Perinatal SARS-CoV-2 Infection and Neonatal COVID-19: a 2021 Update

Abstract

The coronavirus disease 2019 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has swept across the world like an indiscriminating wild-fire. Pregnant women and neonates are particularly vulnerable to this infection compared with older children and healthy young adults, with unique challenges in their management. Due to the unfamiliarity with the consequences of this novel virus and lack of high-quality data, there was heterogeneity in the obstetrical and neonatal management early in the pandemic. The aim of this review is to summarize the impact of SARS-CoV-2 infection during pregnancy on pregnant women, childbirth, and neonatal care and outcomes. A brief review of vaccines currently approved by the United States Food and Drug Administration (FDA) for emergency use and their potential effects on pregnant and lactating women is included.

INTRODUCTION

Coronaviruses are positive sense enveloped, single stranded RNA viruses. Serotypes from the alpha and beta-coronavirus genera can cause human disease. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus, with ~80% homology to SARS-CoV-1 (the agent causing Severe Acute Respiratory Syndrome, or SARS) and even greater homology to some bat coronaviruses, suggesting a zoonotic origin.¹ Like other coronaviruses, SARS-CoV-2 has a “crown” appearance on electron microscopy due to projections of the spike (S) glycoprotein from the envelope (Figure 1). The S protein mediates attachment to human epithelial cells via the angiotensin-converting enzyme (ACE)-2 receptor, which is distributed widely throughout the human respiratory tract epithelium and is also the target of SARS-CoV-1.

Figure 1:

An illustration of the enveloped single stranded RNA virus, SARS-CoV-2. The various proteins in the virus are labelled as S (spike glycoprotein), E (envelope glycoprotein), M (membrane protein) and N (nucleocapsid protein). Angiotensin converting enzyme-2 (ACE-2) is the receptor for the virus in the host cell that facilitates attachment of the virus by the S protein and its subsequent entry into the host cell. The portion of the RNA that encodes the S protein is also shown in the figure. Copyright Satyan Lakshminrusimha- used with permission.

SARS-CoV-2 is more transmissible than SARS-CoV-1, which may be due to stronger binding to the ACE-2 receptor² and more effective transmission of virus from asymptomatic and pre-symptomatic hosts.³ Transmission primarily occurs via respiratory droplets, although airborne and contact transmission may occur to a lesser extent.⁴ Disease caused by SARS-CoV-2 tends to occur in a biphasic manner, with the initial illness thought to be due to direct viral infection, and the subsequent phase being immune-mediated.⁵ Additionally, SARS-CoV-2 infection is known to cause coagulopathy, which may contribute to organ dysfunction as well.

COVID- IMPACT ON PREGNANT WOMEN

In the US, pregnant women with coronavirus 2019 (COVID-19) are significantly more likely to be admitted to an intensive care unit, receive invasive ventilation and extracorporeal membrane oxygenation (ECMO) (Figure 2) compared to non-pregnant women with COVID-19.⁶ Mortality is also higher among pregnant women infected with COVID-19.⁶ These findings may be related to physiological changes of pregnancy, such as increased heart rate and oxygen consumption, shift in cell-mediated immunity, reduced lung capacity secondary to upward diaphragmatic shift and increased risk for thromboembolism.

Figure 2:

Strategies to prevent SARS-CoV-2 infection during pregnancy (A), and benefits and risks of vaccination during pregnancy (B) are illustrated in the figure. Currently FDA approved vaccines (as of January 1, 2021) consist of mRNA of the spike protein in the lipid envelope. The possible benefits and concerns of vaccination during pregnancy are shown in the green and pink boxes respectively. Copyright Satyan Lakshminrusimha- used with permission.

Similar to non-pregnant women, pregnant women with COVID-19 present with cough (50%), fever (32%), myalgia (37%), and shortness of breath. In addition to respiratory symptoms, the placenta may be affected in COVID-19.⁷ The possibility of vertical transmission appears low but placental infection can potentially affect the fetus.^8,9

Measures to prevent COVID-19 during pregnancy include wearing a proper mask, frequent handwashing and most importantly, avoiding crowded areas and parties (including baby showers). Vaccination during pregnancy is a controversial topic as to date, pregnant and lactating women have been excluded from vaccine studies. However, the American College of Obstetrics and Gynecology (ACOG) and the Society of Maternal-Fetal Medicine (SCFM) have issued statements suggesting that pregnant and lactating women should be given a choice to receive the vaccine after discussing individual risks (including the possibility of fever following vaccination) (Figure 3).

