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Background Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro–mediated congenital heart block (CHB). Objectives Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. Methods This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon’s optimal approach. Anti-SSA/Ro–positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. Results By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). Conclusions These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573 )

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p

Background Immune thrombocytopenic purpura (ITP) is a rare autoimmune disorder that involves platelet destruction in the spleen. Eltrombopag (Promacta®), a thrombopoietin agonist, has been used in non-pregnant patients to manage ITP, but few cases of its use in pregnancy have been reported. Case Presentation We present a case of a pregnant patient at 26 weeks of gestation with severe refractory ITP. After first-line therapies failed, the patient was treated with the drug eltrombopag. The patient had no response to initial therapy, and the fetus developed supraventricular tachycardia (SVT). This resolved with maternal digoxin but the patient elected to stop the eltrombopag. The patient refused further experimental and second-line treatments, and after a multidisciplinary meeting a decision was made to deliver by cesarean section at 30 weeks of gestation due to severe refractory ITP and allow other therapies to be tried postpartum. Preeclampsia and neonatal atrial flutter were encountered in the postpartum period but both mother and baby had good outcomes. Conclusion Refractory ITP in pregnancy is not well studied. Eltrombobag could have maternal and fetal side-effects but a multidisciplinary approach to management leads to favorable maternal and fetal outcomes., Highlights • Eltrombopag is a second-line agent for treatment of refractory immune thrombocytopenia that is not well studied in pregnancy. • Fetal side-effects of eltrombopag use have not been established in pregnancy, but low birthweight has been reported. • Fetal supraventricular tachycardia is a possible side-effect of eltrombopag that we saw, but was safely treated with maternal digoxin. • Preeclampsia has been reported with eltrombopag use, as in this case, and the association needs to be further investigated. • Risks and benefits must be weighed for eltrombopag use and timing of delivery in cases of severe refractory immune thrombocytopenia.

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

Background Sickle cell disease (SCD) is a hemoglobinopathy and vasculopathy resulting in vaso-occlusive crises, chronic end-organ damage, and shortened life span. The only curative therapy is allogeneic stem cell transplant (AlloSCT) (Talano/Cairo, EJH, 2015). Unfortunately, only approximately 16% of the sickle cell population has an HLA matched unaffected sibling (Bhatia/Cairo, BMT, 2014). We have demonstrated the safety and efficacy of familial haploidentical transplants (FHI) in this population with 100% engraftment (Cairo et al, JAMA Peds, 2019). However, the incidence of sinusoidal obstructive syndrome (SOS) in SCD AlloSCT recipients is approximately 32% (McPherson, BMT, 2011). Defibrotide primarily targets endothelium and can reduce endothelial cell injury (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996). Corbaciolgu et al (Lancet 2012) demonstrated the safety and efficacy of prophylactic defibrotide in high-risk pediatric AlloSCT recipients to significantly reduce the incidence of SOS. Objective To determine the safety and efficacy of defibrotide prophylaxis for SOS in children, adolescents and young adults (CAYA) with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. Design/Methods Patients with SCD aged 2 to 35 years with high-risk SCD (stroke, ≥2 acute chest syndrome in past 2 years, ≥3 pain crises in last 2 years, abnormal TCD study, ≥1 silent infarct lesion on MRI) were enrolled after being consented (NCT02675959). Patients were in two cohorts (2 to 17.99 years and 18 to 34.99 years of age) for age-based analysis and treatment (Table 1 and 2). All patients received a MAC regimen prior to receipt of an FHI with CD34+ selection and CD3 addback peripheral blood stem cell transplantation (PBSCT), as we have already demonstrated (Cairo et al, ASH, 2018). Defibrotide was given day -10 during conditioning through day +21 following transplant. Baseline studies of organ function and biomarkers were obtained prior to transplantation. Results We have enrolled eight patients, five in cohort 1 (median age 9.9 years) and three in cohort 2 (median age of 24 years) with a gender ratio (M/F) of 4/4. Patients had hemoglobin SS (n=7) or hemoglobin SC (n=1). Patients had either a maternal (n=7) or sibling (n=1) donor. Patients had early neutrophil engraftment (median day +11 (day +7 to day +14)). All tolerated 109 ± 11doses of defibrotide. There were no severe adverse or bleeding events probably or directly related to defibrotide. No patient developed SOS. Conclusion The preliminary data suggests defibrotide is safe and well tolerated in CAYA patients with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. A larger cohort and/or follow-up will be required to confirm these preliminary findings. Supported by FDA R01FD004090 and Jazz Pharmaceuticals.

ObjectivesCardiac manifestations of neonatal lupus (NL) have been associated with significant morbidity and mortality; however, there is minimal information on long-term outcomes of affected individuals. This study was initiated to evaluate the presence of and the risk factors associated with cardiac dysfunction in NL after birth in multiple age groups to improve counselling, to further understand pathogenesis and to provide potential preventative strategies.MethodsEchocardiogram reports were evaluated in 239 individuals with cardiac NL: 143 from age 0–1 year, 176 from age >1–17 years and 64 from age >17 years. Logistic regression analyses evaluated associations of cardiac dysfunction at each age group with demographic, fetal and postnatal factors, using imputation to address missing data.ResultsCardiac dysfunction was identified in 22.4% at age 0–1 year, 14.8% at age >1–17 years and 28.1% at age >17 years. Dysfunction in various age groups was significantly associated with male sex, black race, lower fetal heart rates, fetal extranodal cardiac disease and length of time paced. In 106 children with echocardiograms at ages 0–1 year and >1–17 years, 43.8% with dysfunction at age 0–1 year were also affected at age >1–17 years, while the others reverted to normal. Of children without dysfunction at age 0–1 year, 8.9% developed new dysfunction between ages >1 and 17 years. Among 34 with echocardiograms at ages >1–17 years and >17 years, 6.5% with normal function at age >1–17 years developed dysfunction in adulthood.ConclusionsRisk factors in fetal life can influence cardiac morbidity into adulthood.Although limited by a small number of cases, cardiac dysfunction in the first year often normalises by later childhood. New-onset dysfunction, although rare, can occur de novo after the first year.

