Comparison of in-hospital mortality of COVID-19 between pregnant and non-pregnant women infected with SARS-CoV-2: a historical cohort study

Introduction

World Health Organization (WHO) announced the identification of Severe Acute Respiratory Syndrome Corona Virus type 2 (SARS-CoV-2) that caused Corona Virus Disease-2019 (COVID-19) in 2020 [1, 2]. Up to 17 September 2021, Iran was ranked 8th regarding the number of confirmed cases and 11th concerning the number of deaths (https://covid19.who.int).

Pregnancy is a susceptible period of every woman’s life; however, there are still controversies regarding maternal mortality due to COVID-19 [3], [4], [5], [6], [7]. Older age and history of underlying diseases are among the confirmed risk factors of COVID-19 mortality [8, 9]. This study aimed to compare hospitalized pregnant and non-pregnant women infected with SARS-CoV-2 regarding the mortality rate of COVID-19.

Materials and methods

Results

Among the 32,315 laboratory-confirmed SARS-CoV-2 cases reported to the MCMC, 48.5% (15,682/32,315) were female and 51.5% (16,633/32,315) were male. The proportion of SARS-CoV-2 infected females was significantly lower compared to the infected males (z-statistics=5.4, p<0.001). Among the 15,682 female cases, 34% (5,322/15,682) aged 15–49 years. Additionally, 6.2% (330/5,322) were pregnant and 93.8% (4,992/5,322) were not. The baseline features including demographic characteristics, COVID-19 symptoms, and history of underlying diseases for 5,322 SARS-CoV-2 infected women aged 15–49 years by pregnancy status have been compared in Table 1.

Based on the results, the pregnant women were significantly younger than non-pregnant ones (p<0.001). However, the two groups were similar regarding the history of smoking, opium use, previous COVID-19 infection, COVID-19 symptoms, and vaccination against SARS-CoV-2 (p=0.37, 0.27, 0.58, 0.62, and 0.53, respectively). Pregnant and non-pregnant women also reported similar frequencies of cough, muscular pain, loss of consciousness, loss of sense of smell, loss of sense of taste, convulsion, gastric pain, diarrhea, paresis, plegia, and skin lesions (p=0.27, 0.43, 0.08, 0.76, 0.14, 0.62, 0.25, 0.29, 0.2, 0.49, and 0.3, respectively). However, fever, respiratory distress, nausea, vomiting, anorexia, headache, vertigo, and chest pain were significantly less frequent in the pregnant women (p=0.002, <0.001, 0.001, 0.01, 0.001, <0.001, 0.009, and 0.01, respectively).

The results indicated that the pregnant women were less likely to develop underlying diseases (p<0.001). Nonetheless, the two groups were similar regarding diabetes mellitus, cancer, chronic liver disease, chronic blood disease, HIV/AIDS, chronic renal failure, dialysis status, chronic pulmonary diseases, and chronic nervous disease (p=0.08, 0.1, 0.4, 0.54, 0.65, 0.14, 0.34, 0.09, and 0.13, respectively). However, immune deficiency, cardiovascular diseases, chronic respiratory syndrome, asthma, and HTN were less frequent among the pregnant women (p=0.04, 0.03, 0.005, 0.02, and <0.001, respectively). It should be noted that according to the utilized data, it could not be determined whether the present chronic underlying diseases were associated with pregnancy or not (e.g., gestational diabetes or gestational hypertension).

The fatality rates of COVID-19 were found to be 3.5% (174/4,992) in non-pregnant women and 1.2% (4/330) in pregnant ones.

Clinical manifestations including number of days after the onset of COVID-19 symptoms, ICU admission, mechanical ventilation, long involvement, and death among the 5,322 15–49-year-old women infected with SARS-CoV-2 by pregnancy status have been presented in Table 2.

Discussion

The fatality rate of COVID-19 was 1.2% and 3.5% in hospitalized SARS-CoV-2-infected pregnant and non-pregnant women, respectively. Hospitalized pregnant women were similar to non-pregnant ones regarding the history of smoking, opium use, previous COVID-19 infection, vaccination against SARS-CoV-2, and COVID-19 symptoms. However, they were significantly younger and had fewer underlying diseases. The two groups were also similar in terms of cough, muscular pain, loss of consciousness, loss of sense of smell, loss of sense of taste, convulsion, gastric pain, diarrhea, paresis, plegia, and skin lesions. However, fever, respiratory distress, nausea, vomiting, anorexia, headache, vertigo, and chest pain were significantly less frequent in the pregnant women. Moreover, the two groups were homogeneous concerning the frequency of underlying diseases including diabetes mellitus, cancer, chronic liver disease, chronic blood disease, HIV/AIDS, chronic renal failure, dialysis status, chronic pulmonary diseases, and chronic nervous disease. Nonetheless, immune deficiency, cardiovascular disease, chronic respiratory syndrome, asthma, and HTN were significantly less frequent amongst the pregnant women, which implied that pregnancy was followed by a healthier life. It was also shown that hospitalized pregnant women infected with SARS-CoV-2 were more likely to receive ICU admission compared to non-pregnant ones. However, no differences were detected between the two groups regarding the number of days after the onset of COVID-19 symptoms, mechanical ventilation, and long involvement. After adjusting for age, history of underlying diseases, and ICU admission, a lower in-hospital death was seen in pregnant women compared to non-pregnant ones. Nevertheless, they had to follow the same recommendations as non-pregnant women including avoiding exposure to the virus and receiving medical treatment and vaccination. Yet, further studies are required to address the follow-up of recovered pregnant women, their babies, and puerperium.

