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\begin{document}

\title{Association between gestational diabetes mellitus and allergic diseases
in children}



\author[1]{Zhi Li}%
\author[1]{Mei Yu}%
\author[2]{Pin Wang}%
\author[1]{Hong Qian}%
\author[1]{Yun Fan}%
\author[1]{Xiuzhu Li}%
\author[1]{Qiaoqiao Xu}%
\author[1]{Xinru Wang}%
\author[3]{Xu Wang}%
\author[1]{Chuncheng Lu}%
\affil[1]{Nanjing Medical University}%
\affil[2]{Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital}%
\affil[3]{Nanjing Children's Hospital}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Existing knowledge suggests that gestational diabetes
mellitus was inconsistently associated with children allergic diseases.
The aim of this study was to identify the association between
gestational diabetes mellitus (GDM) and the risk of children allergic
diseases by systematic review. Methods: We searched and retrieved three
databases (PubMed, Web of Science and Cochrane Library) for articles on
the association between GDM and children allergic diseases published
before December 31, 2019. Stata software version 16.0 was used for
statistical analysis. Results: Eight published studies were included in
this meta-analysis. The pooled effect estimates showed the association
between GDM and allergic outcomes, including asthma
(OR:1.13,95\%CI:1.01-1.27), wheezing (OR:1.12,95\%CI:1.08-1.16), and
atopic dermatitis (OR:1.41,95\%CI:1.31-1.53). GDM was not associated
with the risk of allergic sensitization, with a pooled effect estimate
of 1.45 (95\%CI: 0.40, 5.23). Conclusion: GDM may increase the risk of
allergic diseases in children. However, this finding should be validated
with future large-sample epidemiological studies covering a wider
spectrum of allergic diseases.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Gestational diabetes mellitus (GDM) is defined as diabetes that is
diagnosed in the second or third trimester of pregnancy and not overt
prior to gestation (1). Over the past decade, the prevalence of GDM has
been on the rise (2). In 2013, International Diabetes Federation (IDF)
conducted a comprehensive survey based on the data from 47
epidemiological studies in 34 countries and regions around the world.
The global prevalence of hyperglycemia in pregnant women (20-49 years)
was 16.9\%, and that of GDM was 14.2\% for the same group; about 21.4
million live births showed signs related to maternal hyperglycemia (3).
The incidence of GDM varies with countries, and all show an upward
trend.

GDM causes adverse events both in women and children , such as maternal
type 2 diabetes and obesity in children (4, 5). Previous epidemiological
studies have found that GDM may increase the risk of childhood allergic
diseases, including asthma and atopic dermatitis (6, 7). Current
population-based research results are inconsistent. Delayed pneumocyte
differentiation and lung maturation were observed in the offspring in
rodent models of diabetes during pregnancy (8-11). The possible
mechanism for their pathogenesis is that phosphatidylglycerol production
may be inhibited in gestational diabetes, resulting in reduced
surfactants and increased susceptibility to respiratory distress
syndrome, which may also explain the increased risk of persistent
wheezing in human infants born to women with GDM (12).

Food allergy, wheezing, asthma and eczema are the most common allergic
disorders in children (13). Four endpoints were set in the present
study: asthma, atopic dermatitis, food allergy and wheezing. To date,
their association with GDM has not been systematically reviewed, and the
results of existing studies on the association are inconsistent. Thus,
we conducted a meta-analysis to evaluate the findings of previous
epidemiological studies.

\textbf{METHODS}

\textbf{Selection criteria}

\textbf{Inclusion criteria}

1. Epidemiological studies based on human populations, such as cohort
studies, case control studies and cross-sectional studies that identify
the association between gestational diabetes mellitus and allergic
diseases in the children.

2. Exposure factors relating to GDM.

3. Outcomes relating to allergic diseases in children born to GDM women,
including atopic dermatitis, food allergy, asthma, and wheezing.

\textbf{Exclusion criteria}

1. Research articles not published in English.

2. Animal studies, published letters, conference abstracts, editorials
or comments, reviews and lecture materials, randomized controlled
studies.

