Predictors of COVID-19 severity among pregnant patients

Authors

  • Marcin Januszewski Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland https://orcid.org/0000-0001-5098-0156
  • Laura Ziuzia-Januszewska Department of Otolaryngology, Central Clinical Hospital of the Ministry of Interior and Administration, Warsaw, Poland https://orcid.org/0000-0002-8839-6489
  • Alicja A. Jakimiuk Department of Plastic Surgery, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland https://orcid.org/0000-0003-0216-8600
  • Tomasz Oleksik Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland https://orcid.org/0000-0002-3904-097X
  • Marek Pokulniewicz Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
  • Waldemar Wierzba Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland; University of Humanities and Economics in Lodz, Satellite Campus in Warsaw, Warsaw, Poland https://orcid.org/0000-0002-8134-2955
  • Krzysztof Kozlowski Department of Constitutional Law, Jagiellonian University in Krakow, Krakow, Poland https://orcid.org/0000-0002-7439-7165
  • Artur J. Jakimiuk Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland; Center for Reproductive Health, Institute of Mother and Child, Warsaw, Poland https://orcid.org/0000-0002-7373-7690

DOI:

https://doi.org/10.17305/bjbms.2022.7181

Keywords:

COVID-19, pregnancy, SARS-CoV-2, clinical course, predictors, disease severity, lymphocytopenia, hypocalcemia, low total protein, inflammation biomarkers

Abstract

Coronavirus disease 2019 (COVID-19) was declared a pandemic and has spread around the globe, unsparingly affecting vulnerable populations. Effective prevention measures for pregnant women, who are particularly affected, include early identification of those patients at risk of developing in-hospital complications, and the continuous improvement of maternal-fetal treatment strategies to ensure the efficient use of health resources. The objective of our retrospective study was to determine which patient biomarkers on hospital admission correlate with disease severity as measured by disease course classification, the need for oxygen supplementation and higher demand for oxygen, the need for mechanical ventilation, intensive care unit admission, and length of hospital stay. Analysis of 52 PCR SARS-CoV-2 positive pregnant women revealed that the median date of hospital admission was the 30th gestational week, with dyspnoea, cough, and fever as the leading symptoms. The presence of diabetes and hypertension predisposed pregnant women to the severe course of illness. Lung involvement shown by CT scans on admission correlated with the greater clinical severity. The main laboratory predictors of disease progression were lymphocytopenia, hypocalcemia, low total cholesterol, low total protein levels, and high serum levels of C-reactive protein, ferritin, interleukin-6, glucose, lactate dehydrogenase, procalcitonin, and troponin I. Further research with a larger cohort of pregnant women is needed to determine the utility of these results for everyday practice.

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Predictors of COVID-19 severity among pregnant patients

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Published

2022-10-23

How to Cite

1.
Januszewski M, Ziuzia-Januszewska L, Jakimiuk AA, Oleksik T, Pokulniewicz M, Wierzba W, Kozlowski K, Jakimiuk AJ. Predictors of COVID-19 severity among pregnant patients. Bosn J of Basic Med Sci [Internet]. 2022Oct.23 [cited 2022Dec.6];22(6):1005-1. Available from: https://bjbms.org/ojs/index.php/bjbms/article/view/7181

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Section

New and Emerging Medical Entities

INTRODUCTION

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is widespread and globally claims more victims with each passing month [1]. As more alarming data about the characteristics of new SARS-CoV-2 variants emerge and as we witness the natural evolution and increased infection rates of COVID-19, it is increasingly important to be able to prioritize critical care services in situations, where the number of patients may be overwhelming. Prenatal care, which is particularly affected, deserves special attention and continuous improvement of its treatment strategies.

The distribution of disease severity in pregnant women is similar to the distribution seen in non-pregnant populations, with 86% of pregnant women manifesting mild disease, 9% severe, and 5% critical [2].

SARS-CoV-2 affects nearly every organ system [3-7], as well as affecting the mental health of both infected and non-infected pregnant women [8]. Leading symptoms include fever (88.7%), cough (67.8%), fatigue (38%), and the over-production of mucus (33.7%) [4]. Severe COVID-19 is characterized by the development of acute respiratory distress syndrome (ARDS), hypotensive shock, and multiorgan failure and requires the patient’s admission to intensive care unit (ICU) and mechanical ventilation [3-5].

