Pilot Study Analyzing Combination of Point-of-Care Echocardiography and Clinical Correlation in Unveiling Cryptic Multi-Inflammatory Syndrome in Neonates during Coronavirus Disease 2019 Pandemic

Maitri Chaudhuri; Munesh Tomar; Seema Gaonkar; Anuj Rastogi; Arvind Shenoi

doi:10.4103/jiae.jiae_64_21

ORIGINAL RESEARCH

Year : 2022 | Volume : 6 | Issue : 2 | Page : 89-99

Pilot Study Analyzing Combination of Point-of-Care Echocardiography and Clinical Correlation in Unveiling Cryptic Multi-Inflammatory Syndrome in Neonates during Coronavirus Disease 2019 Pandemic

Maitri Chaudhuri¹, Munesh Tomar², Seema Gaonkar³, Anuj Rastogi⁴, Arvind Shenoi³
¹ Department of Pediatric Cardiology, Manipal Hospital, Bengaluru, Karnataka, India
² Department of Paediatrics, LLRM Medical College, Meerut, Uttar Pradesh, India
³ Department of Paediatrics and Neonatology, Cloud Nine Hospital, Bengaluru, Karnataka, India
⁴ Department of Paediatrics, Jaswant Rai Specialty Hospital, Meerut, Uttar Pradesh, India

Date of Submission	25-Nov-2021
Date of Acceptance	11-Jan-2022
Date of Web Publication	23-Mar-2022

Correspondence Address:
Dr. Munesh Tomar
Department of Paediatrics, LLRM Medical College, Meerut - 250 004, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_64_21

Abstract

Introduction: Coronavirus disease 2019 (COVID-19), an extremely contagious pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), originated from Wuhan, Hubei province, in China in December 2019. From April 2020, pediatric epicenters in Europe and the USA reported a new clinical spectrum called “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2” or “multisystem inflammatory syndrome in children,” respectively. The unique feature was immune-mediated multiorgan dysfunction in response to previous COVID exposure. This case series aims to prospectively analyze the incidence, severity, and patterns of cardiac involvement in sick neonates exposed to perinatal SARS-CoV-2 in India. Methods: Twelve neonates presenting with very early-onset multi-inflammatory syndrome in neonates (MIS-N) at two tertiary care centers in India were included. Their clinical profiles, echocardiography findings, and treatment details were recorded. Results: Clinical presentations varied from loss of fetal movement, perinatal depression, prematurity, unusual respiratory distress syndrome, cardiogenic shock, arrhythmias, and multi-organ dysfunction. Echocardiographic markers were severe pulmonary hypertension, significant valvular regurgitation, cardiomegaly, biventricular dysfunction, neonatal coronary artery aneurysms, intracardiac thrombus, pericardial effusion, and arrhythmias. All babies, except one, had positive COVID IgG antibody and high inflammatory markers. Two mothers had antenatal primary contact with COVID patients 4–6 weeks prior to delivery, while 3 (25%) had documented mild COVID infection. All neonates were started on immunosuppressive therapy. Clinical stabilization and declining inflammatory markers were observed within 48–96 h of targeted therapy. All neonates (except one) recovered and were discharged in a stable condition. Follow-up available up to 9 months demonstrated persistent clinical, laboratory, and echocardiographic recovery in all survivors. Conclusion: Infection of pregnant mothers during community transmission during the two COVID-19 waves in India appears to have caused significant immune dysregulation and cardiac damage in neonates. Echocardiography detected significant damage to coronary arteries, pulmonary arterial hypertension, intracardiac thrombus, ventricular dysfunction, and incompetence of valve apparatus in MIS-N. Aggressive immunomodulators with antiplatelet drugs proved lifesaving. Echocardiography is an inexpensive, readily available imaging modality. It should be utilized to save this fragile, extremely special cohort.

