Our patient was a female neonate born at 35 weeks to a 32-year-old mother who was newly diagnosed with Systemic Lupus Erythematosus (SLE) in the first trimester. The mother tested positive for ANA, dsDNA and SS-A antibodies. She received Plaquenil, Atovaquone, Azathioprine, Aspirin and Prednisone during pregnancy. At the mid-gestation anatomy scan, there were no abnormal findings. Fetus had appropriate growth parameters and had normal heart rate of 140–160 beats per minute with a regular rhythm throughout pregnancy. At 34 gestational weeks, the mother presented with new onset systemic hypertension and premature rupture of membranes. After completing a course of betamethasone, she progressed to preterm labor. The baby was born at 35 weeks via spontaneous vaginal delivery. The Apgar scores were 5, 6 and 8 at 1, 5 and 10 minutes of life respectively.
On day of life (DOL) 2, the baby developed new respiratory distress with increased work of breathing and hypoxia, which slightly improved with CPAP. The chest radiograph showed moderate cardiomegaly and pulmonary edema. Laboratory evaluation was remarkable for diffuse end-organ damage with a high blood lactate (5.3 mmol/L), cardiac dysfunction (elevated brain natriuretic peptide > 5000pg/mL) and myocardial injury (troponin I 0.19pg/L). She also had significant transaminitis and coagulopathy (ALT 624 U/L, AST 2513 U/L, Ammonia 98um/L, INR 2.7) (Table 1). CBC, electrolytes, and blood gas were within normal limits. Her electrocardiogram and telemetry showed a normal sinus rhythm with no evidence of heart block (HB) or arrhythmia. An echocardiogram (ECHO) was performed to investigate the cardiac function and showed a structurally normal heart. More specifically, no left sided obstructive heart lesions or coronary artery anomalies were noted, but the ECHO showed severely decreased biventricular function, moderate mitral regurgitation, and no pericardial effusion. There was no echocardiographic evidence of endomyocardial fibroelastosis (EFE).
Table 1
Initial laboratory evaluation
| DOL3 | DOL 5 | DOL9 | DOL18 | DOL24 |
BNP (pg/mL) | > 5000 | > 5000 | > 5000 | 3460 | 746 |
Lactate (mmol/L) | 4 | 4.4 | 2.8 | 0.9 | 0.5 |
ALT (U/L) | 624 | 660 | 218 | 42 | |
AST (U/L) | 2,513 | 1,919 | 121 | | |
PT/INR | 27.5/2.8 | 36.5/3.8 | 15/1.2 | | |
APTT | 37.8 | 79.8 | 27.5 | | |
Ammonia (umol/L) | 98 | 63 | 29 | | |
Creatinine (mg/dL) | 0.93 | | 0.91 | 0.45 | 0.4 |
Urea (mg/dL) | 16 | | 23 | 41 | 48 |
Fibrinogen (mg/dL) | | | | 158 | 230 |
Ferritin | | | 2940 | 1908 | 1440 |
WBCs/PLT/Hb | 8.7k/124k/12.5 | | 37k/75k/10.9 | 19.5k/526k/12.2 | |
Table 2
Literature Review of rhythmic and non-rhythmic cardiac abnormalities associated to NLE
References Cardiac NLE | Year | Cases (newborns or pregnancies) Total | Cases# R cardiac anomalies | Cases # NR anomalies | Systemic Hypertension | Deaths# (%) | Comments |
Buyon et al14 | 1998 | 113 (infants) | 113 | 0 | N | 22 (19%) | National Neonatal Lupus Registry. Multicenter retrospective study on 113 infants with CHB |
Eronen et al8 | 2000 | 91 (infants) | 91 | various cardiac defects associated with CHB: ASD #19, PDA #14, #21 DCM | N | 16 (17%) | Retrospective Finnish study on 91 infants with CHB > 40years. Excluded patients with major structural abnormalities. Interestingly, 21 patients presented DCM with ~ 63% mortality in this subgroup. |
Nield et al6 | 2002 | 3 (infants) | 0 | #3 EFE | N | 2 (66%) | Case series, first description of EFE in absence of Rhythm anomalies |
Cimaz et al15 | 2003 | 128 (infants) 124 (pregnancies) | 2 | 0 | N | 0 | Prospective study on 124 pregnancies with anti-SSA, SSB or both antibodies in two center (Milan and Toronto) |
