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. 2020 Aug 28:fmaa059. doi: 10.1093/tropej/fmaa059

Clinical Features and Outcome of SARS-CoV-2 Infection in Neonates: A Systematic Review

Shashi Kant Dhir 1,#, Jogender Kumar 1,#, Jitendra Meena 1, Praveen Kumar 1,✉
PMCID: PMC7499746  PMID: 32856065

Abstract

Objective

The objective of this study is to systematically synthesize the currently available literature on various modes of transmission (congenital, intrapartum, and postpartum), clinical features and outcomes of SARS-CoV-2 infection in neonates.

Methods

We conducted a comprehensive literature search using PubMed, EMBASE, and Web of Science until 9 June 2020. A combination of keywords and MeSH terms, such as COVID-19, coronavirus, SARS-CoV-2, 2019-nCoV, severe acute respiratory syndrome coronavirus 2, neonates, newborn, infant, pregnancy, obstetrics, vertical transmission, maternal–foetal transmission and intrauterine transmission, were used in the search strategy. We included studies reporting neonatal outcomes of SARS-CoV-2 proven pregnancies or neonatal cases diagnosed with SARS-CoV-2 infection.

Results

Eighty-six publications (45 case series and 41 case reports) were included in this review. Forty-five case series reported 1992 pregnant women, of which 1125 (56.5%) gave birth to 1141 neonates. A total of 281 (25%) neonates were preterm, and caesarean section (66%) was the preferred mode of delivery. Forty-one case reports describe 43 mother-baby dyads of which 16 were preterm, 9 were low birth weight and 27 were born by caesarean section. Overall, 58 neonates were reported with SARS-CoV-2 infection (4 had a congenital infection), of which 29 (50%) were symptomatic (23 required ICU) with respiratory symptoms being the predominant manifestation (70%). No mortality was reported in SARS-CoV-2-positive neonates.

Conclusion

The limited low-quality evidence suggests that the risk of SARS-CoV-2 infections in neonates is extremely low. Unlike children, most COVID-positive neonates were symptomatic and required intensive care. Postpartum acquisition was the commonest mode of infection in neonates, although a few cases of congenital infection have also been reported.

Keywords: breast milk, congenital infection, COVID-19, neonates, pregnancy

INTRODUCTION

Novel coronavirus infection (later termed as COVID-19) was declared a global pandemic on 11 March 2020 and as of 12 June 2020, the number of confirmed cases has reached 7 410 510 and 418 294 (5.6%) deaths have been reported worldwide [1]. A significant number of pregnant females are also affected, as they are equally susceptible to SARS-CoV-2 infection [2]. Neonatal SARS-CoV-2 infections are rare, and till now a handful of cases are reported. Although the newborns are considered at risk for vertical and postpartum horizontal transmission, there is a dearth of data on the clinical features, outcome, mode of transmission and mode of delivery for neonates. Also, there is uncertainty about the transmission of the SARS-CoV-2 virus through the placenta and breast milk [3–9].

Therefore, we performed this systematic review to synthesize the currently available literature on various modes of transmission (congenital, intrapartum and postpartum), clinical features and outcomes of SARS-CoV-2 infection in neonates.

MATERIALS AND METHODS

Search strategy

This study was conducted following the Meta-analysis Of Observational Studies in Epidemiology guidelines [10]. A predefined search strategy was developed, and three investigators (S.K.D., J.M., and J.K.) independently performed a literature search in MEDLINE, EMBASE and Web of Science for the original articles published between 1 December 2019 and 9 June 2020. Terms used for literature search were COVID-19, coronavirus, SARS-CoV-2, 2019-nCoV, severe acute respiratory syndrome coronavirus 2, neonates, newborn, infant, pregnancy, obstetrics, vertical transmission, maternal–foetal transmission, and intrauterine transmission. Specific search strategies were created for each electronic database separately, by using the MeSH terms, Emtree terms and terms described above (Supplementary Table S1). The electronic search was also supplemented by a hand search of bibliography of the included studies and relevant review articles. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines [11]. No language restrictions were used.

