Introduction
After the severe acute respiratory distress virus coronavirus type 2 (SARS-CoV-2)
first appeared in December 2019 and its rapid global spread in spring 2020, in May
2023 more than 765 million people worldwide had been infected with the virus. It
remains unknown how many pregnant women were affected. After one year of pandemic,
at the beginning of 2021 and before the vaccination program started, the
seroprevalence in the German general population was estimated at 2% [1]. Therefore, it can be assumed that 6,000 to
12,000 of the 750,000 women who gave birth in Germany in the first pandemic year
would have acquired SARS-CoV-2 infection during their pregnancy. Reliable global
data are not available. The German COVID-19 Related Obstetric and Neonatal Outcome
Study (CRONOS) in which 130 hospitals participated reported 2,819 infected women by
the end of August 2021, covering about 250,000 births per year [2].
The World Health Organization (WHO) estimated that 20 million people died related to
COVID-19; about 20% of recovered individuals aged 18–64 years are
still suffering from a post-COVID condition [3]. In the early stages of the pandemic, the severity of the disease and
the fatal outcome of many infected persons depended on the efficiency of the health
care system in the respective country, whether the infected person was a member of a
health insurance plan, affected by social deprivation and ethnic minority
disadvantage, access to intensive care treatment, and the availability of
ventilation devices or oxygen [4]. In terms of
health policy, most countries decreed lockdown measures and closed public
facilities, schools and universities; people were forced to take hygienic measures,
such as wearing mouth-nose masks and maintaining a safe distance.
In addition to the known risk factors of severe COVID-19, such as chronic pulmonary
or cardiovascular disease, obesity, and diabetes mellitus (DM), pregnancy is also an
independent risk factor for a severe course of COVID-19, especially when the
infection occurs in the second half of pregnancy [5]. Pregnancies complicated by obesity and varying degrees of
hyperglycemia are predestined for an unfavorable outcome [6]. This applies to overweight or obese women
with gestational diabetes mellitus (GDM) [7]
as well as to women with pre-existing type 1 diabetes (T1DM) or type 2 diabetes
(T2DM), who experience higher blood glucose levels, greater fluctuations of blood
glucose concentrations and, compared to GDM, are in most cases treated
pharmacologically.
After more than three years of the pandemic, there has been a dramatic change in
virus transmission and disease progression [8]. This is due to SARS-CoV-2 itself and its mutant variants, the
availability of vaccination by late 2020, population-level immunity from
vaccination, SARS-CoV-2 infection, or both, the use of pharmacotherapies in the
early stages of contagion, and improvement of clinical care. A recent comprehensive
review summarizes pregnancy outcomes ([Table
1]) [9]. Meanwhile health policy
measures are terminated step by step. In Germany, for example, the obligation to
wear an FFP-2 mask in hospitals, medical practices, and nursing homes was lifted on
April 8, 2023, and the Corona-Warn-App has not been active since May 1, 2023. On May
5, 2023, the WHO announced that there is no longer a “public health
emergency of international concern.”
Table 1 Pregnancy outcomes in 39,716 women with COVID-19,
adapted from a systematic review and meta-analysis of 69 studies with
1,606,543 pregnancies (population-based, cross-sectional, cohort, or
case–control study) published until October 19, 2022 [9].
|
Pregnancy Outcome
|
Studies(n)
|
Women withCOVID-19 (events)(n)
|
Women withoutCOVID-19 (events)(n)
|
Risk Quantification OR (95% CI)
|
|
Preterm delivery
|
50
|
26,084 (2687)
|
955,965 (58,203)
|
1,59 (1.42; 1.78)
|
|
Spontaneous preterm delivery
|
8
|
13897 (783)
|
595,768 (23,322)
|
1.33 (1.20; 1.48)
|
|
Preeclampsia
|
34
|
27732 (2214)
|
1,358,619 (27,732)
|
1.41 (1.30; 1.53)
|
|
Low birth weight
|
12
|
6616 (407)
|
9392 (580)
|
1.52 (1.30; 1.79)
|
|
Cesarean delivery
|
57
|
31,158 (9986)
|
1,453,633(428,304)
|
1.20 (1.10; 1.30)
|
|
Fetal distress
|
7
|
1276(169)
|
6759(577)
|
2.49 (1.54; 4.03)
|
|
NICU admission
|
31
|
9146(1187)
|
131,966(11,210)
|
2.33 (1.72; 3.16)
|
|
IUFD or stillbirth
|
27
|
29,542(256)
|
1,347,386(6730)
|
1.71 (1.39; 2.10)
|
|
Perinatal mortality
|
21
|
4123(27)
|
14,474(106)
|
1.96 (1.15; 3.34)
|
|
Maternal mortality
|
12
|
9633(39)
|
494,811(90)
|
6.15 (3.74; 10.10)
|
|
Placenta abruption
|
12
|
7535(119)
|
116,786(1540)
|
1.40 (1.02; 1.92)
|
|
FGR or SGA
|
27
|
17,372(1520)
|
529,780(34,906)
|
1.12 (1.0; 1.26)
|
|
GDM
|
40
|
31,515(3105)
|
1,177,715(110,637)
|
1.13 (1.04; 2.01)
|
|
Congenital anomalies
|
8
|
3040(40)
|
37,178(333)
|
1.45 (1.04; 2.01)
|
|
Total miscarriages
|
13
|
6696(229)
|
96,729(9674)
|
1.04 (0.68; 1.60)
|
|
Premature rupture of membranes
|
10
|
4272(99)
|
36,495(571)
|
1.36 (0.96, 1.93)
|
|
Postpartum hemorrhage
|
21
|
8635(610)
|
125,111(8027)
|
0.98 (0.78; 1.24)
|
|
Cholestasis
|
7
|
403(24)
|
3830(242)
|
1.34 (0.83, 2.18)
|
|
Chorioamnionitis
|
14
|
3027(236)
|
39,989(2803)
|
1.26 (0.93; 1.72)
|
NICU, neonatal intensive care unit; IUFD, intrauterine fetal death; FGR,
fetal growth restriction; SGA, small für gestational age; GDM,
gestational diabetes mellitus; OR, odds ratio; CI, confidence interval.
