Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Single-Center Experience

Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Single-Center Experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Single-Center Experience Cansu Sivrikaya Yildirim, Hilal Ozkan, Kevser Ustun Elmas, Fatma Kocael, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7324934/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2025 Read the published version in BMC Pediatrics → Version 1 posted 10 You are reading this latest preprint version Abstract Objectives: Neonatal Multisystem Inflammatory Syndrome (MIS-N) is believed to result either from the transplacental transfer of maternal SARS-CoV-2 antibodies or from a delayed hyperinflammatory response triggered by the neonate's own immune reaction to SARS-CoV-2 infection. In this study we aim to explore the clinical presentation, laboratory findings, and current approaches to the diagnosis and management of MIS-N in neonates. Material and Method: A total of 15 infants with MIS-N followed in Bursa Uludag University Neonatal Intensive Care Unit between January 2022 and January 2023 were included in this retrospective study. Results: Six mothers had a history of COVID-19 disease during pregnancy. All of neonates had cardiac involvement (supraventricular tachycardia, persistant sinusal bradycardia or AV block) and 7 infants had respiratory failure. All infants had elevated inflammatory biomarkers and received steroids or/and IVIG. One infant died. Conclusion: The common presentation of MIS-N included cardiac aritmia and respiratory failure. Newborns with MIS-N may be at higher risk for adverse outcomes. Early diagnosis and treatment are important in these patients. neonate multisystem inflammatory syndrome anti SARS-CoV-2 antibodies COVID-19 INTRODUCTION The emergence and global dissemination of Coronavirus Disease 2019 (COVID-19) has been accompanied by a growing number of reports describing multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ( 1 ). The exact pathogenesis of MIS-C is unknown. The most likely hypothesis is post-infective immune dysregulation ( 2 ). Various studies have shown that maternal antibodies and inflammatory cytokines are transfered on to the fetus and these antibodies and cytokines can cause immune activation in the newborn baby ( 3 , 4 ). Recently, multisystem inflammatory syndrome in the newborn (MIS-N) has been defined. Although MIS-C diagnosis and treatment criteria have been defined there are only case series related to MIS-N ( 1 , 4 ). MIS-N may present with different clinical findings, such as cardiac arrhythmia, shock, respiratory failure or sepsis. We present a case series of 15 neonates with multisystem involvement, hyperinflammatory syndrome and positive anti SARS-CoV-2 IgG antibodies, temporally related to maternal antenatal SARS-CoV-2 exposure. To our knowledge, this is the first serie of MIS-N presenting in the neonatal period in Turkey. MATERIALS AND METHODS This retrospective study was performed in Uludag University Neonatal Intensive Care Units (NICU) between January 2022 and January 2023. The study protocol was approved by the Ethics Committee of Uludag University, Faculty of Medicine. Written informed consent was obtained from the parents of all patients included in the study. Definition of MIS-N There is a clear definition of MIS-C in children as described by the World Health Organization (WHO) and Centers for Disease Control (CDC). But there is no agreed definition of MIS-N. We defined criteria of MIS-N according to Pawar et al’s (4) study (Table 1). Laboratory tests SARS-CoV-2 antigens were tested using the real-time polymerase chain reaction (RTPCR) method in nasopharyngeal swabs. Euroimmun anti-SARS-Co-V2 ELISA Ig G and Colloidal Gold rapid test were used for detection of anti-SARS-CoV-2 Ig G in both maternal and neonatal serum samples. In all cases,the baseline investigations included complete blood count (CBC), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, creatinine kinase (CK-MB), troponin (TropT), Pro B-type natriuretic peptide (proBNP), ferritin, lactate dehidrogenase (LDH) and coagulation profile. In cases with suspected cardiac involvement echocardiography (ECHO) was performed. Immunomodulator therapy (intravenous immunoglobulin, IVIG) was based on the guidelines and recommendations. RESULTS The median of gestational age and birth weight were 38 week and 3295 g in all of patients. Of the 15 mothers 8 (53.3%) were symptomatic for COVID-19 during pregnancy, 7 (46.7%) were asymptomatic but serological positive for COVID-19. All of symptomatic mothers had febrile ilness and were in the second trimester. Six out of 15 mothers were not vaccinated before or during pregnancy. Clinical features Clinical characteristics of 15 neonates are shown in Table 2. Individual patient characteristics are shown in Table 3. Cardiac and respiratory All of neonates had cardiac involvement (supraventricular