|
 
 |
| REVIEW ARTICLE |
|
| Year : 2022 | Volume
: 10
| Issue : 1 | Page : 68-75 |
|
Gestational diabetes mellitus and preeclampsia: An increased risk to COVID-19?
Sayuri Padayachee1, Nalini Govender2, Thajasvarie Naicker1
1 Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of Kwazulu-Natal, Durban, Kwazulu-Natal, South Africa
2 Department of Basic Medical Sciences, Faculty of Health Sciences, Ritson Campus, Durban University of Technology, Durban, Kwazulu-Natal, South Africa
| Date of Submission | 08-Dec-2021 |
| Date of Decision | 13-May-2022 |
| Date of Acceptance | 18-May-2022 |
| Date of Web Publication | 23-Jun-2022 |
Correspondence Address:
Prof. Thajasvarie Naicker
Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Private Bag 7, Congella, Durban, KwaZulu-Natal, 4013
South Africa
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/amhs.amhs_288_21
Both gestational diabetes and preeclampsia (PE) are characterized by anti-angiogenic response, endothelial injury, and dysfunction of the maternal vasculature. The ensuing high blood pressure emanates from a renin-angiotensin-system imbalance. The angiotensin-converting enzyme 2 (ACE2) receptor has been implicated in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) entry, and emerging data are in favor of PE development in pregnant women with COVID-19 infection. This review examines the effects of SARS-CoV-2 infection in pregnant women with gestational diabetes mellitus and/or preeclampsia (PE). An online search of all published literature was done through PubMed, Google Scholar, Medline complete, The Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, using the MeSH terms “COVID-19,” “SARS-CoV-2,” “coronavirus,” “gestational diabetes,” “hyperglycemia” and “preeclampsia.” Only articles that were directly applicable to gestational diabetes and PE in COVID-19 was reviewed. We report that up-regulation of ACE2 leads to the overexpression of angiotensin II and AT1 receptor activity (Ang II/AT1). As the damaging effects of Ang II are intensified, SARS-CoV-2 stimulates ACE2 placental activity and Ang II-mediated sFlt-1 expression may contribute to the endothelial damage in SARS-CoV-2 infection through increasing Ang II/AT1 receptor interaction and/or hypoxia-inducible factor-1. This review provides an insight into the association between SARS-CoV-2 infection, gestational diabetes, and PE. As a result of the shared pathogenic traits, we assume that the anti-angiogenic milieu in high-risk pregnancies aggravates the susceptibility of a pregnant woman to high COVID-19 morbidity and mortality. In light of the growing burden of COVID-19 on global health-care systems, we highlight the urgency for appropriate management, treatment, and educational strategies to effectively control glycemic index in pregnancy. Keywords: COVID-19, gestational diabetes mellitus, hyperglycemia, preeclampsia, SARS-CoV-2
How to cite this article:
Padayachee S, Govender N, Naicker T. Gestational diabetes mellitus and preeclampsia: An increased risk to COVID-19?. Arch Med Health Sci 2022;10:68-75 |
How to cite this URL:
Padayachee S, Govender N, Naicker T. Gestational diabetes mellitus and preeclampsia: An increased risk to COVID-19?. Arch Med Health Sci [serial online] 2022 [cited 2022 Aug 17];10:68-75. Available from: https://www.amhsjournal.org/text.asp?2022/10/1/68/347964 |
| Introduction | |  |
The novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in December 2019 and continues to remain a global threat in 2022. The SARS-CoV-2 enters the human host by binding to angiotensin-converting enzyme 2 (ACE2) receptors with a 10–20 times greater affinity than SARS-CoV-1.[1] The ACE2 receptor is abundantly expressed in human alveolar epithelial cells of the lung and endothelial cells of almost every organ in the body.[2]
SARS-CoV-2 infection commonly occurs asymptomatically or in a mildly symptomatic form. In predisposed patients, the risk of severe infection is increased.[3] Moreover, comorbidities such as hypertension, diabetes, and cardiovascular diseases (CVD) predispose infected patients to the development of severe disease or death. Singh et al., in 2020, pooled data from 10 different Chinese studies involving patients with COVID-19 and reported the prevalence of hypertension, diabetes, and CVD to be 21%, 11%, and 7%, respectively.[4] Notably, the syndromic nature of diabetes in patients with COVID-19 has resulted in worse outcomes for patients and/or other concomitant comorbidities.[5] In previous respiratory disease, epidemics such as the influenza A virus (H1N1), SARS, and Middle East Respiratory Syndrome, diabetes was also associated with severe disease development and higher mortality rate.[6] Therefore, it is reasonable to assume that women with gestational diabetes have an increased susceptibility to COVID-19 morbidity/mortality than nondiabetic and nonpregnant women.