Figure 3:

Clinical presentation of COVID-19 during pregnancy.^6,93 Infected pregnant women have reduced cell-mediated immunity, upward shift of the diaphragm leading to decreased lung capacity, increased risk for thromboembolism and an increase in heart rate and oxygen consumption. The yellow box compares the risk of intensive care unit (ICU) admission, invasive ventilation, extracorporeal membrane oxygenation (ECMO) and mortality between pregnant and non-pregnant women with symptomatic COVID-19. The purple box lists the demographic characteristics with higher risk for invasive ventilation, mortality and ICU admission. Copyright Satyan Lakshminrusimha- used with permission.

The American Academy of Pediatrics (AAP) -Section on Neonatal Perinatal Medicine has issued a statement recommending shared decision-making regarding vaccination during pregnancy and lactation. The risk of transmission of the vaccine (i.e., COVID-19 mRNA) across the placenta is unlikely but the transmission of maternal IgG antibodies in response to the vaccine is likely to occur. Antibodies to COVID-19 are found in infants born to COVID-19 mothers and in the breastmilk of mothers with COVID-19.^{10 11} Active immunization with other vaccines has been shown to increase specific IgA levels in breastmilk.¹²

MATERNAL TRANSMISSION TO THE NEWBORN

There are 3 potential mechanisms of maternal transfer of SARS CoV-2 to the infant (Figure 4)¹³

Figure 4:

Potential modes of transmission of SARS-CoV-2 infection from the pregnant woman to the fetus/ newborn. The 3 potential modes include vertical/ maternal-fetal transmission, intrapartum transmission and postnatal transmission.¹³ Copyright Satyan Lakshminrusimha- used with permission.

1. Intrauterine transmission through transplacental hematogenous spread or viral particles in amniotic fluid that are ingested or inhaled by the fetus. This mode appears less likely but there are anecdotal reports suggesting that this is possible.^9,14–18

2. Intrapartum transmission following exposure to maternal infected secretions or feces around the time of birth

3. Postpartum transmission from an infected mother, family member or healthcare worker (probably the most likely mode of transmission pre-vaccine). Transmission from an infected mother is more likely from respiratory secretions and less likely from breastmilk.

DELIVERY OF A NEWBORN BORN TO A MOTHER WITH COVID-19 (Figure 5)

Figure 5:

Delivery room management of a SARS-CoV-2 positive pregnant woman and resuscitation of her newborn. Maternal masking for source containment and complete PPE use by the healthcare clinician inside the birthing room (negative pressure room) are recommended. A 6-feet distance and a curtain as a physical barrier should be kept between the mother and the newborn requiring resuscitation. When positive pressure ventilation (PPV) with a mask is required, the two-person technique with one clinician maintaining an appropriate seal with a facemask and a 2^nd clinician providing PPV could minimize leak and risk of viral transmission. Airborne precautions should be utilized for aerosol generating procedures. AAP: American Academy of Pediatrics. NRP: Neonatal Resuscitation Program. Copyright Satyan Lakshminrusimha- used with permission.