3. Studies just about molecular mechanisms.

4. Poor research design and quality, including statistical
unavailability.

5. Studies unrelated to GDM and children allergic diseases.

\textbf{Search strategy}

We retrieved appropriate articles published by PubMed, Web of Science
and Cochrane library before December 31, 2019 through entering the
following terms:

Atopic dermatitis:

\#1: (maternal) or (pregnancy) or (pregnant women)

\#2: (diabetes) or (diabetes Mellitus) or (endocrine) or (blood glucose)

\#3: (hypersensitivity) or (allergy) or (allergy and immunology) or
(allergic disease) or (eczema) or (atopic dermatitis)

\#4: \#1 AND \#2 AND \#3

Food allergy:

\#1: (maternal) or (pregnancy) or (pregnant women)

\#2: (diabetes) or (diabetes Mellitus) or (endocrine) or (blood glucose)

\#3: (hypersensitivity) or (allergy) or (allergy and immunology) or
(allergic disease) or (food hypersensitivity) or (food allergy) or (food
allergen sensitization)

\#4: \#1 AND \#2 AND \#3

Asthma:

\#1: (maternal) or (pregnancy) or (pregnant women)

\#2: (diabetes) or (diabetes Mellitus) or (endocrine) or (blood glucose)

\#3: (hypersensitivity) or (allergy) or (allergy and immunology) or
(allergic disease) or (asthma) or (respiratory allergy)

\#4: \#1 AND \#2 AND \#3

All retrieved articles were imported to Endnote version X9 for
screening, deduplication, and overall management of the retrieved
records.

\textbf{Study screening and data extraction}

Retrieved articles were independently screened according to titles and
abstracts by two reviewers. Any discrepancy was resolved by discussion.
The same process was employed for full-text screening. The full texts
were assured by cross checking by consensus for validation and accuracy.
The following data as the characteristics of various studies was
extracted from eligible studies: first author's name, publication year,
research design, sample size, country, type of allergic diseases in the
children, effect estimates (odds ratios, hazard ratios, risk ratios or
prevalence ratios) and 95\% confidence interval. All data was imported
to Excel for analysis.

\textbf{Quality assessment}

The quality of included studies and risk of bias were assessed by two
reviewers using Newcastle Ottawa Scale (NOS, a design-specific scale
--case--control vs. cohort study) independently (14). Three items were
contained in NOS, including selection of study subjects, comparability,
exposure assessment and outcome. Eight items were used to identify the
quality of study. In exposure/outcome assessment, each item could be
given one star, and comparability a maximum of two stars. As such, the
total score ranges from zero to nine stars (15). Study inclusion was not
affected by quality score, but considered in sensitivity analysis and
results interpretation.

\textbf{Statistical analysis}

Meta-analysis was conducted using Stata software 16.0 (Stata, College
Station, TX, USA). The outcomes of the dichotomous variables, such as
odds ratio (OR) and hazard risk ratio, were included in this study. The
included effect estimates (OR, PR, RR and HR) were combined together in
subgroup analysis (16, 17). The I\textsuperscript{2} statistical test
was used to assess the heterogeneity of included studies. The findings
with p \textless{} 0.05 were statistically significant. When the
estimated effect was heterogeneous (I\textsuperscript{2}\textgreater{}
50\% or p \textless{}0.05), the random effect model was applied;
otherwise, the fixed effect model was applied. The sensitivity of each
study was assessed by omitting one study at one time to reduce
heterogeneity of the included studies. We did not assess publication
bias because less than ten studies were included (18).

\textbf{RESULTS}

\textbf{Study search and characteristics overview}

We retrieved 2153 articles published before December 31, 2019 about the
outcome of asthma from PubMed (613 articles), Web of Science (548
articles) and Cochrane Library (992 articles). Duplicated articles were
removed automatically (n=358). After reviewing titles and abstracts from
1795 articles, 1782 studies were excluded, including 575 reviews,
lecture materials, and randomized controlled study; 115 animal studies;
1021 studies unrelated to our research objective; 44 molecular mechanism
studies; 25 articles duplicates excluded manually and 2 non-English
studies. Of the remaining 13 full-text publications, five were further
excluded due to various reasons, only abstract, incomplete statistics
and irrelevant exposure. Finally, eight articles were included in this
meta-analysis. (Figure 1)

