key: cord-0917148-03q2wgjh
authors: Salem, Deemah; Katranji, Fawzi; Bakdash, Talah
title: COVID‐19 infection in pregnant women: Review of maternal and fetal outcomes
date: 2020-12-27
journal: Int J Gynaecol Obstet
DOI: 10.1002/ijgo.13533
sha: d237d7920c490587639b5fa55ccd7019cab717e9
doc_id: 917148
cord_uid: 03q2wgjh

Pregnant women, their fetuses, and newborns are likely to represent a high‐risk population during the current coronavirus disease 2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). Literature on the outcomes of COVID‐19 infections during pregnancy is slowly building up. The aim of the present review was to gather evidence from relevant articles published in English from January to August 2020 in Medline and Google Scholar. The review revealed that pregnant women who become COVID‐19‐positive are usually either asymptomatic or mild‐to‐moderately symptomatic, similar to non‐pregnant women. Pneumonia is one of the most common outcomes in pregnant women with COVID‐19. However, it cannot be conclusively said that SARS‐CoV‐2 infection increases the risk of maternal, fetal, and neonatal complications. Pregnant women with COVID‐19 with co‐morbidities have increased risks of complications: there are regional variations in the rates of adverse outcomes reported. Though uncommon, the review shows that vertical transmission is possible. Additionally, the third trimester seems to be the most vulnerable period of infection. This aspect needs to be researched further to activate surveillance programs at the end of second trimester. Overall, it is necessary to monitor pregnant women before and after delivery, and their infants, during this pandemic.

In December 2019, a viral outbreak emerged from Wuhan in the Hubei province of China, reportedly being caused by a novel coronavirus. It has now spread worldwide and is one of the most severe public health threats. 1 The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease was called coronavirus disease 2019 (COVID-19). 1 On March 11, 2020, WHO announced COVID-19 as a "pandemic". 2 The physiologic and immunologic changes during pregnancy may result in systemic effects that predispose women towards complications from respiratory infections leading to maternal and fetal mortality and morbidity. 5, 6 Both SARS-CoV and MERS-CoV were known to be associated with adverse outcomes in pregnant women with greater mortality rates than the general population. 3, 7 With SARS-CoV-2 rapidly spreading, it is reasonable to contemplate that pregnant women are likely to get infected. 4 Worldwide concerns have been raised about the risk of intrauterine transmission of this virus from the mother to the fetus. 8, 9 The clinical characteristics and possibility of transmission of COVID-19 in pregnant women vertically or during delivery are still unclear. [8] [9] [10] The questions that require immediate attention include the following: whether the symptoms of the disease in pregnant women with COVID-19 differ from symptoms in non-pregnant women;

whether complications of the disease and mortality rate are higher in pregnant women than in non-pregnant women; and whether there is a chance of premature delivery or fetal mortality, or even vertical transmission of the disease. 11, 12 Finding answers to these questions are crucial for planning effective obstetrical management for pregnant women with COVID-19.

Given the importance of the issue, the present narrative review collates the literature assessing the effect of COVID-19 infection in pregnancy, including the maternal and fetal outcomes of COVID-19, vertical transmission, as well as the benefits of screening for COVID-19 in pregnant women.

A detailed literature search was carried out using databases such as Medline and Google Scholar. The following search terms were combined using Boolean operators "AND/OR": "COVID-19"; "SARS-CoV-2"; "Maternal effect"; "Maternal outcome"; "Fetal effect"; "Fetal outcome"; "Vertical transmission"; "Pregnancy outcome"; "Antenatal"; "Perinatal"; and "Screening." Relevant literature reporting both maternal and fetal outcomes of COVID-19 during pregnancy and published in English from January 1, 2020, to August 31, 2020, was retrieved. The retrieved literature was filtered to include only systematic reviews, meta-analyses, clinical trials, retrospective real-world studies, case series, and narrative reviews. No randomized trials were retrieved. Publications covering only maternal or fetal outcomes and those for which full text was not available were not included. In addition, publications covering the treatment and/or management of COVID-19 and/or its outcomes in pregnancy were not included in the narrative review. Of the remaining publications, the authors have tried to present a mix of different types of publications reporting unique data.

The principal transmission routes for SARS-CoV-2 include droplets and aerosols, mainly through inhalation of respiratory droplets produced by coughing or sneezing by infected persons. Moreover, transmission also occurs via hand to mouth/nose route from infected droplets deposited on different surfaces and objects. 13, 14 The virus transmission could potentially occur in individuals at a distance of 1 meter from the infected person. 14

Pregnancy causes physiological changes in the respiratory and circulatory systems as well as alterations in immunological reactions.