tachycardia (n=8), persistant sinusal bradycardia (n=4) , AV block (n=1), wide QRS complex bradycardia (n=1)) and 10 infants had respiratory failure. Three patients had cardiac arrest and shock. Ten patients needed invasive or non-invasive mechanical ventilation. Antiarrhythmic therapy was applied in seven patients with supraventricular tachycardia. All of newborns were sinus rhythm on discharge. Distribution of patients with cardiac involvement are shown in Table 4. Renal Four patients had acute renal failure and hemodiafiltration was applied to two of these patients. Hematological Four patients had hematological disorders that disseminated intravascular coagulation (DIC). Fresh frozen plasma was used for treatment. None of the patients had thrombosis. Neurogical Four newborns had encephalopathy. One of them did not cry immediately after birth, had an APGAR score of 5 at the 5th minute, and had a seizure on the second day (case 3). He was treated with anticonvulsant medication. Other newborns were 17, 7, 1 days old (Cases 1, 4 an 11) and had severe encephalopathy. Cutaneus Case 4 had hemorrhagic bullous lesions and on pathological examination, the epidermis had a necrotic appearance and there was leukocytoclastic inflammation. She was treated local medication (antibiotic and epithelial ointment). These lesions resolved within 3 weeks. Laboratory tests Anti-SARS-CoV-2 IgM antibodies were negative in all the neonates, and IgG antibodies were positive. All infants had elevated inflammatory biomarkers and the elevated biomarkers are shown in Table 5. Treatment Fourteen infants were managed with supportive therapy and IVIG. Three patients were treated with methylprednisolone. While 13 out of 15 newborns were discharged, two neonates (case 5 and case 11) died due to multi-organ failure. Detailed clinical and laboratory information of 15 patients is shown in Table 6. DISCUSSION MIS-N is a clinical syndrome characterized by multisystem involvement and a hyperinflammatory state secondary to transient maternal antenatal SARS-CoV-2 infection in babies born to pregnant women with positive anti-SARS-CoV-2 IgG antibodies ( 4 ). Diagnosis is based on clinical presentation and laboratory findings such as elevated inflammatory markers, thrombocytopenia, liver dysfunction, and coagulopathy ( 6 ). Although the diagnostic criteria for MIS-C in childhood have been established by CDC, there is not yet consensus, even between the World Health Organization and CDC, on the diagnostic criteria for MIS-N. The multisystem inflammatory response associated with SARS-CoV-2 is believed to occur through three distinct pathophysiological mechanisms and may lead to multisystem inflammatory syndrome in the neonatal period (MIS-N): a) active infection of the neonate following maternal SARS-CoV-2 infection — a mechanism unique to neonates and distinct from the CDC definition of MIS-C; b) neonatal extrapulmonary multisystem inflammation resulting from active SARS-CoV-2 infection; and c) a delayed hyperinflammatory response triggered by early or late neonatal SARS-CoV-2 infection ( 7 ). Furthermore, the immunological mechanisms are not yet fully understood. Although activation of monocytes and increase in proinflammatory cytokines and complement have been demonstrated in MIS -C, this immunologic mechanism has not been demonstrated in MIS -N because complement does not cross the placenta ( 8 ). Therefore, this case series presents 15 newborns diagnosed MIS -N based on the revised CDC criteria using information from various case series and systematic reviews. MIS-N diagnostic criteria are listed in Table 1 ( 4 , 7 ). The first case was reported in August 2020 by Magboul et al ( 6 ). There are no case series from our country in the literature. The incidence of MIS -N was reported to be 0.1% in one review ( 9 ). The incidence of MIS -N was 24.6% in the patients we observed in our department (Early MIS -N (within the first 72 hours of life) is probably by transplacental transmission of maternal SARS-CoV-2 antibody. Late MIS -N (after 72 hours of life)-presumably due to antibodies produced secondary to neonatal SARS-CoV-2 infection or transplacental transmission of maternal SARS-CoV-2 antibodies ( 10 ). In our study, 11 patients were diagnosed with early MIS-N. It is believed that early MIS -N is caused by vertical transmission, whereas MIS -N in the late stage is caused by horizontal transmission. None of our patients diagnosed with early or late MIS -N had a COVID − 19 history of disease in their parents or caregivers. It can be presumed that MIS-N developed in our patients because of the vertical transition. In addition, the literature has revealed that maternal SARS-CoV-2 infection or exposure to COVID-19 can potentially cause multisystem inflammation in the early neonatal period. In our study, 8 mothers (53.3%) had COVID − 19 symptoms during pregnancy, and 7 mothers (37.5%) were asymptomatic but serologically positive for