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SARS‐CoV‐2 in the context of past coronaviruses epidemics: Consideration for prenatal care

Abstract Since December 2019, the novel SARS‐CoV‐2 outbreak has resulted in millions of cases and more than 200 000 deaths worldwide. The clinical course among nonpregnant women has been described, but data about potential risks for women and their fetus remain scarce. The SARS and MERS epidemics were responsible for miscarriages, adverse fetal and neonatal outcomes, and maternal deaths. For COVID‐19 infection, only nine cases of maternal death have been reported as of 22 April 2020, and pregnant women seem to develop the same clinical presentation as the general population. However, severe maternal cases, as well as prematurity, fetal distress, and stillbirth among newborns have been reported. The SARS‐CoV‐2 pandemic greatly impacts prenatal management and surveillance and raise the need for clear unanimous guidelines. In this narrative review, we describe the current knowledge about coronaviruses (SARS, MERS, and SARS‐CoV‐2) risks and consequences on pregnancies, and we summarize available current candidate therapeutic options for pregnant women. Finally, we compare current guidance proposed by The Royal College of Obstetricians and Gynaecologists, The American College of Obstetricians and Gynecologists, and the World Health Organization to give an overview of prenatal management which should be utilized until future data appear.

What is already known about the topic?
The emergence of severe-acute-respiratory-syndrome coronavirus 2 (SARS-CoV-2) and its consequences during pregnancy have led to an increasing volume of data about the maternal and fetal outcomes of SARS-CoV-2 infections.

What does this study add?
This review summarizes maternal and fetal outcomes found in the literature as of 22 April 2020. This review also provides an overview of current candidate therapeutic options during pregnancy and clinical guidelines for prenatal management of COVID-19-affected pregnancies.
to-human transmission occurs via droplets and fomites. Although transmission through aerosols has been demonstrated in laboratory conditions, 6 its public health relevance remains highly debated.
Recent data have demonstrated the efficacy of contact and droplet protection measures among hospitalized staff, suggesting the lack of significant aerosol transmission. 7 SARS-CoV-1 presented as a novel atypical pneumonia in Hong Kong in June 2003. More than 8000 individuals were infected around the world and the overall case fatality rate (CFR) was estimated to be around 11% according to the WHO. 8 Drastic infectious disease control measures halted the epidemic, and no cases have been reported since 2004. 5 Later in 2012, MERS-CoV emerged in the Middle East. Infected individuals exhibited a severe respiratory illness with a high fatality rate of 34.4%. At the end of November 2019, more than 2400 confirmed cases were reported, the majority in Saudi Arabia. This epidemic was marked by a high rate of nosocomial transmission with 19.1% of cases being healthcare workers. 9 At the end of 2019, the first cases of SARS-CoV-2 were reported in Wuhan, a large city in Southern China, and were linked to the Huanan seafood market. Early Chinese data showed an exponential growth of the number of cases suggesting human-to-human transmission among close contacts. 10 The World Health Organization declared this outbreak a pandemic on 11 March 2020, and strict measures, such as social distancing and public health hygiene protocols, have been taken by many countries to limit the spread of the disease. In many countries, the pandemic is still in its exponential phase as of May 2020. SARS-CoV-2 causes an illness quite similar to the other emerging coronaviruses and was renamed "COVID-19" by the WHO on 11 February 2020. Typical symptoms of COVID-19 pneumonia include fever, dry cough, anosmia, and fatigue. These mild presentations represent 81% of cases according to a large Chinese report of 72 134 cases, 11 whereas 14% and 5% of cases present with severe or critical disease such as respiratory failure, septic shock, and multiple organ dysfunction, respectively. Similar data have been reported in the United States, with 14.3% of patients requiring intensive care management and a mortality rate that has reached 21% among hospitalized patients. 12 The most frequent complications during hospitalization are acute respiratory distress syndrome (ARDS), arrhythmia and shock, as well as thromboembolic diseases. 13,14 Atypical SARS-CoV-2 symptoms, such as diarrhea and nausea, have been frequently reported 15 along with neurological symptoms and complications such as Guillain-Barré. 16 In addition, there are increasing reports of asymptomatic infections. 17,18 This further complicates the calculation of exact mortality rates. 19,20 In a recent model-based analysis, the CFR was estimated to be 0.32% (0.27%-0.38%) in patients <60 years old (yo), 6.4% (5.7%-7.2%) in older patients, and reaching up to 13.4% (11.2%-15.9%) in those >80 yo. 21 3,22 The relative immunosuppressed state as well as the restricted respiratory capacity of pregnancy account for such outcomes. 23 Current data regarding emerging coronaviruses, based mostly on case series, are summarized below.