Pregnancy is associated with a modulated immune response; the SARS infection appears to be strongly associated with severe maternal infection, increased risk of maternal death, and spontaneous abortion.[7] Despite a lack of evidence regarding vertical transmission from mother to baby, the risk and susceptibility to SARS-CoV-2 infection remain a concern in pregnancy. Risk factors for severe COVID-19 are similar to the physiological state of pregnancy than the general population.[8]
The presence of comorbidities such as chronic hypertension, diabetes, gestational diabetes mellitus (GDM), cardiopulmonary diseases, chronic kidney disease stage III–IV, and HIV infection (with < 350 CD4+ T cells) exacerbates the adverse outcomes of COVID-19 infection in pregnancy.[9] This review highlights the potential impact of an abnormal metabolic syndrome in pregnancy and examines the effects of SARS-CoV-2 infection in pregnant women with GDM and/or preeclampsia (PE). A systematic search of the online databases such as PubMed, Medline complete, The Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science was performed using the MeSH terms “COVID-19,” “SARS-CoV-2,” “coronavirus,” “gestational diabetes,” “hyperglycemia,” and “preeclampsia.” Only articles that were directly applicable to gestational diabetes and PE in COVID-19 was reviewed. A manual search of the reference lists of relevant publications and reviews was conducted.
| High-Risk Pregnancies: Gestational Diabetes Mellitus and Preeclampsia | | |
Gestational diabetes mellitus is defined as new onset of hyperglycemia in pregnant women without a prior history of diabetes.[10],[11] The International Diabetes Federation indicates a varying global prevalence of GDM, with hyperglycemia in pregnancy affecting almost 21.4 million live births in women aged 16–49 years.[12] A recent systematic review reports a pooled GDM prevalence rate of 13.6% in Africa compared to differing rates of 9%[13] and 14.8%[14] respectively in other sub-Saharan African countries. Pregnancies complicated by diabetes have a two- to three-fold increased risk of developing hypertensive disorders.[15] In low- and middle-income countries (LMIC), PE is the most common HDP with a prevalence between 1.8% and 16.7%[16] while the global prevalence varies between 0.2% and 9.2%.[17] It is defined as new-onset hypertension after 20 gestational weeks with/without proteinuria and/or multi-organ dysfunction.[18] Studies have shown a correlation between PE and GDM development despite each appearing as unrelated disease entity with specific diagnostic criteria.[19],[20] Both conditions share common risk factors including advanced maternal age, nulliparity, multiple gestation pregnancies, and an increased prepregnancy body mass index.[19] More recently, a higher frequency of PE development in pregnant women with COVID-19 was reported.[20]
Women with GDM have an increased risk of PE development since the underlying pathophysiology shared by both conditions is vascular endothelial dysfunction.[21] The effects of an increased state of insulin resistance (IR) characterized by inflammation, oxidative stress and an angiogenic imbalance, in gestational diabetes contributes to maternal endothelial abnormalities and consequent PE development.[22] Therefore, preexisting vascular dysfunction may accelerate the risks and outcomes of COVID-19 in pregnant women as endothelial injury is the final common pathological event in diabetes and IR, hypertension, and dyslipidemia.[23]
Pregnant women with GDM are more likely to have adverse obstetric and neonatal outcomes from viral infections of the respiratory tract, including the SARS-CoV-2.[24] In general, diabetic individuals are also at risk of influenza and pneumonia due to a reduced level of viral clearance. Notably, patients with diabetes develop a severe type of pneumonia with elevated enzymatic levels of lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, alanine aminotransferase, and γ-glutamyl transferase compared to nondiabetic patients.[25] Comparison of a diabetic versus a nondiabetic cohort has revealed an increase in neutrophils (4.1 [interquartile range (IQR), 2.8–6.9] vs. 2.5 [IQR, 1.6–3.7]), C-reactive protein (CRP) (32.8 [IQR, 11.3–93] vs. 16.3 [IQR, 7.17–43.9]), erythrocyte sedimentation rate (67 [47.5–81] vs. 23 [10–49]), as well as D-dimer coagulation (1.15 [IQR, 0.83–2.11] vs. 0.54 [0.25–1.1]) parameters.[25] In pregnancy, systemic inflammation is also evident, while in severe PE, amplified inflammation, and coagulatory events affect endothelial function.[26] In pregnancies infected with SARS-CoV-2, endothelial injury is induced by hypercoagulation caused by plasminogen activator inhibitor 1 (PAI-1).[26] Thus, thromboembolic events associated with SARS-CoV-2 in pregnancy and PE exacerbates poor maternal outcome.
