COVID-19 in Neonates with Positive RT-PCR Test. Systematic Review.

BACKGROUND: COVID-19 is an infectious disease of variable severity caused by a new coronavirus. Clinical presentation ranges from asymptomatic cases to severe illness. Most cases in newborns appear to be asymptomatic or mild.
OBJECTIVE: To conduct a systematic review of the literature on published studies of COVID-19 in newborns with a positive RT-PCR test.
METHODS: The PubMed and EMBASE databases were searched for infection data in newborns from 1 December 2019-21 May 2021. The mesh terms included "SARS-CoV-2", "COVID-19", "novel coronavirus", "newborns" and "neonates". The selection criteria were as follows: original studies reporting clinical, radiological, laboratory, and outcome data in newborns with a positive RT-PCR test for SARS-CoV-2. Two independent investigators reviewed the studies.
RESULTS: Seventy-two studies that involved 236 newborns were included. The main clinical manifestations were fever (43.2%), respiratory (46.6%), and gastrointestinal (35.2%) symptoms; 60.1% had mild/moderate disease. A total of 52.5% had a chest X-ray; 43.5% were normal, and 24.1% reported consolidation/infiltration images. The most frequent laboratory abnormalities were elevated C reactive protein and elevated procalcitonin and lymphopenia. Mortality was 1.7%.
CONCLUSION: Symptoms of SARS-CoV-2 infection were mild to moderate in most of the newborns. The prognosis was good, and mortality was mainly associated with other comorbidities. Published by Elsevier Inc.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by the SARS-CoV-2 virus (severe acute respiratory syndrome–coronavirus-2), and since its original detection in Wuhan, Hubei Province, China, by the end of December 2019, it had become a rapidly growing global pandemic (1).

SARS-CoV-2 is a novel beta-coronavirus (1,2), and coronaviruses can mutate and recombine quickly, resulting in new viruses that can be transmitted from animals to humans (3).

SARS-CoV-2 is highly infectious and affects all susceptible populations, including children and newborns (4,5). Maternal and neonatal infections have been reported. Transmission of SARS-CoV-2 occurs mainly through direct or indirect contact with infected respiratory secretions or droplets, which are expelled when an infected person coughs, sneezes, or talks. Airborne transmission can also occur during procedures that generate aerosols, and indirect contact transmission through fomites is also possible (6., 7., 8.). To date, evidence supporting vertical transmission is controversial (7,9).

COVID-19 is primarily a respiratory disease, and its severity can range from asymptomatic to fatal cases (1). Infants, young children, and newborns have been reported to have a milder form of the disease than adults (4,5,10., 11., 12.). However, there is also evidence of pneumonia in neonatal early-onset SARS-CoV-2 infection (13). Reports of newborns with SARS-CoV-2 infection are still scarce and mainly consist of case series and case reports (14,15). Until May 2021, some systematic reviews have been published on COVID-19 in pregnant women and their perinatal outcomes. However, some problems can limit the validity of these reviews. For example, they include patients with suspected but not confirmed infection or with only one positive reverse transcriptase-polymerase chain reaction test (RT–PCR) close to the time of birth. Other reviews report maternal and neonatal data, or include all pediatric ages (11,16). A meta-analysis of COVID-19 in newborns includes cases with positive RT–PCR tests and/or the presence of specific IgM, including articles published between December 1, 2019, and August 2020 (17).

This study aimed to systematically review the literature regarding published studies on the main clinical, radiological, and laboratory characteristics, as well as the management and outcome of newborns with COVID-19 with a positive RT–PCR test.

Material and Methods

Search Strategy and Selection Criteria

This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Databases including PubMed and Embase from December 1, 2019–May 21, 2021. There were no restrictions in publication language. The MesH terms used were “SARS-CoV-2”, “COVID-19”, “novel coronavirus”, “newborns” and “neonates”. Inclusion criteria were set as original studies, case series, case reports, and letters to the editor. Narrative and systematic revisions were excluded. References from the included studies and review articles were also analyzed to identify missing studies. An exhaustive review was conducted to avoid duplicate or overlapping cases.

In the included studies, newborns met the following criteria: positive SARS-CoV-2 RT–PCR test and clinical, radiological, laboratory, and patient outcome data. Newborns who had only one positive RT–PCR test at birth, without another confirmatory test, were eliminated to avoid including patients with possible transient colonization.