COVID-19. All symptomatic mothers had febrile illness and symptoms occurred in the second trimester. The serologic response in mother and neonate was confirmed by examination of serum Anti-SARS-CoV-2 Ig G from both mother and neonate. SARS-CoV-2 infection in neonates is asymptomatic in 40–45% ( 11 ). Less than 15% of neonates develop moderate to severe symptoms of respiratory distress, lethargy, poor feeding, vomiting, diarrhea, and hemodynamic instability ( 12 ). In a review of neonates diagnosed with MIS -N, the cardiovascular system [67%], was found to be most commonly affected, followed by the respiratory system [64%], fever [52%], central nervous system [22%], gastrointestinal system [11%], persistent pulmonary hypertension of the newborn (PPHN) [8%], skin involvement [4%] and hematological system [6%], respectively ( 9 ). In our study, all patients had cardiac conduction abnormalities and/or arrhythmias. Involvement of the respiratory system was observed second most frequently. A case series found that maternal SARS-CoV-2 infection may be associated with multisystem inflammation in the neonatal period, as well as thrombosis and AV excitation conduction abnormalities ( 1 ). Four patients presented only when cardiac involvement was present in our study; we did not have any patient with thrombosis. Two patients were found to have cardiac arrhythmias in the fetal period (case 9, case 11). Fetal tachycardia was detected at 33 weeks' gestation in the first patient and at 22 weeks' gestation in the second patient and they were followed up at another health center during the prenatal period without treatment. There is no evidence in the literature that the findings of MIS-N begin in the prenatal period. However, one case report describes two cases of fetal supraventricular tachycardia after administration of Pfizer-BioNTech's vaccine COVID − 19 during pregnancy ( 13 ). To confirm the diagnosis MIS-N, additional inflammatory markers such as CRP, procalcitonin, and ferritin should be elevated, we found a large number of positive markers such as ferritin, CRP, and procalcitonin ( 4 ). Altough, a systematic review reported that D-dimer elevation was most common and ferritin elevation was observed in only 45% of patients; in our study, the most frequently elevated inflammatory markers were ferritin and D-dimer. IVIG, steroids, anticoagulants, and anticytokines may be preferred as specific treatment options, with the first treatment step consisting of supportive therapies (such as respiratory support, perfusion, antibiotic therapy) ( 4 , 7 , 14 ). The most commonly used specific treatment was IVIG (93.3%) among patients who participated in our study, and steroids (26%) were the second most commonly used. A review in the literature reported that 4.2% of patients developed multiple organ failure and the mortality rate was 9–11% ( 9 , 14 ). In our study, 2 patients died due to multiorgan failure, and the mortality rate was 13%, similar to the literature. Both dead patients were late preterm infants with a history of 36 weeks' gestation. CONCLUSION Inadequate recognition of MIS-N can lead to under-reporting of cases and under-diagnosis. The most common systemic findings in MIS-N are cardiac arrhythmias and respiratory failure. Neonates diagnosed with MIS-N have a high mortality and morbidity rate, and the prognosis of these infants can be poor. MIS-N neonates in whom two or more systems are affected, infection should be considered if SARS-CoV2 antibodies and elevated inflammatory markers are present. In these patients, early diagnosis and an appropriate treatment regimen are important. Declarations Conflict of interest The authors report no conflict of interest. Financial status The study has no financial source Acknowledgements No acknowledgements. Authors’ contributions This study was performed in collaboration with all the authors. OH and KN designed the study. SYC, UEK, KF, CCS, CS, HM, UF, BOM collected and analyzed the data. OH and SYC drafted the manuscript. OH, KN, CCS and SYC reviewed and edited the draft. All authors approved the final version of the manuscript. Funding No funding. Data availibilty The authors confirm that the data supporting the findings of this study are available within the article and as additional supporting files. Clinical Trial Number Not applicable. Ethics approval Ethical approval for the study was obtained before the commencement of the study from the Ethics Committee of Uludag University, Faculty of Medicine. The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents of all patients included in the study. Consent for publication Not applicable. Conflict of interests The authors confirm that they have no conflicts of interest to disclose. References More K, Aiyer S, Goti A, Parikh A, Sheikh S, Patel G et al. Multisystem inflammatory syndrome in neonates (MIS‑N) associated with SARS‑CoV2 infection: a case series. Eur J Pediatr 2022; 181:1883-1898. Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MISC) following SARS-CoV-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management. Children 2020; 7: 69 Flannery DD, Gouma S, Dhudasia MB, Mukhopadhyay S, Pfeifer MR, Woodford EC et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transferratios. JAMA Pediatr 2021; 175: 594-600. Pawar R, Gavade V, Patil N, Mali V, Girwalkar A, Tarkasband V et al. Neonatal Multisystem Inflammatory Syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: a case series. Children 2021; 8:572. Centers for Disease Control and Prevention Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). CDC Health Alert Network. https:// www. cdc. gov/ mis/ about. Html, 2020. Magboul S, Khalil A, Alshami A, Alaido M, Alhothi A, Amri MA et al. Refractory multi-inflammatory syndrome in a two weeks old neonate with COVID-19 treated successfully with intravenous immunoglobulin, steroids and anakinra. EuropePMC 2020; 5:4. Lakshminrusimha S, More K, Shah PS, Wynn JL, Sánchez PJ. Multisystem inflammatory syndrome in neonates (MIS-N) associated with perinatal SARS CoV-2 infection: Does it exist?. Semin Fetal Neonatal Med 2023; 28 28(2):101433. Lee D, Pen JL, Yatim A, Dong B, Aquino Y, Ogishi M et al. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science 2022; 379 (2022) eabo3627. Ramaswamy VV, Abiramalatha T, Pullattayil AK, Trevisanuto D. Multisystem inflammatory disease in neonates (MIS-N) due to maternal COVID-19. Semin Fetal Neonatal Med 2023; 28:101431. Galderisi A, Lista G, Cavigioli F, Trevisanuto D. Clinical features of neonatal COVID-19. Semin Fetal Neonatal Med 2023; 28:101430. Raschetti R, Vivanti AJ, Vauloup-Fellous C, Loi B, Benachi A, De Luca D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat Commun 202; 11: 1-10. Gale C, Quigley MA, Placzek A, Knight M, Ladhani S, Draper ES et al. Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance. Lancet Child Adolesc Health 2021; 5: 113-121. Abdallah W, Rechdan JB, Lakkis R, Nassar M, Daou L, Kassis NE et al. Fetal supraventricular tachycardia and maternal COVID-19 vaccination: is there any relationship?. Future Sci OA 2022; 8: FSO812. Shaiba LA, More K, Hadid A, Almaghrabi R, Marri MA, Alnamnakani M et al. Multisystemic inflammatory syndrome in neonates: a systematic review. Neonatology 2022; 119 : 405-417. Tables Tables 1 to 6 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files SupplementaryFile.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 10 Oct, 2025 Reviews received at journal 09 Oct, 2025 Reviews received at journal 27 Sep, 2025 Reviewers agreed at journal 25 Sep, 2025 Reviewers agreed at journal 22 Sep, 2025 Reviewers invited by journal 27 Aug, 2025 Editor assigned by journal 23 Aug, 2025 Editor invited by journal 22 Aug, 2025 Submission checks completed at journal 22 Aug, 2025 First submitted to journal 22 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7324934","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507412960,"identity":"8a3ae59b-ae46-44e0-bfeb-71fade7dade2","order_by":0,"name":"Cansu Sivrikaya 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dissemination of Coronavirus Disease 2019 (COVID-19) has been accompanied by a growing number of reports describing multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The exact pathogenesis of MIS-C is unknown. The most likely hypothesis is post-infective immune dysregulation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVarious studies have shown that maternal antibodies and inflammatory cytokines are transfered on to the fetus and these antibodies and cytokines can cause immune activation in the newborn baby (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Recently, multisystem inflammatory syndrome in the newborn (MIS-N) has been defined.\u003c/p\u003e\u003cp\u003eAlthough MIS-C diagnosis and treatment criteria have been defined there are only case series related to MIS-N (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). MIS-N may present with different clinical findings, such as cardiac arrhythmia, shock, respiratory failure or sepsis.\u003c/p\u003e\u003cp\u003eWe present a case series of 15 neonates with multisystem involvement, hyperinflammatory syndrome and positive anti SARS-CoV-2 IgG antibodies, temporally related to maternal antenatal SARS-CoV-2 exposure.\u003c/p\u003e\u003cp\u003eTo our knowledge, this is the first serie of MIS-N presenting in the neonatal period in Turkey.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis retrospective study was performed in Uludag University Neonatal Intensive Care Units (NICU) \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ebetween January 2022 and January 2023.