Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), is similar to 2 other coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), in causing life-threatening maternal respiratory infections and systemic complications. Because of global concern for potential intrauterine transmission of SARS-CoV-2 from pregnant women to their infants, this report analyzes the effects on pregnancy of infections caused by SARS-CoV-2 and other respiratory RNA viruses, and examines the frequency of maternal-fetal transmission with SARS-CoV-2, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, respiratory syncytial virus (RSV), parainfluenza (HPIV), and metapneumovirus (hMPV). There have been no confirmed cases of intrauterine transmission reported with SARS-CoV-2 or any other coronaviruses—SARS and MERS. Influenza virus, despite causing approximately 1 billion annual infections globally, has only a few cases of confirmed or suspected intrauterine fetal infections reported. Respiratory syncytial virus is an unusual cause of illness among pregnant women, and with the exception of 1 premature infant with congenital pneumonia, no other cases of maternal-fetal infection are described. Parainfluenza virus and hMPV can produce symptomatic maternal infections but do not cause intrauterine fetal infection. In summary, it appears that the absence thus far of maternal-fetal transmission of the SARS-CoV-2 virus during the COVID-19 pandemic is similar to other coronaviruses, and is also consistent with the extreme rarity of suggested or confirmed cases of intrauterine transmission of other respiratory RNA viruses. This observation has important consequences for pregnant women because it appears that if intrauterine transmission of SARS-CoV-2 does eventually occur, it will be a rare event. Potential mechanisms of fetal protection from maternal viral infections are also discussed.

One of the most serious consequences of infectious diseases is their potential to be transmitted from pregnant women to their unborn fetuses. The occurrence of this process—intrauterine vertical transmission—has been known for many decades to occur with specific microbial pathogens. In 1971 a group of investigators in Atlanta, Georgia, led by André Nahmias, MD,1  developed an acronym to identify 4 of the most frequent causes of vertically transmitted infections that were recognized at that time.2  This acronym—TORCH—represented Toxoplasma, Other, Rubella virus, Cytomegalovirus, and the 2 Herpes simplex viruses (type 1 and type 2)—this group has been expanded subsequently to include syphilis, listeriosis, parvovirus, coxsackie virus, Trypanosoma cruzi, and others.2  Since that time, vertical transmission from pregnant women to their fetuses has been a major problem with emergent viral diseases, such as the human immunodeficiency virus (HIV),3,4  Ebola virus,57  and, most recently, Zika virus.810  These emerging viral diseases have resulted in major epidemics; caused significant perinatal morbidity and mortality, including maternal, fetal, and neonatal death; and continue to be significant public health problems for pregnant women and their infants. The 2 most important mechanisms for transmission of microbial agents from mother to infant include maternal hematogenous infection and ascending infection.11  Most TORCH agents (with the notable exception of herpes simplex viruses) and emerging viral diseases are transmitted to the fetus via the maternal hematogenous route via the maternal-fetal interface—organisms circulating in the maternal bloodstream during pregnancy enter the placenta from uterine arteries, circulate in the intervillous space, and can pass to the fetus through the chorionic villous tree where they enter the fetal circulation.11,12  Fortunately, not all infectious diseases that occur in women during pregnancy are transmitted to their fetuses—this includes most bacterial infections as well as some viral agents.11,13  Although no intrauterine transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has yet been reported, there have been adverse outcomes reported in the infants of women with coronavirus disease 2019 (COVID-19), although causality from the infection cannot yet be determined. These include preterm labor and delivery, premature rupture of membranes, intrauterine growth restriction, low birth weight, intrauterine fetal distress, feeding intolerance, asphyxia, pneumonia and respiratory distress, and stillbirth.14 

The development of the COVID-19 pandemic has resulted in levels of morbidity and mortality throughout the world that have not been seen since the H1N1 influenza pandemic of 1918—it is the deadliest pandemic to have occurred in more than 100 years and its significance as a public health problem continues to increase.15,16  The causative virus, SARS-CoV-2, is a newly described coronavirus belonging to the family Coronaviridae and genus Betacoronavirus, the same genus as 2 previously described coronavirus pathogens of humans that have resulted in previous epidemic disease—SARS-CoV, causing SARS, and Middle East respiratory syndrome coronavirus (MERS-CoV), causing MERS.17 

SARS-CoV-2 was first identified in December 2019, when it was recognized as the etiologic agent of an outbreak of life-threatening upper and lower respiratory tract infection in Wuhan, Hubei Province, China.1719  Since that time the infection has rapidly become a global pandemic, resulting in 152 551 deaths as of April 19, 2020.15  As is often the case with a newly emergent infection, little is known of the effect of COVID-19 on pregnant women and their infants. There has been global concern for potential intrauterine transmission of SARS-CoV-2 that has resulted in an increasing number of reports of pregnant women with COVID-19 and their neonates.14,2028  Although several early-onset neonatal infections have been reported,29,30  as well as an infant with elevated immunoglobulin (Ig) M antibody to the virus,31  to date there have been no confirmed cases of intrauterine vertical transmission of SARS-CoV-2. Previous epidemics of related coronavirus diseases—SARS and MERS—resulted in significant maternal and perinatal morbidity and mortality, but although the number of cases of maternal infection was small, there were no confirmed cases of intrauterine maternal-fetal transmission from those 2 pathogens.17 

“Respiratory viruses” is a colloquial term used to identify viruses that are detected predominantly in patients with respiratory tract infections. Because SARS-CoV-2 and other coronaviruses are RNA viruses whose primary means of transmission is via the respiratory route, we decided to analyze the most pathogenic respiratory RNA viruses that infect humans to evaluate their capabilities of causing disease in pregnant women and, importantly, their potential for intrauterine transmission from an infected woman to the fetus (Table).

SARS AND SARS-CoV

The severe acute respiratory syndrome coronavirus, or SARS-CoV, is an enveloped, positive-sense, single-stranded RNA virus belonging to the family Coronavirdae, genus Betacoronavirus. SARS-CoV was the first coronavirus to cause an epidemic. The virus initially emerged as a potentially severe respiratory tract infection during the SARS epidemic of 2002–2003, which began in November 2002 in China's Guangdong Province, where it was initially believed to be an atypical pneumonia or a “flu outbreak.” Unfortunately, China failed to report the occurrence of this illness to the World Health Organization until February 2003; by then it had spread within China and to other countries. By July 31, 2003, there were 8422 probable cases, leading to 916 deaths in 29 countries, with most cases occurring in mainland China and Hong Kong. Almost one-third (30%) of infections occurred in health care workers. By the close of the epidemic the global case fatality rate was 11%.17,32,33 

Pregnant women who became infected with SARS-CoV were adversely affected. In Hong Kong the clinical outcomes among pregnant women with SARS were worse than among SARS-infected women who were not pregnant.34  Among a cohort of pregnant women in Hong Kong who developed SARS infection, 4 of the 7 women (57%) who developed SARS during the first trimester sustained spontaneous miscarriages, probably due to the hypoxia that was caused by SARS-related acute respiratory distress. Among a cohort of 5 women who presented after 24 weeks' gestation, 4 had preterm deliveries (80%).35 

In a case-control study performed to determine the effects of SARS on pregnancy, 10 pregnant and 40 nonpregnant women with SARS were evaluated at the Princess Margaret Hospital in Hong Kong.32,36  Three deaths occurred among the pregnant women with SARS (maternal mortality rate of 30%), but there were no deaths in the nonpregnant group of SARS-infected women (P = .006). Renal failure (P = .006) and disseminated intravascular coagulation (P = .006) occurred with more frequency in pregnant women with SARS compared with the nonpregnant SARS group. Six pregnant women with SARS (60%) were admitted for intensive care, and 4 (40%) required endotracheal intubation, compared with 12.5% needing intubation (P = .06) and 17.5% requiring intensive care (P = .01) in the nonpregnant group.

