Multisystem Inflammatory Syndrome in Neonates following Maternal SARS-CoV-2 COVID-19 Infection

Key Point

• Acute severe acute respiratory syndrome-coronavirus-2 infection during pregnancy and peripartum period can occur.

• Neonates born to mothers with novel coronavirus disease 2019 can present with a multisystem inflammatory syndrome (MIS).

• Diagnostic and management criteria for MIS in neonates is not known.

On September 29, 2021, the Centers for Disease Control and Prevention (CDC) issued an emergency health advisory alerting the health network of the perils of novel coronavirus disease 2019 (COVID-19) during pregnancy.[1] As of September 27, 2021, more than 125,000 pregnant women have been reported to have laboratory-confirmed COVID-19 resulting in 22,000 hospitalizations and 161 deaths.[1] Maternal SARS-CoV-2 infection also increases the risk of adverse neonatal outcomes. In a recent issue of the American Journal of Perinatology, Divekar et al report a preterm infant born to a mother with an acute severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection presenting with features similar to multisystem inflammatory syndrome in children (MIS-C). This article reviews various case reports on neonatal COVID-19 focusing on controversies in the diagnosis of MIS-C in the neonatal period.

By September 30, 2021, approximately 5.9 million children had been infected with SARS CoV-2 in the United States.[2] During the COVID-19 surge in September 2021, 26.7% of new cases in the United States were identified in children <18 years of age. This surge with the delta variant of SARS-CoV-2 was associated with an increase in hospitalizations among children and adolescents.[3] In addition to acute SARS CoV-2 infection, children can also be hospitalized secondary to a postinfectious inflammatory syndrome. This condition was described by investigators from the United Kingdom at the peak of the pandemic in Europe in a cluster of children who developed a hyperinflammatory syndrome and shock 2 to 4 weeks after documented or presumed acute SARS-CoV-2.[4] On May 14, 2020, CDC published an online Health Advisory that summarized the manifestations and labeled this condition as an MIS-C related to COVID-19. By August 27, 2021, a total of 4,661 MIS-C patients had been reported in the United States leading to 41 deaths.[5] A total of 98% patients with MIS-C had reverse-transcription polymerase chain reaction (RT-PCR) or serological evidence of SARS-CoV-2 infection.[5] The majority of these children were Hispanic (30%) or Black (31%)[5] and presented at a median age of 9 years. Only 3.2% of the reported MIS-C patients in the United States were infants <1 year of age. Anecdotal case reports have described an MIS-C-like syndrome in the neonatal period ([Table 1]).[5] [6]

Table 1 Clinical features, treatments, and outcomes of neonatal multisystem inflammatory syndrome (MIS-N) associated with SARS-CoV-2 infection published in English literature (alphabetical order—first author)

