key: cord-0713908-vfwcukoy
authors: Juan, J.; Gil, M. M.; Rong, Z.; Zhang, Y.; Yang, H.; Poon, L. C.
title: Effects of coronavirus disease 2019 (COVID‐19) on maternal, perinatal and neonatal outcomes: a systematic review
date: 2020-05-19
journal: Ultrasound Obstet Gynecol
DOI: 10.1002/uog.22088
sha: b34d698bc2a26de380d3d1641b79b055bde1c20a
doc_id: 713908
cord_uid: vfwcukoy

OBJECTIVE: To evaluate the effects of coronavirus disease 2019 (COVID‐19) on maternal, perinatal and neonatal outcomes by performing a systematic review of available published literature on pregnancies affected by COVID‐19. METHODS: We performed a systematic review to evaluate the effects of COVID‐19 on pregnancy, perinatal and neonatal outcomes. We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data until 20 April 2020 (studies were identified through PubMed alert after that date). For the research strategy, combinations of the following keywords and MeSH terms were used: SARS‐CoV‐2, COVID‐19, coronavirus disease 2019, pregnancy, gestation, maternal, mothers, vertical transmission, maternal‐fetal transmission, intrauterine transmission, neonates, infant, delivery. Eligibility criteria included laboratory‐confirmed and/or clinically diagnosed COVID‐19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non‐peer‐reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting, and unreported maternal or perinatal outcomes. No language restrictions were applied. RESULTS: We identified a high number of relevant case reports and case series, but only 24 studies, including a total of 324 pregnant women with COVID‐19, met the eligibility criteria and were included in the systematic review. These comprised nine case series (eight consecutive) and 15 case reports. A total of 20 pregnant patients with laboratory‐confirmed COVID‐19 were included in the case reports. In the combined data from the eight consecutive case series, including 211 (71.5%) cases of laboratory‐confirmed and 84 (28.5%) of clinically diagnosed COVID‐19, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks. The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. The rate of severe pneumonia reported amongst the case series ranged from 0 to 14%, with the majority of the cases requiring admission to the intensive care unit. Almost all cases from the case series had positive computer tomography chest findings. All six and 22 cases that had nucleic‐acid testing in vaginal mucus and breast milk samples, respectively, were negative for SARS‐CoV‐2. Only four cases of spontaneous miscarriage or abortion were reported. In the consecutive case series, 219/295 women had delivered at the time of reporting, and the majority of these had Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. Apgar scores at 1 and 5 min ranged from 7 to 10 and 7 to 10, respectively. Only eight neonates had birth weight <2500 g and nearly one‐third of cases were transferred to the neonatal intensive care unit. There was one case each of neonatal asphyxia and neonatal death. In 155 neonates that had nucleic‐acid testing in throat swab, all, except three cases, were negative for SARS‐CoV‐2. There were seven maternal deaths, four intrauterine fetal deaths (one with twin pregnancy) and two neonatal deaths (twin pregnancy) reported in a non‐consecutive case series of nine cases with severe COVID‐19. From the case reports, two maternal deaths, one neonatal death and two cases of neonatal SARS‐CoV‐2 infection were reported. CONCLUSIONS: Despite the increasing number of published studies on COVID‐19 in pregnancy, there are insufficient good‐quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID‐19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications. In order to answer specific questions in relation to the impact of COVID‐19 on pregnant women and their fetuses through meaningful good‐quality research, we urge researchers and investigators to present complete outcome data and reference previously published cases in their publications, and to record such reporting when the data of a case are entered into a registry or several registries. This article is protected by copyright. All rights reserved.

With over 3 million individuals infected worldwide, as of 2 May 2020, 1 the coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health crisis. 2, 3 Most cohort studies have focused on evaluating the effects of COVID-19 on the general population, 2-4 and there are insufficient data on its impact on vulnerable populations, such as pregnant women.

