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Many people are worrying...


...that pregnant women are more likely to have poor outcomes from SARS-CoV-2 infection

This piece is courtesy of Dr. Lisa Bebell, Dr. Laura Brenner, and Dr. Tiara Calhoun with advisory review by Dr. Jeannie Kelly (MFM, Washington University in Saint Louis), and Dr. Jonathan Hirshberg (MFM/Critical Care Fellow at Washington University in Saint Louis).
The FLARE Four:
  1. Small case series from prior coronavirus outbreaks (SARS, MERS) have suggested poor outcomes in pregnant patients.
  2. Preliminary reports about COVID-19 in pregnancy indicate that pregnant women do not experience substantially worse outcomes. 
  3. Similarly, only rare reports indicate neonatal complications in COVID-19.
  4. Management of pregnant patients with SARS-CoV-2 does not differ significantly from standard critical care of non-pregnant patients. 
Why have people been worried pregnant women with COVID-19 could do poorly?
Concerns have been raised about COVID-19 in pregnancy due to small studies from prior coronavirus epidemics (SARS, MERS) in which increased complication rates in pregnant women were reported. Additional concern has been raised based on data from prior influenza outbreaks, which have also been associated with worse outcomes in pregnancy.
  • Small case series from the SARS outbreak (SARS-CoV), suggested that maternal mortality was as high as 25% in pregnancy and that there were poor birth outcomes among neonates (Rasmussen et al. 2020; Wong et al. 2004; Jeong et al. 2017). 
  • According to a 2019 report, there have been 11 reported symptomatic cases of MERS in pregnant women (Alfaraj, Al-Tawfiq, and Memish 2019). Six (54%) of these patients required ICU admission. Realizing the limitations of these data, the reported maternal and infant mortality of 27% (3/11) is similar to the overall MERS case fatality rate of 35%. 
  • During the H1N1 influenza epidemic in 2009, pregnant women accounted for only 1% of cases but 5% of deaths (Poon et al. 2020). In a retrospective review of 788 pregnant patients in the US in 2009 with H1N1, 509 were admitted to the hospital and 115 (22.6%) were admitted to the ICU. 30% had preterm delivery. Patients who were treated early in the 3rd trimester were less likely to be admitted to the ICU (Siston et al. 2010). Thus the outcomes of pregnant patients were worse than the general population with H1N1 influenza. 
What about COVID-19?
Are pregnant women at greater risk?
Published data on the outcomes of SARS-CoV-2 in pregnancy are limited, but suggest severe disease is NOT more common in pregnancy. 
  • Breslin et al. describe 43 mothers with RT-PCR confirmed SARS-CoV-2 infection in 2 hospitals in New York (Breslin et al. 2020). One third were asymptomatic at the time of testing. Applying COVID-19 disease severity characteristics as described by Wu and McGoogan in the Chinese CDC cohort (Wu and McGoogan 2020), 37 (86%) women had mild disease, four (9.3%) severe disease, and two (4.7%) critical illness - overall similar to the non-pregnant population. Of note, both women requiring critical care in this report were obese and had poorly-controlled type 2 diabetes, and one also had poorly-controlled hypertension and asthma. 
  • Chen et al. found similarly in a case series of 118 pregnant women in Wuhan, China, of which 109 (92%) had mild disease, and 9 (8%) had severe disease (hypoxemia), 1 of whom received noninvasive mechanical ventilation (L. Chen et al. 2020). Of note, among the 9 who developed severe disease, 6 developed these severe manifestations only after delivery. 93% of the births during this period were done via cesarean section with 61% of those done due to concern of the effect of COVID-19 on the pregnancy. 64% of reported women were infected with SARS-CoV-2 in the 3rd trimester.
Are pregnant women more likely to spread SARS-CoV-2 infection?
While the asymptomatic carrier rate in the general population is unknown and dependent on overall disease prevalence, modeling estimates have suggested a range from 18-33% (Mizumoto et al. 2020). Recently, asymptomatic carriage was reported in 14% of women presenting in labor to a New York City hospital (Sutton et al. 2020), though it is not clear from this single center report that this carriage rate is any different than the general public. However, pregnant women, especially those in the third trimester, do have increased exposure to the healthcare system, and a single pregnant patient has contact with numerous providers during delivery. This finding has led to universal screening of pregnant women admitted for labor and delivery in some hospitals, including MGH.
Is it true that neonates can be infected in utero?
It is unknown whether SARS-CoV-2 is vertically transmitted. 

The majority of reports to date have not revealed evidence of symptomatic or asymptomatic neonatal infection in children born to SARS-CoV-2 positive mothers. Nevertheless, some data do suggest the possibility of vertical transmission. 

In one series, of the 70 neonates born to mothers with SARS-CoV-2 infection, none had neonatal asphyxia and the 8 neonates who underwent  throat swabs testing were all negative for SARS-CoV-2 infection (L. Chen et al. 2020). Among nine pregnant patients with RT-PCR-confirmed COVID-19 pneumonia in Wuhan delivering by Cesarean in the 3rd trimester, six underwent SARS-CoV-2 RT-PCR testing of amniotic fluid, cord blood, neonatal throat swabs and breastmilk; all samples tested negative (H. Chen et al. 2020). Several others have reported similar findings (S. Chen et al. 2020; Karimi-Zarchi et al. 2020; Breslin et al. 2020; Schwartz 2020; W. Liu et al. 2020).