Study selection

A predefined set of criteria was used for the assessment of the eligibility of the studies for this systematic review. Studies enrolling neonates and/or pregnant mothers and reporting data on COVID-19 testing of the neonates were considered eligible for the review. Initially, two researchers (J.M. and S.K.D.) independently screened the title and abstract for the eligibility. Later three authors (S.K.D., J.M. and J.K.) examined the full-text articles for inclusion and exclusion criteria. Studies were included if they met the following criteria: (i) studies reporting the neonatal outcome of pregnancy with RT-PCR proven SARS-CoV-2 infection, (ii) studies reporting clinical manifestations, disease severity, laboratory investigations and outcome of RT-PCR proven SARS-CoV-2 infection in neonates (postnatal age < 29 days for the term and postmenstrual age up to 44 weeks for preterm neonates), (iii) all types of study designs: cohort, cross-sectional studies, case–control studies, case series and case reports. Correspondences or letters fulfilling the above criteria were also included. We excluded: (i) studies with term neonates aged more than 28 days and preterm neonates with postmenstrual age more than 44 weeks, (ii) studies reporting COVID-19-positive pregnancy without any neonatal outcomes, (iii) studies not reporting the neonatal COVID-19 status, (iv) studies reporting about other serotypes of coronavirus or testing methods other than RT-PCR, (v) narrative or systematic review, (vi) conference proceedings and (vii) editorial, perspective, etc. not meeting the inclusion criteria.

Data extraction and quality assessment

A structured performa was used for the data extraction. Two investigators independently extracted the desired data from the full-text of the eligible studies. The details of extracted data parameters are given in Supplementary AppendixTable S2. The studies published in Chinese language were first translated to English language using Google translation and then the desired data were extracted. Any disagreement between two investigators was resolved through discussion with the third investigator (J.K.). A researcher (J.K.) independently rechecked the extracted data for its accuracy and completeness. The quality of the included studies in this systematic review was assessed using the Newcastle Ottawa scale [12]. Two investigators (S.K.D. and J.K.) independently assigned an overall risk of bias to each eligible study, and if they disagreed, another researcher (J.M.) was involved to resolve the discrepancy.

Data synthesis and statistical analysis

We summarized the relevant clinical details of the neonates and pregnant mothers described in the included studies. Clinical details, demographics, the time of doing RT-PCR for SRS-CoV-2 infection in neonates and outcomes of the SARS-CoV-2-positive neonates were summarized separately. Mother was considered to have SARS-CoV-2 (COVID-19) infection only if the RT-PCR from nasopharyngeal/oropharyngeal swab was positive [13]. Neonate was considered to have COVID-19 infection if the RT-PCR from nasopharyngeal/oropharyngeal swab from infant or blood from neonate/umbilical cord or amniotic fluid or tissue sample from the foetal side of the placenta was positive for SARS-CoV-2 [13]. The neonates with SARS-CoV-2 infection were further classified to characterize the mode of transmission (congenital, acquired intrapartum and acquired postpartum) [13]. Percentages and mean/median values were calculated to describe categorical and continuous variables, respectively. SPSS v23 was used for statistical analysis.

RESULTS

Study selection and characteristics

We found a total of 1313 records. The detailed process of selection of final included studies for this systematic review is described in Fig. 1. After removing 741 duplicates, 578 articles were screened for eligibility through titles and abstracts. A total of 384 articles were excluded, and 194 articles were retrieved for full-text assessment. After a thorough screening of full-text articles, 85 (45 case series/cohort and 41 case reports) publications were included for the qualitative synthesis. Quality assessment was done for 45 studies, of which 9 were rated as good, 21 as fair, and 15 of poor quality by the Newcastle Ottawa scale [12].

Fig. 1.

Fig. 1.

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PRISMA flow diagram.

Clinical details

Forty-five studies [3, 5, 7, 14–55] described 1992 pregnant women with gestation ranging from 5 to 41 weeks. Birth was reported amongst 1125 (56.5%) of these. The mode of delivery was available for 1114 pregnancies, and caesarean section (65%) was more frequent than vaginal delivery. A total of 1141 neonates were born of which, 281 (25%) were preterm (<37 weeks). SARS-CoV-2 testing was done for 1005 (88%) neonates and 39 (3.9%) turned out to be positive on RT-PCR (Table 1). Forty-one case reports [4, 6, 8, 56–93] described 43 mother-baby dyads, of which 16 (37.2%) were preterm (<37 weeks), 9 (21%) were low birth weight (<2500 g) and 27 (62.8%) were born by caesarean section (Table 2). All 43 were tested for SARS-CoV-2 infection using nasopharyngeal or oropharyngeal specimen and 19 neonates (44.2%) have positive RT-PCR for SARS-CoV-2.

Table 1.

