Impact of Maternal SARS-CoV-2 Infection on the Fetus and Newborn

History of Perinatal Coronavirus Infections

Before the worldwide pandemic, data on coronavirus infection in pregnancy were limited despite two previous large epidemics. A 2020 systematic review and meta-analysis found only 12 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) and 33 cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections in pregnancy, all of which were from case reports, case series, or small retrospective cohort studies. However, evidence showed that the case fatality rate appeared higher in pregnant women with more disease severity than in nonpregnant individuals. A case-control study compared 10 pregnant to 40 nonpregnant women affected by severe acute respiratory syndrome (SARS) in Hong Kong and showed a 60% rate of intensive care unit (ICU) admission in pregnancy compared with 17.5% in nonpregnant patients. Case fatality rate was also increased in pregnant patients at 40% compared with no deaths in nonpregnant individuals. A total of 11 cases of MERS in pregnancy were found in one literature review that reported a 64% ICU admission rate and a 27% case fatality rate. A more recent review quoted the overall maternal mortality rate at 18% and 25%, for the SARS-CoV-1 and MERS-CoV epidemics, respectively.

Pregnancy Outcomes During Previous Coronavirus Epidemics

Pregnancy outcomes from prior coronavirus epidemics can provide some insight into disease severity in pregnancy during the current SARS-CoV-2 pandemic ( Table 13.1 ). A systematic review and meta-analysis evaluated different clinical features of pregnant patients infected with one of the coronaviruses known to cause severe disease in humans. Fever, cough, and fatigue were the most common clinical features, with prevalence ranging from 50% to 78% in MERS-CoV and 80% to 97% in SARS-CoV-1, and the pooled prevalence of all clinical symptoms was 26% (95% CI, 15.2–40.1). Pneumonia was the most common diagnosis in pregnant patients with a prevalence of 71.4% in MERS-CoV and 88.9% in SARS-CoV-1. Lymphocytopenia and elevated C-reactive protein (CRP) were the most common laboratory findings. MERS-CoV was the predominant causative agent of severe cases among infected pregnant women, with a prevalence of 77%, followed by SARS-CoV-1 (48%). None of the studies reported documented transmission of MERS-CoV or SARS-CoV-1 from the mother to the fetus.

Table 13.1

Summary of Perinatal Outcomes During the SARS-CoV-1 and MERS-CoV Epidemics

Perinatal Effects	SARS-CoV-1 (n = 33)	MERS-CoV (n = 12)
First-trimester miscarriage	38.1% miscarriage	No data on miscarriage
Second-/third-trimester loss	One fetus in a twin gestation	Two fetuses (at 20 wk and at 34 wk)
Prematurity	12% <34 wk preterm birth 21.7% <37 wk preterm birth 12.5% preterm premature rupture of membrane	33.3% <34 wk preterm birth
Fetal growth and placental effects	12.5% fetal growth restriction No cases of preeclampsia	Single placental abruption at 37 wk 5.7% preeclampsia
Delivery and postnatal outcomes	38.5% >37 wk birth 50% cesarean delivery 22.2% “normal” vaginal delivery 33% fetal distress 10% perinatal deaths None of the studies reported Apgar score <7 at 5 min, neonatal asphyxia, or NICU admission	80% >37 wk birth 66.7% cesarean delivery 16.7% “normal” vaginal delivery 33.3% perinatal deaths No report of fetal distress, Apgar score <7 at 5 min, neonatal asphyxia, or NICU admission
Maternal outcomes	54.5% maternal ICU admission 12.5% maternal death	33.3% maternal ICU admission 40% maternal death
Neonatal outcomes	No report of maternal vertical transmission RDS and bowel perforation in neonate at 26 wk RDS, necrotizing enterocolitis, and patent ductus arteriosus in neonate at 28 wk	No report of maternal vertical transmission 1 neonatal death at 24 wk (birth weight 240 g because of extreme prematurity) 2 stillbirths

ICU, Intensive care unit; NICU, neonatal ICU; RDS, respiratory distress syndrome.