Keywords: Echocardiography, intracardiac thrombus, multisystem inflammatory syndrome in children, multi-inflammatory syndrome in neonates, neonatal coronary aneurysm, pulmonary hypertension in neonate, severe acute respiratory syndrome-coronavirus-2

How to cite this article:
Chaudhuri M, Tomar M, Gaonkar S, Rastogi A, Shenoi A. Pilot Study Analyzing Combination of Point-of-Care Echocardiography and Clinical Correlation in Unveiling Cryptic Multi-Inflammatory Syndrome in Neonates during Coronavirus Disease 2019 Pandemic. J Indian Acad Echocardiogr Cardiovasc Imaging 2022;6:89-99

How to cite this URL:
Chaudhuri M, Tomar M, Gaonkar S, Rastogi A, Shenoi A. Pilot Study Analyzing Combination of Point-of-Care Echocardiography and Clinical Correlation in Unveiling Cryptic Multi-Inflammatory Syndrome in Neonates during Coronavirus Disease 2019 Pandemic. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2022 [cited 2023 Jun 10];6:89-99. Available from: https://jiaecho.org/text.asp?2022/6/2/89/340639

Introduction

The global pandemic from severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) rages unabated across nations, ethnicities, socioeconomic strata, comorbidities, and public health measures. India suffered two staggering waves unwitnessed for a century since the occurrence of Spanish flu. The arrival of extremely contagious Omicron variant is a new challenge.

Cardiac literature in adults, from the beginning, reported serious cardiovascular involvement in coronavirus disease 2019 (COVID-19). These manifestations were grouped into four main categories: coronary events, arrhythmias, heart failures, and thromboembolic episodes.^[1] Simultaneous pediatric reviews in the early 2020 provided a false reassurance that children were relatively spared from severe COVID-19.^[2],[3],[4]

However, from the late April 2020, there was a paradigm shift with discovery of a novel, postimmune, multiorgan involvement, usually associated with fever, after a lag phase of 3–6 weeks after the original viremic insult. This was named as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 in the United Kingdom and multisystem inflammatory syndrome in children (MIS-C) in the USA, respectively. There were both clinical and serological similarities with Kawasaki disease (KD) and the severe COVID-19 cytokine storm seen in adults.^[5] More than 80% of MIS-C cases had immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies against SARS-CoV-2 and only one-third were SARS-CoV-2 reverse transcription–polymerase chain reaction (RT-PCR) positive.^{[6],[7],[8],[9],[10]}

Global systematic reviews in 2020 found equivocal evidence for in utero transmission among 1316 pregnant women across 39 studies. This was in spite of Wang et al. reporting the first neonatal nasopharyngeal swab positivity for SARS-CoV-2 infection from Wuhan, China, in March 2020.^[11] Western literature also pointed out that in spite of the immature immune systems and diminished angiotensin-converting enzyme-2 receptor expression, 12% of the infected neonates have more severe infection requiring neonatal intensive care unit (NICU) care than 3% of the older children.^[12]

Unlike MIS-C where infection and inflammation occur in the same subject, neonatal MIS-C (referred hereafter as multi-inflammatory syndrome in neonates [MIS-N]) is peculiar in that inflammation in neonate is mostly secondary to maternal infection. Thus, MIS-N conjoins two separate individuals unified by the viral sequelae, a prototype of mother–fetus–neonate as a single dyad.

This report describes 12 neonates with MIS-N. The evidence of SARS-CoV-2 exposure was positive anti-SARS-CoV-2 IgG antibodies in ten neonates, positive RT-PCR in one neonate, and epidemiological tracing in the remaining one.

Aim of the study

The aim of this study was to analyze the constellation of echocardiographic markers in very early-onset MIS-N in India.

Methods

This observational, multicenter study was conducted at tertiary care government and private sector NICUs simultaneously in North and South India from March 2020 to June 2021. The study cohort comprised sick newborns in the NICU where pediatric cardiologists were consulted to exclude cardiac etiologies of decompensation. The neonatal COVID status was unknown to the cardiologists and treating team at the time of admission.

The maternal and neonatal clinical presentations, treatment, and outcomes were reviewed from electronic medical records by the same team. Institutional review board approvals were obtained. Cardiac evaluation (electrocardiographic [ECG] and serial echocardiographic examinations) was performed on the day of birth/presentation and then serially in the NICU and outpatient department according to the protocol.