The titles and abstracts were reviewed by two independent researchers (AAL, PMR); disagreements between the two were resolved with a third investigator (HG).

Data Extraction and Quality Assessment

Data collected from full-text articles included study design, publication date, country, language, number of cases, maternal COVID-19, or SARS-CoV-2 infection, contact with suspected or confirmed cases, gestational age, birth weight, sex, diagnostic tests, neonatal specimen, age at diagnosis, age at onset of symptoms, comorbidity, clinical, radiological and laboratory data, treatment, and outcome.

The severity of the disease was evaluated according to the criteria established by Fang F, et al. and was grouped into 5 categories: asymptomatic, mild, moderate, severe, and critical (18).

Two independent reviewers used the tool Murad MH, et al. (19) proposed to evaluate the methodological quality of case reports and case series. The tool consists of four domains (selection, ascertainment, causality, and reporting) with eight questions to aid a quality score, and according to Della Gatta AN, et al. (20), a study was classified as “good quality” if all four domains were met, “intermediate quality” if three domains were met and “poor quality” if one or two domains were satisfied.

Data Analysis

A qualitative synthesis of the included studies was performed. Categorical variables are presented as frequencies and percentages, while continuous variables are expressed as medians and ranges. It should be noted that in many studies, not all data were registered.

The present research involved secondary use of published data. The IRB approved the study.

Results

With the search strategy, 1,587 articles were found in the databases, and after eliminating duplicates, 781 titles and abstracts were screened. Of the latter, 160 were selected for full-text review, but only 72 studies fulfilled the selection criteria (Figure 1 ). Of the 72 full-text articles included, 62 were case reports or case series, nine were cohort studies (13,21., 22., 23., 24., 25., 26., 27., 28.), and one was a cross-sectional study (29). In the 72 studies, 1,246 newborns were reported; however, 1,010 patients were excluded because 630 were born to COVID-19-positive mothers but had a negative RT–PCR test, 308 were infants, 69 did not underwent RT–PCR tests, and three newborns had only positive SARS-CoV-2 antibodies. Thus, this systematic review comprised data from 236 newborns. Supplementary Table 1 summarizes the data of the 72 included studies (13., 14., 15.,21., 22., 23., 24., 25., 26., 27., 28., 29., 30., 31., 32., 33., 34., 35., 36., 37., 38., 39., 40., 41., 42., 43., 44., 45., 46., 47., 48., 49., 50., 51., 52., 53., 54., 55., 56., 57., 58., 59., 60., 61., 62., 63., 64., 65., 66., 67., 68., 69., 70., 71., 72., 73., 74., 75., 76., 77., 78., 79., 80., 81., 82., 83., 84., 85., 86., 87., 88., 89.).

Figure 1

Flow diagram (PRISMA) of the study selection process.

General Characteristics of Newborns

All 236 newborns had positive SARS-CoV-2 RT–PCR tests, mainly performed in respiratory specimens: 48.6% (107/220) had nasopharyngeal swabs and 37.7% (83/220) had nasopharyngeal and oropharyngeal swabs. Other samples included nasal and respiratory secretions by tracheal aspiration or bronchoalveolar lavage, blood, stool, and anal swabs. In 16 newborns, specimen data was not specified.

The age of diagnosis ranged from 0 (day of birth) to 78 d, with a median of 10 d. The newborns with a positive RT–PCR test at birth were retested between 1 and 18 d, confirming the infection. Three patients had more than 28 d of postnatal life; however, these patients were premature, and at the time of diagnosis, two were 38 weeks, and one was 35 weeks of postconceptional age; therefore, they were also included.

One hundred and fifty-five newborns had a history of maternal COVID-19, most of which (92.9%) were confirmed by a positive RT–PCR test and suspected in the rest. In 65 newborns, data on maternal illness/infection were not specified. Fifteen newborns presented symptoms at birth; 13/15 were born to mothers with a positive RT–PCR test, 10/13 mothers were positive between 6 h and 16 d before delivery, and three at delivery time. Seven neonates presented symptoms in the first 24 h of life, six of their mothers had a positive RT–PCR test, and five of the six presented symptoms between one and two days before delivery.

In 99 of 173 neonates, there was a history of family members with COVID-19, including 49 confirmed by RT–PCR test and 50 suspected cases. In 63 neonates, data of infected contacts were not referred.