Severe disease risk factors include comorbidities, advanced age, male sex, obesity, and genetic predispositions [3,4,5,9]. Severe COVID-19 is mainly an immune-mediated disorder triggered by the SARS-CoV-2 infection promoting excessive inflammation and hypercoagulable states [10].

During pregnancy, physiological adaptations of the respiratory tract, immunomodulation, hypercoagulability, processes that increase insulin resistance, and the development of hypertension, predispose SARS-CoV-2-infected women toward a severe course of illness, leading to maternal and fetal mortality and morbidity [10-14].

Data emerging from meta-analyses in the literature show that pregnant women may have an increased risk of developing severe symptoms and a higher risk of pneumonia, ICU admission, the requirement for invasive ventilation and extracorporeal membrane oxygenation (ECMO), and death [15-17].

Moreover, serious adverse outcomes have been observed among pregnant women with previous coronavirus infections, namely, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [18], influenza [19,20], and respiratory syncytial virus [21].

There is currently no prognostic biomarker available to identify pregnant patients who are at imminent risk of a severe course of COVID-19, with all associated maternal and fetal complications, and who require immediate medical attention.

The objective of our study was to determine to determine, in which patient characteristics and laboratory results on hospital admission correlate with disease severity as measured by disease course classification, the need for oxygen supplementation and higher demand, the need for mechanical ventilation, ICU admission, and length of hospital stay.

MATERIALS AND METHODS

Study population

This retrospective single-center study was undertaken in the Department of Obstetrics and Gynecology, at the Central Clinical Hospital of the Ministry of the Interior and Administration in Warsaw, Poland. The study group comprised 52 pregnant women with COVID-19 who had been admitted for treatment between 15 May 2020 and 26 April 2021.

Inclusion criteria, similar to admission indications for pregnant women with COVID-19, were temperature >39°C despite the use of acetaminophen, respiratory rate >30/min, SpO2 <95% measured at time of admission without oxygen supplementation, patient requiring oxygen, and critical disease. COVID-19 was confirmed using a PCR test prior to admission.

Exclusion criteria were that the patient was admitted to hospital for obstetric and/or other non-COVID-19-related reasons.

Clinical course of the disease

According to the guidelines of the Polish Association of Epidemiologists and Infectiologists, patients were divided into four cohorts based on the severity of their symptoms and test results, corresponding to the relative course of their illness: mild, moderate, severe, and critical [22].

Mild cases were characteristically clinically stable with mild upper respiratory tract symptoms. Moderate cases included clinical indicators as well as lung involvement shown on imaging. Patients in the severe cohort demonstrated respiratory failure and peripheral SpO2 <90%. Those in the critical cohort were characterized by ARDS, hypotensive shock, multiorgan failure, and loss of consciousness [22].

Study procedures

On admission, all women underwent complete blood biochemistry and urine tests, a coagulation profile, and in cases where moderate, severe, or critical forms of COVID-19 were suspected, a CT chest scan (without contrast) was performed.

We analyzed the following data: age of patient, body mass index (BMI), gestational age, initial vital signs and symptoms, pre-existing comorbidities such as diabetes mellitus, hypertension, hypothyroidism, asthma, and any history of smoking.

Ethical statement

The research project was approved by the local Bioethics Committee (Decision Number104/2021).

Statistical analysis

We used Statistica 13.3 (StatSoft Poland) for our data analysis. Mean values and standard deviations were used to describe the study groups. In case of skewed distributions, the median was calculated as a measure of central tendency, and the scatter of data was shown in relation to the 25th and 75th percentiles. Qualitative variables were presented as percentages. Spearman’s rank correlation was used to assess correlation. In case of qualitative variables, the Chi-square test was used to compare the frequencies of the studied characteristics. Differences were considered statistically significant at p < 0.05. Logistic regression was performed to analyze the association of patient characteristics and laboratory parameters and the risk of severe-to-critical disease. Non-linear data were categorized. Variables with more than 20% of their values missing were not considered in this analysis, in other cases, missing values were analyzed as a separate category. Comparisons between the four disease severity groups were performed using the Kruskal–Wallis test followed by pair-wise comparison using Dunn’s post hoc test for continuous variables, and Pearson’s chi-square test for categorical variables. As there was only one patient with a critical course of the disease, the severe and critical groups were combined in the analysis as a new grouping, severe-to-critical disease.

