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.
| 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 |
| 33.3% <34 wk preterm birth |
| Fetal growth and placental effects |
|
|
| Delivery and postnatal outcomes |
|
|
| Maternal outcomes |
|
|
| Neonatal outcomes |
|
|
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%.
Miscarriage and Pregnancy Loss
Currently available data on rates of miscarriage and pregnancy loss are limited and inconsistent. Overall reported miscarriage rates associated with SARS-CoV-2 infection reported by moderate- to high-quality studies are low at less than 2.5%. However, one review including 637 participants reported miscarriage rates of 16.1% and 3.6% for first- and second trimester infections, respectively. Although miscarriage may occur in the setting of COVID-19, determining causality has been challenging. found 3 fetal deaths before 20 weeks gestation among 141 pregnancies complicated by critical to severe COVID-19 compared with 6 among 499 patients with mild to moderate disease, and 4 among 579 women with asymptomatic SARS-CoV-2 infection. Few studies have reported rates of pregnancy termination; however, one study reported a rate of 0.1% in a cohort of patients with first- and second-trimester infections. Indications for termination were related to the patient’s anxiety for potential SARS-CoV-2–associated adverse pregnancy outcomes.
Fetal Outcomes
Data on fetal outcomes continue to evolve. Rates of fetal distress in pregnancies complicated by SARS-CoV-2 infection vary between 7.8% and 61.1%, with the largest sample reporting a rate of 8.5%. Within a multinational cohort study conducted by fetal distress was reported in 12.3% of pregnancies complicated by SARS-CoV-2 infection compared with 8.4% in those without. Reported rates of stillbirth are low, with the two largest collected series of deliveries reporting a rate of 0.6% and 0.9%. , Additionally, found the rates of fetal death reported in pregnant patients with severe or critical COVID-19 after 20 weeks gestation were 1 in 141 (0.07%) compared with 4 in 499 (0.008%) with mild to moderate disease and 5 in 579 (0.009%) among asymptomatic pregnancies.
Overall, pregnancies complicated by underlying comorbidities in addition to SARS-COV-2 infection are at higher risk for adverse outcomes compared with pregnancies complicated by SARS-COV-2 infection alone. However, data remain incomplete and inconsistent, with many studies containing a large degree of heterogeneity regarding methods and included populations. Data available early in the pandemic focused mostly on infections in the last trimester and near delivery. In addition, testing availability was not universal, which affected the reported number of cases and related outcomes. Moreover, not all studies stratify data by classification of disease severity (mild, severe, critical) but rather between asymptomatic and symptomatic women.
Manifestations of SARS-CoV-2 in the Placenta and Other Organs
Vertical Transmission: Why Are We Concerned?
Teratogenicity and fetal morbidity are known to be associated with many viral infections, such as Zika virus and so-called TORCH infections (toxoplasmosis, other [parvovirus B19, syphilis, varicella zoster virus (VZV)], etc.), rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV). The transmission rates for these pathogens range from as low as 0.2% to 0.4% for CMV and VZV, to as high as 17% to 33% for parvovirus B978-0-323-87539-4. The transplacental passage of infectious pathogens tends to occur with increasing frequency as gestational age increases, whereas detrimental effects on the fetus increase at earlier gestational age.
The teratogenic risk associated with SARS-CoV-2 infection in pregnancy remains unknown. At the beginning of the pandemic, there was a concern that SARS-CoV-2 infection in pregnancy may have detrimental effects similar to those of other TORCH infections; however, that has not been the case. Vertical transmission rates have been reported as high as 7.9%, but most studies have found a much lower rate, around 3.2%. However, these data remain limited by the indirect measures of possible vertical transmission used by most studies. Fetal infection can be conclusively determined only by the direct demonstration of the presence of the SARS-CoV-2 virus in fetal tissues, which often are not available for study.
In addition to direct in-utero fetal infection, indirect fetal effects are also a concern with maternal SARS-CoV-2 infection. One systematic review found several cohort studies and case reports describing an association between maternal SARS-CoV-2 infection and placental evidence of maternal vascular malperfusion, particularly with maternal vessel injury and intervillous thrombi. One may speculate that SARS-CoV-2 may result in the activation of endothelial damage pathways predisposing to the development of hypertensive disorders of pregnancy, which in itself is associated with poor maternal and neonatal outcomes (i.e., prematurity, growth restriction, low birth weight) in the short and long term. This is one of the many issues that remain open for study.