This study was conducted to survey US pediatric specialists about administration of respiratory syncytial virus (RSV) immunoprophylaxis, communication patterns among physicians and parents, and barriers to access. Separate surveys were sent to neonatologists, pediatricians, pediatric pulmonologists, and pediatric cardiologists. Most physicians (≥93.5%) routinely recommended immunoprophylaxis to high-risk children. Most respondents (≥71.8%) reported that >50.0% of eligible infants and young children received each monthly dose throughout the RSV season, with the first dose most commonly administered before discharge from the birth hospitalization. To ensure receipt of subsequent doses, specialists frequently scheduled a follow-up visit at the end of the current appointment. All specialists reported insurance denials as the biggest obstacle to the administration of immunoprophylaxis to high-risk children. These findings may be used to improve adherence to immunoprophylaxis by enhancing education and physician-parent communications about severe RSV disease prevention, and by reducing known barriers to use of this preventive therapy.

Neonatal lupus (NL) is an autoimmune disease that is acquired in utero after the transplacental passage of maternal autoantibodies reactive against Ro and La antigens. It is characterized by varying degrees of heart block and can be associated with an erythematosus rash. NL occurs in 1% to 2% of babies born to mothers with anti-Ro (also known as anti-SSA) and anti-La (also known as anti-SSB) antibodies. It is not necessary for these women to have clinical manifestations of an autoimmune disease. The most serious complications of NL involve the heart, but other manifestations include the liver as well as cutaneous and hematologic systems. Cardiac involvement includes first-, second-, and third-degree heart block as well as endocardial fibroelastosis in isolation or accompanying conduction system disease. NL is the etiology most commonly associated with isolated congenital heart block, accounting for up to 95% of all cases. This chapter will review the epidemiology, pathophysiology, clinical considerations, candidate biomarkers, and current guidelines regarding management of pregnancies complicated by NL.

Background There are no longitudinal studies regarding the long term cardiac health of children with cardiac manifestations of neonatal lupus (NL). This study was performed to evaluate risk factors for morbidity and provide evidence-based guidance regarding the course of cardiac NL. Methods Echocardiograms throughout life were evaluated in 240 individuals born with cardiac NL from the Research Registry for Neonatal Lupus: 142 were available from ages 0–1 years, 174 from ages 1–17 years, and 65>17 years. A composite adverse outcome defined as qualitatively decreased left ventricular (LV) function or concurrent use of cardiac medications was assessed. Aortic dilation (root or ascending aorta z-score >2.0) was also recorded. Analyses were performed to associate the composite adverse outcome and aortic dilation with maternal medications, pacing, and fetal disease status, including a severity score based on mortality risk factors such as lower fetal heart rate and extranodal disease. Results The composite adverse outcome for cardiac dysfunction was identified in 21.1% of echos in children ages 0–1, 13.2% ages 1–17% and 29.2% ages>17. In 89 children in which echos were available at ages 0–1 and 1–17, 6/16 with dysfunction at ages 0–1 were also affected at ages 1–17, while 10 reverted to normal. Among those without dysfunction at age 0–1, 8/90 developed new worsening of cardiac function during age 1–17. In 35 cases with echos at ages 1–17 and >17, 3/3 cases with dysfunction at age 1–17 were also affected at >17, and 2/32 developed new dysfunction in adulthood. Cardiac dysfunction was significantly associated with number of years paced at all ages (p 17 (p=0.048, 0.005 respectively) and lowest heart rate in utero associated with dysfunction at age 17 (p=0.026, 0.023). Higher fetal severity score associated with postnatal dysfunction in ages 0–1 and 1–17 groups (p=0.013, 0.001). Aortic dilation was present in 13.4% at ages 0–1% and 14.9% at ages 1–17, but at >17, dilation only occurred in 9.2%. There was no association of postnatal cardiac dysfunction or aortic dilation with maternal medication use, maternal rheumatic disease, fetal age at heart block detection or gestational age of birth. Conclusions Cardiac dysfunction in the first year normalizes by later childhood in the majority of cases, possibly due to the short term effects of cardiac pacing or resolution of inflammation with the clearance of maternal autoantibodies. However, new onset dysfunction can occur after the first year of life. Aortic dilation can continue for longer periods, but may decrease in frequency with age. Nevertheless, cardiac dysfunction is present in roughly 30%, and in adulthood there are associations with fetal extranodal disease and heart rate at detection. Patients who develop morbidity in utero may have subclinical damage or be more susceptible to future insults that manifest later in life, which can be exacerbated by prolonged pacing. Close monitoring and aggressive treatment of early extranodal disease in cardiac NL may have long term benefit in preventing subsequent morbidity.

ObjectivesExtension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit.MethodsIn this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation.ResultsIn Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified.ConclusionsThese data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.