It is recognized that pregnant women are at an increased risk of acquiring viral respiratory infection and developing severe pneumonia due to the physiologic changes in their immune and cardiopulmonary systems. 5, 6 Lessons learned from the two previous notable coronavirus outbreaks, the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), suggest that pregnant women are particularly susceptible to adverse outcomes, including the need for endotracheal intubation, admission to an intensive care unit (ICU), renal failure and death. [7] [8] [9] The first study describing the clinical characteristics and investigating the possibility of vertical transmission of SARS-CoV-2 in nine pregnant women with laboratory-confirmed COVID-19, demonstrated that the severity of COVID-19 in pregnant women was similar to that in non-pregnant adults and that there was no evidence of vertical transmission as SARS-CoV-2 was not detected in amniotic-fluid, cord-blood and neonatal throat swab samples in six cases. 10 To date, the largest series reporting on both pregnancy and neonatal outcomes, including a total of 99 COVID-19-infected pregnant women, demonstrated that COVID-19 during pregnancy was not associated with an increased risk of adverse outcomes, such as spontaneous preterm birth. 11 None of the 100 neonates born to these women was infected with SARS-CoV-2. 11 Based on very scarce data to-date, conflicting evidence from nuclei acid-based testing and antibody testing in neonates born to mothers with COVID-19 has raised further controversy in relation to the risk of vertical transmission during pregnancy. 12, 13 The objective of this study was to perform a systematic review of available published literature on pregnancies affected by COVID-19 in order to evaluate the effects of COVID-19 on maternal, perinatal and neonatal outcomes.

We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data, until 20 April 2020 (studies were identified through PubMed alert after 20 April 2020). For the search strategy, combinations of the following keywords and MeSH terms were used: SARS-CoV-2, COVID-19, coronavirus disease 2019, pregnancy, gestation, maternal, mothers, vertical transmission, maternal-fetal transmission, intrauterine transmission, neonates, infant. The search strategy is provided in Appendix S1.

Of note, at the peak of the SARS-CoV-2 outbreak in the Hubei province, China, cases with relevant symptoms, significant epidemiological history and typical computed tomography (CT) chest findings were clinically diagnosed as COVID-19 pneumonia without the need of laboratory confirmation. Therefore, eligibility criteria included laboratory-confirmed and/or clinically diagnosed COVID-19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non-peer-reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting, and unreported maternal or perinatal outcomes. No language restrictions were applied.

Relevant titles were selected from the first screening and abstracts of citations were reviewed independently by two reviewers (J.J. and M.M.G.) to identify all potentially relevant articles. We identified a high number of case reports and case series. After the first screening of titles and abstracts, we decided to repeat the screening procedure and exclude case reports from China or case series that included fewer than 10 cases from China, in order to avoid duplication of cases as there have since been several cohort series published. The potentially relevant articles were fully evaluated by the same reviewers. The reference lists of the relevant original and review articles were searched for additional reports. Full-text articles were retrieved for further consideration for inclusion. Disagreements were resolved by a third author (L.C.P.), who also independently reviewed the final included articles to confirm they met the inclusion criteria. The review was registered in PROSPERO on 23 April 2020, 14 prior to data extraction (registration number: CRD42016032409).

Two authors (J.J. and M.M.G.) extracted the information (population, outcome, study design and results) from the selected studies. A modified version of the Cochrane Public Health Group Data Extraction and Assessment Template, 15 which was previously piloted by the researchers, was used to tabulate the findings of the included articles. The methodological quality of the studies was assessed independently by the two same authors using the Joanna Briggs Institute (JBI) tool for case series and case reports. 16 Publication bias was considered high since all the included studies were either case series or case control in design. The quality of this review was validated using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool. 17 The following information was extracted from the included studies: author names, institution and country, study design, sample size, maternal age, gestational age at admission, symptoms at admission, pregnancy complications, gestational age at delivery, mode of delivery, disease severity, laboratory and radiological findings, maternal and neonatal outcomes, sample collection (amniotic fluid, cord blood, placenta, maternal vaginal secretion, urine, feces and breast milk, neonatal pharyngeal swab, neonatal blood, neonatal urine, neonatal feces, neonatal gastric juice). Any evidence of maternal to fetal transmission of SARS-CoV-2 was also recorded. Not all studies reported on all assessed variables. The denominators reported in the results were generated from papers that provided such data. Studies that did not report on a specific outcome were recorded as non-reported (NR). We contacted directly the authors of the studies when further clarification on their data was needed, such as overlapping cases in different studies published by the same group or to complete outcome data. Details of the requested data and responses of the authors, or lack of response, are provided in Table S1 .