Friedman et al16 | 2008 | 98 (pregnancies) | 6 | 0 | N | 2(~ 2%) | Multicenter Prospective study on 127 pregnant women with anti-SSA antibodies followed during pregnancy (16–24 weeks0 and postnatally (3 ys) |
Guettrot-Imbert et al7 | 2011 | 5(fetuses and newborn) | 0 | #5 (EFE) | N | 1 (20%) | Case series, 5 fetal cases of EFE in absence of CHB. Death was a therapeutic abortion |
Ambrosi et al17 | 2012 | 351(children) | 149 | 0 | N | 0 | Swedish registry. Retrospective study on 145 families with positive antibodies |
Lanos et al18 | 2012 | 18 (Fetuses) | 15 | #3 (Pancarditis #2, EFE #1) | N | 18 (100%) | Retrospective Autoptic analysis on fetuses and neonates that dies for cardiac complications of maternal lupus |
Singavalanija et al19 | 2014 | 34 (infants) | 5 | 0 | N | 2 | Retrospective analysis on NL Single center 20 years in Thailand |
Jakobsen et al20 | 2015 | 84 (pregnancies), 62 (infants) | 1 | #6 (ASD/VSD, NS) | N | 0 | Retrospective study on 84 pregnant lupus pregnancies in single center in Denmark |
Levesque et al9 | 2015 | 214 (fetuses or neonates) | 214 | DCM#35 (~ 18% of the babies born alive) | N | 49 | French National registry Retrospective Multicenter study on 214 patients with CHB, 2nd largest CHB cohort and first French registry. In this study ~ 18% of the baby born alive presented DCM with 40% mortality |
Yi-Qun-Li21 | 2015 | 123 (infants) | 14 | #5 (ASD#1, LA en largement #1, PFO #3) | N | 2 (1.6%) | Retrospective study on 12 cases of neonatal lupus in China |
Abdwani et al22 | 2018 | 147 (pregnancies) | 0 | 0 | N | 0 | Retrospective study in single center in Oman |
Diaz et al23 | 2021 | 324 (infants) | 18 | 12 (EFE #7, Myocarditis #5) | N | unknown | Retrospective Multiethnic cohort of 324 children born from 270 by Anti-Ro positive mothers at Sick Hospital for Children Toronto |
Braga et al24 | 2021 | 183(newborns) | 2 | 0 | N | 1 | Retrospective study conducted on 215 pregnancies from 143 patients with SLE single center study in Portugal |
Erazo-Martinez25 | 2021 | 43(newborns) | 2 | 0 | N | 1 (2%) | Retrospective study conducted on 48 pregnant women with SLE single center Colombia |
R cardiac anomalies: Rhythm, NR: Non-Rhythm cardiac anomalies; CHB: congenital heart block, ASD: Atrial septal defect; VSD: ventricular septal defect; PDA: Patent ductus arteriosus DCM: dilated cardiomyopathy; EFE: Endocardial Fibroelastosis |
Given the maternal history of SLE and high titers of maternal anti-Ro60 (SS-A) antibodies, the index of suspicion for NLE was high. Given the absence of NLE specific manifestations like HB, EFE or skin lesions, the initial differential was broad including infectious, metabolic, and autoimmune etiologies of cardiac and hepatic dysfunction. Cultures and titers to investigate infectious etiologies were all negative. Plasma amino acids, urine organic acids, urine reducing substances and acylcarnitine and carnitine profile values were all within normal limits ruling out the common inborn errors of metabolism. The initial thrombocytopenia and anemia associated with increased AST and ferritin raised concern for macrophage activation syndrome (MAS) in the context of maternal alloimmune antibodies, but the quick resolution of the thrombocytopenia and the clinical course did not fit with MAS diagnostic criteria4. Other rare disorders like Gestational autoimmune liver disease (GALD) and Hemophagocytic lymphohistiocytosis (HLH) were also considered and ruled out given the improvement in the hepatic function after vigorous hemodynamic support by increasing circulating volume. The perinatal history did not suggest hypoxic fetal insult to the myocardium, therefore we