Zhang et al37  described 5 pregnant women, all primagravidas, from Guangzhou, China, who became infected with SARS at the peak of the epidemic. Of the 5 women, 2 developed infection in the second trimester, and 3 became infected in the third trimester. Two women acquired SARS from the hospital, and the other 3 cases were community acquired. All 5 pregnant women had fever and abnormal chest radiographs; 4 had cough; 4 developed hypoalbuminemia; 3 had elevated alanine aminotransferase levels; 3 had chills or rigor; 2 had decreased lymphocytes; and 2 had decreased platelets. One pregnant woman needed intensive care, but all women recovered and there were no maternal deaths. None of the 5 infants had evidence of SARS.

Yudin et al38  reported a 33-year-old pregnant woman in Canada with a fever, dry cough, and abnormal chest radiograph demonstrating patchy infiltrates at 31 weeks' gestation. Following a 21-day stay in the hospital, during which she did not require ventilatory support, her convalescent antibody titers were positive for coronavirus infection. She had a normal labor and delivery, and her newborn girl had no evidence of infection.

There were no confirmed cases of intrauterine maternal-fetal transmission of SARS-CoV identified among these and other pregnant women infected with SARS during the 2002–2003 epidemic, although maternal deaths, miscarriages, and preterm deliveries occurred as a result of the infection.17 

MERS AND MERS-CoV

MERS is caused by a coronavirus—MERS-CoV—belonging to the genus Betacoronavirus, similar to SARS-CoV. It is a newly emergent coronavirus that was initially described from Saudi Arabia in September 2012 following its isolation from a man who died months earlier from severe pneumonia and multiple organ failure. Since then there have been more than 2494 confirmed cases of MERS, resulting in upwards of 858 deaths globally.39  MERS is characterized by sporadic zoonotic transmission events and transmission between infected patients and their close contacts (ie, intrafamilial transmission).40  Nosocomial outbreaks occurring in health care settings resulting from poor infection control and prevention are widely known to be characteristic of MERS.39  The clinical presentation of MERS is variable from being asymptomatic to developing severe pneumonia and acute respiratory distress syndrome, septic shock, and multiple organ failure, often resulting in death. Most persons with MERS develop severe acute respiratory illness accompanied by fever, cough, and shortness of breath. Progression to pneumonia is swift with MERS and typically develops within the first week, with at least one-third of patients also presenting with gastrointestinal symptoms. MERS progresses much more rapidly to respiratory failure and has a higher case fatality rate (approximately 34.4%) than does SARS.39,41  In contrast to infections with SARS-CoV, MERS-CoV produces a generally mild disease in healthy persons but is clinically more severe in patients who are immunocompromised or who have underlying comorbidities.39 

MERS infections occurring in pregnant women can cause adverse obstetrical outcomes including maternal death, premature delivery, intensive care treatment for newborns, and perinatal death, but similarly to SARS there have been no confirmed cases of transmission of the virus from pregnant woman to fetus.17  Among 11 pregnant women who became infected with MERS-CoV while pregnant, 10 (91%) developed obstetric complications or had adverse outcomes. These included 6 newborns (55%) needing intensive care, of whom 3 (27%) died, and 2 infants delivered prematurely for severe maternal respiratory failure—no maternal-fetal transmission occurred.42,43  In another report there were 5 pregnant women among 1308 cases of MERS-CoV infection described by the Saudi Arabia Ministry of Health between November 2012 and February 2016.44  All 5 women, ranging in age between 27 and 34 years and who had exposure during the second or third trimester, required intensive case and developed poor obstetric outcomes. A total of 2 of the 5 women died, and 2 neonates died, including 1 stillbirth and 1 neonatal death occurring after an emergency cesarean delivery. In Jordan during the 2012 MERS-CoV outbreak in Zarqa, a second-trimester stillbirth (5 months' gestational age) occurred as a result of maternal exposure to MERS-CoV.45 

SARS-CoV-2 AND COVID-19

Coronavirus disease 2019 (COVID-19) is a novel viral disease caused by a newly identified coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first detected in Wuhan, China, in December 2019. SARS-CoV-2 is the seventh coronavirus to cause human infection and is, like SARS-CoV and MERS-CoV, a positive-sense, single-stranded RNA virus and member of the genus Betacoronavirus.1519  It is also similar to MERS-CoV and SARS-CoV in that it is believed to have zoonotic origins, having a close similarity with bat coronaviruses.46  As a result of the rapid spread, increasing incidence outside of China, severe and life-threatening features of the infection, and the number of affected countries, the World Health Organization declared the rapid spread of SARS-CoV-2 a pandemic on March 11, 2020.47 

The clinical features and effects of COVID-19 are currently being studied, and new information is constantly being disclosed. A significant percentage of infected persons are asymptomatic, but this number appears variable and is not exactly known because of issues with surveillance and limitations of testing during the pandemic. Most symptomatic persons develop mild disease resembling an upper respiratory infection, with the most common symptoms being fever, cough, chest tightness, and dyspnea; additional findings can include gastrointestinal symptoms and diarrhea, myalgia, conjunctivitis, sore throat, and neurologic symptoms, including headache, anorexia, lethargy, impaired consciousness, acute cerebrovascular disease, anosmia, and dysgeusia. Severe disease can occur that involves infection of the lower respiratory tract that leads to acute respiratory distress syndrome, respiratory failure, requirement for intensive care and mechanical ventilation, and systemic complications and multiorgan disease, including sepsis, septic shock, and multiorgan dysfunction syndrome.48,49 

Multiple individual case reports as well as descriptions of cohorts of pregnant women with COVID-19 have been published describing their clinical course, laboratory and radiologic findings, and details of their birthing by cesarean delivery, or, in fewer cases, vaginal delivery.2031,5053  There have now been at least 108 pregnant women with COVID-19 reported, reports that also describe the clinical and laboratory features of most of their newborn infants, including virologic status for SARS-CoV-2.54  Thus far, there have been no laboratory-confirmed cases of intrauterine transmission of SARS-CoV-2 from an infected pregnant woman to her fetus.54  There have been a few cases in which early neonatal infection with SARS-CoV-2 has occurred, but because testing of neonates was delayed from 30 hours to 2 days following delivery it cannot be definitively established that they developed COVID-19 prior to delivery, and their infection may have occurred in the interval between delivery and testing.29,53  In a single case laboratory, testing of a newborn performed at 2 hours following delivery from a mother with COVID-19 revealed that the infant had developed IgM- and IgG-specific antibodies to SARS-CoV-2 together with elevated cytokines, but multiple nasopharyngeal swabs from the infant were negative for the virus.31  A variety of specimens have also been tested using reverse transcriptase–polymerase chain reaction (RT-PCR) for the presence of SARS-CoV-2 following delivery of women with COVID-19—these include placenta, umbilical cord blood, amniotic fluid, maternal blood, vaginal secretions, and breast milk—and all have been negative for the virus.

