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\begin{document}

\title{Gestational diabetes is associated with SARS-CoV-2 infection during
pregnancy: A case-control study}



\author[1]{Anda-Petronela Radan}%
\author[1]{Mihaela-Madalina Fluri}%
\author[1]{Konstantinos Nirgianakis}%
\author[1]{Beatrice Mosimann}%
\author[1]{Bettina Schlatter}%
\author[1]{Luigi Raio}%
\author[1]{Daniel Surbek}%
\affil[1]{Inselspital University Hospital Bern}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: to investigate a possible bi-directional association between
gestational diabetes (GDM) and the SARS-CoV-2 infection during
pregnancy. Design: case-control study with prospective data collection
for the case group and 1:2 matching with historical controls Setting:
University Hospital of Bern, Switzerland Population: 224 pregnant women:
75 cases with SARS-CoV-2 infection during pregnancy, matched 1:2 with
controls based on parity, BMI and ethnicity. Methods: SARS-CoV-2
infection was diagnosed by RT-PCR. Screening for GDM was performed by
75mg oral glucose tolerance test at 26 weeks' gestation in all women.
Main Outcomes: Prevalence of GDM was calculated in both groups.
Multivariate binary logistic regression analysis was performed to assess
risk factors for GDM and inpatient COVID-19 management. Results: 34.6\%
of the patients in the case group suffered from GDM, vs. 16.1\% in the
control group (p=0.002). 35.7\% patients were diagnosed with GDM after
the SARS-CoV-2 infection, vs. 33.3\% diagnosed before infection
(OR(95\%CI) 1.11(0.40-3.08), p=0.84), with no correlation between the
time-point of infection and GDM diagnosis. SARS-CoV-2 (OR(95\%CI) 2.79
(1.42, 5.47), p=0.003) and BMI (OR(95\%CI) 1.12 (1.05, 1.19), p=0.001)
were significant independent risk factors for GDM. Conclusions: The
significantly higher rate of GDM among women with SARS-CoV-2 infection
during pregnancy, as compared to matching controls, suggests that GDM
increases the risk of infection. On the other hand, SARS-CoV-2 during
pregnancy might increase the risk of developing GDM. Vaccination and
caution in using protective measures should be recommended to pregnant
women, particularly those with co-morbidities. Funding: none Keywords:
SARS-CoV-2, gestational diabetes, COVID-19%
\end{abstract}%



\sloppy


\emph{Introduction}

Diabetes mellitus (DM) is one of the most frequent comorbidities in
individuals with SARS-CoV-2 infection {[}1, 2{]}. Evidence shows that
individuals suffering from diabetes present a higher rate of hospital
admission and a higher mortality as compared to non-diabetic subjects
{[}1, 3, 4{]}.

Analogue to the general population, pregnant women suffering from
preexisting diabetes seem to present with a higher severity degree of
SARS-CoV-2 infection {[}5, 6{]}. An international case control analysis
comparing data stratified by the severity of maternal disease identified
pulmonary comorbidities, hypertensive disease and DM as risk factors
associated with a severe form of SARS-CoV-2 infection in pregnancy
{[}5{]}. Furthermore, it has been previously suggested that
hyperglycemia generally increases viral replication and decreases
anti-viral response, making a causal relationship between diabetes and
SARS-CoV-2 biologically plausible {[}7,8{]}. However, there is limited
data so far whether these elaborations also apply to gestational
diabetes (GDM).

GDM is a major public health issue, with an abrupt increase in
prevalence in the last decade, as international committees report a
so-called `metabolic pandemic` {[}9,10{]}. According to The
Hyperglycemia and Adverse Pregnancy Outcome Study, the level of
glycaemia during pregnancy is directly linked to the presence of adverse
obstetrical outcomes {[}11{]}.

Prevalence of GDM lies worldwide between 9,3\% and 25,5\% {[}11{]}. A
British study described a 33.8\% increase in GDM since the onset of the
pandemic, attributing this mainly to reduced exercise levels and
psychical stress {[}12{]}.