These are the primary factors that are likely to make pregnant women more vulnerable to viral infections. 15 The common changes in the respiratory system that are likely to increase the susceptibility of a pregnant woman to respiratory infections include reduced functional residual volumes, elevation of the diaphragm, relaxation of ligaments in the ribs, increased pulmonary hypertension resulting in hyperventilation, and even hypoxic respiratory failure. 15, 16 Altered cell immunity increases pregnant women's risk of an immunocompromised state, thereby making them more prone to develop worst outcomes. 15, 16 Moreover, viral infection in pregnancy can result in modification of the cardiovascular system, increased metabolic rate and consumption of oxygen, higher pulmonary vascular resistance, and even heart failure. 15 Additionally, during the third trimester of pregnancy, the probability of physical dyspnea is high (due to increased maternal oxygen demands, gestational anemia, and consumption of fetal oxygen) leading to further worsening of breathing difficulties. 16 It is important to note that pregnant women are susceptible to SARS-CoV-2 infection. 4 However, despite there being many respiratory, circulatory, and immunological factors that could increase a pregnant woman's risk of SARS-CoV-2 infection, the data available so far do not reflect an increased risk. In their literature review, Selim et al. 17 report very small absolute risks of SARS-CoV-2 infection in pregnancy. Also, there is no evidence to date that pregnant women are more susceptible to SARS-CoV-2 infection than non-pregnant women. 17 In general, the unique immunologic changes of pregnancy are thought to suppress the virulence of the virus. 17 The symptoms of COVID-19 in pregnant women are thought to be due to the direct effect of the virus on the mothers. 17 The disease course of SARS-CoV-2 in pregnant women seems to be either asymptomatic or with mild to moderate symptoms (fever and cough), similar to non-pregnant women. 16, 18, 19 In pregnant women presenting with severe symptoms (e.g. hypoxia, pneumonia, etc.), enhanced angiotensin-converting enzyme 2 (ACE-2) expression is thought to be linked to severity of symptoms. 17 A recent meta-analysis reported that less than 20% of pregnant women need admission to the intensive care unit (ICU). 20 In a Chinese study on hospitalized pregnant women with COVID-19, 77% had fever and 23% reported dyspnea. Of these cases, 23%

improved with treatment and discharged with ongoing pregnancy, while 46% had preterm labor at 32-36 weeks of pregnancy. Only 7.6% developed severe pneumonia and even multi-organ dysfunction, requiring ICU care and extracorporeal membrane oxygenation. 4 The rate of critical care in pregnant women with COVID-19 was similar to that reported in the general population (7.6% vs 5%). 4 Chen et al. 21 reported epidemiological, clinical, and laboratory characteristics and outcomes of 118 pregnant women with confirmed SARS-CoV-2 infection in China. Among them, 92% had mild disease and 8% had severe disease with hypoxemia. The condition of one patient was critical, requiring non-invasive mechanical ventilation, which was continued even after delivery. Six women developed severe disease after delivery; 94% were discharged without any complications and no death was reported. 21 The risk of severe disease among pregnant women was comparable with the risk reported in the general population suffering from COVID-19 across mainland China. 21

COVID-19 infection is very new. Data on clinical outcomes of pregnant women suffering from COVID-19 are therefore relatively scarce. 22 Selim et al. 17 report that SARS infection (but not SARS-CoV-2 infection) has been associated with a higher risk for intrauterine growth retardation, premature births, and spontaneous abortion. This is also reflected in a publication that shows that compared to maternal outcomes in SARS-CoV and MERS-CoV infections, the maternal outcomes in SARS-CoV-2 are more favorable, with lower morbidity and mortality, with case fatality rates of 18%, 25%, and 0%, respectively. 16 However, recently a meta-analysis of 13 publications (n = 114) reported preterm births, neonatal pneumonia, and respiratory distress syndrome in infants born of COVID-19-positive mothers. 20 There are also regional variations in the rate of maternal and neonatal complications. A meta-analysis by Dubey et al. 23 reported that the rates of cesarean deliveries and adverse pregnancy outcomes were substantially higher in Chinese studies (91% and 21%) compared to American (40% and 15%) and European studies (38% and 19%). Similarly, the rates of preterm births were lower in American studies (12%) compared to Chinese and European studies (17% and 19%, respectively). Therefore, since the infection is new, care should be taken to monitor COVID-19-positive pregnant women to prevent adverse maternal and fetal outcomes.

The reported maternal and fetal outcomes in pregnant women infected with COVID-19 are outlined in Table 1 .