Impacts of SARS-CoV-2 Infection on the Pregnant Mother

Epidemiology of Maternal SARS-CoV-2 Infection

As the SARS-CoV-2 pandemic continues to evolve, more data become available on the impact on pregnant patients. As of June 14, 2021, the Centers for Disease Control and Prevention (CDC) has reported 97,293 cases in pregnancy and 106 maternal deaths related to SARS-CoV-2 infection in the United States alone. In June 2020, the CDC released surveillance data evaluating SARS-CoV-2-related outcomes in pregnancy. Among 326,335 women aged 15 to 44 years with positive test results for SARS-CoV-2, pregnant women (which encompassed only 28% of all women of reproductive age) were more likely to be hospitalized, admitted to an ICU, and receive mechanical ventilation. However, the overall absolute increase in rates of ICU admission and mechanical ventilation were low among pregnant and nonpregnant women (1.5% vs. 0.9% for ICU admission, respectively, and 0.5% vs. 0.3% for mechanical ventilation, respectively). Moreover, SARS-CoV-2–related death rates were similar in the pregnant and nonpregnant populations.

Since the onset of the first reported case in 2019, over 6200 new studies have been published on maternal and child health and nutrition related to SARS-CoV-2 per the repository compiled by the Johns Hopkins Center for Humanitarian Health. This rapid and overwhelming increase in available evidence results from studies with varying degrees of bias and quality. Early reports found that SARS-CoV-2 during pregnancy was likely to be associated with severe maternal morbidity similar to prior coronavirus epidemics. However, the SARS-CoV-2 virus has surprised scientists in that it behaves like no other respiratory infection, involving multiple extrapulmonary organs. More recent data suggest that the mortality rate of pregnant patients due to SARS-CoV-2 is lower than with SARS-CoV-1 and MERS-CoV, but still higher than in the nonpregnant population. Finally, similar to the nonpregnant population, disparities in social determinants of health among Hispanic and Black pregnant patients exist and act as barriers to health and well-being, which has led to disproportionate SARS CoV-2 infection rates and deaths in these populations.

Today, the data continue to evolve. Initial studies available early in the pandemic focused mostly on infections occurring in the last trimester of pregnancy near delivery. In addition, early testing availability was variable, which affected the reported number of cases and outcomes related to them. In comparison, more recent studies include infections occurring in all trimesters, as well as in the periconception and postpartum periods. As with other congenital infections, as data and cases become more readily available, the clinical findings and recommendations in pregnancy will continue to evolve.

Maternal SARS-CoV-2 Infection

Physiological Changes in Pregnancy

Physiological changes that occur in pregnancy may help explain the effects seen on morbidity and mortality in pregnancies affected by SARS-CoV-2 infection (see Table 13.1 ). Those most significantly affected are the respiratory and immunological systems, and hypercoagulability increases in pregnancy.

Respiratory System

Lung physiology is altered in pregnancy secondary to hormonal patterns. Progesterone leads to decreased plasma partial pressure of carbon dioxide, higher tidal volumes, and lower functional residual capacity (FRC) (by 9.5%–25%). Reduced FRC subsequently causes functional ventilation-perfusion mismatch and ineffective airway clearance, potentially contributing to the enhanced severity of lower respiratory tract infections. Expiratory reserve volume decreases during the second half of pregnancy (8%–40% at term), as a result of reduction in residual volume by 7% to 22%. Inspiratory capacity increases and maintains a stable total lung capacity. Because the respiratory rate remains unchanged in pregnancy, minute ventilation increases significantly (by up to 48%) during the first trimester and plateaus in the second and third trimesters. The increase in minute ventilation results in a physiological respiratory alkalosis. Finally, the increased metabolic demand of pregnancy increases oxygen consumption by 20%.

