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 Table of Contents  
Year : 2022  |  Volume : 17  |  Issue : 3  |  Page : 289-293

Intrauterine onset of multisystem inflammatory syndrome in a neonate temporally associated with maternal COVID-19

1 Department of Paediatrics, Amala Institute of Medical Sciences, Thrissur, Kerala, India
2 Department of Cardiology, Amala Institute of Medical Sciences, Thrissur, Kerala, India

Date of Submission05-Jan-2022
Date of Acceptance20-Jun-2022
Date of Web Publication27-Aug-2022

Correspondence Address:
Dr. Shiji Joseph
Department of Paediatrics, Amala Institute of Medical Sciences, Amala Nagar, Thrissur - 680 555, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_4_22

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Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 is a rare but often life-threatening clinical entity that presents 3–6 weeks after SARS-CoV-2 infection with high fever, organ dysfunction, and strongly elevated markers of inflammation. Unlike MIS-C, where SARS-CoV-2 infection and multisystem inflammation occur in the same subject, maternal SARS-CoV-2 infection may cause a similar hyperinflammatory syndrome in neonates called multisystem inflammatory syndrome in neonates (MIS-N) due to transplacental transfer of antibodies. The clinical profile of these babies remains obscure due to a lack of published literature. Our case highlights the need for practicing pediatricians to be vigilant and to have a high index of clinical suspicion of MIS-N in all critically ill neonates irrespective of antenatal COVID-19 status of mother.

Keywords: Coronavirus infectious disease antibody, cytokine storm, multisystem inflammatory syndrome in children, multisystem inflammatory syndrome in neonates, neonates, prolonged corrected QT interval, severe acute respiratory syndrome-coronavirus-2

How to cite this article:
Nitya U S, Devassy BM, Joseph S, Anila A P, George R, Sreenivasan V K. Intrauterine onset of multisystem inflammatory syndrome in a neonate temporally associated with maternal COVID-19. Indian J Rheumatol 2022;17:289-93

How to cite this URL:
Nitya U S, Devassy BM, Joseph S, Anila A P, George R, Sreenivasan V K. Intrauterine onset of multisystem inflammatory syndrome in a neonate temporally associated with maternal COVID-19. Indian J Rheumatol [serial online] 2022 [cited 2022 Oct 2];17:289-93. Available from:

  Introduction Top

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the human coronavirus responsible for the highly transmissible coronavirus infectious disease-2019 (COVID-19). The World Health Organization declared COVID-19 as a Public Health Emergency of International Concern on January 30, 2020, and subsequently, a pandemic on March 11, 2020.[1] The outbreak began in Wuhan City, China, and has been posing a threat to human health and public safety since then. However, pediatricians around the globe were reassured, since children were only mildly symptomatic with the infection in most cases. Later, the National Health Service in England came with a warning about cases of older school-aged children and adolescents presenting with fever, hypotension, severe abdominal pain, and cardiac dysfunction. They had evidence of COVID-19 infection either by reverse transcription-polymerase chain reaction (RT-PCR) positivity or by antibody testing and had laboratory findings of cytokine storm, including high serum IL-6 levels, requiring inotropes to increase cardiac output with the rare need for respiratory support.[2] The complication mentioned is the rare multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19, presenting 3–6 weeks after infection with SARS-CoV-2. Immunomodulatory therapy using intravenous (IV) immunoglobulin, corticosteroids, anticoagulants, antiplatelet agents, and other biologicals when indicated is the currently accepted modality of treatment. There is an entity called multisystem inflammatory syndrome in neonates (MIS-N) which occurs secondary to maternal SARS-CoV-2 infection[3],[4],[5],[6],[7] due to transplacental transfer of antibodies. Owing to a lack of literature and atypical features in neonates, MIS-N has not been well described and a high index of clinical suspicion is required in all critically ill neonates born to mothers who had coronavirus infectious disease-2019 (COVID-19).