SARS-CoV mediated pancreatic islet cell damage is not a newly described
phenomenon, as earlier experiences with MERS and SARS teach us {[}9{]}.
DM is a multifactorial disease, whose development is linked to genetic
and environmental influences. Indeed, a causal relationship between
viral infections and acute glycemic decompensation with onset of Type I
diabetes has been previously described. To date, several viruses have
been suggested as promoters for the development of Type I diabetes in
humans, including Coronavirus {[}1, 10{]}.

In this context, increasing evidence shows that SARS-CoV-2 can trigger
severe diabetic ketoacidosis in persons with new-onset Type I diabetes,
most probably due to high angiotensin converting enzyme 2 (ACE2)
expression in the endocrine part of the pancreas {[}9{]}. The mechanism
seems to involve cell apoptosis with decreased pancreatic insulin
secretion {[}13, 14{]}.

The aim of our study was to investigate a possible bidirectional
association between GDM and SARS-CoV-2 infection during pregnancy, as
well as to evaluate the plausibility of a physiopathological background,
by using a case-control approach.

\emph{Methods}

We included 224 pregnant women in our case-control study. The case group
consisted of 75 women with SARS-CoV-2 infection during pregnancy,
irrespective of the severity of the symptoms. We included all SARS-CoV-2
positive women who were managed at our tertiary referral hospital
between May 2020 and July 2021. Data from these individuals were
collected prospectively within the international COVI-Preg register
{[}15{]}. Cases were matched 1:2 with a historical cohort of women who
delivered before the SARS-CoV-2 pandemic between 01.01.2016 and
31.10.2019, based on parity, body mass index (BMI) and ethnicity. In one
woman, only one matching control was found, so that the control group
consisted of 149 individuals. Screening for GDM by 75mg oral glucose
tolerance test (OGTT) was performed at 26 weeks' gestation in all 224
women. Normal blood sugar values were defined as follows: fasting
\textless{} 5,1mmol/l, one hour after glucose ingestion \textless{}
10mmol/l, two hours after glucose ingestion \textless{} 8,5mmol/l. All
women where OGTT was not available were previously excluded.

First trimester was defined as conception to 13 + 6 weeks, second
trimester from 14 + 0 to 26 + 6 weeks and third trimester as more than
27 + 0 weeks of gestation.

Diagnosis of COVID-19 infection in the case group was made by
identification of SARS-CoV-2-PCR in a nasopharyngeal swab.

At birth, clinical data on maternal and fetal outcomes were collected.

Written informed consent and institutional review board approval were
obtained (2020-00832). The study was performed in accordance with the
principles of the Declaration of Helsinki.

No external funding was received for performing this study.

\emph{Statistical Analysis}

Mean values and SD were calculated for continuous variables and
percentages for the qualitative variables. A student t-test and Fisher's
exact test was used to compare continuous parametric variables and
binary variables between the two groups, respectively. Possible risk
factors for gestational diabetes and inpatient COVID-19 management were
determined with multivariate binary logistic regression analysis. A
logistic regression analysis was also performed to identify if the time
of COVID-19 infection during pregnancy was associated with the diagnosis
of gestational diabetes. Missing data were excluded from the analysis.
Significance was set at a p-value of \textless{}0.05. Statistical
analysis was carried out with SPSS 25.0 software (SPSS, USA).

\emph{Results}

Baseline characteristics of the study population are depicted in Table
1. Altogether, 26/75 (34.66\%) of the patients in the case group
suffered from gestational diabetes vs. 24/149 (16.1\%) in the control
group (p=0.002). The rate of preterm delivery was 17.3\% in the case
group vs. 7.6\% in the control group (p=0.04). Neonatal outcomes were
collected in all the other women and are also summarized in Table 1.

Multivariate logistic regression analysis showed that SARS-CoV-2 (OR
(95\%CI) 2.79 (1.42, 5.47), p=0.003) and BMI (OR (95\%CI) 1.12 (1.05,
1.19), p=0.001) were significant independent risk factors for GDM (Table
2).