| SARS-CoV-1
A total of 25 cases of SARS-CoV-1 infection among pregnant women were identified in the literature. [24][25][26][27][28][29][30] Infections were observed in the first trimester (n = 7), second trimester (n = 4), and third trimester (n = 14). Among the 25 cases of SARS-CoV, 3 maternal deaths (12%) were recorded, 10 patients required intensive care unit (ICU) admission (40%) with or without mechanical ventilation. Compared with nonpregnant women, the rates of ICU admission and maternal death were significantly higher and independent of the trimester of infection, including two patients in their first trimester. In one case, SARS-CoV-1 RNA was amplified within the cerebrospinal fluid and associated with seizures suggesting encephalitis. 26  Iranian patients with third trimester infections. [42][43][44] All women presented with typical symptoms, including dyspnea. They were previously healthy except two patients known for hypothyroidism and one patient with suspected gestational diabetes. Maternal age was between 22 and 49 yo and two women had dichorionic/diamniotic twin gestations. All women were admitted to the ICU, intubated and ventilated, and died from cardiopulmonary collapse or multiple organ failure (MOF). One had septic shock and disseminated intravascular coagulation (DIC) before progressing to heart failure. Intrauterine fetal death was described among four patients (4 of 9) with gestational ages between 24 and 30 weeks gestation (WG). CS was performed in other cases (5 of 9) with gestational age between 30 and 38 WG.

| MERS-CoV
Cohort studies have reported a rate of severe disease requiring ICU admission of 6.9% to 8% (n = 9 of 118; n = 8 of 116), including three requiring mechanical ventilation among Chinese patients. In the Italian cohort, a total of 17% of pregnant women (n = 7 of 42) required either oxygen supplementation through continuous positive airway pressure or ICU admission, whereas in the American cohort, four (9.3%) presented with severe disease and two (4.7%) required ICU admission without mechanical ventilation.
Severe complications in pregnant women are similar to what has been described in the general population and include MOF, respiratory failure requiring mechanical ventilation, and even extracorporeal membrane oxygenation, as described in a patient at 35 WG. 45 In the latter, the patient required an emergency Cesarean section for maternal resuscitation and the newborn unfortunately died due to an intrauterine asphyxia. The mother had MOF, needed mechanical ventilation before extracorporeal membrane oxygenation for a total of 7 days. She was discharged from hospital 6 weeks later.
Two cases of cardiomyopathy related to COVID19 were reported by Juusela et al. 46 The first pregnant woman was 45 yo, had a BMI of 44.6 m 2 /kg, and was diagnosed with diet-controlled gestational diabetes. She delivered via Cesarean at 39 WG for severe preeclampsia and tested positive to SARS-CoV-2 on postpartum day 1 with evidence of fever, tachypnea, and suspicious chest imaging. She was then diagnosed with acute heart failure after an echocardiogram was performed, showing a moderately reduced left ventricular ejection fraction (LVEF) of 40% with global hypokinesis. On day 5 postpartum, the mother required mechanical ventilation and was still intubated at the time of publication. The second patient was a 26 yo women with no relevant medical history. She was admitted for respiratory symptoms necessitating nasal oxygen support. Due to the previous experience, an echocardiogram was completed and showed a moderately reduced LVEF of 40% to 45% with global hypokinesis. She rapidly developed severe features leading to a Cesarean section at 34 WG.
At the time of publication, she was postpartum day 1 and did not require oxygen support.
Although current data suggest that most pregnant women with COVID-19 will have an uncomplicated clinical course, severe complications must be anticipated. Nevertheless, the observed rates appear similar to those for nonpregnant patients between 20 and 40 yo. In a recent analysis based on a Chinese cohort, the actual rate of severe disease was 173 of 1170 (9.8%) among 20 to 39 yo patients; after adjusting for demographic factors, the expected rate of severe disease was 0.6% to 8.6%. 21 Breslin et al also reported a similar rate of complications in pregnant women compared with nonpregnant adults 41 : 86% vs 80% with mild clinical symptoms, 9.3% vs 15% with severe symptoms, and 4.7% vs 5% requiring ICU admission, respectively. We should point out, however, that complications in the general population mainly impacted the elderly and patients with comorbidities. When comparing pregnant woman to their typical age group, they qualify as a highrisk group for adverse maternal outcomes. 47 Therefore, although the majority of infected pregnant women seem to demonstrate a mild clinical course, pregnancies should be approached with caution considering the potential critical complications reported in several cases published so far report. More exhaustive data, however, are needed to understand the additional risk pregnancy may pose to women with a COVID-19 infection.

