Impact of COVID-19 on Neonates and Mothers: Addressing Perinatal SARS-CoV-2 Infection

Coronaviruses are positive-sense enveloped single-stranded RNA viruses. Serotypes of the a- and b-coronavirus genera can cause human diseases. The new severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is a b coronavirus, with 80% homology to SARS CoV-1 (agent that causes severe acute respiratory syndrome, or SARS) and even greater homology to some bat corona viruses, suggesting a zoonotic origin.(1)

Like other corona viruses, SARS-CoV-2 has a “crown” appearance in electron microscopy caused by projections from the envelope spike (S) glycoprotein.

S protein mediates binding to human epithelial cells through the angiotensin-converting enzyme (ACE)-2 receptor, which is widely distributed throughout the human respiratory tract epithelium and is also the target of SARS-CoV-1 . SARS-CoV-2 is more transmissible than SARS-CoV-1, which may be a result of stronger binding to the ACE-2 receptor (2) and more efficient transmission of the virus from asymptomatic and pre-symptomatic hosts. (3)

Transmission occurs primarily through respiratory droplets, although contact and airborne transmission may occur to a lesser extent. 4)

The disease caused by SARS-CoV-2 tends to occur in a biphasic manner , with the initial disease believed to be the result of direct viral infection and the subsequent phase mediated by the immune system.(5) Additionally, it is known that SARS-CoV-2 infection causes coagulopathy, which can also contribute to organ dysfunction.

In the United States, pregnant women positive for coronavirus disease 2019 (COVID-19) are significantly more likely to be admitted to an intensive care unit and receive invasive ventilation and extracorporeal membrane oxygenation (ECMO) compared to non-pregnant women who they have 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, change in cell-mediated immunity, reduced lung capacity secondary to upward diaphragmatic displacement, and increased risk of thromboembolism.

Like non-pregnant women, pregnant women with COVID-19 present with cough (50%), fever (32%), myalgia (37%) and respiratory distress. In addition to respiratory symptoms, the placenta can be affected in COVID-19. (7) The possibility of vertical transmission seems low, but placental infection can potentially affect the fetus. (8) (9)

Measures to prevent COVID-19 during pregnancy include wearing a proper mask, washing your hands frequently, and most importantly, avoiding crowded areas and places (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 Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have issued statements suggesting that pregnant and lactating women should have the option of receiving the vaccine after discussing individual risks (including the possibility of fever after vaccination).

The Section on Neonatal Perinatal Medicine of the American Academy of Pediatrics (AAP) has issued a statement recommending shared decision-making regarding vaccination during pregnancy and breastfeeding. The risk of transmission of the vaccine (i.e., COVID-19 messenger RNA [mRNA]) across the placenta is unlikely, but transmission of maternal immunoglobulin (Ig) G antibodies in response to the vaccine is likely.

Antibodies against COVID-19 are found in babies born to mothers with COVID-19 and in the breast milk of mothers with COVID-19. (10) (11)

Active immunization with other vaccines has been shown to increase levels of specific IgA in breast milk.  

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

1 . Intrauterine transmission through transplacental hematogenous dissemination or viral particles in the amniotic fluid that are ingested or inhaled by the fetus. This mode seems less likely, but there are anecdotal reports that suggest this is possible. (9) (14) (15) (16) (17) (18)

2. Intrapartum transmission after exposure to infected maternal 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 pre-vaccine transmission). Transmission from an infected mother is most likely through respiratory secretions and less likely through breast milk.

Pregnant women with suspected COVID-19 (symptomatic or recent positive household contact) should be prioritized for SARS-CoV-2 testing, while universal screening can be used in areas with high prevalence. (19)

The timing and mode of delivery and anesthesia in pregnant women with suspected/confirmed SARS-CoV-2 infection depend on obstetric indications. A cesarean section rate of 24% to 41% has been reported in pregnant women infected with COVID-19 in hospitals in the United States. (20) (21) (22)

Prenatal steroids may be administered to infected pregnant women at risk of preterm birth (from 34-36 weeks) until more evidence is available due to the possible benefits of promoting fetal lung maturity and decreasing maternal mortality. (23) (24) The delivery room or operating room must be equipped to function as a negative pressure isolation room with the door closed.