Background Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, and cardiac dysfunction: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D. Objectives Identification of maternal and fetal biomarkers associated with development and morbidity of cardiac NL should provide clues to pathogenesis with translational implications for management. Methods Cord (139) and maternal (135) blood samples collected during pregnancies at risk for cardiac NL were available for study. Levels of cord and maternal CRP, cord NT-proBNP, and cord troponin I were evaluated using multiplex assays. Cord and maternal vitamin D were assessed by liquid chromatography-mass spectrometry. MMP-2, uPA, uPAR, and plasminogen were evaluated using ELISA. Results Cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in cardiac NL-affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of cardiac NL development, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality in cardiac NL. Maternal CRP and cord troponin I levels did not differ between the groups. Cord and maternal vitamin D levels were not significantly associated with cardiac NL, but average maternal vitamin D level during pregnancy was positively associated with longer time to postnatal pacemaker placement. Conclusions These data support the association of fetal reactive inflammatory and fibrotic components with development and morbidity of cardiac NL. Following CRP and NT-proBNP levels after birth can potentially monitor severity and progression of cardiac NL. MMP-2 and the uPA/uPAR/plasminogen cascade provide therapeutic targets to decrease fibrosis. Although decreased vitamin D did not confer increased risk, given the positive influence on postnatal outcomes, maternal levels should be optimized.

Background: Venous thromboembolism (VTE) is a major complication in children and adolescents because of its association with significant morbidity and mortality (Raffini, Pediatrics 2009). Neonates represent the largest group at risk in the pediatric population, however, adolescents account for approximately 25% of pediatric patients who develop primary VTEs. This may in part be related to the similar risk factors between adults and adolescents such as obesity, smoking, and use of oral contraceptives (Kuhle, Thromb Haemost 2004). Fan et al, PBC, 2017 reported on the safety and efficacy of enoxaparin administered by subcutaneous injection in pediatric patients with primary VTEs in which 38% of patients had complete resolution of their VTE on imaging after 3 months of therapy and 39% had partial resolution. Novel oral anticoagulants, direct factor Xa (FXa) inhibitors, are approved in adults for secondary VTE prophylaxis with established efficacy and safety and without the need of subcutaneous injection or frequent blood monitoring compared to oral warfarin (Male et al, Thromb Res 2019). Apixaban, a selective inhibitor of FXa, compared to vitamin K antagonists, has a rapid onset of action, few drug-drug interactions and a predictable anticoagulant response that enables fixed dosing. In addition, they have less variability in pharmacokinetic and pharmacodynamic responses than warfarin, and have a wider therapeutic index (Garcia, J Thromb Haemost 2013). Similarly, compared to subcutaneous heparin, no injections are required and no pharmacodynamic monitoring is needed. Hypothesis: Secondary prophylaxis with Apixaban (Eliquis®) will be safe, well tolerated and prevent secondary VTEs in children and adolescents with a newly diagnosed primary VTE. Methods: Children weighing > 40 kg and having experienced a primary VTE were eligible to receive apixaban within 72 hrs of VTE diagnosis. A thrombophilia workup was performed including, but not limited to, Factor V Leiden, Protein C and S, and prothrombin gene mutation. Eligible consented patients were administered apixaban 10 mg twice daily P.O. for 7 days followed by 5 mg twice daily until day 90, similar to that used in the AMPLIFY trial in adults (Agnelli, J Thromb Haemost 2015). Treatment began within 72 hours of diagnosis of VTE and transition from other anticoagulants was permitted. Patients unable to tolerate oral medications, with personal or family history of bleeding disorder, history of significant head injury and/or history of intracranial hemorrhage, were excluded from this study. Results: Fifteen patients have been enrolled to date with a median age of 16 yrs (12 - 21 years) and were seventy three percent females (11 females, 4 males). Forty percent of patients were enrolled with primary pulmonary emboli, the remaining with new onset deep venous thrombosis. Line associated clots were included in the study. There were no episodes of bleeding, classified as Grade I-IV hemorrhage (CTCAE), or other adverse events and no patients required dose modifications. There were also no significant changes in creatinine or liver function throughout the course of apixaban administration. Of the 11 patients that completed the day 30 evaluations, 55% showed resolution of their primary thrombus at 30 days with the remainder showing significant decrease in the size of the thrombus (Fig. 1). Fig. 2 illustrates the change from baseline to Day 30 in a child with a pulmonary embolus. There were no patients that experienced increase of their thrombus or any new VTE, which equates to 100% successful VTE secondary prophylaxis. The average INR range was 1.04 (0.92-1.19). The average anti-Xa level was 1.05 four hours after apixaban treatment while the average trough level was 0.88. Conclusions: Our preliminary results suggest that apixaban is safe and well tolerated in children and adolescents for the secondary prophylaxis of patients with a newly diagnosed primary VTE. Additionally, all patients had a decrease in the size of their thrombus with 50% experiencing complete resolution as early as 30 days. There was no evidence of toxicity secondary to apixaban and no requirement to monitor anticoagulant activity. We plan to continue to enroll patients on this study to further validate the safety and efficacy of apixaban. Future directions will include investigating apixaban in children < 40 kg and in neonates with primary VTEs as secondary prophylaxis. Disclosures Friedman: MedImmune: Speakers Bureau; Astra Zeneca: Speakers Bureau. Cairo:Osuka: Research Funding; Miltenyi: Other: MTA; Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau.