Based on a literature search in PubMed of reviewed articles and reference lists on
SARS-CoV-2/COVID-19 and pregnancy from December 1, 2019, to May 31, 2023,
this review is focused on pregnant women with DM or GDM and closely related issues.
Our aim is first to summarize, based on the existing literature, the effects of
COVID-19 on the different forms of hyperglycemia during pregnancy and on pregnancy
outcomes, and second, to describe the effects of hyperglycemia on COVID-19 in
pregnant women.
Pathogenesis of COVID-19 related to glucose metabolism
The entry of SARS-CoV-2 into the body is mediated by its binding to the
angiotensin-converting enzyme 2 (ACE2) receptor [10], initially in the upper respiratory tract, with secondary
systemic inflammation and virus entry into target organs. In DM, the entry of
the virus may be facilitated by an increase of ACE2 receptor expression by
hyperinsulinemia, which is further enhanced by the glycoprotein dipeptidyl
peptidase4, which functions as a surface receptor for coronaviruses [11]. DM may be associated with complement
defects, immunodeficiency, and increased inflammatory activity. In nonpregnant
hospitalized individuals with COVID-19 hyperglycemia and inflammation are
independently associated with a severe course [12].
Even with subclinically elevated blood glucose levels, which are indicative of
oxidative stress, there is an increased structural glycation of the SARS-CoV-2
spike protein, which was demonstrated by increased levels for methylglyoxal and
glycated albumin [13]. The virus uses its
glycosylated trimeric spike proteins to bind to the ACE2 receptor [14]. The oxidative stress on the placenta
and other organs mediated by advanced glycation end products (AGEs) and its
receptor (RAGE) may explain why pregnant women with overweight and obesity or
GDM are more at risk compared to women within the reference range of blood
glucose or insulinemia.
Morphologically, the endocrine and exocrine pancreas is a target organ for
SARS-CoV-2 [15]. A German cooperation
showed that SARS-CoV-2 infects cells of the human exocrine and endocrine
pancreas ex vivo and in vivo. They demonstrated that human ß-cells
express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured
human β-cells. Infection is associated with morphological,
transcriptional, and functional changes, including numbers of insulin-secretory
granules in ß-cells and impaired glucose-stimulated insulin secretion.
Therefore, SARS-CoV-2 infection of the human pancreas contributes to metabolic
dysregulation observed in patients with COVID-19.
Moreover, SARS-CoV-2 could affect the placenta by specific placentitis. This is
characterized by a triad of histopathological findings with massive perivillous
fibrin deposition, chorionic histiocytic intervillositis, and trophoblast
necrosis, which together can lead to placental parenchymal destruction with
subsequent insufficient oxygen supply to the fetus. These functional and
morphological changes are associated with stillbirth and neonatal death. This,
in turn, is a consequence of maternal viremia since direct infection of the
fetus via vertical transmission has very rarely been observed [16].
Pregnancy complications and outcomes
In general, the severity of COVID-19 was threefold greater in T1DM and T2DM
outside of pregnancy [17] compared to
non-diabetic women. A population study from England showed that in T1DM severe,
even fatal courses of COVID-19 were associated with the quality of glycemic
control and the BMI [18]. This was
confirmed by results from a large, prospective UK biobank study: diabetes was
associated with an excess risk of COVID-19-associated mortality [19]. There was also a strong association
between a severe course of COVID-19 and admission to the intensive care unit or
death from newly discovered diabetes or hyperglycemia at the time of hospital
admission [20].
During the first pandemic wave, a systematic review found that pre-existing DM
was a risk factor with an odds ratio (OR) of 2.51 (95% CI 1.31; 4.80)
for a severe course in the mother (admission to ICU, invasive ventilation,
extracorporeal membrane oxygenation [ECMO]), while this could not be confirmed
for GDM: OR 1.23 (0.70; 2.14) [21]. In a
Brazilian study using data from the national Acute Respiratory Distress Syndrome
database, severe diabetes was a risk factor for maternal death: OR 1.8
(95% CI 1.0; 3.3) [4], here the
authors reported 124 maternal deaths, with a COVID-19-related maternal mortality
of 12.7%. At the beginning of the pandemic, an ICU admission had to be
calculated in 5–10% of cases, the frequency of invasive
ventilation was registered at 1–2%, and the rate of maternal
death was around 1% [22].
COVID-19, lockdown, and pre-existing diabetes mellitus
A study by the INTERCOVID group demonstrated an increased risk of COVID-19 in
2,184 pregnant women with pre-existing DM (relative risk [RR] 1.94 (95%
CI 1.55; 2.24), and women with periconceptional BMI>25
kg/m² (RR 1.20, 95% CI 1.06; 1.37) [1], evaluated from March
2020–February 2021 [23].
An analysis of 1,219 deliveries from 33 hospitals in the USA up to July 2020
showed an increasing proportion of pre-existing DM in asymptomatic cases with
SARS-CoV-2 of 2.9%, in a moderately severe course of 3.6%, and
in a severe course of 9.9% with a statistically significant trend
(p=0.002) [24]. Only the severe or
critical course was associated with adverse pregnancy outcomes such as preterm
delivery, RR 3.53 (95% CI 2.42; 5.14); peripartal mortality was
calculated at 0.3%.