Staffing within the Dominican Republic should be limited to essential healthcare workers (1 to 3 obstetric physicians and 1 to 2 pediatricians) who care for the mother-child dyad. Additional staff should wait outside and be signaled to enter if necessary.

Careful hand hygiene should be performed by physicians before donning and doffing personal protective equipment (PPE), including N95 mask (preferred) or surgical mask (acceptable) with face shield/goggles, isolation gown, and gloves. (19) The pregnant woman must wear a surgical mask. Visitors may be limited to only the support person necessary for the woman; Telemedicine/video-based interactions with visitors can be valuable, if available.

The World Health Organization (WHO) supports deferring cord clamping and early skin-to-skin contact in newborns of mothers with COVID-19. (25) (26) (27) After discussing the pros and cons of these interventions based on the available evidence, shared decision making with parents is encouraged. (28)

If a pregnant woman has significant COVID-19 illness and requires invasive mechanical ventilation, delivery may need to be performed in the intensive care unit. Caesarean section has been reported in a pregnant woman with COVID-19 who was receiving ECMO. (29)

Neonatology doctors must attend births according to the specific policies of the hospital or health center where they are located. Currently data suggests that only 1.6% to 2% of babies born to women who test positive for SARS-CoV-2 around the time of delivery test positive in the first 1 to 3 days after birth (AAP National Surveillance and Epidemiology Registry of Perinatal COVID-19 Infection / NPC-19 registry accessed December 14, 2020).

All neonatology physicians must don a gown and gloves and wear an N95 mask and face shield or eye protection goggles or an air-purifying respirator (with eye protection). (30) Because it is not known whether a newborn might require an aerosol-generating procedure soon after birth, appropriate precautions should be taken to minimize the risk of infection.

Aerosol-generating procedures in the delivery room include T-tube and mask ventilation, bag-mask ventilation, intubation, aspiration, high-flow oxygen therapy at more than 2 L/min, continuous positive airway pressure (CPAP). ) and mechanical ventilation.(31)

During mask ventilation, it is best to use the 2-person technique with 1 subject holding the mask with both hands to ensure a good seal and reduce air leaks and the second person performing bag-mask ventilation or handling the T-tube. .

The use of video laryngoscopy can be used to reduce the risk to the physician during intubation.

Transport of a newborn of a COVID-19 positive mother from the delivery room to the NICU or nursery should take a predetermined path in a closed incubator with minimal exposure to other personnel.   

There is no current strong evidence to suggest that SARS CoV-2 can be transmitted from an infected mother to the newborn through breast milk; rather, breast milk may be beneficial by providing protective antibodies against SARS-CoV-2 infection. (31) (32)

The nutritional, immunological and developmental benefits of breastfeeding, if the mother’s health permits, outweigh the potential risk of transmission, given that babies usually have mild illness. (33) (34)

Newborns are more likely to acquire the infection through horizontal transmission from an infected person, mother, or other caregiver; Therefore, the importance of maintaining adequate respiratory hygiene when an infected person is in contact with a newborn cannot be too great.

An infected mother should wear a surgical mask, wash her hands and breasts with soap and water before breastfeeding, and breastfeed her baby. Alternatively, the baby may be fed expressed breast milk by a healthcare provider. Between feedings, the baby’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 AAP, support protecting breastfeeding during this pandemic. (35)

It is worth mentioning that although the passage of Remdesivir (an antiviral medication used to treat moderate to severe SARS-CoV-2 disease) to an infant through breast milk is unknown, no adverse events have been reported in a newborn. whose mother received remdesivir therapy for Ebola infection. (36) The Medical Academy of Breastfeeding does not recommend discontinuing breastfeeding when nursing mothers receive an mRNA-based liposomal vaccine. 