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of Uludag University, Faculty of Medicine. Written informed consent was obtained from the parents of all patients included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of MIS-N\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is a clear definition of MIS-C in children as described by the World Health Organization (WHO) and Centers for Disease Control (CDC). But there is no agreed definition of MIS-N. We defined criteria of MIS-N according to Pawar et al\u0026rsquo;s (4) study (Table 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory tests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 antigens were tested using the real-time polymerase chain reaction (RTPCR) method in nasopharyngeal swabs.\u0026nbsp;Euroimmun anti-SARS-Co-V2 ELISA Ig G and Colloidal Gold rapid test were used for detection of anti-SARS-CoV-2 Ig G\u0026nbsp;in both maternal and neonatal serum samples.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn all cases,the baseline investigations included complete blood count (CBC), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, creatinine kinase (CK-MB), troponin (TropT), Pro B-type natriuretic peptide (proBNP), ferritin, lactate dehidrogenase (LDH) \u0026nbsp;and coagulation profile.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn cases with suspected cardiac involvement echocardiography (ECHO) was performed. \u0026nbsp; Immunomodulator therapy (intravenous immunoglobulin, IVIG) was based on the guidelines and recommendations.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe median of gestational age and birth weight were\u0026nbsp;38\u0026nbsp;week and \u0026nbsp;3295\u0026nbsp;g in all of patients.\u003c/p\u003e\n\u003cp\u003eOf the 15 mothers 8 (53.3%) were symptomatic for COVID-19 during pregnancy, 7\u0026nbsp;(46.7%) were asymptomatic but serological positive for COVID-19. \u0026nbsp;All of symptomatic mothers had febrile ilness and were in the second trimester. Six out of 15 mothers were not vaccinated before or during pregnancy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical characteristics of 15 neonates are shown in Table 2. Individual patient characteristics\u003c/p\u003e\n\u003cp\u003eare shown in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCardiac and respiratory \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll of neonates had cardiac involvement (supraventricular tachycardia (n=8), persistant sinusal bradycardia (n=4) , AV block (n=1), wide QRS complex bradycardia (n=1))\u0026nbsp;and 10 infants had respiratory failure. Three patients had cardiac arrest and shock. Ten patients needed invasive or non-invasive mechanical ventilation. Antiarrhythmic therapy was applied in seven patients with supraventricular tachycardia. \u0026nbsp;All of newborns were sinus rhythm on discharge. Distribution of patients with cardiac involvement are shown in Table 4.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRenal\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFour patients had acute renal failure and hemodiafiltration was applied to two of these patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHematological\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFour patients had hematological disorders that disseminated intravascular coagulation (DIC). \u0026nbsp;Fresh frozen plasma was used for treatment. None of the patients had thrombosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNeurogical\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFour newborns had encephalopathy. One of them did not cry immediately after birth, had an APGAR score of 5 at the 5th minute, and had a seizure on the second day (case 3). He was treated with anticonvulsant medication. \u0026nbsp;Other newborns were 17, 7, 1 days old (Cases 1, 4 an 11) and had severe encephalopathy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCutaneus\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCase 4 had hemorrhagic bullous lesions and on pathological examination, the epidermis had a necrotic appearance and there was leukocytoclastic inflammation. She was treated local medication (antibiotic and epithelial ointment). These lesions resolved within 3 weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory tests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnti-SARS-CoV-2 IgM antibodies were negative in all the neonates, and IgG antibodies were positive. All infants had elevated inflammatory biomarkers and the elevated biomarkers are shown in Table 5.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFourteen infants were managed with supportive therapy and IVIG. \u0026nbsp;Three patients were treated with methylprednisolone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile 13 out of 15 newborns were discharged, \u0026nbsp;two neonates (case 5 and case 11) died due to multi-organ failure. \u0026nbsp;Detailed clinical and laboratory information of 15 patients is shown in Table 6.