Neonatal lupus is an autoimmune disease that is acquired in utero from antibodies produced by the maternal immune system against Ro and La antigens. It is characterized by varying degrees of heart block and can be associated with an erythematosus rash. Neonatal lupus occurs in 1–2% of babies born to mothers with anti-Ro (also known as anti-SSA) and anti-La (also known as anti-SSB) antibodies. It is not necessary for these women to have clinical manifestations of an autoimmune disease. The most notorious complications of neonatal lupus involve the heart. These include first-, second-, and third-degree heart block as well as endocardial fibroelastosis (EFE). Neonatal lupus is the etiology most commonly associated with isolated congenital heart block, accounting for up to 95% of all cases. This chapter will review the pathophysiology and current guidelines regarding management of pregnancies complicated by neonatal lupus.

Children with hemodynamically significant congenital heart disease (CHD) are at elevated risk of morbidity and mortality due to respiratory syncytial virus (RSV) disease compared to their healthy peers. Previous studies have demonstrated lower RSV hospitalization risk among all children with CHD at 12-23 months of age versus 0-11 months of age. However, RSV hospitalization risk at 12-23 months of age by specific CHD diagnosis has not been characterized. Both case-control and cohort studies were conducted using data from the US National Inpatient Sample from 1997 to 2013 to characterize relative risk of RSV hospitalization among children 12-23 months of age with CHD. Related CHD diagnoses were combined for analysis. Hospitalizations for RSV and unspecified bronchiolitis were described by length of stay, mechanical ventilation use, mortality, and total charges. Over the 17-year period, 1,168,886 live birth hospitalizations with CHD were identified. Multiple specific CHD conditions had an elevated odds ratio or relative risk of RSV hospitalization. Mean total RSV hospitalization charges were significantly higher among children with CHD relative to those without CHD ($19,650 vs $7,939 in 2015 dollars) for this period. Compared to children without CHD, children with Ebstein's anomaly, transposition of the great arteries, aortic stenosis, heterotaxia, and aortic arch anomalies had 367-, 344-, 203-, 117- and 47-fold increased risk of inpatient RSV mortality, respectively. Unspecified bronchiolitis hospitalization odds and relative risk across CHD diagnoses were similar to those observed with RSV hospitalization; however, unspecified bronchiolitis hospitalizations were associated with shorter mean days of stay and less frequently associated with mechanical ventilation or mortality. Among children with more severe CHD diagnoses, RSV disease remains an important health risk through the second year of life. These data can help inform decisions regarding interventions to protect children with CHD from severe RSV disease during their second year of life.

In the absence of structural heart disease, the great majority of cases with complete congenital heart block will be associated with the maternal autoantibodies directed to components of the SSA/Ro – SSB/La ribonucleoprotein complex. Usually presenting in fetal life before 26 weeks’ gestation, once third-degree (complete) heart block develops, it is irreversible. Therefore, investigators over the past several years have attempted to predict which fetuses will be at risk for advanced conduction abnormalities by identifying a biomarker for less-severe or incomplete disease, in this case PR interval prolongation or first-degree atrioventricular block. In this state-of-the-art review, we critically analyze the various approaches to defining PR interval prolongation in the fetus, and then analyze several clinical trials that have attempted to address the question of whether complete heart block can be predicted and/or prevented. We find that, first and foremost, definitions of first-degree atrioventricular block vary, but that the techniques themselves are all similarly valid and reliable. Nevertheless, the task of predicting those fetuses at risk, and who are therefore candidates for treatment, remains challenging. Of concern, despite anecdotal evidence, there is currently no conclusive proof that a prolonged PR interval predicts complete heart block.

Within the last decade the prevalence of adult patients living with congenital heart disease equals that seen in children. This expanding population poses a challenge to clinical cardiologists who will be caring for patients with the clinical manifestations of this condition. Neonatal lupus is a model of passively acquired auto-immunity and is responsible for the majority of clinical cases of congenital heart block. This review will focus on the presentation, pathophysiology, and the long-term follow up of congenital heart block associated with neonatal lupus, as well as discuss important diagnostic tests, familial implications, and pacemaker issues associated with the care of an adult with congenital heart block.

Allogeneic stem cell transplantation (AlloSCT) from HLA-matched unaffected sibling donors (MSD) has been successful for high-risk SCD, and is the only known curative therapy (Freed/Cairo et al, BMT, 2012). We have recently demonstrated 100% event free survival and absence of sickle cell symptoms following reduced toxicity conditioning and HLA matched sibling bone marrow or cord blood AlloSCT (Bhatia/Cairo et al, BMT, 2014). However, 5 out of 6 children who might benefit from this therapy lack an HLA matched family donor. Identifiable matched unrelated adult donors (URD) in this ethnic group are extremely limited and results from unrelated cord blood transplants are poor (Radhakrishnan K/Cairo et al., BBMT 2013, Kamani et al., BBMT, 2012). We previously demonstrated the use of positive CD34 selection followed by T cell add back (2 x 105 CD3/kg) from unrelated donors in pediatric recipients with both malignant and nonmalignant disease lead to 100% engraftment with minimal acute GVHD (aGVHD). In a high-risk FHI TCD thalassemia study, 16/22 cases engrafted without aGVHD and with 90% overall survival (Sodani et al., Blood, 2010). FHI TCD AlloSCT could expand the donor pool and improve outcomes for patients with high risk SCD. This SCD consortium trial is investigating the safety, feasibility, EFS, donor chimerism, graft failure, aGVHD and chronic GVHD (cGVHD), and infectious mortality after FHI TCD AlloSCT in high-risk SCD patients ([Figure 1][1]). High risk features included one or more of the following: ≥1 CVA, ≥2 ACS, ≥3 VOC in past 2 years, or 2 abnormal TCDs. Patients (2-20.99 yrs) without an 8/8 HLA MSD or URD and who have ≥1 high-risk SCD features were eligible. Patients received hydroxyurea 60 mg/kg/d and azathioprine 3mg/kg/d, day -59 – day -11, fludarabine (30mg/m2/d x5d), busulfan (3.2 mg/kg/d x4d [