Study	Age/sex/ethnicity or country	Maternal infection	Neonatal PCR/antigen testing	Neonatal serology	Laboratory studies	Clinical features	Treatment	Outcome
Amonkar et al[17]	6-day-old term/M/India	Asymptomatic; anti-SARS-CoV-2 nucleocapsid+	Negative	Anti-SARS-CoV-2 nucleocapsid+	Elevated inflammation markers	Right leg gangrene and aortic thrombus	Heparin, tPA, and steroids	Midtibial amputation
Antúnez-Montes et al[33]	3 patients, < 1 month/Mestizo/Latin America	No data	No data	Positive serology	No data	No data	IVIg, steroids, tocilizumab, and inotropes	Not known
Khaund Borkotoky et al[34]	Full term/12 days/India	IgG + (typical COVID-19 symptoms 3 weeks before delivery)	Negative	IgG+ IgM− On day 18	CRP, troponin, NT-pro BNP, ferritin, D-dimer, and thrombocytopenia	Fever, PPHN, CT-lung ground glass opacities, abdominal distension, feed intolerance, and vasculitis rash	Dexamethasone, PPV, inotropes, sildenafil, and furosemide	Discharged and doing well at 2 months
Diggikar et al[14]	14 days/F (7 days when RT-PCR was positive)/India	6 days after delivery	Positive	Negative	Elevated D-dimer, CRP, CSF-normal cell count, and protein	Seizures and coronary aneurysm	IVIG, steroids, and heparin	Discharged and normal coronaries in 2 weeks
Divekar et al[11]	7 days/F (30 weeks' premature)/Hispanic/The United States	30 weeks, asymptomatic, antigen positive	Negative × 2	IgM− IgG+	Elevated BNP, D-Dimer, troponin, and thrombocytopenia	MSOF, echo—depressed function, and pathological coronary artery dilation	IVIg, and PPV	Complete recovery and discharge
Diwakar et al[16]	19-day-old term/M/India	Symptomatic at 38 weeks, RT-PCR+	Negative	IgG+	Neutropenia, and elevated inflammation markers	Fever, diarrhea, and rash	IVIg	Discharged, well on follow-up
Dufort et al[35]	One neonate between 14 and 28 days/The United States	Positive, asymptomatic	Negative × 2	No data	Troponin (51 ng/L), echo normal coronary arteries	Fever, left breast cellulitis, myocarditis, and shock	No data	Discharged home
Godfred-Cato et al[8]	2 weeks/The United States	Not known	Not known	No data	No data	Brief mention in a case series	No data
Kappanayil et al[21]	24 days/F/full term/India	31 weeks gestation, mildly symptomatic	Negative	IgM− IgG+	Elevated CRP, D-dimer, AST/ALT, NT-pro BNP, WBC, troponin	MSOF, no fever, echo—poor function, and no coronary dilation	IVIg, steroids, inotropes, PPV, and heparin	Prolonged course, on afterload reduction and aspirin
McCarty et al[19]	At birth/The United States	32 weeks, symptomatic at delivery; RT-PCR + . Preeclampsia and placental infarcts	Negative	Not mentioned	Lymphopenia, thrombocytopenia, and CRP elevation	Fever, leukocytosis, RDS, and PPHN	Surfactant, PPV, iNO, and antibiotics,	Discharged
More et al[13]	5 neonates (3-F, 2-M) 1–30 days old/India	Positive history -3; IgG+ in 3;	Negative in 2 infants	IgG + all infants	Elevated inflammation markers,	Respiratory distress, encephalopathy, and shock	IVIg, steroids, and inotropes	2 deaths
Pawar et al[12]	20 neonates (10-F; 10-M) 1–5 days old/India	Third trimester (83%); Second trimester (11%)	Not done	IgG + (in 18 infants) IgM− in all infants	Elevated CRP, procalcitonin, D-dimer, LDH, and BNP	Arrhythmias, dilated coronaries, intracardiac thrombus, and shock	IVIg, steroids, heparin, and inotropes	2 deaths
Saha et al[15]	8-day-old term/F/India	Asymptomatic	Negative	Positive on day 25	Thrombocytopenia, and elevated inflammation markers	Fever, rash, diarrhea, edema, pulmonary hemorrhage, renal failure, LV dysfunction, and seizures	IVIg, steroids, and heparin	Discharged home at 50 days age
Shaiba et al [18]	2 neonates, 36 weeks/F/day 1 and 32 weeks/F/day 3/Saudi Arabia	Symptomatic, positive RT-PCR 19 days before delivery; symptomatic positive RT-PCR	Negative × 7; Positive × 6; final swab neg on day 29	IgG+ IgM− IgG−	Lymphopenia, thrombocytopenia, coagulopathy, elevated CRP, BNP, LDH, and CK	Left ventricular dysfunction, PPHN, hypoxemia; RDS, and myocarditis	Dobutamine, iNO, IVIg, steroids, IVIg, and steroids	Both babies recovered and discharged home
Zhu et al[36]	Two neonates, 34 weeks/M-1; F-1/China	Positive	Negative	Not done	Leucopenia, CRP, and elevated CKMB	Male infant: MSOF, gastric bleeding, shock; female infant: fever, GI hemorrhage, and DIC	Male: platelet transfusion, PRBCs, plasma, female: IVIg, platelets and plasma, heparin, and steroids	Male infant died; female infant survived

Abbreviations: (−), negative; (+), positive; ALT, alanine transaminase; AST, aspartate aminotransferase; BNP, brain-type natriuretic peptide; CK, creatinine kinase; CKMB, CK myocardial band; COVID-19, novel coronavirus disease 2019; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; F, female; GI, gastrointestinal; Ig, immunoglobulin; iNO, inhaled nitric oxide; IVIg, intravenous Ig; LDH, lactic acid dehydrogenase; LV, left ventricle; M, male; MSOF, multisystem organ failure; PPHN, persistent pulmonary hypertension of the newborn; PPV, positive pressure ventilation; PRBCs, packed red blood cells; RDS, respiratory distress syndrome; RT-PCR, reverse-transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; WBC, white blood cell.