Seventy-four percent were newborns at full term (154/208) and 26% were premature. In 11.8% (n=28) of the cases, gestational age was not reported. Birth weight ranged from 900–4400 g (median 3120 g) in 116 neonates and was unknown in the rest. Of the 212 neonates for whom sex was reported, 123 (58%) were male.

Fifty-three neonates (22.4%) had some type of comorbidity, mainly prematurity; in nine (3.8%), the data were unknown.

Clinical Characteristics Associated with SARS-COV-2 Infection

Summarized clinical data of 236 newborns are represented graphically in Figure 2 . The primary clinical manifestation was fever in 43.2%, which was followed by respiratory signs and symptoms in 46.6% (including respiratory distress, tachypnea, and cough). Gastrointestinal manifestations were reported in 35.2% of patients, such as decreased feeding and diarrhea. Neurological alterations were found in 23.7% of the neonates, mainly lethargy. Less frequent manifestations included cutaneous in 6.8% and cardiovascular in 3.8% (including tachycardia, hypotension, acidosis, and/or delayed capillary refill time).

Figure 2

Clinical characteristics in 236 neonates with SARS-CoV-2 infection.

According to COVID-19 severity, 142 (60.2%) were classified as mild/moderate, 63 as severe (26.7%), 4 as critical (1.7%), and 27 (11.4%) neonates as asymptomatic.

Radiological Findings and Laboratory Tests

In 142 neonates, reports of radiological studies were available; 88% of them had a chest X-ray, of which 43.2% were normal. The main abnormal findings on radiographs were consolidation or infiltration images (24.0%) and ground-glass opacities (15.2%). Chest CT (computed tomography) was performed in 21 neonates, and ground-glass opacities were reported in nine neonates. Only 12 neonates had a lung ultrasound, and five of them reported signs of pulmonary edema of varying degrees Table 1. summarizes the findings on chest X-rays, chest CT, and lung ultrasound.

Table 1

Radiological findings in 236 neonates with SARS-COV-2 infection

	n	%
Not reported	94	44.5
Chest X-ray	125/142	88.0
Normal	54	43.2
Consolidation/infiltration	30	24
Bilateral ground glass opacities	19	15.2
Abnormal (not specified)	7	5.6
Bilateral diffuse opacification	6	4.8
Others	9	7.2
Chest computed tomography	21	14.8
Normal	1	4.8
Ground glass opacities	9	19.0
Bilateral pulmonary lesion	3	14.2
Others	8	38.0
Lung ultrasound	12	8.4
Normal	1	8.3
Signs of pulmonary edema of varying degrees	5	41.7
Coalescent B-lines and consolidation	2	1.4
Others	4	33.3

Some children had more than one radiological study.

Twelve percent of the laboratory data were normal. The most frequent abnormal test was elevated C reactive protein in 16.6%, elevated procalcitonin in 11%, and lymphopenia in 9.4% Table 2. summarizes the laboratory findings.

Table 2

Laboratory data in 236 neonates with SARS-CoV-2 infectiona

	n	%
Not reported	44	18.6
Normal laboratory tests	23/192	12.0
Elevated C reactive protein	32	16.6
Elevated procalcitonin.	21	11.0
Lymphopenia	18	9.4
Neutropenia	17	8.8
Elevated lactate	17	8.8
Elevated liver function tests	14	7.3
Elevated D-dimer	9	4.7
Thrombocytopenia	9	4.7
Elevated interleukin (IL-6)	6	3.1
Leukopenia	6	3.1
Elevated creatine kinase	5	2.6
Elevated lactate dehydrogenase	5	2.6
Elevated lymphocytes	2	1.0
Others	19	9.9

Abnormal values according to established parameters for newborns and local laboratories.

Management

Almost half of the newborns (48.2%) were admitted to a neonatal intensive care unit (NICU), while 26.6% were admitted to a pediatric ward and 6% to a neonatology ward. There was no information for 37 (15.6%) neonates regarding area of hospitalization. The median hospital stay was 12 d (range 1–69). Ten newborns were still hospitalized at the time of publication. In 31 (13.1%) newborns, the length of hospital stay was not reported.

Twenty-four neonates required invasive mechanical ventilation, 32 received noninvasive ventilation (nCPAP), and 61 were given supplemental oxygen by nasal cannula.

One hundred and four (46%) neonates received empirical antibiotics, and 45 (19.9%) received antiviral therapy (oseltamivir, acyclovir, remdesivir, lopinavir/ritonavir, hydroxychloroquine, and azithromycin). The use of immunomodulators (intravenous immunoglobulin, corticosteroids, and alpha interferon) was not frequent (5.3%). Only 54 (23.9%) newborns were breastfed (Table 3 ).