These respiratory changes ensure appropriate oxygenation of the fetus, potentially at the expense of the mother, whose ability to compensate is reduced during respiratory illness. For example, during the 2009 H1N1 influenza epidemic, pregnant mothers were at a significantly higher risk for respiratory complications and hospitalization. SARS-CoV-2 disease affects the lower respiratory tract and can lead to rapid bilateral lung involvement. This may predispose pregnant patients to an increased risk for hypoxic respiratory failure. If pregnancy is further complicated by other comorbidities, such as obesity, expiratory reserve volume, functional residual capacity, and lung compliance are more compromised, triggering increased disease severity.

The Immune System

The immunological changes that occur during pregnancy allow a genetically and immunologically foreign fetus to survive. This requires significant maternal immunomodulation, with a delicate balance between innate and humoral immunity. The consequence of this immunosuppression has been postulated to increase maternal susceptibility to various pathogens, including viruses.

Peripheral blood mononuclear cells (PBMCs) are the primary immune cells of the immune system. They include T, B, and natural killer (NK) cells, as well as circulating monocytes. Recognition of pathogens by these cells produces a cascade of immune molecules, including cytokines and chemokines. There is strong evidence demonstrating a shift in cytokine profile of successful pregnancies, such that there is a reduction in T helper type 1 (Th1) cytokines (interferon-gamma [IFN-g] and interleukin-2 [IL-2]) with a simultaneous increase in Th2 cytokines (IL-4 and IL-10), compared with nonpregnant patients. On the other hand, there is an increased ratio of Th1 to Th2 cytokine production in failed pregnancies.

Additionally, research has demonstrated that the balance between Th17 and T regulator (Treg) cells also plays a role in pregnancy. Th17 cells produce predominately inflammatory cytokines such as IL-17A. In contrast, Treg cells produce mainly antiinflammatory cytokines, such as IL-4 and transforming growth factor-beta (TGF-β), and inhibit autoimmune responses. In pregnancy, the ratio of Treg/Th17 is shifted such that a higher level of Treg cells help support the mother’s immune tolerance to the fetus.

The severity of SARS-CoV-2 disease can be reflected in the cytokine profile. Studies of nonpregnant patients found activation of both Th1 and Th2-biased immune cells. Patients requiring ICU-level care were found to have higher plasma levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, and tumor necrosis factor-α. ²² Additionally, the ratio of Treg/Th17 cells shifted in favor of Th17 cells (proinflammatory) in patients with more severe SARS-CoV-2 infections. The immunological changes that occur in pregnancy were initially thought to impair adaptive immune response and increase release of proinflammatory cytokines, leading to systemic inflammation and potentially severe organ damage. However, more recent data are now supporting the theory that the physiological shift toward a Th2- and Treg-predominant environment in pregnancy may in fact result in a less severe form of COVID-19, by preventing the excessive inflammatory response usually observed in SARS-CoV-2 patients with severe disease. ^, However, characterization of the immune response in pregnant patients with COVID-19 has yet to be fully elucidated.

Hypercoagulable State and Endothelial Dysfunction

Pregnancy is a physiologically hypercoagulable state. Most notably there is a significant change in coagulation, with increased factor VII, VIII, and X; von Willebrand factor activity; and marked increases in fibrinogen and d -dimer (increases to 50% above baseline normal range of 0.3–1.7 mg/L by the third trimester). Thrombin generation markers (prothrombin F1 and 2 as well as thrombin-antithrombin complexes) are also increased. Protein S and activated protein C levels decrease during pregnancy. Fibrinolytic activity is reduced with plasminogen activator inhibitor type 1 (PAI-1) levels increased by five-fold and increases in placentally derived PAI-2, particularly during the third trimester. Pregnancy is associated with a four- to six-fold increased risk of venous thromboembolism (VTE), and this risk is further increased in the postpartum period.