SARS-CoV-2 infection – associations with incident diabetes
mellitus
The literature on this topic ranges between case reports and analyses of
“big data,” mostly outside pregnancy. Before the pandemic, new
manifestation of T1DM in pregnant women had been rare
(estimated<0.3% per 100,000 pregnancies) and T2DM was de novo
diagnosed in no more than 1–3% of GDM pregnancies; the majority
of cases was detected without symptoms during GDM screening. In CRONOS we
registered three women with newly diagnosed T2DM in the group of 101
pre-existing diabetes cases (3%), in one case with ketoacidosis,
published in part [25]. During the years
before the pandemic, from an international evaluation the incidence of T1DM in
children and adolescents increased every year, therefore more females with T1DM
will reach their reproductive years and become pregnant. The SWEET study group
analyzed 17,280 cases from 2018–2021 and found no rise of the slope in
pediatric new-onset T1DM during the pandemic [26].
The question of whether SARS-CoV-2 in pregnant women is a trigger for
autoimmunity in symptomatic as well as in asymptomatic cases following T1DM can
thus far not be answered. This also applies to T1DM without autoimmunity with a
consecutive continuous need for insulin because of possible viral β-cell
destruction. The majority of new cases of T1DM occurs before reproductive age or
in young adulthood. From the low prevalence of pre-existing diabetes during
pregnancy, the impact of COVID-19 on an excess incidence may be evaluated from
long-lasting observations. Additionally, it is not known if new-onset diabetes
is likely to remain permanent [27]. In a
large study in COVID-19 patients with 13% new-onset diabetes,
40.6% of the survivors regressed to normoglycemia or prediabetes [28].
With regard to T2DM, the findings are different, because at a young age the
disease is rare but continuously increasing, and in most cases associated with a
higher BMI. Currently, it cannot clearly be answered whether the incidence of
T2DM increases as a result of a SARS-CoV-2 infection per se. This requires years
of follow-up observations in which numerous influencing factors, such as reduced
exercise during lockdown, changed eating habits, increase in BMI, post-COVID
condition, and postpartum lifestyle modifications after GDM should be
considered. Additionally, in both T1DM and T2DM, COVID-19 with a severe course
could contribute to an early unmasking of as yet undiagnosed diabetes.
Recent clinical data on new-onset T1DM are conflicting, mostly evaluated in
children, adolescents, and young adults [29]
[30]
[31]
[32]. From the results of an analysis of more than 80 million
deidentified patient electronic records globally in the first 15 months of the
pandemic from the Tri-NetX COVID-19 research network, the authors concluded that
the incidence of T1DM among patients with COVID-19 below 30 years of age is not
greater when compared with the age-, sex-, and BMI-matched population without
COVID-19 [33].
A large two-year population-based cohort study from Canada, conducted in 2020 and
2021, analyzed 125,987 RT-PCR positive individuals compared with 503,948
unexposed individuals [34]; 51.2%
of participants were females, and of these 64.1% in the exposed group
and 70.1% in the unexposed group were aged 18 to 39 years. During the
median follow-up of 257 days, the researchers observed a statistically
significant higher incidence rate in the male exposed group vs. the male
unexposed group, with a hazard ratio (HR) of 1.17 (95% CI 1.06; 1.28).
The incident rate of diabetes in females was higher in those admitted to the
hospital (adjusted hazard ratio [aHR] 1.94; 95% CI 1.,30; 2.88) or
transferred to the ICU (aHR 2.71; 95% CI 1.18; 6.18). COVID-19 was
associated only with non-insulin-dependent diabetes.
In summary, it is unknown to what extent pregnancy represents an additional
independent diabetogenic influence or aggravates known risk factors in infected
women or their exposed offspring. Up to now there are signals and hypotheses,
but no reliable evidence. Researchers from the U.S. stated that the putative
induction of T1DM through direct and/or indirect effects of SARS-CoV-2
infections remains unproven [35]. Wiliam
Cefalu from the US National Institutes of Health (NIH) raised concern that a
significant amount of work has to be done to understand the reasons behind
reports of increased diabetes cases after SARS-CoV-2 infection [36].
Euglycemic ketoacidosis and fulminant type 1 diabetes
Euglycemic diabetic ketoacidosis (EDKA) is a well-described and serious
complication in pregnant women with and without diabetes. Before the pandemic,
it was most commonly seen in pregnant women with T1DM. By definition, metabolic
acidosis is present with an increased anion gap due to ketonemia, but glucose
does not exceed 250 mg/dl (13.9 mmol/l). Some authors even see
the limit at 200 mg/dl (11.1 mmol/l). The relatively low glucose
level, which often is measured in the normal range, repeatedly leads to
misjudgments and delays in diagnosis, which must be verified by a blood gas
analysis. The cause of low blood glucose levels is usually a poor general
condition, e. g., associated with nausea and vomiting, and as a
consequence of reduced or even no food intake. We found nine case reports in
pregnant women related to COVID-19 ([Table
2]) [37]
[38]
[39]
[40]
[41]
[42]
[43]
[44].
Table 2 Case reports of pregnant women with COVID-19 and
euglycemic diabetic ketoacidosis (EDKA). ns, not specified; wks,
gestational week; ICU, intensive care unit; DKA, diabetic
ketoacidosis.
|
Case 1
|
Case 2
|
Case 3
|
Case 4
|
Case 5
|
Case 6
|
Case 7
|
Case 8
|
Case 9
|
|
Reference no.
