**4. Discussion**

Susceptibility to respiratory pathogens and severe cases of pneumonia during pregnancy occur due to immunological and cardiopulmonary changes that can make pregnant women more vulnerable to hypoxia [8]. **Figure 2** summarizes the main changes in pregnancy and its susceptibility to COVID-19.

The pulmonary system of pregnant women also undergoes complex changes due to their pregnancy status. There is a compression of the diaphragm by the uterus, leading to a decrease in thoracic compliance and total lung capacity [8]. In addition, pneumonia caused by COVID-19 rapidly progresses from focal to bilateral pulmonary consolidation, predisposing these patients to hypoxemic respiratory failure [5] (**Figure 2**). Symptoms started between 5.8 and 29.9 weeks of pregnancy and between 5.7 and 30.7 weeks of hospital stay [9].

In the cardiovascular system (**Figure 2**), the pregnant woman undergoes profound physiological changes. There is a myocardial hypertrophy with enlarged cardiac chambers, which leads to an increase in cardiac output that reaches a maximum of 30–40% between the 28th and 36th week, when it stabilizes until childbirth; there is a gradual increase in heart rate that reaches its maximum peak between the 28th and 36th weeks [10]; total peripheral resistance is reduced by up to 30% from the 8th–12th week of gestation, remaining at these levels until term [11]; finally, there is an increase in central venous pressure in the lower portions of the body, especially from the second trimester onwards, due to the action of the uterine volume on the pelvic veins and inferior vena cava [12].

This overload of the cardiovascular system becomes dangerous as the pregnant woman faces the potential aggressions of COVID-19 (**Figure 2**). According to the

### **Figure 2.**

*Actions of SARS-CoV-2 to the cardiovascular, respiratory and immune systems and their physiological alterations in pregnancy. Source: Authors (2021).*

### *Analysis of the Factors That Influence the Clinical Outcome of Severe Acute Respiratory… DOI: http://dx.doi.org/10.5772/intechopen.99915*

literature, regardless of being pregnant or not, it is postulated that SARS-CoV-2 causes myocardial damage by at least three mechanisms: (I) Hyperexpression of ACE2 receptors (Angiotensin II receptor) in the cardiovascular system – it would lead to a greater affinity of the virus for the cells of the cardiac system, causing direct damage to the cells by SARS-CoV-2; (II) Myocardial damage caused by the "Cytokine Storm" – with aggression from the immune system directly to the cardiomyocyte cells; and (III) the Severe Acute Respiratory Distress syndrome (ARDS) would cause hypoxemia, leading to myocardial ischemia [13]. Thus, pregnant women, due to the physiological overload of the cardiovascular system, theoretically, would have more severe cases of COVID-19.

Additionally, in the case of pregnant women, another factor should be considered: the immunotolerance changes in the innate and adaptive systems caused by pregnancy (**Figure 2**). In the gestational immune system [14] there is a complex humoral response in signaling. What happens is an alteration in the signaling pattern, especially in CD4+ T lymphocytes. In this context, there is an important decrease in the immune response by Th1 lymphocytes and an increase in the response mediated by Th2 lymphocytes. In practice, this contributes to increased maternal susceptibility to intracellular pathogens and viral infections, which causes an increase in gestational morbidity in a broad and general way [15]. Thus, Th1 type cytokines are pro-inflammatory agents that contain interleukins (IL-1a, IL-1b, IL-6, IL-12) and interferon-gamma (IFN-g), while Th2 type cytokines are antiinflammatory drugs agents that contain interleukins (IL-4, IL-10, IL-13) and transforming growth factor-beta (transforming growth factor β, TGF-β). Patients with SARS-CoV-2 demonstrated preferential activation of Th1 immunity, resulting in a considerable increase in pro-inflammatory cytokines for at least two weeks after the onset of the disease, which would cause severe lung damage [13].

Consistent with literature data, pregnancy with the presence of Acute Respiratory Syndrome is more associated with maternal and neonatal complications such as premature birth, intrauterine growth restriction, spontaneous abortion, orotracheal intubation, ICU admissions, disseminated intravascular coagulation and acute renal failure [16, 17]. A North American cohort that evaluated 8,207 pregnant women with 83,205 women of childbearing age (15–44 years), both groups with laboratory confirmation for SARS-CoV-2 showed a mortality rate lower than 1% (0.2% - being 16 pregnant and 208 not pregnant). The authors further report that pregnant women had higher admission rates than their controls (31.5% vs. 5.8%, respectively). In addition, pregnant women had a higher incidence of ICU admissions compared to non-pregnant women (1.5% vs. 0.9%, respectively) and also had greater need to use invasive mechanical ventilation (0.5% vs. 0.3%) [18]. A prospective cohort conducted in Mexico through the "COVID-19 National Data Registry of Mexico" compared 5,183 pregnant women with 175,905 non-pregnant women with COVID-19 confirmed by RT-PCR. According to the authors, pregnant women had higher odds ratios (OR) for deaths (1.84; 95%CI, 1.26–2.69), pneumonia (1.86; 95% CI, 1.60–2.16), and ICU admissions (1.86; 95%CI, 1.41–2.45) compared to nonpregnant women [19].