RESULTS

Gestational age ranged from 17 to 37 weeks. Four patients were at 17-22 weeks of gestation, 14 were at 24-28, 17 were at 29-33, 15 were at 34-36, and 2 patients were at >37 weeks of gestation. The mean age of the patients was 31.9 ± 4.79 years. Mean BMI at admission was 28.36 (9.88) kg/m2. None of the patients reported a history of smoking. Symptoms on admission were: dyspnea (n = 48, 92.31%), cough (n = 47, 90.38%), fever (n = 33, 63.46%), fatigue and muscle aches (n = 22, 42.31%), smell and taste disorders (n = 14, 26.92%), headache (n = 12, 23.08%), sore throat (n = 6, 11.54%), and nasal discharge (n = 5, 9.62%). Coexisting diseases were diabetes (n = 9, 17.65%), hypertension (n = 5, 10.00%), hypothyroidism (n = 18, 35.29%), and asthma (n = 2, 3.85%). Mild, moderate, severe, and critical COVID-19 accounted for n = 9 (17.31%), n = 25 (48.08%), n = 17 (32.69%), and n = 1 (1.92%) cases, respectively. The main outcomes measured were length of hospitalization (median = 8 [range = 2-23] days), the need for oxygen supplementation (n = 42, 80.77%), median oxygen flow rate (median = 4 [range = 0-15]), requirement for high-flow therapy (n = 9, 17.31%), and the need for ICU admission (n = 2, 3.85%). There were no cases of tracheal intubation, mechanical ventilation, or ECMO. The median lung involvement seen by CT imaging was 20% (IQR = 11), ranging from 1% to 60%. The most common abnormalities shown in the laboratory results that were elevated C-reactive protein (CRP) (94.23%), elevated D-dimer (90.63%), elevated interleukin 6 (IL-6) (88.46%), elevated fibrinogen (88%), hypoproteinemia (66.67%), decreased vitamin D (62.22%), elevated lactate dehydrogenase (LDH) (56%), hyperglycemia (48.78%), anemia (48.08%), elevated alkaline phosphatase (ALP) (46.15%), elevated aspartate aminotransferase (AST) (40.38%), lymphopenia (38.46%), neutrophilia (30.77%), elevated alanine transaminase (ALT) (30%), and elevated bile acids (35.71%). Data regarding patients’ characteristics, clinical course parameters, and laboratory abnormalities are presented in Table 1.

TABLE 1: Clinical characteristics of 52 pregnant COVID-19 patients

Main predictors of severe course of illness

Diabetes as a comorbidity was correlated with the need for high-flow oxygen therapy and higher oxygen flow. Hypertension was correlated with oxygen flow demand during hospitalization. The percentage of lung involvement correlated with four of the six main outcomes: the severity of the course of the COVID-19, the oxygen flow (l/min), the need for high-flow oxygen therapy, and the need for ICU admission (Table 2).

TABLE 2: Correlation of comorbidities and COVID-19 severity

Lymphocytopenia, low levels of serum calcium, total cholesterol and total protein levels, high levels of serum CRP, ferritin, IL-6 glucose, LDH, procalcitonin (PCT), and high-sensitivity (hs) troponin I predicted a severe course of illness as measured by disease course classification, the need for oxygen supplementation, higher demand for oxygen supplementation, length of hospital stay, the need for mechanical ventilation, and ICU admission. The results are presented in Table 3. Patients’ characteristics and laboratory markers compared across four severity categories are presented in Table 4. Univariate logistic regression revealed that diabetes (odds ratio [OR] 10.18, 95% CI 1.83-56.54; p = 0.008), gestational age < 32 weeks (OR 5, 95% CI 1.36-18.43; p = 0.016), lung involvement on CT imaging > 20% (OR 5.8, 95% CI 1.54-21.81, p = 0.009), lymphocyte count < 1(x103/μl) (OR 27.43, 95% CI 3.26-231.58; p = 0.002), calcium level ≤ 2.15 (mmol/l) (OR 5.56, 95% CI 1.61-19.22; p = 0.007), CRP > 75(mg/l) (OR 9.11, 95% CI 2.38-34.85; p = 0.001), IL-6 > 60 (pg/ml) (OR 16.5, 95% CI 1.8-151.58; p = 0.013), procalcitonin > 0.2(ng/ml) (OR 5.11, 95% CI 1.49-17.56; p = 0.010), LDH > 270 (U/l) (OR 3.73, 95% CI 1.04-13.45; p = 0.044), total cholesterol ≤ 180 (mg/dl) (OR 5.65, 95% CI 1.53-20.93; p = 0.010), total protein level ≤ 6.3 (g/dl) (OR 9, 95% CI 1.79-45.34; p = 0.008), hs-troponin I > 6 (ng/ml) (OR 12.69, 95% CI 1.35-119.34), and glucose > 99 (mg/dl) (OR 6, 95% CI 1.48-24.27; p = 0.012) were associated with increased risk of severe-to-critical COVID-19.

