key: cord-313275-znrvkmee authors: Bwire, G. M.; Njiro, B. J. title: A systematic review on the levels of antibodies in COVID-19 virus exposed but negative newborns: a possible vertical transmission of IgG/ IgM date: 2020-06-12 journal: nan DOI: 10.1101/2020.06.09.20127118 sha: doc_id: 313275 cord_uid: znrvkmee Background Currently, there is no doubt on human-to-human transmission of Coronavirus Disease 2019 (COVID-19). Now, the debates remain on whether, vertical transmission of Severe Respiratory Syndrome Virus 2 (SARS-CoV-2) and antibodies against the virus do exist. We therefore, conducted a systematic review to determine the immunoglobulin G and M (IgG/IgM) levels among infants born to mothers with COVID-19. Methods The systematic search was done using PubMed/MEDLINE and Google Scholar database. The research included studies on IgG/ IgM against SARS-CoV-2 among infants born to mother with COVID-19 published in English from December 1, 2019 onwards. Data were extracted by two independent authors in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines. We synthesized a narrative from eligible studies and performed two tailed non-parametric Mann-Whitney test to determine and compare the median IgG/IgM levels. Results In total, 486 abstracts were screened and 63 full-text articles were assessed. Of 63 articles, 6 met the inclusion criteria for qualitative analysis. Two articles were included in quantitative analysis of anti-SARS-CoV-2 IgG/ IgM levels. The median antibody levels was 75.49AU/mL (range: 7.25AU/mL- 140.32AU/mL ) and for 3.79AU/mL (range: 0.16AU/mL-45.83AU/mL) (P = 0.0041) for anti-SARS-CoV-2 IgG and IgM, respectively. Conclusion There were high levels of IgG but low IgM against SARS-CoV-2 (using <10 AU/mL as a reference range) among COVID-19 virus exposed but negative newborns. This review suggest a possible natural passive immunity (IgG/ IgM) against COVID-19 virus. Currently, there is no doubt on human-to-human transmission of Coronavirus Disease 2019 . Now, the debates remain on whether, vertical transmission of Severe Respiratory Syndrome Virus 2 (SARS-CoV-2) and antibodies against the virus do exist. We therefore, conducted a systematic review to determine the immunoglobulin G and M (IgG/IgM) levels among infants born to mothers with COVID-19. The systematic search was done using PubMed/MEDLINE and Google Scholar database. The research included studies on IgG/ IgM against SARS-CoV-2 among infants born to mother with COVID-19 published in English from December 1, 2019 onwards. Data were extracted by two independent authors in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines. We synthesized a narrative from eligible studies and performed two tailed non-parametric Mann-Whitney test to determine and compare the median IgG/IgM levels. In total, 486 abstracts were screened and 63 full-text articles were assessed. Of 63 articles, 6 met the inclusion criteria for qualitative analysis. Two articles were included in quantitative analysis of anti-SARS-CoV-2 IgG/ IgM levels. The median antibody levels was 75.49AU/mL (range: 7.25AU/mL-140.32AU/mL ) and for 3.79AU/mL (range: 0.16AU/mL-45.83AU/mL) (P = 0.0041) for anti-SARS-CoV-2 IgG and IgM, respectively. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint Since the first case report of Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Wuhan, China (1), several studies have reported human-to-human transmission of SARS-CoV-2 leading to Coronavirus Disease 2019 (COVID-19) (2,3). However, evidence on mother to child transmission is still limited, World Health Organization (WHO), reported no evidence on motherto-child transmission when infection manifests in the third trimester by testing amniotic fluid, cord blood, vaginal discharge, neonatal throat swabs or breastmilk (4) . But with the current rising . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 12, 2020. On the other hand, natural passive immunity and detection of specific IgG and IgM antibodies to SARS-CoV-2 in infants born to COVID 19 confirmed mothers have been indicated in some studies where the newborns tested negative for the virus (8) . Primarily, IgM and IgG antibodies detection tends to indicate recent exposure/ first line of defense to SARS-CoV-2, whereas the detection of COVID-19 virus IgG antibodies indicates past exposure or recovery from the virus/ disease (9) . Moreover, while IgG easily cross the placenta, it is unlikely for IgM to be transferred from mother to fetus due to its large molecular structure (10) . However, studies have reported both IgG/ IgM detection in infants born to mothers with COVID-19 but themselves did not contract the disease (11) (12) (13) (14) . In this regard, a systematic review was conducted to determine the magnitude of IgG/ IgM in infants born to mothers with COVID-19 but tested negative for SARS-CoV-2. A systematic review protocol was developed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (15 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint Articles were systematically searched from