Data From Neonatal RT-PCR Tests on Nasopharyngeal Swab, Amniotic Fluid, Placenta, Urine, Cord Blood, and Anal or Rectal Swabs
Nasopharyngeal Sampling
Both the American Academy of Pediatrics (AAP) and the CDC recommend nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) testing of all neonates born to mothers with suspected or confirmed SARS-CoV-2 infection during pregnancy. , Case reports, single-center cohort studies, retrospective reviews, and systematic reviews have published data on nasopharyngeal RT-PCR testing of neonates born to mothers with COVID-19 during pregnancy. The overwhelming majority of neonates in these studies had negative nasopharyngeal RT-PCR testing. published a systematic review including 37 studies containing 365 pregnant women with SARS-CoV-2 infection and 302 of their neonates. Of the 302 neonates, 219 underwent nasopharyngeal RT-PCR testing with only 11 in 219 (5%) testing positive. Similarly, conducted a multinational cohort study on mothers with SARS-CoV-2 infection in pregnancy and their neonates. Nasopharyngeal testing was performed on 416 neonates born to SARS-CoV-2–infected mothers. Of the 416 neonates, 54 (12.9%) had positive test results within the first 48 hours after birth. Studies reporting positive nasopharyngeal RT-PCR results in neonates were variable in timing of specimen collection from shortly after birth to up to 1 week of life. , , Currently, there are no recommendations for routine RT-PCR testing of amniotic fluid, placenta, cord blood, urine, and/or anal or rectal samples for SARS-CoV-2 in exposed neonates. Most of the data collected from these sites comes from case reports or small cohort studies.
Amniotic Fluid
The majority of RT-PCR testing performed on amniotic fluid produced negative results. a
a References , , , , , .
A single case report documented positive RT-PCR testing of amniotic fluid in a mother with severe COVID-19. Neonatal cord blood and nasopharyngeal RT-PCR testing obtained at 2 hours after birth were negative. However, amniotic fluid and repeat nasopharyngeal testing obtained at 24 hours after birth were positive.Placental Tissue
Testing of placental tissue is uncommon and has yielded predominantly negative results. , , , , A placental analysis from eight cohort or case series studies yielded a pooled positive RT-PCR rate of 7.7% (2/26) of all tested placentas of SARS-CoV-2–infected mothers. However, evidence of placental viral infection does not guarantee intrauterine vertical transmission to the fetus. Transplacental infection not only requires detection of viral RNA in the placenta but also in amniotic fluid before the onset of labor; cord or neonatal blood, body fluid, or respiratory samples; or demonstration of viral particles by electron microscopy, immunohistochemistry studies, or in situ hybridization in fetal/neonatal tissues.
One case report demonstrated positive placenta RT-PCR testing in a mother and neonate with positive nasopharyngeal RT-PCR swabs. Histological examination of placental tissue showed multiple areas of infiltration with inflammatory cells and early infarction. One study reported histopathological findings in 16 placentas from mothers with SARS-CoV-2 infection during pregnancy. Despite lack of significant differences in acute or chronic inflammatory pathological processes compared with controls, placentas of SARS-CoV-2–infected mothers did have higher rates of decidual arteriopathy and other maternal vascular malperfusion features that have been associated with adverse outcomes. Two additional case reports found SARS-CoV-2 localization and damage predominantly to the syncytiotrophoblast cells at the maternofetal interface. , In contrast, a single-center review compared 101 placentas from mothers with SARS-CoV-2 infection during pregnancy to 121 controls and found no significant difference in chorioamnionitis, fetal vascular malperfusion, or maternal vascular malperfusion between the two groups.
Cord Blood and Urine
Testing umbilical cord blood of neonates born to mothers with SARS-CoV-2 infection during pregnancy has largely produced negative results. b
b References , , , , , , .
Although rarely performed, two studies including 20 neonates reported negative urine RT-PCR results in all neonates. ,Anal and Rectal Swabs
Anal and rectal RT-PCR swabs performed on neonates also produced predominantly negative results. c
c References , , , , , , , .
In a cohort study of 33 neonates born to mothers with SARS-CoV-2 infection, only 3 had positive anal swab samples, which were obtained on postpartum days 2 and 4.Conflicting Data on Antibody Testing in Neonates
In adults, SARS-CoV-2 immunoglobulin M (IgM) and IgG antibody testing is a useful tool for detecting recent or past infection. IgM antibodies are produced early in the immune response and are the first immunoglobulin class synthesized by infants. IgG antibodies are produced later and remain present after IgM levels fall. Unlike IgG, IgM antibodies do not cross the placenta. In neonates, although the presence of SARS-CoV-2 IgG antibodies likely represents transplacental transfer of maternal immunoglobulins, IgM presence shortly after birth may provide support for intrauterine vertical transmission. Currently, antibody testing is not recommended to evaluate for acute infection in neonates and children.