These findings are indicative of defective innate and adaptive immune responses, with concomitant elevated susceptibility to infection.[27] The inflammatory response to viral infections in diabetic patients is also associated with an increased risk of a cytokine storm.[28] This risk of infection may be reduced slightly by adequate glycemic control through frequent monitoring of blood glucose levels[6] since mismanagement of glycemic control impairs the immune response.[28]
| Establishing the Links between Gestational Diabetes, Preeclampsia, and COVID-19 | | |
Angiotensin-converting enzyme 1/angiotensin-converting enzyme 2 imbalance
As a central regulator of the systemic renin-angiotensin-system (RAS), ACE2 plays a crucial role in maintaining electrolyte and fluid homeostasis. The RAS enzymatic cascade is centralized around the conversion of angiotensin-II (Ang II) by ACE to angiotensin 1-7 (Ang 1-7). Ang II exerts oxidative, pro-inflammatory, and vasoconstrictive effects through its affinity to AT1 and AT2 receptors.[29] Ang 1-7 binds to the Mas receptor (MasR) and opposes the effects of the ACE2-Ang II-AT1/2 system by mediating anti-oxidant, anti-inflammatory, and vasodilatory effects.[29]
The SARS-CoV-2 binds to ACE2 and reduces ACE2 mediated conversion of Ang II to Ang 1-7 resulting in an ACE1/ACE2 imbalance [Figure 1]. The up-regulation of ACE2 receptors promotes Ang II formation with the concurrent degradation of Ang 1-7 and subsequent decrease in ACE2 expression.[30] A study by Yang et al., in 2020, showed increasing concentrations of circulating Ang II peptides with higher SARS-CoV-2 viral load.[31] The down-regulation of ACE2 and its subsequent anti-inflammatory effects results in alveolar wall thickening, edema, inflammatory infiltration, and bleeding in patients with COVID-19.[5] | Figure 1: The effect of SARS-CoV-2 infection, the RAAS and sFlt-1 on endothelial dysfunction in pregnancy.[83] In pregnant women with COVID-19, Ang II and Ang 1-7 are dysregulated. In PE, Ang II type I receptor AA that binds to AT1, which increases sFlt-1, PAI-1, reactive oxygen species, tissue factor and NADPH through excess AT1-receptor activation. Ang II/AT1 limits trophoblast invasion through TGF-β1 and PAI-1. Excess sFlt-1 levels in PE downregulates the bioavailability of VEGF and PlGF, which is further exacerbated in SARS CoV-2 infection, causing endothelial injury. SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2, AA: Agonistic autoantibody, TGF-β1: Transforming growth factor-β1, PAI-1: Plasminogen activator inhibitor-1. PE: Preeclampsia
Click here to view |
| Glycemic Control in the Context of COVID-19 | | |
The ensuing metabolic disturbance of COVID-19 may emanate from the severe state of IR and decreased insulin secretion as a result of the direct effect of ACE2 on pancreatic β-cell dysfunction.[32] Due to the high expression of ACE2 receptors in pancreatic islets, SARS-CoV-2 injures β-cells cause acute insulin-dependent diabetes mellitus.[33] During the early stages of the COVID-19 pandemic in the United Kingdom, a large number of patients with COVID-19 developed diabetic ketoacidosis or hyperglycemia, and in some cases both.[32] Acute hyperglycemia up-regulates cellular expression of ACE2 thus facilitating SARS-CoV-2 viral entry. In contrast, chronic hyperglycemia down-regulates ACE2 expression and increases cell susceptibility to the virus by inducing cellular damage, hyperinflammation, and respiratory distress.[34] In addition, chronic hyperglycemia and diabetes mismanagement are linked to defective T-cell activity with alterations in lymphocyte proliferation and impaired functioning of neutrophils and macrophages.
Lymphocytopenia has been reported in COVID-19-positive patients and correlates with prognosis.[35] There is a lack of published data on the risks of COVID-19 infection in patients with type 1 diabetes or gestational diabetes, however, the outcomes are unlikely differ from type 2 diabetes. In fact, type 1 diabetics have an increased predisposition of developing acute hyperglycemia.[28] At the onset of infection, hyperglycemia in the pulmonary vasculature increases viral replication of the influenza virus, however, viral replication is significantly reduced after cellular treatment with glycolytic inhibitors.[36] Therefore, one can expect glucose abnormalities and poor diabetes control to increase susceptibility to SARS-CoV-2 infection with resultant increased complications and adverse outcome.
| Preeclampsia Development and COVID-19 | | |
An increased incidence of PE has been observed in pregnant women with COVID-19.[7],[37] SARS-CoV-2 infection induces endotheliitis in several organs resulting in endothelial cell infection and immune cell-mediated endothelial cell injury.[20] Notably, endothelial cell injury is the hallmark of PE development, however COVID-19 endotheliitis may initiate microvascular dysfunction characterized by vasoconstriction and subsequent ischemia.[20] The resultant coagulation abnormality and vascular damage significantly mimics the pathogenic model of PE. Moreover, an exacerbated hypercoagulable state in PE has also been reported in COVID-19.[38] In patients with more severe disease, the hypercoagulable state promotes macro- and micro-vascular thrombosis.[39] It is evident that the SARS-CoV-2 pathophysiology is a parodist of PE; hence a risk factor for COVID-19 infection.