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eMIS-N is a clinical syndrome characterized by multisystem involvement and a hyperinflammatory state secondary to transient maternal antenatal SARS-CoV-2 infection in babies born to pregnant women with positive anti-SARS-CoV-2 IgG antibodies (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Diagnosis is based on clinical presentation and laboratory findings such as elevated inflammatory markers, thrombocytopenia, liver dysfunction, and coagulopathy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although the diagnostic criteria for MIS-C in childhood have been established by CDC, there is not yet consensus, even between the World Health Organization and CDC, on the diagnostic criteria for MIS-N. The multisystem inflammatory response associated with SARS-CoV-2 is believed to occur through three distinct pathophysiological mechanisms and may lead to multisystem inflammatory syndrome in the neonatal period (MIS-N): a) active infection of the neonate following maternal SARS-CoV-2 infection \u0026mdash; a mechanism unique to neonates and distinct from the CDC definition of MIS-C; b) neonatal extrapulmonary multisystem inflammation resulting from active SARS-CoV-2 infection; and c) a delayed hyperinflammatory response triggered by early or late neonatal SARS-CoV-2 infection (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Furthermore, the immunological mechanisms are not yet fully understood. Although activation of monocytes and increase in proinflammatory cytokines and complement have been demonstrated in MIS -C, this immunologic mechanism has not been demonstrated in MIS -N because complement does not cross the placenta (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Therefore, this case series presents 15 newborns diagnosed MIS -N based on the revised CDC criteria using information from various case series and systematic reviews. MIS-N diagnostic criteria are listed in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The first case was reported in August 2020 by Magboul et al (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). There are no case series from our country in the literature.\u003c/p\u003e\u003cp\u003eThe incidence of MIS -N was reported to be 0.1% in one review (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The incidence of MIS -N was 24.6% in the patients we observed in our department (Early MIS -N (within the first 72 hours of life) is probably by transplacental transmission of maternal SARS-CoV-2 antibody. Late MIS -N (after 72 hours of life)-presumably due to antibodies produced secondary to neonatal SARS-CoV-2 infection or transplacental transmission of maternal SARS-CoV-2 antibodies (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In our study, 11 patients were diagnosed with early MIS-N. It is believed that early MIS -N is caused by vertical transmission, whereas MIS -N in the late stage is caused by horizontal transmission. None of our patients diagnosed with early or late MIS -N had a COVID \u0026minus;\u0026thinsp;19 history of disease in their parents or caregivers. It can be presumed that MIS-N developed in our patients because of the vertical transition. In addition, the literature has revealed that maternal SARS-CoV-2 infection or exposure to COVID-19 can potentially cause multisystem inflammation in the early neonatal period. In our study, 8 mothers (53.3%) had COVID \u0026minus;\u0026thinsp;19 symptoms during pregnancy, and 7 mothers (37.5%) were asymptomatic but serologically positive for COVID-19. All symptomatic mothers had febrile illness and symptoms occurred in the second trimester. The serologic response in mother and neonate was confirmed by examination of serum Anti-SARS-CoV-2 Ig G from both mother and neonate.\u003c/p\u003e\u003cp\u003eSARS-CoV-2 infection in neonates is asymptomatic in 40\u0026ndash;45% (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Less than 15% of neonates develop moderate to severe symptoms of respiratory distress, lethargy, poor feeding, vomiting, diarrhea, and hemodynamic instability (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In a review of neonates diagnosed with MIS -N, the cardiovascular system [67%], was found to be most commonly affected, followed by the respiratory system [64%], fever [52%], central nervous system [22%], gastrointestinal system [11%], persistent pulmonary hypertension of the newborn (PPHN) [8%], skin involvement [4%] and hematological system [6%], respectively (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In our study, all patients had cardiac conduction abnormalities and/or arrhythmias. Involvement of the respiratory system was observed second most frequently. A case series found that maternal SARS-CoV-2 infection may be associated with multisystem inflammation in the neonatal period, as well as thrombosis and AV excitation conduction abnormalities (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Four patients presented only when cardiac involvement was present in our study; we did not have any patient with thrombosis. Two patients were found to have cardiac arrhythmias in the fetal period (case 9, case 11). Fetal tachycardia was detected