key: cord-0833499-2fcon39t
authors: Narang, Kavita; Enninga, Elizabeth Ann L.; Gunaratne, Madugodaralalage D.S. K.; Ibirogba, Eniola R.; Trad, Ayssa Teles A.; Elrefaei, Amro; Theiler, Regan N.; Ruano, Rodrigo; Szymanski, Linda M.; Chakraborty, Rana; Garovic, Vesna D.
title: SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review
date: 2020-05-30
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.011
sha: 240267e88f730f0530a3e04b45dcc11bca55b84b
doc_id: 833499
cord_uid: 2fcon39t

Abstract The global pandemic of SARS-CoV-2, the cause of Coronavirus disease 2019 (COVID-19), has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities. Data from previous pandemics and seasonal influenza suggest that pregnant women may be at increased risk for infection-associated morbidity and mortality. Physiological changes in normal pregnancy and metabolic and vascular changes of high-risk pregnancies may affect pathogenesis or exacerbate the clinical presentation of COVID-19. Specifically, SARS-CoV-2 enters the cell via the angiotensin converting enzyme 2 (ACE2) receptor, which is upregulated in normal pregnancy. Upregulation of ACE2 mediates conversion of Angiotensin II (vasoconstrictor) to Angiotensin 1-7 (vasodilator) and contributes to relatively low blood pressures, despite upregulation of other components of the renin angiotensin aldosterone system. As a result of higher ACE2 expression, pregnant women may be at an elevated risk of complications from SARS-CoV-2 infection. Upon binding to ACE2, SARS-CoV-2 causes its downregulation, thus lowering Angiotensin 1-7 levels, which can mimic/worsen vasoconstriction, inflammation, and pro-coagulopathic effects that occur in preeclampsia. Indeed, early reports suggest that, among other adverse outcomes, preeclampsia may be more common in pregnant women with COVID-19. Medical therapy, during both pregnancy and breast feeding, relies on medications with proven safety, but safety data are often missing for medications in the early stages of clinical trials. We summarize guidelines for medical/obstetric care and outline future directions for optimization of treatment and preventive strategies for pregnant patients with COVID-19 with the understanding that relevant data are limited and rapidly changing.

• Pharmacological therapy is limited to medications with proven safety during pregnancy and lactation; safety data are often unavailable for medications in early stages of clinical trials.

• The current recommendations are based on a limited number of studies. Future, large, likely multi-center, studies will be critical in improving our understanding of the pathophysiology and clinical characteristics of COVID-19 and pregnancy, which may optimize COVID-19 preventive and treatment strategies during normal and high risk pregnancies. World-wide population studies to date have identified several patient characteristics, including age and comorbid conditions, as risk factors for poor outcomes, but data on pregnant patients are limited. Based on data from prior pandemics, pregnant women 3 are at higher risk of acquiring infection and dying compared to non-pregnant women. The current review will provide a multidisciplinary summary of the management of COVID-19 during pregnancy using an evidence base that has been published since identification of the first patients in Wuhan City, China, in December 2019.

The capsid of SARS-CoV-2 contains a RNA genome complexed with a nucleocapsid protein.

The membrane surrounding this nucleocapsid contains 3 proteins common to all coronaviruses, spike protein, membrane protein M, and small membrane protein E [ Figure 1a and reference 4]. 4 Viral entry occurs via 2 routes. The first occurs when the spike protein attaches to the angiotensin converting enzyme 2 (ACE2) receptor, releasing the viral genome and nucleocapsid protein into the host cell cytoplasm. 5 The other pathway is the direct plasma membrane route via 

The ACE 2 enzyme plays a key role in in the conversion of Angiotensin I (Ang I) to Ang 1-9 and Ang II to Ang 1-7 (vasodilatory, anti-thrombotic, and anti-inflammatory activities) (Figure 2) .

The hormonal profile of normal gestation is characterized by an early increase of all of the components of the renin angiotensin aldosterone system (RAAS), including ACE 2. 7 This raises the possibility that pregnant women may be at a greater risk for SARS-CoV-2 infection. In addition, low blood pressure in pregnant women is maintained through a balance between being refractory to the pressor effects of Angiotensin II (Ang II) and increased levels of Ang-(1-7), which exhibit systemic vasodilatory responses. 8, 9 In preeclampsia, a pregnancy specific hypertensive disorder that affects 3.5% of all pregnancies 10 and clinically is characterized by multisystem involvement and, commonly, proteinuria, this balance is lost, with an overexaggerated Ang II blood pressure response. 11 Preeclampsia has also been associated with decreased maternal plasma Ang-(1-7) levels. 9 As SARS-CoV-2 not only binds to ACE2, but also causes its downregulation, 12 infections during pregnancy may potentiate RAAS abnormalities i.e., increased Ang II relative to decreased Ang-(1-7), that are present in preeclampsia. COVID-dysfunction, and coagulation abnormalities. Notably, ACE2 receptors are also expressed by endothelial cells 13 and endothelial cell infection and immune cell-mediated endothelial injury has been recently described in COVID-19. 14 storm is mediated via immune responses, which are significantly modified in pregnancy, and may contribute to COVID-19 laboratory and clinical characteristics during pregnancy.