Congenital complete heart block associated with transplacental passage of maternal autoantibodies reactive with SSA/Ro and SSB/La is a rare disease with significant fetal, neonatal, and childhood morbidity and mortality. We present the case of dichorionic, diamniotic twins (female twin A and male twin B) exposed to maternal Ro and La autoantibodies with different disease expression. Twin A (female) had Mobitz type I second degree atrioventricular (AV) block (Wenckebach); twin B (male) had normal sinus rhythm. Both twins had structurally normal hearts but demonstrated echocardiographic evidence of endocardial fibroelastosis (EFE). Following maternal dexamethasone 4 mg once daily, twin A reverted to sinus rhythm in utero; twin B remained in sinus rhythm throughout pregnancy. Echocardiograms after delivery demonstrated resolution of EFE in both fetuses, and EKGs confirmed sinus rhythm. However, at five months of age, Holter monitor demonstrated first degree AV block and intermittent Wenckebach in twin A. Twin B remains in sinus rhythm. This case is one of only three in the literature that describes Mobitz type I second degree atrioventricular block presenting in fetuses exposed to maternal SSA and SSB autoantibodies and is the first case that we have seen reported in twins. Importantly, this case also adds to the growing body of literature describing EFE as a presentation of neonatal lupus with or without conduction system abnormalities, emphasizes the spectrum of cardiac conduction abnormalities in neonatal lupus syndrome, and raises interesting questions about discordant disease expression in twins.

Background SCD is a chronic debilitating disease secondary to frequent veno-occlusive events resulting in chronic organ damage, including cerebral vasculopathy, acute chest syndrome (ACS), pulmonary hypertension and a significantly shortened life-span (Bunn et al, NEJM, 1997; Lanzkron et al, PHR, 2013; Platt et al, NEJM, 1994). Importantly, SCD survivors also develop significant defects in neurocognition, especially processing speed and have a poor HRQL (Stotesbury et al, Neurology, 2018); Vichinsky et al, JAMA, 2010; Panepinto et al, BJH, 2005). To date the only cure for SCD patients has been HLA matched sibling AlloSCT following either myeloablative (MAC) or reduced toxicity conditioning (RTC), (Walters et al, NEJM, 1996; Bhatia/Cairo et al, BMT, 2014; Talano/Cairo et al, EJH, 2015; Gluckman et al, Blood, 2017). Unfortunately, only approximately 15% of patients have an unaffected HLA matched sibling donor (Mentzer et al, AJPHO, 1994). We previously demonstrated the safety and efficacy of CD34 enrichment and mononuclear cell (MNC) addback (2 x 105 CD3/kg) in pediatric matched unrelated donor recipients (Geyer/Cairo et al, BJH, 2012). We now report the long term results of MAC and familial HISCT utilizing CD34 enrichment and MNC (CD3) addback in high risk SCD recipients. Methods SCD patients with one or more high risk features (cerebral vasculopathy, repetitive ACS, repetitive VOC, abnormal TCD requiring RBC TX) underwent MAC and parental HISCT consisting of hydroxyurea, azathioprine, fludarabine, busulfan, cyclophosphamide, thiotepa, r-ATG and TLI and PBSCT utilizing CD34 enrichment (10x106 CD34/kg) (Miltenyi®) and MNC addback (2x105 CD3/kg) and tacrolimus AGVHD prophylaxis x 100 days as we have previously described (Talano/Cairo et al, ASH, 2017). Donor chimerism in WBC and RBC (CD71) enriched fractions was determined centrally as we have previously described (Geyer/Cairo et al, BJH, 2012). AGVHD & CGVHD were determined utilizing the Glucksberg and NIH consensus criteria, respectively. Transthoracic echocardiogram, TRJ velocity, PFTs, MRI/MRA were performed at baseline and 2 years. Neurocognitive testing utilizing DIVERGT screening was performed at baseline and 2 years as we have previously described (Vichinsky et al, JAMA, 2010; Krull et al, JCO, 2008). HRQL testing utilized the CHRIS-General and CHRIs-HSCT (age appropriate) at baseline and Days +45, 100, 180, 365 and 730 post HISCT as we have previously described (Kelly/Parsons et al, PBC, 2012). Results Among the 19 HISCT recipients, the mean±SEM age was 13.1±1.2 years (3.3-20.0) years, gender 12/7 (M/F). There were 18 parental haploidentical donors with mean±SEM age of 41.3±1.8 (30-55) years, gender 15/3 (F/M). The mean±SEM CD34 enriched PBSC infused was 10.94±0.4x106/kg and MNC addback (2 x 105 CD3/kg). The median time to neutrophil and platelet engraftment was day +9 and +19, respectively. The 1yr mean±SEM whole WBC and RBC (CD71) mixed donor chimerism was 97.1±1.4 and 96.4±2.0%, respectively. The cumulative incidence of grade II-IV AGVHD and CGVHD was 6.2% and 6.7%, respectively (Figure 1A). The probability of 1yr EFS was 90% (CI95 64-97%). In comparison from baseline to 2yr post HISCT, PFTs were stable to improved with a significant improvement in conductance (sGAW) (p Conclusion MAC and familial HISCT utilizing parental donors and CD34 enrichment and MNC addback (2 x 105 CD3/kg) in high risk patients with SCD was well tolerated, resulted in rapid hematological reconstitution, long term stable WBC and RBC (CD71) donor chimerism, low cumulative incidence of A+CGVHD and stable to improved pulmonary and cardiac function. There was also a significant improvement in processing speed and emotional and physical HRQL 2yrs post HISCT. This study was registered at clinicaltrials.gov (NCT02675959) and conducted under IND (14359) (MSC) and supported in large part by FDA R01FD004090. Figure 1 Figure 1. Disclosures Cairo: Janssen: Research Funding. Parsons:Seattle Genetics: Research Funding. Friedman:MedImmune/AstraZeneca: Consultancy, Speakers Bureau. Vichinsky:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Protagonist: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Objective Identifying the frequency of recurrent cardiac manifestations of neonatal lupus (NL) in a second child is critical to understanding the pathogenesis of anti-SSA/Ro–mediated injury and would improve counseling strategies regarding future pregnancies and power the design of clinical prevention trials. Accordingly, this study was undertaken to address the recurrence rates of cardiac NL and associated risk factors in a large US-based cohort. Methods Families enrolled in the Research Registry for Neonatal Lupus were evaluated for rates of recurrence of cardiac NL and potential risk factors, with a focus on pregnancies immediately following the birth of an affected child. Results The overall rate of recurrence of cardiac NL in 161 pregnancies of 129 mothers with anti-SSA/Ro antibodies was 17.4% (95% confidence interval 11.1–23.6%). Analysis of the potential risk factors among 129 mothers with a pregnancy immediately following the birth of a child with cardiac NL showed that the maternal diagnosis was not associated with the outcome in a subsequent pregnancy. In this group, 23% of mothers who were either asymptomatic or had an undifferentiated autoimmune syndrome, compared with 14% of mothers with systemic lupus erythematosus or Sjogren's syndrome, had a second child with cardiac NL (P = 0.25). The recurrence rate was not statistically significantly different in mothers who had taken steroids compared with those who had not taken steroids (16% versus 21%; P = 0.78). The antibody status of the mother was not predictive of outcome in subsequent pregnancies. Moreover, death of the first child with cardiac NL was not predictive of recurrence of cardiac NL in a subsequent pregnancy (P = 0.31). The risk of cardiac NL was similar between male and female children (17.2% versus 18.3%; P = 1.0). Conclusion In this cohort, the overall recurrence rate for cardiac NL was 17%. The recurrence rate appeared to be unaffected by maternal health, use of steroids, antibody status, severity of cardiac disease in the first affected child, or sex of the subsequent child.