Vertical transmission of SARS-CoV-2 appears to be rare due to the lack of viremia and non-overlapping expression of ACE-2 and transmembrane serine protease 2. (37) (38) Neonatal infection has been reported in 1% to 3% of US births to mothers with COVID-19, with lower chances of infection if the mother tested positive more than 14 days before delivery. (22) (39) (40)

Premature birth (12.9%, compared to the 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 neonatal infection rate did not increase with vaginal births, rooming-in or breastfeeding. (42) (43)

Separation of mother and baby and admission to the NICU may be necessary for premature infants (<34 weeks gestation) and for underlying medical conditions or symptomatic illness requiring higher levels of care for the infant or mother. Preterm and full-term infants admitted to the NICU with respiratory distress could potentially require respiratory support and aerosol-generating procedures (such as CPAP, endotracheal intubation, and need for surfactants).(30)

Intubation should be performed by an experienced neonatologist using appropriate personal protective equipment. Infants should be closely monitored for signs and symptoms of SARS CoV-2 infection, which may include fever, cough, rhinorrhea, respiratory distress, poor feeding behavior, lethargy, vomiting, diarrhea, rash, and edema. (39) (44) (45) (46) (47)

SARS-CoV-2 RNA testing with reverse transcriptase (polymerase chain reaction) is recommended for all newborns of mothers with suspected or confirmed COVID 19 at 24 and 48 hours after birth (or a single test at 24-48 h) using a nasopharyngeal, oropharyngeal or nasal swab. (26)

Asymptomatic SARS-CoV-2-positive newborns can be discharged from the hospital after ensuring close follow-up. An infected mother who has been afebrile for 24 hours without antipyretics and is improving is unlikely to be contagious 10 days after the onset of symptoms and can safely care for her baby. (26)

The immature immune system, passive transfer of maternal IgG antibodies, and lower ACE-2 expression may result in less inflammation, milder disease, and accelerated recovery in infants and children compared to adults. (11) (48)

However, newborns have been reported to have more severe disease (in 12% of infected newborns) compared to older children (3% of older children required intensive care unit care) in a systematic review. (47)(49)

Neonates positive for SARS-CoV-2 should be clinically monitored and isolated. Doctors caring for these newborns should use full PPE. Early-onset neonatal COVID-19 (onset of illness between 2 and 7 days after birth) is likely caused by perinatal transmission (intrapartum or more commonly, immediately after birth).

Most infected newborns are asymptomatic (20%) (22) (47) (50) or have mild symptoms such as rhinorrhea and cough (40%-50%) (39) (45) (47) and fever (15). % -Four. Five%). (45) (50) (51) Moderate to severe symptoms such as respiratory distress (12%-40%), poor feeding, lethargy, vomiting and diarrhea (30%), and clinical evidence of multiple organ failure were also observed. (39) (45) (46)

Laboratory evidence of COVID-19 infection in a newborn may include leukocytosis, lymphopenia, thrombocytopenia, and nonspecific findings of elevated inflammatory markers.(52)

Treatment of symptomatic COVID-19 positive newborns is primarily supportive. Adequate respiratory support, such as CPAP, is recommended for respiratory distress.

Endotracheal intubation is more likely to be indicated if there is specific lung pathology of the newborn (such as surfactant deficiency and meconium aspiration) rather than COVID-19 lung disease. (53) A viral filter could be placed in the expiratory branch of the ventilator circuit to minimize the risk of infection to healthcare workers through aerosolization. (30)

Most symptomatic SARS-CoV-2 infections in newborns are diagnosed beyond 5 to 7 days after birth (late-onset neonatal COVID-19). (39)

Postnatal transmission through neonatal exposure to maternal respiratory secretions or exposure to infected healthcare workers or households.

Contacts probably play an important role in the late onset of newborn infection, although intrapartum exposure to maternal secretions and body fluids may also contribute. (13) Many affected newborns had negative initial RT-PCR test results (at 24 and 48 hours after birth) before initial hospital discharge and were readmitted with symptoms suggestive of COVID-19. (54)

In a cohort study of 61 newborns with SARS-CoV-2 infection requiring hospitalization and treatment, 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 them were premature). (39) One third of infected newborns required respiratory support and supplemental oxygen.