Although no intrauterine transmission of the virus has yet been reported, there have been adverse outcomes occurring in the infants of women with COVID-19. These include preterm labor and delivery, premature rupture of membranes, intrauterine growth restriction, low birth weight, intrauterine fetal distress, feeding intolerance, asphyxia, pneumonia, and respiratory distress. However, because of multiple factors, including comorbid conditions existing in the mother and fetus, small sample size, and the lack of fetal and placental infection, it is difficult at this time to ascribe one or more of these outcomes directly to COVID-19 with any certainty. There has been 1 case of an adverse fetal outcome that is ascribable to maternal SARS-CoV-2 infection—a stillborn infant whose mother developed severe complications of COVID-19, including pneumonia requiring mechanical ventilation, extracorporeal membrane oxygenation, and multiorgan dysfunction syndrome.21  In that case, although there was a fetal death, the infant was reported as being negative for infection. There have been no reports of adverse effects of COVID-19 in pregnant women during the first trimester, and it currently remains unknown whether this infection will be associated with miscarriages and early pregnancy losses, as are SARS and MERS.17 

Maternal complications from COVID-19 infection have been reported that are similar to those occurring in nonpregnant adults. For those pregnant women who developed respiratory disease it has been typically non–life-threatening, including pneumonia accompanied by radiologic findings of patchy pulmonary infiltrates, ground-glass opacities, and consolidation.55  However, in a few cases there have been pregnant women with COVID-19 who have developed severe pneumonia and life-threatening disease. In a report from New York City the infection status of 2 pregnant women was unknown until after delivery, when they developed medical complications, were admitted for intensive care, and were found to have COVID-19—their infants were negative for the virus.56 

PARAINFLUENZA VIRUS

Human parainfluenza viruses are enveloped, single-stranded RNA viruses belonging to the family Paramyxoviridae. There are 4 types of HPIVs (types 1 through 4) and 2 subtypes (4a and 4b). Parainfluenza viruses can cause a wide spectrum of respiratory tract illnesses, including conjunctivitis, otitis media, pharyngitis, croup, tracheobronchitis, and pneumonia. Among children younger than 5 years, HPIVs are the second most frequent cause of acute respiratory illness leading to hospitalization—they are ahead of influenza viruses and exceeded only by RSV.57  Epidemics of HPIVs can occur seasonally, where they account for up to 40% of pediatric hospitalizations for lower respiratory tract infections and 75% of croup cases.58  Human parainfluenza viruses can also produce infections in adults, especially the elderly and those who are immunocompromised.

Although there is scant information available on the effects of HPIV infection occurring during pregnancy, there has never been a confirmed report of intrauterine transmission of the virus to a fetus. In one case report from 1996, a multigravida with a previous history of 3 missed abortions had an elective termination of pregnancy at 22 weeks' gestation for fetal ventriculomegaly and hydrocephalus.59  She had developed increasing antibody titers to HPIV type 3, but no respiratory symptoms were mentioned. Following the termination procedure pathologic examination of the placenta showed no abnormalities, but the autopsy revealed lungs with multiple areas of pneumonia, necrosis, and an inflammatory reaction consisting primarily of mononuclear cells but also neutrophils and giant cells. In retrospect, it is difficult to ascribe any of the findings in this fetus to HPIV infection with any degree of confidence.

Young infants have serum IgG antibodies against HPIVs that are derived from the pregnant woman during gestation. These antibodies are transferred across the placenta during the last trimester of pregnancy and can provide some protection during the first months of extrauterine life.57,60 

METAPNEUMOVIRUS

Human metapneumovirus is an enveloped, nonsegmented, negative-sense, single-stranded RNA virus that is a member of the new virus family Pneumoviridae, created in 2016 as a member of the order Mononegavirales.61  There are currently 5 species in this family that are divided into 2 genera—Metapneumovirus and Orthopneumovirus.62  In addition to the hMPV the family Pneumoviridae includes another important respiratory pathogen of humans, RSV, also termed the human orthopneumovirus. There are 2 main genotypes (A and B), as well as at least 4 genetic subtypes (A1, A2, B1, and B2) of hMPV.63 

Following its discovery in 2001 from stored nasopharyngeal specimens taken from children with respiratory disease,64  hMPV has been recognized to be a common cause of upper and lower respiratory infections, especially in children, as well as among immunocompromised persons and the elderly.63,6567  Human metapneumovirus causes approximately 5% to 25% of all respiratory infections in infants and children, and is responsible for between 5% and 15% of childhood hospitalizations for lower respiratory tract disease.6870  The infection is so prevalent that virtually all children will have been infected with hMPV by the time they reach 5 years of age.71 

There are few data available on hMPV during pregnancy. Among nonasthmatic pregnant women with upper respiratory tract infections, 17.2% were positive by PCR for hMPV.72  The median duration of maternal symptoms in a study from Nepal was 5 days, and almost one-half (43.6%) of pregnant women with hMPV also had a viral coinfection, most frequently due to rhinovirus and followed by coronavirus and parainfluenza.69  Birth outcomes in the Nepal study revealed no differences in birth weight or frequency of premature delivery between infants from pregnant mothers with and without hMPV infection. However, women having hMPV infection during pregnancy were 1.7 times (P = .03) more likely to have a small-for-gestational age newborn compared with uninfected women. No mothers developed severe pulmonary disease, and there were no cases of newborns reported with respiratory infection.

There have been 4 case reports of hMPV infection occurring in pregnant women, none of whom transmitted hMPV to their fetus.7375  Emont et al73  reported 2 pregnant women with confirmed hMPV infection. In the first case a 40-year-old pregnant woman with a respiratory panel positive only for hMPV infection received intensive care for respiratory decompensation—she had an uncomplicated vaginal delivery of a 3600-g female infant with no signs of infection. In the second case a 36-year-old gravida 4, para 2 woman at 31 weeks' gestation developed respiratory symptoms, a respiratory pathogen panel was positive only for hMPV infection, and she later delivered a healthy, 3230-g baby girl at 39 weeks' gestation with no respiratory infection. Haas et al74  described a 24-year-old pregnant woman at 30 weeks' gestation with fever and urinary tract infection that progressed to respiratory insufficiency; she delivered a baby girl 6 weeks later with no evidence of infection. Fuchs et al75  described an 18-year-old pregnant woman at 36 weeks 2 days' gestation with multiple comorbid conditions and severe respiratory disease requiring intensive care. Following a cesarean delivery, her respiratory viral panel was found to be positive for hMPV. The neonate required face mask ventilation during the initial few minutes of life, but she quickly stabilized and had no evidence of hMPV infection.

RESPIRATORY SYNCYTIAL VIRUS

Human RSV, also known as human orthopneumovirus, is an enveloped, nonsegmented negative-sense RNA virus of the Pneumovirus genus, Pneumovirinae subfamily, and Paramyxoviridae family.76  Respiratory syncytial virus shares the Paramyxoviridae family with such prevalent pathogens as parainfluenza, measles, and mumps viruses. Respiratory syncytial virus is divided into 2 groups, termed A and B, that are based upon variability in the antigen reactions against viral fusion (F) and attachment (G) glycoproteins.77 

This virus was first described in 1901 as “acute catarrhal bronchitis.”78  Respiratory syncytial virus is the most common respiratory pathogen in infants and young children, with an incidence of 33.1 million acute lower respiratory tract infections, 3.2 million hospital admissions, and 59 600 in-hospital deaths in children younger than 5 years. Infants younger than 6 months account for 45% of RSV-related hospitalizations and deaths.79  Respiratory syncytial virus has been experimentally demonstrated to cross the rodent placenta from the respiratory tract of an infected dam to infect the lungs of the fetal rats.80 

Maternal RSV infections are generally uncommon and constitute from 2% to 9.3% of women with symptomatic respiratory illnesses.81,82  One study found that pregnant women testing positive for RSV had symptoms averaging 3 days with presentation of fever, cough, and/or rhinorrhea. Respiratory syncytial virus subtype A made up most of these cases and showed coinfection with viruses such as coronavirus, rhinovirus, parainfluenza 2, hMPV, and bocavirus.81  There were no maternal deaths; all 7 infants were liveborn and with some complications occurring, including low birth weight (1 case) and preterm delivery (2 cases), that were close to an expected rate in noninfected patients.