|
[37]
|
[38]
|
[39]
|
[40]
|
[41]
|
[42]
|
[43]
|
[43]
|
[44]
|
|
Country
|
USA
|
Iran
|
Quatar
|
Spain
|
France
|
Netherlands
|
UK
|
UK
|
Chile
|
|
Age
|
32
|
35
|
35
|
29
|
36
|
21
|
34
|
34
|
36
|
|
BMI (kg/m²)
|
obese
|
ns
|
ns
|
31.5
|
35.2
|
ns
|
25
|
28
|
31.5
|
|
Parity
|
0
|
3
|
2
|
ns
|
7
|
0
|
3
|
1
|
3
|
|
Gestational week of hospital admission
|
28+3
|
34+5
|
29
|
34
|
32
|
37+6
|
35
|
36+3
|
35
|
|
Diabetes class
|
GDM
|
GDM
|
GDM
|
GDM
|
GDM
|
Non-diabetic
|
T2DM
|
Non-diabetic
|
Non-diabetic
|
|
Diabetes therapy
|
Insulin
|
Insulin
|
Basic
|
ns
|
Basic
|
ns
|
Insulin
Metformin
|
ns
|
ns
|
|
COVID-19
|
Pneumonia
|
Pneumonia
|
Pneumonia
|
Pneumonia
|
Dyspnea
|
Pneumonia
|
Pneumonia
|
Pneumonia
|
Pneumonia
|
|
Vaccinated
|
+
|
ns
|
ns
|
ns
|
ns
|
ns
|
ns
|
ns
|
ns
|
|
Blood glucose (mg/dl/mmol/l)
|
174 (9.7)
|
70 (3.9)
|
85 (4.7)
|
169 (9.4)
|
112 (6.2)
|
85 (4.7)
|
79 (4.4)
|
76 (4.2)
|
66 (3.7)
|
|
HbA1c (%/mmol/mol)
|
ns
|
ns
|
4.6 (26.8)
|
7.2 (55.2)
|
6.1 (43.2)
|
ns
|
11.5 (102)
|
ns
|
ns
|
|
pH
|
7.29
|
7.33
|
7.26
|
Metabolic acidosis
|
7.22
|
7.34
|
6.87
|
7.25
|
7.31
|
|
HCO3- (mmol/l)
|
8
|
8.2
|
9.6
|
ns
|
5.8
|
8.7
|
6.2
|
7.1
|
8.2
|
|
Base excess (mmol/l)
|
–19
|
–9.5
|
–11.8
|
ns
|
ns
|
–14.6
|
–27.2
|
–20.2
|
ns
|
|
Anion gap (mmol/l)
|
21
|
21
|
14
|
ns
|
ns
|
23
|
21
|
ns
|
25.4
|
|
Blood ketone (mmol/l)
|
ns
|
ns
|
4.6
|
ns
|
15.4
|
ns
|
5.2
|
6.8
|
ns
|
|
ICU mother and DKA therapy
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
|
Outcome mother
|
C-section
29+0 wks
|
C-section
35+3 wks
|
Vaginal
40 wks
|
C-section
36 wks
|
Preeclampsia
C-section
32 wks
|
C-section
38+3 wks
|
Emergency
C-section35 wks
|
C-section
34 wks
|
Vaginal
38+2 wks
|
|
Outcome neonate
|
APGAR 5‘ 2
Intubation
|
Apgar 5‘ 9
|
normal
|
normal
|
Female
2445 grams
|
Apgar 5‘ 8
Acidosis
|
Apgar 5‘ 8
Acidosis
Hypogly-cemia 20 mg/dl
1.1 mmol/l
|
Apgar 5‘ 10 normal
|
Apgar 5‘ 9 norma
l2750 grams
|
COVID-19 was associated with severe pulmonary symptoms or pneumonia in all cases.
GDM was present in five cases, T2DM in one case, no diabetes was known in three
cases, and T1DM was not present in any case. The glucose levels were at most 174
mg/dl (9.7 mmol/l) and in six cases even<100
mg/dl (5.6 mmol/l). All women received standard intensive care
with ketoacidosis management, delivery by cesarean section usually took place
shortly after the mother had recompensated, and four of the nine newborns were
in critical condition; six of nine children were born premature. No fatal
outcome has been observed in mothers and neonates. These cases clearly show that
the severity of metabolic acidosis does not correlate with the levels of blood
glucose, and some symptoms of ketoacidosis could be confused with pregnancy
complications, e. g., preeclampsia or preterm labor.
Additionally, researchers from London/UK reported four cases with EDKA
with concomitant COVID-19 and symptomatic breathlessness caused by pneumonia,
presenting between 31 and 34 weeks of gestation [45]. They used a pregnancy-specific reference range for arterial
blood gas interpretation adjusted to the physiologic trend to compensated
respiratory alkalosis in late pregnancy. These women, aged 25 to 41 years, were
negatively screened for GDM with a 50 gram test at 28 weeks with results from 92
to 113 mg/dl (5.1 to 6.3 mmol/l). Blood glucose results at
presentation were not available. The authors pointed out that tachypnea in
pregnant women with COVID-19 could be aggravated from ketoacidosis with an
increased breathing rate. All women were successfully recompensated with
standard corrective treatment.
Recently, the first case of fulminant type 1 diabetes mellitus (FT1DM) has been
reported in a 34-year old Chinese woman five weeks after mild COVID-19 [46]. FT1DM is characterized by a very short
history of less than one week, marked symptoms with high blood glucose and
relatively low HbA1c, absolute insulin deficiency, severe ketoacidosis, elevated
pancreatic enzymes, and no evidence of autoimmunity. The manifestation is
typical in pregnant women of Southeast Asian or Japanese origin; one case in a
German woman has already been reported [47]. From case series, the stillbirth and neonatal death rate was
about 66%. The etiology is unknown, and some cases were associated with
viral infections.