Details of included studies (case series and cohort)

Author Date of publication Country Study design Study quality Pregnant women (n) Gestational age (weeks) Vaginal delivery (total delivered) Live births (n) Preterm, n (%) Birth weight (g) Neonates tested(n) COVID- positive neonates
Breslin et al. [14] 9 April 2020 USA Retrospective Fair 43 37 (32–38)a 10 (18) 18 1 (5) – 18 0
Buonsenso et al. [15] 21 April 2020 Italy Observational Poor 7 8–37b 0 (2) 2 1 (50) 2300, 3390 2 2
Campbell et al. [46] 26 May 2020 USA Case series Poor 30 Term 20 (30) 30 0 3370 (621)c 30 0
Cao et al. [16] 10 April 2020 China Retrospective Fair 10 33–40b 2 (10) 11 4 (36) 2050–3800b 4 0
Chen et al. [3] 12 February 2020 China Retrospective Fair 9 36–39b 0 (9) 9 4 (44) 1880–3730b 6 0
Chen et al. [17] 16 March 2020 China Case series Poor 4 37–39b 1 (4) 4 0 3050–3800b 3 0
Chen et al. [18] 28 March 2020 China Observational Fair 5 38–41b 3 (5) 5 0 3235–4050b 5 0
Chen et al. [19] 17 April 2020 China Retrospective Poor 118 – 5 (68) 68 14 (21) – 8 0
Chen et al. [20] 10 March 2020 China Case series Poor 17 – 0 (17) 17 3 (18) – 0 0
Chen et al. [21] 08 May 2020 China Case series Poor 3 – 0 (2) 2 1 (33) – 2 0
Fan et al. [22] 17 March 2020 China Case series Fair 2 36–37b 0 (2) 2 0 2890, 3400 2 0
Ferrazzi et al. [23] 07 April 2020 Italy Retrospective Fair 42 – 24 (42) 42 11 (26) 840–4040b 42 3
Govind et al. [24] 07 May 2020 England Observational Fair 9 36.8 (27–39)a 1 (9) 9 7 (78) – 9 1
Hernández et al. [47] 05 June 2020 Spain Case series Good 3 39 – (3) 3 1 (33) 1135–3700b 3 3
Hantoushzadeh et al. [25] 24 April 2020 Iran Case series Fair 9 32.7 (28–38)a 0 (5) 6 5 (83) 1180–3200b 6 1
Hirshberg et al. [26] 01 May 2020 USA Case series Fair 5 25–31b 0 (3) 3 3 (100) 1500–2110 3 0
Huang et al. [27] 08 May 2020 China Retrospective Poor 8 28–39b 1 (6) 6 3 (50) 1520–4200b 6 0
Kayem et al. [44] 31 May 2020 France Case series Poor 617 22–37b 94 (181) 190 50 (28) – 190 2
Khan et al. [28] 19 March 2020 China Case series Fair 3 34–39b 3 (3) 3 1 (33) 2890–3730b 3 0
Khan et al. [48] 27 March 2020 China Case series Fair 17 35–41b 0 (17) 17 3 (18) 2300–3750b 17 0
Knight et al. [49] 08 June 2020 UK Case series Fair 427 38 (36–40)a 106 (253) 259 63 (24) – 259 12
Li et al. [45] 30 March 2020 China Case–control Good 16 38 (0.2)a 3 (16) 17 4 (23) 3066 (560)c 3 0
Liao et al. [29] 29 April 2020 China Retrospective Good 10 38 (1.43)a 10 (10) 10 1 (10) 3283 (449)c 7 0
Liu et al. [30] 27 February 2020 China Retrospective Fair 13 32–38b 0 (10) 10 7 (70) – 9 0
Liu et al. [31] 17 March 2020 China Observational Fair 10 38 (1.5)c 1 (10) 10 2 (20) 3293 (425)c 10 0
Liu et al. [32] 07 March 2020 China Retrospective Poor 15 37 (1)c 1 (11) 11 – – 11 0
Martinez-Perez et al. [50] 08 June 2020 Spain Case series Poor 82 – 41 (82) 82 25 (30) 910–4750b 82 5
Ochiai et al. [51] 04 June 2020 Japan Case series Poor 52 38 0 (2) 2 0 3715, 2805 2 0
Pereira et al. [5] 22 May 2020 Spain Observational Good 60 32 (5–41)a 18 (23) 23 2 (9) – 23 0
Pierce-Williams et al. [33] 04 May 2020 USA Cohort Good 64 34 (4.2)c 8 (32) 32 19 (59) 2403 (858)c 33 1
Qadri and Mariona [52] 20 May 2020 USA Case series Poor 16 22–40b 8 (12) 12 1 (8) 2830–4215b 12 0
Qiancheng et al. [34] 22 April 2020 China Retrospective Fair 28 38 (36–39)a 5 (22) 23 1 (4) 2915–3390b 22 0
Salvatori et al. [35] 15 May 2020 Italy Case series Fair 2 39–41b – (2) 2 0 3120, 4440 2 2
Sun et al. [36] 19 April 2020 China Case series Fair 3 31–37b 0 (3) 3 2 (67) – 3 1
White et al. [53] 04 June 2020 USA Case series Good 3 39 2 (3) 3 0 – 2 2
Wu et al. [37] 05 May 2020 China Case series Fair 13 5–38b 1 (5) 5 2 (40) 2300–3910b 5 0
Xu et al. [38] 28 April 2020 China Retrospective Fair 5 34–39b 4 (5) 5 2 (40) 2450–3760b 5 0
Yan et al [39] 17 April 2020 China Retrospective Good 116 38.4 (37–39)a 14 (100) 100 21 (21) 3108 (526)c 86 0
Yang et al [40] 5 April 2020 China Prospective Good 7 36–38b 0 (7) 7 4 (57) 2096 (660)c 6 0
Yu et al. [41] 24 March 2020 China Retrospective Fair 9 39 (37–41)a 0 (7) 7 0 3000–3500b 3 1
Zeng et al. [7] 26 March 2020 China Prospective Poor 6 – – (6) 6 – – 6 0
Zeng et al. [42] 26 March 2020 China Cohort Fair 33 – 0(33) 33 4(12) – 19 3
Zeng et al. [54] 21 May 2020 China Case series Poor 16 37 (34–41)a 4 (16) 12 3 (25) 3175 (478)c 16 0
Zhang et al [55] 25 March 2020 China Case series Good 16 29 (2.9)c 0 (10) 10 1 (10) – 10 0
Zhu et al. [43] 10 February 2020 China Case series Poor 9 31–39b 2 (9) 10 5 (50) 1720–3800b 10 0
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a