Due to the lack of studies with a design that would allow us to perform a meta-analysis, we opted to perform a narrative synthesis using the Synthesis Without Meta-analysis (SWiM) reporting guideline (intended to complement the PRISMA guidelines in these cases). 18 Summary statistics (numbers and ranges) were calculated to show sample distribution, where appropriate including only studies in which a consecutive (all cases) cohort had been reported. Figure 1 summarizes the selection of articles for inclusion in the systematic review. The initial database search identified 554 records which, after exclusion of duplicates, were screened for the eligibility criteria. Of 52 studies assessed in full text, 36 were excluded due to overlapping cases, being case reports from China or missing outcome data (Table S2) . PubMed alerts were reviewed daily until submission, and contributed eight additional studies. Two-thirds of papers in the Chinese language were identified through both PubMed and Chinese databases. Finally, 24 studies, including a total of 324 pregnant women with COVID-19, met the eligibility criteria and were included in the review. These comprised nine case series, 11, [19] [20] [21] [22] [23] [24] [25] [26] published between 4 March 2020 and 28 April 2020, and 15 case reports, [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] published between 25 March 2020 and 28

April 2020 (Table 1a ,b). Of the nine included case series, eight were consecutive and reported on a total of 295 pregnant patients. 11, 19, [21] [22] [23] [24] [25] [26] Of these, 211 (71.5%) cases had laboratory-confirmed and 84 (28.5%) had clinical diagnosed COVID-19. The 15 case reports included a total of 20 pregnant patients with laboratory-confirmed COVID-19. [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] We recorded data related to maternal and perinatal characteristics, the clinical manifestations of COVID-19 at admission, including laboratory testing, treatment received and maternal, perinatal and neonatal outcomes. The majority of the cases originated from China, 11,21-25 but cases from Australia (1 case report), 38 Canada (1 case report), 40 France (1 case report), 40 Korea (1 case report), 37 Iran (2 case reports and 1 case series), 20, 35, 41 Italy (1 case report and 1 case series), 26, 29 Peru (1 case report), 28 Spain (2 case reports), 27, 31 Sweden (1 case report), 30 Turkey (1 case report) 34 and USA (4 case reports and 1 case series) 19, 32, 33, 36, 39 were also included. We differentiated cases that were laboratory-confirmed from those that were clinically diagnosed, but data from the two types of diagnosis were combined for presentation. A laboratoryconfirmed case of COVID-19 was defined as a positive result on quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay of maternal pharyngeal swab specimens. As mentioned, at the peak of the COVID-19 outbreak in Hubei province, China, cases with relevant symptoms, significant epidemiological history and typical chest CT findings were clinically diagnosed as COVID-19, as the viral nucleic acid test was reported to have a false-negative rate of 30%. 42 Quality assessment of the included studies is reported in Tables S3 and S4. The inclusion of eight case series with consecutive cohorts partly mitigated the high publication bias expected from case reports.

In the combined data from consecutive case series, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks (Table   1a ). The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. Based on the case series by Yan et al 11 (Table 2b) . 35, 41 The first case was a 27-year-old woman at 30 weeks' gestation who complained of fever, cough and myalgia for 3 days. Her admission laboratory tests showed leukopenia and thrombocytopenia, accompanied by elevated CRP and lactate dehydrogenase levels. 35 Soon after admission, her temperature was noted at 40°C and her respiratory rate was 55 per min, accompanied by suprasternal and intercostal retraction. Immediate blood tests showed metabolic alkalosis while the patient was under non-invasive ventilation. She was eventually intubated for mechanical ventilation due to worsening acute respiratory distress syndrome (ARDS) based on clinical and radiological findings. On day 2 of admission, the patient had spontaneous onset of labor and delivered vaginally a cyanotic neonate with no signs of life that did not respond to neonatal cardiopulmonary resuscitation. One day after birth, the mother developed multiorgan failure (ARDS, acute kidney injury, and septic shock) and died. 35 The second case was a 22-year-old woman at 32 weeks' gestation who experienced dyspnea, myalgia, anorexia, nausea, non-productive cough and fever for 4 days 22 . On admission, she was treated with Azithromycin, Ceftriaxone, Kaletra, Tamiflu and hydroxychloroquine. Based on the CT chest findings, lymphopenia, worsening pneumonia symptoms and an unfavorable cervix for induction, a Cesarean delivery was indicated at 33 weeks' gestation. A preterm female infant, weighing 2350 g, was delivered uneventfully, with Apgar scores of 8 and 9 at 1 and 5 minutes,