The patient’s OGTT test result at 25 weeks of gestation was negative
[46]. She presented at 34 weeks of
gestation with a one-day history of polydipsia, nausea, and vomiting in a
dehydrated condition; her pre-pregnancy BMI was 21 kg/m² and
none of her family members had T1DM or T2DM. Obstetric evaluation showed uterine
contractions every 20 s, fetal heart rate was 114 bpm and the contraction stress
test was abnormal. Initial lab results showed arterial pH of 7.08, bicarbonate
of 8.6 mmol/l, β-hydroxybutyrate of 5.8 mmol/l, blood
glucose of 522 mg/dl (29 mmol/l), HbA1c of 5.9%, an
extremely low C-peptide level of 0.02 ng/ml, negative results for islet
cell autoantibodies, and slightly elevated amylase and lipase. She tested
positive for IgG antibodies against SARS-CoV-2. The patient underwent an
emergency C-section for acute fetal distress and recovered after standard
ketoacidosis management. Acute pancreatitis was ruled out with a CT scan
thereafter. The newborn had a poor Apgar score of three both at 5 and 10 min,
was transferred to NICU but died afterward.
A comment is required on this case. The emergency cesarean section due to fetal
indication was dangerous because the pregnant woman’s ketoacidosis had
not been adequately compensated. Fetal heart rate recovers after compensation of
the maternal ketoacidosis. Invasive interventions, including C-sections, should
be delayed until metabolic acidosis is sufficiently corrected.
Gestational diabetes mellitus (GDM)
Definition of GDM
In Germany GDM is defined according to the “International Association
of Diabetes in Pregnancy Study Groups (IADPSG)” criteria [48]. A two-step procedure is required:
between 24–28 weeks of pregnancy a 50-g non-fasting 1-hour screen is
performed, if positive with a threshold of 135 mg/dl (7.5
mmol/l), followed by a fasting diagnostic 75-g oral glucose
tolerance test (OGTT) of two hours’ duration [49]. Currently, there are no
internationally accepted strategies or glycemic thresholds for GDM diagnosis
[50].
Early reports from the first wave
In a report from Wuhan on 41 pregnant women up to February 2020, four
pregnant women with GDM were mentioned for the first time [51]. The first German case of a
pregnant woman with GDM and a moderately severe course of COVID-19 with
obstetric complications (oxygen supplementation, fever, dyspnea, vaginal
bleeding, and need for tocolysis) from the Freiburg University Hospital was
reported on April 6, 2020 [52]. At
that time, 116 cases had been published worldwide, and the first pregnant
woman without diabetes who died of COVID-19 from Iran was reported [53]. In August 2020 there were already
reports of more than 10,000 infected pregnant women, with comorbidities
mostly with overweight/obesity and GDM but also with pre-existing
diabetes at a lower rate. A large systematic review using data from 40
studies up to January 2021 with more than 3.5 million pregnancies before and
during the pandemic found an increase in maternal death, stillbirth,
ruptured ectopic pregnancies, and maternal depression, but no increase of
GDM [54].
GDM Prevalence and outcomes during the pandemic
Before the pandemic, the global GDM prevalence was 14% of
pregnancies, with a range of 7.8% in Europe and 27.6% in
Middle East and North Africa [55]. The
evaluation of the German perinatal statistics proved that GDM prevalence
increased continuously from 4.42% in 2013 to 6.81% in 2019,
and to 7.86% in 2021 with no obvious acceleration during the
pandemic. A recent analysis of pregnant women using maternity care in German
statutory health insurance found a slight increase in GDM from 12.9%
in 2015 to 16.3% in 2020 [56].
These significant differences in the prevalence rates are probably due to
different data resources, e. g. health record data vs. ICD
codes.
The possible increase in the prevalence of GDM during the pandemic may be due
to several reasons, such as behavioral changes during lockdown, direct
damage to pancreatic beta cells by the virus, or an infection-induced
increase in insulin resistance. The following results can be derived from
numerous studies on this question:
-
GDM prevalence is increasing possibly associated with changes in
screening procedures or lifestyle changes [57]
[58]
[59]
[60]
[61]
[62];
-
GDM prevalence does not change or is decreasing [63]
[64]
[65]
[66];
-
GDM is associated with a severe course of COVID-19 or insulin therapy
[23]
[67];
-
Gestational weight gain (GWG) as a risk factor for GDM increases
[68].
Taken together, from the existing literature there is some evidence that
during the first two years of the pandemic and with low vaccination rate GDM
prevalence increased locally, probably secondary to changes in lifestyle,
such as less exercise, increasing BMI during lockdown, and GWG. Severe
COVID-19 was associated with more GDM cases, and women with insulin-treated
GDM had a higher risk of COVID-19; this might be a sequelae of
hyperinsulinemia and an associated higher degree of insulin resistance or
β-cell dysfunction. A comparison of studies is difficult because of
different diagnostic strategies for GDM in the respective countries.
Therefore, systematic reviews and meta-analyses are needed in this
field.
Change in strategy on screening and diagnosis
Soon after the onset of the pandemic, professional societies from the UK,
USA, Canada, Australia, New Zealand, Italy, France, and Japan adjusted their
guidelines on GDM diagnosis adapted to the pandemic [69]
[70]
[71]
[72]
[73]
[74]. Essentially, the
aim was to prevent pregnant women from longer stays in places with an
increased risk of infection, such as outpatient clinics as well as journeys
with public transport. Researchers from Basildon/UK performed
calculations showing that if fasting plasma glucose is used exclusively,
with an overall GDM prevalence of 18.2%, only a small percentage of
7.2% of all GDM cases are overlooked [75], while others did not share this
view [76]
[77].
A deeper analysis of this question was presented by a group from Queensland,
Australia [78]. Based on 75-g OGTT
results from 26,242 pregnant women during 2015 with a GDM prevalence of
15% according to the IADPSG criteria (of which 57.3% showed
an increased fasting value of>92 mg/dl/5.1
mmol/l), they calculated using a receiver operating characteristic
analysis that a fasting blood glucose>83 mg/dl (4.6
mmol/l) has the best sensitivity of 54% and specificity of
77% to be predictive of an elevated value 1 h or 2 h after OGTT.
