Based on these
studies, the sample size was calculated.[18]
Results
The study population consisted of 79 cases in the patients' group with the sex ratio
of 63 females to 16 males and 301 participants in the control group (64.8 females
vs. 35.2% males). All of the participants were between 1 and 16 years of age.
The prevalence of breastfeeding among the patients and the control group was 92.4
and 93.7%, respectively, while the prevalence of exclusive breastfeeding had decreased
down to 34.2% in the patients' group versus 42.9% in the control group. The mean duration
of breastfeeding within two groups and the mean age of diagnosis in the exclusive/nonexclusive
breastfed children were devoid of statistical significance.
The prevalence of systemic side effects of SLE based on the breastfeeding and exclusive
breastfeeding status is illustrated in [Table 1]. The mean differences between groups were not significant.
Table 1
The main clinical side effects of childhood-onset SLE based on the breastfeeding status
|
Overall prevalence (%)
|
Nonbreastfeeding (%)
|
Breastfeeding (%)
|
Exclusive breastfeeding (%)
|
p-Value
|
|
Renal involvement
|
53.2
|
50
|
53.4
|
48.1
|
0.6[a]
|
|
Neurological involvement
|
38
|
16.7
|
39.7
|
48.1
|
0.2[a]
|
|
Cardiac involvement
|
10.1
|
16.7
|
9.6
|
3.7
|
0.5[a]
|
Abbreviation: SLE, systemic lupus erythematosus.
a Not significant.
The investigation showed a remarkable significance between the delivery method and
disease occurrence. In patients' group, 54.5% (43/79 patients) of the infants were
born by cesarean section (C-section), but in healthy group this rate was 28.6% (86/301
subjects). Thus, those born with the C-section method were associated with the higher
prevalence of childhood-onset SLE (p < 0.001).
The mean duration of breastfeeding in the control and patients' group was 17.147.8
months versus 18.548.14 months, respectively, which was not statistically significant.
The mean age at diagnosis in children with breastfeeding history was 9.315.94 years,
which was higher than the non-breast milk group with an average of 8.165.9 years;
however, this difference was also devoid of statistical significance. The comparison
of mean age at diagnosis in children who had a 6-month history of exclusive breastfeeding
was following the same order between both the study groups. Birth weight and other
evaluated perinatal factors were not significantly associated with childhood-onset
SLE.
Discussion
In this study, the relationship between breast milk consumption, exclusive breastfeeding,
and duration of lactation with the incidence and onset of SLE has been studied in
a group of children younger than 16 years of age. Involvement of vital organs has
been evaluated as well.
Several studies have been conducted to investigate the effect of breast milk consumption
on the occurrence of autoimmune disease such as type 1 diabetes, celiac disease, and
inflammatory bowel disease.[10] Some studies have found conflicting results while seeking the relationship between
breastfeeding and juvenile idiopathic arthritis (JIA).[19]
[20]
[21] On the other hand, a few studies have been done on the role of breast milk in SLE,
especially on the childhood-onset subgroup. This study has investigated this relation
for the first time.
In this study, the prevalence of breast milk consumption and exclusive breastfeeding
was higher in the control group, but this difference was not statistically significant.
Harvard's cohort study on the adulthood SLE also had a similar outcome.[18]
Although there were no significant differences, the frequency of breastfeeding and
exclusive use of breast milk in the control group was higher than the patient group,
and also in patients with a history of breastfeeding and exclusive use of breast milk,
the mean age of disease occurrence was higher. These differences could be clinically
important.
In our study, the prevalence of renal and neurological involvement among patients'
group with a positive history of breastfeeding was higher than those who did not breastfeed
their children. However, the prevalence of cardiac involvement in the breastfed was
less than in the non-breastfed children. This heterogeneity is likely to be the result
of small sample size, especially in the nonbreastfed arm. Although neither of these
comparisons was statistically significant, the association of breastfeeding and involvement
of vital organs in the SLE patients could not be excluded. Moreover, in a study on
the association between breastfeeding and JIA in 2016, breastfeeding had reduced the
disease severity, but there was not any confirmed data about SLE presentations to
be influenced by the feeding methods during infancy.[19] A comparison also was made to investigate the relationship between exclusive breastfeeding
and SLE complications, but as it is shown in [Table 1], these differences were devoid of statistical significance.
The most important finding in this article was the positive association between the
delivery method and the incidence of disease. Therefore, the incidence of childhood
SLE was significantly higher in the C-section method in comparison to normal vaginal
delivery (NVD). However, there was no positive significance among the delivery method
and other clinical factors, for instance, the age at diagnosis and presentations.
The probable hypothesis could be the impact of C-section on the formation of newborn's
gut flora. Meanwhile, it has been suggested that the primary flora formation of the
gut is a determinant factor for improving autoimmune diseases via dysregulating immune
modulators.[14]
[15] The CD4+ T cells dysregulation may play a pivotal role as the underlying molecular
mechanism in SLE pathogenesis.[22] On the other hand, presence of an undetermined genetic or environmental factor could
commonly affect the mode of delivery and predisposition to childhood-onset SLE.
Based on recent studies, the impact of birth weight on the incidence of childhood-onset
SLE is controversial. In the present study, the same as a Swedish one, high birth
weight had no significant influence on the disease onset and incidence.[23] However, some other studies have investigated that high birth weight is positively
correlated with adulthood SLE incidence.[18]
There were some limitations in the present study that need to be addressed in the
future investigations. The most important limitation was the unavailability of appropriate
data on the indication of choosing C-section over NVD. Therefore, there would be several
cases of elective C-sections among the case group without any common genetic or environmental
predispositions to specific diseases. The sample size has to be bigger in each group,
especially in the nonbreastfed arm. Some parents did not remember the details about
their children feeding status. Therefore, it is suggested to use the patients' documented
health and growth information to avoid data loss.
This observation suggests that the mode of delivery can affect the incidence of childhood-onset
SLE. However, more researches are recommended to assess the exact mechanisms and details.