PubMed/MEDLINE and Google scholar. We also searched from the websites of key healthcare organizations such as WHO and Centre for Disease Control and Prevention. Similarly, a grey literature search (e.g. pre-prints) was done with help of Google. Data from December 31, 2019 to May 18, 2020 conducted in human beings and published in English language. We developed a rigorous systematic search strategy with the help from health sciences librarian who has systematic review experience. The strategy was developed for PubMed/MEDLINE (Additional file 1) using keywords and MeSH (MEDLINE). Keywords such as vertical transmission, passive immunity, antibody, immunoglobulin, mother, child, infant, newborn, SARS-CoV-2 and COVID-19 were used. Two reviewers (GMB and BJN) independently screened the titles and abstracts, and a full-text articles for inclusion. Disagreements on study eligibility were resolved by consensus, and/or a third reviewer was consulted if necessary. The selected studies were included based on pregnant mother with laboratory-confirmed COVID-19 virus infection using quantitative real-time polymerase chain reaction (qRT-PCR) or dual fluorescence PCR, patient pregnant on admission, maternal clinical characteristics including maternal and perinatal outcomes and infection control and prevention measures during and after delivery were assessed before decision to include the article. This review included, letter to the editor, correspondence, editorial, research article (case report, case series, cross-sectional, clinical trial, cohort, case control study) but excluding articles on reviews, opinions and perspectives. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint 6 All article citations pooled from database searches were exported into EndNote software version X7 (Thomson Reuters, 2015) for managing the duplicates and for title and abstract screening. Identified publication(s) were analyzed using criteria based on levels of IgG/ IgM against SARS-CoV-2 ( Fig. 1) . The reviewers (GMB and BJN) independently extracted the variables of interest from the selected studies. Data extraction was done using Excel spreadsheet 2010 (Microsoft Corporation, Redmond, WA) ( Table 1 ). The primary endpoints were birth outcomes, such as COVID-19 infection, IgM and IgG against SARS-CoV-2. PRISMA-P guideline (15) recommends a quality assessment of the included literature, but most of the extracted studies were case reports with one participant per study and only one retrospective study with 6 participants. In this regard, authors decided not to perform the risk assessment as described previously (16) . Data not enough to perform heterogeneity and meta-analysis. However, reviewers were stringent on inclusion criteria, to minimize the methodological errors. Since the extracted data on IgG/ IgM levels were not normally distributed. We performed two tailed non-parametric Mann-Whitney test to determine and compared the median antibody levels (Prism 7 software; GraphPad Software, USA). The narrative was written by the lead reviewer (GMB) and then checked independently by reviewer (BJN). The variables that were missing from included articles were recorded as not reported. No statistical test was performed for missing data. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint A total of 510 literatures were pooled after a systematic search. Out of 510 articles, 63 (12.4%) were eligible for full-text assessment. Of 63 full-text assessed articles, 6 (9.5%) reported about IgG/IgM against SARS-CoV-2 where 2 articles had a quantified (reported the metric values) IgG/IgM levels (14, 17) , 2 articles reported unquantified detection of IgG/IgM (11, 12) . Two articles reported that no IgG/ IgM was detected from the newborns samples tested (18, 19) . Except for one study which was a retrospective study (17) , the remained studies (11, 12, 14, 18, 19) included for qualitative analysis were case reports where one study reported an infant who tested positive for COVID-19 virus (19) . For the rest of the articles infants tested negative for the virus. In terms of mode of delivery, 3 delivered through vaginal route and 3 by cesarean route. Preterm deliveries were reported in two studies (14, 19) . Three studies reported an assay employed in IgG/ IgM quantification (12, 17, 18) . The median antibody levels detected in COVID-19 exposed newborns who tested negative for the virus after delivery but were born to mothers with COVID-19 were 75.49AU/mL (range: 7.25AU/mL-140.32AU/mL ) and for 3.79AU/mL (range: 0.16AU/mL-45.83AU/mL) (P = 0.0041) for anti-SARS-CoV-2 IgG and IgM, respectively. Study by Alzamora et al., (19) found that, newborns who tested positive for SARS-CoV-2 had not antibodies against the virus during the time of sample collection. Presence of antibodies was not detected in an infant born at 34 +2 weeks by vaginal route (18) . This child tested negative for COVID-19 virus too. There was strongly . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint 8 positive IgG and weakly IgG in Italian baby delivered by cesarean route (11) while Buonsenso et al., (11) reported weakly positive IgG and absence of IgM. This review was conducted to determine the magnitude of IgG/ IgM against SARS-CoV-2 in infants born to mothers with COVID-19. Overall, six articles reported on antibodies detection for SARS-CoV-2 in newborns, five of them infants tested negative for the virus (11, 12, 14, 17, 18) whilst one study a child tested positive for the virus (19) . Using the reference range of <10 AU/mL (17) , this study found high levels of antibodies (75.49AU/mL) for IgG and low levels (3.79AU/mL) of IgM against SARS-CoV-2 among the exposed but negative newborns. High levels of IgG were similar from other findings which described its small molecular structure (10) and ability to start crossing the placenta at the beginning of the end of the second trimester (17) . Generally, IgM are highly expressed as the first line antibodies during the time where the disease is active whereas IgG detection usually indicates the long time infection or recovery from the past infection (9) . Furthermore, IgM are large in molecular structure making them unlikely to cross the placenta (10). However, detection of IgM in the recent studies (12, 14, 17) suggest the possibility that, anti-SARS-CoV-2 IgM can cross the placenta. Immunological experience form other respiratory infection such as influenza, indicated that natural transplacental influenza antibodies protect infants during the first few months of life (20) . Additionally, artificial maternal influenza antibodies significantly reduced the rate of laboratoryconfirmed influenza in the infants (21) . That experience can be employed to study the generated IgG/ IgM against SARS-CoV-2 and find out their protective effect to the newborns. In this review one case reported absence of IgG/IgM against the SARS-CoV-2 but infant tested positive for the . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint 9 virus (19) . Also, study reported negative serological test from his mother on the date of birth. The reason for this can be the explained from the recently acquired infection where IgM (first antibodies to be produced) seroconverts after day 5 from symptom onset (22). Given the time since the first case of COVID-19 (December 31, 2019), this study is limited by the small number of participants obtained from few pooled studies. However, in the fight against the limited known COVID-19 pandemic, every available scientific information should be timely employed to guide the ongoing therapeutic and vaccine research and development. There were high levels of IgG but low IgM against SARS-CoV-2 (using <10 AU/mL as a reference range) among COVID-19 virus exposed but negative newborns. This review suggest a possible vertical transmission of anti-SARS-CoV-2 IgM. These findings were necessary to inform the ongoing vaccine development and research on the background natural passive immunity among COVID-19 exposed newborns. In addition, evidence are revealing the possibility of vertical transmission of anti-SARS-CoV-2 IgG/ IgM among the exposed newborns but who tested negative for the virus. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 12, 2020. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint Novel Coronavirus ( 2019-nCoV ) [Internet]. WHO Bulletin Early dynamics of transmission and control of COVID-19: a mathematical modelling study COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses World Health Organization. WHO Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study Antibodies in Infants Born to Mothers With COVID-19 Pneumonia Tests for IgG and IgM antibodies for severe acute respiratory Training and Fit Testing of Health Care Personnel for Reusable Elastomeric Half-Mask Respirators Compared With Disposable N95 Respi Delivery in Asymptomatic Italian Woman with SARS-CoV-2 Infection Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis The placentas of patients with severe acute respiratory syndrome: A pathophysiological evaluation Neonatal Late Onset Infection with Severe Acute Respiratory Syndrome Coronavirus 2 Delivery in Asymptomatic Italian Woman with SARS-CoV-2 Infection Antibodies in Infants Born to Mothers with COVID-19 Pneumonia Possible Vertical Transmission of SARS-CoV-2 From and Infectd Mother to Her Newborn Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation Maternal and perinatal outcomes with COVID-19 : A systematic review of 108 pregnancies Antibodies in Infants Born to Mothers With COVID-19 Pneumonia Tests Vaginal Delivery Report of a Healthy Neonate Born to a Convalescent Mother with COVID-19 Severe COVID-19 during Pregnancy and Possible Vertical Transmission Protection of Infants from Infection with Influenza A Virus by Effectiveness of maternal influenza immunization in mothers and infants The authors have declared that no competing interests exist. The authors received no specific funding for this work. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. . https://doi.org/10.1101/2020.06.09.20127118 doi: medRxiv preprint