Original article

Neonates with SARS-CoV-2 infection: spectrum of disease from a prospective nationwide observational cohort study

DOI: https://doi.org/10.4414/smw.2022.w30185
Publication Date: 27.05.2022
Swiss Med Wkly. 2022;152:w30185

Petra Zimmermannabc, Anita Ukaab, Michael Buettcherd, Yves Fougèree, Margherita Plebanie, Christa Rellyf, Hanna Schmidg, Nicole Ritzdgh, Swiss Paediatric Surveillance Unit (SPSU)

a Department of Community Health, Faculty of Science and Medicine, University of Fribourg, Switzerland

b Department of Paediatrics, Fribourg Hospital, Fribourg, Switzerland

c Infectious Diseases Research Group, Murdoch Children’s Research Institute, Parkville, Australia

d Paediatrics and Paediatric Infectious Diseases, Children’s Hospital Lucerne, Cantonal Hospital Lucerne, Switzerland

e Pediatric Infectious Diseases and Vaccinology Unit, Department Women-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland

f Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Switzerland

g Paediatric Infectious Diseases and Vaccinology, University of Basel Children’s Hospital Basel, Switzerland

h Department of Paediatrics, The Royal Children's Hospital Melbourne, The University of Melbourne, Australia

Summary

BACKGROUND: Coronavirus disease 2019 (COVID-19) can be more severe in infants than in older children. To date, only a few case series have reported data on neonates with COVID-19, including mostly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection. This study summarises nationwide epidemiological data, clinical characteristics, treatment and outcomes of neonates presenting with symptomatic SARS-CoV-2 infection.

METHODS: Data were prospectively collected through the Swiss Paediatric Surveillance Unit from hospitalised neonates with laboratory-confirmed SARS-CoV-2 infection (positive polymerase chain reaction on a respiratory sample) from 1 March 2020 to 31 September 2021. All 29 paediatric hospitals in Switzerland reported cases.

RESULTS: In total, 73 neonates were included; 7 (10%) were preterm. The median age at presentation was 17 days (interquartile range [IQR] 11–23); 40 (55%) were female. The majority of neonates (64, 88%) were admitted from home. Nine (12%) had a pre-existing medical condition. Overall, the most common symptom recorded was fever in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%). Twenty (27%) neonates presented with fever without a source. Seven (10%) neonates were admitted to an intensive care unit (5 for respiratory failure and 2 for monitoring). One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3–5). Two (3%) were treated with corticosteroids and 1 (1%) with remdesivir. In total, 60 (82%) neonates had contact with a known or suspected SARS-CoV-2 index case. All of the 71 neonates for whom data were available were discharged to their homes without symptoms.

CONCLUSION: In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short period of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, the presence of SARS-CoV-2 should not deter from the search for a serious bacterial infection. Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

Introduction

Coronavirus disease (COVID-19) is generally a mild disease in children [1–10]. Although, it has been reported that infants infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) get more severely ill compared with older children [11–16], there are, however, only a few case series summarising the presentation and outcomes of neonates suffering from COVID-19. Most reports to date include mainly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection [6, 11, 17–23]. Approximately 2 to 5% of neonates born to women with COVID-19 during pregnancy are infected with SARS-CoV-2 [24–27]. Up to 60% of neonates infected in the first days after birth remain asymptomatic [18, 21–23]. If symptoms are reported, they include fever, respiratory distress, feeding difficulties and vomiting [18, 21–23]. Data on neonates infected with SARS-CoV-2 after the perinatal period is sparse. As fever and other infectious signs and symptoms in the first month of life trigger extensive investigations and empirical antibacterial treatment, it is important to define the clinical characteristics and burden of neonatal COVID-19.

In this study, we summarised epidemiological data, clinical characteristics, treatment and outcomes of hospitalised neonates with symptomatic COVID-19 from a nationwide active surveillance system of SARS-CoV-2 infections in children. The inclusion only symptomatic neonates in our study clearly distinguishes our data from previous studies, which mostly included asymptomatic neonates who were exposed to infected mothers.