at 33 weeks' gestation in the first patient and at 22 weeks' gestation in the second patient and they were followed up at another health center during the prenatal period without treatment. There is no evidence in the literature that the findings of MIS-N begin in the prenatal period. However, one case report describes two cases of fetal supraventricular tachycardia after administration of \u003cem\u003ePfizer-BioNTech's\u003c/em\u003e vaccine COVID \u0026minus;\u0026thinsp;19 during pregnancy (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). To confirm the diagnosis MIS-N, additional inflammatory markers such as CRP, procalcitonin, and ferritin should be elevated, we found a large number of positive markers such as ferritin, CRP, and procalcitonin (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Altough, a systematic review reported that D-dimer elevation was most common and ferritin elevation was observed in only 45% of patients; in our study, the most frequently elevated inflammatory markers were ferritin and D-dimer.\u003c/p\u003e\u003cp\u003eIVIG, steroids, anticoagulants, and anticytokines may be preferred as specific treatment options, with the first treatment step consisting of supportive therapies (such as respiratory support, perfusion, antibiotic therapy) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The most commonly used specific treatment was IVIG (93.3%) among patients who participated in our study, and steroids (26%) were the second most commonly used.\u003c/p\u003e\u003cp\u003eA review in the literature reported that 4.2% of patients developed multiple organ failure and the mortality rate was 9\u0026ndash;11% (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In our study, 2 patients died due to multiorgan failure, and the mortality rate was 13%, similar to the literature. Both dead patients were late preterm infants with a history of 36 weeks' gestation.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eInadequate recognition of MIS-N can lead to under-reporting of cases and under-diagnosis. The most common systemic findings in MIS-N are cardiac arrhythmias and respiratory failure. Neonates diagnosed with MIS-N have a high mortality and morbidity rate, and the prognosis of these infants can be poor. MIS-N neonates in whom two or more systems are affected, infection should be considered if SARS-CoV2 antibodies and elevated inflammatory markers are present. In these patients, early diagnosis and an appropriate treatment regimen are important.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has no financial source\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo acknowledgements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in collaboration with all the authors. OH and KN designed the study. SYC, UEK, KF, CCS, CS, HM, UF, BOM collected and analyzed the data. OH and SYC drafted the manuscript. OH, KN, CCS and SYC reviewed and edited the draft. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availibilty\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article and as additional supporting files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained before the commencement of the study from the Ethics Committee of Uludag University, Faculty of Medicine. The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents of all patients included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that they have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMore K, Aiyer S, Goti A, Parikh A, Sheikh S, Patel G et al. Multisystem inflammatory syndrome in neonates (MIS‑N) associated with SARS‑CoV2 infection: a case series. Eur J Pediatr 2022; 181:1883-1898.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MISC) following SARS-CoV-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management. Children 2020; 7: 69\u003c/li\u003e\n \u003cli\u003eFlannery DD, Gouma S, Dhudasia MB, Mukhopadhyay S, Pfeifer MR, Woodford EC et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transferratios. JAMA Pediatr 2021; 175: 594-600.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePawar R, Gavade V, Patil N, Mali V, Girwalkar A, Tarkasband V et al. Neonatal Multisystem Inflammatory Syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: a case series. Children 2021; 8:572.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCenters for Disease Control and Prevention Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). CDC Health Alert Network. https:// www. cdc. gov/ mis/ about. Html, 2020.\u003c/li\u003e\n \u003cli\u003eMagboul S, Khalil A, Alshami A, Alaido M, Alhothi A, Amri MA et al. Refractory multi-inflammatory syndrome in a two weeks old neonate with COVID-19 treated successfully with intravenous immunoglobulin, steroids and anakinra. EuropePMC 2020; 5:4.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLakshminrusimha S, More K, Shah PS, Wynn JL, S\u0026aacute;nchez PJ. Multisystem inflammatory syndrome in neonates (MIS-N) associated with perinatal SARS CoV-2 infection: Does it exist?. Semin Fetal Neonatal Med 2023; 28 28(2):101433.