Pregnant women with suspected COVID-19 (symptomatic or recent positive household contact) must be prioritized for SARS-CoV-2 testing, while universal screening may be employed in areas with high prevalence.¹⁹ The timing and mode of delivery and anesthesia in pregnant women with suspected/confirmed SARS-CoV-2 infection are dependent on obstetrical indications. A cesarean section rate of 24–41% has been reported in pregnant women infected with COVID-19 from hospitals in the US.^20–22 Antenatal steroids may be administered to infected pregnant women at risk of preterm delivery (including 34–36 6/7 weeks) until more evidence is available because of the potential benefits of promoting fetal lung maturity and decreasing maternal mortality.^23,24 The delivery room (DR)/ operating room (OR) should be equipped to function as a negative pressure isolation room with the door remaining closed. Personnel inside the DR should be limited to essential healthcare workers (1–3 obstetric and 1–2 pediatric clinicians) caring for the mother-infant dyad. Additional personnel should wait outside the DR/OR and be given a cue to enter if needed (Figure 5). Careful hand hygiene must be performed by clinicians prior to donning and doffing of personal protective equipment (PPE), which include N95 mask/higher respirator (preferred) or surgical mask (acceptable) with face-shield/goggles, isolation gown and gloves.¹⁹ The pregnant woman should wear a surgical mask. Visitors may be limited to only the necessary support person for the woman; telemedicine/video-based interactions with visitors may be valuable, if available.

The World Health Organization (WHO) endorses deferring cord clamping and early skin-to-skin contact in neonates born to COVID-19 mothers.^25,26 After discussion of the pros and cons of these interventions based on the available evidence, shared decision-making with the parents is encouraged.²⁷

If a pregnant woman has significant COVID-19-related illness and requires invasive mechanical ventilation, delivery may need to be conducted in the intensive care unit setting. There have been reports of cesarean section performed on a pregnant woman with COVID-19 on ECMO.²⁸

NEONATAL RESUSCITATION

Neonatal clinicians should attend deliveries based on their hospital/center-specific policies. Maternal COVID-19 alone is not a specific indication for attending a delivery. Current data suggest that only 1.6% to 2% of infants born to women who test positive for SARS-CoV-2 near the time of delivery test positive in the first 1–3 days after birth (AAP National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection/ NPC-19 registry accessed on 12/14/2020). All neonatal clinicians should don a gown and gloves and use an N95 respirator mask and a face shield or eye-protection goggles or an air-purifying respirator (with eye protection).²⁹ Because it is not known if a newborn might require an aerosol generating procedure soon after birth, adequate precautions must be taken to minimize the risk of infection (Figure 5). Aerosol generating procedures in the DR include T-piece and mask ventilation, bag-mask ventilation, intubation, suctioning, high-flow oxygen therapy at > 2 liters per minute, continuous positive airway pressure (CPAP) and mechanical ventilation.³⁰

During mask ventilation, it is better to use the two-person technique with one provider holding the mask with both hands to ensure a good seal and reduce air-leak and the second person performing bag mask ventilation or managing the T-piece resuscitator (Figure 5). The use of videolaryngoscopy may be considered to reduce risk to the clinician during intubation.

Transport of an infant born to a COVID-19 positive woman from the DR to the neonatal intensive care unit (NICU) or newborn nursery should take a predetermined path in a closed incubator with minimal exposure to other personnel.

BREASTFEEDING IN TERM INFANTS BORN TO MOTHERS WITH COVID-19

There is no current compelling evidence suggesting transmission of SARS-CoV-2 can occur from an infected mother to her baby via breast milk; rather, breast milk may be of benefit by providing protective antibodies against SARS-CoV-2 infection.^31,32 The nutritional, immunological and developmental benefits of breastfeeding, if permitted by the mother’s health, outweigh the potential transmission risk given that infants typically have mild illness.^33,34 Newborns are more likely to acquire infection via horizontal transmission from an infected mother or another care provider; thus, the importance of maintaining appropriate respiratory hygiene when an infected person is in contact with a newborn cannot be overemphasized. An infected mother should wear a surgical mask, wash her hands and breasts with soap and water before feedings, and breastfeed the infant. Alternatively, the infant can be fed expressed breast milk by a healthy care provider. Between feedings, the infant’s crib (or incubator) should be placed at least 6 feet from an infected mother’s bed, preferably behind a physical barrier (such as a curtain).²⁹ Both international and national societies including the WHO and the AAP support protecting breastfeeding during this pandemic.³⁵

It is worth mentioning that although passage of remdesivir (an antiviral medication used for the treatment of moderate to severe SARS-CoV-2 disease) to an infant via breastmilk is unknown, no adverse events were reported in a newborn whose mother received remdesivir therapy for Ebola infection.³⁶ The Academy of Breastfeeding Medicine does not recommend cessation of breastfeeding when lactating mothers receive an mRNA based liposomal vaccine (see section on vaccines below).