Although RSV annually infects tens of millions of persons, there have just been 2 reports suggestive of intrauterine transmission of the virus—one based on cord blood analysis by PCR and the other a symptomatic neonate. A retrospective study has shown low levels of PCR-detectable RSV nucleic acid in 57.7% of umbilical cord blood samples of infants from RSV-positive mothers; however, there was no overt disease noted in the infants.83  One case of suspected intrauterine RSV infection has been reported in which a preterm infant (35 weeks) was delivered via cesarean delivery for reduced fetal movement; following delivery he had symptoms and imaging studies suggestive of respiratory distress syndrome. The neonate required ventilatory support and was found to be positive for anti-RSV IgM, IgA, and IgG titers. An RSV PCR was positive, whereas 40 other viral and bacterial respiratory pathogens were negative. Maternal RSV was also positive for anti-RSV IgM, IgA, and IgG, which was consistent with maternal complaints of cough during the second trimester of pregnancy. Breast feeding was withheld, the infant improved at 17 days of life, and then tested negative for RSV.84 

INFLUENZA

Influenza viruses A and B are enveloped, single-stranded RNA viruses belonging the family Orthomyxoviridae. Influenza type A, responsible for most seasonal cases and pandemics, is able to undergo periodic antigenic shifts of glycoproteins, haemagglutinin (H), and neuraminidase (N), leading to several subtypes.85  Influenza-like illnesses have been reported since 412 BC, with large-scale pandemics including the 1918 “Spanish flu,” 1958 “Asian flu,” 1968 “Hong Kong flu,” and the 2009 “Swine flu” pandemic. Influenza is a highly contagious respiratory virus which infects up to approximately 10% (1 billion) of the global population each year. In the United States it is the seventh leading cause of death and is estimated to have caused between 9 million and 45 million illnesses, 140 000 to 810 000 hospitalizations, and 12 000 to 61 000 deaths annually since 2010.86  Annual influenza vaccination guidelines have led to the significant decrease in morbidity and mortality for both mothers and infants up to 6 months of life.87 

Pregnant and recently postpartum women are more likely to develop severe complications from influenza than are nonpregnant adults, including progression to pneumonia, need for hospitalization, intensive care admission, maternal death, and adverse perinatal and neonatal outcomes.88  Pregnant women with influenza are 4 to 18-times more likely to require hospitalization than are nonpregnant infected women.89  For the fetus, maternal influenza infection causes increased risk of pregnancy loss, stillbirth, preterm birth, neonatal intensive care unit admission, growth restriction, and neonatal death.

Extensive surveillance, case reporting, and research have demonstrated that influenza virus does cross the placenta, but considering the tremendous prevalence of the infection, intrauterine fetal infection is at most infrequent and, more probably, rare. Evidence for intrauterine influenza transmission of influenza exists from antigen and antibody testing in the infant brain, amniotic fluid, fetal heart, and cord blood,9092  and another report found 3 of 186 placentas had positive viral antigen testing and notable pathologic changes to the placenta.93 

During the 2009 H1N1 (swine flu) pandemic an estimated 11% to 21% (700 million to 1.4 billion people) of the world population became infected, and there were 4 case reports of suspected H1N1 vertical transmission in newborns of infected mothers.9497  All 4 infants were delivered by cesarean delivery, had severely ill mothers positive for H1N1, and were tested immediately after birth, prior to contact with the mother. An infant born at 36 weeks tested positive for H1N1 after his mother had respiratory failure and required assisted ventilation.94  A preterm newborn was born at 31 weeks with postnatal findings of respiratory distress and tested positive for H1N1; her mother had cardiopulmonary failure and died on day 7.95  In the third report, a full-term newborn had a throat swab positive by RT-PCR for H1N1 after developing respiratory distress requiring ventilatory support on day 1; her mother had respiratory distress and required ventilatory support for 14 days.96  A fourth case involved a newborn born at 32 weeks who tested positive for H1N1 and also required intubation for respiratory distress.97 

In 2012 a pregnant woman in the Sóc Trăng Province of Vietnam died from complications of influenza H5N1 at 36 weeks' gestation.98  Her newborn was delivered by cesarean delivery and developed early-onset neonatal pneumonia; throat swabs and paired serum samples from the infant were negative for the virus.

In addition to these reports from humans, experimental animal studies have also suggested the potential for transplacental transmission of H3N2, H5N1, and influenza B.99 

DISCUSSION

Even before the emergence of SARS-CoV-2 as a cause of COVID-19 and pandemic pneumonia, respiratory infections caused by RNA viruses were some of the most prevalent infectious diseases and posed significant public health problems for many decades. Although influenza causes close to 1 billion annual infections worldwide, noninfluenza RNA virus infections have also been important contributing sources of morbidity and mortality.100  It is fortunate that among pregnant women having viral infections, most viruses do not cross the placental barrier, but when they do, they can cause devastating fetal illness, including birth defects, miscarriage, abnormalities of growth and development, neurologic injuries, fetal death, preterm delivery, and neonatal complications. In past epidemics of viral disease, pregnant women and their infants have frequently had the poorest outcomes of any group, especially in those situations where specific antiviral medications and effective vaccines were nonexistent or unavailable.

As SARS-CoV-2 rapidly spread from Wuhan, China, creating the COVID-19 pandemic, there has understandably been a high degree of concern and anxiety about its effects on pregnant women, fetuses, and neonates. Fortunately, as increasing data have become available on the effects of SARS-CoV-2 during pregnancy it is becoming more evident that most pregnant women with COVID-19 will not develop severe or life-threatening illness. However, a small minority of pregnant women are having, and will continue to develop, severe disease both during and following pregnancy,101,102  similar to the severe and life-threatening illness from COVID-19 occurring in some infected nonpregnant women in the reproductive age group. At this time, it is too early to know if pregnant women have a differing susceptibility to developing symptomatic infection or clinical disease spectrum compared with those infected women who are not pregnant.

No cases of confirmed intrauterine transmission of SARS-CoV-2 have yet to be reported from pregnant women with COVID-19.14,54  This is not unexpected; during previous epidemics of infections caused by 2 related coronaviruses—SARS-CoV and MERS-CoV—there were also no cases of intrauterine viral transmission to the fetus.17  Although the numbers of infected pregnant women were small, both SARS and MERS did result in both maternal as well as perinatal morbidity and mortality.17  Similarly to coronaviruses, other respiratory RNA viruses are not easily transmitted from infected mothers to their fetus. Metapneumovirus and parainfluenza virus are widely prevalent pathogenic RNA respiratory viruses that have never been documented to demonstrate maternal-fetal transmission. Respiratory syncytial virus, a seasonally prevalent respiratory RNA virus that infects both children and adults, has been associated with just 2 episodes of potential intrauterine transmission. Influenza viruses, the prototypical respiratory RNA viruses producing epidemics and pandemics, have been described to infect the placenta and the fetus in several reports. Placed in context, however, influenza causes almost 1 billion infections per year, and when compared with the few reports of intrauterine infection that have been described, transplacental passage of this virus is probably an exceedingly rare event.