Inclusion Criteria

The inclusion criteria for MIS-N were adapted from Pawar et al.^[13]

A neonate <28 days of age at the time of presentation
Laboratory or epidemiological evidence of SARS-CoV-2 infection in the mother

Positive SARS-CoV-2 testing by RT-PCR, serology (IgG or IgM), or antigen during pregnancy
Symptoms consistent with SARS-CoV-2 infection during pregnancy
COVID-19 exposure with confirmed SARS-CoV-2 infection during pregnancy
Serological evidence in the neonate (positive SARS-CoV-2 IgG antibodies but not IgM)

Clinical criteria

Severe infection requiring hospitalization AND
Two or more organ systems affected (cardiac, respiratory, renal, gastrointestinal, neurological, cutaneous, hematological, and temperature instability such as fever or hypothermia) OR
Cardiac atrioventricular conduction arrhythmias OR coronary artery dilatation/aneurysms (without involvement of second organ system)

Laboratory evidence of inflammation

Elevation of one or more of the following; C reactive protein (CRP), erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase (LDH), interleukin-6, or elevated neutrophils or reduced lymphocytes; low albumin

Exclusion of alternative diagnosis such as maternal systemic lupus erythematosus, other etiology of perinatal asphyxia, viral or bacterial sepsis.

COVID-19 exposure was documented by real-time RT-PCR positivity and/or serology (IgG antibodies specific to SARS-CoV-2).

Laboratory markers were divided into two groups:

Inflammatory markers: Total and differential leukocyte count, platelet counts, CRP, D-dimer, fibrinogen, ferritin, LDH, interleukin-6, renal and hepatic function tests
Cardiac biomarkers: High-sensitive troponin I, brain natriuretic peptide/N-terminal-prohormone as per local availability and affordability.

Exclusion criteria

Neonates with preexisting congenital heart disease, congenital coronary anomalies, abnormal anomaly scan, major extracardiac anomalies, genetic aberrancies, maternal preeclampsia, early-onset intrauterine growth retardation due to placental–fetal etiologies, positive blood or urine culture, or positive septic panel at presentation were excluded from the study.

Results

Out of the 12 neonates diagnosed and treated as MIS-N, 11 (91%) presented during the second wave in 2021 while only 1 neonate (patient number 4) was born during the first wave in 2020. Ten neonates were serology positive (COVID IgG positive), one RT-PCR positive, while one neonate was RT-PCR negative but epidemiological, laboratory, and echocardiographic criteria positive for MIS-N.

All mothers except one tested negative for COVID RTPCR while nine mothers had positive SARS-CoV-2 IgG. Two families refused testing and one mother tested COVID positive by RT-PCR. IgM SARS-CoV-2 antibody assay performed in three neonates (1, 2, and 3) was negative. The same could not be performed in the rest 9 neonates due to financial constraints.

Peripartal maternal and neonatal clinical presentations, laboratory parameters, and outcomes of these 12 neonates are displayed in [Table 1], [Table 2] and [Figure 1], [Figure 2].

Table 1: Demographic data of multisystem inflammatory syndrome in neonates

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Table 2: Laboratory values in neonates with multi-inflammatory syndrome in neonates

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Figure 1: Marker of severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) infection and deranged lab values in neonates diagnosed with 'multi-inflammatory syndrome in neonates'. CRP: C reactive protein, LFT: Liver function test, RFT: Renal function test, RTPCR: Reverse transcription–polymerase chain reaction

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Figure 2: Echocardiographic abnormalities in neonates diagnosed with 'multi-inflammatory syndrome in neonates'. FO: Foramen ovale, LV: Left ventricle, MR: Mitral regurgitation, PAH: Pulmonary arterial hypertension, PE: Pericardial effusion, TAPSE: Tricuspid annular plane systolic excursion, TR: Tricuspid regurgitation

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The most common maternal concern was fetal distress manifesting as decreased fetal movement; the time taken to reach the delivery center was a mean of 11.6 h (range 8–14 h).