TABLE 3: Correlations of patient`s general and clinical characteristics and COVID-19 outcomes
TABLE 4: Association of patients’ characteristics and COVID-19 severity

DISCUSSION

In our study, the median date of the pregnant women’s hospital admission was the 30th gestational week (range = 17-37th week). Because COVID-19 is an immune-mediated intracellular viral infection, it may pose a threat during pregnancy due to the special immunological adaptations that improve a pregnant woman’s tolerance to the fetal semi-allograft late in the second trimester and the increased inflammatory response in the third trimester [10,14,23-25]. In addition, hypertension, diabetes, and cardiovascular diseases that develop during the third trimester may predispose pregnant women to the severe course of illness. Therefore, we advise vaccination in the second trimester for maternal and fetal benefits [26].

We found that median lung involvement was 20%, with a range of 1-60%, and as lung involvement at the time of admission correlated with 4 of the 6 main outcomes – the severity of the course of the COVID-19 disease, oxygen flow (l/min), the need for high-flow oxygen therapy, and the need for ICU admission – lung involvement may be considered as a predictor of disease aggravation. Based on the pathophysiology of COVID-19 progression, it seems like a truism to claim that the greater lung involvement is, the greater the severity of the disease, which is corroborated in our findings. However, the previous studies in pregnant women report contrasting results: One indicating greater lung involvement among pregnant women, and another reporting that lung involvement was similar in both pregnant and non-pregnant subjects [27,28].

Several previous studies have attempted to determine which laboratory parameters correlate with disease severity among pregnant women with COVID-19. Those studies found that subjects’ laboratory results largely mirrored those in the adult non-pregnant population, especially regarding lymphopenia and inflammation parameters.

Severe COVID-19 is associated with higher levels of inflammatory markers than in mild disease. Therefore, tracking these markers may permit early identification of patients at risk of disease progression. Likewise, a link between increased cardiac markers and disease aggravation with a few potential pathomechanisms is well established in the literature [29]. COVID-19 can cause direct or indirect heart injury: cardiomyocyte viral infection, cytokine-mediated systemic inflammation, supply-demand mismatch, and micro- and macrovascular thrombosis [29-31].

Lymphopenia has been identified as the most distinctive predictive parameter [32-34]. In a study by Lombardi et al., lymphocyte values at admission correlated with the oxygen need. CRP levels were found to be the inflammatory biomarker that better mirrored the course of the disease than D-dimer or ferritin levels, which were not reliable predictors of a poor outcome [32]. The retrospective study of 217 pregnant women with COVID-19 by Bozkurt et al. showed that elevated LDH, CRP, IL-6, and ferritin levels coupled with low albumin levels on hospital admission were predictive parameters for a more severe course of illness, and that elevated serum levels of blood urea nitrogen and creatine were the most predictive parameters for ICU admission [35]. Data support that the host’s immune system overreaction (cytokine storm syndrome or cytokine release syndrome) may play an important role in the pathogenesis of SARS [36]. SARS-CoV infection may lead to hyper-induction of the immune system, causing increased levels of cytokines, e.g., IL-6 and chemokines, all of which have been observed in SARS patients. However, there are also contradicting results [37]. Data have shown that IL-6 levels are also significantly higher in COVID-19 patients with severe disease compared with those with a non-severe condition. Therefore, IL-6 is a prognostic marker for serious COVID-19 cases in pregnant [38] and non-pregnant cohorts [39-41].

Our study identified a positive correlation between exact glucose values at admission and poorer patient outcomes. This observation suggests that the elevated blood sugar levels we observed may be the result of physiological stress triggered by the disease. COVID-19 disrupts glucose regulation, rendering poor glycemic control, and necessitating particularly careful management in patients with diabetes [42,43]. Indeed, prior work has shown that even in cases of well-controlled pre-existing diabetes, hyperglycemia was commonly observed in acutely ill hospitalized patients and linked to adverse outcomes [44,45]. It seems that COVID-19 may lead to high blood glucose levels in patients with normal glycemic status by modulating immune and inflammatory responses, directly affecting morbidity and mortality [46-48]. In a study by Charoenngam et al. in patients without a history of diabetes, hyperglycemia on the day of admission was shown to have a statistically significant association with mortality, ICU admission, intubation, acute kidney injury, and severe sepsis/septic shock, after adjusting for potential confounders. Therefore, it could be a strong indicator of a high inflammatory burden, leading to a higher risk of severe COVID-19 [49]. Thereby, we recommend that clinicians pay more attention to the blood glucose status of pregnant women with COVID-19, even those who may not have been diagnosed with diabetes prior to admission.