Mothers of infected newborns tested positive for SARS-CoV-2 in 26% of cases and 52% of infected newborns had close contact with an infected individual. (39) Lethargy, apnea, fever or hypothermia, tachycardia, tachypnea, hypoxemia, hypotension and radiographic findings such as ground glass opacities with worsening disease have been found. (50) (55) (56)

Age less than 1 month was associated with a 3-fold increased risk of admission to intensive care. (57) Leukocytosis, thrombocytopenia, elevated lactate (55%), elevated C-reactive protein (29%) and lymphopenia (9%) have been observed. (39) (58) Disseminated intravascular coagulation may also occur (46) For newborns infected with COVID-19, management remains supportive and includes supplemental oxygen, respiratory support, fluid resuscitation, and temperature control.

Currently, evidence is lacking for the use of antiviral medications and steroids in neonatal COVID-19.

Use of remdesivir has been reported in 2 newborns: a 22-day-old child with late-onset severe COVID-19 who improved clinically and tolerated treatment well (59) and a 4-day-old child who continued to deteriorate and received dexamethasone and convalescent plasma. , required invasive ventilation until 13 days of age and finally improved.(60)

Multisystem inflammatory syndrome in children (MIS-C) is a new condition following COVID-19 infection in children, and is characterized by fever, inflammation markers, and high levels of 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 similar to Kawasaki disease. (62) (63)

The median age has been reported to be between 5 and 9 years, as opposed to Kawasaki disease which is typically seen between 6 months and 5 years of age, MIS-C is rare in infants, and has been reported only 4 % of MIS-C cases in children younger than 1. (64)

Neonatal MIS-C (MIS-N) has been reported rarely (65). A 49-day-old male infant, whose family member tested positive when the infant was 2 weeks of age, presented with severe gastrointestinal manifestations (including diarrhea) with biopsy-confirmed colitis, hypoalbuminemia, severe anemia, elevated serum D-dimer and ferritin, and thrombocytosis in the early phase and later thrombocytopenia. (66)

Serum brain natriuretic peptide was elevated and echocardiogram showed mitral regurgitation but normal coronary arteries. The infant was treated with intravenous immunoglobulin and methylprednisolone pulse therapy with subsequent improvement. Lima et al showed a 33-week gestation fetus with worsening pericardial effusion on ultrasound in a pregnant woman with positive COVID serology (IgM and IgG) and recent fever.(67)

An emergency cesarean section was performed, and the baby’s nasopharyngeal and oropharyngeal swabs and blood samples at birth were positive for SARS-CoV-2 in PCR tests. Two days after birth, the baby developed hemodynamic instability, requiring pericardiocentesis with subsequent clinical improvement.

Cardiac enzymes and plasma proinflammatory cytokines were elevated, consistent with a hyperinflammatory response. Of note is a fatal case, a case of MIS-C was reported in the NICU in a 7-month-old baby born at 26 weeks of gestation who was hospitalized from birth and acquired acute SARS-CoV-2 infection from a unknown source.(68)

The infant subsequently developed cardiovascular collapse with increased markers and echocardiographic evidence of myocarditis. (68) Recently, a 4-hour-old full-term infant born to a mother with no history of COVID-19 was reported to develop persistent pulmonary hypertension of the newborn (PPHN) and subsequently had multisystem involvement (fever, bilateral ground-glass opacities, necrosis enterocolitis-like intestinal tract, vasculitic rash, and increased inflammatory markers and D-dimer.

Both the mother and the baby tested positive for IgG antibodies against SARS CoV-2, suggesting that transplacental exposure to IgG could have contributed to the cytokine storm in the newborn. (69) This baby was treated with dexamethasone. in addition to the management of persistent pulmonary hypertension of the newborn that led to complete recovery. More studies are needed in children under 1 year of age. to elucidate risk factors for developing MIS-C and clarify predictors of disease severity.