Disruption of the endothelium is thought to occur during SARS-CoV-2 infection, and concern has been raised for possible exacerbation of an enhanced thrombotic state in pregnancy. Endothelial disruption occurs either directly through signaling effects or indirectly through increased proinflammatory mediator production and subsequent deregulation of the coagulation cascade. Pericytes with high expression of angiotensin-converting enzyme-2 (ACE2) are the target cells of SARS-CoV-2, found in most organs such as heart, lung, kidney, vessels, brain, and others, including the placenta, and result in endothelial cell and microvascular dysfunction. Severe SARS-CoV-2 appears to resemble complement-mediated thrombotic microangiopathies. Autopsy studies revealed generalized thrombotic microangiopathy and endothelial dysfunction together with pulmonary embolus and deep venous thrombosis in SARS-CoV-2 infected patients. Some suggested that inactivation and downregulation of ACE2 occurs by formation of viral-ACE2 complex after SARS-CoV-2 placental infection. This then causes lowering of plasma angiotensin levels, which in return potentiates vasoconstriction and procoagulopathic state, leading to early-onset, severe preeclampsia. The extent of the clinical impacts of endothelial dysfunction during SARS-CoV-2 infection in pregnancy remains to be fully evaluated.

Clinical Findings of Maternal SARS-CoV-2 Infection

Clinical presentation of SARS-CoV-2 varies in pregnancy. A systematic review of 571 pregnancies reported an asymptomatic rate of 15% in pregnant women with SARS-CoV-2–positive tests. The clinical findings are similar to those of nonpregnant women. Fever, cough, and dyspnea are the most common symptoms. ^, Others included myalgia, malaise, sore throat, diarrhea, and shortness of breath. Overall, presence of any SARS-CoV-2 symptoms is thought to be associated with increased maternal morbidity and mortality. Specifically, severe pregnancy and neonatal complication rates were highest in pregnant patients if fever and shortness of breath were present for 1 to 4 days, reflecting systemic disease.

There are no major differences between pregnant and nonpregnant women with SARS-CoV-2 in terms of laboratory findings, with elevated CRP being the most common finding (99%). Lymphopenia is another common biomarker. In nonpregnant individuals, significantly elevated d -dimer level (up to 12- to 17-fold the upper normal range in pregnancy) is considered a poor prognostic indicator of SARS-CoV-2 disease. ^, One study found higher d -dimer levels in those requiring ICU admission versus those who did not (median d -dimer 2.4 mg/L vs. 0.5 mg/L P = .0042). Another study observed higher d -dimer levels in nonsurvivors compared with survivors of SARS-CoV-2 disease (2.12 mg/L vs. 0.6 mg/L, P ≤ .001). Given the expected rise in d -dimer level during pregnancy, it remains unclear whether d -dimer elevation would indicate a similarly poor prognosis in pregnancy. The International Society of Thrombosis and Hemostasis (ISTH) suggests that those with a significant d -dimer elevation may warrant hospitalization regardless of symptoms. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and platelets are also considered valuable markers in pregnancy. There have been reports of increased hematological complications in pregnant women with COVID-19 compared with those without infection, although the evidence is still limited.

The majority of pregnant patients with pulmonary findings on chest imaging had ground-glass opacities (81.6%), bilateral lung involvement (79.2%), or a consolidation (17.6%), similar to nonpregnant patients.

Maternal and Obstetric Outcomes in SARS-CoV-2 Infection

Although the body of evidence on maternal outcomes in pregnancies affected by SARS-CoV-2 infection continues to expand at a rapid pace, several comprehensive studies have been published. A large study conducted by the Maternal-Fetal Medicine Unit (MFMU) Network including 1219 patients from 33 hospitals in 14 states reported that mothers with severe or critical SARS-CoV-2 disease and their neonates are at increased risk for a number of perinatal complications, including cesarean birth, hypertensive disorders of pregnancy, preterm birth, VTE, neonatal ICU (NICU) admission, and lower birth weight, compared with asymptomatic mothers. However, data remain incomplete and, at times, inconsistent with many studies because of a large degree of heterogeneity regarding methods and included populations.