In 11/75 (14.66\%) patients, SARS-CoV-2 infection occurred in the first
trimester of gestation, in 19/75 (25.33\%) in the second and in 37/75
(49.33\%) in the third trimester. In eight patients, time-point of
infection was unknown (10.66\%). Of these, three suffered from GDM.

Out of 28 patients infected with COVID-19 [?] 26 week of pregnancy, 10
(35.7\%) had a positive OGTT (GDM diagnosis) afterwards. This is similar
to the 13/39 (33.3\%) of patients with positive OGTT before infected
with COVID (Chi-Square 0.84) (Table 3, Figure 1).

89.33\% of the patients (67/75) in the case group suffered from
asymptomatic, mild or moderate SARS-CoV-2 infection, according to the
National Institutes of Health \textbf{(} NIH) criteria for severity of
the disease {[}14{]}. 12\% (9/75) of the patients had severe or critical
illness with inpatient management. Of these, 5.33\% (4/75) required
intensive care unit (ICU) admission and ventilation. These four patients
underwent an emergency delivery because of SARS-CoV-2 infection. No
patient deaths were recorded.

Of the nine patients with inpatient management, four (44.44\%) suffered
from GDM. Of the four patients who required admission at the ICU, two
suffered from GDM (50\%). Regression analysis of factors associated with
inpatient COVID-19 management (inpatient vs. outpatient) showed no
significance for GDM, time-point of infection or BMI (Table 4).

\emph{Discussion}

Main findings

The main finding of our study is a significantly higher rate of
gestational diabetes in a SARS-CoV-2 infected pregnant population, when
compared to historical controls, which raises concerns about the
association between GDM and SARS-CoV-2 infection during pregnancy. All
though no statistical correlation was found between the time point of
infection in regards to OGTT, previous data on DM and COVID-19 during
pregnancy would support in a first line that those patients with GDM are
more prone to SARS-CoV-2 infection. On the other hand, multivariate
regression analysis found BMI and COVID-19 to be independent risk
factors for GDM in our cohort, supporting the theory of the
virus-triggered diabetes onset. This is to our knowledge the first
case-control study providing evidence, even if limited, for a possible
causal relationship between COVID-19 and onset of GDM.

As stated before, the hyperglycemic level directly correlates with
adverse obstetrical outcome {[}9,10{]}. What the severity of infection
is concerned, to date, only a clear association between previously
existing diabetes and severe course of SARS-CoV-2 infection could be
established {[}18, 19{]}. Being able to determine the severity of the
SARS-CoV-2 infection based on the NIH classification is one of the
strengths of our study. All though the size of our cohort does not allow
us to make a statement regarding the severity of SARS-COV-2 in relation
to GDM, 50\% of the women requiring ICU admission in our cohort suffered
from GDM, which is alarming. On a deeper analysis\emph{,} body mass
index, GDM and time point of infection none correlated with inpatient
management of SARS-CoV-2 infection, thus with the degree of severity
(Table 4). Since previous large reports could clearly show a correlation
between high BMI and severity of infection, we believe that our results
are a consequence of the small number of women with inpatient management
and ICU admission, thus lack of statistical power to demonstrate a
possible association {[}19{]}.

With an European rate of GDM of 16.3\% and worldwide of up to 25.5\%,
these results are of concern and call for consequences in the management
of pregnant patients suffering from GDM or at risk for GDM in the
context of the pandemic {[}16{]}.

A recently published multicentric study with similar design reports an
association between insulin dependent GDM and COVID-19 diagnosis in
pregnancy, yet over 80\% of the participants were SARS-CoV-2 positive at
the time-point of delivery, making the assessment of a bi-directional
association difficult {[}14{]}. Until larger case-control studies are
available, it remains open if this association is uni- or bidirectional,
meaning if SARS-CoV-2 also plays a pathophysiological role in the
genesis of GDM. Possible mechanisms of SARS-CoV-2 induced metabolic
decompensation with onset of diabetes were described in the introduction
of this report and are, at least on a theoretical basis, conceivable
{[}9,10{]}. Several epidemiological studies note a seasonal distribution
of gestational diabetes, which reinforces the `viral theory` of onset of
diabetes, with extension to pregnant women {[}9,10{]}.