Inflammation is concomitant with PE development; an increased expression of inflammatory markers, tumor necrosis factor-α, interleukin-6 and CRP can cause IR.[40] Increased IR consequently leads to dyslipidemia characterized by low high-density lipoprotein, increased triglycerides, and postprandial lipemia.[41] In PE, dyslipidemia can aggravate placental ischemia resulting in a vicious cycle of ischemia-inflammation-IR-dyslipidemia-ischemia.[42] The immune response observed in COVID-19 is similar to that of GDM and PE, therefore pregnant women with GDM and/or PE may have an increased susceptibility to COVID-19 infection during pregnancy [Figure 2]. More recently, a case of second trimester COVID-19-associated PE and SARS-CoV-2 infection was associated with an increased SARS-CoV-2 invasion of the placental intervillous macrophages.[37] These findings suggest that SARS-CoV-2 infection contributes to placental inflammation and consequent development of early-onset PE.[37] | Figure 2: Schematic diagram of the role of SARS-CoV-2 in pregnancy complicated by gestational diabetes mellitus and PE development. In pregnancy, increased ACE2 receptor activity has a direct effect on pancreatic β-cell function resulting in heightened immunity and insulin resistance with enhanced hyperglycaemia. Oxidative stress, hypoxia, endothelial dysfunction, and potential acute respiratory distress syndrome follows. SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2, ACE2: Angiotensin-converting enzyme 2
Click here to view |
| Ang II-Mediated sFlt-1 Expression in PE and COVID-19 | | |
The female reproductive system represents a large source of ACE2 expression, with the placenta expressing a two-fold increase in total ACE2 activity compared to other reproductive organs.[43] These data are consistent with the findings of the transient overexpression of ACE2 for modulating local hemodynamics during pregnancy.[43] ACE2 expression increases throughout pregnancy with increased expression already at 24 gestational weeks.[44] The local generation of Ang II by placental ACE2 activates AT1 receptors on trophoblast cells.[45] Ang II influences vasoconstriction, angiogenesis, and cell growth in normal pregnancy through Ang II/AT1 interaction.[46] Ang II contributes to the pathology of hypertension and atherosclerosis by promoting the growth of vascular smooth muscle cells which in turn induces cellular hypertrophy.[47]
In women with PE, circulating Ang II is not increased however, sensitivity to Ang II is exaggerated as demonstrated by an overexpression of the AT1 receptor, compared to normotensive pregnant women.[48] As a result, Ang II/AT1 limits trophoblast invasion via transforming growth factor-β1 and plasminogen activator inhibitor-1 (PAI-1) dysregulation [Figure 1]. Placental RAS may therefore be a key mediator in placental angiogenesis and trophoblast invasion.[46] Interestingly, excessive sFlt-1 plasma levels in COVID-19 infected patients correlate with respiratory symptom severity, endothelial dysfunction, and elevated incidence of organ failure,[49] similar to that demonstrated in PE.[50] In pregnant women with COVID-19, the pathological imbalance between Ang II and Ang 1-7 under hypoxic conditions results in an increased sFlt-1/PlGF ratio [Figure 1].[51] Under hypoxic conditions, hypoxia-inducible factor-1 regulates sFlt-1 expression, and increase with concomitant sFlt-1 expression.[52] These observations offer an explanation for the increased sFlt-1/PlGF ratio in COVID-19, providing a strategy for assessing the direct effects of endothelial dysfunction on PE development and severity of SARS-CoV-2 infection.
An earlier study investigating Ang II-mediated sFlt-1 levels in pregnant versus nonpregnant mice after Ang II infusion, demonstrated a significant Ang II-induced sFlt-1 elevation in pregnant mice at gestational day 15 in contrast to nonpregnant mice, through the AT1 receptor and calcineurin pathway.[53] This group further suggests that Ang II may positively regulate the synthesis and release of sFlt-through its interaction with the AT1 receptor, indicative of a regulatory role for Ang II/AT1 in modulating circulating sFlt-1in pregnancy. Excess sFlt-1 increases angiotensin sensitivity thereby reducing phosphorylation of endothelial nitric oxide (NO) synthase. Consequently, NO formation is decreased with a concomitant increase in oxidative stress.[54] These findings may also explain the increased sFlt-1 observed in PE since preeclamptic women carry an Ang II type I receptor agonistic autoantibody (AA) that binds to AT1. The AT1-AA increases the levels of sFlt-1, PAI-1, reactive oxygen species, tissue factor, and NADPH through excess AT1-receptor activation,[55] thereby enhancing the anti-angiogenic state of PE through endothelial dysfunction [Figure 1].
Similar to PE, COVID-19 also down-regulates ACE2 expression while ACE2 receptor activity is enhanced.[56] The increased ACE2 receptor activity in placental cells namely the extravillous trophoblast, syncytiotrophoblast, and cytotrophoblast cells presents the possibility of placental infection by SARS-CoV-2 and the high binding affinity of SARS-CoV-2 to ACE2 with resultant placental dysfunction and pregnancy complications.[1]
ACE2 down-regulation stimulates Ang II/AT1 interaction and subsequently promotes inflammation and oxidative stress by inducing the production of ROS in vascular smooth muscle cells.[57] The resultant vascular endothelial injury is similar to the pathogenic outcomes of the maternal syndrome of PE, therefore women with PE may have an increased susceptibility for SARS-CoV-2. Ang II/AT1 also modulates insulin levels by directly affecting insulin secretion from pancreatic islets.[57] Insulin signaling is affected as the Ang II/AT1 interaction stimulates multiple serine phosphorylation of the insulin receptor β-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase of the insulin signaling cascade.[58] The overexpression of AT1 stimulates the release of endothelial ET-1, ROS production through NADPH oxidase and leads to an increased expression of ICAM-1 [Figure 2].[59] Therefore, as a regulator of insulin signaling, Ang II can directly and indirectly affect IR and endothelial dysfunction, creating a vulnerable environment for SARS-CoV-2 infection in pregnant women with gestational diabetes or PE.