Maternal Morbidity and Mortality

SARS-CoV-2 infection in pregnancy is consistently associated with substantial increases in severe maternal morbidity and mortality. The MFMU Network study found the rate of severe to critical SARS-CoV-2 disease to be 12% in pregnant patients. Maternal ICU admission occurred in 4.8%, and maternal death occurred in 0.3% of this population. Another large systematic review reported a maternal mortality rate of 0.02%, ICU admission rate of 4%, mechanical ventilation rate of 3%, and extracorporeal membrane oxygenation (ECMO) rate of 0.2% among pregnant women. Conversely, conducted a systematic review that investigated 117 published reports involving 11,758 pregnant women from high- and middle-income countries and found a mortality rate for COVID-19 of 1.30% and a rate of severe pneumonia of up to 14%. A 2021 multinational cohort study including 18 countries found a similar risk for maternal mortality of 1.6%. Mortality was reported to be 22 times higher in pregnant women with COVID-19 compared with nonpregnant women. These rates exceed reported rates from studies conducted in the United States likely because of disparities of maternity services between lower- and higher-income countries. However, one factor that all studies agree on is the high prevalence of comorbidities in pregnant women with increased rates of severe morbidity and mortality associated with COVID-19. reported a comorbidity rate of 20% in deceased pregnant individuals. Advanced maternal age was most prevalent; other comorbidities included diabetes, obesity, asthma, and cardiovascular disease, including essential hypertension, gestational hypertension, preeclampsia, and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.

Mode of Delivery

Although the safest mode of delivery in patients with SARS-CoV-2 infection is not clear, overall an increased rate of cesarean delivery (CD) in women with COVID-19 has been reported. The MFMU Network study reported a cesarean birth rate of 36.9%. This rate was even higher (59.6%) in expecting mothers with severe or critical COVID-19. One summary of 39 systematic reviews reported a CD rate between 52.3% and 95.8%. Rates of CD, in which the primary indication was COVID-19, varied between 7.7% and 60.4%. In particular, one review found that maternal SARS-CoV-2 infection was the primary indication for 49.6% (59/119) of preterm CD and 65.7% (159/242) of term CD. Vaginal delivery rates ranged between 4.2% and 44.7%.

Hypertensive Disorder of Pregnancy

An increase in hypertensive disorders of pregnancy has been reported in pregnant patients diagnosed with SARS-CoV-2 infection. The overall risk of a hypertensive disorder in pregnancies affected by COVID-19 was 23.4%, with 40.4% in women with severe to critical disease. A multinational cohort study reported by found a rate of pregnancy- induced hypertension of 8.2% in those with SARS-CoV-2 disease compared with 5.6% in unaffected pregnancies. Furthermore, 8.4% of pregnancies complicated by COVID-19 had a diagnosis of preeclampsia, eclampsia, or HELLP syndrome, compared with 4.4% of those without.

Risk for Preterm Birth, Preterm Labor, and Premature Rupture of Membranes

Infection with SARS-CoV-2 during pregnancy has a demonstrated increased risk for preterm birth. In a large network study conducted in the United States, overall risk for preterm birth before 37 weeks was reported as 16.9% in pregnancies complicated by COVID-19. In this study, the rate of preterm birth was 41.8% in patients with severe to critical COVID-19 compared with 11.9% in asymptomatic women. reported a 22.5% rate of preterm birth before 37 weeks in patients with COVID-19 compared with 13.6% in unaffected pregnancies. Overall, reported rates of preterm deliveries vary between 14.3% and 63.8% for pregnancies complicated by COVID-19. Two large studies found spontaneous preterm birth rates of 5% and 6.4%, and another review reported a medically indicated preterm birth rate of 21.4%. Another study described a medically indicated preterm birth rate of 18.8% in pregnant women with COVID-19 compared with 8.9% in normal pregnancies. Reported rates of preterm labor range between 22.7% and 32.2%. Premature rupture of membranes (PROM) also ranges between 2.5% and 26.5%. Data for preterm PROM are even more limited, with a reported range of 6.4% to 16.1%.

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