key: cord-1002212-fllqdn4s
authors: Rozycki, H.J.; Kotecha, S.
title: Covid-19 in pregnant women and babies: What pediatricians need to know
date: 2020-06-13
journal: Paediatr Respir Rev
DOI: 10.1016/j.prrv.2020.06.006
sha: 539d1c1cfd0316550f1fbdec4c2c44b4ffcf1777
doc_id: 1002212
cord_uid: fllqdn4s

Beginning in late 2019, a novel coronavirus labeled SARS-CoV-2 spread around the world, affecting millions. The impact of the disease on patients and on health care delivery has been unprecedented. Here, we review what is currently known about the effects of the virus and its clinical condition, Covid-19 in areas of relevance to those providing care to neonates. While aspects of pregnancy, including higher expression of the cell receptor for the virus, ACE2, could put these women at higher risk, preliminary epidemiological information does not support this. Viral carriage prevalence based on universal screening show that rates vary from 13% in “hot spots” such as New York City, to 3% in areas with lower cases. Vertical transmission risks are unknown but 3.1% of 311 babies born to mothers with Covid-19 were positive within a week of birth. The clinical description of 26 neonates < 30 days of age showed no deaths and only one requiring intensive care. Risks for breast-feeding and for milk banks are discussed.

In late 2019, a respiratory infection began to spread amongst residents in the city of Wuhan China. It was quickly attributed to a previously unknown coronavirus, which was given the name novel SARS-CoV-2. The clinical disease was subsequently named Covid-19 and as of this writing (late May, 2020), has affected over 5.7 million people in virtually every country and region in the world, accounting for over three hundred and sixty thousand deaths. Initial epidemiological reports indicate that those over 65 years of age and/or who have pre-existing conditions are at increased risk for Covid-19. These risk factors including asthma and other chronic lung diseases, diabetes, morbid obesity, significant cardiovascular disease, or immune compromise (1) . Some have included pregnancy as a risk factor for Covid-19 (2) . The purpose of this review is to describe the current information available at the time of writing regarding the potential and known effects of this novel SARS-CoV-2 in pregnant women, their fetuses, and their newborns, to help inform neonatologists who might be called upon to counsel expectant mothers and to care for their babies. Like all information about this disease, this is a rapidly developing field. After initial case reports, enough data and experience have rapidly accumulated to inform their clinical care. However, it is very important to note that virtually all reports to date are based on selective, often anecdotal case accrual, primarily using only hospitalized patients or those sick enough to seek hospital care. There are limited data at present about the prevalence of affected individuals in the population as a whole, which may differ from current estimates, as the estimated number of asymptomatic individuals may be as high as 52% (3) . It is likely, therefore, that any estimate rates or proportions will be lower than what is currently reported. It must also be noted that, while the need and benefit for rapid dissemination of medical information has been very beneficial during this pandemic, the careful peer review process has, of necessity, been placed on hold, for example, by rapid releases of pre-prints. It is therefore likely that some of our current understanding may later change as further data are more carefully scrutinized.

Pregnancy as Risk Factor SARS-Cov-2 closely resembles the original coronavirus species which caused the SARS epidemic of 2002-03, with 79% gene sequence homology (4) . That epidemic affected nearly 8500 individuals with an overall case fatality rate estimated to be 9% (5) . In a case series from Hong Kong of a dozen pregnant women, there was a 25% mortality rate, along with three first trimester miscarriages, and two of the infants were growth restricted (6) . As a result, some authors suggested that pregnancy was a significant risk factor for SARS morbidity and mortality.

This was true during the last world-wide pandemic, Spanish flu of 1918-19 (7) as well as during the 1957 H2N2 influenza season, where half the women between 18 and 49 who died did so from influenza (8) . For these historical precedents, there are possible biological factors that might explain the amplified the risk of coronavirus infection during pregnancy. Diabetes is more common during pregnancy; there is relative immunosuppression of the TH1 response, making pregnant women more susceptible to viral infections (9) ; and expression of the ACE2 membrane protein, the receptor for both SARS-Cov and SARS-Cov-2 is relatively increased during pregnancy (10) .

With rapid publication, several series of Covid-19 infection in pregnancy cases have now been published. Table 1 presents data from fifteen studies that included more than 3 subjects (11 -26) . These include 511 subjects, 82.5% diagnosed by SARS-Cov-2 RT-PCR, the others by current clinical criteria. The vast majority presented with symptoms and were then diagnosed, meaning that those who are asymptomatic or who have mild disease are most likely underrepresented. This, therefore, might be best viewed as a current snapshot of the most significantly affected pregnant women.