Note: Modified from an original table: courtesy, Dr. Abhay Divekar with permission. Some additional information about these cases was obtained through direct communication with the corresponding authors.

The CDC case definition of MIS-C includes patients younger than 21 years who demonstrated fever, involvement of at least two organ systems, laboratory evidence of inflammation, and laboratory confirmation of current or recent SARS-CoV-2 infection. Patients are excluded if they have another plausible explanation for the illness. The phenotype of MIS-C appears to vary with the age of the patient. Young children more frequently present with conjunctival findings, rash, and abdominal pain and less commonly with respiratory symptoms. Patient's age had no significant effect on the incidence of coronary dilation (18.3% at 0–4 years vs. 14.6% at 18–20 years).[7] In addition, young children with MIS-C had a lower incidence (16–18%) of preceding clinical illness consistent with COVID-19 compared with young adults 18 to 20 years of age (63%).[7] Analysis of 85 infants (<12 months, youngest being 2-week old) showed that rash (62.4%), diarrhea (55.3%), and vomiting (55.3%) were the most common signs and symptoms.[8] Serious findings, such as hypotension (21.2%), pneumonia (21.2%), and coronary artery dilation or aneurysm (13.9%), led to ICU admission in 32.9% of these infants.[8]

Cases of acute SARS-CoV-2 infection and MIS-C have been reported in neonates ([Table 1]). Raschetti et al presented a systematic review of 176 published cases of neonates suspected to have SARS-CoV-2 infection and identified 97 neonates with clinical illness.[9] Among these infants, 44% developed fever and respiratory, gastrointestinal, neurological, and hemodynamic signs of illness occurred in 53, 36, 19, and 10%, respectively. Most had positive RT-PCR for SARS CoV-2 and two had immunoglobulin (Ig)-M titers above threshold.[9] These cases are consistent with an acute SARS-CoV-2 infection acquired in the perinatal or early postnatal periods ([Table 2]).[10]

Table 2 Clinical manifestations of COVID-19 in the neonatal period (with possibility of overlap in some patients)

Condition	Primary source of SARS CoV-2 infection	Transmission	Pathogenesis	Age of neonate at disease manifestation	Presentation
Early neonatal COVID-19	Mother	Perinatal	Acute infection	Typically, <7 days after birth	Respiratory distress, apnea, or asymptomatic[23]
Late neonatal COVID-19	Family members (including mother)	Horizontal (postnatal transmission)	Acute infection	Typically, 2–3 weeks after birth	Respiratory distress, congestion, and apnea
MIS-C	Self (neonate with early neonatal COVID-19 with or without clinical signs)	Primary SARS-CoV-2 infection leading to cytokine or antibody surge	Immune mediated	Typically, 2–6 weeks after primary infection	Multisystem inflammation, coronary dilation, thrombosis, ↑ and inflammatory markers[14]
MIS-N[a]	Mother (or fetus)	Transplacental antibodies or fetal infection	Immune mediated	Typically, <7 days after birth	Multisystem inflammation, coronary dilation,[11] thrombosis, AV conduction block, and ↑ inflammatory markers[12] [13]

Abbreviations: COVID-19, novel coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; MIS-N, multisystem inflammatory syndrome in neonate; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.

^a It is not clear if this is truly a distinct presentation of COVID-19 in the neonatal period.