CARE OF TERM AND PRETERM INFANTS BORN TO MOTHERS WITH COVID-19

Vertical transmission of SARS-CoV-2 appears to be uncommon due to lack of viremia and non-overlapping expression of ACE-2 and transmembrane serine protease-2.^37,38 Neonatal infection was reported in 1–3% of births to COVID-19 mothers in the US, with lower chances of infection if the mother tested positive >14 days prior to delivery.^22,39,40 Preterm birth (12.9%, compared to the national average of 10.2% in 2019), low birth weight, cesarean section and NICU admissions were frequently observed among COVID-19 deliveries.^20,41 Contrary to initial beliefs, the rate of neonatal infection was not increased with vaginal delivery, rooming-in or breastfeeding.^42,43

Mother-infant separation and NICU admission may be required for preterm infants (<34 weeks’ gestation) and for underlying medical conditions or symptomatic illness requiring higher level of care for either the infant or mother. Preterm and term infants admitted to the NICU with respiratory distress could potentially require respiratory support and aerosol generating procedures (such as CPAP, endotracheal intubation and surfactant).³⁰ Intubation should be performed by the most experienced neonatal clinician utilizing appropriate PPE. Infants should be monitored closely for symptoms and signs of SARS-CoV-2 infection, which may include fever, cough, rhinorrhea, respiratory distress, poor feeding, lethargy, vomiting, diarrhea, rash and edema (Figure 6).^39,44–47

Figure 6:

A schematic describing the clinical presentation of early-onset and late-onset neonatal COVID-19 and multi-system inflammatory syndrome in neonates (MIS-N). The mechanism of MIS-N is thought to be a neonatal hyperimmune response to maternal antibodies against SARS-CoV-2 and has not been clearly described in the literature. Neonates with MIS-N could be critically ill with myocarditis, myocardial dysfunction, coronary aneurysms, disseminated intravascular coagulation (DIC), necrotizing enterocolitis-like illness, hypoxemia and renal failure. Copyright Satyan Lakshminrusimha- used with permission.

Testing for SARS-CoV-2 RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) is recommended for all neonates born to mothers with suspected or confirmed COVID-19 at 24 and 48 hours after birth (or a single test at 24–48hr) by a nasopharyngeal, oropharyngeal or nasal swab.²⁶ Asymptomatic SARS-CoV-2 positive neonates can be discharged home after ensuring close follow-up. An infected mother who has been afebrile for 24 hours without antipyretics and improving, is not likely to be contagious 10 days after onset of symptoms²⁶ and can safely care for her infant.

NEONATES WITH SARS-CoV-2 INFECTION

The immature immune system, passive transfer of maternal IgG antibodies and lower ACE-2 expression, may result in less inflammation, milder illness and hastened recovery in infants and children compared to adults.^11,48 Neonates, however, have been reported to have more severe illness (in 12% of infected neonates) compared to older children (3% of older children required ICU care) in a systematic review.^47,49 SARS-CoV-2 positive neonates should be clinically monitored and isolated. Complete PPE should be used by clinicians while caring for these neonates, as described above. Early-onset neonatal COVID-19 (onset of illness between 2–7 days after birth) is likely caused by perinatal transmission (intrapartum or more commonly, immediate post-natal). The majority of infected neonates are either asymptomatic (20%)^22,47,50 or have mild symptoms such as rhinorrhea and cough (40–50%)^39,45,47 and fever (15–45%) (Figure 6).^45,50,51 Moderate to severe symptoms such as respiratory distress (12–40%), poor feeding, lethargy, vomiting and diarrhea (30%), and clinical evidence of multiorgan failure has been observed as well (Figure 6).^39,45,46 Laboratory evidence of COVID-19 infection in a neonate may include leukocytosis, lymphopenia, thrombocytopenia, and non-specific findings of elevated inflammatory markers.⁵²

