Multisystem inflammatory syndrome in neonates (MIS-N): a systematic review

Recently, a new pattern of multisystem inflammatory syndrome following an infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged globally. The initial cases were described in the adult population followed by sporadic cases in the pediatric population also. By the end of 2020, similar reports were recognised in the neonatal age group. The purpose of this study was to systematically review clinical characteristics, laboratory parameters, treatment, and outcomes of neonates with multisystem inflammatory syndrome in neonates (MIS-N). A systematic review was conducted after registering with PROSPERO and electronic databases including MEDLINE, EMBASE, PubMed, SCOPUS, Google Scholar, and Web of Science were searched from January 1st 2020 till September 30th 2022. A total of 27 studies describing 104 neonates were analysed. The mean gestation age and birth weight was 35.9 ± 3.3 weeks and 2255.7 ± 783.7 g respectively. A large proportion (91.3%) of the reported cases belonged to the South-East Asian region. The median age of presentation was 2 days (range: 1–28 days) with cardiovascular system being the predominant system involved in 83.65% followed by respiratory (64.42%). Fever was noted in only 20.2%. Commonly elevated inflammatory markers were IL-6 in 86.7% and D-dimer in 81.1%. Echocardiographic evaluation suggested ventricular dysfunction in 35.8% and dilated coronary arteries in 28.3%. Evidence of SARS-CoV-2 antibodies (IgG or IgM) was seen in 95.9% neonates and evidence of maternal SARS-CoV-2 infection, either as history of COVID infection or positive antigen or antibody test, was noted in 100% of the cases. Early MIS-N was reported in 58 (55.8%) cases, late MIS-N in 28 (26.9%), and 18 cases (17.3%) did not report the timing of presentation. There was a statistically increased proportion of preterm infants (67.2%, p < 0.001), and a trend towards increased low birth weight infants, in the early MIS-N group when compared to the infants with late MIS-N. Fever (39.3%), central nervous system (50%), and gastrointestinal manifestations (57.1%) were significantly higher in the late MIS-N group (p = 0.03, 0.02, 0.01 respectively). The anti-inflammatory agents used for the treatment of MIS-N included steroids 80.8% which were given for a median of 10 (range 3–35) days and IVIg in 79.2% with a median of 2 (range 1–5) doses. The outcomes were available for 98 cases, of whom 8 (8.2%) died during treatment in hospital and 90 (91.8%) were successfully discharged home.

   Conclusion: MIS-N has a predilection for late preterm males with predominant cardiovascular involvement. The diagnosis is challenging in neonatal period due to overlap with neonatal morbidities and a high risk of suspicion is warranted, especially in presence of supportive maternal and neonatal clinical history. The major limitation of the review was inclusion of case reports and case series, and highlights need of global registries for MIS-N.