INTRODUCTION

The COVID-19 pandemic has caused more than 615 million confirmed cases and more than 6.5 million deaths worldwide ¹. In Peru, despite initial containment measures, there were more than four million cases, with Metropolitan Lima, Arequipa and Piura being the departments with the most confirmed cases, and Lima, Piura and La Libertad having the highest mortality rates ².

The clinical manifestations of patients infected with COVID-19 occur approximately 7 to 14 days after the infection ³. Flu-like symptoms are the most common ones and may progress to severe illness with respiratory failure and the need for mechanical ventilation, admission to the intensive care unit or death ³. The Peruvian Ministry of Health (MINSA) classifies COVID-19 infection by severity: asymptomatic, mild, moderate and severe ⁴. This classification can be applied to vulnerable patients, such as pregnant women.

Due to metabolic and physiological changes, pregnant women may present alterations in the immune system, making them more susceptible to COVID-19 ⁵. Immunological adaptations have been described, such as a decrease in the number of CD4+, CD8+ and natural killer lymphocytes, which could be associated with a lower response to viral infections such as SARS-CoV-2 ⁶. It has also been reported that pregnant women with symptoms of COVID-19 infection are more prone to maternal and perinatal complications ⁷.

Several systematic reviews have described that pregnant women with COVID-19 have higher maternal mortality rates ⁸, greater maternal stress ⁸, ruptured ectopic pregnancies ⁹, postpartum hemorrhage ¹⁰, cesarean deliveries ^8,10-12, preterm delivery ^8,10-12 and premature rupture of membranes ¹². Likewise, abnormal APGAR scores ⁹, neonatal asphyxia ⁹, stillbirth ^8,9, fetal death ⁸ and low birth weight ¹⁰ were found in children born to infected mothers. In Peru, several studies have shown similar results ^13-15. These findings raise the hypothesis that symptoms in COVID-19-infected pregnant women may be associated with adverse maternal and perinatal outcomes.

Although several studies have assessed the association between severe symptoms of infection and adverse maternal-perinatal outcomes ^16,17, none have evaluated whether differences exist depending on the presence or absence of infection symptoms. Considering that most infected pregnant women are asymptomatic ¹⁰, the results of a study that evaluates this hypothesis could reinforce the evidence on the need to prioritize the care of pregnant women in a health system with structural problems, such as the Peruvian one ¹⁸. Therefore, this study aimed to determine the association between symptoms of COVID-19 infection and adverse maternal-perinatal outcomes in a referral hospital.

MATERIALS AND METHODS

RESULTS

During 2020, 272 pregnant women in labor were admitted to Santa Rosa Hospital and diagnosed with COVID-19, of whom 50.3% had symptoms of infection. Of all the pregnant women, 89.3% did not have complete prenatal controls, 35.7% had an adverse maternal outcome and the most frequent maternal complication was premature rupture of membranes. Of the 272 newborns born to infected pregnant women, 16.5% had adverse outcomes, the most frequent being acute fetal distress (7%). Other general characteristics are shown in Table 1.

During the bivariate analysis between symptoms of COVID-19 infection and adverse maternal outcomes, we found significant differences between premature rupture of membranes (p<0.001) and postpartum hemorrhage (p=0.010) (Table 1). Significant differences were found between adverse perinatal outcomes and having an Apgar <7 at 1 minute (p=0.040), low birth weight (p=0.010), prematurity (p=0.029) and acute fetal distress (p=0.030) (Table 1). While individually, not all adverse outcomes were found to be associated with symptoms of COVID-19 infection; when grouped together, we found an association between being symptomatic with adverse maternal (p<0.001) and adverse perinatal outcomes (p<0.001) (Table 1).

The adjusted multivariate analysis showed that symptoms of COVID-19 infection increased the risk of maternal complications as a whole (PR= 2.32 95%CI:1.61-3.34). The disaggregated analysis showed that COVID-19 infection increased the risk of premature rupture of membranes (PR= 2.73 95%CI:1.51-4.94), and preeclampsia (PR= 2.73 95%CI: 1.51-4.94) (Table 2). Similarly, symptoms of COVID-19 infection were found to increase the risk of perinatal complications as a whole (PR= 2.51 95%CI: 1.34-4.68), and in the disaggregated analysis, it increased the risk of acute fetal distress (PR=2.99 95%CI: 1.07-8.38) (Table 3).

DISCUSSION

Our results show that 3 out of 10 pregnant women with symptoms of COVID-19 infection had adverse maternal outcomes and 2 out of 10 newborns of infected mothers had adverse perinatal outcomes. Having symptoms of COVID-19 infection nearly tripled the risk of preterm rupture of membranes and preeclampsia. Likewise, it tripled the risk of acute fetal distress.