Median (IQR).

b

Range.

c

Mean (SD).

Table 2.

Details of included studies (case reports)

Author Date of publication Country No. of COVID+ mothers COVID+ neonates (n) Gestation (weeks) Birth weight (g) Mode of delivery Apgar (1/5 min) Symptoms
Aghdam et al. [56] 1 April 2020 Iran 1 1 – 3460 CS – Fever, lethargy, mottling, tachypnoea, RD
Aguilar et al. [57] 27 April 2020 Spain 1 1 – – – – Seizures, Hypertonia, Fever, Watery stools
Alzamora et al. [58] 18 April 2020 Peru 1 1 33 2970 CS 6/8 RD, cough
Blauvelt et al. [59] 8 May 2020 USA 1 0 28 1880 CS 4/8 HMD, leukopenia, mild acidosis
Carosso et al. [60] 14 April 2020 Italy 1 1 37 3120 VD 9/10 Asymptomatic
Cook et al. [86] 19 May 2020 UK – 1 27 – – – Poor feeding, dyspnoea, respiratory failure, shock
De Socio et al. [61] 1 May 2020 Italy 1 0 40 – VD 10/10 Asymptomatic
Fontanella et al. [92] 29 May 2020 Netherlands 1 0 40 – CS 9/9 Asymptomatic
Groß et al. [8] 21 May 2020 Germany 2 2 – – – – Breathing difficulty
Han et al. [62] 16 April 2020 Korea 1 1 38 3730 VD – Fever, nasal blockage, tachycardia, cough
Iqbal et al. [63] 1 April 2020 USA 1 0 39 – VD 8/9 Asymptomatic
Jain et al. [93] 5 June 2020 India 2 0 Term 2865/– CS –/– Asymptomatic/second-asphyxia, shock, ventilated
Kirtsman et al. [64] 14 May 2020 Canada 1 1 40 2930 CS 9/9 Hypothermia, feeding difficulty, hypoglycaemia
Kuhrt et al. [65] 8 May 2020 England 1 0 32 2190 CS 8/9 Ventilated
Lang et al. [6] 8 May 2020 China 1 0 35 – CS 9/10 Asymptomatic
Lee et al. [66] 31 March 2020 Korea 1 0 37 3130 CS 9/10 Asymptomatic
Li et al. [67] 5 March 2020 China 1 0 35 – CS – Asymptomatic
Li et al. [68] 5 May 2020 China 1 0 35 2700 CS 1/1 Birth asphyxia, died
Li et al. [69] 2020 China 1 1 38 – CS – –
Liao et al. [70] 26 March 2020 China 1 0 35 – CS – –
Lorenz et al. [71] 12 May 2020 Germany 1 1 40 – VD 9/9 Fever, encephalitis like symptoms, cough
Lowe et al. [72] 15 April 2020 Australia 1 0 40 – VD 9/9 Asymptomatic
Lu et al. [73] 23 April 2020 China 1 0 38 3470 CS 9/9 Asymptomatic
Lyra et al. [74] 20 April 2020 Portugal 1 0 39 3110 CS 8/9 Asymptomatic
Mehta et al. [87] 16 May 2020 USA 1 1 28 925 CS 5/6 Asymptomatic
Munoz et al. [75] 22 April 2020 USA 1 1 36 – – – Hypotension, hypothermia, tachypnoea
Peng et al. [4] 6 April 20 China 1 0 35 2600 CS 9/10 HMD, tachypnoea, apnoea
Perrone et al. [88] 21 May 2020 Italy 1 0 32 – VD – Asymptomatic
Piersigilli et al. [76] 7 May 2020 Belgium 1 1 26 960 CS 5/8 HMD, PDA, pneumothorax
Salik and Mehta [89] 25 May 2020 USA 1 1 37 1900 – – Tetralogy of Fallot
Sharma et al. [77] 20 April 2020 India 1 0 38 – CS – Asymptomatic
Sinelli et al. [78] 1 May 2020 Italy 1 1 – – VD 9/10 RD
Wang et al. [85] 28 February 2020 China 1 0 30 1830 CS 9/10 Asymptomatic
Wang et al. [79] 12 March 2020 China 1 1 40 3205 CS 8/9 Vomiting, lymphopenia, deranged LFT
Wang et al. [90] 22 March 2020 China 1 1 38 3030 VD – Vomiting
Xia et al. [80] 17 March 2020 China 1 0 37 3100 CS 9/10 –
Xiong et al. [81] 7 April 2020 China 1 0 38 3070 VD 9/10 Asymptomatic
Yilmaz et al. [91] 17 May 2020 Turkey 1 0 38 2900 CS 9/10 Asymptomatic
Zamaniyan et al.[82] 17 April 2020 Iran 1 1 32 2350 CS 8/9 Fever
Zambrano et al. [83] 25 March 2020 Honduras 1 0 32 1500 VD – –
Zhou et al. [84] 28 April 2020 China 1 0 37 – CS – –
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CS, caesarean section; HMD hyaline membrane disease; LFT, liver function tests RD, respiratory distress; VD, vaginal delivery.

We identified a total of 58 SARS-CoV-2 RT-PCR-positive neonates. The clinical details, demographics and outcome of these neonates are described in Table 3. Of these 58 neonates, maternal COVID testing details were available for 53 and all were positive for SARS-CoV-2 infection. The perinatal characteristics and clinical features of SARS-CoV-2-positive neonates are summarized in Table 4. Most of the neonates became symptomatic beyond 24 h of birth. Among term neonates, 10 had onset of symptoms in first week (7 on Day 2 of life itself), 3 each in second and third weeks and 4 in fourth week of life. Except one (Meconium aspiration syndrome), none of these term infants had any other neonatal illness to explain the symptoms. In preterm, only one had symptoms on first day, one on second day and rest five had at or beyond Day 7 of life. Among all COVID-positive neonates, 22 (38%) required ICU admission and 10 (17%) were ventilated (invasive and non-invasive). Separate details for invasive and non-invasive ventilation were not available as most except one [71] did not report it clearly.

Table 3.

Clinical details, mode of transmission and outcome of COVID-positive neonates (n=58)

Author Neonates (n) Mother COVID + MOD GA (weeks)/ weight (g) NP swab positive (DOL) NP swab negative (DOL) Direct breast feeding Clinical features ICU stay MV Final outcome Mode of transmission
Aghdam et al. [56] 1 – CS Term/3460 15 – – Fever, mottling, respiratory distress Yes No Discharged Postpartum acquired
Aguilar et al. [57] 1 – – – 26 – Yes Seizures, fever, irritability, watery stools Yes No Discharged Postpartum acquired
Alzamora et al. [58] 1 Yes CS 33/2970 1 – No Respiratory distress Yes Yes – Not assigneda
Buonsenso et al. [15] 2 Yes CS 38/3390 15 – Yes Asymptomatic No No Discharged Postpartum acquired
35/2300 – 1 No Asymptomatic No No Discharged Congenital (confirmed)b
Carosso et al. [60] 1 Yes VD 37/3120 At birth 3 – Asymptomatic No No Discharged Congenitalc
Cook et al. [86] 1 – – 27/– 56 – – Poor feeding, dyspnoea, respiratory failure, shock Yes Yes Admitted Postpartum acquired
Ferrazzi et al. [23] 3 Yes VD – 1 – Yes Asymptomatic – – – Not assigneda
CS – 3 – Yes Asymptomatic – – – Postpartum acquired
VD Term/– 3 – No GI and respiratory Yes Yes – Postpartum acquired
Govind et al. [24] 1 Yes CS 38/4165 – – No Desaturation, fever Yes Yes – Postpartum acquired
Hernández et al. [47] 3 Yes VD Term/3700 2 10 – MAS Yes Yes Discharged Postpartum acquired
Yes VD Preterm/1135 78 84 – – Yes Yes Discharged Postpartum acquired
Yes VD Term/3550 6 13 – Asymptomatic No No Discharged Postpartum acquired
Groß et al. [8] 2 Yes – – 4 – Yes Respiratory distress No No Discharged Postpartum acquired
11 24 Yes Respiratory distress, hypoxia – No Discharged Postpartum acquired
Han et al. [62] 1 Yes VD 38/3730 27 – Yes Fever, cough, vomiting Yes No Discharged Postpartum acquired
Hantoushzadeh et al. [25] 1 Yes CS 30/– 7 – No Pneumonia Yes – Admitted Postpartum acquired
Kayem et al. [44] 2 Yes – – – – – Asymptomatic/hypoxia – – – Details not available
Kirtsman et al. [64] 1 Yes CS 35/2930 At birth 7 Yes Asymptomatic No No Discharged Congenital (probable)d
Knight et al. [49] (individual patient details not available) 6 Yes 2 VD, 4 CS 3 preterm <12 h – – – – – – Not assigneda
3 Term
6 Yes 2 VD, 4 CS 4 preterm >12 h – – – 1 – – Postpartum acquired
2 Term
Li et al. [69] 1 Yes CS 38/– 3 – – Asymptomatic No No Discharged Postpartum acquired
Lorenz et al. [71] 1 Yes VD 40/– 2 – – Lethargy, pneumonia, encephalitis syndrome (fever, seizures, altered sensorium) Yes CPAP Discharged Postpartum acquired
Martinez-Perez et al. [50] 5 Yes CS Term/– 10 – Yes COVID symptoms – – – Postpartum acquired
Yes CS Term/– 10 – Yes COVID symptoms – – – Postpartum acquired
Yes VD Preterm/– 1 2 – Asymptomatic No No – Not assigneda
Yes VD Preterm/– 1 2 – Asymptomatic No No – Not assigneda
Yes CS – 1 2 – Asymptomatic No No – Not assigneda
Mehta et al. [87] 1 Yes CS 28/925 3 – No Asymptomatic Yes No Admitted Postpartum acquired
Munoz et al. [75] 1 – – 36/– 17 – – Hypotension, tachycardia, hypothermia, tachypnoea Yes Yes Discharged Postpartum acquired
Piersigilli et al. [76] 1 Yes CS 26/960 7 21 No HMD, pneumothorax Yes Yes Admitted Postpartum acquired
Pierce-Williams et al. [33] 1 Yes – – 2 – – Asymptomatic – – Discharged Postpartum acquired
Salik and Mehta [89] 1 Yes – 37/1.9 7 13 – Tet spells, tachypnoea, pneumonia Yes Yes – Postpartum acquired
Salvatori et al. [35] 2 Yes – 41/4440 18 – Yes Asymptomatic No No Discharged Postpartum acquired
39/3120 10 – Yes Cough, diarrhoea, poor feeding No No Discharged Postpartum acquired
Sinelli et al. [78] 1 Yes VD Term/– 2 – No Hypoxia, cyanosis, poor sucking Yes No Discharged Postpartum acquired
Sun et al. [36] 1 Yes VD 37/– 6 – No Asymptomatic No – – Postpartum acquired
Wang et al. [90] 1 – VD 38/3030 23 – Yes Vomiting – No Discharged Postpartum acquired
White et al. [53] 2 Yes VD 39 17 – Yes Fever, shock, rhinorrhoea, hypoxia Yes No Discharged Postpartum acquired
Yes CS 39 25 – Yes Fever, rhinorrhoea, desaturation Yes No Discharged Postpartum acquired
Wang et al. [79] 1 Yes CS 40/3205 2 17 Yes Vomiting, deranged LFT, pneumonia No No Discharged Postpartum acquired
Yu et al. [41] 1 Yes CS 39/3250 2 17 – Respiratory distress Yes No Discharged Postpartum acquired
Zamaniyan et al. [82] 1 Yes CS 32/2350 1 – No Fever No No – Congenital (confirmed)e
Zeng et al. [42] 3 Yes CS 40/3250 2 6 – Lethargy, fever Yes No Discharged Postpartum acquired
40/3360 2 6 – Lethargy, vomiting Yes No Discharged Postpartum acquired
31/1580 2 7 – HMD, sepsis Yes Yes Admitted Postpartum acquired
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BPD, bronchopulmonary dysplasia; CS, caesarean section; DOL, day of life; GA, gestational age; ICU, intensive care unit; MAS, meconium Aspiration syndrome; MOD, mode of delivery; NP, nasopharyngeal swab; VD, vaginal delivery.

a

NP swab positive on Day 1 but other tests not done, so difficult to tell whether it was congenital/intrapartum or postpartum.

b

Placenta, umbilical cord blood and breast milk positive, baby’s NP swab-negative.

c

Same NP sample negative at 37 h. Placenta-negative, SARS-CoV-2 IgG antibodies positive.

d

NP swab taken at birth and placental swab (foetal side) positive.

e

Amniotic fluid PCR positive.

Table 4.

Summary of perinatal characteristics and clinical symptoms of COVID-positive neonates (n=58)

Parameters Number (%)
Gestational age
 Term (≥37 weeks) 29 (50)
 Preterm (<37 weeks) 20 (34.4)
  ≥28 weeks 3 (5.2)
  29–33 weeks 4 (6.9)
  34–36 weeks 3 (5.2)
  Exact gestation not given 10 (17.2)
Details not available 9 (15.5)
Mode of delivery
 Vaginal 18 (31)
 Caesarean 29 (50)
Details not available 11 (19)
Mode of transmission
 Congenital 4 (6.9)
 Postpartum acquired 41 (70.7)
 Intrapartum acquired 0 (0)
Could not assigned 13 (22.4)
Clinical features
 Asymptomatic 13 (22.4)
 Fever 9 (15.5)
 Respiratory symptoms (respiratory distress/hypoxia/ desaturation/cough, etc.) 24 (41.4)
 Gastrointestinal symptoms 5 (vomiting—4 and diarrhoea—1) (8.6)
 Lethargy 3 (5.2)
 Poor feeding 3 (5.2)
Details not available 13 (22.4)
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The outcome (discharge/death) has been reported for 31 neonates of which 26 have been discharged to home and 5 were still admitted. No mortality has been reported in SARS-CoV-2-infected neonates.

Mode of transmission

To understand the mode of transmission as well as to maintain the uniformity in reporting we classified the SARS-CoV-2-infected neonates into various categories [13]. Of these 58 live-born SARS-CoV-2 cases, 4 (7%) were congenital in origin (2 confirmed, 1 probable and 1 not sure), 41 were acquired in the postpartum period and the remaining 13 neonates could not be classified due to non-availability of complete details.

SARS-CoV-2 secretion in breast milk

A few studies tested breast milk for the SARS-CoV-2 virus and have reported conflicting results [3, 6, 8, 19, 37, 64]. Initial studies did not find any SARS-CoV-2 RNA in breast milk [3, 6, 19, 22, 67, 69]. However, recently few authors reported detection of SARS-CoV-2 in breast milk [8, 37, 64].

DISCUSSION

This review summarizes the perinatal characteristics, clinical features and outcome of RT-PCR proven SARS-CoV-2 infection in neonates. As described previously, the total number of reported paediatric cases is quite less than the adults of which the neonates are just a handful. Most of the reported neonatal infections are acquired in the postpartum period, and the overall prognosis is excellent.

Unlike older children and adults in which most of the infections are clinically asymptomatic, two-thirds of the neonatal cases were symptomatic [94]. As given in results, most of the neonates were clinically well before appearance of symptoms, suggesting that these symptoms are unlikely to be due to the prematurity or other non-COVID illness. Similar to the children and adults, respiratory symptoms were the predominant manifestations in neonates too, however, unlike them, fever was seen in one-fifth of the cases only [94–96]. Like older children, about 10% of the neonates had gastrointestinal manifestations, and the overall prognosis of SARS-CoV-2 infection in neonates is better than adults [94–97]. Although the frequency of SARS-CoV-2-positive neonates is extremely low, a significant proportion of the affected neonates requiring intensive care and mechanical ventilation suggests that the disease in neonates is more severe than older children [96–98].

Although the protective effect of caesarean section against SARS-CoV-2 transmission to neonate lacks evidence and most of the guidelines advise to reserve a caesarean section for obstetric indication only, the proportion of caesarean section was much more than vaginal deliveries [99, 100]. Higher rates for caesarean delivery may be due to either clinician preference or maternal sickness or comorbidities. Due to population-based differences in mode of delivery like Chinese having preference for caesarean section even in non-COVID pregnancies, we analysed the data as per country of origin of the study [101]. Caesarean section rate for COVID-19 pregnancies in China was found to be as high as 86% when compared with 53% in other countries. Also, data suggest an overall preference for caesarean delivery worldwide.

Many studies have highlighted the association of COVID-19 and increased preterm deliveries [5, 23]. In our review also about one-fourth of the neonates were born premature, which is much more than overall global (10.6%) and China’s (6.9%) preterm birth rate [102]. The exact reason for the higher preterm birth rate could not be delineated from this review.

Since the beginning of the pandemic, there is a debate about vertical transmission of SARS-CoV-2 infection. Early reports from China suggested that the intrauterine vertical transmission is unlikely [3–6, 9]. However, the detection of antibodies in cord blood and neonate raised concerns [7]. Ideally, to prove a vertical transmission, testing of placental tissue, amniotic fluid before rupture of membranes, umbilical cord blood, neonatal blood in the first 12 h and neonatal throat/nasopharyngeal swab for RT-PCR in the immediate postpartum period are recommended [13]. Initial studies that tested all these specimens did not find any evidence to suggest vertical transmission [22, 41, 85]. However, recently published reports suggest otherwise [15, 60, 64, 82]. Lack of intrapartum transmission in this review suggests that vaginal delivery may not be a risk factor for COVID-19 transmission to the neonate and it has been supported by many studies documenting the absence of SARS-CoV-2 in vaginal secretions [37, 103]. However, the intrapartum transmission cannot be ruled out with certainty as its diagnosis requires neonate’s nasopharyngeal swab testing immediately after birth (after cleaning the baby) and at 24–48 h age. However, in most reports, neonates were first tested beyond 24–48 h after birth. Also, recently SARS-CoV-2 has been documented in vaginal secretions too [64]. Overall, evidence suggests that congenital infection is possible but the incidence is extremely low and most of the cases are acquired in the postpartum period only.

Although the separation of COVID-19-positive mother from the infant might decrease the risk of postpartum transmission, it deprives the neonate of the benefits of breastfeeding. Although earlier studies advocated the safety of breast milk, detection of SARS-CoV-2 RNA from breast milk in recent studies is of concern [3, 6, 8, 19, 22, 37, 64, 67, 79, 104]. Further exploration of the safety of breast milk feeding is warranted [8, 37, 64]. As of now, considering the huge survival benefits of breast milk feeding against unknown potential threat associated with SARS-CoV-2 transmission, breast milk feeding (direct or expressed) should be given to the infants as and when the clinical condition of mother and baby permits. Mother should take adequate respiratory and hand hygiene precautions.

A number of organizations have established registries for a better understanding of COVID-19 in pregnancy and the neonatal period; however, generally their data are not available in the public domain. Data summary from the National registry for surveillance and epidemiology of perinatal COVID-19 infection (NPC-19 registry) maintained by the neonatal group of the American Academy of Pediatrics (AAP) is open to public [105]. Until 13 June 2020, there were 176 participating centres from all across the world and they enrolled 747 COVID-19-positive mothers. COVID testing was done for 624 only, of which 25 (4%) were positive. They did not provide separate data on the clinical course and outcome of COVID-positive neonates. This registry includes published and unpublished cases from various countries.

We used an extensive search strategy without any language restrictions in order to capture a global picture of COVID-19. When compared with previous reviews in which almost all the studies were from China, this review contains studies from many other countries [2, 106, 107]. Therefore, the results are likely to be representative of larger population. We included the neonatal age group only because the detailed information on clinical features, mode of transmission and outcome in this age group were lacking. To ensure uniformity, we included studies reporting RT-PCR-based diagnosis of COVID-19 only and classified cases using an explicit standard classification system [13]. This review also has several limitations too. The main limitation arises from the nature of the included studies. One-third of the neonatal data is from the case reports which are expected to have high publication bias and are not suitable for inferential statistics. Also, the included case series lack internal controls and represent low-quality evidence. Furthermore, the information on indications for preterm birth and caesarean section was not reported. There is a paucity of data on mode of transmission as only a few studies tested all the required maternal and foetal samples to ascertain the mode of transmission. Although we used structured exhaustive criteria to assign the mode of transmission, but due to limited numbers, inadequate testing of required specimens and lack of standard criteria for classifying the mode of transmission, it is difficult to assign the mode of transmission with certainty. Although we followed an extensive process to exclude duplicates, the possibility of a case report later published as a part of a larger retrospective cohort cannot be ruled out with certainty.

However, given the urgency of the situation and lack of large prospective cohort studies, it would still be valuable to synthesize and critically analyse these data for future case management as well as in the planning of further studies. Also, substantial data from various registries are expected in the future which may guide us better in understanding the disease and its management.

CONCLUSIONS

The limited low-quality evidence suggests an extremely low risk of SARS-CoV-2 infections in neonates. Unlike children most of the neonates with proven SARS-CoV-2 infection were symptomatic, and a significant proportion of them required intensive care. Postpartum infection is the commonest mode of acquisition in neonates, although a few cases of congenitally acquired infection are also reported.

SUPPLEMENTARY DATA

Supplementary data are available at Journal of Tropical Pediatrics online.

Conflict of interest: All authors declare no competing interests.

Supplementary Material

fmaa059_Supplementary_Data
Click here for additional data file. (15.5KB, docx)

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