  Case Report Top

The term, appropriate for gestational age, a female baby with a birth weight of 2750 g, born by emergency LSCS (Indication-fetal bradycardia) was referred to us at 36 h of life in view of persistent bradycardia and two episodes of bilious vomiting. Mother had a history of COVID-19 in the first trimester (1st month) of pregnancy. There was no history of pregnancy-induced hypertension, gestational diabetes mellitus, antepartum hemorrhage, or any other comorbidities in the mother and she was RT-PCR negative at the time of delivery. She was not vaccinated against COVID-19. At admission, the baby had poor activity, cold peripheries, and feeble peripheral pulses with a heart rate of 75 beats/min and a respiratory rate of 70 breaths/min. Her SpO2 was 99% with a delayed capillary refill time of 4 s. The baby was in shock with erythematous rash over the eyelids, cheek, chest, and upper abdomen. There were no cardiac murmurs; the chest was clear, no hepatosplenomegaly, and no focal neurological deficits. The baby was given IV fluid bolus with normal saline. In view of fluid refractory shock, the baby was started on ionotropic supports. The shock was corrected but bradycardia persisted (70 beats/min). Electrocardiogram (ECG) showed bradycardia with prolonged corrected QT interval (QTc) (629 ms) [Figure 1] and echocardiogram (echo) showed structurally normal heart. Ultrasonography of the abdomen ruled out the gastrointestinal obstruction and had features suggestive of acute parenchymal liver disease and cholecystitis. First-line blood investigations showed elevated inflammatory markers with C-reactive protein of 4.7 mg/dl (<0.6 mg/dl) and altered coagulation profile (INR: 1.69, PT-19.5, APTT-44). Blood and urine cultures were sterile. In view of the clinical presentation with persistent bradycardia and multiorgan involvement with elevated inflammatory markers and in the absence of other plausible diagnoses, MIS-N was suspected. Total COVID antibody level (VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Test, chemiluminescent immunoassay) then sent was reactive with a titer of 551 Au/ml. No IgM antibodies were detected. Further maternal COVID antibody titer sent was also reported positive. We then proceeded with second-tier investigations which showed elevated D-dimer (1690), pro-B-type natriuretic peptide (413), ferritin (234), and lactate dehydrogenase (415) which added to our diagnosis.
Figure 1: Electrocardiogram showing bradycardia and prolonged QT interval

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Treatment was initiated with IV immunoglobulin (2 g/kg over 24 h) as a single dose. Injection of methylprednisolone at a dose of 5 mg/kg/day was given for the first 3 days which was then halved to 2.5 mg/kg/day for the next 2 days. It was then changed to oral prednisolone (2 mg/kg/day in two divided doses) once the baby tolerated oral feeds well. Once the baby's general condition was stable and the platelet counts improved, she was started on low-dose aspirin at 3 mg/kg/day. Repeat echo done on day 7 of admission was normal. Baby improved, ECG (QTc-402 ms) [Figure 2] and inflammatory parameters [Figure 3], [Table 1] became normal and was discharged on low-dose aspirin, tapering doses of oral prednisolone, and oral supplements of Calcium, Vitamin D, and zinc by day 11 of admission. Oral prednisolone was tapered and stopped over 3 weeks. Low-dose aspirin was continued and stopped at 6 weeks after documenting a normal echo. The baby is under regular follow-up and is having adequate weight gain and normal development.
Figure 2: Electrocardiogram post-intravenous immunoglobulin

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Figure 3: Timeline showing a declining trend of inflammatory markers

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Table 1: Trend of inflammatory markers

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  Discussion Top

Maternal history of SARS-CoV-2 infection may be associated with multisystem inflammation, thrombosis, and cardiac conduction abnormalities in neonates. However, common causes with a similar clinical presentation such as sepsis should top the differentials. Nevertheless, taking the current scenario under consideration, MIS-C or MIS-N even though rare should be considered when a history of maternal COVID-19 infection becomes evident or when you have a baby with multiorgan involvement, elevated inflammatory markers in the absence of other plausible diagnoses.

This case illustrates the presentation, clinical course, management, and follow-up of a case of MIS-N with prenatal exposure to SARS-CoV-2 infection. To the best of our knowledge, this is the first case of MIS-N with intrauterine onset of the illness with a history of maternal COVID-19 in the early first trimester.

Pathophysiological mechanisms underlying MIS-C or MIS-N are still unclear. Consiglio et al. showed that there is an autoantibody-mediated inflammation occurring in MIS-C and that the pathophysiology of MIS-C is different from the cytokine storm of acute COVID-19.[8] Studies have shown that in some genetically susceptible children, MIS-C results due to the activation and secretion of pro-inflammatory cytokines as autoantibodies triggered by SARS CoV-2 infection bind to receptors in neutrophils and macrophages.[9],[10]

It is speculated that SARS-CoV-2 infection in the mother leads to the development of protective IgG antibodies against the viral spike protein. These antibodies cross the placenta to provide passive immunity to the newborn.[11] As per the literature, IgG antibodies to the spike protein are protective and a marker of prior infection not having any pathogenic role. On the other hand, autoantibodies against endothelial, gastrointestinal, and immune cells are also produced and may potentially play a role in the inflammatory process.[12] Similarly, antibodies against autoantigens that cross the placenta after a SARS-CoV-2 infection in mother may initiate MIS-N.[13]

We speculate that in our case, the antibodies developed after maternal antenatal SARS-CoV-2 infection in the first trimester have crossed the placenta and triggered the activation and secretion of pro-inflammatory cytokines that resulted in the development of MIS-N.