Mode of delivery was lower section cesarean section in nine while three were born vaginally. Nine (75%) of these mothers had abnormal nonstress test (NST) and/or Doppler at the time of presentation. Eleven (91%) pregnancies were under regular obstetric supervision, except one unbooked mother. Thick meconium-stained amniotic fluid was detected in 41% of neonates. Premature deliveries occurred in 5 (41%) affected pregnancies (1 was extreme preterm [<28 weeks] while 4 were born very preterm [28–33 weeks gestational age]).

IgG antibody was positive (cut-off index accepted as more than 4 times of normal) in 83% of neonates. Serial number 8 neonate was RT-PCR positive, IgG negative while the neonate number 9 was epidemiologically traced to infected RT-PCR-positive grandmother.

Multi-inflammatory syndrome in neonates in the first wave

Only one neonate (serial number 4) had MIS-N in the first wave (2020). The mother had RT-PCR-positive mild COVID infection at 29 weeks. Although MIS-N was unknown to India then, refractory persistence of pulmonary hypertension in neonate (PPHN), catecholamine-resistant shock, elevated creatinine phosphokinase (total and myocardial band), and positive SARS-CoV-2 antibodies on the 4^th day of life were the leading clinical clues. Aggressive neonatal therapy (high-frequency ventilation, inhaled nitric oxide, dopamine, milrinone, epinephrine, norepinephrine, and magnesium sulfate) rescued him. Stress dose hydrocortisone was the only steroid used then.

Multi-inflammatory syndrome in neonates in the second wave

The remaining 11 neonates were delivered during community transmission phase between May and July 2021.

Only neonate number 8 was RT-PCR positive within 24 h of life.

Average birth weight in our cohort was 2048 g (range 650 g–3.19 Kg). Only 3 (12%) neonates had normal Apgar scores. The average day of suspicion for MIS-N was the 2^nd day of life (range day 1–4).

Three (25%) neonates had treatment refractory respiratory distress syndrome (RDS) and 1 had right-sided pneumothorax. Prolonged respiratory support (>7 days) in the form of invasive ventilation or continuous positive airway pressure (CPAP) was required in all, except 3 neonates (neonates number 2, 5 and 11, respectively). All were successfully weaned to room air except one extreme premature who expired due to necrotizing enterocolitis (NEC).

Deranged renal parameters (blood urea nitrogen and creatinine) were seen in 5 (41%) and transaminitis and altered coagulation parameters manifested in 9 (75%) neonates.

Neurological and cutaneous manifestations were conspicuously absent.

Chest roentgenogram

Chest X-ray showed cardiomegaly (cardiothoracic ratio ranging from 60% to 90%) in 91% except in neonate number 5 [Figure 3]a and [Figure 3]b. RDS was evident in 4 (33%) neonates [Figure 3]c while 1 developed tension pneumothorax relieved by emergency chest tube insertion [Figure 3]d.

Figure 3: (a) Chest X-ray frontal view (case 3) taken at day 1 of life showing severe cardiomegaly (cardiothoracic ratio 85%). (b) Chest X-ray of same baby 1 week after receiving intravenous immunoglobulin. (c) Chest X-ray frontal view (case 10) with features of respiratory distress syndrome. (d) Chest X-ray frontal view (case 6) with right-sided pneumothorax with an intercostal drain

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Electrocardiogram

All neonates except one had sinus tachycardia (heart rate 160–190/minute) with normal axis for age. One neonate had atrial bigeminy which reverted to sinus rhythm after anti-inflammatory treatment.