Table 3

Management and care of 236 neonates with SARS-CoV-2 infection

	n	%
Place of health care
Not referred	37	15.6
Neonatal Intensive Care Unit	96/199	48.2
Pediatric ward	53	26.6
Neonatology ward	12	6.0
Postnatal ward	12	6.0
Pediatric intensive care unit	11	5.5
Rooming-in	5	2.5
Home	10	5.0
Management	226	95.8
Support care/symptomatic treatment.	85	37.6
Isolation	55	24.3
Intravenous fluids	9	3.9
Resuscitation	5	2.2
Support
Respiratory support a
Conventional mechanical ventilation	24	10.6
Noninvasive ventilation (nCPAP)	32	14.1
Supplemental Oxygen	61	27
Drugs
Empirical antibiotics	104	46.0
Antivirals	45	19.9
Immunomodulators	12	5.3
Feeding (Breastmilk)	54	23.9

One neonate required conventional mechanical ventilation and high-frequency ventilation, one required extracorporeal membrane oxygenation (ECMO) and one required inhaled nitric oxide. Twenty-one infants required more than one respiratory support modality

Outcome

Four deaths (1.7%) were reported. One newborn with Down syndrome and atrioventricular septal defect who developed methicillin-resistant Staphylococcus epidermidis sepsis and died after 21 d of hospitalization in a NICU due to neonatal acute respiratory distress syndrome; a premature infant of 900 g, 28 weeks of gestational age, died on the 7 d of life with respiratory failure and bleeding; another premature infant of 34 weeks gestational age, weight 2100 g with respiratory distress and pulmonary hemorrhage; and the final infant with a cause of death unrelated to SARS-CoV-2.

Supplementary Table 1 describes the clinical, radiological, laboratory, and management and outcome data of the 236 neonates included.

Quality Assessment of the Included Studies

Of the 62 articles evaluated using the Mayo Evidence-Based Practice Center tool for case reports and case series, fifteen (24.2%) were classified as good quality, 32 (51.6%) as intermediate quality, and fifteen (24.2%) as low quality.

Discussion

This systematic review describes information exclusively on COVID-19 in neonates with a confirmed infection by RT–PCR test, and, as far as we know, it is the first time that complete information of newborns with a positive confirmatory test is summarized. In five newborns, RT–PCR was performed at birth because their mothers had confirmed infection. Additional tests during the follow-up were also positive. In most of the patients (94.5%), the test was performed on a respiratory specimen.

In 72.4% of the newborns, there was a confirmed maternal history of SARS-CoV-2 infection, although the data related to possible acquisition times were not complete in all the cases. Vertical transmission has been questioned since the beginning of the pandemic. A recent systematic review that included 936 SARS-CoV-2 tested newborns born to pregnant women with COVID-19 infection found that maternal-to-fetal transmission of the virus might occur in approximately 3.2% during the third trimester (90). In our review, 21 newborns presented symptoms at birth or in the first 24 h, and most of their mothers had a confirmed infection, indicating acquisition of the virus in the period close to delivery. Infection during the first trimester has been even more challenging to confirm. As most infections were postnatally acquired, the importance of maintaining preventive measures during hospitalization and at home is emphasized.

This review, which included 236 newborns, found that only 11.4% were asymptomatic, in contrast with the systematic review by Raschetti R, et al. (17) that found 55.7% (97/176) asymptomatic cases, but like the review by Liguoro I, et al. that reported 20% of asymptomatic neonates but only included 25 cases (11). Most of the symptomatic cases presented a mild or moderate illness; however, 26.7% had severe illness, and 1.7% were critical, which is like the distribution among older children (11). Raschetti R, et al. did not mention the severity of the disease (17). The most common symptoms were comparable in the reviews, with respiratory registered as the main symptom, followed by general (fever), and finally gastrointestinal and neurological symptoms occurring at the same frequency (17). It is difficult to discern the role of SARS-CoV-2 infection during the neonatal period in clinical manifestations due to the patients’ comorbidities.

Approximately half of the neonates were admitted to the NICU (48.2%), and in addition to prematurity, underlying conditions, or symptomatic illness, hospitalization indications were isolation, observation, and monitoring. A significant proportion of neonates were successfully managed in neonatal or postnatal wards. The Centers for Disease Control and Prevention (CDC) of the U.S.A. recommends admission to the NICU for infants at higher risk for severe illness, such as preterm neonates and neonates with underlying medical conditions or those needing higher levels of care (91).