focused on genetic and inflammatory etiologies as potential causes of the cardiomyopathy. Given the concerning trends of the baby’s cardiac and hepatic function during DOL2-4 (Table 1), the baby was started on NLE treatment while awaiting serological confirmation for NLE and completing the diagnostic work-up. The patient received IVIG on DOL5 and was started on Methylprednisolone 2mg/kg BID for two weeks, then 1 mg/kg/day BID for an additional two weeks3. After initiation of therapy for NLE, the cardiac function improved significantly with consequently better systemic perfusion and improved hepatic function (Table 1). DOL9 ECHO showed normal ventricular function bilaterally. BNP showed improving trends starting DOL18 and liver function also normalized rapidly in the first week of life. On DOL7, the lupus autoimmune work up resulted with positive SS-A antibody and ANA antibody with speckled pattern, confirming the diagnosis of NLE.
Surprisingly, during the initial presentation, the baby was hypertensive despite the biventricular dysfunction and the hypertension persisted even after starting milrinone infusion (1 mcg/kg/min). Systemic blood pressure remained above 99th percentile for age during the first week and Nicardipine infusion (1 mcg/kg/min) was started on DOL 5 as a second anti-hypertensive agent (Fig. 1). A work-up for hypertension included renal and bladder ultrasound which showed normal renal anatomy without evidence of renal artery stenosis. Normal urine calcium levels excluded nephrocalcinosis. Ultimately, urinalysis showed elevated urine protein: creatinine ratio and beta-2-microglobulin, suggestive of antibody-mediated tubular injury potentially causing nephrogenic hypertension. Strikingly, the hypertension persisted, thus a continuous infusion of Esmolol starting at 100 mcg/kg/min was initiated as a third anti-hypertensive agent on DOL15 (Fig. 1). Systemic blood pressure showed an improving trend in the fourth week of life and continuous infusions of anti-hypertensive medications were gradually weaned off: first Milrinone (DOL21), then Esmolol (DOL25), finally Nicardipine (DOL28). Enteral Amlodipine was then started and continued for the following month with good control of the hypertension
Our patient’s clinical course was further complicated by new onset respiratory distress and hypoxemia requiring intubation on DOL13 and escalation to high frequency oscillator ventilation (HFOV) with iNO (inhaled Nitric oxide) to improve ventilation/perfusion mismatching. The baby received broad spectrum antibiotics (cefepime) and a second dose of IVIG for concerns of Lupus pneumonitis but showed no improvement in her respiratory status. The echocardiogram showed no evidence of cardiac dysfunction or pulmonary hypertension. There was no clear understanding of the pathophysiology of her lung disease, however, we can speculate it was a combination of inflammation, altered endothelial permeability, and fluid overload from her renal dysfunction. With appropriate respiratory support and gentle diuresis, the respiratory status improved, and we were able to wean the respiratory support back down to CPAP by DOL 30 and was weaned to room air by DOL 40.
Over the next two months, the patient improved slowly. Her anti-hypertensive medications were transitioned to oral clonidine and amlodipine and then weaned off. She was discharged home by 2 months of age with a normal ECHO, blood pressure and renal function. She was tapered off hydrocortisone at 4 months of age with a normal subsequent ACTH stimulation test. At the 18 month high-risk infant visit, she displayed a normal neurologic exam and normal development for her age.