We evaluated the efficacy of dexamethasone (DEX) in anti-SSA/Ro-exposed fetuses newly diagnosed with congenital heart block. Previous use of DEX has been anecdotal with varying reports of therapeutic benefit. This was a multicenter, open-label, nonrandomized study involving 30 pregnancies treated with DEX (22 with third-degree block, 6 with second-degree block, 2 with first-degree block) and 10 untreated (9 with third-degree block, 1 with first-degree block). Initial median ventricular rates, age at diagnosis, and degree of cardiac dysfunction were similar between groups. Six deaths occurred in the DEX group. There was no reversal of third-degree block with therapy or spontaneously. In fetuses treated with DEX, 1/6 with second-degree block progressed to third-degree block and 3 remained in second-degree block (postnatally 1 paced, 2 progressed to third degree); 2 reverted to normal sinus rhythm (NSR; postnatally 1 progressed to second degree). DEX reversed the 2 fetuses with first-degree block to NSR by 7 days with no regression at discontinuation. Absent DEX, the 1 with first-degree block detected at 38 weeks had NSR at birth (overall stability or improvement in 4 of 8 in the DEX group vs 1 of 1 in the non-DEX group). Median gestational birth age was 37 weeks in the DEX group versus 38 weeks in the non-DEX group (p = 0.019). Prematurity and small size for gestational age were restricted to the DEX group. Pacemaker use and growth parameters at birth and 1 year were similar between groups. In conclusion, these data confirm the irreversibility of third-degree block and progression of second- to third-degree block despite DEX. A potential benefit of DEX in reversing first- or second-degree block was supported in rare cases but should be weighed against potential steroid side effects such as growth restriction.

Neonatal lupus syndrome is a model of passively acquired autoimmunity in which the pregnant woman's serum contains specific antibodies to 52 or 60 kd SSA/Ro and/or 48 kd SSB/La, which cross the placenta and are associated with the development of congenital heart block in the fetus and/or a transient rash or various liver and blood cell abnormalities in the newborn. To date, congenital heart block is a permanent condition that entails significant morbidity and mortality, with nearly all affected infants requiring pacemakers and with an 80% cumulative probability of survival at 3 years of age. An intensive search is on for the specific etiopathophysiology and for new clinical tools to approach and treat this disease.

Congenital heart block (CHB) can occur in association with structural heart disease, such as atrioventricular septal defects, left atrial isomerism, and abnormalities of the great arteries, with tumors, such as mesotheliomas, or as an isolated defect. In 1928, Aylward reported the occurrence of CHB in two children whose mother "suffered from Mikulicz's disease." This curious clinical observation was further solidified by the 1970s, with reports of CHB in children whose mothers had autoimmune diseases and that the maternal sera contained antibodies to Ro ribonucleoproteins. It was subsequently reported that many mothers also had antibodies to La. Other abnormalities affecting the skin, liver, and blood elements were associated with anti-Ro/La antibodies in the maternal and fetal circulation, and are now grouped under the heading of neonatal lupus syndromes. Neonatal lupus was termed because the cutaneous lesions of the neonate resembled those seen in systemic lupus erythematosus.