Echocardiography findings in multi-inflammatory syndrome in neonates

The constellation of echocardiographic findings in these neonates is displayed in [Table 3] and [Figure 2]. Cardiomegaly was a universal finding; 75% had severe right heart enlargement, proportionate to the severity of PPHN. The mean left ventricular (LV) function at presentation (expressed as LV ejection fraction [LVEF]) was 49.5% (range 10%–60%). Cardiac dysfunction (LVEF below 55%) was recorded in 5 (41%) neonates. The EF was calculated with the neonates on inotropic supports in all except 3 (case 3, 5, and 11). Quantitative echocardiography revealed decreased tricuspid annular plane systolic excursion (TAPSE) as marker of right ventricular (RV) dysfunction [Figure 4]a, which gradually normalized following specific therapy. As per the available data, normal value for TAPSE ranges from a mean of 0.44 cm (Z-score ± 2: 0.30–0.59 cm) in preterm neonates in the 26^th week of gestation to 1.03 cm (Z-score ± 2: 0.85–1.21 cm) in term neonates in the 41^st week of gestation.^[14]

Table 3: Echocardiography findings in neonates with MIS-N

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Figure 4: (a) Right ventricular function assessment by TAPSE (case 1). TAPSE 0.62 cm suggestive of poor right ventricular function. Normal value of TAPSE is 1.03 cm (Z-score ± 2: 0.85-1.21 cm) in term neonates. (b) Pulmonary artery pressure assessment by tricuspid regurgitation jet peak velocity from apical four-chamber view. A peak velocity of 432 cm/s (peak gradient 75 mmHg) marked severe pulmonary arterial hypertension (case 12). (c) Continuous wave Doppler interrogation across ductus arteriosus in case 9 showing bidirectional shunt across ductus arteriosus with severe pulmonary arterial hypertension. (d) Parasternal short axis view at level of great vessels showing dilated coronary arteries. Both left and right coronaries (marked by arrows) are dilated (case 2). (e) Parasternal short-axis view (case 11) showing large thrombus in left atrial appendage protruding into left atrium. TAPSE: Tricuspid annular plane systolic excursion

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Pulmonary arterial hypertension was observed in 83%; out of which 50% had suprasystemic pulmonary artery pressure [Figure 4]b and [Figure 4]c. Presence of PPHN in such a clinical background was a false trail. It confused the neonatologists to consider the “garden variety” PPHN or cyanotic congenital heart diseases as the etiology. When the standard treatment protocol for PPHN failed, pediatric cardiologists were involved for detailed analysis.

Unusual echocardiographic findings such as coronary changes were discovered with high frequency, broad-band (10–12Hz) transducer in parasternal short-axis view in 50% of neonates. All coronary dataset were communicated in Z-scores. Z-scores >2 but <2.5 were considered as dilatation, ≥2.5 to <5 as small aneurysms, ≥5 to <10 Z-score or absolute dimension <8 mm as moderate aneurysms, and ≥10 Z-score or absolute dimension ≥8 mm as giant aneurysms as per the 2017 American Heart Association guidelines. Coronary dilatation/small aneurysm at birth or within 96 h of life were seen in 7 (58%) in this series. Such early coronary changes are rather undescribed till now. Very early-onset KD in neonates is a sensitive marker of MIS-N during pandemic [Figure 4]d.

Other echocardiographic clues were giant left atrial thrombus in neonate number 11 [Figure 4]e and presence of new-onset, unexplained, more than mild atrioventricular valvular regurgitation. Pericardial effusion (without tamponade) was observed when meticulously imaged from subcostal view. Five (41%) had bidirectionally shunting foramen ovale while two had complete right-to-left shunting across it. The clinical and echocardiographic findings were simultaneously analyzed to unearth an odd pattern.

Treatment protocol

All neonates were managed in NICU by a multidisciplinary team. In addition to supportive care, respiratory augmentation (invasive ventilation, CPAP, or oxygen by nasal prongs), first-line broad-spectrum intravenous (IV) antibiotics were started from the 1^st day in all neonates.

Once echocardiographic data alerted to probable MIS-N, additional confirmatory inflammatory and cardiac markers were tested. When all three matched positive, anti-inflammatory drugs were started- intravenous immunoglobulin (IVIG) with steroid (n = 8), steroids only (n = 2), and IVIG only (n = 2). Subcutaneous low-molecular-weight heparin (LMWH) (1 mg/kg twice daily) was given in newborns with intracardiac thrombus, elevated D-dimer (above 2 ng/ml), acceptable platelets and coagulation parameters, and absence of clinical or radiological hemorrhage.