As shown in Table 1 , a small proportion were in the first or second trimester (10 and 20 subjects respectively). There were eight spontaneous miscarriages and seven elective terminations due to concerns about the potential effects of SARS-CoV-2 on the fetus. In pregnancies beyond 23 weeks gestational age, one report from Iran noted that five out of nine had intrauterine fetal demise (14) , but this has not been replicated in any other published studies to date. More than two thirds (68.1%) of the births were by caesarian section, most probably reflecting the fact that these reports preferentially included symptomatic mothers.

To understand SARS-CoV-2 and pregnancy in a more comprehensive manner, it will be important to acquire more data from asymptomatic and mildly affected mothers. Estimates of asymptomatic rates in pregnant women are preliminary and quite variable. One study from New York reported that, in the first five days of universal testing for women presenting to the Labor and Delivery unit, 12 women were lab-test positive but were asymptomatic (27) . Of note, 8 of them (67%) developed intrapartum or post-partum fever. It was not possible to differentiate the cause of the fever between clinical chorioamnionitis or Covid-19 but other reports also suggest that fever occurs after delivery in affected mothers. In another, larger series from New York, 33 of 215 screened women were positive (15.3%) (28) . However, only four (1.9% of the whole screened population or 12.1% of the positive group) were symptomatic, although three (1.4%, 9.1% respectively) of the asymptomatic patients did develop fever peri-natally or post-natally. Another study from New York screening asymptomatic women scheduled to deliver during the first two weeks of April also had a 15% positive rate (24/155) (29) .

In contrast, of 635 pregnant women admitted to Northwestern Hospital in Chicago, only 23 (3.6%) were positive, including ten who were asymptomatic (30) . This is similar to the experience in Richmond Virginia where 6 of 177 (3.4%) patients undergoing general screening upon presentation to the labor and delivery unit were positive. Virginia has approximately the same population as New York City but only one fifth the number of confirmed cases (31) . These observations probably reflect how the prevalence of SARS-Cov-2 colonization in pregnant women is likely to reflect that of the general population.

Covid-19 for the benefit of the neonate should they be born prematurely is not very clear (32) .

There are no systematic data available as yet for this infection, so recommendations are primarily based on our experience with other viruses, especially pneumonia due to influenza virus, where corticosteroid use was associated with a higher mortality rate and higher rates of ICU admission (33) . These considerations have led to the recommendation that treatment decisions be individualized, based on the risk to and condition of the mother and the potential benefit to the infant. An asymptomatic or mildly symptomatic mother at 24 -26 weeks' gestation is a very different scenario compared to a mother who is in the Intensive Care Unit (ICU) on a ventilator at more than 34 weeks gestational age.

Many viruses, including rubella, cytomegalovirus, varicella zoster and zika, are well known to be teratogenic to the fetus. These include rubella, cytomegalovirus, varicella zoster and zika. Coronaviruses are associated with 20% of upper respiratory tract infections, involving the four main sub-types but none of these are of specific concern during pregnancy (34). There were two cases of intrauterine growth restriction in babies born during the 2002-03 SARS outbreak, although the underlying etiology was not investigated (6) . In the other human coronavirus epidemic, Middle East Respiratory Syndrome MERS-CoV, there was no reported evidence for teratogenicity among the 12 pregnant patients (35) . Similarly, up to mid-May 2020, there have not been any reports of congenital abnormalities in infants born to mothers with Covid-19 or who are positive for SARS-CoV-2. Whilst these data are encouraging, additional data accumulation is urgently required to confirm these observations.

As shown in Table 1 , 322 offspring of Covid-19 mothers were tested after birth, and 10 were noted to be positive (3.1%). It is not possible, however, to know when and by which route (prenatal, perinatal like herpes simplex, or postnatal) the virus passed to the neonate, as few samples were reported to have been obtained immediately after birth or was sampling done serially. In addition, it is not clear if the infants who tested positive were separated from their mothers beginning immediately after birth, so it is not possible to determine if these were cases of postnatally acquired virus.

On the other hand, an initial case report from China described elevated IgG and IgM against SARS-CoV-2 drawn at 2 hours of age, born to a mother with Covid-19. However, the baby had 5 negative RT-PCR nasopharyngeal tests (36) . In another study of six infants born to Covid-19 mothers who had blood and nasopharyngeal samples obtained at birth (37) two had elevations in their IgG and IgM antibodies against SARS-CoV-2, although neither had viral RNA detected. These results taken together raise the possibility that the fetus responds with an immune response to virus at some point prior to delivery, but they need to be confirmed by larger, more systematic studies, using validated serological assays are required to establish the true nature of the associations between SARS-CoV-2 and neonatal infections (38) .

