DISCUSSION
In this study, we examined the effect of GDM on children allergic
diseases. Based on eight studies (two case-control studies and six
cohort studies), this meta-analysis found that compared to the normal,
the children born to GDM women were at a 17% higher risk of allergic
diseases (OR:1.17, 95%CI:1.10-1.25). Based on the types of allergic
diseases, we conducted a subgroup analysis to reduce heterogeneity
(25),providing that the effect estimates of each allergic disease: 1.13
(OR:1.13,95%CI:1.01-1.27) in asthma group, 1.12
(OR:1.12,95%CI:1.08-1.16) in wheezing group, and 1.41
(OR:1.41,95%CI:1.31-1.53) in atopic dermatitis group. GDM may increase
the risk of allergen sensitization, but the relationship was not
statistically significant (OR:1.45,95%CI:0.40-5.23). We also explored
the source of heterogeneity in the study design. No heterogeneity was
found in the case-control study, but higher heterogeneity in the cohort
study. For sensitivity analysis, we excluded studies in clearly-defined
GDM patients and not clearly defined GDM patients respectively, and
found that children born to GDM women regardless of whether GDM was
clearly defined all confronted an increased risk of developing allergic
diseases (OR:1.10,95%CI:1.04-1.17;OR:1.19,95%CI:1.10-1.28)
In previous studies, Rusconi et al. (19) found an association between
maternal diabetes during pregnancy and early-onset wheezing in children
(OR:1.72, 95%CI:0.99–3.00). Kumar et al. (22) found that GDM increased
the risk of atopic dermatitis (OR:7.2, 95%CI:1.5-34.5) and early
allergen sensitization in childhood (OR:5.7, 95%CI:1.2-28.0). In a
Swedish record linkage study, Aspberg et al. (26) reported that maternal
diabetes was associated with a 19% higher risk of having a child who
would be prescribed with anti-asthmatic medication (OR: 1.19,
95%CI:1.12–1.28).
In the study of childhood asthma, Paula’s findings (7) were inconsistent
with ours (OR:1.13, 95%CI: 1.01-1.27), probably because the children of
their studies were all born as very preterm (<32 weeks)(OR:
0.96, 95%CI: 0.58-1.69) and late preterm (34+0–36+6weeks) (OR: 0.78,
95%CI: 0.63-1.11). The inconsistency may also be related to sample
size, and uncontrolled confounding factors, such as antenatal steroids
and early-life feeding, or exclusivity of breastfeeding. In the study of
children wheezing, the results of Rusconi et al. (19)(OR: 0.94, 95%
CI:0.47-1.86) and Liu et al. (21) (OR: 0.85, 95%CI:0.67-1.09) were
inconsistent with ours (OR:1.12, 95% CI:1.08-1.16). Only children with
late-onset wheezing were studied in both studies. Liu et al. did not
explain the results of late-onset wheezing unassociated with GDM.
Rusconi believed that the misclassification of children in the
late-onset wheezing group could lead to the inconsistent results. In the
study of atopic dermatitis in children, the results of Kumar et al. (22)
(OR: 0.74, 95%CI:0.11-4.91) and Paula et al. (7)(OR: 0.62,
95%CI:0.23-1.69) were inconsistent with ours (OR: 1.41,
95%CI:1.31-1.53). In both studies, only children born as premature
(<37 weeks and moderate preterm 32+0–33+6 weeks) were
included. The reasons that preterm is not related to GDM have been
described above. In the studies about children’s allergen sensitization,
the three sets of results reported by Kumar et al (OR: 0.37,
95%CI:0.07-1.88) (OR: 0.26, 95%CI:0.04-1.64) (OR: 0.38,
95%CI:0.07-2.19)(22) were inconsistent with ours (OR: 1.45,
95%CI:0.40-5.23). The children studied by Kumar et al. were all born as
preterm.
Currently, no mechanisms are revealed to interpret the association
between GDM and childhood allergic diseases. We explored the possible
mechanisms through this meta-analysis. In GDM, fetal exposure and
limited response to high cord blood glucose (27) may cause fetal
hyperinsulinemia, hypoxia (28), and ultimate lung immaturation. In
addition, the maternal autoantibody may cross the placenta to directly
act on the fetal lung development (29). An epidemiological study of
human adults in the Netherlands revealed a link between GDM and atopic
diseases in early childhood, and the mediatory role of insulin
resistance mediates between obesity and allergen sensitization (30).
Mothers with GDM have higher levels of TNF-α, leptin and visfatin, and
lower levels of adiponectin. Adiponectin can reduce allergic
inflammation in mouse models. Therefore, GDM-decreased adiponectin may
have a negative impact on the development of infant immunology (31-34).
Apart from this, maternal diabetes predisposes mothers to premature
births who carry a greater risk of neonatal alveolar surfactant
deficiency. In addition, high blood sugar level may significantly
inhibit fetal alveolar surfactant synthesis and secretion during late
pregnancy (35, 36). Further researches are needed to determine the
mechanisms between GDM and children allergic diseases.