All neonates with coronary ectasia and aneurysms were started on tablet aspirin (3 mg/kg once daily postfeed) and continued till normalization of Z-scores.

Outcome

All neonates except one improved and were successfully weaned off supports. Dramatic reduction in CRP levels in all babies is demonstrated in [Figure 5].

Figure 5: C-reactive protein levels at day 1 of life, on the day of suspicion of multi-inflammatory syndrome in neonates and 3 days postanti-inflammatory treatment in neonates with 'multi-inflammatory syndrome in neonates'. The chart shows dramatic reduction in level of C-reactive protein postanti-inflammatory treatment

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One neonate, born extreme preterm, expired from NEC on the 20^th day of life after resolution of laboratory and echocardiographic markers of MIS-N.

Discussion

MIS-N is a hitherto under-recognized entity, and the clustering of our cohort during the second wave alerted us to it. Mechanisms proposed to explain fetal–neonatal involvement in SARS-CoV-2 infection are as follows:

Vertical transmission of SARS-CoV-2 to the newborn has been noted.^[15] A meta-analysis of 176 papers documenting confirmed neonatal SARS-CoV-2 infections reported that 30% were due to vertical transmission and that 55% of infected neonates developed COVID-19 symptoms^[16]
Transplacental transfer of maternal IgG antibodies occur in response to maternal SARS-CoV-2 infection.^{[17],[18],[19],[20]} Antibody-dependent enhancement responses have been implicated in induced immune injury where low-titer neutralizing antibodies may accentuate viral-triggered immune responses perpetuating the cascade of inflammatory cytokines^{[8],[16],[21],[22]}
Postnatal-acquired infection from maternal or other caregivers by aerosol, droplet, or surface transmission.^[13]

^[12]

We also postulate a fourth mechanism. Maternal infection with SARS-CoV-2 leads to vertical transmission of virus to fetus. Fetal infection leads to the formation of fetal IgG and IgM antibodies. Latter generate fetal inflammatory response syndrome. An article by Furth van et al. in 1965 supports our hypothesis of fetal immune response.^[23] Furth et al. demonstrated synthesis of IgM and IgG in spleen culture, starting from the 20^th week of gestation. However, this needs further research.

In our case series, majority of neonates (75%, n = 9) demonstrated elevated IgG to SARS-CoV-2 reflecting either transplacental transfer of antibody or fetal infection with subsequent antibody generation.

Published data about MIS-N record similar pattern of multiorgan involvement, especially cardiac, elevated inflammatory markers, and response to immunosuppressants (IVIG and steroids).^{[13],[15],[24]}

Although these neonates clinically presented as perinatal asphyxia and meconium aspiration, advanced echocardiography first excluded congenital cyanotic heart disease, and subsequently, alerted us to red flags such as elevated coronary Z-scores and unexplained cardiac thrombus. The clustering of neonatal KD (within 4 days of birth) coinciding with COVID-19 waves prompted us to investigate for advanced laboratory markers of inflammation.

It was crucial to exclude early-onset neonatal sepsis which produces similar clinical and laboratory mimics. CRP and procalcitonin, which were previously considered as markers of bacterial sepsis, reincarnated as very sensitive markers of inflammation. Culture-negative blood and urine samples, sent before initiation of antibiotics, ruled out sepsis as the primary etiology. Simultaneous Biofire PCR respiratory and meningitis panel yielded negative results.

A previous Indian article published by Pawar et al. showed cardiac involvement in 90% of their neonates in the form of arrhythmias (44%), coronary dilatation (12%), ventricular dysfunction (20%), and intracardiac thrombus (8%).^[13] Few other case reports showed cardiac involvement in neonatal MIS-C in the form of PPHN and ventricular dysfunction.^{[15],[24],[25]} Our data recorded a higher preponderance of coronary abnormalities (58%) unlike Pawar et al. This could be due to heightened awareness and proactive examination for these markers. PPHN and right-sided cardiomegaly were also more common than LV dysfunction noted in less than half of the patients.