Studies evaluating antibody testing shortly after birth on neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy have produced conflicting results. Three studies from Wuhan, China evaluated 36 neonates born to SARS-CoV-2–positive mothers with RT-PCR and antibody testing shortly after birth. Of the 36 neonates, 26 and 9 had IgG and IgM levels above the normal reference range, respectively. However, all neonates were asymptomatic and none had positive RT-PCR swabs of the throat or anus. In a separate study, cord blood samples of 37 neonates born to SARS-CoV-2–positive mothers were evaluated for IgG and IgM antibodies. Of the 37 neonates tested, 23 had elevated cord blood IgG and 1 had elevated IgM levels. In the neonate with IgM antibodies, nasopharyngeal RT-PCR testing was negative and placental pathology was indicative of feto-maternal hemorrhage, which suggested leakage of IgM antibodies into the fetal circulation rather than intrauterine vertical transmission.
It is plausible that the presence of IgM antibodies in infants from these studies was the result of leakage from maternal to fetal circulation, which is supported by the absence of symptoms or positive RT-PCR results in these infants. Conversely, the presence of IgM antibodies in these infants may provide evidence for intrauterine vertical transmission. At this time, both hypotheses remain plausible, but more research is needed.
Transplacental passage of IgG antibodies from mother to neonate may confer passive immunity to the neonate in utero and after birth. evaluated IgG antibody levels in mothers with SARS-CoV-2 infection during pregnancy and in their neonates after birth. A strong, direct relationship was found between maternal IgG level and maternal oxygen requirement and neonate IgG levels, suggesting that maternal disease severity is associated with higher IgG levels in neonates at birth. A study by examined the duration of elevated IgG levels in neonates born to mothers with SARS-CoV-2 infection. In that study, neonatal IgG levels remained elevated for up to 180 days after birth, and maternal infection in the second trimester was associated with a longer duration of IgG elevation compared with the third trimester. What remains unknown, however, is the IgG level needed to provide immunity to neonates after birth.
Treatment and Interventions in Pregnancy
Treatment and interventions vary between the outpatient and inpatient setting. The management of hospitalized pregnant women with SARS-CoV-2 infection is not substantially different from that of nonpregnant patients. However, pregnancy status may confer a lower threshold for admission. Inpatient monitoring may be necessary for pregnant patients with moderate to severe signs and symptoms of SARS-CoV-2 infection, oxygen saturation less than 95%, presence of comorbid conditions (uncontrolled hypertension, inadequately controlled gestational or pregestational diabetes, chronic renal disease, chronic cardiopulmonary disease, or immunosuppressive states), or fevers greater than 39°C despite acetaminophen.
Once admitted, management requires a multispecialty team–based approach that may include consultation with obstetrics, maternal-fetal medicine, infectious disease, pulmonary and critical care, neonatology, and pediatric specialists. Fetal and uterine contraction monitoring should be performed when appropriate, based on gestational age, and delivery planning should be individualized. In most cases, the timing of delivery should be dictated by obstetric indications rather than maternal diagnosis of SARS-CoV-2 infection. Most importantly, potentially effective treatment for SARS-CoV-2 infection should not be withheld from pregnant women because of theoretical concerns related to the safety of therapeutic agents in pregnancy.
Diagnostic chest radiographs and chest computed tomography (CT) scans may be required. Although radiation exposure during pregnancy should be minimized, radiography, CT, or nuclear medicine imaging techniques in addition to ultrasonography or magnetic resonance imaging (MRI) should not be withheld from pregnant patients, if medically indicated. If these techniques are necessary, in addition to ultrasonography or MRI, they should not be withheld from pregnant patients.
A large number of medical therapeutic options have been investigated for the treatment of SARS-CoV-2 infection, but data remain limited in pregnancy. Proposed therapies have included antiviral drugs, corticosteroids, monoclonal antibodies, and convalescent plasma. None of these therapies have absolute contraindications in pregnancy; however, pregnant patients have been excluded from almost all clinical trials. The RECOVERY trial is an ongoing randomized clinical trial (RCT) investigating use of multiple therapies to prevent death in patients with SARS-CoV-2. This trial was the first to include pregnant women.
Corticosteroids
Corticosteroids are well-known immunomodulators that can reduce inflammatory response. The RECOVERY trial demonstrated that dexamethasone for up to 10 days resulted in lower 28-day mortality among people requiring invasive mechanical ventilation and a small but statistically significant decrease in mortality risk among those requiring supplemental oxygen but not intubation for SARS-CoV-2. However, this benefit was not seen in patients not requiring respiratory support. Use of dexamethasone in pregnancy has been associated with risk for cleft palate and impaired fetal growth when used in the first trimester. , Neonatal concerns regarding its use later in pregnancy include maternal hyperglycemia leading to neonatal hypoglycemia and the potential for the development of maternal adrenal insufficiency. However, given the significant benefit of reduction in mortality among patients with SARS-CoV-2, this treatment should not be withheld from pregnant COVID-19 patients. The maternal benefits outweigh the risks of neonatal harm. If glucocorticoids are indicated for fetal lung maturity, dexamethasone can be dosed at 6 mg intramuscularly (IM) every 12 hours for 48 hours (four doses) followed by up to a total of 10 days of 6 mg dexamethasone orally (PO) or intravenously (IV) daily to provide transplacental fetal benefit. If glucocorticoids are not indicated for fetal lung maturity, 6 mg dexamethasone (PO/IV) daily for up to 10 days has been recommended for nonpregnant patients.