However, there have been three provocative reports indicating the possibility of vertical transmission. In one case series, 3 neonates born to 33 infected mothers were diagnosed with early-onset (i.e. day two of life) symptomatic SARS-CoV-2 (L. Zeng et al. 2020). Another case report of a potential vertical transmission involved a mother with confirmed SARS-CoV-2 infection who became critically ill and underwent cesarean delivery with immediate isolation of the newborn. The neonate’s nasopharyngeal swab was positive 16 hrs after delivery (Alzamora et al. 2020). In these cases, the timing of the PCR testing post-delivery might mean that the disease was obtained from hospital transmission, but vertical transmission remains a possibility. Dong et al. report the presence of plasma SARS-CoV-2 IgM and IgG in a neonate aged 2 hours who was born to a woman infected with SARS-CoV-2, though the neonate had a negative RT-PCR NP swab (Dong et al. 2020). An additional study showed elevated IgM levels in 2 infants (H. Zeng et al. 2020). (Detectable neonatal IgM suggests an acute infection in the infant as IgM does not cross the placental barrier.) Overall, these case reports do not definitively prove the occurrence of vertical transmission, particularly in light of the larger series discussed above, and should be balanced against the majority of reports indicating otherwise.
Even if neonates are not infected, might they have worse outcomes in the setting of maternal infection?
Zhu et al. examined 10 neonates born to mothers with COVID-19. Nine of the neonates were tested for SARS-CoV-2 and were negative; 1 neonate died and 4 were still hospitalized at the time of writing. Of note, 3 of the neonates were < 34 weeks gestation and 2 of those born before 34 weeks were twins.  This series, by no means definitive, suggests neonates born to mothers with COVID-19 may be at risk for worse outcomes (Zhu et al. 2020). A meta-analysis of 41 pregnant women with confirmed SARS-CoV-2 suggests 41% risk of preterm birth, 9% risk of neonatal intensive care unit admission, and 7% risk of early neonatal death (Di Mascio et al. 2020). In a case-control study of 34 pregnant women with COVID-19 (14 PCR-confirmed and 16 clinically diagnosed) and 242 controls, Li et al. found a higher rate of preterm delivery due to maternal complications in the COVID-19 group compared to controls, although the result was not significant and may have been confounded by a higher rate of chronic illness in the COVID-19 group (Li et al. 2020). It is also important to note that the results from the Li et al. cohort are difficult to interpret since over 50% of this cohort was diagnosed clinically rather than PCR-proven. 

In another case-control study of 16 pregnant COVID-19 patients and 45 controls, Zhang et al. found no significant difference in fetal distress, birth weight, meconium staining, or preterm birth between groups. No neonates tested positive for SARS-CoV-2 after birth (10/16 were tested by PCR) (Zhang et al. 2020).

Thus, the data are limited and reported outcomes vary. Some case series suggest poor neonatal outcomes (but are limited by small numbers and incomplete data), while other series indicate no difference in outcomes. Importantly, it is possible that the reported poor neonatal outcomes are related to maternal illness from SARS-CoV-2 rather than from direct effect of the virus on the fetus.
Is there any reason to treat critically-ill pregnant COVID-19 patients differently than other patients?
Since pregnant women are excluded from most critical care trials, recommendations for management of ARDS in pregnancy are generally based on expert opinion and theoretical risk to the fetus. A multidisciplinary approach to management in this patient population is beneficial for care. Providers should manage severe COVID-19 in pregnant women generally as one would manage other adult patients, with a few additional points worth emphasizing:
  • Remdesivir is available for compassionate use in pregnancy: though there is no evidence for efficacy in treating COVID-19, it appears safe in pregnancy based on use during Ebola outbreaks (Mulangu et al. 2019).
  • Hydroxychloroquine is commonly used in pregnancy for autoimmune disease: though there is no evidence for efficacy in treating COVID-19, as pregnant women have been excluded from trials (Talabi and Clowse 2020).
  • Tocilizumab crosses the placenta. Limited data suggest it may be safe in pregnancy.
  • Pulmonary vasodilator therapy with nitric oxide, sildenafil, and epoprostenol is considered safe.
  • Neuromuscular blockade with cisatracurium and vecuronium is considered safe.
  • ECMO can also be used successfully in pregnancy (Pham et al. 2013).
  • Prone positioning is safe in pregnancy but should be performed with OB guidance and adequate bolstering to avoid abdominal compression (Schnettler, Al Ahwel, and Suhag 2020).
  • Cardiac arrest lasting > 4 minutes in a pregnant woman 20 weeks’ gestation or greater is an indication for immediate bedside hysterotomy and delivery to improve maternal outcomes (Jeejeebhoy Farida M. et al. 2015).
  • Steroids, specifically betamethasone and dexamethasone, are commonly used for fetal lung maturity up to 37 weeks of pregnancy (Roberts et al. 2017). There is some concern that corticosteroids may worsen COVID-19 (March 24th FLARE), but these data are evolving. Generally, the benefit of steroids to the fetus may support use up to 34 weeks of gestation, but use should be addressed on a case-by-case basis.
In sum
Published data on SARS-CoV-2 in pregnancy are limited, but suggest maternal mortality similar to all-comers, no definite vertical transmission, and the possibility of increased neonatal complications. Pregnant women with severe COVID-19 should generally be managed like other adult patients. If available, collaboration with a multidisciplinary team including experts in maternal-fetal medicine and neonatology should be prioritized.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Prior FLAREs can be found here.
Thank you for everything you are doing!
 - MGH FLARE
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References:
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