In a case series by Pawar et al.[13] out of 20 babies, 18 had a history of maternal COVID-19 infection, out of which one had a maternal infection in the first trimester and two had maternal COVID-19 infection in the second trimester, similar to our case with maternal COVID-19 infection in the early antenatal period. In the same case series, there were six babies who presented on day 1 with features of MIS-N, all of them had recent maternal COVID-19 exposure within 3–8 weeks before delivery when compared to our case in which the maternal COVID-19 infection was in the first trimester.

Kappanayil et al.[6] reported a case of MIS-N who presented on day 24 of life with cardiogenic shock due to severe myocarditis. Even though our baby did not have echocardiographic features of myocarditis, the baby had shock possibly due to severe bradycardia (intrauterine onset) by day 2 of life. As in our case, in the case series by Pawar et al.,[13] the baby who had prenatal COVID-19 exposure in the first trimester had bradycardia with prolonged QTc.

Our baby responded well to the currently approved treatment with IVIg, methylprednisolone, aspirin, and other supportive measures as reported in other published cases on MIS-N.[6],[13]

After an extensive literature search, two publications relevant to our study were found which have been summarized in the table below [Table 2].
Table 2: Comparison of index case with other published cases

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  Conclusion Top

We report a case of MIS-N in a baby who was admitted at 36 h of life with intrauterine onset of bradycardia which was persistent. At the presentation, the baby was in shock with rashes over the body. ECG showed prolonged QTc. Both maternal and neonatal serum samples showed IgG antibodies against SARS-CoV-2 spike protein as detected by quantitative antibody assay. In view of multiorgan involvement, elevated inflammatory markers with laboratory evidence of IgG antibodies to SARS-CoV-2, and in the absence of other plausible explanations, we made a diagnosis of MIS-N. The baby was treated with IVIg and steroids. The baby showed a dramatic response to treatment and the inflammatory markers normalized within 1 week.

MIS-C usually presents 3–6 weeks after SARS-CoV-2 infection; however, in neonates with MIS-N, there is no published literature enlightening us regarding the time frame within which a baby can present with MIS-N after prenatal exposure to SARS-CoV-2 infection. Furthermore, there is a dearth of evidence to say that maternal COVID-19 in the early first trimester can lead to MIS-N which warrants further study.

Informed consent

Written informed consent was taken from the baby's parents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

World Health Organization. Naming the Coronavirus Disease (COVID-19 and the Virus That Causes it; 2020. Available from: virus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causesit. [Last accessed on 2020 Sep 17].  Back to cited text no. 1
Rowley AH. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol 2020;20:453-4.  Back to cited text no. 2
McCarty KL, Tucker M, Lee G, Pandey V. Fetal inflammatory response syndrome associated with maternal SARS-CoV-2 infection. Pediatrics 2021;147:e2020010132.  Back to cited text no. 3
Divekar AA, Patamasucon P, Benjamin JS. Presumptive neonatal multisystem inflammatory syndrome in children associated with coronavirus disease 2019. Am J Perinatol 2021;38:632-6.  Back to cited text no. 4
Khaund Borkotoky R, Banerjee Barua P, Paul SP, Heaton PA. COVID-19-related potential multisystem inflammatory syndrome in childhood in a neonate presenting as persistent pulmonary hypertension of the newborn. Pediatr Infect Dis J 2021;40:e162-4.  Back to cited text no. 5
Kappanayil M, Balan S, Alawani S, Mohanty S, Leeladharan SP, Gangadharan S, et al. Multisystem inflammatory syndrome in a neonate, temporally associated with prenatal exposure to SARS-CoV-2: A case report. Lancet Child Adolesc Health 2021;5:304-8.  Back to cited text no. 6
Shaiba LA, Hadid A, Altirkawi KA, Bakheet HM, Alherz AM, Hussain SA, et al. Case report: Neonatal multi-system inflammatory syndrome associated with SARS-CoV-2 exposure in two cases from Saudi Arabia. Front Pediatr 2021;9:652857.  Back to cited text no. 7
Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020;183:968-81.e7.  Back to cited text no. 8
Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: Review of clinical presentation, hypothetical pathogenesis, and proposed management. Children (Basel) 2020;7:69.  Back to cited text no. 9
Kabeerdoss J, Pilania RK, Karkhele R, Kumar TS, Danda D, Singh S. Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: Immunological mechanisms, clinical manifestations and management. Rheumatol Int 2021;41:19-32.  Back to cited text no. 10
Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women: A cohort study. Am J Obstet Gynecol 2021;225:303.e1-17.  Back to cited text no. 11
Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). Cell 2020;183:982-95.e14.  Back to cited text no. 12
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 (Basel) 2021;8:572.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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