To summarize, cardiac involvement in our cohort was as cardiomegaly (100%), PPHN (40%), more than mild tricuspid regurgitation (83%) and mitral regurgitation (33%), small pericardial effusion (50%), LV dysfunction (41%), RV dysfunction (83%), and coronary dilatation (50%), while arrhythmia and left atrial thrombus were seen in one case each.

The most prevalent arrhythmia reported by Pawar et al. was long corrected QT interval (QTc) with 2:1 conduction.^[13] In our case series, only one neonate had hemodynamically stable, premature atrial ectopics with dominant sinus rhythm. None in this cohort had serious tachy or brady-arrhythmias unlike the findings of Pawar et al.

Lessons learned from the COVID-19 waves in India

Why MIS-N happens? The most common mechanism affecting our fetal–neonatal series was SARS-CoV-2 IgG antibodies triggering a hyperimmune response (75%). A detailed maternal and neonatal immunological study could not be performed due to resource limitations. Hence, we propose this as a clinician's hypothesis proved indirectly by rapid response to anti-inflammatory drugs. Direct neonatal RT-PCR positivity reflecting neonatal active infection was found in only 1 case
As SARS-CoV-2 is constantly mutating, newer aspects are discovered by clinicians working in densely populated, under-vaccinated, inadequate home isolation settings in resource-limited nations. The delta strain in 2021 was more fetotoxic than 2020 strain (Lineage B.1.617). Hence, our data contradict Western literature published in annum 2020 which concluded that perinatal transmission was a rare phenomenon
The dataset of this observational study was obtained from 12 unvaccinated pregnant mothers. The Indian government announced priority vaccination in pregnancies from July 2021 onward. Future research will inform whether antenatal vaccination will reduce the burden of COVID in unborn fetus^[26]
In our series, although 75% of pregnant mothers had asymptomatic infection (self-reporting), the neonates developed serious MIS-N. We hypothesize that the self-reported severity of maternal infections in pregnancy may not linearly correlate with severity of fetal–neonatal cardiac and multiorgan damage. The responsibility of echocardiographer increases more in such background
Advanced research (beyond predelivery maternal RT-PCR) comparing maternal and neonatal/cord IgM and IgG antibodies to SARS-CoV-2, placental histopathology, cytokines, tumor necrosis factor alpha, etc., are required to explain this clinical paradox^[27],[28]
Unexplained abnormal NST and Doppler during pandemic waves should alert the obstetrician. This was seen in 75% in our series. We propose this as a surrogate marker of impending fetal–neonatal cardiorespiratory compromise in limited resource setting. Dismal Apgar scores in this background even with aggressive resuscitation warrants urgent neonatal echocardiogram by trained pediatric cardiologists to promptly evaluate and treat cardiac decompensation
In contrast to another contemporary Indian case series from Pawar et al.,^[13] we detected premature ectopic beats in only one neonate. Serious arrhythmias noted by them such as prolonged QTc, second-degree heart block, and supraventricular tachycardia were not observed in spite of continuous ECG monitoring in the NICU. The similarity between both these studies is demonstration of cardiac compromise as the most common feature. Both these studies emphasize on assessment of coronary arteries. Unexplained coronary dilatation and aneurysms in the 1^st week of life with MIS-N scenario should be considered a vital cardiac red flag and prompt immediate therapy. The pediatric cardiologist should also proactively perform detailed coronary imaging beyond Z-scores. This includes exclusion of ectasia, irregularity of lumen, beaded appearance, perivascular brightness, thrombus, absence of distal tapering, and more than 1.5 times difference in the size of adjacent coronary artery segments. All these can be performed by bedside echocardiography with highest frequency broad-band neonatal transducers

Likewise unexplained shock (cardiogenic/vasoplegic), refractory PPHN should alert the maternal–neonatal team to consider MIS-N