Remdesivir
Remdesivir is a broad-spectrum antiviral drug that effectively inhibits replication of SARS-CoV-2 in vitro. To date, data are mixed about its clinical use in patients with SARS-CoV-2 infection and data on use in pregnancy are limited. A single small case series of six pregnant women exposed to remdesivir while being treated for Ebola did not find any adverse pregnancy outcomes. It should be noted that remdesivir was given outside of the first trimester in all case reports. A case series of 86 women (67 were pregnant, 19 immediately postpartum) given remdesivir on a compassionate use basis for severe SARS-CoV-2 infection found a high rate of clinical recovery, but rates of preterm delivery were high (likely related to severe SARS-CoV-2). Nevertheless, these data are difficult to quantify in the absence of a control arm. Remdesivir can be given in pregnancy if the benefits outweigh the potential risks and could be offered to pregnant patients meeting criteria for compassionate use.
Immune Modulators
Monoclonal antibodies inhibit a single cytokine and thus have the benefit of molecular precision. These agents provide a focused inhibition of a single pathway, avoiding the broad side effect profile of corticosteroids. On the other hand, monoclonal antibodies are also exceedingly expensive and often have limited availability. Tocilizumab is an IL-6 monoclonal antibody that can cause immune suppression by inhibiting IL-6, a proinflammatory cytokine associated with the SARS-CoV-2–related cytokine storm. It is commonly used for treatment of rheumatoid arthritis. It has been offered for SARS-CoV-2 treatment as part of the RECOVERY trial. Small trials in nonpregnant adult patients showed that tocilizumab reduced the chance of progression to the composite outcome of mechanical ventilation or death in hospitalized patients with SARS-CoV-2 pneumonia who were not receiving mechanical ventilation.
Janus kinase (JAK) inhibitors, such as baricitinib, are a different type of immunomodulator with the ability to inhibit the intracellular signaling pathway of multiple cytokines known to be elevated in severe COVID-19, including IL-2, IL-6, IL-10, IFN-g, and granulocyte-macrophage colony-stimulating factor (GM-CSF). It also acts against SARS-CoV-2 through the impairment of AP2-associated protein kinase 1 (AAK-1), which regulates endocytosis in alveolar type II cells, and prevents SARS-CoV-2 cellular entry and infectivity. Finally, it improves lymphocyte counts in infected patients. In three case series, baricitinib treatment was associated with both an improvement in oxygenation and a reduction in select inflammatory markers. A recent clinical trial (ACTT-2 Trial) showed that combination treatment with baricitinib and remdesivir was safe and superior to remdesivir alone for the treatment of hospitalized patients with COVID-19 complicated by pneumonia.
Based on experimental animal studies, use of immunomodulators is not expected to increase the risk for congenital malformations, but data are scarce in pregnancy. Because these agents are potentially effective against SARS-CoV-2 infection, use should be considered on an individual basis and not be withheld from pregnant women because of theoretical concerns related to safety of the fetus.
Convalescent Plasma
In previous epidemics, patients with SARS, MERS, H1N1 influenza, and Ebola infections have been treated using plasma collected from recovered patients. , One explanation for the efficacy of convalescent plasma therapy is that antibodies from convalescent plasma might suppress viremia. Two RCTs of nonpregnant patients with severe or life-threatening COVID-19 failed to show a difference in clinical status or overall mortality between patients treated with convalescent plasma compared with placebo or standard treatment. , Despite these findings, several cases have reported using convalescent plasma in the management of pregnancies complicated by SARS-CoV-2 infection with rapid deterioration. , At this time, pharmacological use of convalescent plasma is considered investigational and efficacy remains unclear.
Unique Considerations in Pregnancy
Antithrombotic Prophylaxis
As mentioned earlier, pregnancy is a hypercoagulable state that poses an increased risk for venous thrombotic events. Hemostatic and thromboembolic complications have been reported in 0.98% and 0.28% of pregnant women with SARS-CoV-2 infection, respectively. Additional studies demonstrated that hematological complications are more commonly observed in pregnant women with SARS-CoV-2 infection (1.26%) than in pregnant women without (0.45%). There is no consensus on antepartum and postpartum anticoagulation guidelines at this time; however, various recommendations have been made.