The hospital stay was variable, from 1–69 d (median 12), but in most cases, length of hospitalization was related to comorbidities, mainly involving premature newborns <35 weeks of gestational age and newborns with a severe or critical illness.

Several theories have been proposed to explain the mild expression of COVID-19 in children. One of them is that SARS-CoV-2 needs the presence of an angiotensin-converting enzyme 2 (ACE2) receptor to enter the cell; ACE2 receptors are expressed in the epithelium of the human airways and the pulmonary parenchyma. ACE2 is less mature in young children, so it may not function properly as a receptor for SARS-CoV-2; in addition, the ACE2-induced response in alveolar epithelium cells in children may be lower than that in adults (92., 93., 94.).

Another possible explanation is that in young children, the inflammatory response is less intense due to the immaturity of their immune system (95), but infection can also progress to moderate or severe disease. It is essential to have a reliable medical history of contacts and be aware of subtle symptoms and signs to provide adequate management and follow-up.

Findings on chest X-rays were like those reported in other ages (96,97). Raschetti R, et al. (17) reported that lung imaging was abnormal in 64% of cases, which is like the 56.8% reported in this review.

Laboratory data highlight the elevation of procalcitonin and C-reactive proteins. In the complete blood count, the most common alteration was lymphopenia. Even though these abnormalities are found in adult patients, although frequencies are much lower (98).

To date, there is no definitive recommendation for specific treatment of children with COVID-19, and it is not surprising that treatment provided to newborns was diverse. Intended antiviral treatment included oseltamivir, hydroxychloroquine, azithromycin, lopinavir/ritonavir, acyclovir, and remdesivir. These treatments are not approved for the management of COVID-19 pediatric patients. The FDA issued an Emergency Use Authorization (EUA) for remdesivir on May 1, 2020, to treat suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease (99,100). Nevertheless, a systematic review by Ansems K, et al. (101) found that based on available evidence, remdesivir probably has little or no effect on all-cause mortality at up to 28 d in hospitalized adults with COVID-19, and there is uncertainty about the effects of remdesivir on clinical improvement and mortality. There is no recommendation for its use in newborns.

Regarding feeding practices, only 23.9% of newborns were reported to be exclusively breastfed. At the beginning of the pandemic, some guidelines recommended discontinuing breastfeeding for babies born to mothers with proven or suspected COVID-19 (102). Currently, this recommendation has changed, and all babies must be breastfed, as no evidence demonstrates the transmission of infection from a mother to her child through breast milk. If the mother confirms the infection, she must wear a facial mask during breastfeeding and comply with preventive measures such as hand hygiene. If the newborn also has a positive RT–PCR test, health care personnel must wear personal protective equipment. At home, recommendations are similar when caring for a COVID-19 patient (103., 104., 105., 106.).

According to the analysis presented here, the prognosis of newborns with COVID-19 can be considered good, with a mortality rate of less than 2%. Only four deaths were reported, two in premature newborns, one in a patient with Down syndrome, congenital heart disease, and sepsis, and one of a cause not related to COVID-19. Ten newborns were still hospitalized at the time of publication of the case, so their outcome is not known, although to that moment, they were in good medical condition.

One of the study limitations is that most of the publications included in the review correspond to a level of evidence 4, according to the Oxford CEBM (Evidence-based Medicine Classification Center) (107). That means in the case reports and case series, only nine were retrospective cohort studies, and one was cross-sectional; in addition, 24.2% were of poor quality according to the tool used for evaluation. Many of the published articles focus on pregnant women with SARS-CoV-2 infection, and the characteristics of newborns are seldom described in detail. There is no follow-up of infected neonates, especially asymptomatic neonates, so we do not know if they subsequently developed symptoms or if patients with mild/moderate illness persist with symptoms or sequelae that appear later in life, like adult patients with long COVID (108).

Conclusions

Symptoms of COVID-19 in the neonatal period are mild. The mortality seems to be low, and it was associated with comorbidities. Neonates born to SARS-CoV-2-positive mothers should be followed up for timely detection of the disease and possible progression of the infection. As vaccination progresses and mothers are protected, fewer cases are expected to occur in newborns.

Conflicts of Interest

None of the authors have declared any potential conflicts of interest.