According to these results, only 17.7% of all tested women with
fasting values of 85–90 mg/dl (4.7–5.0
mmol/l) would need an OGTT. Unfavorable end points of pregnancy were
compared with the Hyperglycemia and Adverse Pregnancy Outcome study data. It
was shown that comparing pregnant women with GDM vs. without GDM with a
fasting glucose<85 mg/dl (4.7 mmol/l), there were
only minimal or no statistically significant risk differences.
Developing countries such as India, Sri Lanka, Pakistan, and Bangladesh use a
different approach [79]. They perform
a 75-g OGTT in a non-fasting state with a single measurement of blood
glucose after two hours, measured both in venous plasma and in capillary
blood. GDM diagnosis is confirmed with a result>140 mg/dL
(7.8 mmol/l), which is recommended by the Diabetes in Pregnancy
Study Group in India and in accordance with the WHO definition of impaired
glucose intolerance. OGTT could also be carried out in the home; with a
population of approx. 1.7 billion in this region, many pregnant women cannot
reach medical offices, polyclinics, or laboratories. The women have to
travel long distances, which they cannot cope with when they are
fasting.
A scoping review with 40,336 pregnant women from 13 studies showed that
despite the aforementioned suggestions for protecting pregnant women from
infection, the OGTT is the most effective test to identify abnormal glucose
in pregnancy in concordance with some hyperglycemia-associated outcomes,
e. g., neonatal hypoglycemia. For this reason, the prompt return to
standard local guidelines post-pandemic is supported [80].
Follow-up care
Structured follow-up care after GDM is of great importance because of the
mother’s risk of developing T2DM and cardiovascular disease.
According to expert consensus, follow-up begins 6–12 weeks
postpartum with a 75-g OGTT. In recent years, less than 50% of women
in Germany made an appointment for the OGTT. An evaluation of the GestDiab
registry for the years 2015–2017 of 12,991 women after GDM showed
that only 38.2% took the test. Thereafter, 19.3% of women
took the test in the recommended period of up to three months after birth
[81]. This is a missed opportunity
of 60% of starting measures to prevent type 2 diabetes or detecting
cardiovascular risks. According to German data, at this very early stage
after birth, 35–43% of women already have prediabetes and
0.4–3% converted to T2DM. As initial follow-up requires a
post-pregnancy appointment, there was concern that women with GDM would not
attend these appointments for fear of infection.
An alternative to GDM follow-up to avoid additional risk of infection was
proposed by researchers from Providence, Rhode Island, USA. The mothers
participated in an OGTT on the second postpartum day in the maternity
hospital [82]; adherence to this
approach was 99% of 300 women. The prognosis for prediabetes or DM
in the mother one year after delivery did not differ from an examination
4–12 weeks postpartum. However, many professional societies no
longer recommend or strictly reject OGTT during puerperium. The remaining
relevant question is whether a SARS-CoV-2 infection during pregnancy
represents an independent risk factor in addition to the established risk
factors for the development of T2DM in the mother, such as obesity or
insulin therapy. It is therefore important that these women are followed up
as completely as possible.
Vaccination and treatment in early stage of disease
Vaccination against SARS-CoV-2 infection/COVID-19
In a recent systematic review (30 studies, 862,272 individuals, 308,428
vaccinated and 553,844 unvaccinated) the authors stated that vaccination
against COVID-19 during pregnancy is safe and highly effective in preventing
maternal SARS-CoV-2 infection in pregnancy, without increasing the risk of
adverse maternal and neonatal outcomes, and is associated with a reduction
in stillbirths, preterm births, and neonatal ICU admissions. Maternal
vaccination did not reduce the risk of neonatal SARS-CoV-2 infection during
the first six months of life during the omicron period [83]. A retrospective, observational,
matched-cohort study with 45,232 pregnant women aged 16 to 49 years who had
received one or two doses of a COVID-19 vaccine immediately preceding or
during pregnancy found that the frequency of all medically attended acute
adverse effects was less than 1% [84].
Authors from multiple official national US health centers came to the result
that evidence has consistently demonstrated that COVID-19 mRNA vaccines are
safe when given during pregnancy for both pregnant women and infants, and
COVID-19 mRNA vaccines protects pregnant women and their infants who are too
young to receive COVID-19 vaccines. Monovalent vaccine effectiveness was
lower during omicron predominance, and bivalent vaccines may improve
protection against omicron variants. Effectiveness of mRNA vaccines is
similar in pregnant women and nonpregnant women of comparable age for the
prevention of SARS-CoV-2 infection and hospitalizations [85].
A large cohort study from California, USA, involving 12,706 females found
that post-COVID-19 new-onset DM risk was higher in unvaccinated (OR 1.78;
95% CI 1.35; 2.37) vs. vaccinated patients (OR 1.07; 95% CI
0.64; 1.77) [86].
From indirect evidence it could be assumed that pregnant women with DM or GDM
may benefit to the same extent from vaccination compared to non-diabetic
women. Vaccination might mitigate new-onset DM after SARS-CoV-2
infection.
Treatment with monoclonal antibodies
The use of monoclonal antibodies (mAbs) against SARS-CoV-2 in the early stage
of the infection in cases with incomplete immune protection or high risk for
a severe course of COVID-19 is an established option of therapy outside
pregnancy. Randomized controlled trials have excluded pregnant persons and
specific data on diabetes comorbidity are sparse. From case series, therapy
with mAbs appears to be safe and effective including for GDM and DM [87]
[88].
A large retrospective, propensity score-matched cohort study from the UPMC
Health System insurance (Pittsburgh, PA, USA) from April 2021 to January
2022 included 994 women with a median gestational age of 179 days and mild
to moderate COVID-19; 552 unvaccinated women received mAbs, and most were
treated with sotrovimab; others received bamlanivimab and etesevimab or
casirivimab and imdevimab [89].