respectively. The amniotic fluid tested positive for SARS-CoV-2 by qRT-PCR. The immediate post-delivery nasal and throat swabs of the newborn tested negative for SARS-CoV-2, however, repeat testing 24 hours later was positive. Such results raised the possibility of vertical transmission. The mother underwent peritoneal dialysis due to ARDS on day 4 and 6 postpartum, and required intubation and mechanical ventilation due to sudden oxygen desaturation to 70% on day 10 postpartum. She developed emphysema after intubation that resolved spontaneously on day 12 postpartum, however, her condition deteriorated dramatically and she died on day 15 postpartum. 41

Based on the consecutive case series, the rates of gestational diabetes, hypertensive disorders of pregnancy and pre-eclampsia did not appear to be higher in pregnant women with COVID-19 compared to pregnant women without (Table 4a ). There were only a few cases with hypothyroidism and placenta previa/acreta. A quarter of the cases (72/295) had not been delivered at the time of reporting. Only four cases of spontaneous miscarriage or abortion were reported. In the 219 cases that were delivered, including two with twin pregnancy, the majority had a Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. The Apgar scores at 1 and 5 minutes ranged from 7 to 10 and 7 to 10, respectively (Table 5a ). Only eight neonates had birth weight < 2500 g. Nearly one-third of the neonates were transferred to the neonatal intensive care unit (NICU), mainly due to the need of investigations and monitoring as a result of maternal infection. There was one case each of neonatal asphyxia and neonatal death in the consecutive case series. Of the 19 neonates for which laboratory testing results were reported, only four and two neonates had increased white blood cells count and CRP, respectively (Table 6a ). There were no cases of lymphocytopenia and thrombocytopenia. Of note, 29, 29, 155, 19, 19 and 19 cases had nucleic-acid testing in amniotic fluid, cord blood, neonatal throat swab, neonatal feces, neonatal urine and neonatal gastric juice samples, respectively. All samples, except three neonatal throat swab samples from the series of Ferrazzi et al 26 , were negative for SARS-CoV-2. In the Iranian case series of nine non-consecutive cases with severe COVID-19, there were two cases of intrauterine fetal death (IUFD) that remained undelivered at the time of maternal death (1 with twin pregnancy) and two further cases of IUFD amongst the remaining seven cases. 20 An additional two neonatal deaths occurred, as part of a twin pregnancy. 20 In one case report the neonatal throat swab tested positive for SARS-CoV-2 (Table   6b ). 28 The mother was a 41-year-old woman with pre-existing diabetes mellitus and significant COVID-19 exposure from immediate family members. She presented at 33 weeks' gestation with a 4-day history of malaise, fatigue, low-grade fever, and progressive shortness of breath. The nasopharyngeal swab of the patient was positive for SARS-CoV-2. The patient developed severe respiratory failure requiring mechanical ventilation on day 5 of disease onset. She was started on azithromycin, hydroxychloroquine, meropenem, vancomycin, and oseltamivir. The patient underwent a preterm Cesarean delivery due to compromised respiratory status. Neonatal isolation was implemented immediately after birth, without delayed cord clamping or skin-to-skin contact. The neonate weighed 2970 grams, with Apgar's scores of 6 and 8 at 1 and 5 minutes, respectively. The neonate was not exposed to family members. Breastfeeding was not initiated. The neonate was placed in the NICU with no other COVID-19 cases, as this was the first pediatric case at the institution. Chest X-ray showed no abnormalities. At 16 hours after delivery, the neonatal nasopharyngeal swab tested positive for SARS-CoV-2 by RT-PCR, which was repeated 48 hours later and remained positive. However, anti-SARS-CoV-2 IgM and IgG were negative at birth. The possibility of postpartum neonatal infection cannot be completely excluded because of the delay in testing. The newborn required ventilatory support for 12 hours, after which he was extubated and placed on continuous positive airway pressure, with favorable outcome.