The Royal College of Obstetricians and Gynaecologists (RCOG) current guidelines (as of February 2021) recommend that all pregnant women and women who are within 6 weeks postpartum, admitted with confirmed or suspected SARS-CoV-2 infection, be offered prophylactic low-molecular-weight heparin (LMWH) during admission and continued for at least 10 days after discharge. One study demonstrated that hematological complications are more commonly observed in pregnant women with SARS-CoV-2 infection (1.26%) than in pregnant women without (0.45%). ,
The Canadian ISTH (Subcommittee for Women’s Health Issues in Thrombosis and Hemostasis) has also suggested weight-adjusted VTE prophylaxis with LMWH in all pregnant and postpartum women admitted to hospital with SARS-CoV-2 infection in the absence of active bleeding and with a platelet count above 30 × 10 9 /L, provided urgent delivery is not anticipated or timing is beyond 24 hours postpartum. They also recommended careful and individualized VTE risk assessment for outpatient anticoagulation after discharge from the hospital, varying between a 10- to 14-day course of LMWH to 2 to 6 weeks for postpartum women. For women at low risk for VTE, hydration, appropriate nutrition, mobilization, and control of pyrexia were encouraged. Use of antiembolic stockings at home may be beneficial but the authors acknowledge that these recommendations are based on limited evidence.
Cardiomyopathy
Although SARS-CoV-2 presents predominantly with pulmonary manifestations, there are reports of cardiovascular complications such as cardiomyopathy, viral myocarditis, myocardial infarction, and arrhythmias. Data are limited to case reports; however, a 33% incidence of cardiomyopathy has been reported. , It is unknown whether the rate of developing SARS-CoV-2–associated cardiomyopathy is exacerbated in the pregnant population or similar to the rate in nonpregnant patients. One theory involves a higher level of inflammatory markers, such as IL-6, as a common pathophysiology for pregnancy-associated cardiomyopathy and SARS-CoV-2–related cardiomyopathy. reviewed inflammatory markers in over 3900 SARS-CoV-2 patients and found that survivors had lower levels of IL-6 than nonsurvivors.
Further studies are needed to investigate whether pregnancy affects the chance of developing SARS-CoV-2–related cardiomyopathy compared with that of the general population. Moreover, cardiomyopathy should be considered in the differential of pregnant patients with worsening clinical status in cases of severe COVID-19 and an echocardiographic evaluation should be considered given the assumed higher risk for cardiovascular complications after SARS-CoV-2 infection.
Mechanical Ventilation
Mechanical ventilation includes both noninvasive and invasive modalities. Both modalities are used in patients with worsening severe respiratory distress syndrome related to SARS-CoV-2. Among obstetric patients, the most common diagnosis of a severe respiratory illness requiring mechanical ventilation is acute respiratory distress syndrome (ARDS) caused by infection or preeclampsia. ARDS is a main finding in patients with critical SARS-CoV-2 pneumonia; however, to date there are still only a few reported cases of mechanical ventilation as a result of SARS-CoV-2 infection in pregnancy. A systematic review of 295 pregnant women found a rate of 1.8% for invasive mechanical ventilation and of 12.4% for noninvasive ventilation.
Extracorporeal Membrane Oxygenation
ECMO can provide respiratory support (venovenous [VV]-ECMO) or both respiratory and circulatory support (venoarterial [VA]-ECMO). Acute respiratory distress in the obstetric population because of viral pneumonia requiring ECMO during the midtrimester of pregnancy is rare. Until 2016, only 45 cases of ECMO in pregnancy had been reported in the literature worldwide, and most cases occurred during the H1N1 pandemic.
ECMO in the setting of pregnancy presents unique challenges. Major hemorrhage is the most common complication, with bleeding occurring in various sites: intracranial, uterine, lung, upper gastrointestinal (GI), and the cannulation site. If major bleeding is present, immediate delivery is necessary. Cannula dislodgement, thrombosis, hemolysis, and infections are additional concerns of ECMO in pregnancy.
Reported survival rates for pregnant patients on ECMO have been significantly higher than the overall survival for nonpregnant adults requiring ECMO for pulmonary (59%) or cardiac (43%) causes, with maternal survival rates ranging from 70% to 80% and fetal survival rates from 65% to 72%. However, the data are inadequate about the safety of ECMO in pregnancy. In a 10-year study of ECMO in 54 pregnant women with cardiopulmonary failure, only 60% of mothers and fetuses survived. Another systematic review showed that ECMO in the peripartum period has been successfully used with a maternal survival rate of 75.4%. Survival varied depending on the indication for ECMO. Nevertheless, ECMO has the potential to increase the survival rates of both mother and fetus and should be considered as salvage therapy for peripartum women with reversible forms of cardiorespiratory failure. Multidisciplinary care is necessary for optimal management of the mother and fetus in patients affected by severe respiratory failure related to SARS-CoV-2 refractory to conventional therapies.