Overall, children are a small minority of diagnosed Covid -19 cases. The incidence in South Korea among children as of May 16, 2020 was 3.4 cases/100,000, one eighth the rate in the elderly population. There were also no deaths reported in those under 9 years of age (39) . This is consistent with observations from other countries. In the United States, as of April 2, 2020, only 398 (0.3%) of the 149,370 Covid-19 patients were under 1 year of age (40) Current recommendations in most countries, including the US, are to test all babies born to mothers who are either positive for or who are suspected of having Covid-19 (41) . The US Centers for Disease Control adopted this approach in late May, 2020 due to concerns that the disease may be more severe in neonates. Over two dozen neonates (less than 30 days old at presentation) have been reported in the medical literature as of May 21, 2020. Table 2 summarizes the available information (22) (23) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) . Two thirds were born to mothers with Covid-19, the others presumably acquired the virus from household contacts. Three were preterm. Fever was noted in 48%, respiratory symptoms in 30%, and emesis or diarrhea in 37%.

Many reports listed lethargy or changes in neurological status, poor feeding, and other nonspecific symptoms. Notably, three (11%) were asymptomatic. Only one baby, who presented at 3 weeks of age with nasal congestion, poor feeding, and lethargy, progressed to hypotension and respiratory failure requiring intensive care (52) . Encouragingly, there were no deaths.

One question that frequently arises is whether those called to attend at the delivery of a newborn should wear coronavirus-resistant personal protective equipment since positive pressure ventilation, which can generate aerosols, is a potential intervention at each delivery.

Considerations include the availability of the equipment, whether mothers presenting for delivery are being routinely screened, and what is known regarding the baseline rate of positive tests in the general population, including those who are asymptomatic.

For newborn infants born to mothers who have or are suspected to have Covid-19, viral RT-PCR testing from the nasopharynx, oropharynx or nares is recommended beginning after 24 hours of life (57) . Until proven negative with at least two tests 24 hours apart, these babies should be kept separate from any other neonates. Separation of SARS-CoV-2 positive mothers and negative or status-unknown babies is still encouraged, but it is acknowledged that this is not based on evidence-based data of post-natal transmission. If the decision is made to keep the mother-baby pair together, there are guidelines for physical distancing, maternal hand hygiene and face mask use. Breast-feeding should still be encouraged, which will affect whether the mother and infant are separated (unless expressed breast milk is considered as an option) (58).

Regarding breast-feeding, there are no extensive reports about whether SARS-CoV-2 is present in breast milk. Two publications indicate that the virus can be detected in breast milk (58, 61) . Further information may modify current guidelines that breastfeeding may be advisable in Covid-19 mothers under strict measures of infection control (physical distancing when not feeding, mother wearing mask, thorough cleaning) (57, 58) . Human milk banks have added Covid-19 questions to their donor screening and requirements for pre-donation quarantine. During the common Holder pasteurization process, the breast milk is raised to 62.5 o C for thirty minutes. The infectivity of the SARS-CoV-2 virus was eliminated when the virus was exposed to temperature of 56 o C for thirty minutes (62) .

A definitive recommendation for adding testing for the presence of SARS-CoV-2 by RT-PCR to the evaluation for early-or late-onset neonatal sepsis is not yet possible, given the paucity of data, especially in the absence of any known risk. As outlined in Table 2 , neonates are affected, both before 72 hours and after. Note that all the neonates reported in Table 2 had a history of exposure to either tested or symptomatic Covid-19 contacts. Until more extensive epidemiologic studies are published, health care professionals will have to factor the prevalence in the obstetric and general population as well as local testing practice to decide.

Overall, it may be that children are relatively protected from Covid-19 in general and in the severity of disease when they do acquire due to the observation that there is a linear relationship between age and the ACE2 receptor (63) . Of note, this was only sampled from the nasal epithelium, and did not include any neonates.

Although the attack rate in children is far lower than in any other age group, a worrisome complication has become apparent. Termed multiorgan inflammatory syndromechildren (MIC-S), over a hundred children have had this Kawasaki Syndrome-like condition, including some who were asymptomatic for Covid-19 but tested positive, by RT-PCR or serology (64) . To date, we are unable to find any cases in a child under the age of one year.