All case series, except one 20 

This systematic review has demonstrated that, first, the most common reported symptoms of COVID-19 are fever, cough, dyspnea/shortness of breath, fatigue and myalgia; second, on admission, most cases have patchy shadowing or ground-glass opacity on CT of the chest, and normal or low leukocyte, lymphocytopenia and raised CRP are the most common laboratory findings observed in pregnant patients with COVID-19; third, the rate of severe pneumonia reported amongst the case series ranged from 0 to 14%; fourth, of the 324 pregnant women included, seven maternal deaths were reported in a case series of nine non-consecutive cases with severe COVID-19 and two amongst the case reports (as of 28 April 2020); fifth, COVID-19 does not appear to increase the risk of adverse pregnancy outcomes such as preeclampsia; sixth, only a few cases of spontaneous miscarriage or abortion have been reported in pregnancies with COVID-19; seventh, there is a lack of completeness of pregnancy outcome data; eighth, based on women who had delivered at the time of reporting, the gestational age at delivery ranged from 28 to 41 weeks and the majority of cases had Cesarean delivery; and ninth, among the consecutive case series there have been three reported cases of neonates testing positive for SARS-CoV-2, and in the case reports there has been one case each with positive SARS-CoV-2 in amniotic fluid and neonatal throat swab.

At present, there is much controversy relating to the possibility of vertical mother-tobaby transmission of SARS-CoV-2. In the two earlier studies, with a combined total of 10 pregnant women with COVID-19 in the third trimester, amniotic fluid, cord blood and neonatal throat-swab samples tested negative for SARS-CoV-2, suggesting there was no evidence of vertical transmission in women who developed COVID-19 pneumonia in late pregnancy. 10, 43 In another series, a neonate born to a pregnant woman with COVID-19 that tested positive for SARS-CoV-2 in the pharyngeal swab sample 36 hours after birth, but it was subsequently confirmed that qRT-PCR testing of the placenta and cord blood was negative for SARS-CoV-2, suggesting that intrauterine vertical transmission might not have occurred. 44, 45 Two research letters 12 The second case of maternal death that was reported by Karami et al underwent autopsy and histopathologic evaluation of paraffin-embedded lung tissue that showed alveolar spaces with focal hyaline membrane, pneumocyte proliferation and metaplastic changes. 35 There was evidence of viral pneumonia (viral cytopathic effect including multinucleation and nuclear atypia and a mild increase in alveolar wall thickness). These findings are comparable to observations in non-pregnant cases. 51 The Iranian case series reported the maternal death of seven pregnant women presenting with severe COVID-19 during the latter second or third trimester over a 30day interval. 20 All cases received a three-drug regimen, which included oseltamivir 75 mg PO every 12 hours for 5 days, hydroxychloroquine sulfate 400 mg PO daily or chloroquine sulfate 1000 mg tablet PO as a single dose and lopinavir/ritonavir 400/100 mg PO every 12 hours for 5 days. There were two key features in these cases. First, the average maternal age in this series (36.7 ± 7.3 years versus 30.3 ± 3.6 years) was higher than that in others. 20 Second, according to the authors, none of the pregnant patients had pre-existing comorbidities, such as hypertension, cardiovascular disease and asthma. 20 The authors believed that the COVID-19 pregnant patients did not receive suboptimal care and raised concern regarding the potential for maternal death among pregnant women diagnosed with COVID-19 in the latter trimester. Notably, the authors did not provide details of cause(s) of death. 20

