SARS-CoV-2 in diabetic pregnancies: a systematic scoping review

Currently, we face two pandemics at the same time. On the one hand, we suffer from an increasing diabetes mellitus (DM) pandemic and on the other hand from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. By focusing on the WHO, 67,530,912 million people are diagnosed with COVID-19, globally, including 1,545,140 deaths deaths (as of December 09, 2020) [1]. Already at the beginning of the SARS-CoV-2 pandemic, it was quickly assumed that certain groups such as elderly, pregnant women and those with multiple or chronic comorbidities, such as diabetes mellitus, are more likely to get infected and are at increased risk to suffer from a severe course of Coronavirus Disease 2019 (COVID-19)[2‐4]. Hence, pregnant women become a particularly vulnerable group if they are diagnosed with diabetes mellitus and are also infected with the novel corona virus. Very up to date, there are serious concerns regarding potential adverse effects on maternal, fetal, and neonatal outcomes [5] and that SARS-CoV-2 might be vertically transmitted [6]. Therefore, diabetic pregnancies clearly need special care, but, clinical implications of COVID-19 are currently unknown [7].

Referring to the International Diabetes Federation (IDF), 463 million people are diagnosed with diabetes mellitus in 2019, worldwide [8]. National and international scientific committees call diabetes mellitus a metabolic pandemic [9‐11], which is clearly associated with increased comorbidities and complications, such as obesity, Metabolic Syndrome (MetS), cardiovascular disease (CD), increased morbidity, hospitalizations, mortality as well as emerging costs for the global health system, in general [9]. In the context of the diabetes pandemic, pregnancies complicated by diabetes are occurring worldwide, with the result that hyperglycemia in pregnancy (HIP) has the fastest growing prevalence. In 2019 and with reference to the IDF, approximately 20 million (16%) of live births suffered from some form of HIP [8]. Looking closer, approx. 84% of HIP were defined as gestational diabetes mellitus (GDM), approx. 7.9% were diagnosed prior to pregnancy with type 1 diabetes (T1D) and type 2 diabetes (T2D), and approximately 8.5% were first observed with T1D and T2D in pregnancy [8]. Depending on the country, the prevalence of GDM ranged between approximately 2.1% and approximately 37.5% in 2019 [8]. In Europe, the prevalence of GDM is estimated at about 16.3%, whereas the prevalence in North America and Caribbean is approximately 20.8%, and 27.0% in South East Asia [8]. In all cases, the estimated number of unreported cases is not included. Moreover, GDM is mostly diagnosed in the second or third trimester and defined as not clearly overt diabetes prior to gestation [12]. Although there are various regional variations and different screening and diagnosis guidelines worldwide, risk factors leading to GDM, such as maternal age, obesity, rising gestational weight gain, seem to be the same, globally [13, 14]. Gestational diabetes mellitus is clearly associated with adverse pregnancy and birth (short-term) outcomes for mother and offspring, e.g. increased risks of preeclampsia, hypoxia, caesarean sections, macrosomia and shoulder dystocia, hypoglycemia [13, 15]. Furthermore, GDM is closely associated with adverse long-term outcomes in mothers and children, such as a subsequent increased risk of T2D, obesity, MetS and CD or even depression [15‐17].

Having the concepts and mechanisms of trans-generational programming (“fetal, perinatal and in utero programming”) in mind, intra-uterine exposure to increased levels of hyperglycemia “program” the offspring for life-long consequences to e.g. obesity, glucose intolerance, T2D, insulin resistance, MetS, high blood pressure, CD early on [18‐24]. In a side note, trans-generational programming (or “fetal programming”, “perinatal programming”), means a perturbation during prenatal development phase, which may lead to dysfunctions in organs and metabolic regulation, that, in turn, might lead to life-long diseases like impaired glucose intolerance (IGT), DM, obesity, MetS, CD, etc. in later life [21, 22, 24‐26]. These life-long consequences may be “programmed” during (pre-)gestation by different molecular mechanisms, such as pro-inflammation, hypoxia, oxidative stress, over- or underexpression of transporters and enzymes, dysbalance in hormone production as well as epigenetic modifications, such as Histone modification and DNA methylation, based on changes in the intra-uterine milieu (Fig. 1) [22].

Analyzes of the transgenerational and complex interplay of COVID-19, diabetes mellitus and pregnancy are urgently needed. The purpose of this systematic scoping review was to summarize the current literature on SARS-CoV-2 in diabetic pregnancies, including identification of novel potential pathophysiological mechanisms and interactions as well as clinical outcomes and features, screening, and management approaches.

We identified n = 1,938 citations without duplicates for COVID-19 and Diabetes Mellitus, n = 985 for COVID-19 and pregnancy, n = 70 for COVID-19 and GDM/diabetic pregnancies. In total, we screened n = 3,003 citations based on titles/abstracts (n = 10 were added through manual research), and selected n = 49 articles based on our eligibility criteria. The PRISMA flow chart is shown in Supplementary Figure 1. Supplementary Table 2 provides a list of the included studies.

Although various COVID-19 registers have already been set up (CRONOS – COVID-19 Related Obstetric and Neonatal Outcome Study, Germany; COVID-19 PRIORITY – Pregnancy CoRonavIrus Outcomes RegIsTrY, USA; COVID-NET – A Weekly Summary of U.S. COVID-19 Hospitalization Data, USA; New Zealand Registry of Covid-19 in Pregnancy; CHOPAN –Coronavirus Health Outcomes in Pregnancy and Newborns, Australia; PregCOV-19LSR – COVID-19 in Pregnancy Living Systematic Reviews, UK), the published data are currently insufficient. In general, pregnant women with diabetes mellitus are more likely to get infected and are at an increased risk of a severe course of COVID-19. The prognosis of pregnant women with DM and COVID-19 may be associated with potential underlying mechanisms such as a simplified viral uptake by ACE2, a higher basal value of pro-inflammatory cytokines, being hypoxemic as well as platelet activation, embolism, and preeclampsia. In the context of “trans-generational programming” and COVID-19, life-long consequences may be “programmed” during gestation by pro-inflammation, hypoxia, over- or under-expression of transporters and enzymes, and epigenetic modifications based on changes in the intra-uterine milieu. Furthermore, first evidence suggests that COVID-19 may cause new onset diabetes mellitus, and that vertical transmission from mother to baby might be possible. Given the challenges in clinical management, the complex and trans-generational interplay between COVID-19 and diabetic pregnancies, further research and evidence-based recommendations are urgently needed. Moreover, digital medicine is a future-oriented and effective approach in the context of clinical diabetes management, particularly in the face of the current syndemic, the possibilities of which we need to better understand and analyze.

One limitation is the language restriction. Since this is a special and rapidly developing topic, we have included different article types such as comments, letters, etc. and generally many different study designs. Since there is only a small amount of literature on the topic so far, we have decided on a systematic scoping review, which makes it possible to show a broad range of evidence regardless of quality and type and serves as an overview and starting point for further research in the individual subtopics. Further research is urgently needed to understand the mechanisms, epidemiology, and health care systems and infrastructures needed to most effectively prevent, diagnose and treat women with SARS-COV-2 and diabetes in pregnancy.