As more and more data become available, it is becoming clear that maternal complications are common in pregnant women infected with SARS-CoV-2. 20, 23 Maternal complications in mothers positive for COVID-19 mostly included pneumonia. 4, [24] [25] [26] Other reported complications are premature rupture of membranes (PROM), pre-term deliveries, fetal distress, increased cesarean deliveries, lymphopenia, elevated C-reactive protein, gestational hypertension, diabetes, pre-eclampsia, placenta previa, oligohydramnios, polyhydramnios, hypothyroidism, abnormal umbilical cord, and sinus tachycardia. 4, 12, 20, 23, [26] [27] [28] [29] [30] [31] In the past, SARS infection was found to increase the risk of fetal distress, and gestational diabetes and pre-eclampsia are known to be higher in MERS infection, but no such correlation can be established for SARS-CoV-2. 31 However, morbidity and mortality were found to be quite low in pregnant patients with COVID-19. 11, 12, 21, 24, 28, 30, 32, 33 In general, a systematic review of the literature shows that pregnant women positive for COVID-19 with co-morbidities are more likely to develop complications than those without. 34 

Pneumonia is one of the most common outcomes in pregnant women infected with COVID-19. However, the majority were asymptomatic upon admission to hospital, and none experienced severe respiratory failure during hospital stay and none died. 26 In another single-center Chinese study, mild pneumonia was diagnosed in all pregnant patients with COVID-19 at the time of admission to hospital for delivery. However, no acute respiratory distress syndrome and aggravation of pneumonia were observed in the whole course. 22 Even though all parturient patients required oxygen support, none required mechanical ventilation and the recovery was good. 22 In their single-center case-control study (n = 55; 13 cases, 42 controls), Yang et al. 36 reported that pregnant women with confirmed SARS-CoV-2 infection did not have expectoration, myalgia, or dyspnea; however, their pulmonary CT scan images resembled COVID-19 pneumonia with ground-glass opacity (46.2%), patch-like shadow (23.1%), pleural effusion (38.5%), and pleural thickening (7.7%). Although the pleural effusion was significantly higher in pregnant women than non-pregnant women, none showed any adverse effects. 36 In a case series from Iran with nine pregnant women in the second or third trimester, the initial symptoms at the time of presentation in all of them were fever, dry cough, and dyspnea, and three patients later developed COVID-19 pneumonia. Seven women died and two survived: one was critically ill and dependent on a ventilator; and the other was cured after a prolonged hospital stay. Neither of them had pre-existing co-morbidities. 37 

Reports of worse clinical outcomes in pregnant women with COVID-19, and even death, are also reported from countries outside of TA B L E 1 Pregnancy outcomes in women with COVID-19 seen in various studies Author 

Neonatal outcomes of COVID-19 mostly included preterm birth (39%), fetal distress (43%), intrauterine growth retardation (10%), miscarriage (2%), and perinatal death (7%). 16 

The risk of vertical transmission can theoretically exist in COVID-19 since angiotensin-converting enzyme 2 (ACE-2) receptors are significantly expressed in the placenta with which SARS-CoV-2 may bind and enter. Intrauterine vertical transmission may typically occur through trans-placenta, or ingestion or aspiration of cervicovaginal secretions. 32, 43 Multiple studies confirmed the absence of SARS-CoV-2 isolates in the amniotic fluid, cord blood, breast milk sample, and neonatal throat swabs of the infected mother, indicating that intrauterine transmission, transmission during vaginal delivery, or through lactation was not possible. 11, 12, 16, 32, 42 In the majority of the cases, the infected women gave birth to healthy babies with an Apgar score above 7 and negative reverse transcription polymerase chain reaction (RT-PCR) test results. 11, 22, 32 Moreover, for pregnant women from areas of high prevalence, universal testing is strongly recommended due to an increased probability of presentation of asymptomatic patients to labor and delivery units from these areas. 47 It is important to note that RT-PCR is often not able to detect SARS-CoV-2 infection and therefore some pregnant women with COVID-19 pneumonia may be missed unless a CT scan is performed. 30 

The present narrative review has several limitations. Most of the studies included in the systematic reviews and meta-analyses are from China. Thus, there is regional bias due to genetic and environ- with co-morbidities. There are regional variations in the rates of adverse outcomes reported. Though vertical transmission is noted in very few cases, the review shows that it is possible. Additionally, the third trimester seems to be the most vulnerable period of infection and this aspect needs to be researched further to activate surveillance programs at the end of the second trimester. Further studies are warranted to assess whether the higher rates of adverse outcomes reported in mothers with COVID-19 with co-morbidities are due to the co-morbidities or whether the SARS-CoV-2 infection worsens the disease course in these mothers. Multicenter global trials are required to look into the reasons for regional variations and understand why some regions report very few adverse outcomes.

This would be helpful in developing a screening, diagnostic, and management algorithm to reduce adverse outcomes in mothers with COVID-19.

The authors acknowledge Turacoz Healthcare Solutions (www.turac oz.

com) for assistance with the manuscript writing.

DS was responsible for the design, planning, and writing of the manuscript. FK and TB were responsible for the literature data analysis for the review.

The authors have no conflicts of interest.

https://orcid.org/0000-0002-7986-1780

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