Management of symptomatic COVID-19 positive neonates is mostly supportive. Appropriate respiratory support, such as CPAP, is recommended for respiratory distress. Endotracheal intubation is more likely to be indicated if there is neonate-specific lung pathology (such as surfactant deficiency and meconium aspiration syndrome) rather than COVID-19 lung disease.⁵³ A viral filter could be placed in the expiratory limb of the ventilator circuit to minimize risk of infection to healthcare workers by aerosolization.³⁰

LATE-ONSET NEONATAL COVID-19 INFECTION

The majority of symptomatic SARS-CoV-2 infections in neonates are diagnosed beyond 5–7 days after birth (late-onset neonatal COVID-19).³⁹ Post-natal transmission by neonatal exposure to maternal respiratory secretions or exposure to infected healthcare workers or household contacts probably plays a major role in late-onset neonatal COVID-19 infection, although intra-partum exposure to maternal secretions and body fluids may contribute as well.¹³ Many affected neonates had negative initial RT-PCR testing (at 24 and 48 hours after birth) prior to initial discharge from the hospital and were readmitted with symptoms suggestive of COVID-19.⁵⁴ In a cohort study of 61 neonates with SARS-CoV-2 infection requiring in-patient management, hyperthermia, coryza, mild respiratory symptoms, apnea, poor feeding or vomiting and lethargy were commonly reported.³⁹ Chest radiographs were abnormal with nonspecific opacities in 56% and ground-glass changes in 28% (half of those were preterm).³⁹ A third of the infected neonates required respiratory support and supplemental oxygen. Mothers of infected neonates tested positive for SARS-CoV-2 in 26%, and 52% of the infected neonates had close contact with an infected individual.³⁹ Lethargy, apnea, fever or hypothermia, tachycardia, tachypnea, hypoxemia, hypotension and radiographic findings of ground-glass opacities have been reported with worsening illness.^50,55,56 Age < 1month has been associated with a 3-fold higher risk of critical care admission.⁵⁷ Leukocytosis, thrombocytopenia, elevated lactate (55%), raised C-reactive protein (29%) and lymphopenia (9%) have been observed.^39,58 Disseminated intravascular coagulation may also occur.⁴⁶

Management of neonates infected with COVID-19 remains supportive including supplemental oxygen, respiratory support, fluid resuscitation and temperature control. Currently, there is lack of evidence for use of antiviral medications and steroids in neonatal COVID-19. Use of remdesivir has been reported in a two newborns: a 22-day old with severe late-onset COVID-19 who clinically improved and tolerated the treatment well⁵⁹, and a 4-day old who continued to deteriorate and received dexamethasone and convalescent plasma, required 13 days old invasive ventilation and ultimately improved.⁶⁰

NEONATAL MIS-C

Multi-system inflammatory syndrome in children (MIS-C) is a novel condition following COVID-19 infection in children, and is characterized by fever, elevated inflammatory markers, and high levels of both pro- and anti-inflammatory cytokines.⁶¹ Children with MIS-C frequently present with symptoms related to the cardiovascular system (shock, left ventricular dysfunction, elevated cardiac enzymes, coronary artery abnormalities), gastrointestinal system (nausea, vomiting and diarrhea mimicking gastroenteritis or inflammatory bowel disease), or with mucocutaneous symptoms resembling Kawasaki Disease (KD).^62,63 The median age of children with MIS-C has been reported between 5–9 years old, as opposed to KD which is typically 6 months-5 years of age. MIS-C is infrequent in infants, with the Centers for Disease Control and Prevention reporting only 4% of MIS-C cases occurred in children <1 year of age.⁶⁴