| Management Strategies for Pregnancies at High Risk for COVID-19 | | |
Despite limited data on the impact of COVID-19 in pregnant women with diabetes and high blood pressure, it is plausible that these women are more vulnerable to infection compared to healthy pregnant women. As a result of the overburdened health-care settings in LMICs, pregnant women with diabetes remain largely underdiagnosed, subsequently, the background prevalence of GDM cannot be truly estimated.[60]
The traditional first-line treatment for GDM is insulin therapy, however, in LMIC, access to insulin treatment and medical therapies may be limited due to cost factors and restricted health services. In such settings, medical nutrition therapy (MNT) may be an alternative to insulin therapy on timely diagnosis of diabetes in pregnancy. For prevention of SARS-CoV-2 in pregnant women with GDM or PE, an intense clinical MNT plan should be implemented to include frequent blood glucose and pressure monitoring, dietary and lifestyle changes, stress management, and optimized cardio-metabolic control.[28],[34] In the event that MNT fails to improve glycemic control, the administration of oral agents (metformin; glyburide) are the next line treatment.[61] Pregnant patients who display a dry cough, excessive sputum production, onset of fever (38.1°C–39.0°C), or a sudden increase in blood glucose level should be advised to immediately consult their physician.[62]
Furthermore, the use of drugs for viral infections in pregnancy and intensive care support for women with high-risk pregnancies remains an urgent priority, especially in the context of COVID-19.[63] Taking these obstetric predicaments into account, it remains obvious that pregnant women should be included in vaccination programs specifically designed for the immune alterations. The COVID-19 vaccination may decrease the risk of contracting severe disease as well as reduce maternal mortality.[62],[64] Noteworthy, pregnant women should be informed of the risks and benefits of vaccination by their clinicians prior to consent.
Glycosylated hemoglobin (HbA1c) is a useful indicator in the diagnosis and prevention of diabetes, reflecting glycemic levels before the onset of infection.[65] It quantifies glycated hemoglobin as an indicator of blood glucose control over a 3-month period, however, its clinical value across the trimesters of gestational diabetes is controversial due to increased red cell turnover.[66],[67],[68] Nonetheless, current clinical practice recommendations of the American Diabetes Association suggest that glucose levels should ideally be close to normal at HbA1C <6.5% (48 mmol/mol) for pregnant women.[69] A simple HbA1c estimate at the onset of COVID-19 infection may be useful for the prognosis of diabetes and/or control of hyperglycemia in the first trimester of pregnancy.[60] All suspected COVID-19 cases during pregnancy require consistent screening and long-term pre-natal follow-up.[70] In addition, nondiabetic pregnant women who may have tested positive for the virus should be monitored for new-onset GDM, which may be initiated by SARS-CoV-2.[34]
Controversies exist regarding the use of ACE inhibitors (ACEi) and Ang II receptor blockers (ARB) in SARS-CoV-2-infected patients.[71] ACE2 levels are augmented by both drugs and demonstrate the potential to either reduce inflammation associated with SARS-CoV-2 infections or amplify viral entry into host cells.[72],[73] For example, Enalapril, a well-known ACEi elevates kidney expression of ACE2[74] whereas lisinopril and losartan in combination increase ACE2 and downregulate cardiac Ang II plasma levels.[75] Moreover, ACEi and ARB-induced ACE2 elevations correlate with the use of anti-diabetic drugs. Large-scale clinical studies are however required to expand our understanding regarding the amplified ACE2 levels, and the molecular mechanisms involved in the SARS-CoV-2 etiology in pregnancy and HDP.
A recent study observed a PE-like syndrome induced by COVID-19 in 42 pregnant women (66). Notably, PE and the hemolysis, elevated liver enzymes, low platelet count syndrome were identified in 62.5% of cases.[76] Previous reports indicate that several disorders imitate the syndromic nature of PE due to similarities in clinical and laboratory findings (viz., vasospasm, platelet activation, microvascular thrombosis, maternal vascular dysfunction, and reduced tissue perfusion).[77] Angiogenic profiling has proven useful in distinguishing PE from its imitators, as the sFlt-1/PlGF ratio remains highly specific to placental insufficiency.[78] Along with COVID-19 screening of pregnant women, the sFlt-1/PlGF ratio should be utilized as a diagnostic measure for the early detection of PE to decrease the risk of developing COVID-19 infection.
