Multisystem inflammatory syndrome following COVID 19 infection has been observed in neonates. It resembles Kawasaki disease in its clinical features and serologically. Vertical transmission of maternal transplacental COVID Ig-G antibodies is being considered. MIS-C presents as a syndrome with inflammation of organs and tissues most commonly heart, kidneys, digestive system, eyes, skin and brain. (Multisystem inflammatory syndrome in children (MIS-C) and COVID-19 - Symptoms and causes, 2021) Most neonates would suffer from mild respiratory distress during COVID 19 infection MIS-C is a rare complication following COVID and can become life threatening hence it is important we study the possible risk factors and causes. We report three cases of term deliveries with Multisystem inflammatory syndrome with possible vertical transmission. When tested for COVID Ig-G antibodies two of the neonates were positive while one was negative.

Case 1 A 2.7 kg male infant was born to a 22-year-old mother after 37 weeks of gestation. At 2 days of life, the baby was brought to the NICU for excessive jitteriness associated with respiratory distress. The mother had no history of pregnancy induced hypertension or gestational diabetes. Course in NICU: The baby was readmitted to the NICU at 31 days of life with complaints of persistent high-grade fever since 3 days and loose stools for 2 days. He also had a macular rash over body since one day. A sepsis screen was done and he was started on broad spectrum IV antibiotics (Injection Meropenem and Injection Vancomycin) The sepsis screen came out strongly positive with TLC-21000 and CRP-48 and polymorphonuclear leucocytosis. The baby was then symptomatically treated for fever and loose stools with oral paracetamol and probiotics following which baby showed clinical improvement in 48 hours. Repeat sepsis screen after 48 hours showed normalization of TLC -11000 however CRP was markedly raised -96 mg/L. In view of rising inflammatory markers, history was reviewed when father gave a history of having Covid related symptoms around the time of delivery with family having similar symptoms. The baby was then investigated with Covid antibody profile which showed IgG positive and IgM negative. RT-PCR for Covid-19 was negative. Following suspicion of MIS-C, baby was evaluated for other inflammatory markers which were strongly positive (D-Dimer 10600 ng/ml, Pro-BNP 780 pg/ml, LDH 350 units/L, S.Ferritin 704 ng/ml, Troponin –I <0.01ng/ml). Hence he was diagnosed with MIS-C. Baseline Coagulation profile was done which showed INR 1.4, PT 18 sec, APTT 33. 2-D echo was done which showed normal coronary arteries and normal systolic and diastolic function. Blood culture showed growth of MSSA and IV antibiotics were given for 7 days. In view of raised D-dimers and Pro-BNP, baby was given IVIG (2g/kg) over 2 days IV Steroids (Inj Methylprednisolone 2mg/kg for 5 days, Inj LMW Heparin 100units/kg/od (prophylactic dose, sc), oral Aspirin (5 mg/kg/day). Inflammatory markers were repeated after 5 days of above treatment following which they remarkably improved (CRP 15 mg/L, D- Dimer 150 ng/ml, Pro-BNP 950 pg/ml, LDH 301 units/L, S.Ferritin 706 ng/ml) . In view of persistent raised markers, the baby was continued on oral steroids (Prednisolone, LMW Heparin and oral Aspirin). We planned to repeat markers after 5 days and taper doses of steroids. Baby showed marked clinical improvement with disappearance of fever, rash and loose stools over 48 hours and improved feeding and activity. Baby was discharged and advised to review back with reports after 5 days, and decide on further treatment. The baby was also previously admitted due to Klebsiella sepsis with meningitis and thrombocytopenia and neonatal seizures Seizures were controlled with 4 anticonvulsants and there was no recurrence of seizures during NICU stay. The baby had a right sided inguinal hernia, which was reducible. Pediatric surgeon opinion was taken who advised surgical correction 6 weeks after MIS-C in view of procoagulant state, or emergency surgery if s/o obstruction/strangulation present. INVESTIGATIONS: NEONATAL SCREENING TSH: 0.726 MIU NEUROSONOGRAM: NORMAL 2 D ECHO: NORMAL MRI BRAIN: NO SIGNIFICANT ABNORMALITY IN THE BRAIN AT DISCHARGE The baby was hemodynamically stable, euthermic, alert and on direct breastfeeds Vitals: H/R 130/min, RR 40/min, SPO2 97 % on room air, CFT <2 seconds, pulses well felt RS: AE bil equal, clear CVS: S1, S2 normal. P/A: soft CNS: cry, tone, activity normal. AF level Day of Admission Tests done Results Day 1 Sepsis screen-TLC 21000 Day 1 Sepsis screen-CRP 48mg/L Day 3 Repeat screening-TLC 11000 Day 3 Repeat screening-CRP 96mg/L Day 3 RT-PCR Negative Day 4 D-Dimer 10600ng/ml Day 4 Pro-BNP 780pg/ml Day 4 LDH 350 units/L Day 4 Serum ferritin 