Neonatal MIS-C (MIS-N) has rarely been reported (Figure 6).⁶⁵ A 49 day old male infant whose family member tested positive when the infant was 2 weeks old, presented with severe gastrointestinal manifestations (including diarrhea with colitis that was confirmed by biopsy), hypoalbuminemia, severe anemia, elevated serum D-dimer and ferritin and thrombocytosis in the early phase, and subsequent thrombocytopenia.⁶⁶ Serum brain natriuretic peptide (BNP) was elevated and his echocardiogram showed mitral regurgitation but normal coronary arteries. The infant was managed with intravenous immunoglobulin and pulse methylprednisolone therapy with subsequent improvement. Lima et al reported a 33-week gestation fetus with worsening pericardial effusion by ultrasound in a pregnant woman with positive COVID serology (IgM and IgG) and recent febrile illness.⁶⁷ An emergency cesarean section was performed and SARS-CoV-2 PCR from the infant’s nasopharynx, oropharynx, and blood at birth were positive. Two days after birth, the infant developed hemodynamic instability prompting pericardiocentesis with subsequent clinical improvement. Cardiac enzymes and plasma proinflammatory cytokines were elevated, consistent with a hyper-inflammatory response. Of note, a fatal case of MIS-C in the NICU was reported in a 7-month-old infant born at 26 weeks’ gestation who was hospitalized since birth and acquired acute SARS-CoV-2 infection from an unknown source.⁶⁸ The infant subsequently developed cardiovascular collapse with elevated inflammatory markers and echocardiographic evidence of myocarditis.⁶⁸ Recently a 4-hour old term infant born to a mother without history of COVID-19 has been reported to have presented with persistent pulmonary hypertension (PPHN) and subsequently had multisystem involvement (fever, bilateral ground glass opacities, necrotizing enterocolitis-like illness, vasculitic rash, elevated inflammatory markers and D-dimer). Both mother and infant tested positive for IgG antibody against SARS-CoV-2, suggesting that transplacental exposure to maternal IgG could have contributed to cytokine storm in the newborn.⁶⁹ This infant was treated with dexamethasone in addition to management of PPHN followed by complete recovery. Further study in children less than 1 year of age is needed to elucidate the risk factors for developing MIS-C and to clarify predictors of disease severity.

VACCINES AGAINST COVID-19

Recently two vaccines manufactured by Pfizer-BioNTech and Moderna have been approved by the US FDA under Emergency Use Authorization.^70,71 Both vaccines consist of a lipid nanoparticle encapsulated, nucleoside-modified mRNA that encodes the SARS-CoV-2 spike (S) glycoprotein (that mediates host cell attachment, a prerequisite for viral entry). The lipid nanoparticle preferentially targets dendritic cells, which interact with other cells within the lymphatic system (Figure 7).⁷² Once injected, the lipid layer breaks down, releasing the mRNA. The mRNA is constructed so that the S protein code is inserted between the start and stop signals for translation, and additional code is included to increase protein translation. The host cell translates the mRNA to produce the S protein, which is then presented on the cell surface to T- and B- lymphocytes, which in turn produce an immune response to the protein, resulting in cell-mediated immunity and antibody production.

Figure 7:

Active immunization against SARS-CoV-2 viral infection. Currently the US FDA approved vaccines (Pfizer-BioNTech and Moderna) consist of spike (S) protein mRNA within a lipid nanoparticle. Other vaccines that are being evaluated at present include Covaxin (Bharat Biotech) and Coronavac (Sinovac) (inactivated virion vaccines), Astra Zeneca (Oxford), Gamaleya (Sputnik V), GSK-Sanofi and NVX-CoV2373 (Novavax). Astra Zeneca (and Janssen) vaccine involves a modified chimpanzee adenovirus acting as a vector for the viral S protein that is injected as a vaccine. Gamaleya has 2 different adenoviruses as vectors (Ad26 and Ad5 spike vaccines) for the initial and booster doses due to concern that immune response to same vector could lower immune response to the booster. Novavax consists of the combination of purified viral S protein with a saponin-based matric-M as an adjuvant. GSK-Sanofi COVID vaccine is also an S-protein mixed with an adjuvant. All vaccines cause active immunization by a) the dendritic cells engulfing lipid nanoparticles, b) host cells expressing S protein presenting to T- and B- lymphocytes inducing cellular and humoral immunity. Copyright Satyan Lakshminrusimha- used with permission.