| Fetal and neonatal outcomes
SARS-CoV-1 and MERS-CoV infections during pregnancy were associated with adverse fetal and neonatal outcomes.

| SARS-CoV-1
A report on 12 pregnant women suffering from SARS-CoV-1 (2002-2003 pandemic) was published, 29 and the rate of adverse fetal/neonatal outcomes was 66% (8 of 12) in this series. Four of the seven patients (57%) infected during the first trimester experienced miscarriages. Two others decided to terminate their pregnancy after recovering from SARS, and the last had an uncomplicated pregnancy.
Among the five patients infected during the second or third trimester, four (four of five, 80%) had a preterm delivery, including one for fetal distress (one of five, 20%). Two neonates exhibited respiratory distress syndrome and other complications related to prematurity (necrotizing enterocolitis). All placentas of these patients (five of five, 100%) weighed below the fifth percentile, of which two had abnormal anatomo-pathology results (thrombotic vasculopathy with avascular fibrotic villi and/or placental infarct). 48 When the infection occurred during the week before birth, no fetal growth restriction (FGR) was noted (zero of two). When the infection occurred 1 month or more before birth, two fetuses (two of three, 33%) had FGR with oligohydramnios, related to the abnormal placentas presented above.
Another Chinese series 24 reported fetal demise in one of five (20%) fetuses exposed to SARS-CoV-1 during the second or third trimester of pregnancy.

| MERS-CoV
Eleven fetuses/neonates from mothers infected with MERS-CoV have been described. 36,49,34 Among them, three (3 of 11, 27%) had fetal or neonatal demise: two intra-uterine fetal deaths at 20 and 34 weeks, and one neonatal demise at 24 weeks due to extreme prematurity. 34,31 Abruption was identified on placental examination from these fetuses and from another liveborn neonate who presented with fetal distress at 37 weeks. 35