Clinical presentation. Congenital heart block (CHB) in the absence of major structural abnormalities is associated with maternal antibodies to Ro (SS-A) and La (SS-B). CHB is most commonly diagnosed between 18 and 24 wk of gestation, and may be first, second or third degree (complete). Mortality approaches ∼20%, and most surviving children require pacemakers. Affected infants may develop cardiomyopathy. Abnormalities in the skin, liver and blood of neonates are also associated with anti-Ro/La antibodies, and are usually self-limiting; these manifestations and CHB are collectively referred to as neonatal lupus syndromes (NLS).Investigation of pathogenesis. Recent studies demonstrate that Ro/La ribonucleoproteins appear on the surface of apoptotic fetal cardiocytes and are recognized by their cognate antibodies, promoting an inflammatory response. Mice immunized with Ro/La proteins have offspring with conduction abnormalities.In vitro, human serum and IgG with anti-Ro/La antibodies affect the conducting properties of isolated animal heart tissue.Diagnostic problems. If fetal bradycardia is identified, a 2-dimensional and M-mode fetal echocardiographic and Doppler ultrasound should be obtained to determine whether there is an atrial arrhythmia or atrioventricular (AV) block, and to what degree, and whether there are major structural abnormalities of the heart. The mother’s serum should be tested by ELISA for anti-Ro and/or anti-La antibodies.Therapeutic options. To date, only anecdotal and retrospective evidence guidesin utero therapy of CHB. A prospective trial is currently underway to evaluate the efficacy of maternal oral dexamethasone in treating newly identified first, second or third degree block. Established third-degree block appears to be irreversible. Dexamethasone and sympathomimetics may be of some benefit in treating hydrops fetalis. In pregnant women with anti-Ro/La antibodies, prophylactic therapy is not indicated but serial echocardiographic analysis is strongly recommended, with emphasis on the mechanical PR interval to identify a reversible block.Conclusion. CHB occurs in ∼1–5% of pregnancies in mothers with antiRo/La antibodies, independent of the mother’s disease status, and in ∼15–20% of pregnancies following the birth of a child with NLS. Treatment of CHB identifiedin utero is not established but guidelines are provided. Serial echocardiographic monitoring of high-risk pregnancies, using the mechanical PR interval to identify first degree block, may afford the earliest opportunities for therapeutic intervention

The classic cardiac manifestation of neonatal lupus is congenitalheart block, attributed to antibodymediated inflammation and subsequent fibrosis of the atrioventricular(AV) node. In consideringthe pathologic process of injury it may be that tissue damage results in a range of conduction abnormalities. Identification of less-advanced degrees of block or of fibrosis around the AV node without any conduction abnormality on EKG would support this pathologic model, and serve as a potential marker for treatment if the conduction defect could be shown to progress. To ascertain the spectrum of arrhythmias associated with maternal anti-SSA/Ro-SSB/La antibodies, records of all children enrolled in the Research Registry for Neonatal Lupus were reviewed. Of 187 children with congenital heart block whose mothers have anti-SSA/Ro-SSB/La antibodies, nine had a prolonged PR interval on EKG at birth, four of whom progressed to more advanced AV block. A child whose younger sibling had third degree block was diagnosed with first degree block at age 10 years at the time of surgery for a broken wrist. Two children diagnosed in utero with second degree block were treated with dexamethasone and reverted to normal sinus rhythm by birth, but ultimately progressed to third degree block. Four children had second degree block at birth: of these, two progressed to third degree block. Sinus bradycardia (< 100 bpm) was present in three (3.8%) of 78 fetuses for whom atrial rates were recorded by echocardiogram. Of 40 neonates for whom EKGs were available, the mean atrial rate was 137± 20 bpm (range 75–200). These data have important research and clinical implications. In contrast to the AV node, permanent sinoatrial nodal involvement is not clinically apparent. Perhaps many fetuses sustain mild inflammation, but resolution is variable, as suggested by the presence of incomplete AV block. Since subsequent progression of less-advanced degrees of block can occur, an EKG should be performed on all infants born to mothers with anti-SSA/Ro-SSB/La antibodies.

Cutaneous neonatal lupus can occur with negative SSA/Ro or SSB/La but positive non-SSA/SSB ribonucleoprotein (RNP) maternal autoantibodies (Provost et al., 1987). No fetal-cardiac manifestations, however, have been reported in association with isolated maternal RNP autoantibodies. We report the first association of transient first-degree atrioventricular block (AVB) in a fetus exposed to maternal anti-RNP in the absence of SSA/Ro-SSB/La autoantibodies.