Recently 2 vaccines manufactured by Pfizer-BioNTech and Moderna were approved by the US Food and Drug Administration, both under emergency use authorization. (70) (71)

The vaccines consist of a nucleoside-modified mRNA encapsulated in lipid nanoparticles that encodes the SARS-CoV-2 spike (S) glycoprotein (which mediates host cell attachment, a prerequisite for viral entry).

The lipid nanoparticle preferentially targets dendritic cells, which interact with other cells in the lymphatic system.(72) Once inoculated, the lipid layer breaks down, releasing the mRNA. The mRNA is constructed so that the S protein code inserts signals between the start and end for translation, and additional code is included to increase protein translation.

The host cell translates the mRNA to produce protein S, 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 production. of antibodies.

The Pfizer-BioNTech vaccine is administered in 2 doses, 21 days apart, to people 16 years of age and older. (73) The Moderna vaccine is administered in 2 doses, 28 days apart, for people over 18 years of age. (74)

Both vaccines are more than 90% effective in preventing laboratory-confirmed COVID-19 symptoms. (75) (76) (77) Both vaccines can 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 to 2 days, are mild, and resolve within 2 to 3 days. Blinded randomized placebo-controlled trials are currently recruiting (NCT04368728) or planning to recruit (NCT04649151) children aged 12 to 17 years 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 vaccines in pregnant women and children, efficacy against new and mutant strains of SARS-CoV-2, and the possible need for new vaccines targeting mutant strains of SARS-CoV -2. (80) (81)  

Due to the uncertainty surrounding the virus, substantial heterogeneity was observed in perinatal management early in the pandemic. Practices such as mother-child separation, cesarean section, early cord clamping, and avoidance of breastfeeding as a precaution could alter neonatal colonization with maternal microbiota, hinder mother-infant bonding, and predispose the infant to iron deficiency anemia and increased frequency of infections. respiratory and gastrointestinal in childhood. (82)

Long-lasting effects of SARS-CoV-2 infection have been observed in adults, with persistent cough and dyspnea and the potential for persistent lung inflammation, bronchiectasis, fibrosis, and pulmonary vascular disease. (83) (84)

Neonates with no or mild symptoms may remain hypoxemic for a variable period before becoming overtly symptomatic similar to what has been observed in infected adults. (85) In fact, newborns can be silent carriers of the virus in the airway epithelium with prolonged asymptomatic shedding of the virus. (86)

It is speculated that chronic airway inflammation may result in airway remodeling and thickening, predisposing newborns to childhood asthma.

Vascular effects and thromboembolism have significantly contributed to COVID-19 mortality in adults and have been attributed to an increase in proinflammatory cytokines, (87) systemic inflammation, and endothelial injury from viral replication and attachment leading to a state prothrombotic. (46)

Furthermore, there is a lack of evidence on the consequences of maternal SARS-CoV-2 infections on the fetus in the first trimester, and the incidence of early fetal loss, congenital defects, and teratogenicity has not yet been explored. (88) (89) (90)

Long-term follow-up of exposed neonates is warranted to evaluate respiratory, cardiovascular, and neurodevelopmental outcomes. Furthermore, the psychosocial impact on future generations is still unknown.

Maternal and neonatal care during the COVID-19 pandemic has been a challenge for doctors. This is due to the vulnerability of these populations, lack of high-quality evidence on management strategies and outcomes of infected patients, need for separation or isolation of parents from their babies, during sudden and overwhelming increases in infections. infections in hospitals and the difficulty in ensuring adequate follow-up care.

Pregnant women and newborns with SARS-CoV-2 infection should be monitored through the various national registries available (such as the National Registry of Surveillance and Epidemiology of Perinatal Infection by COVID-19 -NPC-19). (91)

The advent of vaccines in the current scenario has provided a ray of hope towards the end of this pandemic. The effects of vaccination on viral transmission are unknown. If a large enough population were immunized by the vaccine, transmission may be reduced by a decrease in symptomatic COVID-19.

Vaccinated individuals can be asymptomatic carriers of the virus. It remains to be seen whether 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 regulations, with the use of masks and social distancing, viral transmission can continue despite vaccination.