In the context of SARS-COV-2, it seems that the clinical consequences caused by COVID-19 are influenced by the patient's age and pre-existing comorbidities [20]. Sentilhes et al. observed that women had one or more known maternal characteristics associated with severe maternal morbidity, such as: age over 35 years, overweight, gestational hypertension, diabetes and preexisting asthma, which are warning aspects for monitoring and managing pregnant women infected with COVID-19 [21]. Study by Knight et al. showed that almost half (41% - 175) of pregnant women with SARS-CoV-2 admitted to UK hospitals and evaluated in their prospective cohort were at the age of 35 or over [22].

A systematic review carried out in 2021 reported that, in general, patients with non-communicable chronic diseases such as obesity, diabetes mellitus and systemic arterial hypertension have higher morbidity and mortality rates when they acquire COVID-19 compared to the general population [23]. In our study, approximately 80 and 50% of the pregnant patients were overweight or obese, respectively, before pregnancy and had associated conditions, such as systemic arterial hypertension (SAH). Obesity is considered an aggravating factor because it weakens lung function through mechanical and inflammatory pathways. In synergy with COVID-19, obesity, asthma, and mechanical stress caused by high uterine volume can increase the risk of premature birth [24]. Another study pointed out that 18.5% of pregnant women had at least one comorbidity before pregnancy: asthma, SAH, or obesity [21]. A cohort carried out in the United Kingdom based on the "UK Obstetric Surveillance System" showed that of the 427 pregnant women admitted to hospital units with SARS-CoV-2 infection, 69% (281) were overweight or obese and 34% (145) had other pre-existing comorbidities. Around 10% of the admitted pregnant women needed O2 support and 1% died [22]. However, it is not always possible to determine the relationship between COVID-19 complications and the comorbidities of pregnant women. In a study of 116 cases, of which nine patients (7.8%) had gestational diabetes and five (4.3%) presented hypertensive disorders, including pre-eclampsia, the authors indicated that there is not necessarily a direct relationship between comorbidities and pregnancy complications associated with COVID-19 [25].

The symptomatology of pregnant women with COVID-19 is not different from that observed in the general population. A review study summarizes in **Figure 3** the main clinical manifestations of COVID-19 in pregnant women in epidemiological studies:


### *Analysis of the Factors That Influence the Clinical Outcome of Severe Acute Respiratory… DOI: http://dx.doi.org/10.5772/intechopen.99915*

The data in **Figure 3** are compatible with subsequent studies. A meta-analysis carried out by an Italian group showed that the most common symptoms of pregnant women with SARS-CoV-2, MERS and SARS were fever (82.6%), cough (57.1%) and dyspnea (27.0%) [27]. Rasmussen et al. reported that the most common symptoms of COVID-19 are fever, cough, myalgia, headache, and diarrhea [28].

After analyzing 46 pregnant women with COVID-19 in a retrospective study, most cases were treated in outpatient settings (78.3%, 36/46) or were asymptomatic (6.5%, 3/46), with dyspnea being the main symptom. However, seven pregnant patients (15.2%) were hospitalized due to COVID-19, one of whom was admitted to the intensive care unit (ICU). The authors believe that pregnant women should be considered a high-risk population for the severe form of COVID-19, particularly in the second and third trimesters of pregnancy, especially if they are obese [24]. A cross-sectional, descriptive and quantitative study carried out in the city of Wuhan, China and published in the New England Journal of Medicine in April 2020, reports that of the pregnant women who acquired COVID-19, 55 out of 106 (52%) were nulliparous and 75 out of 118 (64%) had been infected with SARS-CoV-2 in the third trimester. The most common symptoms in 112 women were fever (75%) and cough (73%). Most (92%) had the disease in its mild form and 8% had hypoxemia and severe forms, and of these patients one required intensive care support with mechanical ventilation. Interestingly, COVID-19 was more severe among patients in the immediate postpartum period [29].

