The main contribution of present analysis was testing the ABC2-SPH model developed from a cohort of 3978 patients (12), based on clinical and laboratory characteristics upon hospital presentation, in an external validation with 85 pregnant women from 19 Brazilian hospitals. Even though the ABC2-SPH model presented very high discrimination in external validation in cohorts of general hospitals (12), this model failed to discriminate the adverse clinical results in pregnant women. Calibration curves showed that the ABC2-SPH model overestimated the risk of death, or the composite of mechanical ventilation or death in pregnant women. Additionally, the risk of severe/critical progression of COVID-19 was underestimated in cases of low probability and overestimated in cases of higher probability of the outcome (Figure 2).
Our interpretation is that the set of prognosis markers of COVID-19 in pregnancy are not the same as the ones for the non-pregnant population admitted with the disease. This finding itself could contribute to an understanding of the poor outcomes as COVID-19 maternal mortality. According to Brazilian data, pregnancy complicated by COVID-19 is a serious burden for the hospital maternity services. Pregnant women accounted for 0.8/1000 of 20,350,142 confirmed cases in the country until Aug/2021 (19, 20). However, the rate of mortality was 10.5%, 3.8 times higher than the rate of 2.8% of the national mortality (19).
Across the studies in non-pregnant populations, male sex, increasing age and underlying illness, such as cardiovascular diseases and diabetes, increased the risk of poor outcomes (21, 22). The ABC2-SPH predictive model was developed upon a set of covariates upon hospital presentation to predict death: age, chronic diseases (hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation or flutter, cirrhosis, cancer, chronic obstructive pulmonary disease and previous stroke), heart rate and SpO2/FiO2 ratio, allied to low platelets, C-reactive protein and urea (12). Such predictors might score differently in pregnant women, since they are deeply modified by physiologic adaptations, such as the increase in heart rate, which itself may overestimate the risk estimated by the score in at least 5%, and maternal response to infections. Our analysis reveals how distinct these groups are in terms of age, laboratory analysis, and in-hospital complications. Previous diabetes, blood pressure, respiratory rate, heart rate, SpO2/FiO2 ratio, neutrophils-to-lymphocytes ratio, and blood urea nitrogen at admission as associated with severe COVID-19. Preexisting comorbidities as diabetes and chronic hypertension have been shown to be associated with an increased risk for COVID-19 adverse outcomes in pregnant women (23, 24).
Most pregnant women were young and healthy before the admission due to COVID-19, which partially explains why abnormal vital signals and inflammatory markers are associated with the in-hospital severe/critical progression, instead of pre-existent comorbidities. Neutrophil-to-lymphocyte ratio and C-reactive protein were higher in the severe and critical COVID-19 group when compared to mild one. In fact, this ratio has been observed to be the most consistent abnormal hemocytometric finding in COVID-19 patients (25). In the multivariate modeling of ABC2-SPH score (12), C-reactive protein is the inflammatory marker which was significant in the final model. We hypothesize that inflammatory markers could be covariables even more relevant for pregnant women, scoring proportionally higher than for general patients. Besides, physiological adaptations to the pregnancy affect the organ system in the maternal body, modifying, as well the response to infections.
The existing evidence is conflicting on whether pregnancy is an immunological contributor to severe progression of COVID-19 (26). A successful pregnancy depends on a responsive immune system, which explains reports of universal COVID-19 testing during pregnancy, that the vast majority is asymptomatic or has mild COVID-19 (26, 27). The unit maternal and feto–placental immune system is responsive, protecting both the mother and the fetus against treats from the environment (28). The placenta is a selective barrier, able to protect the developing fetus against infections, including SARS-CoV-2 virus infection (29). It also acts as an immunity-modulating organ, regulating immune responses of cells present both at the implantation site and systemically (30). However, evidence of fetal vascular malperfusion or thrombosis has been observed in COVID-19, which may be related to an exacerbated maternal systemic inflammatory response and hypercoagulable state (31, 32).
Notwithstanding, cardiopulmonary adaptive changes during pregnancy may increase the risk of hypoxemia and contribute to the increased severity of viral infections (33). The circulatory system is significantly adjusted during pregnancy, starting early in its course, driven by peripheral vasodilatation, increased heart rate and stroke volume, reduced pulmonary vascular resistance, and reduced pulmonary residual capacity. These changes may affect the course of viral infections (9, 33). For these reasons, although we believe that vital signals at admission might contribute to scoring in predictive models of COVID-19 outcomes during pregnancy, the expected cut offs are affected by physiological changes during pregnancy and might not coincide with non-pregnant women. Besides, with hemodilution and rising glomerular filtration rate, there are modifications in the reference values for hemoglobin levels, proteins, creatinine, and urea (9), interfering in the performance of scores based on laboratory values. Therefore, it is comprehensible that scores used to predict mortality in general adults have limitations when used among pregnant women (34).
Another aspect of COVID-19 disease in pregnant women grounds on the overactivated renin–angiotensin system. This system plays a relevant role in maternal hemodynamic adaptations and in placentation and hypertensive disturbs during pregnancy (35). SARS-CoV-2 uses the protein angiotensin-converting enzyme the receptors 2 (ACE2) to invade cells, with potential implications for increased susceptibility to the virus during pregnancy (36). Obstetric outcomes were not the target in the current approach, even though they could be affected by COVID-19 (3, 5, 37).
Yet, this analysis has expected limitations that may affect the interpretation. Our sample size of pregnant women is limited. Maternal mortality was lower than Brazilian national rates (20), and the frequency of chronic hypertension was low. A specific predictive model for COVID-19 prognosis for inpatient pregnant women was not proposed. The results also do not apply to antenatal care since the inclusion criteria was pregnant women admitted with COVID-19. As a retrospective analysis, the quality of data as incompletude might have occurred. Thus, we reduced the risk of inaccuracies by performing several quality checks and rechecking hospital medical records whenever necessary.
Based on our results, we warn against the use of non-pregnant COVID-19 prognosis scores in pregnant women to predict adverse outcomes without proper validation. While insufficient control of pandemic keeps worldwide, fast and efficient assessment of prognosis of the COVID-19 is of utmost importance for early identification of cases at higher risk of worse outcome in this highly vulnerable group of women. Although several studies developed and validated risk scores to estimate prognosis in COVID-19 patients, there is a lack of scores focused on pregnant women specificities. Studies using data pools across national systems or healthcare data sharing frameworks are necessary to rapidly join and use clinical information relevant to COVID-19 during the pregnancy. Martinez-Portilla et al. reported a national model to predict death among women of reproductive age with COVID-19, highlighting pregnancy as a risk factor for death, pneumonia and intensive care unit admission (38); however without proposing a prediction model. Villar et al. provided consistent evidence that COVID-19 substantially increases maternal morbidity and mortality, and neonatal complications, in a multinational prospective cohort study, without proposing a risk score (5). Evidence-based modelling could provide a proper prognosis score assessment tool that will help guide decision-making, develop patient care plans, and better allocate resources. Additionally, we believe that a team of intensive care with the support of obstetrics specialists is necessary to make better decisions around COVID-19 upon pregnancy, identifying and prioritizing the care of those who have a higher risk of morbidity and mortality.