We found a lower proportion of adverse maternal-perinatal outcomes compared to a Peruvian study that reported 48.8% of obstetric complications ¹³ and a study in Kuwait that reported that 26.6% of pregnant women had preterm delivery ²⁵. In contrast, our results are similar to those of a systematic review that reported that, among pregnant women with symptoms of COVID-19 infection, 18% had preterm delivery, 19% had low birth weight and 14% had fetal distress ³². The differences may be associated with the way in which the variables were defined and the way in which the study samples were selected, resulting in varying prevalence. For example, the Peruvian study ²⁶ classified the Apgar variable according to different scores to determine depression in the newborn (≤5 points), whereas we used scores <7 as a cut-off point. It is important to point out that, at the beginning of the pandemic, Peru had a collapsed health system, where structural deficiencies did not improve significantly during the pandemic ¹⁸; this, together with mobility restrictions, probably caused poor prenatal control and, therefore, increased the risk of maternal-perinatal complications. Nevertheless, it is possible that following national recommendations on the management of pregnant women during the pandemic could have had a positive effect ³³.

The association between symptoms of COVID-19 infection and maternal-perinatal complications was significant. These results are similar to a systematic review of 42 studies that found that symptomatic pregnant women had an increased risk of preterm delivery when compared to asymptomatic pregnant woman ¹⁶. Likewise, a multinational cohort study conducted in 18 countries found that gestational age at delivery was 0.8 weeks lower in symptomatic than in asymptomatic pregnant women ²⁷. Overall, the presence of any symptom increased the association with adverse outcomes.

Although asymptomatic women diagnosed with COVID-19 infection were at limited risk for most outcomes, there was still an association with preeclampsia ²⁷. The presence of fever and shortness of breath, alone or in combination with any group of symptoms, was strongly associated with the risk of preterm delivery ²⁷. Another study in the United States found that, compared with asymptomatic patients, adverse perinatal outcomes were more frequent among pregnant women with severe disease, including hypertensive disorders of pregnancy and preterm delivery ²⁸. In contrast, mild to moderate infection was not associated with adverse perinatal outcomes compared with asymptomatic patients ²⁸.

Although the reasons for the association between symptoms of COVID-19 infection and adverse maternal-perinatal outcomes are unclear, it may be related to the role of immune cell imbalance in symptomatic cases, particularly in severe cases ²⁹. During normal pregnancy, the ratio of regulatory T lymphocytes (Treg) to T-helper 17 (Th17) lymphocytes shifts towards Treg cells, which proliferate systematically. Several studies mention that the decrease in the number of Treg cells as well as the increase in Th17 cells are associated with pregnancy complications such as miscarriage, preeclampsia and preterm labor ³⁰. Dysregulation of these two cells towards an increase in Th17 cells has been described in patients with symptoms of COVID-19 infection, resulting in uncontrolled systemic inflammation, which worsens with the severity of the infection ²⁹. SARS-CoV-2 infection may cause a systemic inflammatory response associated with the pathogenesis of preterm delivery or a suboptimal environment for fetal growth and development ¹⁶. Similarly, hypercoagulability is associated with the occurrence of preeclampsia ³⁴. Additionally, poor placental vascular perfusion has also been reported by placental histopathological studies in patients with symptoms of COVID-19 infection at the time of delivery, which may contribute to poor growth, fetal death or premature delivery or hypertensive disorders ^16,31. In that regard, a quasi-experimental study in the Netherlands found that symptom mitigation measures for COVID-19 infection were associated with a decrease in the incidence of preterm delivery ³⁵. However, by mechanisms not entirely understood, symptoms are not associated with all complications; thus, a systematic review did not find symptoms of COVID-19 infection associated with gestational diabetes ¹⁶.

Although cases and mortality due to COVID-19 have decreased, this infection will persist in the community. In this sense, our results could influence medical care and referral strategies in the case of infected pregnant women.

This research has some limitations. First, the cross-sectional study was developed in 2020 during the first wave of the pandemic; therefore, the effect that new variants may have on the presence of symptoms in infected pregnant women was not considered. On the other hand, the lack of control of socioeconomic variables could affect some maternal outcomes such as postpartum hemorrhage, prematurity or low birth weight. Besides, the diagnosis of most patients was made with IgG/IgM immunological tests which, although not the current standard, was recommended by MINSA during 2020, which may alter the prevalence of infected pregnant women and the frequency of their complications. The data were obtained from medical records filled out by hand by the attending physician, so there may be omissions at the discretion of the evaluator. Finally, the study was carried out in a MINSA hospital, so its results cannot be generalized to other institutions in the country. However, one of the strengths of this study is that it was carried out in a category III national referral hospital with comprehensive obstetric care.

In conclusion, symptoms of COVID-19 infection in infected pregnant women and their newborns were associated with a higher probability of developing adverse outcomes in a referral hospital in Peru. Strategies regarding prevention and timely detection of COVID-19 symptoms in pregnant women should be improved. In addition, it is necessary for health personnel to continue monitoring the newborns of infected pregnant women before, during and after delivery, due to the high risk of complications.