The factors inherent in this observed inhibition of respiratory RNA viruses to undergo intrauterine vertical transmission reside in both the virus as well as the host, and a detailed analysis is beyond the scope of this communication to discuss. At the host level, the maternal-fetal interface, composed of cells of both maternal and fetal origin, is one of the most significant factors in determining the propensity of infectious agents to undergo maternal-fetal transmission. The placenta is a key component of this maternal-fetal interface, acting as a barrier between the maternal and fetal compartments. In addition to its functions in producing hormones that support the pregnancy and in organizing placental transport functions, the syncytiotrophoblast immunologically defends the fetus from a variety of infectious agents. Its location at the surface of the chorionic villi, in direct contact with the mother's blood circulating in the intervillous space, is optimal for interacting with both maternal and fetal microenvironments in order to physically and immunologically form a barrier to infection. Experimental studies have demonstrated that not only are primary human trophoblasts resistant to infection by a variety of viruses,103  but they also can transfer resistance in cell culture to both RNA and DNA viruses of perinatal significance.104  This viral resistance is at least partially mediated by microRNAs (miRNAs, small noncoding RNAs approximately 22 nucleotides in length) from the chromosome 19 miRNA cluster (C19MC). This is the largest miRNA cluster occurring in humans and is almost exclusively expressed in the placenta.105  C19MC miRNAs are highly expressed in exosomes released from primary human trophoblast cells and are present in the plasma of pregnant women.106  In addition, there is experimental evidence that primary human trophoblasts release type III interferon IFNλ1, a signaling protein that functions in both an autocrine and a paracrine manner to protect trophoblast and nontrophoblast cells from infections with specific viruses.107 

Following access to the gravid uterus through the maternal bloodstream, passage of a virus is not only dependent on the avoidance of such protective factors as the innate immune system and the placental syncytiotrophoblast barrier, but also on its tropism for cells at the maternal-fetal interface. For SARS-CoV-2, the spike (S) protein of the virus has been demonstrated to facilitate its entry into host cells. This process is dependent on binding of the surface unit, S1, of the S protein to a cellular receptor, which facilitates viral attachment to the surface of target cells.108  It is currently believed that the cell receptor for SARS-CoV-2 is angiotensin-converting enzyme 2, termed ACE-2.46  ACE-2 is a type I transmembrane metallocarboxypeptidase that is expressed in cells of the lung, kidney, and gastrointestinal tract, these tissues being targets of SARS-CoV-2.109  Viral entry into a host cell requires the priming of the S protein by cellular proteases, in which the S protein is cleaved at the S1/S2 and the S2′ site. The serine protease TMPRSS2 is necessary for S protein priming.110  This process permits the fusion of viral and cellular membranes, a process driven by the S2 subunit. One of the factors that will regulate transmissibility of SARS-CoV-2 from the mother to her fetus will likely be the availability of cells at the maternal-fetal interface bearing the ACE-2 receptor and having the necessary associated enzymes such as TMPRSS2S to facilitate viral binding.108 

Placental pathology has proven to be a useful technique for understanding the nature of and potential risk factors for maternal-fetal infection. Some TORCH infections, which have an association with increased likelihood of fetal transmission in early gestation, have been associated with such inflammatory placental abnormalities as villitis, chronic histiocytic intervillositis, and Hofbauer cell hyperplasia. These pathology abnormalities are not typically present in the placentas of women with respiratory RNA infections. If and when intrauterine transmission of SARS-CoV-2 occurs, examination of the placenta will be of critical importance in localization of the virus and characterization of the spectrum of microscopic abnormalities that result from placental infection, as has previously been performed with TORCH infections, and Zika and Ebola virus diseases.

Although research is in progress to better understand the effects of COVID-19 on pregnant women and the fetus, it appears that if intrauterine transmission of SARS-CoV-2 does eventually occur, it will likely be a rare event and that most fetuses will be uninfected at the time of their birth.