The Pfizer-BioNTech vaccine is given in 2 doses 21 days apart, to individuals ≥16 years of age.⁷³ The Moderna vaccine is given in 2 doses 28 days apart, to individuals ≥18 years of age.⁷⁴ Vaccine efficacy is >90% for both vaccines in preventing symptomatic laboratory confirmed COVID-19.^75–77 Both vaccines may cause local adverse reactions such as pain and swelling at the injection site, and/or systemic reactions such as fatigue, headache or fever. Most reactions occur within the first 1–2 days, are mild, and resolve within 2–3 days. Blinded randomized placebo-controlled trials are currently recruiting (NCT04368728) or planning on recruiting (NCT04649151) 12–17 year old children to study the safety, immunogenicity and efficacy of these vaccines.^78,79 Twelve women who were included in the Pfizer-BioNTech trial and received the vaccine subsequently became pregnant and did not experience any adverse effects.⁷⁰ More evidence is required on the safety of the vaccines in pregnant women and children, the effectiveness against the new and mutant strains of SARS-CoV-2 and the potential need for development of newer vaccines targeting the mutant strains of SARS-CoV-2.^80,81

LONG-TERM IMPACT OF NEONATAL COVID-19

Due to the uncertainty surrounding the virus, there was substantial heterogeneity in perinatal management early in the pandemic. Practices such as mother-infant separation, cesarean section, early cord clamping and avoidance of breastfeeding to err on the side of caution, could alter neonatal colonization with maternal microbiota, hamper mother-infant bonding and breastfeeding, and predispose the infant to iron deficiency anemia and increased frequency of respiratory and gastrointestinal infections in infancy.⁸²

Long lasting effects of SARS-CoV-2 infection have been noted in adults with persistent cough and dyspnea, and a potential for lingering lung inflammation, bronchiectasis, fibrosis and pulmonary vascular disease.^83,84 Infected neonates with no or mild symptoms may possibly remain hypoxemic for a variable time-period before becoming overtly symptomatic similar to what has been observed in infected adults.⁸⁵ Indeed, neonates may be silent carriers of the virus in their airway epithelia with prolonged asymptomatic shedding of the virus.⁸⁶ We speculate that chronic airway inflammation could result in airway remodeling and thickening, predisposing to childhood asthma.

Vascular effects and thromboembolism have significantly contributed to COVID-19 mortality in adults and have been attributed to increased proinflammatory cytokines,⁸⁷ systemic inflammation and endothelial injury from viral replication and attachment leading to a prothrombotic state.⁴⁶ Additionally, there is lack of evidence on the consequences of early/ first trimester maternal SARS-CoV-2 infections on the fetus, and the incidence of early fetal losses, congenital defects and teratogenicity is yet to be explored.^88–90 Long-term follow-up of exposed neonates to assess the respiratory, cardiovascular and neurodevelopmental outcomes is warranted. Furthermore, the psychosocial impact on future generations remains to be understood.

CONCLUSION

Maternal and neonatal care during the COVID-19 pandemic has been a challenge to healthcare clinicians. This is due to the vulnerability of these populations, lack of high-quality evidence in management strategies and outcomes of infected patients, need for separation or isolation of parents from their infants, overwhelming of hospital systems during infection surges and difficulty in ensuring adequate follow-up care. Pregnant women and neonates who had SARS-CoV-2 infection should be monitored through the various available national registries (such as The National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection: NPC-19).⁹¹

The advent of vaccines in the present scenario has offered a ray of hope towards nearing the end of this pandemic. Effects of vaccination on viral transmission remain unknown. If a large enough population was immunized by the vaccine, reduced transmission may occur due to a decrease in symptomatic COVID-19. Vaccinated individuals could be asymptomatic carriers of the virus. It remains to be seen if asymptomatic viral carriage will be affected by widespread vaccination, although it is plausible that this will also decrease.⁹² However, in the absence of strict masking and social distancing, viral transmission may continue in spite of vaccination.

Abbreviations:

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

COVID-19

Corona virus disease 2019

AAP

The American Academy of Pediatrics

MIS-C

Multi-system inflammatory syndrome in children

MIS-N

Multi-system inflammatory syndrome in neonates

DR

Delivery room

PPE

Personal protective equipment

WHO

The World Health Organization

ECMO

Extracorporeal membrane oxygenation

ACOG

The American College of Obstetrics and Gynecology

SCFM

Society of Maternal Fetal Medicine

NPC-19 registry

AAP National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection

DIC

Disseminated intravascular coagulation