In our study, calcium serum levels were negatively correlated with three measured clinical outcomes: the length of hospitalization (days), the severity of the course of COVID-19 (1-4), and oxygen flow (l/min). These findings were consistent with previously published reports which have showed that low serum calcium levels are associated with disease severity and a poor prognosis for patients with COVID-19 [50-53]. In a study by Zhang et al. low serum calcium levels were the most predictive feature of COVID-19 diagnosis of all models tested [54]. The cause of hypocalcemia in COVID-19 patients is not clear. It is commonly found in the laboratory results in patients diagnosed with viral infections and pneumonia [55], and several mechanisms may be suggested. Firstly, the pro-inflammatory cytokines in COVID-19 patients inhibit parathyroid hormone (PTH) secretion, and the resulting impaired response to PTH causes an imbalance of calcium levels [56]. According to the previous studies, levels of the disease progression indicators CRP, PCT, IL-6, and D-dimer are found to be significantly higher in COVID-19 patients with hypocalcemia. When this is coupled with calcium serum levels which are negatively correlated with these indicators, it means that these patients may have a greater inflammatory response [50,51,53]. Secondly, the occurrence of hypocalcemia may be associated with calcium inflow due to hypoxemic tissue damage. Another theory is that modification of calcium levels is crucial for the survival and replication of the SARS-CoV-2, since calcium is used in virus structure formation, entry, gene expression, virion maturation, and release [57]. Pregnancy also often leads to vitamin D deficiency resulting in hypocalcemia due to impaired intestinal absorption and thus an inadequate intake of calcium [58]. Finally, calcium is predominantly bound to albumin in plasma, and a decrease in serum albumin or total protein levels, mainly occurring in the third trimester, will cause hypocalcemia [59].

Our work showed that low total protein serum levels are a predictive factor for both a longer time to clinical improvement and a greater severity of disease, and as such this predictor can provide useful information for clinicians caring for pregnant women with COVID-19. Several mechanisms were proposed, including anti-oxidative and anti-inflammatory values of albumin [60,61], downregulation of albumin and prealbumin caused by the cytokine storm [62], and dysregulation of the immune system triggered by low protein serum levels [63]. The previous studies have indicated that serum albumin [64-66], prealbumin [62], and total protein levels are poor prognosis parameters among non-pregnant cohorts [63]. As mentioned earlier, total protein and albumin levels decrease because of the physiological processes of pregnancy during the third trimester. This condition poses a major threat to pregnant SARS-CoV-2 infected women as outlined in a study by Bozkurt et al. [35].

Our study showed that on admission, disrupted total cholesterol levels correlate with a greater severity of disease and with five out of the six main outcomes: the length of hospitalization (days), the severity of the course of COVID-19 (1-4), oxygen flow (l/min), the need for oxygen supplementation, and the need for ICU admission. The role of cholesterol in immunity is well established in numerous observational studies. In addition, dynamic changes in lipid levels caused by SARS-CoV-2 might be explained by several hypotheses. Firstly, the production of apolipoproteins and lipoproteins might be impaired by liver damage [67] and cytokine activity [68], and secondly, capillary leakage may occur, relocating them to extravascular compartments [69]. A study by Wei et al. demonstrated that patients with COVID-19 develop hypolipidemia during early stages of the disease and that abnormalities in lipid metabolism progressively became worse in association with the severity of the disease [70]. Lower levels of total cholesterol, low-density lipoprotein, and high-density lipoprotein (HDL) were linked to higher mortality rates and poorer prognoses in patients with COVID-19 [70-73]. Moreover, high CRP/HDL-C ratios were established as an independent predictor of in-hospital mortality [74]. However, none of these previously published studies involved pregnant women.

The main limitations of our investigation include its single-center nature, as well as its small and homogeneous cohort of patients. Moreover, we evaluated markers on admission, and not their response to disease progression and treatment.