| SARS-CoV-2
With regards to SARS-CoV-2 infection during pregnancy, several case-series and case reports show that similar adverse fetal and neonatal outcomes could occur. Overall, we included 142 cases with fetal and/or neonatal outcomes available at the time of this review. Among them, 40 (28%) were born prematurely (<37 weeks) and 20 (14%) had adverse outcomes (FGR, fetal or neonatal demise, severe symptoms at birth). Congenital or perinatal transmission was suspected in 6 of 115 (5%) newborns tested. Details of all cases available are presented in Table 1.
In a case-control study, 51  Yu et al also reported a series of seven newborns from infected mothers during the third trimester, without adverse outcomes. One of these neonates had a positive SARS-CoV-2 PCR 36 hours after birth, leading to the suspicion of a perinatal transmission. Liu et al 53 described briefly the outcomes of 13 newborns from infected mothers. Induced prematurity was noted in 54% (7 of 13) but none had neonatal complications. In the New-York series, 41 which presented the outcomes of 18 infants from infected mothers, all but one had negative neonatal testing for SARS-CoV-2. One infant had an "indeterminate" test result, which was clinically managed as a "presumptive negative" diagnosis, as this result may reflect low level detection. In this series, three (3 of 18, 17%) instances of fetal distresses were noticed, one infant (1 of 18, 6%) was premature and one (1 of 18, 6%) presented with RDS with a concern for sepsis.
Hydroxychloroquine use in pregnant women has raised concerns in the past especially for an increased risk of cardiac malformation 71 and its retinal and ototoxicity, 72,73 related to the use of chloroquine and not hydroxychloroquine, findings which were not confirmed in more recent case series. 74,75,76,77 In the most recent systematic review and meta-analysis conducted in 2016, Kaplan and Koren 78 found no increase "in the rates of major congenital craniofacial and cardiovascular, nervous system and genitourinary malformations in the infants." However, there was a significant increase in the spontaneous abortion rate, which could be associated with the underlying disease activity rather than the treatment. That being said, (hydroxy)chloroquine is one of the antimalarial drugs considered compatible with pregnancy in all trimesters for prophylaxis and treatment of malaria. 79,80 A recent article gathered evidence on its use during lactation and found that it was compatible with breastfeeding, 81 concluding that hydroxychloroquine could be used for the treatment of COVID-19 infection, in usual rheumatological doses (200-400 mg/d) if proven to be effective.
The lopinavir-ritonavir combination is used as part of the HAART regimen to treat HIV infected women during pregnancy. 82 In a systematic review that included 4864 LPV/r-exposed pregnancies, the authors reported the rate of congenital abnormalities to be similar to that of the general population. However, the stillbirth rate was higher than in the general population in the UK (9.2 per 1000 infants against 4.7 per 1000 infants in 2013). 83 There has been general concern regarding protease inhibitor exposure in utero and its association with an increased risk of preterm birth 84 ; however, to our knowledge, this risk has not been evaluated specifically for lopinavir and ritonavir alone and could be associated with the underlying disease activity rather than the treatment. Finally, moderate adverse events such as  50 Li et al (2020) 51 Breslin et al (2020) 41 Yu et al (2020) 52 Liu et al (2020) 53 Chen et al (2020) 54 Zeng et al (2020) 55 Liu et al (2020) 56 Zhang et al (2020) 57 Yin (2020) 58 Yang et al (2020) 59 Case reports 60 gastro-intestinal symptoms 85 and an increased risk for alteration in fasting glycemia 86 were reported. Lopinavir and ritonavir are drugs considered compatible with pregnancy in all trimesters for HIV treatment and has been associated with very low excretion into breastmilk. 79,80 Regarding remdesivir, no adverse effect was reported in pregnant participants in a RCT on Ebola virus. 87 Safety data on remdesivir in pregnancy are still scarce.
Oseltamivir was used during the 2009 influenza A/H1N1 pandemic and notably in pregnant mothers. In the most recent population-based study 88  Oseltamivir could be considered compatible with pregnancy in all trimesters if proven effective in COVID-19 treatment and has been associated with very low excretion into breastmilk. 79,80 The Interferon alpha drug is used to treat essential thrombocythemia, chronic myelocytic leukemia, or hepatitis B and C in pregnant women. In a recent review including 43 exposed women, Sakai et al found that no adverse event had required discontinuation of the treatment but alerted physicians to "pay attention to (…) rare adverse events, such as impaired liver function, interstitial pneumonia, and attempts at suicide." 91 Safety data on INFα in pregnancy are scarce, but its similarity to beta interferon, of which safety data during pregnancy are substantial and reassuring, makes it compatible in pregnancy if proven effective for COVID-19 infection.
Regarding darunavir, no embryotoxicity or teratogenicity of this molecule was found in animal studies. 92 In a brief review of darunavir use in pregnant women, the authors concluded that it is a well-tolerated molecule that has few minor adverse effects. 93 Darunavir is considered compatible with pregnancy in all trimesters for HIV treatment despite its lack of safety data in pregnancy as its maternal benefit outweighs the potential unknown risks. 79,80 Animal studies have demonstrated embryotoxicity of baricitinib, 94 and no safety data are available in human.
Analysis of the Roche Global Safety Database does not suggest a substantially increased risk of malformations with the use of TCZ.
However, an increased rate of preterm birth and low birth weight children was possibly associated with TCZ exposure and could be associated with the underlying disease activity rather than the treatment. 95 Safety data in pregnancy are limited and due to treatment-induced immunosuppression, an increased risk of maternal-fetal infections is theoretically possible in pregnant women treated with TCZ.
Finally, serum from convalescent COVID-19 patients and hyperimmune globulins specific to the novel coronavirus are currently being evaluated as therapeutic options. 96 Specific hyperimmune globulins have been used in several indications during pregnancy, including prevention of mother to child transmission of infectious diseases such as Hepatitis B virus (HBV) 97 and Cytomegalovirus, 98 as well as convalescent serum recently in the Ebola virus disease (EBV). 99 In a systematic review assessing the benefits and safety of hyperimmune globulins to prevent HBV mother to child transmission in 2440 pregnant women, only one study mentioned adverse events consisting in swelling in two women. 97 More recently, convalescent serum to treat the EBV was evaluated in a nonrandomized comparative study of 99 patients that included eight pregnant women. No serious adverse reaction was associated with the transfusion. 99 Two cases of pregnant women report the use of convalescent serum to treat SARS-CoV-2 infection. 45,100 In the first case of a 31-yo pregnant woman, no serious adverse event related to the use of convalescent plasma was reported but its relative contribution to survival could not be determined due to other concomitant treatments. The authors concluded that its clinical benefit remained unknown. 45 In the second case of a 35-yo pregnant woman with severe comorbidities who received both convalescent serum and remdesivir, no conclusion regarding safety or benefit of convalescent plasma could be drawn by the authors. 100 Data on the use of specific hyperimmunoglobulins to prevent infections in pregnant women seem reassuring as well as those on the use of convalescent serum although they are more scarce. If they proved to be effective in COVID-19 treatment, convalescent serum and specific hyperimmunoglobulins directed against SARS-CoV-2 could be considered compatible with pregnancy in all trimesters.

