Obstetric Management of COVID-19 in Pregnant Women

The 2019 novel coronavirus disease (COVID-19), which is caused by the novel beta coronavirus, SARS-CoV-2, is currently prevalent all over the world, causing thousands of deaths with relatively high virulence. Like two other notable beta coronaviruses, severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 can lead to severe contagious respiratory disease. Due to impaired cellular immunity and physiological changes, pregnant women are susceptible to respiratory disease and are more likely to develop severe pneumonia. Given the prevalence of COVID-19, it is speculated that some pregnant women have already been infected. However, limited data are available for the clinical course and management of COVID-19 in pregnancy. Therefore, we conducted this review to identify strategies for the obstetric management of COVID-19. We compared the clinical course and outcomes of COVID-19, SARS, and MERS in pregnancy and discussed several drugs for the treatment of COVID-19 in pregnancy.


INTRODUCTION
The COVID-19 outbreak emerged in 2019. The causative pathogen for COVID-19 was identified as a novel beta coronavirus, SARS-CoV-2, which is genetically related to severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV; Lu et al., 2020). Furthermore, SARS-CoV-2 and SARS-CoV-1 share the same cellular receptor, angiotensin-converting enzyme 2 (ACE2), despite amino acid variation at some key residues (Chan et al., 2020). All three coronaviruses can cause severe infectious respiratory disease. Currently, COVID-19 has spread across multiple countries (Holshue et al., 2020;Hui et al., 2020), and it is reasonable to speculate that some pregnant women have been infected. However, little is known about the clinical course and the obstetric management of COVID-19 in pregnancy. Available data could be drawn from cases of pregnancy complicated with SARS and MERS. This review was conducted to investigate the clinical course and outcome of COVID-19 in pregnancy and to discuss several drugs that could be used for pregnant women with COVID-19.

COMPARISON OF COVID-19, SARS, AND MERS IN PREGNANCY
We searched PubMed and the China National Knowledge Infrastructure Database for literature that was published up to March 30, 2020, using the keywords "coronavirus, " "pregnant, " or "neonate." Data about pregnancy with COVID-19, SARS, and MERS were extracted and compared by gestational age. Table 1 shows maternal clinical characteristics, and Table 2 shows treatment and perinatal outcomes of the three coronavirus infections in pregnancy.
Twenty-nine cases of COVID-19 during pregnancy were found in five reports (Chen H. et al., 2020;Chen S. et al., 2020;Yu et al., 2020;Zhao et al., 2020;Zhu et al., 2020). One patient was infected in the second trimester , and the others in the third trimester (Chen H. et al., 2020;Chen S. et al., 2020;Yu et al., 2020;Zhu et al., 2020). The pregnant woman infected in the second trimester had symptoms of fever, cough, malaise, and subsequently dyspnea. Blood counts showed lymphopenia, and computed tomography (CT) revealed diffused bilateral infiltrates in the lungs. She was given lopinavir/ritonavir, interferon α-2b, methylprednisolone, abidol, and gamma globulin successively. After 18 days of treatment, her condition improved, and virus nucleic acid testing for SARS-CoV-2 was negative twice. Thus, she continued with the pregnancy. On the other hand, the main symptoms of the other 28 patients infected in the third trimester were fever (89.3%), cough (35.7%), and myalgia (14.3%). CT images of 27 patients showed multiple patchy ground-glass shadows in the lungs. Three patients had elevated liver enzymes and nine developed fetal distress. In 17 patients who had detailed treatment data, all patients received oxygen support via a nasal cannula, 14 patients underwent antiviral therapy, and 16 patients underwent antibiotic treatment. As a result, 26 patients delivered via cesarean section and two patients via vaginal delivery. All neonates survived except for one. It should be noted that in the study by Zhu et al. some neonates born to mothers with COVID-19 had adverse neonatal outcomes such as premature labor, respiratory distress, thrombocytopenia accompanied by abnormal liver function, and even death .
With regard to SARS, 19 cases have been reported during pregnancy (Zhang et al., 2003;Robertson et al., 2004;Wong et al., 2004;Yudin et al., 2005). Seven patients became infected in the first trimester, five patients in the second trimester, and seven patients in the third trimester. The most common symptoms of infected pregnant women included fever (100%), cough (78.9%), and myalgia (68.4%). Lymphocytopenia was observed in 15 pregnant women, and chest radiographs of all pregnant women indicated viral infection in the lungs. Twelve pregnant women were given antiviral drugs, 14 pregnant women were given antibiotic drugs, and 12 pregnant women were given corticosteroids. Spontaneous miscarriage was observed in four out of seven patients who were infected in the first trimester. Three of the 19 pregnant women died; however, all the neonates who were delivered in the second or third trimester survived. Two cases suffered from fetal growth restriction and oligohydramnios, four cases developed fetal distress, and there was one case of spontaneous preterm birth.
Eleven cases of pregnancy with MERS were reported (Payne et al., 2014;Alserehi et al., 2016;Assiri et al., 2016;Malik et al., 2016;Park et al., 2016;Alfaraj et al., 2019). One patient was infected in the first trimester, five patients in the second trimester, and six patients in the third trimester. Most pregnant women presented with dyspnea (72.7%), cough (63.6%), and fever (54.5%); their chest radiographs revealed typical signs of viral infection. Unfortunately, there were no detailed treatmentrelated data. The woman infected in the first trimester continued pregnancy after her virus nucleic acid testing for MERS-Cov turned negative. Two patients had stillbirths, and one patient developed placental abruption. Three pregnant women and three neonates died.