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLee D, Pen JL, Yatim A, Dong B, Aquino Y, Ogishi M et al. Inborn errors of OAS\u0026ndash;RNase L in SARS-CoV-2\u0026ndash;related multisystem inflammatory syndrome in children. Science 2022; 379 (2022) eabo3627.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRamaswamy VV, Abiramalatha T, Pullattayil AK, Trevisanuto D. Multisystem inflammatory disease in neonates (MIS-N) due to maternal COVID-19. Semin Fetal Neonatal Med 2023; 28:101431.\u003c/li\u003e\n \u003cli\u003eGalderisi A, Lista G, Cavigioli F, Trevisanuto D. Clinical features of neonatal COVID-19. Semin Fetal Neonatal Med 2023; 28:101430.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRaschetti R, Vivanti AJ, Vauloup-Fellous C, Loi B, Benachi A, De Luca D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat Commun 202; 11: 1-10.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGale C, Quigley MA, Placzek A, Knight M, Ladhani S, Draper ES et al. Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance. Lancet Child Adolesc Health 2021; 5: 113-121.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAbdallah W, Rechdan JB, Lakkis R, Nassar M, Daou L, Kassis NE et al. Fetal supraventricular tachycardia and maternal COVID-19 vaccination: is there any relationship?. \u0026nbsp;Future Sci OA 2022; 8: FSO812.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eShaiba LA, More K, Hadid A, Almaghrabi R, Marri MA, Alnamnakani M et al. Multisystemic inflammatory syndrome in neonates: a systematic review. Neonatology 2022; 119 : 405-417.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"neonate, multisystem inflammatory syndrome, anti SARS-CoV-2 antibodies, COVID-19 ","lastPublishedDoi":"10.21203/rs.3.rs-7324934/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7324934/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e Neonatal Multisystem Inflammatory Syndrome (MIS-N) is believed to result either from the transplacental transfer of maternal SARS-CoV-2 antibodies or from a delayed hyperinflammatory response triggered by the neonate's own immune reaction to SARS-CoV-2 infection. In this study we aim to explore the clinical presentation, laboratory findings, and current approaches to the diagnosis and management of MIS-N in neonates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and Method: \u003c/strong\u003eA total of 15 infants with MIS-N followed in Bursa Uludag University Neonatal Intensive Care Unit between January 2022 and January 2023 were included in this retrospective study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Six mothers had a history of COVID-19 disease during pregnancy. All of neonates had cardiac involvement (supraventricular tachycardia, persistant sinusal bradycardia or AV block) and 7 infants had respiratory failure. All infants had elevated inflammatory biomarkers and received steroids or/and IVIG. One infant died.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe common presentation of MIS-N included cardiac aritmia and respiratory failure. Newborns with MIS-N may be at higher risk for adverse outcomes. Early diagnosis and treatment are important in these patients.\u003c/p\u003e","manuscriptTitle":"Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Single-Center Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 11:12:42","doi":"10.21203/rs.3.rs-7324934/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-10T09:29:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-09T08:44:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-27T04:51:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"123259391181542818111059600978134415771","date":"2025-09-25T15:48:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18108183623534454990023240537254056820","date":"2025-09-22T08:50:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-27T07:04:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-23T12:11:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-22T20:36:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-22T14:43:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-08-22T14:40:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6bbcba94-2b7e-4115-8d9d-1c994c7c747b","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T15:59:09+00:00","versionOfRecord":{"articleIdentity":"rs-7324934","link":"https://doi.org/10.1186/s12887-025-06421-x","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-12-30 15:57:06","publishedOnDateReadable":"December 30th, 2025"},"versionCreatedAt":"2025-09-03 11:12:42","video":"","vorDoi":"10.1186/s12887-025-06421-x","vorDoiUrl":"https://doi.org/10.1186/s12887-025-06421-x","workflowStages":[]},"version":"v1","identity":"rs-7324934","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7324934","identity":"rs-7324934","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}