The current study estimated a lower rate of in-hospital fatality for COVID-19 in comparison to SARS and MERS (1.2% vs. 25.8 and 28.6%) during pregnancy [2]. In parallel to the current findings, in-hospital fatality rate of COVID-19 was reported to be lower in pregnant women than in no-pregnant ones (0.8% vs. 3.5%) in the USA [10].

Previously, symptomatic pregnant women with COVID-19 reported similar frequencies of cough and respiratory distress to their non-pregnant counterparts. Nonetheless, headache, muscle pain, fever, and diarrhea were reported to be less frequent [8, 11, 12]. In the current study, however, the frequency of cough, muscle pain, and diarrhea was the same in the two groups, while headache, respiratory distress, and fever were significantly less frequent among the pregnant women. However, one study done in Egypt reported no significant difference between the two groups in this regard [13]. Diabetes mellitus and cardiovascular diseases were among the most important comorbidities responsible for death due to COVID-19 during pregnancy [2, 14, 15]. Nevertheless, the current study findings indicated that the frequency of diabetes mellitus was the same in the two groups and cardiovascular diseases were significantly less frequent among the pregnant women.

Two confirmed risk factors in pregnancy were higher age and underlying diseases [16, 17], which was in line with the risk factors detected in the current investigation.

Regarding the in-hospital clinical manifestations of COVID-19 in pregnancy, some studies revealed that hospitalized pregnant women had a higher odds of ICU admission compared to non-pregnant ones [8, 18], which was in agreement with the current study findings. Other studies also reported similar mechanical ventilation in the two groups [13, 18, 19]. Some studies, however, reported a higher rate of mechanical ventilation [8, 19].

There are discrepancies regarding the effect of SARS-CoV-2 infection on maternal mortality. The association has been shown to diverge based on the adjusted risk factors in the model. Some studies have reported higher mortality rates in pregnant women compared to no-pregnant ones. For instance, one systematic review and meta-analysis including 31,469 women reported a higher rate of maternal mortality adjusting on mechanical ventilation. A cohort study on 10,366 women also revealed a higher rate of maternal mortality adjusting on background demographic and medical factors. Finally, a historical cohort study including 240 pregnant women reported that the in-hospital fatality rate was 13.6 folds higher in pregnant women [8, 18, 20, 21]. However, some studies have reported no significant association between the pregnancy status and in-hospital death due to COVID-19. As an example, a cohort study including 64 pregnant women done in Egypt revealed the same crude odds of death in pregnant women. Another historical cohort study including 22,493 women in the USA showed the same mortality after adjusting for comorbidities and age. A systematic review and meta-analysis including 31,710 women also reported the same mortality rates adjusting on comorbidities and age [8, 13, 19]. Some studies, however, have indicated a lower rate of in-hospital death due to COVID-19 in pregnant women compared to no-pregnant ones. For example, a historical cohort study including 1,062 pregnant and 9,815 non-pregnant ones in the USA demonstrated substantially lower rates of in-hospital mortality within the ICU admitted group. Another historical cohort study including 97,712 women in Brazil revealed that pregnant women had a lower risk of in-hospital mortality after adjustment for sociodemographic factors, epidemiological characteristics, and comorbidities. They concluded that pregnancy appeared to have a favorable effect on SARS-CoV-2 infection [10, 22]. In addition, some systematic reviews and meta-analyses have reported lower rates of maternal mortality due to COVID-19 [7, 8, 22, 23].

A prior epidemiological study revealed that female gender was 50% less likely to expire due to COVID-19 in comparison to male gender [18]. Accordingly, females in the reproductive ages (15–49 years) experienced a 60% decline in severe clinical manifestations compared to their aged-matched males in the control group [18, 24]. Generally, the immunological response to SARS-Cov-2 infection relies on the appropriate function of the immune system; the immune system adapts during pregnancy to allow for the implantation and growth of the semi-allogenic fetus [25], [26], [27]. The altered immune response during pregnancy may be partially induced by the inflammatory response to the pathogenesis of infection as well as by the circulating progesterone that has immiuno-dualatory properties [28]. Progesterone also has the ability to repair damages caused by viruses [29]. Considering no intra-uterine transmission for SARS-CoV-2 [3, 7, 30, 31], both the infected mother and her healthy fetus may fight against SARS-CoV-2. The abovementioned reasons alongside the fact that the pregnant women were found to be younger and healthier and had no physiological problems can justify the lower mortality rate of COVID-19 in pregnant women compared to their non-pregnant counterparts.