References

References
1
Nahmias
AJ
,
Walls
KW
,
Stewart
JA
,
Herrmann
KL
,
Flynt
WJ
Jr
.
The TORCH complex–perinatal infections associated with toxoplasma and rubella, cytomegol- and herpes simplex viruses [abstract]
.
Pediatr Res
.
1971
;
5
(
8
):
405
406
.
2
Schwartz
DA
.
The origins and emergence of Zika virus, the newest TORCH infection: what's old is new again
.
Arch Pathol Lab Med
.
2017
;
141
(
1
):
18
25
. doi:.
3
Newell
ML
.
Vertical transmission of HIV-1 infection
.
Trans R Soc Trop Med Hyg
.
2000
;
94
(
1
):
1
2
. doi:.
4
Gumbo
F
,
Duri
K
,
Kandawasvika
G
,
Kurewa
NE
,
Mapingure
MP
,
Munjoma
MW
, et al.
Risk factors of HIV vertical transmission in a cohort of women under a PMTCT program at three peri-urban clinics in a resource-poor setting
.
J Perinatol
.
2010
;
30
:
717
723
. doi:.
5
Bebell
LM
,
Oduyebo
T
,
Riley
LE
.
Ebola virus disease and pregnancy: a review of the current knowledge of Ebola virus pathogenesis, maternal, and neonatal outcomes
.
Birth Defects Res
.
2017
;
109
(
5
):
353
362
. doi:
6
Schwartz
DA
,
Anoko
JN
,
Abramowitz
S
,
eds
.
Pregnant in the Time of Ebola: Women and Their Children in the 2013-2015 West African Epidemic
.
New York, NY
:
Springer;
2019
.
7
Schwartz
DA
.
Being pregnant during the Kivu Ebola virus outbreak in DR Congo: the rVSV-ZEBOV vaccine and its accessibility by mothers and infants during humanitarian crises and in conflict areas
.
Vaccines
.
2020
;
8
(
1
):
38
. doi:.
8
Alvarado
MG
,
Schwartz
DA
.
Zika virus infection in pregnancy, microcephaly, and maternal and fetal health: what we think, what we know, and what we think we know
.
Arch Pathol Lab Med
.
2017
;
141
(
1
):
26
32
. doi:.
9
Ritter
JM
,
Martines
RB
,
Zaki
SR
.
Zika virus: pathology from the pandemic
.
Arch Pathol Lab Med
.
2017
;
141
(
1
):
49
59
. doi:.
10
Schwartz
DA
.
Viral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection
.
Arch Gynecol Obstet
.
2017
;
295
(
6
):
1361
1368
. doi:.
11
Schwartz
DA
.
The pathology of pregnancy
.
In
:
Strayer
DS
,
Saffitz
JE
,
eds
.
Rubin's Pathology. Clinicopathologic Foundations of Medicine. 8th ed
.
Philadelphia, PA
:
Wolters Kluwer;
2020
:
555
581
.
12
Nahmias
AJ
,
Panigel
M
,
Schwartz
DA
.
Hematogenous infections of the placenta–an interdisciplinary and evolutionary perspective
.
Placenta
.
1994
;
15
(
1
):
107
136
. doi:.
13
Racicot
K
,
Mor
G.
Risks associated with viral infections during pregnancy
.
J Clin Invest
.
2017
;
127
(
5
):
1591
1599
. doi:.
14
Schwartz
DA
.
An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2
:
maternal coronavirus infections and pregnancy outcomes [published online ahead of print March 17
,
2020]
. Arch Pathol Lab Med. doi:.
15
World Health Organization
.
Coronavirus disease 2019 (COVID-19) situation report 90
. .
16
Boyce
M
,
Katz
R.
The 1918 influenza pandemic and COVID-19
.
PBS American Experience
. .
17
Schwartz
DA
,
Graham
AL
.
Potential maternal and infant outcomes from Coronavirus 2019-nCoV (SARS-CoV-2) infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections
.
Viruses
.
2020
;
12
:
194
.
18
Zhu
N
,
Zhang
D
,
Wang
W
,
Li
X
,
Yang
B
,
Song
J
, et al.
A novel coronavirus from patients with pneumonia in China, 2019
.
N Engl J Med
.
2020
;
382
(
8
):
727
733
.
19
Branswell
H.
Cause of Wuhan's mysterious pneumonia cases still unknown, Chinese officials say
.
STAT News
.
January
5,
2020
. .
20
Chen
H
,
Guo
J
,
Wang
C
,
Luo
F
,
Yu
X
,
Zhang
W
, et al.
Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records
.
Lancet
.
2020
;
395
(
10226
):
809
815
. doi:.
21
Liu
Y
,
Chen
H
,
Tang
K
,
Guo
Y.
Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy
[published online ahead of print
March
4,
2020]
.
J Infect.
doi:. .
22
Li
Y
,
Zhao
R
,
Zheng
S
,
Chen
X
,
Wang
J
,
Sheng
X
, et al.
Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China
.
Emerg Infect Dis.
2020
;
26
(
6
). doi:.
23
Yu
N
,
Li
W
,
Kang
Q
,
Xiong
Z
,
Wang
S
,
Lin
X
, et al.
Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study
[published online ahead of print
March
24,
2020]
.
Lancet
. doi:. .
24
Fan
C
,
Lei
D
,
Fang
C
,
Li
C
,
Wang
M
,
Liu
Y
, et al.
Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry?
[published online ahead of print
March
17,
2020]
. Clin Infect Dis. doi:. https://pubmed.ncbi.nlm.nih.gov/32182347/.
25
Lei
D
,
Wang
C
,
Li
C
,
Fang
C
,
Yang
W
,
Cheng
B
, et al.
Clinical characteristics of pregnancy with the 2019 novel coronavirus disease (COVID-19) infection
.
Chin J Perinat Med.
2020
;
23
(
3
).
26
Zhu
H
,
Wang
L
,
Fang
C
,
Peng
S
,
Zhang
L
,
Chang
G
, et al.
Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia
.
Transl Pediatr.
2020
;
9
(
1
). doi:. http://tp.amegroups.com/article/view/35919/28274.
27
Wang
X
,
Zhou
Z
,
Zhang
J
,
Zhu
F
,
Tang
Y
,
Shen
X.
A case of 2019 novel coronavirus in a pregnant woman with preterm delivery
[published online ahead of print
February
28,
2020]
.
Clin Infect Dis.
2020
. doi:. https://pubmed.ncbi.nlm.nih.gov/32119083/.
28
Zhang
I
,
Jiang
Y
,
Wei
M
,
Cheng
BH
,
Zhou
XC
,
Li
J
, et al.
Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province
.
Zhonghua Fu Chan Ke Za Zhi
.
2020
;
55
(
0
):
E009
.
29
Zeng
L
,
Xia
S
,
Yuan
W
,
Yan
K
,
Xiao
F
,
Shao
J
, et al.
Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China
[published online ahead of print
March
26,
2020]
.
JAMA Pediatr.
doi:. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2763787.
30
Schwartz
DA
.
Vertical transmission of severe acute respiratory syndrome coronavirus 2 from the mother to the infant
[published online ahead of print July 20, 2020]
.
JAMA Pediatr
.
2020
. doi:
31
Dong
L
,
Tian
J
,
He
S
,
Zhu
C
,
Wang
J
,
Liu
C
, et al.
Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn
[published online ahead of print
March
26,
2020]
.
JAMA.
2020
. doi:. https://jamanetwork.com/journals/jama/fullarticle/2763853.
32
World Health Organization
.
Consensus document on the epidemiology of severe acute respiratory syndrome (SARS)
. .
33
Little
B.
SARS pandemic: how the virus spread around the world in 2003
.
History
.
March 17,
2020
. .
34
Maxwell
C
,
McGeer
A
,
Tai
KFY
,
Sermer
M.
No. 225–management guidelines for obstetric patients and neonates born to mothers with suspected or probable severe acute respiratory syndrome (SARS)
.
J Obstet Gynaecol Can
.
2017
;
39
:
e130
e137
. doi: .
35
Wong
SF
,
Chow
KM
,
Leung
TN
,
Ng
WF
,
Ng
TK
,
Shek
CC
, et al.
Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome
.
Am J Obstet Gynecol
.
2004
;
191
:
292
297
.
36
Lam
CM
,
Wong
SF
,
Leung
TN
,
Chow
KM
,
Yu
WC
,
Wong
TY
, et al.
A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome
.
BJOG
.
2004
;
11
:
771
774
.
37
Zhang
JP
,
Wang
YH
,
Chen
LN
,
Zhang
R
,
Xie
YF
.
Clinical analysis of pregnancy in second and third trimesters complicated severe acute respiratory syndrome
.
Zhonghua Fu Chan Ke Za Zhi
.
2003
;
38
:
516
520
.
38
Yudin
MH
,
Steele
DM
,
Sgro
MD
,
Read