Adverse events were rare, demonstrated in 1.4% of women. The
treatment group included 2.2% of women with preexisting DM and
3.8% with GDM. There was no difference in any obstetric-associated
outcome among 778 women who delivered, comparing mAbs treated women vs.
vaccinated controls. Furthermore, there were no differences in the composite
28-day COVID-19-associated outcome and in non-COVID-19-related hospital
admission.
Other pharmacotherapies
A detailed presentation of other pharmacotherapies, such as antiviral drugs
or glucocorticoids, is beyond the scope of this review. Two comprehensive
reviews from 2022 and 2023 are recommended for further information [90]
[91]. Conclusive studies of diabetic pregnant women are not
available. However, it should be mentioned that treatment of severe COVID-19
with glucocorticoids in women with DM or GDM can lead to increased blood
glucose, metabolic imbalances, and ketoacidosis.
Registries on pregnancies with SARS-CoV-2 infection
In a rapidly spreading pandemic with severe disease progression and high
morbidity and mortality, it is necessary to quickly gain substantial
knowledge in order to be able to intervene in a targeted manner. In
addition, the counseling of pregnant women or women who wish to become
pregnant urgently needs to be adapted to the current situation. On this
basis, numerous registries have been set up worldwide to collect data. The
evaluation of the registries, in turn, is the basis for developing
guidelines, which must be dynamically adapted to new findings over the
course of time. Some important registries are listed in [Table 3]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103].
Table 3 Registries recruiting pregnant women with
SARS-CoV-2 infection or COVID-19.
|
Registry
|
Country
|
Recruited participants (n)
|
Last updated
|
Results/Remarks
|
Ref.
|
|
CRONOS
|
Germany, Austria
|
8,850
|
February 2023
|
See Diabetes mellitus in the CRONOS Registry
|
[92]
|
|
COVI-PREG
|
Switzerland
|
1,402 Pre-Delta
|
September 2022
|
Delta period associated with higher risk of severe
maternal adverse outcome; risk of hospitalization during
omicron period high.
|
[93]
[94]
|
|
International
|
|
262 Delta
|
|
391 Omicron
|
|
COVID-19 PRIORITY
|
USA
|
1,333
|
June 2023
|
Estimated study completion March 31, 2024.
|
[95]
|
|
COVID-NET
|
USA
|
452,041
|
April 2023
|
34.9% pregnancies in 2020–2022, not yet
published.
|
[96]
|
|
IRCEP
|
USA
International
|
17,318
|
August 2021
|
See Social determinants of health
|
[97]
|
|
PAN-COVID
|
UK
|
8,239
|
March 2021
|
Infection associated with indicated preterm birth;
proportion of stillbirths higher in participants
delivering within 2 weeks of infection vs.
those>2 weeks after infection. Higher than
expected proportion affected by eclampsia.
|
[98]
[99]
|
|
PregCOV-19LSR
|
UK
Living Systematic Review
|
1,219,384
|
May 2022
435 studies
|
Less likely COVID-19-related symptoms of fever and
myalgia, more likely to need ICU. Risk factors: high
maternal age and BMI. Higher proportion of preterm
births.
|
[17]
[100]
[101]
|
|
NPC-19
|
USA
|
7,542
|
February 2023
|
Early in the pandemic, SARS-CoV-2 was acquired by
newborns at a variable rate without apparent short-term
effect. Before widespread availability of vaccines, more
than expected numbers of preterm births and maternal
in-hospital deaths observed.
|
[102]
|
|
Q-PRECIOUS
|
Qatar
|
500
|
March 2021
|
Infection with more Qatari women, older, grand
multiparous, higher proportion with DM and GDM, higher
BMI compared with national data.
|
[103]
|
CRONOS (COVID-19 Related Obstetric and Neonatal Outcome Study
in Germany), COVI-PREG (International COVID-19 and Pregnancy
Registry), COVID-19 PRIORITY (Pregnancy CoRonavIrus Outcomes
RegIsTrY), COVID-NET (A Weekly summary of U.S. COVID-19
Hospitalization Data), IRCEP (International Registry of
Coronavirus [COVID-19] Exposure in Pregnancy), PAN-COVID
(Pregnancy and Neonatal Outcomes in COVID-19: a global registry of
women with suspected COVID-19 or confirmed SARS-CoV-2 infection in
pregnancy and their neonates; understanding natural history to guide
treatment and prevention), PregCOV-19LSR (COVID-19 in
Pregnancy Living Systematic Reviews), NPC-19 (The American
Academy of Pediatrics National Registry for the Surveillance and
Epidemiology of Perinatal Coronavirus Disease 2019).
Q-PRECIOUS (Active national perinatal registry,
consisting of women diagnosed with COVID-19 during their
pregnancies).
Diabetes mellitus in the CRONOS Registry
Data extraction from the CRONOS registry on November 1, 2022, resulted in
7,810 pregnant women with confirmed SARS-CoV-2 infection, of these 541
(6.92%) were diagnosed with GDM and 101 (1.29%) had
pre-existing diabetes, which is not different from the obstetric background
population. The most comprehensive CRONOS study, analyzing 3,481 women up to
June 2022, showed that DM of the mother was a risk factor for neonatal
transfer to the NICU or perinatal mortality if delivery took place within
four weeks after infection, with an OR of 4.9 (95% CI: 1.7; 14.2
[2].
A study on maternal and neonatal outcomes comparing 65 pregnancies with
medically assisted reproduction with 1,420 women who conceived spontaneously
found no statistical difference in pre-existing diabetes, at 1.5 vs.
1.3% (p=0.58) [104].
The analysis of 101 of 2,650 mothers in CRONOS with a documented ICU stay
showed that GDM was the most common comorbidity at 16%, followed by
preexisting diabetes at 4% [105]. A study on pregnancy outcomes on 211 women with obesity
(20.1%), compared to 839 women without obesity, showed significantly
higher frequency of GDM (20.4% vs. 7.6%, p<0.001).