The most important lesson learned was immediate confirmation by laboratory parameters and institution of aggressive supportive and specific therapy once MIS-N was suspected after echocardiography. In our series, the maximum rate of therapeutic response was noted within 96 h. The dramatic normalization of CRP can be used as an inexpensive monitoring tool.
However, we propose individual, customized treatment as data regarding the use of antiplatelets and anticoagulants in extreme preterms is still limited. Whether they can provoke major hemorrhagic milieu needs to be considered. We hope that our study will lead to formulation of targeted neonatal focused MIS-N therapy. Extrapolation from adult or pediatric protocols may not be suitable in all neonates. However, detection of intracardiac thrombus is a class I recommendation to start anticoagulation.
Similar confusion remains whether aspirin and IV methyl prednisolone predisposes these extreme preterms to complications such as NEC. The risk–benefit ratio of LMWH in giant coronary aneurysms and intracardiac thrombi also needs to be considered
A multidisciplinary teamwork by obstetricians, neonatologists, pediatric cardiologists, and fetal medicine specialists, all aware of this new emerging disease is the need of this hour. The maternal–fetal team needs to cohesively collect data about maternal COVID exposure, fetal scans, antenatal NST, antenatal Doppler, placental coiling index, and placental histopathological evidence of viral inflammation. Immediate upscaling of pediatric echocardiography skills and coronary imaging is needed before a possible third wave.

Limitations

This was an observational study of neonates presenting to NICU with unusual clinical disturbances during the second COVID-19 wave in India. Pediatric cardiologists were only consulted when standard operating protocols failed. Hence, the diagnosis was accidental, but response was miraculous.

Still, the sample volume is miniscule compared to the actual ground scenario. We therefore propose a national population-based registry capturing the incidence of MIS-N. A randomized controlled trial could not be conducted during the pandemic. The registry may answer many queries.

We could not include maternal mortality, still births in COVID pregnancies in this study due to lack of national registry.

As Indian health-care systems were overwhelmed during the second wave, we had to rely on self-reporting of symptoms by mothers during the antenatal period.

Cord blood serology and inflammatory markers could not be evaluated as the disease itself was new to us. Routine placental gross and histopathological studies were done. However, exclusive evaluation for SARS-CoV-2 virus or hyperimmune placental inflammation was not available. Sensitization for same needs to be highlighted.

IgM antibodies were assayed in only three patients. All neonates could not afford complete MIS-C panel due to financial issues.

Advanced neonatal and pediatric cardiology expertise also needs to be upgraded immediately during this pandemic, at least before the next wave.

Although combination of IVIG and IV methylprednisolone is recommended as the first-line therapy in MIS-C, these costly therapeutic medications could not be afforded by all neonates in this series. Hence, best practice judgment of the treating clinical team was employed to save lives.

A very important limitation was absence of Indian Z-scores for coronary arteries for neonates and preterms. We had to therefore rely on extrapolation of Z-scores from Japanese or Caucasian ethnicity. This study should kick-start data collection and formulation of Indian Z-scores for Indian children from Indian centers. Another important pointer is that there are no universally accepted Z-scores for circumflex coronary artery in the pediatric population.

Lack of neonatal autopsy in India is another scientific hindrance.

Conclusion

Infection of pregnant mothers during community transmission phase of the two COVID-19 waves in India appears to have caused significant immune dysregulation and extensive cardiac damage in neonates. Echocardiography detected silent, significant damage to coronary arteries, cardiac rhythm, cardiac function, and competence of valve apparatus in MIS-N. Without echocardiography, this cohort would have developed long-term coronary artery disease and presented in adulthood similar to “missed KD.” Unusual cardiac features including coronary aneurysms, refractory PPHN, catecholamine-resistant shock, intracardiac thrombus, cardiomegaly, and myocarditis during the community transmission should alert the medical fraternity to utilize cardiology services immediately. Aggressive immunomodulators (IVIG, steroids) with aspirin in antiplatelet dose proved lifesaving. Although the safety profile of such drugs in neonates (especially preterms) is unknown, the risk–benefit ratio is tilted toward benefit in potentially fatal conditions. Echocardiography is an inexpensive, readily available imaging modality. It should be utilized to save this fragile, extremely special cohort.

Financial support and sponsorship

Nil.

Conflicts of interest

Munesh Tomar is an editorial board member of the Journal of The Indian Academy of Echocardiography & Cardiovascular Imaging. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and their research groups.

There are no other conflicts of interest.

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