Vaccine in Pregnancy
Several vaccines are now available for use worldwide. Although pregnant individuals were excluded from initial phase III vaccine trials, professional organizations continue to support vaccines not being withheld from pregnant and lactating persons. Regarding vaccine safety in pregnancy, developmental and reproductive toxicity studies have not found adverse outcomes related to fetal development, pregnancy, delivery, or postpartum complication. Early data from the CDC SARS-CoV-2 vaccine symptom monitoring system, V-safe, demonstrated no difference in side effects between pregnant and nonpregnant individuals who received the mRNA SARS-CoV-2 vaccines. Furthermore, no differences in adverse pregnancy outcomes, including miscarriage, small for gestational age, preterm birth, or neonatal death were found in 827 completed pregnancies compared with historical rates before the SARS-CoV-2 pandemic.
Antibody response is similar in those vaccinated during pregnancy compared with nonpregnant individuals. A study evaluating 131 pregnant individuals found similar levels of vaccine-induced antibody titers from mRNA SARS-CoV-2 vaccines compared with those in nonpregnant individuals. Moreover, pregnant individuals who received the vaccine in pregnancy had higher antibody titers than those observed from natural SARS-CoV-2 infection in pregnancy.
Vaccination during pregnancy may provide fetal protection through passive immunity. Multiple studies have demonstrated the presence of vaccine-produced antibodies in cord blood and breast milk. Increased rates of vaccine-associated IgG antibodies were found in cord blood samples of patients who received both doses of SARS-CoV-2 mRNA vaccine (Pfizer/BioNTech or Moderna) before delivery. , Additionally, cord blood antibodies were present in samples obtained more than 3 weeks after vaccine administration. , In summary, SARS-CoV-2 vaccines have the ability to reduce the risk for severe maternal morbidity and mortality and provide protection to neonates through passive immunity.
Breastfeeding
The SARS-CoV-2 pandemic has raised concerns regarding the possibility and effects of mother-infant transmission of SARS-CoV-2 through breastfeeding and close infant contact. Breastfeeding has many benefits for both mothers and neonates. One case report described detection of SARS-CoV-2 RNA in milk samples from a mother for 4 consecutive days, coinciding with mild maternal symptoms and a SARS-CoV-2–positive diagnostic test of the newborn. A case series of 15 mothers with SARS-CoV-2 infection found detectable RNA in breastmilk samples of 4 mothers (26.7%). The throat swab samples from these mothers’ infants were also found to be positive for SARS-CoV-2 RNA. Three of the four mothers were breastfeeding. Although it is not known whether SARS-CoV-2 can be transmitted through breastmilk, or if any potentially transmitted viral components are infectious, suspected or confirmed maternal SARS-CoV-2 infection is not considered a contraindication to infant feeding with breastmilk. Moreover, the benefits of breastfeeding may outweigh the risks of SARS-CoV-2 infection in infants.
Individuals with suspected or confirmed SARS-CoV-2 can still transmit the virus through respiratory droplets while in close contact with the infant, including while breastfeeding. Nevertheless, evidence supports the safety of direct breastfeeding in SARS-CoV-2–positive mothers who practice infection prevention measures. , Therefore obstetrician-gynecologists and other maternal care practitioners should counsel women with suspected or confirmed SARS-CoV-2 who intend to feed their infants with breastmilk on how to minimize the risk for transmission, including breastmilk expression with a manual or electric breast pump and precautions to avoid spreading the virus (hand hygiene and wearing a mask or cloth face covering, if possible, while breastfeeding).
Impact of SARS-CoV-2 Infections on the Fetus and Newborn
Prevention of Neonatal SARS-CoV-2 Infection
At the beginning of the pandemic, the lack of understanding of peripartum transmission risk to the neonate led to varying management of SARS-CoV-2–exposed neonates among hospitals regarding rooming-in versus separation of the mother-infant dyad and allowance of direct breastfeeding. Not surprisingly, breastfeeding rates were lower in separated neonates. Despite this heterogeneity in care, none of the 70 exposed neonates in a US study tested positive for SARS-CoV-2. Fortunately, time has afforded the medical community the ability to understand peripartum transmission risk and develop evidence-based best practices to aid in prevention of neonatal infection. Close contact with a SARS-CoV-2–positive mother or caretaker is likely the primary route of infection in neonates rather than vertical transmission. , Interestingly, maternal SARS-CoV-2 viral load does not appear to be associated with neonatal positivity or severity of illness.
After delivery, neonates with suspected or confirmed perinatal exposure do not necessarily require NICU admission unless the neonate needs intensive care for other reasons or a facility lacks the means to care for a neonate requiring isolation. Previously, there were concerns about the safety of rooming-in. An observational multicenter cohort study followed perinatally exposed neonates who roomed-in. These neonates could participate in skin-to-skin care and breastfeed. Mothers wore surgical masks when near their neonates and practiced infection prevention hygiene. All neonates were kept in a closed isolette when not being held. Results support the notion that perinatal transmission of SARS-CoV-2 is unlikely to occur if infection prevention measures are undertaken. None of the neonates tested positive on serial screening. Similarly, a multicenter study in Italy examining rooming-in found this practice to be safe.