This systematic review has several strengths. We undertook a meticulous process in identifying duplicate reporting: (i) case reports from China were excluded, (ii) when a hospital had published their cases more than once, only the paper with the most data or published on the later date was included, (iii) we were able to identify the duplicates from our own publication, 11 which is the biggest cohort series with available pregnancy outcome data from China and (iv) when necessary, we contacted the corresponding authors of included studies using their native language, i.e. Chinese and Spanish, thus increasing the chance of receiving a response from them. Moreover, we did not apply any language restrictions in order to capture a global picture of the impact of COVID-19 on pregnancy and perinatal outcomes, and most importantly, we had the capability to ensure that data from China could be accurately interpreted and recorded.

This study also has several major limitations. The main limitation arises from the nature of the included studies. Although case reports are an important source of knowledge, they are not suitable for inference statistics and are expected to suffer from high publication bias. On the other hand, the main limitation of case series is the lack of internal controls; thus, they typically yield very low-quality evidence. However, at this point in time when higher-quality studies on COVID-19 in pregnancy are yet to be conducted, both case reports and case series provide valuable and necessary information to guide clinicians in their decision making. We included papers that reported at least one maternal, perinatal or neonatal outcomes. Given the severity of the pandemic and the urgent need of knowledge sharing, we felt that it would still be valuable to include papers that had provided limited pregnancy outcome data. In view of the low rate of miscarriage, it is likely that asymptomatic cases with SARS-CoV-2 infection resulting in a miscarriage were not identified and, therefore are underreported.

In our opinion, it was simply a failure of appropriate diagnosis and there was no reporting/publication bias. We were unable to include the second biggest cohort series with available pregnancy outcome data from China because the data were pooled from a national registry. 52 Despite contacting the corresponding author directly, it was not possible to identify the actual sources of cases. All 68 pregnant patients with pregnancy outcome data were cases from Wuhan, and the authors did not make reference to previously published cases. In our publication 11 , we included 77 cases from Wuhan and we had strong reasons to believe that there was significant overlap between the two series; therefore, we regrettably had to exclude the data from Chen et al 52 

China. We also learned that pregnant women with COVID-19 could have been transferred to other hospitals, which made it difficult to determine duplicate reporting as cases could have been reported by both the admitting and receiving hospitals. We decided to combine laboratory-confirmed and clinically diagnosed COVID-19 cases in our analysis because both groups had similar outcomes. 11 We believed it was important to include the clinically diagnosed cases in this review as clinically diagnosed cases had typical COVID-19 chest CT findings and significant epidemiological exposure. As of 28 April 2020, seven cases and two cases of maternal death had been reported in the non-consecutive case series 20 and amongst the case reports 35,41 , respectively. Traditionally, any maternal death requires an extensive process of investigation and therefore it is not immediately reported and made public. It was not possible to determine COVID-19-related maternal case fatality rate and such data will only come to light at the end of the pandemic.

In conclusion, despite the increasing number of published studies, there are insufficient good-quality data to draw unbiased conclusions with regard to the severity of COVID-19 or specific complications the disease in pregnant women, as well as vertical transmission, perinatal and neonatal complications. In order to answer specific questions in relation to the impact of COVID-19 on pregnant women and their fetuses through meaningful good-quality research, we urge researchers and investigators to present complete outcome data and reference previously published cases in their publications, and to record such reporting when the data of a case are entered into a registry or several registries. This article is protected by copyright. All rights reserved. 

This article is protected by copyright. All rights reserved. Accepted Article Accepted Article 

This article is protected by copyright. All rights reserved. Accepted Article Accepted Article 

This article is protected by copyright. All rights reserved. Accepted Article Accepted Article 

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Figure 1: Flowchart showing inclusion of studies in systematic review

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This article is protected by copyright. All rights reserved. negative † This article is protected by copyright. All rights reserved.# One twin pregnancy. † 24 hours after birth, throat swab became positive. * Additional information for this study was retrieved from Buonsenso et al 2020 53 .NR: not reported. CRP: C-reactive protein; IgG: immunoglobulin G; IgM: immunoglobulin M.

This article is protected by copyright. All rights reserved. Accepted Article Accepted Article