Methods

Study design and population

The study was designed as a prospective nationwide observational cohort study recording detailed epidemiological, clinical, therapeutic and outcome data of hospitalised neonates ≤28 days of age with laboratory-confirmed SARS-CoV-2 infection (a positive SARS-CoV-2 polymerase chain reaction [PCR] test on a respiratory sample). Neonates without symptoms were excluded from detailed analysis. Data were collected anonymously through the Swiss Paediatric Surveillance Unit (SPSU, http://www.spsu.ch) from 1 March 2020 to 31 September 2021. All 29 hospitals in Switzerland that have a paediatric and/or neonatology department participated and submitted cases monthly. Upon notification the investigators sent the reporting centres an electronic clinical report form through REDCap or in paper form (the questionnaire is provided in the appendix) [15]. If data were not submitted within one month a reminder was sent. Data were collected at one timepoint either during or after the hospitalisation. There was no outpatient follow-up. All data were reviewed by the investigators and further clarified with the reporting physician when needed. All missing data are indicated were applicable. The study received ethics approval by the ethics committee (Ethikkommission Nordwest- und Zentralschweiz (EKNZ 2020-01130). All collected data were anonymous, therefore according to the ethics approval no informed consent was necessary.

Statistical analysis

Continuous data are summarised using median, interquartile range (IQR), mean, standard deviation and range. Categorical data are presented as percentage. R (Version 1.2.5019) was used for designing figures.

Results

Study population

In total, 80 neonates were reported in our database. Four neonates were excluded from the analysis because they were entered in duplicate, two because they were asymptomatic and one because he was not hospitalised. Of the 73 neonates included, 7 (10%) were preterm (table 1). Forty (55%) were female. The median age of the neonates at presentation was 17 days (IQR 11–23) days. Most of the neonates were Caucasian (54, 74%), followed by Arabic (3, 4%), Black (3, 4%), Asian (2, 3%) and Hispanic (1, 1%). Ethnicity was not reported for 10 (14%) neonates. The majority of neonates (64, 88%) were admitted from home, 8 (11%) were transferred from another hospital and 1 (1%) preterm neonate was admitted from the delivery room. Nine (12%) neonates had a pre-existing medical condition (prematurity 7 [10%], trisomy 21 1 [1%], intrauterine growth restriction 1 [1%]).

Table 1

Baseline characteristics of neonates with SARS-CoV-2 infection (n = 73).

SexFemale, n (%)40 (55)
Age at presentation in daysMedian (IQR)17 (11–23)
Mean (SD; range)17 (7; 1–28)
Gestational age at birth in weeks*Median (IQR)40+0 (38+4–40+6)
Mean (SD; range)39+1 (2+4; 29+1–41+4)
Birth weight in g**Median (IQR)3475 (3110–3625)
Mean (SD; range)3335 (610; 1300–4560)
Weight on admission in gMedian (IQR)3700 (3400–4000)
Mean (SD; range)3680 (680; 1370–5200)
Ethnicity Caucasian, n (%)54 (74)
Arabic, n (%)3 (4)
Black, n (%)3 (4)
Asian, n (%)2 (3)
Hispanic, n (%)1 (1)
Unknown, n (%)11 (15)
Pre-existing medical conditionTotal9 (12)
Prematurity, n (%)7 (10)
Trisomy 21, n (%)1 (1)
Intrauterine growth restriction, n (%)1 (1)
Admitted fromHome, n (%)64 (88)
Other hospital, n (%)8 (11)
Delivery room, n (%)1 (1)

* Data missing for one neonate

** Data missing for two neonates

IQR: interquartile range; SD: standard deviation

Symptoms

Overall, the most common symptom reported was fever, in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%) (fig. 1). Further symptoms included feeding difficulties in 11 (15%), cough in 10 (14%), diarrhoea in 10 (14%), vomiting in 8 (11%), abdominal pain in 3 (4%), pharyngitis in 3 (4%), rash in 2 (3%) and jaundice in 1 (1 %) neonate.

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Figure 1

Distribution of symptoms in neonates with SARS-CoV-2 infection.

Fever was the only symptom in 20 (27%) neonates; all of these were admitted for fever of unknown source. A total of 20 (27%) neonates did not have fever, of these 13 presented with respiratory symptoms, 5 with gastrointestinal symptoms, and one each with feeding difficulties and rash.

Diagnostics

Seventy-two (99%) neonates had a positive SARS-CoV-2 PCR test on nasopharyngeal swab. One neonate did not have a nasopharyngeal swab and was diagnosed with positive PCR on tracheal aspiration. Two neonates additionally had a SARS-CoV-2 PCR test on tracheal aspirations, which was positive. In one neonate, a SARS-CoV-2 PCR test was done on stool, which was negative. No serology test was done.