DIAGNOSIS AND TREATMENT OF COVID-19 IN PREGNANCY
The diagnosis of COVID-19 in pregnancy is mainly based on epidemiological history, clinical manifestations, chest radiography, and etiological tests (National Health Commission of the People's Republic of China, 2020). This is similar to the evidence of diagnosis for SARS and MERS in pregnancy. According to our literature review, most pregnant women infected by the three coronaviruses had an epidemiological contact history. Fever, cough, myalgia, and dyspnea are the major symptoms. CT images revealed typical signs of viral infection in the lungs. Nasopharynx swab or sputum was positive in the virus nucleic acid test. Lymphopenia and elevated liver enzymes were commonly seen in pregnant women with COVID-19 and SARS.
According to the seventh guidelines published by the National Health Commission of China, the treatment of COVID-19 mainly involves oxygen therapy, antiviral therapy, and supportive treatment (National Health Commission of the People's Republic of China, 2020). At present, there is no antiviral drug for the treatment of COVID-19; therefore, identifying an antiviral drug against COVID-19 in pregnancy is imperative.
Interferon-alpha is a broad-spectrum antiviral drug that activates antiviral protein genes and modulates immune cell function (Totura and Bavari, 2019). For SARS-CoV-1 and MERS-CoV, interferon-alpha was effective at reducing viral replication in vitro and in vivo (Cinatl et al., 2003;Falzarano et al., 2013a,b). Regarding its safe use in pregnant women, one systematic review suggested that interferon-alpha does not significantly increase the risk of adverse perinatal outcomes above general population rates (Yazdani Brojeni et al., 2012).
Lopinavir/ritonavir is a human immunodeficiency virus (HIV) protease inhibitor that was found to target the SARS-CoV-1 nonstructural protein 3CLpro in vitro (Lu, 2020). During the SARS-CoV-1 epidemic, lopinavir/ritonavir combined with ribavirin reduced the viral load and decreased the rate of death or ARDS (Chu et al., 2004). Lopinavir/ritonavir also increased the viral clearance rate and survival rate in patients with MERS (Chan et al., 2015). Lopinavir/ritonavir was also administered to pregnant women with HIV. It was found that HIV proliferation was effectively suppressed during pregnancy and through 1 year postpartum (Cohan et al., 2015). Furthermore, the rate of preterm deliveries, low-birth-weight neonates, stillbirths, and birth defects did not increase (Roberts et al., 2009;Cohan et al., 2015).
Frontiers in Microbiology | www.frontiersin.org In addition, ribavirin and favipiravir are representative of a guanosine analog. Mechanically, ribavirin and favipiravir can inhibit virus RNA synthesis by viral RNA-dependent RNA polymerase and inhibit mRNA capping (Totura and Bavari, 2019). In the previous literature, ribavirin was administered to pregnant women with SARS. However, it was found that ribavirin at the concentration of typical human regimens could not significantly inhibit coronavirus replication in vitro (Shen et al., 2016). Furthermore, meta-analyses have found that its role was limited in the treatment of coronavirus-related respiratory syndromes (Stockman et al., 2006;Morra et al., 2018). The resistance might be explained by nsp14 exoribonuclease being expressed by coronavirus. As nsp14 exoribonuclease can function as an excision nucleoside analog due to its proofreading activity (Minskaia et al., 2006), it is speculated that COVID-19 might also be resistant to ribavirin or favipiravir (Chan et al., 2020).
In contrast, remdesivir, a nucleoside analog, could act against both SARS-CoV-1 and MERS-CoV in vitro (Sheahan et al., 2017). In vivo, remdesivir was more effective than lopinavir/ritonavir combined with interferon-β in decreasing the viral load of mice infected with MERS-CoV (Sheahan et al., 2020). The mechanism involved is that it can interfere with the nsp12 polymerase even in the setting of nsp14 exoribonuclease proofreading activity (Agostini et al., 2018). As expected, remdesivir was proved to be effective in the inhibition of SARS-CoV-2 replication in vitro (Wang et al., 2020a). However, data about its safety during pregnancy are absent.
Initially, chloroquine was used as an antimalarial drug. It was later found to act against SARS-CoV-1 in primate cells either before or after exposure to the virus (Vincent et al., 2005). Recently, chloroquine was found to inhibit the proliferation of SARS-CoV-2 in vitro (Wang et al., 2020a). The mechanism involved might be that it interferes with terminal glycosylation of ACE2 (Vincent et al., 2005). As to its safety in pregnancy, chloroquine was not shown to be associated with birth weight, gestational age, growth, or development of newborns, neurological development, and visual acuity in infants in the previous literature (Villegas et al., 2007;Ward et al., 2007;Divala et al., 2018).
Arbidol, which is a broad-spectrum antiviral drug whose mechanism involves inhibition of enveloped virus membrane fusion, has also been used (Blaising et al., 2014). Arbidol and arbidol mesylate were effective in suppressing the proliferation of SARS-CoV-1 in vitro (Khamitov et al., 2008). Furthermore, arbidol was effective against SARS-CoV-2 in vitro (Wang et al., 2020b). In Russia, arbidol was administered to pregnant women with influenza (Bulgakova et al., 2017). In our the studies included in our literature review, arbidol was found to have been administered to pregnant women with COVID-19 Zhao et al., 2020). However, its safety in pregnancy requires further research.
In summary, interferon-alpha, lopinavir/ritonavir, and chloroquine could be administered to pregnant women with COVID-19 after patients were fully informed of these drugs' benefits and risks. Remdesivir and arbidol are promising antiviral drugs against COVID-19; however, their safety in pregnancy requires further research. In addition, antibiotics and corticosteroids are recommended in pregnancy with COVID-19 if necessary (Mer and Richards, 1998;Wong et al., 2003). However, antibiotics should not be used without indication, and high doses of glucocorticoids should be avoided as much as possible (National Health Commission of the People's Republic of China, 2020).