It is essential that pregnant women receive screening procedures to identify and manage high-risk pregnancies with placental complications. As PE is a high-risk factor for women with gestational diabetes, a low-dose aspirin regimen (LDA; 60–150 mg/day (usual dose 81 mg/day) should be administered at 12 gestational weeks as a preventative measure and continued until delivery.[69],[79] The usage of nonsteroidal anti-inflammatory drugs (NSAIDs) including LDA and ibuprofen is controversial for COVID-19 treatment.[80] Nonetheless, NSAIDs have been implicated in delaying pathogen clearance during infection and modifying neutrophil function.[81] However, currently, there is no available data to confirm a negative association between LDA and the risk of disease progression of SARS-CoV-2. It is also possible that the benefits of LDA intake in PE prevention outweighs the risk of adverse outcome in relation to COVID-19 infection.[82]
| Conclusion | | |
Pregnant women with gestational diabetes mellitus and PE have their increased susceptibility to COVID-19 infection. In this synergy, Ang II regulates insulin signaling thereby affecting IR and endothelial dysfunction, creating a vulnerable environment. Furthermore, ACE2-mediated placental damage, oxidative stress, the anti-angiogenic state, and an exaggerated immune response create a vulnerable system for attack by SARS-CoV-2. In light of the regulatory roles of the RAS in pregnancy and in SARS-CoV-2 infection, it is likely that an up-regulation of the ACE2 receptor and resultant overexpression of the Ang II/AT1 receptor cascade contributes to the vascular endothelial damage. Notably, the main pathological feature of GDM, PE, and SARS-CoV-2 is vascular endothelial injury. Since IR and hyperglycemia are strongly associated with vasoconstriction and vascular endothelial dysfunction, effective glycemic control measures must be implemented and closely monitored to improve the prognosis of diabetes in pregnancy. This may prevent the development of PE and subsequent development of SARS-CoV-2 on exposure. Future studies are required to assess the direct effect of SARS-CoV-2 on pancreatic β-cell disease pathology and angiogenic signaling in pregnancy.
Acknowledgments
The authors would like to thank Ms. Girija Naidoo, for her editorial assistance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-3.  |
| 2. | Cristelo C, Azevedo C, Marques JM, Nunes R, Sarmento B. SARS-CoV-2 and diabetes: New challenges for the disease. Diabetes Res Clin Pract 2020;164:108228. |
| 3. | Lisco G, De Tullio A, Giagulli VA, Guastamacchia E, De Pergola G, Triggiani V. Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: A review. Endocrine 2020;70:441-53. |
| 4. | Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr 2020;14:283-7. |
| 5. | Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: Understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol 2020;8:782-92. |
| 6. | Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr 2020;14:211-2. |
| 7. | Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA. Placental pathology in COVID-19. Am J Clin Pathol 2020;154:23-32. |
| 8. | Wastnedge EA, Reynolds RM, van Boeckel SR, Stock SJ, Denison FC, Maybin JA, et al. Pregnancy and COVID-19. Physiol Rev 2021;101:303-18. |
| 9. | López M, Gonce A, Meler E, Plaza A, Hernández S, Martinez-Portilla RJ, et al. Coronavirus disease 2019 in pregnancy: A clinical management protocol and considerations for practice. Fetal Diagn Ther 2020;47:519-28. |
| 10. | Mahdizade Ari M, Teymouri S, Fazlalian T, Asadollahi P, Afifirad R, Sabaghan M, et al. The effect of probiotics on gestational diabetes and its complications in pregnant mother and newborn: A systematic review and meta-analysis during 2010-2020. J Clin Lab Anal 2022;36:e24326. |
| 11. | |
| 12. | International Diabetes Federation. IDF Diabetes Atlas. IBrussels, Belgium: International Diabetes Federation; 2013. |
| 13. | Natamba BK, Namara AA, Nyirenda MJ. Burden, risk factors and maternal and offspring outcomes of gestational diabetes mellitus (GDM) in sub-Saharan Africa (SSA): A systematic review and meta-analysis. BMC Pregnancy Childbirth 2019;19:450. |
| 14. | Muche AA, Olayemi OO, Gete YK. Prevalence and determinants of gestational diabetes mellitus in Africa based on the updated international diagnostic criteria: A systematic review and meta-analysis. Arch Public Health 2019;77:36. |
| 15. | Innes KE, Wimsatt JH. Pregnancy-induced hypertension and insulin resistance: Evidence for a connection. Acta Obstet Gynecol Scand 1999;78:263-84. |
| 16. | Lakew Y, Reda AA, Tamene H, Benedict S, Deribe K. Geographical variation and factors influencing modern contraceptive use among married women in Ethiopia: Evidence from a national population based survey. Reprod Health 2013;10:52. |
| 17. | Umesawa M, Kobashi G. Epidemiology of hypertensive disorders in pregnancy: Prevalence, risk factors, predictors and prognosis. Hypertens Res 2017;40:213-20. |