The findings by Pierce-Williams et al. pointed out that, within the sample universe analyzed, 73% of the pregnant women with severe manifestations of COVID-19 required O2 supplementation, and 95% were intubated. Among women with the severe form of the disease, 70% developed acute respiratory distress syndrome (ARDS), 20% were placed in a prone position (in gestational ages at 26 to 31 weeks), and 20% required reintubation [9]. Systematic review conducted by Juan et al. refers to seven maternal deaths, four intrauterine fetal deaths (one with twin pregnancy) and two neonatal deaths (twin pregnancy) reported in a nonconsecutive case series of nine cases with severe COVID-19. In the case reports, two maternal deaths, one neonatal death and two cases of neonatal SARS-CoV-2 infection were stated [30].

However, these findings are not unanimous in the literature. A crosssectional, descriptive and prospective study conducted in Utah, India, which analyzed 65 pregnant women with positive RT-PCR for COVID-19, showed that 88.4% were asymptomatic [31]. An Iranian review study points out that pregnant women with comorbidities are more likely to have more severe clinical pictures of COVID-19, although it is inconclusive for the authors that COVID-19 alone can increase maternal-fetal risk [32]. A second review study published in 2021 comparing outcomes between pregnant and non-pregnant women with SARS-CoV-2, MERS (Middle East respiratory syndrome coronavirus) and SARS (Severe acute respiratory syndrome coronavirus) concluded that there is no evidence that pregnant women are more susceptible to coronavirus infection in general, or that those infected with these viruses are more likely to develop severe pneumonia. Similar to non-pregnant women, pregnant women with MERS had the highest mortality, followed by those with SARS and COVID-19 [33]. These findings are corroborated by a retrospective and multicentric cohort carried out in 2020 [34] in which it was observed that the mortality rate among pregnant women (110 patients) compared to non-pregnant women (224 patients) did not show statistically significant differences. However, pregnant women had lower saturation rates and global lymphocyte counts than their peers in a statistically significant way.

The prospective cohort study by Prabhu et al. analyzed 675 women admitted for delivery, 10.4% tested positive for COVID-19, of whom 21.4% had at least one symptom, demonstrating that there are significant outcome differences between pregnant women who tested positive and negative for SARS-CoV-2 and symptomatic and asymptomatic ones. The rate of cesarean section was 15% higher among women who were infected with the virus, in addition to demonstrating that postpartum complications, including fever and hypoxia, occurred in 12.9% of the women infected versus 4.5% of the women not infected. In that same study, placental perfusion diseases, possibly thrombi in fetal vessels, were frequent in approximately 48% of the infected women [35].

The worsening of the clinical condition of pregnant women with COVID-19 raises great concern with potential outcomes that include spontaneous abortion, premature birth, and fetal morbidity and mortality [24]. The severe consequences for the fetus result from the oxygen supply deficit caused by maternal respiratory disease, leading to hypoxemia due to the reduction of the partial pressure of oxygen [14]. The study by Allotey J et al. showed that among pregnant women and recently pregnant women with COVID-19, the chance of premature births was high compared to pregnant women who did not have the disease [36].

A meta-analysis conducted by Mascio et al., which outlined complications caused by coronavirus diseases, such as SARS, MERS, and COVID-19, in pregnant women, found that those with COVID-19 had the highest incidence of premature birth, achieving 41% against 24% for SARS. However, this group had the lowest mortality rate (7%) [27, 35]. This low fetal mortality rate was corroborated by studies such as that by Wong et al., in which SARS had a mortality rate of 25% and induced abortions in up to 57% of the whole sample [17].

Furthermore, literature shows that advanced maternal age can be considered a risk factor for the severe form of the disease during pregnancy [36]. In this scenario, pregnant women over 35 years of age affected by COVID-19 require special attention [7, 37]. According to our data, the lethality rate among pregnant women with SARS caused by COVID-19 in the 30–39 age group is 5.8%, increasing to 8.7% in the 40–49 age group, and exceeding 15% in the 50–59 age group.

### **4.1 Limitations**

As biases in this study, those inherent in the secondary nature of the data should be highlighted. First, the underreporting of cases - only people who sought health services were notified. Consequently, mild or asymptomatic cases were not counted; secondly, the dependence on correctly filling out the notification forms; and, finally, the limited availability of information in the Brazilian Government's databases.

### **5. Conclusion**

Comparing the lethality rate observed in pregnant women with SARS caused by COVID-19 with that caused by other etiologic agents shows the severity of SARS-CoV-2 in this group and that its potential for lethality is greater in the second trimester of pregnancy. Likewise, it indicates that the older the age group, the greater the lethality of the virus. In addition to the variables analyzed, other variables related to the presence of comorbidities and quality of care for pregnant women should be considered in the model in future studies to determine the risk level for these women and the required specialized conduct.

*Analysis of the Factors That Influence the Clinical Outcome of Severe Acute Respiratory… DOI: http://dx.doi.org/10.5772/intechopen.99915*
