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, 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.
Disclosure statement: The author(s) report(s) no conflict of
interest.