COVID-19, Pregnancy, and Diabetes Mellitus

Abstract

During the severe acute respiratory distress virus coronavirus type 2 (SARS-CoV-2) pandemic, many women were infected during their pregnancies. The SARS-CoV-2-induced coronavirus disease 19 (COVID-19) has an impact on maternal health and pregnancy outcomes; peripartum and perinatal morbidity and mortality are increased. Pregnancy is considered a risk factor for severe COVID-19 course. Additional risk factors during pregnancy are diabetes mellitus, gestational diabetes mellitus (GDM), and obesity. Systemic inflammation can lead to severe metabolic dysregulation with ketoacidosis. The endocrine pancreas is a target organ for SARS-CoV-2 and the fetal risk depends on inflammation of the placenta. Up to now there is no evidence that SARS-CoV-2 infection during pregnancy leads to permanent diabetes in mothers or their offspring via triggering autoimmunity or beta cell destruction. The frequently observed increased prevalence of GDM compared to the years before the pandemic is most likely due to changed lifestyle during lockdown. Furthermore, severe COVID-19 may be associated with the development of GDM due to worsening of glucose tolerance. Vaccination with a mRNA vaccine is safe and highly effective to prevent infection and to reduce hospitalization. Registries support offering evidence-based recommendations on vaccination for pregnant women. Even with the current omicron virus variant, there are increased risks for symptomatic and unvaccinated pregnant women.

Zusammenfassung

Während der Pandemie mit dem Severe acute respiratory distress virus coronavirus type 2 (SARS-CoV-2) infizierten sich viele schwangere Frauen. Die SARS-CoV-2 induzierte Corona virus disease 19 (COVID-19) beeinflusst die mütterliche Gesundheit und die Schwangerschaft; peripartale und perinatale Morbidität und Mortalität sind erhöht. Die Schwangerschaft gilt als Risikofaktor für einen schweren COVID-19-Verlauf. Darüber hinaus sind Diabetes mellitus, Gestationsdiabetes mellitus (GDM) und Adipositas weitere Risiken. Die systemische Inflammation kann zu schweren Stoffwechselentgleisungen mit Ketoazidose führen. Das endokrine Pancreas ist Zielorgan für SARS-CoV-2 und die fetale Gefährdung ist mit Placenta-Inflammation assoziiert. Bis jetzt gibt es keine Beweise, dass eine SARS-CoV-2-Infektion in der Schwangerschaft via Autoimmunität-Triggerung oder β-Zell-Destruktion zu permantem Diabetes bei den Müttern oder ihren Kindern führt. Die oft beobachtete erhöhte GDM-Prävalenz im Vergleich zu den Jahren vor der Pandemie ist am ehesten auf veränderten Lebensstil während des Lockdowns zurückzuführen. Ein schwerer COVID-19-Verlauf ist mit einer Verschlechterung der Glukosetoleranz assoziiert und kann somit einen GDM induzieren. Die Impfung mit einem mRNA-Impfstoff ist sicher und hoch effektiv zur Infektionsprophylaxe und Reduktion von Hospitalisierungen. Register haben dazu beigetragen, für schwangere Frauen faktengestützte Impfempfehlungen auszusprechen. Auch unter der aktuellen Omikron Virusvariante bestehen für symptomatisch erkrankte und ungeimpfte schwangere Frauen erhöhte Risiken.

Key words

SARS-CoV-2 - Pregnancy - Diabetes mellitus - Pandemic

Schlüsselwörter

SARS-CoV-2 - Schwangerschaft - Diabetes mellitus - Pandemie

Abbreviations

ACE2 Angiotensin converting enzyme 2

AGE Advanced glycation endproducts

BMI Body mass index

CDC Center of Disease Control and Prevention

CI Confidence interval

CT Computerized tomography

DM Diabetes mellitus

ECMO Extracorporal membrane oxygenation

EDKA Euglycemic diabetic ketoacidosis

FFP-2 Filtering face piece 2 (EN 149:2001)

FT1DM Fulminant type 1 diabetes mellitus

GAD Glutamatdecarboxylase

GDM Gestational diabetes mellitus

GWG Gestational weight gain

HAPO Hyperglycemia and Adverse Pregnancy Outcomes

HR Hazard ratio

IADPSG International Association of Diabetes in Pregnancy Study Groups

ICU Intensive care unit

mRNA Messenger ribonucleotide acid

NICU Neonatal intensive care unit

NIH National Institutes of Health

OGTT Oral glucose tolerance test

OR Odds ratio

RAGE Receptor of advanced glycation endproducts

RR Relative risk

RT-PCR Real time polymerase chain reaction

SARS-CoV-2 Severe acute respiratory distress virus coronavirus type 2

T1DM Type 1 diabetes mellitus

T2DM Type 2 diabetes mellitus

UPMC University of Pittsburgh Medical Center

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.