We retrieved 1431 articles published before December 31, 2019 about the
outcome of atopic dermatitis from PubMed (723 articles), Web of Science
(240 articles), and Cochrane Library (468 articles). Duplicated articles
were removed automatically (n=133). After reviewing the titles and
abstracts of 1,298 articles, 1,291 studies were excluded, including 453
reviews, presentation materials and randomized controlled studies;106
animal studies; 707 studies unrelated to our research objective; 11
molecular mechanism studies; 13 repeated studies, and 1 non-English
study. Of the \textbackslash{}soutleft remaining seven full-text
articles, one written in an abstract was excluded. In the end, six
studies were included for analysis. (Figure 1)

We retrieved 1,374 articles published before December 31, 2019 on the
outcome of food allergy from PubMed (697 articles), Web of Science (223
articles) and Cochrane Library (454 articles). Duplicated articles were
automatically removed (n = 123). After reviewing the titles and
abstracts of 1251 articles, 1243 studies were excluded, including 426
reviews, lecture materials and randomized controlled studies; 102 animal
studies; 690 items unrelated to the research objective; 16 molecular
mechanism studies; 9 repeated studies. Of the remaining eight full-text
publications, one abstract was excluded. Finally, seven articles were
included .(Figure 1)

To sum up, a total of eight articles were included. (Table 1)Several of
them provided multiple sets of outcomes, with different effect estimates
and 95\% confidence intervals. Six studies were cohort studies; two were
case-control studies. All studies were human population based. In the
two case-control studies, the size of case groups ranged from 916 to
14,803, and the size of control groups ranged from 16,527 to 1,386,029;
and the size of cohort studies ranged from 131 to 965,224.

\textbf{Relationship between GDM and children allergic diseases}

Overall, GDM was associated with the risk of children allergic diseases,
with a pooled effect estimate of 1.17 (95\%CI: 1.10, 1.25). Considering
the heterogeneity of the included studies (I\textsuperscript{2} =65.8\%,
P=0.000), random effect model was used to show the relationship between
GDM and children allergic diseases. The results were shown in Figure 2.

\textbf{GDM and children asthma}

Four studies were included in the subgroup analysis. The study
population of one of study was divided into four groups based on preterm
or term delivery (Very preterm \textless{}32 weeks; Moderate preterm
32+0--33+6 weeks; Late preterm 34+0--36+6 weeks; Term [?]37 weeks)(7). The
pooled effect estimate between GDM and children asthma was 1.13 (95\%
CI: 1.01, 1.27). Due to the heterogeneity of the study
(I\textsuperscript{2} = 58.3\%, P = 0.026), a random effect model was
used to show the relationship between GDM and children asthma .(Figure
3(a) )

\textbf{GDM and children wheezing}

Three studies about wheezing, though different in types, were included
in subgroup analysis. The endpoints were set as transient early
wheezing, persistent wheezing and late-onset wheezing (19), or ever
wheezing and recurrent wheezing (20). Due to a variety of types of GDM
(presentational type 1 diabetes, presentational type 2 diabetes, and
gestational diabetes), wheezing (early-onset transient wheezing,
early-onset persistent wheezing, late-onset wheezing), 9 sets of data
were derived from Liu's study (21). GDM was associated with the risk of
wheezing in children, with a pooled effect estimate of 1.12
(95\%CI:1.08, 1.16). Due to heterogeneity of the studies with
(I\textsuperscript{2} =54.6\%, P=0.015), a fixed effect model was used
to show the relationship between GDM and wheezing. (Figure 3(b) )

\textbf{GDM and children atopic dermatitis}

Subgroup analyzes included two studies. The merger effect estimate
between GDM and atopic dermatitis was 1.41 (95\% CI: 1.31, 1.53). In
Rajesh Kumar's study(22), children were divided according to full-term
delivery and preterm delivery. The children with atopic dermatitis were
divided into four groups (premature delivery \textless{}32 weeks;
moderate preterm delivery 32 + 0--33 + 6 weeks; premature delivery 34 +
0--36 + 6 weeks; semester [?] 37 weeks) (7). Due to the heterogeneity of
the study (I\textsuperscript{2} = 35.0\%, P = 0.174), a fixed effect
model was used to show the relationship between gestational diabetes and
atopic dermatitis. (Figure 3(c) )