During pregnancy, the maternal immune system must adjust to tolerate the semi-allogeneic fetus while maintaining its ability to respond to pathogenic insult. 22, 23 This is also known as T helper (Th) 2 polarization. However, near the end of pregnancy a switch to Th1 immunity occurs and the maternal immune system becomes pro-inflammatory, leading to the sequence of events that occur prior to parturition (i.e. cervical dilation, contractions). Data on immune responses to SARS-CoV-2 in pregnant women are lacking at this time, while data from prior pandemics suggest that pregnancy may increase the risk of acquiring infection and dying compared to nonpregnant women. 3 The timing of infection during gestation may induce differences in maternal immune responses, viral clearance and ultimately perinatal outcomes. As the first and third trimesters are pro-inflammatory to promote implantation and labor, 24 pregnant women infected with SARS-CoV-2 during these trimesters may be at higher risk of exaggerated responses to virus (cytokine storm). Furthermore, high levels of stress and inflammation occur during labor, and the physiologic changes that occur in a mother's body after the baby is born could lead to poor maternal SARS-CoV-2 outcomes postpartum. This has been observed clinically, where pregnant women with mild symptoms upon admission to the hospital for delivery required postpartum hospital admission for respiratory symptoms. 25 infection, other short and long term effects from inflammation may adversely impact the developing fetus. These require further characterization. Maternal immunity may be passed on to protect the fetus, conferring passive immunity. IgG specific to the 2003 SARS-CoV outbreak strain was found not only in maternal blood, but also in amniotic fluid and cord blood. 31 Another possible source of antibodies could be breast milk, but this has yet to be determined.

Significant physiological changes to respiration occur during pregnancy 32 including increased secretions and congestion in the upper airways, increased chest wall circumference and upward displacement of the diaphragm. These changes result in decreased residual volume (RV) and

increased tidal volume (TV) and air trapping, slightly decreased airway resistance, stable diffusion capacity, increased minute ventilation, and increased chemosensitivity to carbon dioxide. Hemodynamic changes include increased plasma volume of 20-50%, increased cardiac output and decreased vascular resistance. 32 These changes result in a state of physiological dyspnea and respiratory alkalosis as well as an increased susceptibility to respiratory pathogens.

As has been seen with other viral respiratory infections, the early symptoms of COVID-19 Preeclampsia is an example of a common pregnancy-related complication that may be exacerbated by, or may exacerbate, COVID-19, as discussed above. The picture becomes further complicated because the two processes share common laboratory abnormalities. Thus, it may be difficult to discern whether certain abnormal laboratory findings are due to SARS-CoV-2 infection or preeclampsia, and this interplay may have treatment implications. For example, thrombocytopenia 36 and liver function abnormalities, 37 both of which are diagnostic criteria for preeclampsia with severe features, are also associated with worsening COVID-19 disease.

Physiological changes in normal pregnancy and metabolic and vascular changes in high-risk A recent multicenter cohort study of severe COVID-19 disease in pregnant patients from 12 US institutions reported that patients were usually admitted with severe disease seven days after onset of symptoms, and typically were intubated 2 days after admission. 64 Fifty percent of women required delivery resulting in a high rate of preterm birth.

Neonatal outcomes are shown in Table 1 Postpartum care Mother and baby separation or discouraging breastfeeding is not advised unless the mother is acutely ill. However, mothers are advised to follow appropriate respiratory hygiene by wearing masks during skin to skin contact and breastfeeding. Mothers should wash hands before handling their babies, touching pumps or bottles and avoid coughing while their babies are feeding. All surfaces and breast pumps should be sanitized after each use. In an effort to limit infection exposure, hospital length of stay should be decreased to 1 day for vaginal deliveries and 2 days for CD. Postpartum visits should be performed through telehealth and patients advised to continue compliance with social distancing after discharge. The method of telehealth should be individualized based on institution resources and availability. 

No drugs have been proven to be effective and safe to use for the treatment of COVID-19 to date. Table 3 outlines the medications or therapies used in various research protocols under investigation, as well as their safety for use in pregnancy. In addition, as the pro-coagulatory state of pregnancy may contribute to thrombotic risks associated with COVID-19, thromboprophylaxis, which is currently advised for COVID 19 patients, 87 should be considered for pregnant patients as well.

There are 6 total candidate vaccines under phase 1 or 2 clinical trials and 77 more candidate assessment for safety in pregnancy is conducted after initial safety data become available from clinical studies. 90 Although it is essential to guarantee safety, an unfortunate impact of delaying research in pregnancy is that vaccinations for pregnant women may also be delayed. This is especially problematic during a pandemic or epidemic, as evident from lessons learned from the Ebola outbreak. 91

The presented data are preliminary, collected over a period of 4 months and likely to change once large datasets become available. However, the projected course of COVID-19 on the morbidity and mortality of pregnant patients during these challenging times is unprecedented.

Racial disparities are known to exist in the obstetric literature. 92 Global health crises subject racial and ethnic minorities, as well as patients with immunocompromised comorbidities, to poorer outcomes. We envision that national and international perinatal societies will focus on the unique challenges faced by vulnerable patient populations that are burdened with physical, emotional and social crises, with a focus on improving outcomes for all pregnant patients.

In conclusion, given differing physiology during gestation, pregnancy represents a vulnerable state that may be associated with a greater risk for SARS-CoV-2 infection and subsequent worse -Advise patients to: 1) Practice respiratory hygiene during feeding, 2) wear a mask 3) Wash hands before and after touching the baby 4) Routinely clean and disinfect surfaces they have touched.

-During separation, encourage dedicated breast pumping -Routine precautionary separation of a healthy baby and mother is not advised -Encourage good hygiene and appropriate PPE for COVID-19 positive patients -No contraindication to NSAID use -Encourage telehealth for postpartum visit -Limit F2F visits only for medically necessary concerns

Laboratory diagnosis of emerging human coronavirus infections -the state of the art

Binding of virus to ACE2 causes its downregulation and may increase Ang II relative to Ang-(1-7), thus favoring vasoconstriction, which can mimic/worsen vascular dysfunction in preeclampsia Figure Legend: 1-Lungs, 2-Heart, 3 -Kidneys, 4-Placenta and endothelial cells , 5-Intestine