Conclusion and outlook

The SARS-CoV-2 pandemic has now lasted for more than 3.5 years. The initially apocalyptic landscape is in the past. A sense of “life as normal” has returned in many countries, with global mobility moving towards pre-pandemic status. However, this does not apply equally in all countries. The interaction between science and politics has often shown dissonance; science itself has repeatedly given up recognized regulations for serious publication and flooded the public with unverified facts. Social media and conspiracy theories have also contributed to insecurity and vaccination hesitancy, especially in pregnancy.

In addition to the usual risk factors for a severe course of COVID-19, such as obesity or pre-existing diabetes, pregnancy is confirmed to be an independent risk factor for increased morbidity and mortality. Risks to mothers and their newborns increase when women with pre-existing diabetes become pregnant, or women who are overweight or obese develop GDM during pregnancy or if they are treated with insulin, and if COVID-19 occurs at or shortly after GDM diagnosis. Hyperglycemia or ketoacidosis on hospital admission is also a risk factor per se. To be a member of an ethnic minority and living in precarious social conditions has an unfavorable influence on the development and progression of the disease. Studies in which DM or GDM were specifically investigated are rare but indirect conclusions could be drawn if diabetes cases were included in the cohorts or subgroup analyses were performed. Future registries with pregnant women and SARS-CoV-2 infection should include a matched comparison group without infection from the beginning in order to reliably compare clinically relevant outcomes. Policy makers should take the opportunity to build and promote structures for this purpose in order to be better prepared in the future.

The rapid development and approval of vaccines against COVID-19, especially the mRNA vaccines, can be considered a success story. With the start of the global vaccination programs from December 2020, large parts of the population were vaccinated, in Germany 85.5% of the population, reaching herd immunity. However, the vaccination rates in pregnant women are still significantly lower, e. g., 21.4% of 383 women with GDM and SARS-CoV-2 infection or COVID-19 in the CRONOS registry since vaccination has been available (submitted for publication).

We have learned some lessons from the pandemic. Pregnant women with DM or GDM are a vulnerable group, and women are concerned about their children in the event of an infection. The probability of a next virus pandemic should not be trivialized, either due to new viruses or dangerous SARS-CoV-2 variants. The registry structures that have been set up can be restarted immediately, if necessary, and comparison groups should be added. In addition, telemedicine and digitization of health record data and blood glucose results allow the continuous care of pregnant women with all forms of DM and GDM without interruption, and to discuss and mitigate fears and worries.

Meanwhile, the SARS-CoV-2 virus mutants have weakened in their pathogenic effect, and the risks for pregnant women are no longer as high as at the beginning of the pandemic. However, the omicron dominants are still a cause for concern among symptomatic and unvaccinated women [122]. For this reason, vaccination is indispensable now and in the future because the effect of pharmacotherapy in case of infection is still limited. Currently, in June 2023, the extremely contagious omicron variant XBB.1.5 is on the rise in Germany and is already dominant in the USA. We do not know yet whether this will lead to serious COVID-19 in pregnant women, but if it does, we will register it soon.

Conflict of Interest

The authors declare that they have no conflict of interest.

Contributors' Statement

All authors are members of the CRONOS research network. H.J.K. and U.P. prepared the first draft of the manuscript. K.S.W. and T.P.L. assisted in literature search and plausibility checks of study data. U.S-G., T.G., and M.R. assisted in interpretation of study results. All authors edited, reviewed, and approved the manuscript and made suggestions to its final content. This review received no funding.

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Publication History

Received: 24 June 2023

Accepted after revision: 06 September 2023

Article published online:
02 November 2023