PERINATAL OUTCOMES OF COVID-19 IN PREGNANCY
Due to impaired cellular immunity and physiological changes, mild pneumonia is more likely to develop into severe pneumonia in pregnant women, and severe pneumonia is deleterious for the fetus (Lam et al., 2004;Goodnight and Soper, 2005). Thus, timely pregnancy termination may be beneficial for both mothers and infants if the disease advances. As to the mode of pregnancy   Pathological examination of placentas from women with COVID-19 showed various degrees of fibrin deposition inside and around the villi with local syncytial nodules, concomitant with the morphology of chorionic hemangioma or massive placental infarction (Chen S. et al., 2020). Further, the results from SARS-related pregnancies revealed increased intervillous, subchorionic fibrin, or extensive fetal thrombotic vasculopathy (Ng et al., 2006). It was speculated that these placental pathological morphological changes were caused by hypoxia during coronavirus infection, and they may result in IUGR, meconium-stained amniotic fluid, or fetal distress. Similarly, miscarriage and stillbirth could also result from hypoxia caused by coronavirus infection. Therefore, pregnant women with COVID-19 should be closely monitored, even after their nucleic acid test for SARS-Cov-2 turns negative.
In the studies included in our literature review, all pregnant women with COVID-19 and their neonates survived except for one neonate . However, several pregnant women with SARS or MERS died or had a stillbirth, and some neonates failed to survive. It is speculated that COVID-19 during pregnancy might be less severe than SARS or MERS during pregnancy. This is consistent with the conclusion that the mortality rate of COVID-19 is less than that of SARS or MERS (Han et al., 2020;Liao et al., 2020).
Amniotic fluid, cord blood, placenta, and the fetal membrane from pregnant women with COVID-19, SARS, and MERS were all negative when tested with a viral nucleic acid test for SARS-CoV-2, SARS-CoV-1, and MERS-CoV, respectively, in the studies included in our literature review. This could be partly explained by the different distribution of their cellular receptors. The ACE2 protein is mainly expressed on lung alveolar epithelial cells and enterocytes of the small intestine (Hamming et al., 2004). However, ACE2 mRNA expression was found to be low in cells from the early maternal-fetal interface with single-cell RNA-sequencing technology. Hence, it is speculated that the ratio of SARS-CoV-2-infected mother-to-fetus transmission will be relatively low (Zheng et al., 2020). Even if SARS-CoV-2 could not transmit from mothers to babies, it could be transmitted by close contact because coronavirus also exists in the sweat glands and the distal convoluted tubules of the kidney in addition to the intestinal and respiratory tracts (To and Lo, 2004;Zhou et al., 2017). Therefore, the neonates of pregnant women with COVID-19 should be isolated for at least 14 days and should not be breastfed (National Health Commission of the People's Republic of China, 2020).

CONCLUSION
This research has provided some strategies for the obstetric management of pregnant women with COVID-19. To some extent, clinical characteristics were similar among pregnancies with COVID-19, SARS, and MERS. It seems that COVID-19 during pregnancy is milder than SARS and MERS during pregnancy. However, pregnant women with COVID-19 should be closely monitored, even after their etiological tests turn negative. Maternal separation is necessary even if there was no vertical transmission. Interferon-alpha, lopinavirritonavir, and chloroquine could be good candidates for the treatment of COVID-19 during pregnancy, but more work is needed to explore their effectiveness and safety. In addition, remdesivir and arbidol, which are potential drug treatments for COVID-19, require further research on their safety during pregnancy.