SE
,
Kopplin
P
,
Gough
KA
.
Severe acute respiratory syndrome in pregnancy
.
Obstet Gynecol
.
2005
;
105
:
124
127
.
39
Hui
DS
.
Epidemic and emerging coronaviruses (severe acute respiratory syndrome and Middle East respiratory syndrome)
.
Clin Chest Med
.
2017
;
38
:
71
86
. doi:.
40
Memish
ZA
,
Sumla
AL
,
Al-Hakeem
RF
,
Al-Rabeeah
AA
,
Stephens
GM
.
Family cluster of Middle East respiratory syndrome coronavirus infections
.
N Engl J Med
.
2013
;
368
:
2487
2494
. doi:.
41
Centers for Disease Control and Prevention
.
Middle east respiratory syndrome (MERS) overview
. .
42
Favre
G
,
Pomar
L
,
Musso
D
,
Baud
D.
2019-nCoV epidemic: what about pregnancies?
Lancet
.
2020
;
395
(
10224
):
e40
. doi:.
43
Alfaraj
SH
,
Al-Tawfiq
JA
,
Memish
ZA
.
Middle East respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy: report of two cases & review of literature
.
J Microbiol Immunol Infect
.
2019
;
52
:
501
503
.
44
Assiri
A
,
Abedi
GR
,
Almasry
M
,
Bin Saeed
A
,
Gerber
SI
,
Watson
JT
.
Middle East respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from Saudi Arabia
.
Clin Infect Dis
.
2016
;
63
:
951
953
. doi:.
45
Payne
DC
,
Iblan
I
,
Alqasrawi
S
,
Al Nsour
M
,
Rha
B
,
Tohme
RA
, et al.
Stillbirth during infection with Middle East respiratory syndrome coronavirus
.
J Infect Dis.
2014
;
209
;
1870
1872
. doi:.
46
Zhou
P
,
Yang
XL
,
Wang
XG
,
Hu
B
,
Zhang
L
,
Zhang
W
, et al.
A pneumonia outbreak associated with a new coronavirus of probable bat origin
.
Nature
.
2020
;
579
(
7798
):
270
273
. doi:.
47
World Health Organization
.
WHO Director-General's opening remarks at the media briefing on COVID-19
11
March
2020
. .
48
Centers for Disease Control and Prevention
.
Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19)
.
March
30,
2020
. .
49
Zhou
F
,
Yu
T
,
Du
R
,
Fan
G
,
Liu
Y
,
Liu
Z
, et al.
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
.
Lancet
.
2020
;
395
(
10229
):
1054
1062
. doi:
50
Dashraath
P
,
Wong
JLJ
,
Lim
MXK
,
Lim
LM
,
Li
S
,
Biswas
A
,
Choolani
M
, et al.
Coronavirus disease 2019 (COVID-19) pandemic and pregnancy
[published online ahead of print
March
23,
2020]
.
Am J Obstet Gynecol
. doi:. .
51
Li
N
,
Han
L
,
Peng
M
,
Lv
Y
,
Ouyang
Y
,
Liu
K
, et al.
Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study
[published online ahead of print March 30
,
2020]
.
Clin Infect Dis.
2020.03.10.20033605
. doi:. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa352/5813589.
52
Breslin
N
,
Baptiste
C
,
Gyamfi-Bannerman
C
,
Miller
R
,
Martinez
R
,
Berstein
K
, et al.
Coronavirus 2019 disease infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals
[published online ahead of print April 9
,
2020]
.
Am J Obstet Gynecol MFM
. doi:. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144599/.
53
Wang
S
,
Guo
L
,
Chen
L
,
Liu
W
,
Cao
Y
,
Zhang
J
, et al.
A case report of neonatal 2019 coronavirus disease in China
[published online ahead of print
March
12,
2020]
.
Clin Infect Dis.
doi: .
54
Zaigham
M
,
Andersson
O.
Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies
[published online ahead of print April 7
,
2020]
.
Acta Obstet Gynecol Scand
. doi:. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13867.
55
Liu
H
,
Liu
F
,
Li
J
,
Zhang
T
,
Wang
D
,
Lan
W.
Clinical and CT imaging features of the COVID-19 pneumonia: focus on pregnant women and children
[published online ahead of print March 11
,
2020]
.
J Infect.
doi:. .
56
Caron
C
,
Van Syckle
K.
The babies were delivered: no one realized the mothers had the virus
.
The New York Times
.
March
28,
2020
. .
57
Schmidt
AC
,
Schaap-Nutt
A
,
Bartlett
EJ
,
Schomacker
H
,
Boonyaratanakornkit
J
,
Karron
RA
, et al.
Progress in the development of human parainfluenza virus vaccines
.
Expert Rev Respir Med
.
2011
;
5
(
4
):
515
526
. doi:.
58
Branche
AR
,
Falsey
AR
.
Parainfluenza virus infection
.
Semin Respir Crit Care Med
.
2016
;
37
(
4
):
538
554
. doi:
59
Seidman
DS
,
Nass
D
,
Mendelson
E
,
Shehtman
I
,
Mashiach
S
,
Achiron
R.
Prenatal ultrasonographic diagnosis of fetal hydrocephalus due to infection with parainfluenza virus type 3
.
Ultrasound Obstet Gynecol
.
1996
;
7
(
1
):
52
54
. .
60
Gellin
B
,
Modlin
JF
,
Crowe
JE
.
Influence of maternal antibodies on neonatal immunization against respiratory viruses
.
Clin Infect Dis
.
2001
;
33
(
10
):
1720
1727
.
61
Afonso
C
,
Amarasinghe
GK
,
Bányai
K
,
Bào
Y
,
Basler
CF
,
Bavari
S
, et al.
Taxonomy of the order Mononegavirales: update 2016
.
Arch Virol
.
2016
;
161
(
8
):
2351
2360
. doi:.
62
Rima
B
,
Collins
P
,
Easton
A
,
Fouchier
R
,
Kurath
G
,
Lamb
R
, et al.
ICTV virus taxonomy profile: Pneumoviridae
.
J Gen Virol
.
2017
;
98
:
2912
2913
.
63
Moe
N
,
Krokstad
S
,
Stenseng
IH
,
Christensen
A
,
Skanke
LH
,
Risnes
KR
, et al.
Comparing human metapneumovirus and respiratory syncytial virus: viral co-detections, genotypes and risk factors for severe disease
.
PLoS One
.
2017
;
e0170200
. doi:.
64
van den Hoogen
BG
,
de Jong
JC
,
Groen
J
,
Kuiken
T
,
de Groot
R
,
Fouchier
RA
, et al.
A newly discovered human pneumovirus isolated from young children with respiratory tract disease
.
Nat Med
.
2001
;
7
:
719
724
.
65
Williams
JV
,
Harris
PA
,
Tollefson
SJ
,
Halburnt-Rush
LL
,
Pingsterhaus
JM
,
Edwards
KM
, et al.
Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children
.
N Engl J Med
.
2004
;
350
(
5
):
443
450
. doi:.
66
Bosis
S
,
Esposito
S
,
Niesters
HGM
,
Crovari
P
,
Osterhaus
AD
,
Principi
N.
Impact of human metapneumovirus in childhood: comparison with respiratory syncytial virus and influenza viruses
.
J Med Virol
.
2005
;
75
(
1
):
101
104
. doi:.
67
Shafagati
N
,
Williams
J.
Human metapneumovirus–what we know now
.
F1000Res
.
2018
;
7
:
135
.
68
Feuillet
F
,
Lina
B
,
Rosa-Calatrava
M
,
Boivin
G.
Ten years of human metapneumovirus research
.
J Clin Virol
.
2012
;
53
:
97
105
. doi:.
69
Lenahan
J.L
,
Englund
JA
,
Katz
J
,
Kuypers
J
,
Wald
A
,
Magaret
A
, et al.
Human metapneumovirus and other respiratory viral infections during pregnancy and birth, Nepal
.
Emerg Infect Dis
.
2017
;
23
(
8
):
1341
1349
. doi:.
70
Caracciolo
S
,
Minini
C
,
Colombrita
D
,
Rossi
D
,
Miglietti
N
,
Vettore
E
, et al.
Human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features
.
Pediatr Infect Dis J
.
2008
;
27
:
406
412
. doi:.
71
Domachowske
J.
Pediatric human metapneumovirus
.
Medscape
.
2018
. .
72
Murphy
VE
,
Powell
H
,
Wark
PAB
,
Gibson
PG
.
A prospective study of respiratory viral infection in pregnant women with and without asthma
.
Chest
.
2013
;
144
(
2
):
420
427
.
73
Emont
JP
,
Chung
KS
,
Rouse
DJ
.
Report of two cases of human metapneumovirus infection in pregnancy involving superimposed bacterial pneumonia and severe respiratory illness
.
J Clin Gynecol Obstet
.
2019
;
8
(
4
):
107
110
. doi:
74
Haas
LM
,
de Rijk
NX
,
Thijsen
ST
.
Human metapneumovirus infections on the ICU: a report of three cases
.
Ann Intensive Care
.
2012