In order to perform data analysis in our study, we matched the case
population with historical controls based on parity, BMI and ethnicity.
Since a high BMI and specific ethnicities are known risk factors for
gestational diabetes, the rationale for choice of controls was to
eliminate these cofounding factors from the analysis {[}10{]}.
Furthermore, we decided for parity as a matching criterion with the
intention to analyze presence of GDM in a previous pregnancy as a risk
factor for the current GDM diagnosis (Table 2).

The rationale of choosing historical controls, i.e. pregnancies managed
at our institution prior to the pandemic, was to secure that
asymptomatic, not tested SARS-CoV-2 infected women were not included in
the control group by accident. The timeline for control group was
intentionally kept narrow (three years before the pandemic), in order to
reduce bias that could possibly occur by fluctuations of GDM prevalence
in time.

Although a further cofounding factor for SARS-CoV-2 infection in GDM
affected women could be a higher exposition to hospital visits in these
patients, we mention that management adaptation has been performed in
our center during the major SARS-CoV-2 pandemic surges, i.e. reduction
of consultations or conversion to telemedicine. Nevertheless, no
alteration in diabetes testing regimens occurred, i.e. testing has been
performed analogue to the pre-pandemic period. In both groups, women
where OGTT was not available were excluded, in order to avoid possible
diagnosis biasing. Homogeneity of testing is a major strength of our
study, since standard OGTT was used in every single patient in both
groups, which distinguishes us from previous publications.

In both our study groups, GDM rate was higher than in the general
pregnant population in our country, which could be explained by the
higher proportion of high-risk pregnancies as well as by the high number
of South Asian immigrants being followed at our institution {[}16{]}.

The rate of hospital admission in SARS-CoV-2 infection in our population
was in line with previous reports {[}19{]}. We noted a significantly
higher rate of premature delivery in the case group, as compared to the
controls, where preterm delivery corresponds those of the general
pregnant population {[}20{]}. The 17.33\% rate of preterm delivery is in
line with results from a large previous meta-analysis reporting 17\%
preterm delivery in SARS-CoV-2 infection during pregnancy {[}19{]}.

Strengths and Limitations

One major strength of our study is the prospective data assessment in
the case group and the case-control approach. As mentioned before,
further strengths are represented by the homogeneity of GDM diagnosis in
both groups, as well as the ability to classify the COVID-19 in respect
to the symptoms. The major limitation is the cohort size as well as not
having matched for further comorbidities or lower socioeconomic status
because of incomplete records, which is a known risk factor for both GDM
as well as SARS-CoV-2 infection {[}10,21{]}.

Interpretation

According to CDC reports, only 31\% of the pregnant US population has
been vaccinated against SARS-CoV-2 so far {[}22{]}. We believe it is
safe to extrapolate these numbers to the majority of the developed
economy countries, although recommendations for vaccination in pregnant
women have been issued in a considerable proportion of states worldwide
{[}23{]}. Taking a deeper look at the vaccination rate of the general
population in low-income countries, incidences of 12\% for Asian
countries or even significantly lower in the majority of African states
have been reported {[}24{]}. All though pregnant women are generally
considered to build a young and healthy population, increasingly high
BMI and gestational diabetes rates, as well as maternal age, the wide
spread of the highly contagious variants and still low vaccination
acceptance make SARS-CoV-2 to a highly relevant issue in obstetrics.

Therefore, pregnant women in general and those with GDM in particular
should not only be recommended early vaccination, but also caution in
using protective measures. Moreover, appropriate counseling should be
offered to these patients at risk.

Conclusions: The significantly higher rate of GDM among women with
SARS-CoV-2 infection during pregnancy, as compared to matching controls,
suggests that GDM increases the risk of infection. On the other hand,
SARS-CoV-2 during pregnancy might increase the risk of developing GDM.
Vaccination and caution in using protective measures should be
recommended to pregnant women, particularly those with co-morbidities.