A total of 44 (60%) neonates had further viruses tested on their nasopharyngeal swab; 4 tested positive for picornavirus. Ten (14%) had chest radiography (4 normal, 4 bilateral changes, 1 unilateral changes and 1 preterm neonate with hyaline membrane disease). Six (8%) neonates had echocardiography, all of them were normal, apart from a patent foramen ovale in one neonate. All of the remaining tests were normal (lumbar puncture in 7 [10%], abdominal sonography in 2 [3%], cranial sonography in 1 [1%], cranial magnetic resonance imaging in 1 [1%]) (table 2).

Table 2

Investigations in neonates with SARS-CoV-2 infection.

 n (%)
Nasopharyngeal swab for other viruses43 (59)
– Negative39
– Picornavirus4
Chest radiography10 (14)
– Normal4
– Bilateral changes4
– Unilateral changes1
– Hyaline membrane disease1
Echocardiography6 (8)
– Normal5
– Patent foramen ovale1
Lumbar puncture7 (10)
– Normal6
– Mononuclear-predominate pleocytosis, SARS-CoV-2 PCR negative1
Abdominal sonography2 (3)
– Normal2
Cranial sonography1 (1)
– Normal1
Cranial magnetic resonance imaging1 (1)
– Normal1

Treatment

Seven neonates (10%, 5 term and 2 preterm) needed admission to an intensive care unit, 5 for respiratory failure and 2 for intensive monitoring. One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3–5) and in preterm neonates 6 days (IQR 3–25) (table 3).

Table 3

Admission, treatment and complications in neonates with SARS-CoV-2 infection.

 Term, n = 66Preterm, n = 7
Length of hospital stay in days  
– Median (IQR)4 (3–5)6 (3–25)*
– Mean (SD; range)5 (5; 2–35)12 (6; 2–35)*
Admission to intensive care unit, n (%)5 (8)2 (29)
– Respiratory failure32
– Monitoring20
Oxygen, n (%)14 (21)3 (43)
– Median duration in days (IQR)2 (1–3)nc
– Mean duration in days (SD; range)4 (6; 1–18)nc (nc; 1–9)
High-flow oxygen, n (%)4 (6)0
Noninvasive ventilation, n (%)3 (5)2 (29)
Mechanical ventilation, n (%)1 (2)2 (29)
Inotropic support, n (%)1 (2)0
Corticosteroids, n (%)2 (3)0
Remdesivir, n (%)1 (2)0
Complications2 (3)0
– Central apnoea, n (%)1 (2)0
– Blood stream infection with Strep. pneumoniae and Strep. salivarius, n (%)1 (2)0

IQR: interquartile range; nc: not calculable; SD: standard deviation

* 2 preterm neonates not included as they were still admitted at the time of data analysis.

Of the 73 neonates, 17 (23%) needed supplementary oxygen, 4 (5%) high-flow oxygen, 5 (7%) noninvasive ventilation and 3 (4%) mechanical ventilation (table 3). Two (3%) neonates were treated with corticosteroids and 1 (1%) with remdesivir.

Complications and outcome

Two neonates were reported to have complications. One neonate suffered from central apnoea and one from a blood stream infection with Streptococcus pneumoniae and Streptococcus salivarius on admission (table 3). Two preterm neonates were still admitted at the time of data analysis, all other neonates were discharged to their homes without symptoms.

Transmission

In total, 60 neonates (73%) had contact with a person known or suspected to have a SARS-CoV-2 infection. The distribution is detailed in figure 2.

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Figure 2

Exposure to known or suspected SARS-CoV-2-infected cases in 73 neonates.

Discussion

This nationwide study presents data from active surveillance of symptomatic SARS-CoV-2 infection in neonates in Switzerland during periods when the original virus and alpha and delta variants were circulating. The inclusion of  only symptomatic neonates in our study clearly distinguishes our data from previous studies, which mostly included asymptomatic neonates who were exposed to infected mothers [6, 11, 17–23]. Our cohort mainly presented with fever and symptoms of upper and lower respiratory tract infection. One quarter presented with fever without a source. Most neonates were exposed to a known index case. Strain-specific analysis of the data was not possible.