In a recent report, Divekar et al presented an infant born at 30 weeks' gestational age to a mother with severe preeclampsia and asymptomatic SARS-CoV-2 infection.[11] During the first week after birth, the baby presented with multisystem failure including coronary dilation, ventricular dysfunction, anasarca, coagulopathy, thrombocytopenia, lymphopenia, hepatic dysfunction, and oliguric renal failure. While some of these signs can be attributed to prematurity and maternal preeclampsia, profound cardiac, hepatic, and renal dysfunction and severe edema with coronary dilation cannot be explained based on current literature. In addition, the neonate had IgG (but not IgM) antibodies against SARS-CoV-2 and responded well to intravenous Ig (IVIg). Among older children, the typical gap between signs and symptoms of COVID-19 and MIS-C presentation is 27 days (interquartile range: 21–36 days) in children.[5] A presentation within the first week after birth, as reported by Divekar et al, could be consistent with MIS-C if maternal infection occurred 1 to 5 weeks prior to delivery and resulted in fetal exposure to antibodies and cytokines. The unique feature in this case is that unlike most cases of MIS-C which follow an infection in the affected individual, the primary COVID-19 infection would not have occurred in the infant but in the mother ([Table 2]).

Pawar et al describe 20 neonates with multisystem inflammation and thrombosis born to mothers with a history of acute SARS-CoV-2 infection during pregnancy.[12] Most of these infants had positive titers of IgG SARS-CoV-2 and were treated with IVIg and steroids. More et al have presented five similar cases of MIS-C-like clinical features in neonates (MIS-N).[13] Diggikar et al reported a case of early neonatal acute SARS-CoV-2 infection followed by a multisystem inflammatory response.[14] These and the other reports outlined in [Table 1],[15] [16] [17] [18] [19] [20] [21] suggesting an overlap between four possible manifestations of COVID-19 during the neonatal period ([Table 2]).

Acute SARS-CoV-2 infection during the neonatal period is considered to be mostly due to perinatal or postnatal transmission from the mother or other caretakers and is commonly diagnosed with a positive nasopharyngeal swab RT-PCR or elevated IgM titer.[22] However, nasopharyngeal swabs obtained soon after birth (typically within 3 hours) can show false-positive results,[23] possibly due to contamination by maternal secretions. The American Academy of Pediatrics (AAP) and Red Book online recommend bathing the newborn babies born to COVID-19-positive mothers soon after delivery to remove virus potentially present on skin surface and to test the infant as close to discharge as possible.[24] [25]

The diagnostic criteria for MIS-C during the neonatal period are controversial and evolving. Neonates, especially preterm, may not manifest fever and hence modified criteria have been suggested.[12] A prior history of infection is also unreliable in neonates because most neonates who test positive for SARS-CoV-2 in the perinatal period have no clinical signs of illness.[23] Most of the case reports of neonatal MIS-C have relied on a positive IgG titer against SARS-CoV-2 spike protein.

Infection with SARS-CoV-2 initiates a cell-mediated and humoral immune response that produces antibodies against specific viral antigens such as the nucleocapsid (N) protein and spike (S) protein (such as anti-S protein antibodies that target the spike S1 protein and receptor binding domain [RBD]).[26] IgG and IgM antibodies against S protein can be detected within 1 to 3 weeks of infection[27] [28] or vaccination.[26] [29] Detection of anti-S and anti-N antibodies in a previously unvaccinated patient offers reliable evidence of prior infection although 3 to 4% of infected individuals may not mount an antibody response.[30] With CDC recommending the use of SARS-CoV-2 vaccines during pregnancy,[31] infants born to vaccinated mothers will have elevated IgG titers (maternally derived) against spike protein necessitating better diagnostic tools for the diagnosis of MIS-C in the neonatal period.

In the United States, the prevalence of MIS-C is relatively low (4,661 cases reported) compared with acute SARS-CoV-2 infection among children (5.9 million children infected as of September 2021). During the neonatal period, MIS-C is even more uncommon. More common causes for cardiac dysfunction and elevated troponin or brain-type natriuretic peptide (BNP), such as perinatal asphyxia and bacterial infection, should be considered. The use of glucocorticoids and intravenous immunoglobulin (IVIg) in MIS-N ([Table 1]) are not based on current evidence and warrant further study.

Unapproved Uses

As of October 11, 2021, the use of novel coronavirus disease 2019 vaccines does not have an emergency use authorization by Food and Drug Administration (FDA) for use during pregnancy and lactation. Intravenous immunoglobulin (IVIg) does not have an FDA approved indication for use in multisystem inflammatory syndrome in children (MIS-C).

Publication History

Received: 03 May 2021

Accepted: 24 October 2021

Accepted Manuscript online:
28 October 2021

Article published online:
07 December 2021

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