CONCLUSION

Pregnant women with COVID-19 were hospitalized during their second or third trimester, with dyspnea, cough, and fever as leading symptoms. Concomitant conditions, including diabetes and hypertension, modified the course of illness. CT chest scan at initial presentation may enable medical services required by pregnant patients infected with SARS-CoV-2 to be prioritized. Lymphocytopenia, hypocalcemia, low total cholesterol, low total protein levels, and high serum levels of CRP, ferritin, IL-6, procalcitonin, hs-troponin I, LDH, and glucose measured on hospital admission are good predictors of disease severity and may lead to early identification of patients at risk for developing complications, thereby improving optimization and prevention efforts in this cohort. Further, research with a larger patient sample and risk models is needed to provide useful information for effective health resource management during the COVID-19 pandemic.

REFERENCES

  1. (). . WHO Coronavirus (COVID-19) Dashboard. Available from: https://www.covid19.who.int
  2. , , , , , (). Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women:Two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM. http://doi.org/10.1016/j.ajogmf.2020.100118
  3. , , , , , (). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. http://doi.org/10.1016/S0140-6736(20)30183-5
  4. , , , , , (). China medical treatment expert group for covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. http://doi.org/10.1056/NEJMoa2002032
  5. , , , , , (). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. http://doi.org/10.1001/jama.2020.1585
  6. , , , , , (). The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2;COVID-19):A systematic review and meta-analysis of 148 studies from 9 countries. PLoS One. http://doi.org/10.1371/journal.pone.0234765
  7. , , , , , (). Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections:A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. http://doi.org/10.1016/S2215-0366(20)30203-0
  8. , , , , , (). COVID-19 pandemic-related anxiety in pregnant women. Int J Environ Res Public Health. http://doi.org/10.3390/ijerph18147221
  9. , , , , , (). Hypotheses and facts for genetic factors related to severe COVID-19. World J Virol. http://doi.org/10.5501/wjv.v10.i4.137
  10. , , , , , (). Immunological and physiopathological approach of COVID-19 in pregnancy. Arch Gynecol Obstet. http://doi.org/10.1007/s00404-021-06061-3
  11. , , , , , (). Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women:A retrospective review of medical records. Lancet. http://doi.org/10.1016/S0140-6736(20)30360-3
  12. , , , , , (). Why are pregnant women susceptible to COVID-19?An immunological viewpoint. J Reprod Immunol. http://doi.org/10.1016/j.jri.2020.103122
  13. , , (). Effects of influenza on pregnant women and infants. Am J Obstet Gynecol. http://doi.org/10.1016/j.ajog.2012.06.068
  14. , , (). The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. http://doi.org/10.1038/nri.2017.64
  15. , , , , , (). for PregCOV-19 living systematic review consortium. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy:Living systematic review and meta-analysis. BMJ. http://doi.org/10.1136/bmj.m3320
  16. , , , , , (). Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status-United States, January 22-June 7, 2020. MMWR Morb Mortal Wkly Rep. http://doi.org/10.15585/mmwr.mm6925a1
  17. , , , , , (). CDC COVID-19 response pregnancy and infant linked outcomes team. Update:Characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status-United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. http://doi.org/10.15585/mmwr.mm6944e3
  18. , (). Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women:Lessons from SARS, MERS, and other human coronavirus infections. Viruses. http://doi.org/10.3390/v12020194
  19. , , , , , (). Pandemic H1N1 Influenza in Pregnancy Working Group. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. http://doi.org/10.1001/jama.2010.479
  20. , , , , , (). Novel Influenza A (H1N1) Pregnancy Working Group. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. http://doi.org/10.1016/S0140-6736(09)61304-0
  21. , , , , (). Adverse outcomes in pregnant women hospitalized with respiratory syncytial virus infection:A case series. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa668