;
2
(
1
):
30
. doi:.
75
Fuchs
A
,
McLaren
R
Jr
,
Saunders
P
,
Karakash
S
,
Minkoff
H.
Human metapneumovirus infection and acute respiratory distress syndrome during pregnancy
.
Obstet Gynecol
.
2017
;
130
(
3
):
630
632
. doi:
76
Eiland
LS
.
Respiratory syncytial virus: diagnosis, treatment and prevention
.
J Pediatr Pharmacol Ther
.
2009
;
14
(
2
):
75
85
. doi:
77
Lee
WJ
,
Kim
YJ
,
Kim
DW
,
Lee
HS
,
Lee
HY
,
Kim
K.
Complete genome sequence of human respiratory syncytial virus genotype A with a 72-nucleotide duplication in the attachment protein G gene
.
J Virol
.
2012
;
86
(
24
):
13810
13811
. doi:
78
Collins
PL
,
Fearns
R
,
Graham
BS
.
Respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease
.
Curr Top Microbiol Immunol
.
2013
;
372
:
3
38
. doi:.
79
Shi
T
,
McAllister
DA
,
O'Brien
KL
,
Simoes
EAF
,
Madhi
SA
,
Gessner
BD
, et al.
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study
.
Lancet
.
2017
;
390
(
10098
):
946
958
. doi:.
80
Piedimonte
G
,
Walton
C
,
Samsell
L.
Vertical transmission of respiratory syncytial virus modulates pre- and postnatal innervation and reactivity of rat airways
.
PLoS One
.
2013
;
8
(
4
):
e61309
. doi:.
81
Chu
HY
,
Katz
J
,
Tielsch
J
,
Khatry
SK
,
Shrestha
L
,
LeClerq
SC
, et al.
Clinical presentation and birth outcomes associated with respiratory syncytial virus infection in pregnancy
.
PLoS One
.
2016
;
11
(
3
):
e0152015
. doi:.
82
Chaw
L
,
Kamigaki
T
,
Burmaa
A
,
Urtnasan
C
,
Od
I
,
Nyamaa
G
, et al.
Burden of influenza and respiratory syncytial virus infection in pregnant women and infants under 6 months in Mongolia: a prospective cohort study
.
PLoS One
.
2016
;
11
(
2
):
e0148421
. doi:.
83
Fonceca
AM
,
Chopra
A
,
Levy
A
,
Noakes
PS
,
Poh
MW
,
Bear
NL
, et al.
Infective respiratory syncytial virus is present in human cord blood samples and most prevalent during winter months
.
PLoS One
.
2017
;
12
(
4
):
e0173738
. doi:.
84
Manti
S
,
Cuppari
C
,
Lanzafame
A
,
Salpietro
C
,
Betta
P
,
Leonardi
S
, et al.
Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress
.
Pediatr Pulmonol
.
2017
;
52
(
10
):
E81
E84
. doi:.
85
Bouvier
NM
,
Palese
P.
The biology of influenza viruses
.
Vaccine
.
2008
;
26
(
suppl 4
):
D49
D53
.
86
Centers for Disease Control and Prevention
.
Disease burden of influenza
.
January
10,
2020
. .
87
American College of Obstetricians and Gynecologists
.
Influenza vaccination during pregnancy
.
April
2018
. .
88
Jamieson
DJ
,
Rasmussen
SA
.
Seasonal influenza and pregnancy
.
Up to Date
.
November
15,
2019
. .
89
Yudin
MH
.
Risk management of seasonal influenza during pregnancy: current perspectives
.
Int J Womens Health
.
2014
;
6
:
681
689
. doi:.
90
Conover
PT
,
Roessmann
U.
Malformational complex in an infant with intrauterine influenza viral infection
.
Arch Pathol Lab Med
.
1990
;
114
(
5
):
535
538
.
91
Yawn
DH
,
Pyeatte
JC
,
Joseph
JM
,
Eichler
SL
,
Garcia-Bunuel
R.
Transplacental transfer of influenza virus
.
JAMA
.
1971
;
216
(
6
):
1022
1023
.
92
McGregor
JA
,
Burns
JC
,
Levin
MJ
,
Burlington
B
,
Meiklejohn
G.
Transplacental passage of influenza A/Bangkok (H3N2) mimicking amniotic fluid infection syndrome
.
Am J Obstet Gynecol
.
1984
;
149
(
8
):
856
859
. doi:.
93
Mel'nikova
VF
,
Tsinzerling
AV
,
Aksenov
OA
,
Vydumkina
SP
,
Kalinina
NA
.
Involvement of the afterbirth in influenza
.
Arkh Patol
.
1987
;
49
(
9
):
19
25
.
94
Vásquez
RD
,
Chávez
VM
,
Gamio
IE
,
Muñoz
RI
,
Polar
MF
,
Montalvo
R
, et al.
Probable vertical transmission of the influenza virus A (H1N1): apropos of a case
.
Rev Peru Med Exp Salud Publica
.
2010
;
27
(
3
):
466
469
. doi:
95
Dulyachai
W
,
Makkoch
J
,
Rianthavorn
P
,
Changpinyo
M
,
Prayangprecha
S
,
Payungporn
S
, et al.
Perinatal pandemic (H1N1) 2009 infection, Thailand
.
Emerg Infect Dis
.
2010
;
16
(
2
):
343
344
. doi:.
96
Valvi
C
,
Kulkarni
R
,
Kinikar
A
,
Khadse
S.
2009H1N1 infection in a 1-day-old neonate
.
Indian J Med Sci
.
2010
;
64
(
12
):
549
552
.
97
Cetinkaya
M
,
Ozkan
H
,
Celebi
S
,
Köksal
N
,
Hacimustafaoğlu
M.
Human 2009 influenza A (H1N1) virus infection in a premature infant born to an H1N1-infected mother: placental transmission?
Turk J Pediatr
.
2011
;
53
(
4
):
441
444
.
98
Le
TV
,
Phan
LT
,
Ly
KHK
,
Nguyen
LT
,
Nguyen
HT
,
Ho
NTT
, et al.
Fatal avian influenza A(H5N1) infection in a 36-week pregnant woman survived by her newborn in Sóc Trăng Province, Vietnam, 2012
.
Influenza Other Respir Viruses
.
2019
;
13
(
3
):
292
297
. doi:.
99
Uchide
N
,
Ohyama
K
,
Bessho
T
,
Takeichi
M
,
Toyoda
H.
Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection
.
Mediators Inflamm
.
2012
;
2012
:
270670
. doi:.
100
Dunn
JJ
,
Miller
MB
.
Emerging respiratory viruses other than influenza
.
Clin Lab Med
.
2014
;
34
(
2
):
409
430
. doi:.
101
Breslin
N
,
Baptiste
C
,
Miller
R
,
Fuchs
K
,
Goffman
D
,
Gyamfi-Bannerman
C
, et al.
COVID-19 in pregnancy
:
early lessons [published online ahead of print March 27
,
2020]
.
Am J Ob Gyn MFM
. doi:. https://www.sciencedirect.com/science/article/pii/S2589933320300410.
102
Juusela
A
,
Nazir
M
,
Gomovsky
M.
Two cases of coronavirus 2019-related cardiomyopathy in pregnancy
[published online ahead of print
April
3,
2020]
.
Am J Ob Gyn MFM
. doi:. https://www.sciencedirect.com/science/article/pii/S2589933320300434.
103
Delorme-Axford
E
,
Donker
RB
,
Mouillet
JF
,
Chu
T
,
Bayer
A
,
Ouyang
Y
, et al.
Human placental trophoblasts confer viral resistance to recipient cells
.
Proc Natl Acad Sci U S A
.
2013
;
110
(
29
):
12048
12053
.
104
Bayer
A
,
Delorme-Axford
E
,
Sleigher
C
,
Frey
TK
,
Trobaugh
DW
,
Klimstra
WB
, et al.
Human trophoblasts confer resistance to viruses implicated in perinatal infection
.
Am J Obstet Gynecol
.
2015
;
212
(
1
):
71.e1
71.e8
. doi:.
105
Bortolin-Cavaillé
ML
,
Dance
M
,
Weber
M
,
Cavaillé
J.
C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts
.
Nucleic Acids Res
.
2009
;
37
(
10
):
3464
3473
. doi:.
106
Luo
SS
,
Ishibashi
O
,
Ishikawa
G
,
Ishikawa
T
,
Katayama
A
,
Mishima
T
, et al.
Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes
.
Biol Reprod
.
2009
;
81
(
4
):
717
729
. doi:.
107
Bayer
A
,
Lennemann
NJ
,
Ouyang
Y
,
Bramley
JC
,
Morosky
S
,
Marques
ET
Jr
, et al.
Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection
.
Cell Host Microbe
.
2016
;
19
(
5
):
705
712
. doi:.
108
Hoffmann
M
,
Kleine-Weber
H
,
Schroeder
S
,
Krüger
N
,
Herrler
T
,
Erichsen
S
, et al.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor
.
Cell
.
2020
;
181
(
2
):
271
280
. doi:.
109
Zhang
H
,
Penninger
JM
,
Li
Y
,
Zhong
N
,
Slutsky
AS
.
Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target
.
Intensive Care Med
.
2020
;
46
:
586
590
. doi:.
110
Glowacka
I
,
Bertram
S
,
Müller
MA
,
Allen
P
,
Soilleux
E
,
Pfefferle
S
, et al.
Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response
.
J Virol
.
2011
;
85
:
4122
4134
. doi:.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.