\emph{Disclosure statement:} The author(s) report(s) no conflict of
interest.

\emph{Author's contribution:}

APR: conception and design of the study, acquisition of data, analysis
and interpretation of data, drafting the article

MF: acquisition of data, analysis and interpretation of data

KN: analysis and interpretation of data, statistics, revising the
article

BM: acquisition of data, revising the article critically for important
intellectual content

BS: acquisition of data

LR: analysis and interpretation of data, revising the article critically
for important intellectual content

DS: conception and design of the study, revising the article critically
for important intellectual content

Details of Ethics Approval \emph{-} Institutional review board approval
was obtained from the Ethical Committee of the Canton Berne (reference
number 2020-00832).

Funding: No funding has been received for conducting the study

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\emph{Tables and Figures}

\textbf{Table 1.} Comparison of baseline characteristics and pregnancy
outcomes between the two groups\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Characteristics\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Characteristics\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Cases n= 75\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Controls n= 149\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30.76 \selectlanguage{ngerman}± 4.63\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30.62 \selectlanguage{ngerman}± 4.48\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26.27 \selectlanguage{ngerman}± 5.08\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25.91 \selectlanguage{ngerman}± 5.03\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Parity\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Parity\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (0-7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (0-5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Ethnicity\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Caucasian\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
120 (80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
African\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 (14.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
South Asia\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
East Asia\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mixed\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Twins\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Twins\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GDM\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GDM\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26/75 (34.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24/149 (16.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SGA/IUGR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SGA/IUGR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9/70 (12.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13/139 (9.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Preterm delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Preterm delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13/75 (17.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11/144 (7.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.04\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mode of delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Spontaneous vaginal delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31/66 (47)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
69/140 (49.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Operative vaginal delivery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6/66 (9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15/140 (10.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Primary cesarean section\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19/66 (28.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29/140 (20.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Secondary cesarean section\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10/66 (15.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27/140 (19.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
pHa\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
pHa\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.25 \selectlanguage{ngerman}± 0.078\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.18 \selectlanguage{ngerman}± 0.683\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5Min. Apgar score\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5Min. Apgar score\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8.91 \selectlanguage{ngerman}± 1.01\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8.82 \selectlanguage{ngerman}± 1.40\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fetal transfer to the ICU\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fetal transfer to the ICU\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7/66 (10.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8/136 (5.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ns\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* missing values were excluded from the analysis

\textbf{Table 2.} Regression analysis of factors associated with GDM\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
OR (95\%CI) 222 patients included in the model\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Previous GDM\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.17 (0.18, 7.48)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.87\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.12 (1.05, 1.19)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
COVID-19 infection\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2.79 (1.42, 5.47)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{0.003}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*Cox and Snell R2 = .088. Nagelkerke R2 = .135

Goodness-of-fit test Hosmer \& Lemeshow: \selectlanguage{greek}χ\selectlanguage{english}2= 6.500. df= 8. P= .586

\textbf{Table 3.} Regression analysis of association between time of
COVID-19 infection and GDM diagnosis\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
OR (95\%CI) 67 patients included in the model\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Time of COVID-19 infection ([?] 26 week of pregnancy vs \textgreater{}26
week of pregnancy)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.11 (0.40, 3.08)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.84\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4.} Regression analysis of factors associated with
inpatient COVID-19 management GDM\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
OR (95\%CI) 66 patients included in the model\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.07 (0.91, 1.25)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.41\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
GDM\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.14 (0.22, 5.80)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.88\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Week of pregnancy with COVID-19 infection\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.08 (0.98, 1.20)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.12\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*Cox and Snell R2 = .066. Nagelkerke R2 = .121

Goodness-of-fit test Hosmer \& Lemeshow: \selectlanguage{greek}χ\selectlanguage{english}2= 5.197. df= 7. P= .636

Figure 1. COVID-19 infection reported to the time-point of GDM diagnosis
(OGTT)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

