Discussion
Our findings indicate that prenatal SHS exposure increases the risk of
late-onset AD, especially in
sensitized school-age children. While the relationship between maternal
urine cotinine levels and AD in school-age children could not be
explored, we noted a relationship between higher maternal urine cotinine
levels and the risk of AD symptoms in preschool children (ages 4–6).
These results provide strong scientific support for our observations.
Our analyses of the AD phenotypes have reported the effects of prenatal
SHS exposure on late-onset AD. The present study implies that children
exposed to prenatal SHS are at a higher risk of developing AD with its
onset after age 2, and that screening for these high-risk groups may
help prevent childhood AD earlier. Further studies are warranted to
understand the underlying mechanisms.
A study in Japan reported no relationship between prenatal smoke
exposure and the risk of AD in early childhood up to 3 years, which is
consistent with our observations despite the study’s short follow-up
period (16). Another prospective cohort study reported an association
between prenatal smoke exposure and increased wheezing but decreased
atopic eczema until age 3 (17). Our study investigated data from a
longer follow-up period, allowing recognition of the late-onset
manifestation of AD.
We found that the cumulative effect of SHS on AD was not apparent in
early infancy and was only notable after reaching childhood. Additional
analysis of AD phenotypes revealed that this effect is likely due to an
increase in the late-onset AD
phenotype, which develops after 2
years. While not statistically significant, an incremental relationship
(p<0.1) was observed between higher cotinine levels and the
late-onset AD phenotype. The prevalence of AD in Korea peaks during
infancy and then decreases throughout early childhood (18), suggesting
that AD aggravated by prenatal SHS may occur as the late-onset phenotype
through a different mechanism from conventional AD.
Tobacco smoke induces the formation of hydrogen peroxide and activates
the cellular NOX (nicotinamide adenine dinucleotide phosphatase
oxidase), leading to the translocation and subsequent loss of SR-B1 or
the HDL receptor. This may affect the stratum corneum, composed of 25%
cholesterol (19). Tobacco smoke also exhibits oxidative effects in human
skin fibroblasts (20). DNA methylation is reportedly induced by maternal
smoking in pregnancy, which may mediate the effect of maternal smoking
on AD (21). The methylation status of the TSLP 5’-CpG was significantly
higher in the high-exposure group based on cord blood cotinine, and the
degree of methylation was associated with decreased TSLP protein
expression and increased AD (22). Hence, prenatal tobacco exposure may
affect DNA methylation, leading to delayed AD occurrence. Only 0.23% of
the mothers in the COCOA study reported smoking during pregnancy (data
not shown). Therefore, a study focusing on the effect of SHS on AD will
have high clinical significance in the Korean population.
The relationship between urine cotinine and AD was analyzed to determine
the quantitative effect of prenatal SHS exposure on AD. The relationship
between urine cotinine and smoking status (23) has been demonstrated,
and a significant relationship between “smoking currently permitted in
the whole house” and positive urine cotinine has been reported (9),
indicating that maternal urine cotinine levels are a significant
surrogate marker for SHS exposure. However, no significant relationship
was observed between AD in early childhood (ages 0–3) and cotinine
levels. The definition of AD in the earlier phase of childhood tends to
vary, and a significant portion of patients undergo remission with
various contributors. From this study, school-age (ages 7–9) data were
insufficient for urine cotinine analysis, but a significant relationship
was observed between AD in preschool children (ages 4–6) and urine
cotinine levels during pregnancy, indicating an association between
higher doses of cotinine and AD in childhood.
We applied the mediation model with SHS as exposure, offspring AD as the
outcome, and IgE level as mediator (Supplementary Fig. 1). Total effect
of SHS on atopic AD at school age (ages 7–9) was significant (OR =
2.033, p = 0.029). IgE level at age 3 significantly mediated the
relationship (indirect effect OR = 1.110, p = 0.010, the proportion
mediated = 14.8%), but the level at the other ages (age 1 or 7) had no
indirect effect. These results showed that the IgE level at 3 years of
age is a mediating factor in the relationship between SHS exposure and
AD in sensitized school children. However, further study is warranted
given that this association was not mediated by IgE level at other ages,
and the indirect effect of IgE level was weaker than expected
(Supplementary Fig.1.). Discussion regarding mechanisms related to IgE
are in the online supplement.
There are a few limitations to this study. First, data on SHS exposure
were investigated using questionnaires, and the intensiveness of the
exposure was not considered. While it is typical to measure cotinine in
the second or third trimester to assess the level of smoke exposure
during pregnancy (24, 25), we measured urine cotinine at week 36 per the
COCOA protocol. Nevertheless, exposure status to prenatal SHS is
expected to be consistent through pregnancy since most exposure is
expected to have occurred at home or work.
The main strength of our study is its prospective design. Data on the
SHS exposure of pregnant mothers, their urine cotinine levels, and other
potential confounders were investigated before birth, reducing biases
that may corrupt data. An additional strength is that the assessment of
AD was examined by pediatric allergists using a standardized research
data form, and that phenotypes of AD were assessed. Furthermore, all
children were adjusted for SHS exposure during their first year of life
to distinguish the effects of prenatal and postnatal SHS exposure since
the latter is also a major risk factor for AD(26). Children in the
school age (7–9 years) group were adjusted for SHS exposure from ages 4
to 6. The COCOA cohort is a general population cohort, allowing
generalization of the results of this study, especially in Asian
countries with a low rate of maternal smoking during pregnancy.