Society recommendations have evolved throughout the pandemic. At present, the World Health Organization (WHO), CDC, and AAP support rooming-in with proper infection prevention measures and direct breastfeeding. , , The AAP and CDC suggest that placing the neonate in an isolette incubator in the mother’s room may facilitate distancing and provide protection from aerosolized viral particles. , The WHO and AAP endorse skin-to-skin care. , The AAP also supports delayed cord clamping when indicated. The CDC advises against neonates wearing masks or plastic face shields. SARS-CoV-2–positive mothers can discontinue isolation and precautions when it has been at least 10 days since the onset of symptoms, she has been afebrile for at least 24 hours, and her symptoms have improved.
Neonatal SARS-CoV-2 Infection
Neonatal SARS-CoV-2 infections have been recognized in the literature. The number of cases in neonates is low compared with that in adults. Theories to explain the low infection rates include research demonstrating that SARS-CoV-2 enters cells by ACE2 receptors located in the respiratory tract epithelium and lung parenchyma, which is immature in young children, thus decreasing viral invasion ability. There also may be a decreased intracellular response induced by ACE2 in children. Neonates appear to have protection from SARS-CoV-2 as a result of the presence of fetal hemoglobin, which comprises alpha and gamma chains but not beta chains. SARS-CoV-2 virus attacks the heme on the beta chain in adult hemoglobin leading to hypoxia. , The passage of maternal IgG antibodies across the placenta against SARS-CoV-2 also likely provides protection. One interesting study described developmental regulation and lower expression levels of SARS-CoV-2 spike protein primer transmembrane protease serine 2 (TMPRSS2) in lung tissues of infants and children, possibly adding to their increased protection from severe respiratory illness associated with SARS-CoV-2 infection.
Neonatal infection from perinatal SARS-CoV-2 exposure varies across studies and ranges from 2% to 10.7%. , , , In a retrospective observational study performed in India, SARS-CoV-2 testing was performed in neonates with suspected infection (including neonates with both SARS-CoV-2–positive and SARS-CoV-2–negative mothers); 10.6% (21/198) of neonates were positive. Two of the positive neonates were born to mothers with negative testing. In another retrospective study in India evaluating outborn neonates admitted to the NICU, 4.25% (18/423) were positive. Just 50% of SARS-CoV-2–positive neonates in this study had positive mothers or caretakers. At present, there has not yet been a confirmed case of neonatal mortality as a result of SARS-CoV-2 infection during birth hospitalization. Neonatal fatalities associated with COVID-19 are very rare in general. ,
Symptoms
Largely, SARS-CoV-2 infection is less severe in children compared with adults. A decreased systemic inflammatory response in children with SARS-CoV-2 may contribute to less severe manifestations. However, when illness severity is compared in children, neonates appear to have more severe infections. , Acquired immunity from other viruses may provide some protection in older children. Neonates have not yet had the time to develop this cross immunity. In addition, airways are still small and underdeveloped in neonates, possibly placing them at higher risk for respiratory compromise. found that age younger than 1 month was a significant risk factor for requiring intensive care.
Neonates with SARS-CoV-2 infection are often asymptomatic. , In a meta-analysis of 176 published cases of neonatal SARS-CoV-2, 55% of infected neonates had clinical manifestations. The most common reported symptoms were respiratory distress, fever, neurological sequelae, and GI symptoms. Respiratory symptoms included tachypnea, retractions, and rhinitis. Neurological manifestations comprised abnormalities in tone, irritability, and apnea. GI features were primarily feeding-related difficulties, diarrhea, and emesis. Other noted symptoms included conjunctivitis and rashes. Severe lung disease requiring mechanical ventilation has been reported. It may be difficult to ascertain whether these clinical signs were due to prematurity-related pathological conditions or SARS-CoV-2 in this population. Because SARS-CoV-2–positive neonates were more likely being born prematurely, required respiratory support may be more a complication of prematurity rather than SARS-CoV-2 infection.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and potentially life-threatening condition involving fever, multisystem dysfunction (≥2 organs), inflammation, and current or recent SARS-CoV-2 infection with no alternative diagnosis. Cases appear to be postinfectious rather than related to acute infection. The CDC reports only 3% of MIS-C cases are in those younger than 1 year of age. Despite its rarity, there are documented cases of MIS-C in the neonatal population. reported MIS-C in a neonate born to a mother with SARS-CoV-2 infection at 31 weeks gestation. The mother was negative for SARS-CoV-2 at delivery. The infant became symptomatic with cardiogenic shock and multiorgan dysfunction on day 22 of life. MIS-C was diagnosed given the temporal association with prenatal SARS-CoV-2, evidence of IgG antibodies to SARS-CoV-2, and lack of other plausible explanations.