704ng/ml Day 4 Troponin-I <0.001 ng/ml Day 5 INR 1.4 Day 5 PT 18 seconds Day 5 APTT 33 Day 9 CRP 15mg/L Day 9 D-Dimer 150ng/ml Day 9 Pro-BNP 950pg/ml Day 9 LDH 301units/L Day 9 Serum ferritin 706ng/ml CASE 2 At 37 weeks of gestation a 3.5 kg male infant was delivered to a 34 year old mother. The baby was brought to the NICU at 28 days of life with complaints of dull activity, refusal to accept feeds associated with fever and loose stools since 4 days. Course in NICU: Baby was admitted on day 28 of life with complaints of persistent high-grade fever since 4 days and loose stools for 2 days. Baby was investigated with sepsis screen and started on broad spectrum IV antibiotics (Inj Meropenem and Inj Vancomycin) Sepsis screen was strongly positive with thrombocytopenia (Platelets 21000 and elevated CRP 43). Blood cultures showed growth of Citrobacter koseri and antibiotics were upgraded accordingly (Inj Ciprofloxacin, Inj Collistin and Inj Fluconazole). Repeat blood culture after 7 days of IV antibiotics showed normal growth. Baby was symptomatically treated for fever and loose stools with oral paracetamol and probiotics following which baby showed clinical improvement in 72 hours. Repeat sepsis screen after 48 hours showed deterioration with CRP being markedly raised (145). In view of rising inflammatory markers and persistent thrombocytopenia presumptive diagnosis of post Covid MIS-C was made in view of the above significant history, baby was investigated with Covid antibody profile which was negative. RT-PCR for Covid-19 was negative. Following suspicion of MIS-C, baby was evaluated for other inflammatory markers which were strongly positive (CRP 250, D-Dimer 6380 ng/ml, Pro-BNP 1168 pg/ml, LDH 721 units/L, ProCal 8.1 and IL-6 84). Baseline Coagulation profile was normal. 2-D echo was done which showed normal coronary arteries and normal systolic and diastolic function. Antibiotics were given for 14 days. In view of raised D-dimers and Pro-BNP, baby was given IVIG (2g/kg) over 3 days, IV Steroids (Inj Methylprednisolone 2mg/kg for 5 days, Inj LMW Heparin 1mg/kg/day (prophylactic dose, sc) and oral Aspirin (5 mg/kg/day). Inflammatory markers were repeated after 5 days of above treatment following which they remarkably improved (CRP 33 mg/L). In view of persistent thrombocytopenia, the baby was transfused with Platelet rich plasma. Repeat platelet counts were 1.3 lakhs. A serial drop in Hb was noted due to iatrogenic sampling (Hb 7.7) for which a PRBC was transfused. Repeat Hb is 11.2. Baby showed marked clinical improvement with disappearance of fever and loose stools over 72 hours and improved feeding and activity. Baby was discharged and advised to review back with reports after 5 days, and decide on further treatment. INVESTIGATIONS: NEONATAL SCREENING TSH: 1.57 MIU. 2D ECHO: NORMAL AT DISCHARGE The baby was hemodynamically stable, euthermic, alert and on direct breastfeeds. Vitals: H/R 130/min, RR 40/min, SPO2 97 % on room air, CFT <2 seconds, pulses well felt RS: AE bil equal, clear CVS: S1, S2 normal. P/A: soft CNS: cry, tone, activity normal. AF level. Day of Admission Tests done Results Day 1 platelet count 21000 Day 1 CRP 43 Day 1 Blood culture Citrobacter koseri growth Day 3 CRP 145 Day 3 Covid antibody and PCR Negative Day 4 CRP 250 Day 4 D-Dimer 6380ng/ml Day 4 Pro-BNP 1168pg/ml Day 4 LDH 721 units/L Day 4 Pro Cal 81 Day 4 IL-6 84 Day 4 CRP 33mg/L Day 5 Hb 7.7 Day 6 Repeat platelets 1.3 lakh Day 9 Repeat Hb 11.2 CASE 3 A 34-year-old mother delivered a 2.4 kg male infant after 37 weeks of gestation. The baby was brought to the NICU at 29 days of life with complaints of dull activity associated with fever since 4 days. On admission the baby also has anemia of prematurity and severe dehydration and weight loss Course in NICU: On 29 days of life the baby had complaints of persistent high-grade fever since 3 days and loose stools for 2 days. Baby was investigated with sepsis screen and started on broad spectrum IV antibiotics (Inj Meropenem and Inj Amikacin) pending a blood culture. Sepsis screen was strongly positive (TLC 17000, with polymorphonulcear leucocytosis and elevated CRP 43). Baby was symptomatically treated for fever and loose stools with oral paracetamol and probiotics following which baby showed clinical improvement in 48 hours. Repeat sepsis screen after 48 hours showed normalization of TLC (9000), however CRP was markedly raised (114 mg/L). In view of rising inflammatory markers, history was reviewed when the father gave a history of having Covid related symptoms and deaths around the time of delivery in the family. In view of the above significant history, the baby was investigated with Covid antibody profile which showed IgG positive and IgM negative. RT-PCR for Covid-19 was negative. Following suspicion of MIS-C, the baby was evaluated for other inflammatory markers which were strongly positive (D-Dimer 3260 ng/ml, Pro-BNP 1168 pg/ml, LDH 328 units/L). Baseline Coagulation profile was done which showed INR 1.03, PT 18 sec, APTT 33. 