The findings from our study are in line with those from the currently largest review summarising 176 case reports of neonates with SARS-CoV-2 infection [28]. In this review, neonates also mainly presented with fever and respiratory symptoms. However, compared with our cohort, gastrointestinal symptoms were reported more frequently. This may be explained by the larger proportion of preterm-born neonates included , who often have feeding difficulties, even in the absence of an infection. In contrast to our cohort of symptomatic neonates, the review included neonates who were tested because of exposure to maternal SARS-CoV-2 infection and almost half of them were asymptomatic. This likely explains the age difference at presentation, with a mean age of 5 days versus 17 days in our cohort. In the review, an estimated 30% of infections were vertical. In our study, we could not differentiate between vertically transmitted [29] or post-partum infection, but in 40% of neonates the mother was deemed to be the index case.

Fever and other infectious symptoms in the first month of life usually triggers careful clinical evaluation, extensive investigations, empirical antibacterial treatment and hospital admission. Based on our findings, the differential diagnosis of COVID-19 needs to be added as a possible cause of fever without source for this young age group. It has recently been reported that approximately 15% of infants less than 90 days of age admitted for investigations because of fever are diagnosed with a SARS-CoV-2 infection [30]. However, the detection of SARS-CoV-2 should not preclude further investigations for possible bacterial infection, as shown in our study where one neonate with SARS-CoV-2 infection was bacteraemic with Streptococcus pneumoniae on admission. Similarly, three other studies including infants up to the age of 90 days, although not frequently, also reported bacteraemia and urinary tract infections in infants who tested positive for SARS-CoV-2 [30–32]. Of note, although four neonates with COVID-19 also tested positive for picornavirus, we did not find any co-infections with respiratory syncytial virus or influenza.

The rate of admission to an intensive care unit in term neonates with SARS-CoV-2 infection found in our study is similar to the rates reported in older children (2 to 13%) [1, 7, 8, 33, 34]. In the above mentioned review of case reports of neonates with SARS-CoV-2 infection a larger proportion of neonates were admitted to intensive care; this is likely due to the higher proportion of preterm neonates included [28]. Antiviral or anti-inflammatory treatment was rarely required and complications were rare.

The strengths of our study are the multicentre nationwide study design and the availability of detailed epidemiological and clinical data on symptomatic preterm and term neonates. The limitations include the fact that for infants born preterm it is difficult to distinguish between symptoms attributable to COVID-19 or to prematurity, as well as the lack of laboratory values and long-term follow-up data. Furthermore, we did not have strain-specific data.

Conclusion

In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short duration of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, detecting SARS-CoV-2 infection should not deter from the search for a serious bacterial infection in a neonate. A small proportion of hospitalised neonates requires admission to an intensive care unit.

Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

Availability of data and material

Data collected for the study and the study protocol will be made available to others on request.

Acknowledgments

We thank the representatives of the paediatric units in Switzerland: M. Albisetti; V. Bernet; C. Betti; F. Cachat; P. Caplazi; M-L. Decker; E. Durrer; S. Fluri; M. Gebauer; M. Gehri; E. Giannoni; S. Grupe; M. Horn; A. L’Huiller; T. Karen; E. Kellner; L. Kottanattu; G. Laube; B. Laubscher; J. Llor; F. Luterbacher; H. Madlon; A. Malzacher; M. Martins; J. McDougall; A. Merglen; S. Minocchieri; V. Muehlethaler; T. Neuhaus; A. Niederer; S. Nikorelou; M. Plebani; Ratnasabapathy; T. Riedel; M. Russo; H. Schmid; K. Staudacher; M. Torres Escobar; J. Wildhaber; A. Wörner; A. Zemmouri

We would also like to acknowledge the administrative support by Daniela Beeli, Mirjam Mäusezahl and Fabien Tschagellar, from the Federal Office of Public Health Switzerland.

Authors’ contributions: PZ, AU and NR designed the study, did the data analysis and wrote the first draft. All authors revised the manuscript and approved the final draft.

Financial disclosure

The study was supported by the Swiss Federal Office of Public Health and has received grants from the Swiss Society of Paediatrics and the Paediatric Infectious Disease Group of Switzerland.

Potential competing interests

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflict of interest was disclosed..

Credits

Header image: © Kirill Bodrov | Dreamstime.com

Correspondence

Dr Petra Zimmermann

Department of Community Health

Faculty of Science and Medicine

University of Fribourg

Route des Arsenaux 41

CH-1700 Fribourg

petra.zimmermann[at]unifr.ch

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Appendix: Questionnaire

The appendix is available in the pdf verion of the article.

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