Laboratory and Radiographic Findings
Neonatal SARS-CoV-2 infection can exhibit relatively nonspecific laboratory abnormalities such as leukopenia and lymphopenia, elevated transaminases and elevated nonspecific inflammatory markers, including procalcitonin and CRP. , In a meta-analysis, 64% of infected neonates had abnormal lung imaging on ultrasound or chest x-ray with an interstitial alveolar pattern or a CT scan with ground-glass opacities.
Testing
All neonates born to mothers with either suspected or confirmed SARS-CoV-2 infection should undergo testing irrespective of symptomatology. , The ideal time to test exposed neonates is unknown. Contamination from maternal fluids containing SARS-CoV-2 can cause false positives in those tested early. Additionally, early testing may lead to false-negative results because RNA may not yet be at detectable levels. The CDC and AAP recommend testing at 24 hours of age. , Repeat testing at 48 hours of age is suggested. The CDC recommends repeat testing at 48 hours in those testing negative at 24 hours of life or if results are still pending. If hospital discharge is planned before 48 hours of life, a single test can be performed close to discharge from 24 to 48 hours of life. , If the initial test is positive, the AAP recommends considering follow-up testing at 48- to 72-hour intervals for neonates admitted to the NICU until the neonate has had two negative tests indicating mucosal viral clearance. Testing should be performed using RT-PCR for SARS-CoV-2 RNA. Serological testing is not recommended.
Management
All neonates with suspected or confirmed perinatal exposure to SARS-CoV-2 infection should be bathed directly after birth to help remove possible virus on the skin. Currently, there are no established guidelines for the treatment of neonates with confirmed SARS-CoV-2 infection. Treatment remains largely supportive. Various medications have been used in the treatment of neonatal SARS-CoV-2 infection, including hydroxychloroquine, azithromycin, and remdesivir. , , Data from large trials on therapies is lacking at this time, and further studies are needed to evaluate the safety and efficacy of such medications in the neonatal population. Similarly, treatment of MIS-C is aimed at reducing inflammation and supporting organ function, including mechanical ventilation, inotropic support, antibiotics to treat secondary infections, intravenous immunoglobulin, and steroids as noted in case reports of neonatal MIS-C. , In asymptomatic neonates with SARS-CoV-2 infection diagnosed after birth, outpatient follow-up through 14 days of life is recommended.
Neonatal Outcomes
In addition to pregnancy outcomes associated with SARS-CoV-2 infection, knowledge of neonatal outcomes is essential to develop the best plan of care for these patients. According to data acquired from 15 reviews, low birth weight ranged from 5.3% to 47.4%. The data on Apgar score in neonates is highly heterogenous. Two reviews reported six neonates with scores less than 7 at 1 and 5 minutes. These infants were all born preterm because of fetal distress in mothers with critical SARS-CoV-2 disease. , The meta-analysis by which included the largest number of neonates for this outcome, calculated 2.2% (11/500) of neonates with “abnormal” Apgar scores at 5 minutes. The need for admission to the neonatal ICU varied between 10% and 76.9%. Neonatal mortality rates have been reported at 0.3%, although no deaths have been directly associated with a neonatal SARS-CoV-2 infection. found 2 neonatal deaths in 141 pregnancies with critical to severe COVID-19 compared with 1 in 499 pregnant mothers with mild to moderate disease and 2 in 579 pregnant individuals with asymptomatic disease.
Currently, there is a lack of data on the long-term outcomes of neonatal SARS-CoV-2 infection. It remains to be seen what chronic effects SARS-CoV-2 has on the developing fetus and newborn. Additional research is needed to elucidate the ramifications of neonatal SARS-CoV-2 infection.
Conclusion
SARS-CoV-2–related maternal morbidity and mortality are higher in pregnant compared with nonpregnant individuals. However, the management of SARS-CoV-2 infection in pregnancy remains similar to that in nonpregnant patients. Most importantly, potentially effective treatment for SARS-CoV-2 infection should not be withheld from pregnant women because of theoretical concerns related to safety concerns for the fetus. As data continue to evolve at a rapid pace, key questions remain regarding maternal care considerations during SARS-CoV-2 infection. Despite a higher complication rate in pregnant patients, data on neonatal infectivity rate, development, and outcomes remain reassuring. In general, professional society recommendations support the use of mRNA and adenovirus vaccines approved by the US Food and Drug Administration in pregnancy and the postpartum period, and breastfeeding or using human milk, as medically indicated, from mothers with SARS-CoV-2 infection. Although the risk for vertical transmission is thought to be low, currently there is a lack of data on the long-term outcomes of neonatal SARS-CoV-2 infection.
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