Because there are so few neonates who have been diagnosed with Covid-19, therapeutic recommendations or guidelines based on evidence or clinical experience are not possible. Most of the cases listed in Table 2 received supportive or routine care. At this point, if a baby is critically ill and either positive for SARS-CoV-2 by RT-PCR (not serology), or strongly suspected of having the disease based on exposure history and symptoms, consulting experts in adult disease is advised, given their larger accumulated experience. Any recommended drug therapy will require risk-benefit assessment including adjustments for dose and timing considerations for this specific population. The best hope for the longer term is for a longlasting effective vaccination together with an effective serology test that will identify both recent and past infection with SARS-CoV-2.

.

The rapidity with which SARS-CoV-2 has spread, and the number of cases, and deaths, from Covid-19 is unlike anything seen since at least the Spanish flu pandemic of 1918-19, but a hundred years later, international cooperation and rapid dissemination of experience has permitted those facing the need to care for a patient with a disease they have never seen before to tap into the experience of others. We can expect case reports and small series to be replaced by larger and more systematic studies, followed by prospective trials and long-term follow-up reports. For anyone who may have a patient with SARS-CoV-2 or Covid-19, it is important to follow the medical literature, including consensus expert guidelines. (2) CS (14) Vag (2) Fetal distress (2) Preterm < 3 weeks (2) China (7) (17) Fever (5), Cough (5) SAB (3) CS (18) Vag (2) None None

Italy (42) (4), 34 -37 (7), > 37 (31) Prenatal fever (20), Postnatal fever (6), Cough (18), Dyspnea (8), Lymphopenia (6) CS (24) Vag (18) ICU (4) NICU (3) Italy (77) 26 

Risk Factors of Critical & Mortal COVID-19 Cases: A Systematic Literature Review and Meta-Analysis

Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy

A Systematic Review of Asymptomatic Infections with COVID-19

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome

The Effects of the 1918-1919 Influenza Pandemic on Infant and Child Health in Derbyshire

Deaths from Asian influenza associated with pregnancy

Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening

ACE2 expression and activity are enhanced during pregnancy

Clinical analysis of pregnant women with 2019 novel coronavirus pneumonia

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy

Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic

Coronavirus disease 2019 in pregnant women: a report based on 116 cases

Analysis of the Pregnancy Outcomes in Pregnant Women With COVID-19 in Hubei Province

Coronavirus disease 2019 in pregnancy

Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China

Clinical features and outcomes of pregnant women suspected of coronavirus disease

Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study

Re: Novel Coronavirus COVID-19 in late pregnancy: Outcomes of first nine cases in an inner city London hospital

Radiological findings and clinical characteristics of pregnant women with COVID-19 pneumonia

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis

Clinical Findings and Disease Severity in Hospitalized Pregnant Women With Coronavirus Disease 2019 (COVID-19)

COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals

Universal Screening for SARS-CoV-2 in Women Admitted for Delivery

Testing of Patients and Support Persons for Coronavirus Disease 2019 (COVID-19) Infection Before Scheduled Deliveries

Clinical Implications of Universal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Testing in Pregnancy

Latest Map and Case Count

Antenatal corticosteroids for pregnant women with COVID-19 infection and preterm prelabor rupture of membranes: a decision analysis

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

34. van der Hoek L. Human coronaviruses: what do they cause

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and COVID-19 infection during pregnancy

Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn

Antibodies in Infants Born to Mothers With

Serology assays to manage COVID-19

Weekly report on the COVID-19 situation in the Republic of Korea (as of May 9

CDC Covid-19 Response Team. Coronavirus Disease 2019 in Children -United States

Neonatal Early-Onset Infection With SARS-CoV-2 in 33

Neonates Born to Mothers With COVID-19 in Wuhan, China

A case report of neonatal COVID-19 infection in China

Severe COVID-19 during Pregnancy and Possible Vertical Transmission

SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress

Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2

Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report

COVID-19: Fever syndrome and neurological symptoms in a neonate

First case of neonatal infection due to COVID 19 in Spain

Late-Onset Neonatal Sepsis in a Patient with Covid-19

SARS-CoV-2 Infection in a 2-Week-Old Male With Neutropenia

Managing COVID-19-Positive Maternal-Infant Dyads: An Italian Experience

Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission

Novel Coronavirus Infection in Newborn Babies Under 28

Days in China

Evaluation and Management Considerations for Neonates at Risk for COVID-19

CDC Covid-19 Response Team. Care for Breastfeeding Women: Interim Guidance on Breastfeeding and Breast Milk Feeds in the Context of COVID-19

Coronavirus disease 2019 among pregnant Chinese women: case series data on the safety of vaginal birth and breastfeeding

Detection of SARS-CoV-2 in human breastmilk

Breastfeeding and coronavirus disease-2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies

Stability of SARS-CoV-2 in different environmental conditions

Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic