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Maternal and perinatal outcomes in pregnant women infected by SARS-CoV-2: A meta-analysis

Published:November 13, 2020DOI:https://doi.org/10.1016/j.ejogrb.2020.11.038

      Highlights

      • Severe disease is not common in both pregnant women and neonates.
      • Perinatal transmission occurs rarely and may not be linked to disease severity.
      • Vertical transmission has been assumed in 4 cases.
      • Transmission risk is low when the infection manifests during the third trimester.
      • Further research should provide evidence about the risk of congenital infection.

      Abstract

      Evidence concerning coronavirus disease-19 (covid-19) in pregnancy is still scarce and scattered. This meta-analysis aims to evaluate maternal and neonatal outcomes in covid-19 pregnancies and identify factors associated with perinatal viral transmission. Medline, Scopus, CENTRAL, Web of Science and Google Scholar databases were systematically searched to 3 June 2020. Overall, 16 observational studies and 44 case reports/series were included. Fever was the most frequent maternal symptom, followed by cough and shortness of breath, while about 15 % of infected were asymptomatic. Severe disease was estimated to occur in 11 % of women in case reports/series and in 7 % (95 % CI: 4 %–10 %) in observational studies. Two maternal deaths were reported. The rate of neonatal transmission did not differ between women with and without severe disease (OR: 1.94, 95 % CI: 0.50–7.60). Preterm birth occurred in 29.7 % and 16 % (95 % CI: 11 %–21 %) in data obtained from case series and observational studies, respectively. Stillbirth occurred in 3 cases and 2 neonatal deaths were observed. Vertical transmission was suspected in 4 cases. Fever was the most common neonatal symptom (40 %), followed by shortness of breath (28 %) and vomiting (24 %), while 20 % of neonates were totally asymptomatic. In conclusion, the maternal and neonatal clinical course the infection is typically mild, presenting low mortality rates. The risk of vertical transmission is suggested to be low and may not be affected by the severity of maternal disease. Further large-scale studies are needed to clarify the risk factors associated with viral transmission and severe infection in the neonatal population.

      Keywords

      Introduction

      COVID-19 (coronavirus disease 2019) is an emerging infectious disease, first reported in Wuhan, Hubei region, Canhina, in December 2019 [
      • World Health Organization
      WHO | Pneumonia of unknown cause – China.
      ]. It is caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) which is a single-stranded RNA virus, subgenus Sarbecovirus of the genus Betacoronavirus, probably originated from bats [
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      Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
      ]. COVID-19 rapidly triggered a global health emergency alert and spread to numerous countries, causing the WHO to announce the start of a new pandemic on 12 March 2020 [
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      WHO announces COVID-19 outbreak a pandemic.
      ,
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      • Pandita A.
      • Pillai A.
      • Badatya S.K.
      Perinatal COVID-19: review of current evidence and practical approach towards prevention and management.
      ]. According to the 24th April 2020 WHO bulletin, 2626321 confirmed cases and 181938 deaths have occurred globally so far [].
      Data concerning pregnant women and neonates is still scarce and scattered and evidence regarding management of pregnancy, delivery and neonates in case of suspected or confirmed COVID-19 diagnosis in either the mother or the offspring remains fragmented [
      • Della Gatta A.N.
      • Rizzo R.
      • Pilu G.
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      COVID19 during pregnancy: a systematic review of reported cases.
      ,
      • Zaigham M.
      • Andersson O.
      Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies.
      ]. To date, the incidence of COVID-19 intended as a positive nasopharyngeal swab for SARS-CoV-2 in newborn babies is roughly 1.5 % [
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      A systematic scoping review of COVID-19 during pregnancy and childbirth.
      ] and neonatal symptoms, such as mild respiratory distress and transient thrombocytopenia, seems mainly related to late prematurity or elective C-sections due to severe maternal conditions, rather than to the neonatal infection itself [
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      • Moretti C.
      • Mosca F.
      Breastfeeding and coronavirus disease-2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies.
      ]. Although horizontal transmission seems predominant not only in adulthood but also in infancy and childhood, the shortage of data regarding pregnancies impede to draw conclusions about vertical transmission, which seems rare but still possible [
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      ]. The new challenge for obstetricians and neonatologists during the SARS-CoV-2 pandemic is to find a balance between implementing special measures to ensure the safety of both patients and healthcare providers and encouraging bonding and interaction between the newborn and the mother. Moreover, some questions are still to be addressed, such as the effects of SARS-CoV-2 infection during the first trimester of pregnancy or the causes underlying the apparent lower incidence and severity of COVID-19 in neonates born to affected mothers.
      The purpose of the present study is to systematically accumulate current literature knowledge in the field and evaluate maternal and perinatal outcomes among pregnant women infected by SARS-CoV-2. In this line, this meta-analysis aims to shed light on the transmission pattern of the virus to neonates, as well as to clarify the disease course of COVID-19 infection in this specific population.

      Materials and methods

      Study design

      This meta-analysis was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [
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      ]. The process of study selection was performed in 3 consecutive stages. The titles or abstracts of all electronic articles were initially screened to evaluate their potential eligibility and subsequently, all articles that were presumed to meet the pre-defined eligibility criteria were retrieved as full-texts papers. At the final stage, all studies that were in accordance with the inclusion criteria and did not meet any of the exclusion criteria were included in the present review. Study selection, data collection, quality assessment and data analysis were planned to be independently conducted by two researchers (IB and AP), while any potential discrepancies were resolved by the consensus of all authors.

      Eligibility criteria

      Both observational studies and case reports or case series were included in the present meta-analysis. Studies were deemed eligible if they reported clinical outcomes of neonates born to mothers infected by SARS-CoV-2, as well as of infected neonates independently of maternal infection status. When the same cases were suspected to be both included in case reports and an observational study, the latter one was only included in the analysis. Deduplication of studies was performed by two researchers (IB and AP) and any disagreements were resolved through their consensus. On the other hand, studies not reporting any perinatal outcomes of infected pregnant women and those examining exclusively infants after 28 days of life were excluded from the present study. Moreover, review articles, conference proceedings/abstracts, animal and in vitro studies, as well as unpublished data from clinical registries were not included.

      Literature search

      The literature search was conducted using the Medline, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science databases. Google Scholar database and the full-list of all the included studies (“snowball” method11), were also screened to identify potential additional papers. Search was performed from inception to 3 June 2020 and was based on the following algorithm: “("Coronavirus"[Mesh] OR "COVID-19” [Supplementary Concept] OR "SARS Virus"[Mesh] OR sars-cov OR covid OR novel coronavirus) AND ("Pregnancy"[Mesh] OR "Infant, Newborn"[Mesh] OR pregnan* OR neonat* OR infant* OR newborn). No language restrictions were applied during literature search.

      Data extraction

      The following data were planned to be extracted from each of the included studies: name of first author, country, maternal age, medical history (diabetes mellitus, hypothyroidism or polycystic ovary syndrome), symptoms (fever, cough, shortness of breath, diarrhea, nausea/vomiting, myalgia, fatigue, headache, sore throat, nasal congestion, abdominal pain, chest pain), radiological signs, presence of co-infection (bacterial or influenza), laboratory tests (lymphopenia, thrombocytopenia, increased C-reactive protein, procalcitonin, ferritin, liver function tests and d-dimers), type of treatment, pregnancy outcomes (fetal distress, premature rupture of membranes-PROM, placenta previa, preeclampsia, preterm birth, cesarean section, stillbirth), maternal outcomes (admission to intensive care unit-ICU or death), neonatal outcomes (gender, gestational age, birthweight, 1-minute/5-minute Apgar score, horizontal/vertical transmission, admission to ICU, mechanical ventilation, sepsis and death).

      Quality assessment

      Observational studies of incidence data were evaluated by taking into account the following parameters: sample frame, representativeness and size, subjects and setting, coverage bias, classification bias, outcome measurement, statistical analysis and response rate [
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      • Moola S.
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      ]. The quality of case reports and case series was assessed by judging the potential risk of bias concerning the domains of selection, ascertainment, causality and reporting [
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      Methodological quality and synthesis of case series and case reports.
      ]. For each domain, “Major concerns”, “Some concerns” or “No concerns” of bias risk were assigned independently by two researchers, while any disagreements were resolved by discussion with all authors.

      Data analysis

      The pooled analysis was separately performed for case reports/series which provided individual participant data and observational studies reporting aggregate data. Regarding the analysis of case reports/series, descriptive statistics were calculated and cases were categorized depending on the transmission of SARS-CoV-2 in neonates. Subsequently, maternal characteristics and perinatal outcomes were compared between the two groups. Continuous variables were expressed as median and interquartile range, while the Mann-Whitney U test was implemented to test differences in medians [
      • J W
      Testing for differences with the nonparametric Mann-Whitney U test.
      ]. The comparison of categorical variables was performed using the chi-squared or the Fisher's exact test [
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      Statistical notes for clinical researchers: Chi-squared test and Fisher’s exact test.
      ]. Multivariate logistic regression analysis was performed to assess the relative importance of maternal factors (country, age, comorbidities, symptoms and pregnancy complications) in the prediction of perinatal transmission. Statistical significance was defined as p-value <0.05. Missing data were treated by pair-wise deletion [
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      The prevention and handling of the missing data.
      ].
      Pooling of observational studies was performed by proportion meta-analysis using a random-effects (DerSimonian-Laird) model [
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      Meta-analysis in clinical trials.
      ]. Confidence intervals (CI) were set at 95 %. Inter-study heterogeneity was quantified by calculating the inconsistency index (I2), with values >50 % denoting significant heterogeneity [
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      ]. Publication bias was assessed by the visual inspection of funnel plots and the potential presence of asymmetry was evaluated by the Egger’s regression test [
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      ]. The cut-off of p-value <0.10 was used to define the significance of Egger’s regression test. In case of small-study effects suspicion, the trim-fill method was implemented to provide new estimates accounting for statistically imputed missing studies [
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      The trim-and-fill method for publication bias.
      ]. Meta-regression analysis was used to evaluate the potential influence of country (China vs. other). In case of statistically significant outcomes, subgroup analysis was performed to assess the exact effects of study country. Statistical analysis was conducted in R-3.6.3 (“metafor” [
      • Viechtbauer W.
      Conducting Meta-Analyses in R with the metafor Package.
      ] package).

      Results

      Study selection

      The outcomes of the literature search are schematically illustrated in Fig. 1. Overall, 1,705 records were identified and 1,274 of them were initially screened after removal of duplicates. The majority of them were then excluded for not meeting the eligibility criteria and thus a cohort of 64 articles was retrieved as full-texts. Subsequently, 4 studies [
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      A pregnant woman with COVID-19 in Central America.
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      Covid-19: Nine in 10 pregnant women with infection when admitted for delivery are asymptomatic, small study finds.
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      A pregnant woman with COVID-19 in Central America.
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      Covid-19: Nine in 10 pregnant women with infection when admitted for delivery are asymptomatic, small study finds.
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      Managing COVID-19-Positive maternal–infant dyads: an italian experience.
      ], including a total of 920 neonates born to women with SARS-CoV-2 infection.

      Quality assessment

      The outcomes of risk of bias evaluation are summarized in Appendix 1 (Suppl. Tables 1, 2). Concerning case reports/series, concerns of bias were mainly raised in the domains of ascertainment and reporting due to missing data about exposure and outcomes, while some concerns were assigned in the domain of causality in 3 studies due to inadequate description of maternal baseline characteristics and comorbidities. On the other hand, evaluation of observational studies raised concerns mainly in the domain of sample size, while moderate risk of classification bias may have arisen from studies defining SARS-CoV-2 infection based exclusively on clinical or radiological criteria.

      Outcomes of case reports/series

      The maternal and perinatal outcomes of pregnancies infected by SARS-Cov-2 are presented in Appendices 2–3 (Suppl. Tables 3–4). Overall, 158 cases were included in the individual participant data meta-analysis and the majority of them came from China (91.1 %). The median age of women was 30 years and the most common comorbidity was hypothyroidism (4.9 %). Fever was the most frequent symptom (69.4 %), followed by cough (35 %) and shortness of breath (10.8 %), while 13.4 % of women with the disease were asymptomatic. The vast majority of cases presented radiological signs of pneumonia (98.6 %). Co-infection with influenza virus was uncommon (1.9 %), while bacterial super-infection occurred in 5.1 % of patients. Concerning laboratory tests, lymphopenia and thrombocytopenia were found in 48.3 % and 27.8 % of cases, respectively, while the majority of women presented increased C-reactive protein (69.7 %) and procalcitonin (60.9 %). Serum ferritin and D-dimers were sparsely reported, although when tested, their values were found to be elevated in 58.3 % and 72.2 % of cases, respectively. Treatment options included the administration of hydroxychloroquine (6.3 %), azithromycin (9.9 %), antiviral agents, such as oseltamivir (20.7 %), umifenovir (22.5 %), lopinavir/ritonavir (5.4 %) and interferon (12.6 %), as well as various antimicrobial agents (38.7 %).
      The majority of neonates were delivered by cesarean section (83.5 %), with preterm birth (<37 weeks) occurring in 29.7 % of cases. Other pregnancy complications included premature rupture of membranes (9.5 %), fetal distress (6.1 %), preeclampsia (5.4 %) and placenta previa (2.7 %). Moreover, 17 women (11 %) developed severe disease and were admitted to ICU, while 2 of them (1.3 %) eventually died (Table 1). The median gestational age at delivery was 38 weeks, while the median birthweight was estimated to be 3120 g with 7.9 % of neonates being small-for-gestational age. In addition, stillbirth occurred in 3 cases and 2 neonatal deaths were observed (Table 2). Both neonatal deaths occurred in SARS-CoV-2-negative neonates that were born to mothers with severe disease requiring admission to the ICU.
      Table 1Maternal clinical characteristics and outcomes among pregnancies with and without transmission to neonates. Continuous variables are expressed as median [interquartile range].
      Maternal characteristicsAll patients (N = 158)Transmissionp-value
      Yes (N = 17)No (N = 141)
      China144/158 (91.1 %)13/17 (76.5 %)131/141 (92.9 %)0.072
      Age (years)30 [
      • Pereira A.
      • Cruz‐Melguizo S.
      • Adrien M.
      • Fuentes L.
      • Marin E.
      • Perez‐Medina T.
      Clinical course of coronavirus disease‐2019 in pregnancy.
      ,
      • Knight M.
      • Bunch K.
      • Vousden N.
      • Morris E.
      • Simpson N.
      • Gale C.
      • et al.
      Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study.
      ,
      • Savasi V.M.
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      • Ferrazzi E.
      • Frigerio L.
      • Pellegrino A.
      • et al.
      Clinical findings and disease severity in hospitalized pregnant women with coronavirus disease 2019 (COVID-19).
      ,
      • Lokken E.M.
      • Walker C.L.
      • Delaney S.
      • Kachikis A.
      • Kretzer N.M.
      • Erickson A.
      • et al.
      Clinical characteristics of 46 pregnant women with a SARS-CoV-2 infection in Washington State.
      ,
      • Lantz B.
      The impact of sample non-normality on ANOVA and alternative methods.
      ,
      • Schober P.
      • Boer C.
      • Schwarte L.A.
      Correlation coefficients: appropriate use and interpretation.
      ]
      32.5 [28.25–34]30 [29–33.25]0.558
      History
       Diabetes mellitus3/122 (2.5 %)1/10 (10 %)2/112(1.8 %)0.228
       Hypothyroidism6/122 (4.9 %)4/10 (40 %)2/112 (1.8 %)<0.001
       Polycystic ovary syndrome1/122 (0.8 %)0/10 (0 %)1/112 (0.9 %)1
      Symptoms
       Asymptomatic21/157 (13.4 %)1/16 (6.3 %)20/141 (14.2 %)0.698
       Fever109/157 (69.4 %)12/16 (75 %)97/141 (68.8 %)0.778
       Cough55/157 (35 %)6/16 (37.5 %)49/141 (34.8 %)0.790
       Shortness of breath17/157 (10.8 %)4/16 (25 %)13/141 (9.2 %)0.076
       Diarrhea12/157 (7.6 %)2/16 (12.5 %)10/141 (7.1 %)0.352
       Nausea / vomiting2/157 (1.3 %)1/16 (6.3 %)1/141 (0.7 %)0.194
       Myalgia6/157 (3.8 %)2/16 (12.5 %)4/141 (2.8 %)0.115
       Fatigue15/157 (9.6 %)2/16 (12.5 %)13/141 (9.2 %)0.652
       Sore throat11/157 (7.0 %)1/16 (6.3 %)10/141 (7.1 %)1
       Nasal congestion4/157 (2.8 %)1/16 (6.3 %)3/141 (2.1 %)0.352
       Headache4/157 (2.8 %)0/16 (0 %)4/141 (2.8 %)1
       Abdominal pain2/157 (1.3 %)0/16 (0 %)2/141 (1.4 %)1
       Chest pain3/157 (1.9 %)0/16 (0 %)3/141 (2.1 %)1
      Radiology
       Signs of pneumonia145/147 (98.6 %)16/16 (100 %)129/131 (98.5 %)1
      Co-infection
       Bacterial8/158 (5.1 %)1/16 (6.3 %)7/141 (4.9 %)0.587
       Influenza3/158 (1.9 %)0/16 (0 %)3/141 (2.1 %)1
      Laboratory tests
       Lymphopenia43/89 (48.3 %)5/7 (71.4 %)38/82 (46.3 %)0.256
       Thrombocytopenia10/36 (27.8 %)2/3 (66.7 %)8/33 (24.2 %)0.181
       Increased C-reactive protein46/66 (69.7 %)5/5 (100 %)41/61 (67.2 %)0.312
       Increased procalcitonin14/23 (60.9 %)1/2 (50 %)13/21 (61.9 %)1
       Increased ferritin7/12 (58.3 %)2/2 (100 %)5/10 (50 %)0.470
       Increased liver function tests19/76 (25 %)1/6 (16.7 %)18/70 (25.7 %)1
       Increased d-dimers26/36 (72.2 %)2/2 (100 %)24/34 (70.6 %)1
      Treatment
       Hydroxychloroquine7/111 (6.3 %)2/8 (25 %)5/103 (4.9 %)0.080
       Azithromycin11/111 (9.9 %)2/8 (25 %)9/103 (8.7 %)0.180
       Oseltamivir23/111 (20.7 %)2/8 (25 %)21/103 (20.4 %)0.669
       Umifenovir25/111 (22.5 %)1/8 (12.5 %)24/103 (23.3 %)0.681
       Lopinavir / ritonavir6/111 (5.4 %)1/8 (12.5 %)5/103 (4.9 %)0.369
       Interferon14/111 (12.6 %)2/8 (25 %)12/103 (11.7 %)0.265
       Antimicrobial43/111 (38.7 %)6/8 (75 %)37/103 (35.9 %)0.053
      Complications
       Fetal distress9/148 (6.1 %)0/17 (0 %)9/131 (6.9 %)0.599
       Premature rupture of membranes14/148 (9.5 %)1/17 (5.9 %)13/131 (9.9 %)1
       Placenta previa4/148 (2.7 %)0/17 (0 %)4/131 (3 %)1
       Preeclampsia8/148 (5.4 %)1/17 (5.9 %)7/131 (5.3 %)1
       Preterm birth47/158 (29.7 %)2/17 (11.8 %)45/141 (31.9 %)0.099
       Cesarean section132/158 (83.5 %)16/17 (94.1 %)116/141 (82.3 %)0.310
       Admission to ICU17/155 (11 %)3/17 (17.6 %)14/141 (9.9 %)0.398
       Death2/155 (1.3 %)1/16 (6.3 %)1/141 (0.7 %)0.196
      Bold text indicates statistical significance. ICU: intensive care unit.
      Table 2Clinical characteristics of infected and non-infected neonates. Continuous variables are expressed as median [interquartile range].
      Neonatal characteristicsAll neonates (N = 158)Transmissionp-value
      Yes (N = 17)No (N = 141)
      Male gender52/77 (67.5 %)8/12 (66.7 %)44/65 (67.7 %)1
      Gestational age (weeks)38 [36–39.1]40 [35.35–40]38 [
      • KDIGO
      Chapter 2: Definition, identification, and prediction of CKD progression.
      ,
      • Romagnani P.
      • Remuzzi G.
      • Glassock R.
      • Levin A.
      • Jager K.J.
      • Tonelli M.
      • et al.
      Chronic kidney disease.
      ,
      US renal data system 2016 annual data report: epidemiology of kidney disease in the United States.
      ,
      • Mathew R.O.
      • Bangalore S.
      • Lavelle M.P.
      • Pellikka P.A.
      • Sidhu M.S.
      • Boden W.E.
      • et al.
      Diagnosis and management of atherosclerotic cardiovascular disease in chronic kidney disease: a review.
      ]
      0.111
      Birthweight (g)3120 [2692–3370]3228 [2852–3278]3100 [2692–3400]0.906
      Small-for-gestational age10/127 (7.9 %)2/12 (16.7 %)8/114 (7 %)0.243
      1-minute Apgar score9 [
      • Davanzo R.
      • Moro G.
      • Sandri F.
      • Agosti M.
      • Moretti C.
      • Mosca F.
      Breastfeeding and coronavirus disease-2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies.
      ,
      • De Rose D.U.
      • Piersigilli F.
      • Ronchetti M.P.
      • Santisi A.
      • Bersani I.
      • Dotta A.
      • et al.
      Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.
      ]
      8 [6.5–9]9 [
      • Davanzo R.
      • Moro G.
      • Sandri F.
      • Agosti M.
      • Moretti C.
      • Mosca F.
      Breastfeeding and coronavirus disease-2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies.
      ,
      • De Rose D.U.
      • Piersigilli F.
      • Ronchetti M.P.
      • Santisi A.
      • Bersani I.
      • Dotta A.
      • et al.
      Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.
      ]
      0.077
      5-minute Apgar score10 [
      • De Rose D.U.
      • Piersigilli F.
      • Ronchetti M.P.
      • Santisi A.
      • Bersani I.
      • Dotta A.
      • et al.
      Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.
      ,
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ]
      9 [8.5–10]10 [
      • De Rose D.U.
      • Piersigilli F.
      • Ronchetti M.P.
      • Santisi A.
      • Bersani I.
      • Dotta A.
      • et al.
      Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.
      ,
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ]
      0.111
      Stillbirth3/158 (1.9 %)1/17 (6.25 %)2/141 (1.4 %)0.291
      Neonatal death2/158 (1.3 %)0/17 (0 %)2/141 (1.4 %)1
      Transmission of SARS-CoV-2 was confirmed in 17 cases. The maternal characteristics and perinatal outcomes were similar between pregnancies with and without viral transmission, with the exception of maternal hypothyroidism (Odds ratio: 36.67, 95 % CI: 5.56–241.69). Multivariate regression analysis indicated that hypothyroidism was the only factor associated with increased perinatal transmission (p-value: 0.004), while no association was found for maternal age, other comorbidities, symptoms or pregnancy complications. Importantly, the rate of neonatal transmission did not differ between women admitted to the ICU and those with the non-severe form of the disease (OR: 1.94, 95 % CI: 0.50–7.60) (Table 1). Vertical transmission was assumed to occur in 4 cases [
      • Peng Z.
      • Wang J.
      • Mo Y.
      • Duan W.
      • Xiang G.
      • Yi M.
      • et al.
      Unlikely SARS-CoV-2 vertical transmission from mother to child: a case report.
      ,
      • Alzamora M.C.
      • Paredes T.
      • Caceres D.
      • Webb C.M.
      • Valdez L.M.
      • La Rosa M.
      Severe COVID-19 during pregnancy and possible vertical transmission.
      ,
      • Lingkong Z.
      • Xuwei T.
      • Wenhao Y.
      • Jin W.
      • Xin L.
      • Zhisheng L.
      First case of neonate with COVID-19 in China.
      ,
      • Shuo C.
      • Bo H.
      • Danju L.
      • Xiang L.
      • Fan Y.
      • Yin Z.
      • et al.
      Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases.
      ] due to positive placental/amniotic fluid SARS-CoV-2 polymerase chain reaction (PCR) testing or detection of neonatal IgM antibodies against the virus shortly after delivery. Possible vertical transmission was also suspected in 6 cases due to immediate strict neonatal isolation, although direct evidence was lacking. No neonates born to SARS-CoV-2-positive mothers were breastfed, due to concerns of potential transmission. However, the presence of SARS-CoV-2 in breast milk was tested in 27 cases and all samples were negative. Stool samples were tested in 23 neonates with SARS-CoV-2 being detected in 5 of them (21.7 %). The clinical characteristics of SARS-CoV-2-positive neonates are presented in Table 3. Fever was the most common symptom (40 %), followed by shortness of breath (28 %) and vomiting (24 %), while 20 % of neonates were totally asymptomatic. The outcomes of complete blood count were reported for 8 cases; 2 of them presented lymphopenia and another 2 thrombocytopenia. Moreover, two neonates needed mechanical ventilation, while another one received noninvasive positive pressure ventilation. Neonatal sepsis occurred in two patients and one of them developed septic shock requiring inotropic support, although survived, was extubated and finally discharged.
      Table 3Clinical outcomes of neonates infected by SARS-CoV-2.
      Author; CountryGestational age (w)Birthweight (g)DeliverySymptomsPneumoniaLymphopenia/ ThrombocytopeniaIncreased CRP/PCTTreatmentNICU admissionMechanical ventilationCPAP/ NIPPVDuration of respiratory support (days)SepsisShockInotropesNeonatal deathFollow-up (days)
      Yu N.; China403250CesareanSOBYesNR/NRNR/NRNoNoNoNoNoNoNoNo40
      Zamaniyan M; Iran30.72350CesareanFeverNoNR/NRNR/NRAmpicillin, gentamicinYesNoNoNoNoNoNo7+
      Alzamora MC; Peru332970CesareanCough, SOBNoNR/NRNR/NRNoYesYesCPAP0.5NoNoNoNo6+
      Wang S; China403205CesareanNoYesNR/NRNR/NRNoNoNoNoNoNoNoNo15
      Dong L; China37.73120CesareanNoNoNo/NoNo/NRNoYesNoNoNoNoNoNo25
      Zeng L; China403250CesareanFeverYesNo/NoNo/YesNRYesNoNoNoNoNoNo6+
      40.63360CesareanFeverYesYes/NoNR/NRNRNoNoNoNoNoNoNo6+
      31.31580CesareanSOBYesYes/NoNR/NRNRYesNoNIPPV14YesNoNoNo14+
      Aghdam MK; IranNR3460CesareanFever, coughNoNo/NoNo/NRVancomycin, amikacin, oseltamivirYesNoNoYesNoNoNo14+
      Zhang ZJ; China40NRCesareanSOBYesNR/NRNR/NRNoNoNoNoNoNoNoNoNR
      NRNRCesareanFever, cough, vomitingYesNR/NRNR/NRNoNoNoNoNoNoNoNo23
      NRNRCesareanFeverNoNR/NRNR/NRNoNoNoNoNoNoNoNo30
      40.1NRCesareanNoYesNR/NRNR/NRNoNoNoNoNoNoNoNo16
      Coronado Munoz; USA36NRNRNasal congestion, SOB, feeding intoleranceYesNo/NoYes/YesAmpicillin, gentamycin, vancomycin, cefepime, hydroxychloroquine, azithromycinYesYesNo5YesYesYesNo9
      Khan S; China40.63360CesareanNRNoNR/NRNR/NRNRNRNRNRNRNRNRNRNoNR
      39.13570CesareanNRYesNR/NRNR/NRNRNRNRNRNRNRNRNRNoNR
      Hu X; China403250CesareanNoNoNo/NoNo/NoNoNoNoNoNoNoNoNoNR
      Salvatori G; Italy41.34440NRNoNoNR/NRNR/NRNoNoNoNoNoNoNoNoNR
      393120NRCough, diarrheaNoNR/NRNR/NRNoNoNoNoNoNoNoNo5+
      Alonso Diaz C; Spain38.62500CesareanSOBYesNR/NRNo/NRNoYesNoNoNoNoNoNo13
      Zeng LK; China39NRNRFever, SOB, vomitingYesNo/NoNo/YesNoNoNoNoNoNoNoNo7
      Wang J; China38.63030VaginalFever, cough, vomitingYesNo/YesNo/NoInterferonNoNoNoNoNoNoNo14
      Xiaoyuan F; ChinaNRNRNRFever, vomitingNoNR/NRNR/NRAntimicrobialNoNoNoNoNoNoNo16
      NRNRNRVomitingNoNR/NRNR/NRNoNoNoNoNoNoNoNo16
      NRNRNRDiarrhea, vomitingYesNR/NRNR/NRNoNoNoNoNoNoNoNo15
      NRNRNRFeverYesNR/NRNR/NRAntimicrobialNoNoNoNoNoNoNo13
      NRNRNRFeeding intoleranceYesNR/NRNR/NRNoNoNoNoNoNoNoNo7
      NR: not reported; CRP: C-reactive protein; PCT: procalcitonin; NICU: neonatal intensive care unit; CPAP: continuous positive airway pressure; NIPPV: noninvasive positive pressure ventilation; SOB: shortness of breath.

      Outcomes of observational studies

      Eleven observational studies were included, comprising 762 neonates born to SARS-CoV-2-positive women (Appendix 4, Suppl. Table 5). Proportion meta-analysis indicated that the incidence of asymptomatic pregnant women was 15 % (95 % CI: 9–20 %), while fever was present in 53 % (95 % CI: 44%–62%), cough in 34 % (95 % CI: 23%–46%), shortness of breath in 18 % (95 % CI: 11%–26%) and diarrhea in 3 % (95 % CI: 2%–5%) of women. Severe disease was estimated to occur in 7 % (95 % CI: 4%–10%) of cases. The majority of neonates were delivered by cesarean section (66 %, 95 % CI: 51%–80%), while the rate of preterm birth was calculated at 16 % (95 % CI: 11%–21%) (Appendix 6, Suppl. Figs. 1–8).
      Inter-study heterogeneity was evaluated to be significant as I2 values ranged from 32 % to 91.9 %, being highest in the outcomes of cough (I2: 91.9 %) and cesarean section (I2: 88.3 %). Asymmetry of funnel plots was detected in the outcomes of asymptomatic disease (p-value = 0.036) and severe disease (p-value = 0.006) (Appendix 7, Suppl. Figs. 9–16). The adjusted estimates according to the trim-fill method indicated similar rates of asymptomatic disease (9.1 %), but significantly lower incidence of severe disease (1.8 %) after accounting for potential missing studies. No fetal or neonatal deaths were reported by observational studies, while only 6 cases of viral transmission were described by 2 studies (Suppl. Table 5). Meta-regression analysis indicated that study country exerted significant effects on the outcomes of shortness of breath, severe disease and cesarean delivery (Appendix 6, Suppl. Table 6). Specifically, the incidence of shortness of breath and severe disease was significantly lower in studies conducted in China (7.7 % vs. 28 % and 4.1 % vs. 10.3 %, respectively). Moreover, the rate of cesarean delivery was significantly higher in studies in China (88 % vs. 30 %). The outcomes of the meta-analysis of case reports/series compared to those of observational studies are depicted in Fig. 2.
      Fig. 2
      Fig. 2Comparison of outcomes between case reports/series and observational studies. SOB: shortness of breath; PTB: preterm birth.

      Discussion

      Worldwide, SARS-CoV-2 is taking its toll on health systems and has caused hospitals and healthcare providers to rearrange facilities and habits to ensure the highest degree of safety to patients and workers. The shortage of data regarding COVID-19 in the neonatal age represents a further challenge for obstetricians and neonatologists, who are called to face a rather unknown enemy. Moreover, perinatal care to the mother-neonate dyad requires special considerations due to the peculiarity of their condition, since bonding and close interaction between the mother and her baby are crucial for their well-being. Unfortunately, the paucity of supporting data impedes to draw conclusions at this point. To date, the vast majority of neonatal information is scattered and fragmented, since it is derived from case reports or small case series. To the best of our knowledge, the present meta-analysis is the largest one to date, providing pooled outcomes from 11 observational studies and 44 case reports/case series.

      Maternal outcomes

      The clinical course of Covid-19 is typically mild during pregnancy, with 15 % of infections being asymptomatic. The reported rates of severe disease were significantly higher in studies conducted in countries other than China, probably reflecting publication bias during the first wave of SARS-CoV-2. The most common symptoms were fever and cough, followed by shortness of breath, while gastrointestinal symptoms were rare. Radiological signs of pneumonia were almost ubiquitously present. Cesarean section rates were high, mainly due to concerns about perinatal transmission. The incidence of preterm birth was remarkable (29.7 % in case reports – 16 % in observational studies), although the risk of preeclampsia and placental previa were estimated to be low (5.4 % and 2.7 %, respectively).

      Transmission

      Symptomatic patients with COVID-19 are regarded as the main disseminators, but asymptomatic individuals should not be underestimated. The main transmission routes are droplets, contact, and aerosol transmission, although fecal-oral transmission should be also considered since SARS-CoV-2 RNA has been detected in fecal samples. [
      • Spiezia L.
      • Boscolo A.
      • Poletto F.
      • Cerruti L.
      • Tiberio I.
      • Campello E.
      • et al.
      COVID-19-Related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure.
      ] Our results confirm that horizontal spread from caregivers (primarily the mother) to the neonate is the most likely way of transmission in this population. Hence, it is recommended that in case of asymptomatic or mildly symptomatic SARS-CoV-2 positive mothers, general hygienic measures should be taken. Specifically, the neonate’s crib should be distanced from the mother’s bed by at least two meters and the mother should wear a surgical face mask when breastfeeding or looking after the neonate [
      • Mosca F.
      La gestione del neonato con infezione sospetta o accertata da SARS-CoV-2.
      ].
      Vertical spread remains doubtful, in keeping with the absence of reported cases of intrauterine transmission for SARS-CoV-1 and MERS. [
      • Zumla A.
      • Chan J.F.W.
      • Azhar E.I.
      • Hui D.S.C.
      • Yuen K.-Y.
      Coronaviruses — drug discovery and therapeutic options.
      ] Vertical transmission was suspected in 4 cases due to positive placental/amniotic fluid SARS-CoV-2 PCR testing or detection of neonatal IgM antibodies against the virus shortly after delivery [
      • Peng Z.
      • Wang J.
      • Mo Y.
      • Duan W.
      • Xiang G.
      • Yi M.
      • et al.
      Unlikely SARS-CoV-2 vertical transmission from mother to child: a case report.
      ,
      • Alzamora M.C.
      • Paredes T.
      • Caceres D.
      • Webb C.M.
      • Valdez L.M.
      • La Rosa M.
      Severe COVID-19 during pregnancy and possible vertical transmission.
      ,
      • Lingkong Z.
      • Xuwei T.
      • Wenhao Y.
      • Jin W.
      • Xin L.
      • Zhisheng L.
      First case of neonate with COVID-19 in China.
      ,
      • Shuo C.
      • Bo H.
      • Danju L.
      • Xiang L.
      • Fan Y.
      • Yin Z.
      • et al.
      Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases.
      ]. Alzamora et al. [
      • Alzamora M.C.
      • Paredes T.
      • Caceres D.
      • Webb C.M.
      • Valdez L.M.
      • La Rosa M.
      Severe COVID-19 during pregnancy and possible vertical transmission.
      ] reported a severe presentation of maternal COVID-19 during pregnancy, followed by the finding of positive RT-PCR in nasopharyngeal swab of the neonate at 16 h of life, despite immediate isolation from the mother. Moreover, Dong and coll [
      • Dong L.
      • Tian J.
      • He S.
      • Zhu C.
      • Wang J.
      • Liu C.
      • et al.
      Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn.
      ] described the case of a newborn with early elevated IgM antibodies to SARS-CoV-2 born to a mother with COVID-19.
      Hypothyroidism was suggested as a potential predisposing factor for perinatal transmission. Overall, six women with hypothyroidism were included and neonatal SARS-Cov-2 positivity was detected in 4 of these cases. This association remained significant in multivariate regression analysis after taking into account the effects of country, maternal age, other comorbidities, symptoms and pregnancy complications. The increased incidence of neonatal transmission may be based on the effects of thyroid hormones on placental function and maturation since subclinical hypothyroidism has been linked to increased rates of placental abruption and preterm birth [
      • Casey B.M.
      • Dashe J.S.
      • Wells C.E.
      • McIntire D.D.
      • Byrd W.
      • Leveno K.J.
      • et al.
      Subclinical hypothyroidism and pregnancy outcomes.
      ]. In this context, thyroid hormones have been proposed to affect placental development by modulating inflammatory and apoptotic processes [
      • Chen C.Y.
      • Chen C.P.
      • Lin K.H.
      Biological functions of thyroid hormone in Placenta.
      ], especially by altering the placental immune profile and intrauterine trophoblast migration [
      • Silva J.F.
      • Ocarino N.M.
      • Serakides R.
      Maternal thyroid dysfunction affects placental profile of inflammatory mediators and the intrauterine trophoblast migration kinetics.
      ]. Nonetheless, whether the potential effects of thyroid dysfunction on placental barrier may facilitate vertical SARS-CoV-2 transmission remains to be elucidated by further studies in the field.
      Nonetheless, the understanding of the mechanisms related to vertical transmission remains to be determined. One could speculate that vertical transmission is more likely in case of significant viral load in maternal samples, or critically-ill patients. However, there is currently no evidence to support any conclusion in this respect, while potential answers may be expected from the INTERCOVID study group [

      University of Oxford. Global study to assess the effects of Covid-19 in pregnancy launched | University of Oxford n.d. http://www.ox.ac.uk/news/2020-04-24-global-study-assess-effects-covid-19-pregnancy-launched (Accessed 14 May 2020).

      ].

      Neonatal clinical aspects

      The present findings suggest that the clinical presentation of COVID-19 in neonates may range from asymptomatic to severe respiratory distress. The most common symptoms were fever and dyspnea, although gastrointestinal manifestations, such vomiting and milk refusal may occasionally be the only ones in neonates [
      • Wang J.
      • Wang D.
      • Chen G.
      • Tao X.
      • Zeng L.
      SARS-CoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate.
      ]. Sporadic cases of neonatal infections (pneumonia or sepsis) requiring mechanical ventilation have been also described [
      • Coronado Munoz A.
      • Nawaratne U.
      • McMann D.
      • Ellsworth M.
      • Meliones J.
      • Boukas K.
      Late-onset neonatal sepsis in a patient with covid-19.
      ,
      • Alzamora M.C.
      • Paredes T.
      • Caceres D.
      • Webb C.M.
      • Valdez L.M.
      • La Rosa M.
      Severe COVID-19 during pregnancy and possible vertical transmission.
      ,
      • Zeng L.
      • Xia S.
      • Yuan W.
      • Yan K.
      • Xiao F.
      • Shao J.
      • et al.
      Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.
      ], while Zhu et al. [
      • Zhu H.
      • Wang L.
      • Fang C.
      • Peng S.
      • Zhang L.
      • Chang G.
      • et al.
      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      ] reported on a late-preterm who died on the ninth day of life due to refractory shock, multiple organ failure, and disseminated intravascular coagulation. Some laboratory findings, such as thrombocytopenia and lymphopenia, appear rather common in neonates born to COVID-19 mothers, even when transmission to the offspring is not confirmed either on serology or nasopharyngeal swab; these findings have been proposed to resemble those of certain late-acquired TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes) infections and thus have prompted some authors to suggest the inclusion of SARS-CoV-2 among TORCH complex [
      • Muldoon K.M.
      • Fowler K.B.
      • Pesch M.H.
      • Schleiss M.R.
      SARS-CoV-2: is it the newest spark in the TORCH?.
      ].

      Delivery

      Since the beginning of COVID-19 epidemic in China, in some cases, mothers with suspected or confirmed SARS-CoV-2 infections have undergone cesarean section in the absence of other obstetrical indications with the aim to reduce the odds of intrapartum transmission [
      • Chen H.
      • Guo J.
      • Wang C.
      • Luo F.
      • Yu X.
      • Zhang W.
      • et al.
      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.
      ]. Notably, currently available case series show a higher than expected number of preterm deliveries and cesarean sections. According to our data, the rate of cesarean delivery was 83.5 % and 80 % in case reports and observational studies, respectively. This can be in part explained as a consequence of obstetric decision to deliver due to the severity of the maternal infection (bilateral pneumonia with respiratory insufficiency and shock) [
      • Chandrasekharan P.
      • Vento M.
      • Trevisanuto D.
      • Partridge E.
      • Underwood M.A.
      • Wiedeman J.
      • et al.
      Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection.
      ].
      Since cesarean deliveries entail the exposure of a greater number of health care workers compared with spontaneous vaginal delivery and are linked to an increase in neonatal morbidity, the decision to deliver via cesarean should be cautiously weighted. To date, clear findings on whether spontaneous vaginal delivery favors neonatal infection are lacking. Hence, for the time being, the mode of delivery and anesthesia is best advisable as per maternal and fetal indications and spontaneous vaginal delivery should generally be preferred [
      • Chandrasekharan P.
      • Vento M.
      • Trevisanuto D.
      • Partridge E.
      • Underwood M.A.
      • Wiedeman J.
      • et al.
      Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection.
      ].

      Neonatal care in the delivery room

      Whether skin-to-skin contact increases the risk of SARS-CoV-2 transmission is yet to be clarified [
      • World Health Organization
      ,
      • Wang L.
      • Shi Y.
      • Xiao T.
      • Fu J.
      • Feng X.
      • Mu D.
      • et al.
      Chinese expert consensus on the perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection (First edition).
      ]. It is advisable to share decision-making with the parents before delivery regarding the potential risks and benefits of skin-to-skin care and kangaroo mother care, taking into account also risks of exposure to both the neonate and to health care providers [
      • Chandrasekharan P.
      • Vento M.
      • Trevisanuto D.
      • Partridge E.
      • Underwood M.A.
      • Wiedeman J.
      • et al.
      Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection.
      ]. Delayed cord clamping is unlikely to increase the odds of vertical transmission, since the fetus has exchanged the same blood supply during the entire pregnancy. Therefore, if vertical transmission was possible, it would probably have occurred before delivery. Currently, there is no evidence supporting the abolishment of delayed cord clamping, which is still recommended in all vigorous neonates for at least 60 s [
      • Chandrasekharan P.
      • Vento M.
      • Trevisanuto D.
      • Partridge E.
      • Underwood M.A.
      • Wiedeman J.
      • et al.
      Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection.
      ].

      Breastfeeding

      Despite some authors advocate for a cautious approach and recommend feeding preterm neonates on pasteurized breast milk (donor or maternal) or formula. [
      • Trevisanuto D.
      • Moschino L.
      • Doglioni N.
      • Roehr C.C.
      • Gervasi M.T.
      • Baraldi E.
      Neonatal resuscitation where the mother has a suspected or confirmed novel coronavirus (SARS-CoV-2) infection: suggestion for a pragmatic action plan.
      ] However, according to the present findings, all breast milk samples have been tested to be negative for SARS-CoV-2 and thus breast milk of a COVID-19 mother cannot be regarded as a transmission vehicle. Moreover, similarly to the 2002–2003 SARS-CoV-1 epidemic, specific SARS-CoV-2 antibodies are likely to pass via the breast milk from the COVID-19 mother to the infant within a few days after the onset of the disease, thus possibly modulating the clinical expression of the infant's infection [
      • Davanzo R.
      • Moro G.
      • Sandri F.
      • Agosti M.
      • Moretti C.
      • Mosca F.
      Breastfeeding and coronavirus disease‐2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies.
      ,
      • Vardhelli V.
      • Pandita A.
      • Pillai A.
      • Badatya S.K.
      Perinatal COVID-19: review of current evidence and practical approach towards prevention and management.
      ]

      Strengths and limitations of the study

      The present meta-analysis gathered all the available evidence in the field, by searching 5 literature databases without applying any language restrictions. Both case reports/series and observational studies were included and separately analyzed, providing a comprehensive approach concerning the perinatal effects of SARS-CoV-2 infection. Specifically, analysis of case reports/series provided a cohort of 158 neonates with individual participant data enabling the assessment of factors potentially associated with neonatal transmission of the virus. On the other hand, the present outcomes are limited by inconsistent reporting of important clinical and laboratory characteristics leading to missing data in several variables. Moreover, inter-study heterogeneity of observational studies was estimated to be significant, reflecting potential methodological differences concerning patient selection and outcome reporting. The effects of study country was assessed by conducting meta-regression analysis; importantly, studies conducted in China reported significantly higher incidence of cesarean delivery, reflecting the remarkable variance of labor protocols among different regions. In addition, inter-study heterogeneity may be present, as different periods of evaluation may be characterized by different treatment strategies due to the rapid change of policies regarding the management of the pandemic. It should be also noted that publication bias was suspected, especially regarding the outcome of severe maternal disease, implying that its incidence may be currently overestimated by the available studies in the field.

      Implications for future research

      Many questions regarding the impact of the novel coronavirus SARS-CoV-2 are still to be addressed. Firstly, the possibility of vertical transmission in utero or at birth should be clearly demonstrated, since the sporadic cases of positive nasopharyngeal swabs or IgM testing in neonates might be due to PCR and ELISA assay differences. Greater reliability and reproducibility of assays used worldwide are strongly warranted. Moreover, it is not clear whether a neonate with positive IgM should be considered infected and, consequently, contagious even in case of negative nasopharyngeal swabs. Secondly, data regarding SARS-CoV-2 infection during the first trimester and possible embryotoxicity are still completely lacking. In this respect, a deeper investigation regarding the capacity of SARS-CoV-2 to infect the placenta is also needed. In the present study, hypothyroidism was identified as a potential predisposing factor for perinatal transmission; however, the sample size was small and thus further research is warranted in order to reach firm conclusions about the causality of this relationship. Lastly, preliminary evidence is reassuring about breastfeeding, however more confirmatory data are needed on breast milk and viral load. Importantly, the implementation of point-of-care immune assays and virologic assays would help early identify infected but asymptomatic women who present in labor, aiming to improve perinatal management.

      Conclusions

      Maternal and neonatal COVID-19 infection is linked to a variety of clinical manifestations, although asymptomatic and mild cases are most commonly seen during the third trimester. The incidence of neonatal transmission is suggested to be low and independent of maternal disease severity. Currently, most of the approaches in the management of suspected or confirmed COVID-19 mothers and their offspring are based on little evidence and experts’ opinions. Future large-scale studies are needed in order to clarify the risk of vertical transmission and identify the factors that may predispose for the development of severe neonatal infection.

      Funding

      None.

      Ethical approval

      Not required. The present study is a meta-analysis and is solely based on aggregated data of already published studies.

      Data availability statement

      The data that support the findings of this study are available from the corresponding author upon reasonable request.

      Author contributions

      Conception and design: I. Bellos, A. Pandita.
      Analysis and interpretation of the data: I. Bellos, R. Panza.
      Drafting of the article: I. Bellos, A. Pandita.
      Critical revision for important intellectual content: I. Bellos, R. Panza.
      Final approval of the article: I. Bellos, A. Pandita, R. Panza.
      Statistical expertise: I. Bellos.
      Collection and assembly of data: I. Bellos, A. Pandita.

      Declaration of Competing Interest

      The authors report no declarations of interest.

      Acknowledgement

      None.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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