| 18. | Magee LA, Brown MA, Hall DR, Gupte S, Hennessy A, Karumanchi SA, et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens 2022;27:148-69. |
| 19. | Schneider S, Freerksen N, Röhrig S, Hoeft B, Maul H. Gestational diabetes and preeclampsia-similar risk factor profiles? Early Hum Dev 2012;88:179-84. |
| 20. | Narang K, Enninga EA, Gunaratne MD, Ibirogba ER, Trad AT, Elrefaei A, et al. SARS-CoV-2 infection and COVID-19 during pregnancy: A multidisciplinary review. Mayo Clin Proc 2020;95:1750-65. |
| 21. | Lee J, Ouh YT, Ahn KH, Hong SC, Oh MJ, Kim HJ, et al. Preeclampsia: A risk factor for gestational diabetes mellitus in subsequent pregnancy. PLoS One 2017;12:e0178150. |
| 22. | Baron B. Biochemical dysregulation of pre-eclampsia and gestational diabetes mellitus. London: Intech Open; 2019. |
| 23. | De Lorenzo A, Escobar S, Tibiriçá E. Systemic endothelial dysfunction: A common pathway for COVID-19, cardiovascular and metabolic diseases. Nutr Metab Cardiovasc Dis 2020;30:1401-2. |
| 24. | Moradi F, Ghadiri-Anari A, Enjezab B. COVID-19 and self-care strategies for women with gestational diabetes mellitus. Diabetes Metab Syndr 2020;14:1535-9. |
| 25. | Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev 2020;36:e3319. |
| 26. | Norooznezhad AH, Mansouri K. Endothelial cell dysfunction, coagulation, and angiogenesis in coronavirus disease 2019 (COVID-19). Microvasc Res 2021;137:104188. |
| 27. | Frydrych LM, Bian G, O'Lone DE, Ward PA, Delano MJ. Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality. J Leukoc Biol 2018;104:525-34. |
| 28. | Priya G, Bajaj S, Grewal E, Maisnam I, Chandrasekharan S, Selvan C. Challenges in women with diabetes during the COVID-19 pandemic. Eur Endocrinol 2020;16:100-8. |
| 29. | Alifano M, Alifano P, Forgez P, Iannelli A. Renin-angiotensin system at the heart of COVID-19 pandemic. Biochimie 2020;174:30-3. |
| 30. | Batlle D, Jose Soler M, Ye M. ACE2 and diabetes: ACE of ACEs? Diabetes 2010;59:2994-6. |
| 31. | Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020;63:364-74. |
| 32. | Rayman G, Lumb A, Kennon B, Cottrell C, Nagi D, Page E, et al. Guidance on the management of Diabetic Ketoacidosis in the exceptional circumstances of the COVID-19 pandemic. Diabet Med 2020;37:1214-6. |
| 33. | Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47:193-9. |
| 34. | Bornstein SR, Rubino F, Khunti K, Mingrone G, Hopkins D, Birkenfeld AL, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol 2020;8:546-50. |
| 35. | Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20. |
| 36. | Kohio HP, Adamson AL. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection. Virology 2013;444:301-9. |
| 37. | Hosier H, Farhadian SF, Morotti RA, Deshmukh U, Lu-Culligan A, Campbell KH, et al. SARS-CoV-2 infection of the placenta. J Clin Invest 2020;130:4947-53. |
| 38. | Klok FA, Kruip MJ, van der Meer NJ, Arbous MS, Gommers DA, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-7. |
| 39. | Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thromb Res 2020;194:101-15. |
| 40. | Black KD, Horowitz JA. Inflammatory markers and preeclampsia: A systematic review. Nurs Res 2018;67:242-51. |
| 41. | Goldberg IJ. Clinical review 124: Diabetic dyslipidemia: Causes and consequences. J Clin Endocrinol Metab 2001;86:965-71. |
| 42. | Sonagra AD, Biradar SM, Dattatreya K, Murthy DS. Normal pregnancy – A state of insulin resistance. J Clin Diagn Res 2014;8:CC01-3. |
| 43. | Levy A, Yagil Y, Bursztyn M, Barkalifa R, Scharf S, Yagil C. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integr Comp Physiol 2008;295:R1953-61. |
| 44. | Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One 2020;15:e0230295. |
| 45. | Xia Y, Wen H, Prashner HR, Chen R, Inagami T, Catanzaro DF, et al. Pregnancy-induced changes in renin gene expression in mice. Biol Reprod 2002;66:135-43. |
| 46. | Pringle KG, Tadros MA, Callister RJ, Lumbers ER. The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: Roles in trophoblast invasion and angiogenesis? Placenta 2011;32:956-62. |
| 47. | Miesbach W. Pathological role of angiotensin II in severe COVID-19. TH Open 2020;4:e138-44. |
| 48. | Takeda-Matsubara Y, Iwai M, Cui TX, Shiuchi T, Liu HW, Okumura M, et al. Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change. Am J Hypertens 2004;17:684-9. |
| 49. | Dupont V, Kanagaratnam L, Goury A, Poitevin G, Bard M, Julien G, et al. Excess soluble fms-like tyrosine kinase 1 correlates with endothelial dysfunction and organ failure in critically ill coronavirus disease 2019 patients. Clin Infect Dis 2021;72:1834-7. |
| 50. | Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-58. |
| 51. | Giardini V, Carrer A, Casati M, Contro E, Vergani P, Gambacorti-Passerini C. Increased sFLT-1/PlGF ratio in COVID-19: A novel link to angiotensin II-mediated endothelial dysfunction. Am J Hematol 2020;95:E188-91. |