\textbf{GDM and children allergen sensitization}

One study was included in subgroup analysis, with a pooled effect
estimate of 1.45 (95\%CI:0.40, 5.23). In this study, the sensitization
outcomes included food sensitization, aeroallergen sensitization and
total sensitization (22). Allergen sensitization was defined as specific
IgE\textgreater{}0.10 kUA/L resulting from at least one of the tested
allergens, including food (egg white, milk, peanut, soy, shrimp, wheat,
and walnut) and aeroallergens (dermatophygoides pteronyssinus and
dermatophygoides farinae, German cockroach, cat, dog, and Alternaria
alternata). Similar criterion was used in other studies (23, 24). Due to
the heterogeneity of the studies (I\textsuperscript{2} =70.5\%,
P=0.005), a random effect model was used to show the relationship
between gestational diabetes and sensitization. (Figure 3(d) )

\textbf{Subgroup analysis}

A subgroup analysis was conducted based on the type of epidemiological
study, finding showing that the cohort studies were highly heterogeneous
(I\textsuperscript{2}= 67.7\%, p = 0.000) while the heterogeneous of
case-control studies was reduced to 0 (I\textsuperscript{2}= 0.0\%, p =
0.927). (Figure 4)

\textbf{Sensitivity analysis}

Sensitivity analysis was conducted in clearly-defined GDM patients and
not clearly defined GDM patients respectively.The findings were not
statistically different, with a pooled effect estimate of 1.10
(95\%CI:1.04, 1.17) in clearly-defined GDM patients studies and
1.19(95\%CI:1.10, 1.28) in undefined GDM patients studies. It indicated
the reliability of the studies included in this meta-analysis. A fixed
effect model was uesd in clearly-defined GDM patient studies to show the
heterogeneity of the studies with (I\textsuperscript{2} =57.2\%,
P=0.009) and a random effect model in undefined GDM patients studies
(I\textsuperscript{2}=67.4\%, P=0.000). (Figure 5)

\textbf{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 (\textless{}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
(\textless{}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-\selectlanguage{greek}α, \selectlanguage{english}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.

\textbf{Strengths and limitations}

There are several strengths in this study. First, the basis for research
selection was explicit search strategies and well-defined research
inclusion criteria. Grey literature was examined, and articles in
different languages were included. Second\textbackslash{}soutly, there
is currently no systematic review of studies focusing on the impact of
gestational diabetes on multiple types of children's allergic diseases.
In addition, this study conducted a subgroup analysis on the types of
epidemiological studies and explored the research effectiveness of
different types of epidemiological studies.

There are also some limitations in our study. All the available evidence
was derived from observational studies (cohort, cross-sectional,
case--control), which have an inherent bias. In addition, not all
studies provided information on preterm/term births, therefore, the
confounder may arise from preterm/term status.

\textbf{Conclusion}

GDM is associated with the risk of children allergic diseases,
especially asthma, wheezing, and atopic dermatitis. Future
epidemiological studies with larger sample size should be conducted to
identify this association.

\textbf{Financial support}

This work was funded by the National Key Rearch and Development Program
of China(2019YFC1005100); Outstanding young academic leaders of Qing Lan
Project of Jiangsu Province;the Priority Academic Program Development of
Jiangsu Higher Education Institutions(PAPD).

\textbf{Conflict of interest statement}

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.

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\textbf{Figure legends}

\textbf{Table 1.} Characteristics of the retrieved articles

\textbf{Figure 1.} Flow diagram of the retrieved articles of
asthma,atopic dermatitis,food allergy

\textbf{Figure 2.} Forest plot for the association between gestational
diabetes mellitus and allergic diseases in childhood

\textbf{Figure 3(a).} Forest plot for the association between
gestational diabetes and asthma in children

\textbf{Figure 3(b).} Forest plot for the association between
gestational diabetes and wheezing in children

\textbf{Figure 3(c).} Forest plot for the association between
gestational diabetes and atopic dermatitis in children

\textbf{Figure 3(d).} Forest plot for the association between
gestational diabetes and allergen sensitization in children

\textbf{Figure} \textbf{4.} Subgroup analysis by research design

\textbf{Figure 5(a).} Sensitivity analysis for clearly defined GDM

\textbf{Figure 5(b).} Sensitivity analysis for undefined GDM

\textbf{Hosted file}

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