| Prenatal monitoring
Regarding potential asymptomatic infected pregnant women, the WHO recommends careful monitoring of patients with epidemiological history of contact with infected individuals, whereas ACOG suggests routine antenatal care in this situation (Table 2). An algorithm for assessment and management of symptomatic parturients has been proposed by ACOG, classifying them in three categories of risk: low, moderate, and elevated. For mild presentations, women without comorbidities (low risk) should self-isolate at home, whereas those with health problems, obstetrical issues, or the inability to care for themselves (moderate risk) should be seen in an ambulatory setting.
According to RCOG, pregnant women with moderate symptoms should self-isolate, unless they attend a maternity unit where patients in the second or third trimester meeting public health england (PHE) criteria (≥1 of: (a) clinical/radiological evidence of pneumonia, (b) ARDS, (c) fever ≥37.8 and at least one of acute persistent cough, hoarseness, nasal discharge/congestion, shortness of breath, sore throat, wheezing, or sneezing) should be tested for COVID-19 and treated as infected until results are available. When pregnant women present with severe symptoms (high risk), they should immediately go to an emergency department according to ACOG algorithm. All guidelines agree that administration of corticosteroids for fetal lung maturity is still recommended per protocol in the setting of a high risk of preterm birth when the mother's condition is stable.
Regarding fetal growth surveillance, RCOG recommends an antenatal ultrasound 14 days after acute illness resolution for hospitalized patients, whereas ACOG suggests a third trimester ultrasound for COVID-19 pregnant women infected in second and third trimester. A detailed anatomy ultrasound could be considered for first trimester infections (ACOG).

| Risk of thromboemboloic disease
Data suggest that COVID-19 may be associated with an increased thromboembolic risk with a rate of venous thromboembolism (VTE) of 39% in ICU patients. 14 Therefore, routine VTE prophylaxis for hospi- Other coronavirus epidemics, such as SARS-CoV-1, had a higher impact on pregnant women encompassing 40% of ICU admissions and 12% of mortalities. The MERS-CoV epidemic was even more lethal with a 40% mortality without significant difference of severity between pregnant and nonpregnant women. In this review, we gathered more than 150 cases of SARS-CoV-2 in pregnancy and identified a maternal mortality of 2.7% (nine cases) among those described in the literature. ICU admissions were between 6.9% and 8%. The proportion of severe complications seems to be equal to the nonpregnant population; however, these must still be anticipated in pregnant women. These rates will have to be reviewed when the true denominator (number of infected pregnant women) is known, as a significant proportion of patients remain asymptomatic.
Past coronavirus epidemics were associated with adverse out- These initiatives should provide several datasets available for research aiming to improve pregnant patient care during the COVID-19 pandemic in the near future.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

DATA ACCESSIBILITY
Research data are not shared.

DATA AVAILABILITY STATEMENT
Research data are not shared.