| 52. | Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A, et al. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 2006;291:R1085-93. |
| 53. | Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, et al. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res 2007;100:88-95. |
| 54. | Burke SD, Zsengellér ZK, Khankin EV, Lo AS, Rajakumar A, DuPont JJ, et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin Invest 2016;126:2561-74. |
| 55. | Irani RA, Xia Y. Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin Nephrol 2011;31:47-58. |
| 56. | Du F, Liu B, Zhang S. COVID-19: The role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness. J Thromb Thrombolysis 2021;51:313-29. |
| 57. | Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141-8. |
| 58. | Chhabra KH, Chodavarapu H, Lazartigues E. Angiotensin converting enzyme 2: A new important player in the regulation of glycemia. IUBMB Life 2013;65:731-8. |
| 59. | Caglayan E, Blaschke F, Takata Y, Hsueh WA. Metabolic syndrome-interdependence of the cardiovascular and metabolic pathways. Curr Opin Pharmacol 2005;5:135-42. |
| 60. | Coetzee A, Taljaard JJ, Hugo SS, Conradie M, Conradie-Smit M, Dave JA. Diabetes mellitus and COVID-19: A review and management guidance for South Africa. S Afr Med J 2020;110:761-6. |
| 61. | Thorkelson SJ, Anderson KR. Oral medications for diabetes in pregnancy: Use in a rural population. Diabetes Spectr 2016;29:98-101. |
| 62. | Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical managementl. Nature Reviews Endocrinology 2021;17:11-30. |
| 63. | Khalil A, Kalafat E, Benlioglu C, O'Brien P, Morris E, Draycott T, et al. SARS-CoV-2 infection in pregnancy: A systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinicalMedicine 2020;25:100446. |
| 64. | Sappenfield E, Jamieson DJ, Kourtis AP. Pregnancy and susceptibility to infectious diseases. Infect Dis Obstet Gynecol 2013;2013:752852. |
| 65. | Kaiafa G, Veneti S, Polychronopoulos G, Pilalas D, Daios S, Kanellos I, et al. Is HbA1c an ideal biomarker of well-controlled diabetes? Postgrad Med J 2021;97:380-3. |
| 66. | Balaji V, Madhuri BS, Ashalatha S, Sheela S, Suresh S, Seshiah V. A1C in gestational diabetes mellitus in Asian Indian women. Diabetes Care 2007;30:1865-7. |
| 67. | Thériault S, Giguère Y, Massé J, Girouard J, Forest JC. Early prediction of gestational diabetes: A practical model combining clinical and biochemical markers. Clin Chem Lab Med 2016;54:509-18. |
| 68. | Hinkle SN, Tsai MY, Rawal S, Albert PS, Zhang C. HbA 1c measured in the first trimester of pregnancy and the association with gestational diabetes. Sci Rep 2018;8:12249. |
| 69. | American Diabetes Association. 14. Management of diabetes in pregnancy: Standards of medical care in diabetes-2020. Diabetes Care 2020;43:S183-92. |
| 70. | Luo Y, Yin K. Management of pregnant women infected with COVID-19. Lancet Infect Dis 2020;20:513-4. |
| 71. | Parit R, Jayavel S. Association of ACE inhibitors and angiotensin type II blockers with ACE2 overexpression in COVID-19 comorbidities: A pathway-based analytical study. Eur J Pharmacol 2021;896:173899. |
| 72. | Aronson JK, Ferner RE. Drugs and the renin-angiotensin system in covid-19. BMJ 2020;369:m1313. |
| 73. | Sun P, Lu X, Xu C, Wang Y, Sun W, Xi J. CD-sACE2 inclusion compounds: An effective treatment for coronavirus disease 2019 (COVID-19). J Med Virol 2020;92:1721-3. |
| 74. | Saheb Sharif-Askari N, Saheb Sharif-Askari F, Alabed M, Tayoun AA, Loney T, Uddin M, et al. Effect of common medications on the expression of SARS-CoV-2 entry receptors in kidney tissue. Clin Transl Sci 2020;13:1048-54. |
| 75. | Ferrario CM, Jessup J, Gallagher PE, Averill DB, Brosnihan KB, Ann Tallant E, et al. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int 2005;68:2189-96. |
| 76. | Mendoza M, Garcia-Ruiz I, Maiz N, Rodo C, Garcia-Manau P, Serrano B, et al. Pre-eclampsia-like syndrome induced by severe COVID-19: A prospective observational study. BJOG 2020;127:1374-80. |
| 77. | Sibai BM. Imitators of severe pre-eclampsia. In: Seminars in Perinatology. Vol. 33. WB Saunders; 2009. p. 196-205. |
| 78. | Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-83. |
| 79. | ACOG Committee Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018;132:e44-52. |
| 80. | FitzGerald GA. Misguided drug advice for COVID-19. Science 2020;367:1434. |
| 81. | Voiriot G, Philippot Q, Elabbadi A, Elbim C, Chalumeau M, Fartoukh M. Risks related to the use of non-steroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. J Clin Med 2019;8:786. |
| 82. | Kwiatkowski S, Borowski D, Kajdy A, Poon LC, Rokita W, Wielgos M. Why we should not stop giving aspirin to pregnant women during the COVID-19 pandemic. Ultrasound Obstet Gynecol 2020;55:841-3. |
| 83. | Kametas NA, Nzelu D, Nicolaides KH. Chronic hypertension and superimposed preeclampsia: Screening and diagnosis. Am J Obstet Gynecol 2022;226:S1182-95. |
[Figure 1], [Figure 2]
|
Search Pubmed for