2-D echo was done which showed normal coronary arteries and normal systolic and diastolic function. Blood culture was sterile and IV antibiotics were given for 14 days. In view of raised D-dimers and Pro-BNP, baby was given IVIG (0.5g/kg) over 3 days, IV Steroids (Inj Methylprednisolone 2mg/kg for 5 days, Inj LMW Heparin 1mg/kg/day (prophylactic dose, sc) and oral Aspirin (5 mg/kg/day). Inflammatory markers were repeated after 5 days of above treatment following which they remarkably improved (CRP 10 mg/L). Baby showed marked clinical improvement with disappearance of fever and loose stools over 48 hours and improved feeding and activity. Baby was discharged and advised to review back with reports after 5 days, and decide on further treatment. SEVERE DEHYDRATION/ SIGNIFICANT WEIGHT LOSS Baby was severely dehydrated on admission. Baby was given 2 NS bolus and put on maintenance IV fluids with 10% dehydration correction. RFT was normal. Serum electrolytes were normal. Cause for severe dehydration was improper technique and inadequacy of breastfeeding. Baby gained weight well during NICU stay, and mother was trained in proper breastfeeding and supplemental formula feeds. ANEMIA OF PREMATURITY Baby clinically looked pale on 40 days of life. CBP showed mild anemia (Hb 8.4) for which a PRBC transfusion was given. INVESTIGATIONS: NEONATAL SCREENING TSH: 1.726 MIU. NEUROSONOGRAM: NORMAL 2D ECHO: NORMAL AT DISCHARGE The baby was hemodynamically stable, euthermic, Alec and on direct breastfeeds Vitals: H/R 130/min, RR 40/min, SPO2 97 % on room air, CFT <2 seconds, pulses well felt RS: AE bil equal, clear CVS: S1, S2 normal. P/A: soft CNS: cry, tone, activity normal. AF level Day of Admission Tests Done Results Day 1 TLC 17000 Day 1 CRP 43 Day 3 TLC 9000 Day 3 CRP 114 Day 3 Covid antibody Positive Day 3 RT-PCR Negative Day 4 D-Dimer 3260 ng/ml Day 4 Pro-BNP 1168pg/ml Day 4 LDH 328 units/L Day 5 INR 1.03 Day 5 PT 18 seconds Day 5 APTT 33 seconds Day 5 Blood culture sterile Day 8 CRP 10 mg/L Day 9 Renal Function Tests Noraml Day 9 Serum electrolytes Normal Day 10 Hb 8.4

In this report we have accounted for three cases of neonatal multisystem inflammatory syndrome due to Covid 19 in the pregnancy. Our report emphasized on the gastrointestinal systems of MIS-C.Also there was observed elevated CRP levels and elevated D dimer levels suggesting evidence of coagulopathy. Most children with MIS-C test negative with PCR but have positive antibodies for SARS COV 2. It usually presents 3-4 weeks after COVID-19 infection. There is speculation of placental transfer of protective Ig-G antibodies against Covid 19 that were formed in the mother during infection. Some of these autoantibodies might bind to macrophages and neutrophils and cause release of pro-inflammatory markers that might lead to MIS-C. Treatment would involve supportive care and measures to reduce the inflammation of any vital organs if present. Aspirin to be used in low doses to normalize the platelet count and confirm normal coronary arteries. (Henderson et al., 2021) Besides aspirin, tonoferon was given to our patient to be given for a year. Immunomodulatory therapy should be used to treat MIS-C. IVIG being the top tier therapy followed by glucocorticoids as an adjunctive therapy. (Henderson et al., 2021) Cardiac function and fluid status should be assessed before giving IVIG treatment. (Henderson et al., 2021) For patients who do not respond to IVIG and low dose glucocorticoids high dose IV glucocorticoids should be given.(Henderson et al., 2021) Anakinra may be considered for treatment of MIS-C refractory to IVIG and glucocorticoids in patients with features of macrophage activation syndrome (MAS). (Henderson et al., 2021) 2 D echo, BERA to be done at around 3 months of age and neurological development and growth to be monitored every 3 months till 2 years of age in children with MIS-C to check for any abnormalities.

Majority of the children presenting with COVID 19 have mild symptoms and good outcomes. However, a few develop the rare Multisystem inflammatory syndrome. Some studies have revealed that MIS-C in younger children presents with KD like features and as shock and myocarditis in older children. The molecular mechanism of MIS-C results from maternal placenta is still not clearly understood. MIS-C also presents with such varying clinical features that it poses a challenge to the pediatrician to diagnose and manage it. Hence MIS-C requires further analysis and scrutiny to find the adequate management.

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