BMI was revealed to be an individual risk factor for the severe combined
pregnancy outcome (maternal death, stillbirth, or preterm birth<32
weeks) (OR 1.050, CI 1.005–1.097) [106].
A subgroup analyses of 1,490 unvaccinated pregnant patients with COVID-19,
GDM alone was not associated with adverse maternal outcomes (OR 1.50,
95% CI 0.8; 2.57) [7].
However, severe sequelae of COVID-19, marked by admission to the ICU, viral
pneumonia, or supplemental oxygen requirement, were independently associated
with GDM in women who were overweight or obese. Outcomes were worse in
patients who required insulin and with GDM diagnosed prior to or
concurrently with a symptomatic SARS-CoV-2 infection.
Post-COVID-19 condition
The WHO developed a clinical case definition of post-COVID-19 condition by a
two-round Delphi process, published October 6, 2021: “Post-COVID-19
condition occurs in individuals with a history of probable or confirmed
SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with
symptoms that last for at least 2 months and cannot be explained by an
alternative diagnosis. Common symptoms include fatigue, shortness of breath,
cognitive dysfunction but also others which generally have an impact on
everyday functioning. Symptoms may be new onset, following initial recovery
from an acute COVID-19 episode or persist from the initial illness. Symptoms
may also fluctuate or relapse over time [107].” In Germany this definition was adopted [108].
We are aware of a Brazilian study with 259 symptomatic cases with COVID-19
during pregnancy leading to an increased frequency of post viral fatigue in
27.8% of women six months after infection [109]. Fatigue’s risk and
duration increased with the severity of symptoms; the symptomatic group
included 3.9% of women with DM.
Psychosocial and public health aspects
Social inequality
Many studies pointed out that ethnic minorities and pregnant women from
socially disadvantaged backgrounds have a higher risk of infection with
SARS-CoV-2. Moreover, a severe course of COVID-19 has been reported more
often. COVID-19 mortality has been registered more than twice in Black,
Hispanic, and indigenous people compared to white people [110]
[111]. Using neighborhood geomapping, a group from Chicago, IL,
USA showed that the disproportionately more common SARS-CoV-2 infection
among Hispanics and Black people can also be found in the underserved
population of pregnant women in disadvantaged neighborhoods of Chicago [112]. Information boards (infographics)
can help pregnant women from a socially disadvantaged background or pregnant
women with limited language skills to understand the correct preventive
behavior and how to deal with their newborns [113].
Social determinants of health
The IRCEP group globally analyzed social and demographic characteristics
associated with COVID-19 severity among 4,231 symptomatic participants
during pregnancy, of these 3,168 currently pregnant and 1,063 recently
pregnant [114]. Developing more severe
COVID-19 was higher in women of lower socioeconomic status: poor OR 2.72
(95% CI 2.01; 3.69), lower middle class OR 2.07 (95% CI
1.62; 2.65) vs. wealthy; in women with lower education attainment, high
school OR 1.68 (95% CI 1.39; 2.03), lower than high school OR 1.77
(95% CI 1.25; 2.51) vs. graduate education. Women over 25
years of age had a lower risk of severe COVID-19 compared to women
35–50 years of age, OR 0.62 (95% CI 0.48; 0.80) vs. OR 0.69
(95% CI 0.56; 0.85). Employment in food service was associated with
increased risk of more severe COVID-19, whereas employment in healthcare and
within the home, and primiparity were associated with lower severity.
Pre-pregnancy health had an influence in a graded manner; compared to
healthy women without any health issues, some health issues with good health
status increased COVID-19 severity with an OR of 1.82 (95% CI 1.49;
2.22), and significant health problems with a fair/poor health
status with an OR of 2.36 (95% CI 1.56; 3.57). Another study of the
IRCEP group with 3,819 participants showed that pregnant women with severe
COVID-19 had an increased risk of depressive symptoms (aRR 1.71; 95%
CI 1.18; 2.52) [115].
Telemedicine
In all forms of DM and GDM, the increased use of telemedicine and online
consultations are helpful if personal contact with the doctor or care team
is not feasible. The consultation time can be optimized by online
transmission of blood glucose results before the appointment. An evaluation
of 16.7 million insured persons in the USA showed that telemedical contacts
could reduce personal contacts by around two thirds during the pandemic
[116]. This also had a positive
effect on the care of ethnic minorities living in districts with high
incidences of infection.
In this respect, the pandemic is also bringing a positive boost to
digitization. Apps on smartphones designed for pregnant women can usefully
complete this approach [117]
[118]. In a systematic review with nine
studies, 480 women with GDM and 494 controls, the authors found that
web-based or app-based interventions may contribute to favorable impacts on
fasting blood glucose and probable less insulin requirements [119]. In a qualitative study with 18
culturally and linguistically diverse women, the researchers showed that a
hybrid flexible model, predominantly telephone consultations with some
face-to-face consultations for diabetes appointments, was best accepted
[120]. The general replacement of
face-to-face appointments with telehealth was perceived as reducing care
quality. A randomized trial with 260 healthy Spanish women studied the
effect of an online supervised exercise program vs. controls to prevent GDM
during the COVID-19 pandemic [121].
The program started with 8–10 weeks of pregnancy reduced GDM in the
intervention group significantly (4.9% vs. 16.8%,
p=0.006), and reduced excessive maternal weight gain (11.8%
vs. 30.7%, p=0.001).
All in all, the telemedicine offer makes an important contribution to
ensuring that pregnant women do not interrupt the continuity of their
pregnancy care, e. g., for fear of infection. Contact could be
continuously maintained, and necessary appointments such as blood tests or
ultrasound examinations could be better arranged and organized. Furthermore,
online supervised interventions early in pregnancy to prevent GDM are
feasible and effective.