  22. , , , , , (). Management of SARS-CoV-2 infection:Recommendations of the Polish association of epidemiologists and infectiologists as of March 31, 2020. Pol Arch Intern Med. https://doi.org/10.20452/pamw.15270
  23. , , (). COVID-19 during pregnancy:An overview of maternal characteristics, clinical symptoms, maternal and neonatal outcomes of 10,996 cases described in 15 countries. J Perinat Med. https://doi.org/10.1515/jpm-2020-0364
  24. , , , , , (). H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1006757
  25. , (). Placental immunology and maternal alloimmune responses. Vox Sang. https://doi.org/10.1111/j.1423-0410.2011.01533.x
  26. , (). Evaluation of SARS-CoV-2 spike protein antibody titers in cord blood after COVID-19 vaccination during pregnancy in polish healthcare workers:Preliminary results. Vaccines (Basel). https://doi.org/10.3390/vaccines9060675
  27. , , , , (). Clinical and obstetric characteristics of pregnant women with Covid-19:A case series study on 26 patients. Taiwan J Obstet Gynecol. https://doi.org/10.1016/j.tjog.2021.03.012
  28. , , , , , (). . Clinico-Radiological Features and Outcomes in Pregnant Women with COVID-19:Compared with Age-Matched Non-Pregnant Women. Available from: https://www.ssrn.com/abstract=3556647http://doi.org/10.2139/ssrn.3556647
  29. , , , , , (). Meta-analysis of cardiac markers for predictive factors on severity and mortality of COVID-19. Int J Infect Dis. http://doi.org/10.1016/j.ijid.2021.03.008
  30. , , , , , (). COVID-19 cardiovascular epidemiology, cellular pathogenesis, clinical manifestations and management. Int J Cardiol Heart Vasc. http://doi.org/10.1016/j.ijcha.2020.100589
  31. , , , , , (). A current review of COVID-19 for the cardiovascular specialist. Am Heart J. https://doi.org/10.1016/j.ahj.2020.04.025
  32. , , , , , (). Inflammatory biomarkers in pregnant women with COVID-19:A retrospective cohort study. Sci Rep. https://doi.org/10.1038/s41598-021-92885-7
  33. , , , , , (). . Recognition and Treatment of Severe COVID-19 in Pregnancy:Lessons from a Cohort of 69 Infected Women and an Evidence-based Guideline. https://doi.org/10.22541/au.160616173.35255142/v1
  34. , , , , , (). Symptoms and critical illness among obstetric patients with coronavirus disease 2019 (COVID-19) infection. Obstet Gynecol. https://doi.org/10.1097/AOG.0000000000003996
  35. , , , , , (). Comparison of the clinical and laboratory findings in COVID-19 positive pregnants without comorbidity. Turk J Med Sci. doi:10.3906/sag-2105-116Epub ahead of printhttps://doi.org/10.3906/sag-2105-116
  36. , , , , (). Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. https://doi.org/10.1016/j.cca.2020.06.017
  37. , , , , , (). Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int J Infect Dis. https://doi.org/10.1016/j.ijid.2020.04.041
  38. , , , , , (). The impact of COVID-19 infection on the cytokine profile of pregnant women:A prospective case-control study. Cytokine. https://doi.org/10.1016/j.cyto.2021.155431
  39. , , , , (). Detectable serum SARS-CoV-2 viral load [RNAaemia] is closely correlated with drastically elevated interleukin 6 [IL-6] level in critically ill COVID-19 patients. Clin Infect Dis.
  40. , (). Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. https://doi.org/10.1016/j.medmal.2020.04.002
  41. , , (). Elevated interleukin-6 and severe COVID-19:A meta-analysis. J Med Virol. https://doi.org/10.1002/jmv.25948
  42. , , , , , (). Managing hyperglycemia in the COVID-19 inflammatory storm. Diabetes. https://doi.org/10.2337/dbi20-0022
  43. , , , , , (). COVID-19 and diabetes:A collision and collusion of two diseases. Diabetes. https://doi.org/10.2337/dbi20-0032
  44. , (). The role of hyperglycemia in acute illness:Supporting evidence and its limitations. Nutrition. https://doi.org/10.1016/j.nut.2010.07.013
  45. , , (). Stress-induced hyperglycemia. Crit Care Clin. https://doi.org/10.1016/s0749-0704(05)70154-8
  46. , , , , , (). Diabetes mellitus-a risk factor for unfavourable outcome in COVID-19 patients-the experience of an infectious diseases regional hospital. Healthcare (Basel). https://doi.org/10.3390/healthcare9070788
  47. , , , , , (). The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019:A single-centre, retrospective, observational study in Wuhan. Diabetes Obes Metab. https://doi.org/10.1111/dom.14086
  48. , , , , , (). Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes:A multi-centre retrospective study. Diabetologia. https://doi.org/10.1007/s00125-020-05209-1
  49. , , , (). Association between hyperglycemia at hospital presentation and hospital outcomes in COVID-19 patients with and without type 2 diabetes:A retrospective cohort study of hospitalized inner-city COVID-19 patients. Nutrients. https://doi.org/10.3390/nu13072199
  50. , , , , (). Prevalence and predictive value of hypocalcemia in severe COVID-19 patients. J Infect Public Health. https://doi.org/10.1016/j.jiph.2020.05.029
  51. , , , , , (). Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging (Albany NY). https://doi.org/10.18632/aging.103526
  52. , , , , , (). Low levels of total and ionized calcium in blood of COVID-19 patients. Clin Chem Lab Med. https://doi.org/10.1515/cclm-2020-0611
  53. , , , , , (). Abnormal coagulation function of patients with COVID-19 is significantly related to hypocalcemia and severe inflammation. Front Med (Lausanne). https://doi.org/10.3389/fmed.2021.638194
  54. , , , , , (). Prediction of individual COVID-19 diagnosis using baseline demographics and lab data. Sci Rep. https://doi.org/10.1038/s41598-021-93126-7
  55. , , , , , (). Laboratory abnormalities in patients with bacterial pneumonia. Chest. https://doi.org/10.1378/chest.111.3.595
  56. , (). Hypocalcemia:Updates in diagnosis and management for primary care. Can Fam Physician.
  57. , , , , , (). Predictive modeling of morbidity and mortality in patients hospitalized with COVID-19 and its clinical implications:Algorithm development and interpretation. J Med Internet Res. https://doi.org/10.2196/29514
  58. (). Vitamin D deficiency. N Engl J Med. https://doi.org/10.1056/NEJMra070553
  59. , (). Protein and amino acid requirements during pregnancy. Adv Nutr. https://doi.org/10.3945/an.115.011817
  60. , , , , (). Role of albumin in diseases associated with severe systemic inflammation:Pathophysiologic and clinical evidence in sepsis and in decompensated cirrhosis. J Crit Care. https://doi.org/10.1016/j.jcrc.2015.12.019
  61. , , (). Human albumin:Old, new, and emerging applications. Ann Transplant. https://doi.org/10.12659/AOT.889188
  62. , , , , , (). The association between serum prealbumin and poor outcome in COVID-19-systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. https://doi.org/10.26355/eurrev_202105_25955
  63. , , , , , (). Development and validation of prognostic model for predicting mortality of COVID-19 patients in Wuhan, China. Sci Rep. https://doi.org/10.1038/s41598-020-78870-6
  64. , , , , , (). Low serum albumin and the risk of hospitalization in COVID-19 infection:A retrospective case-control study. PLoS One. https://doi.org/10.1371/journal.pone.0250906
  65. , , , , (). Higher albumin levels on admission predict better prognosis in patients with confirmed COVID-19. PLoS One. https://doi.org/10.1371/journal.pone.0248358
  66. , , , , , (). Serum albumin levels are a predictor of COVID-19 patient prognosis:Evidence from a single cohort in Chongqing, China. Int J Gen Med. https://doi.org/10.2147/IJGM.S312521
  67. , , , , , (). Performance of serum apolipoprotein-A1 as a sentinel of Covid-19. PLoS One. https://doi.org/10.1371/journal.pone.0242306
  68. , , , , , (). Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells. Arterioscler Thromb. https://doi.org/10.1161/01.atv.14.1.8
  69. , , , , , (). Lipoprotein metabolism in patients with severe sepsis. Crit Care Med. https://doi.org/10.1097/01.CCM.0000059724.08290.51
  70. , , , , , (). Hypolipidemia is associated with the severity of COVID-19. J Clin Lipidol. https://doi.org/10.1016/j.jacl.2020.04.008
  71. , , , , , (). Dyslipidemia is related to mortality in critical patients with coronavirus disease 2019:A retrospective study. Front Endocrinol. https://doi.org/10.3389/fendo.2021.611526
  72. , , , , , (). Decreased low-density lipoprotein cholesterol level indicates poor prognosis of severe and critical COVID-19 Patients:A retrospective, single-center study. Front Med (Lausanne). https://doi.org/10.3389/fmed.2021.585851
  73. , , , , (). Association of pre-pandemic high-density lipoprotein cholesterol with risk of COVID-19 hospitalisation and death:The UK Biobank cohort study. Prev Med Rep. https://doi.org/10.1101/2021.01.20.21250152
  74. , , , , , (). Lipid metabolism changes in patients with severe COVID-19. Clin Chim Acta. https://doi.org/10.1016/j.cca.2021.02.011

Conflicts of interest: Authors declare no conflicts of interest.

Funding: Authors received no specific funding for this work.