Objective To compare intervention with fluorinated glucocorticoids to the natural history of untreated congenital heart block (CHB) with respect to conduction abnormalities, associated effusions, ascites, and hydrops fetalis, and the requirement for a pacemaker. Methods Records of all mothers enrolled in the Research Registry for Neonatal Lupus were reviewed. The cohort includes 47 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, and their 50 offspring with CHB, in whom at least 4 echocardiograms were performed after in utero diagnosis. In 28 pregnancies, mothers received dexamethasone 4–9 mg/day for 3–19 weeks or betamethasone 12–24 mg/week for >6 weeks (group A). In 22 pregnancies, fluorinated steroids were not used (group B). Results Third-degree block was present in 21 fetuses in group A and 18 fetuses in group B; none were reversible despite steroid treatment. Three fetuses in group A and 2 in group B progressed from second-degree block, alternating with third-degree block, to permanent third-degree block at birth and postnatally. Of 4 fetuses in group A with second-degree block at presentation, all reverted to first-degree block by birth; 2 remain so at age 4 years, 1 alternates between first-degree and second-degree block at 2 years, and the fourth is in second-degree block at age 4 years. Of 2 fetuses in group B with second-degree block at presentation, both progressed to permanent third-degree block postnatally. Initial echocardiographic evaluation revealed pericardial effusions in 13 group A versus 4 group B fetuses, pleural effusions in 2 group A versus 0 group B, ascites in 8 group A versus 0 group B (P < 0.007), hydrops fetalis in 8 group A versus 0 group B (P < 0.007), and intrauterine growth restriction in 1 group A versus 1 group B. Pericardial effusions resolved and reappeared in both groups. Steroid therapy was most effective in the resolution of pleural effusions (2 of 2), ascites (6 of 8), and hydrops fetalis (5 of 8). Oligohydramnios ensued in 9 group A and 2 group B fetuses. Although fetuses in group A had more complications at presentation than those in group B, there were no significant differences in the duration of pregnancy (35.7 weeks versus 37.0 weeks), the number of deaths (4 versus 1), final degree of heart block, or requirement for a pacemaker (14 versus 11). Conclusion While prospective trials are needed, these data suggest that fluorinated steroids should be considered for fetuses with incomplete block or hydropic changes. Serial echocardiograms are recommended to monitor fetal progress. It remains to be determined whether third-degree block is reversible if therapy is initiated immediately upon detection.

Electrocardiographic repolarization intervals were evaluated to determine the extent of cardiac autonomic dysfunction in patients with familial dysautonomia (FD) and to determine if any of these intervals could serve as a possible predictor of clinical symptoms.Thirty-seven electrocardiograms of patients with FD were retrospectively evaluated. QT, JT, rate-corrected QT and JT intervals were calculated as well as QT and QTC dispersion. Results were compared to normative data and electrocardiograms of 20 age-matched control subjects.In the FD group, prolongation of QTC (450 msec) was noted in 5/37 (13.5%) patients, as compared to 0/20 normal controls (p = NS), and prolongation of JTc (340 msec) in 16/37 (43.3%) patients, as compared to 0/20 normal controls (p0.001). QT and QTC dispersion were abnormal in 3/37 (8.1%) and 5/37 (13.5%), respectively. In the 16 FD patients with prolonged JTc, six had a positive history of syncope, whereas none of the 21 with normal JTc had syncope or symptoms suggesting arrhythmia (p0.003). The positive predictive value of having syncope or symptoms suggestive of arrhythmia with an abnormal JTc is 37.5% (95% CI [15%, 65%]). The negative predictive value is 100% (95% CI [87%, 100%]).In the FD population, the electrocardiographic measure of repolarization that was most frequently abnormal was the JTc interval . Prolongation of the JTc interval was significantly more frequent than prolongation of the QTC interval (p0.001) QT and QTC dispersions were less significantly affected in the FD population, indicating uniform ventricular recovery time. These results suggest that a prolonged JTc interval may be a more sensitive indicator of abnormal ventricular repolarization and cardiac autonomic dysfunction. Due to the known sympathetic denervation inherent in patients with FD, they are at risk for unopposed parasympathetic predominance. FD patients, therefore, are more likely to have brady arrhythmias and asystole rather than polymorphic ventricular tachycardia. The increased incidence of syncope in patients with prolonged JTc suggests that this measure may serve as a helpful marker to predict which FD patients are at increased risk of serious clinical sequelae including bradyarrhythmias with asystole or sudden death.

Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease, including congenital heart block and cardiomyopathy, called cardiac neonatal lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third-degree heart block in NL, although several treatments have shown some effectiveness in incomplete heart block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. β-agonists have been used to increase fetal heart rates in utero. The endurance of β-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.

Mitral valve prolapse (MVP) is known to be associated with thoracic skeletal anomalies. To determine the incidence and risk factors for mitral valve prolapse in the adolescent population with severe idiopathic scoliosis (IS), a prospective follow-up study on 139 adolescent patients with IS from the Pediatric Orthopedic Service was undertaken. Data collected included age, sex, medical and family history, physical exam, electrocardiogram and echocardiogram, spinal x-rays, and pulmonary function tests. MVP was detected by echocardiogram in 13.6% (19/139) of patients with IS as compared with 3.2% in 154 age- and weight-matched controls (p < 0.006). All patients with MVP were asymptomatic and a systolic click or murmur was detected on the single preoperative exam only in 37% (7/19) of them. Patients with MVP and IS weighed less (45.1 ± 2.0 vs 51.8 ± 0.1 kg, p < 0.002) as compared with those IS patients without MVP. The electrocardiogram was abnormal in 21% (4/19) of patients with MVP as compared with only 1.6% (2/120) of patients with IS but no MVP. The two groups did not differ with respect to age at diagnosis, severity of scoliosis, positive family history of scoliosis, or the presence of restrictive lung disease. Though IS was more prevalent in females (79%), the presence of MVP was not related to gender. MVP was persistent in 10 of the 19 patients reevaluated by echocardiogram 2–4 years after spinal surgery. We conclude that MVP is four times more common in patients with severe IS than in the normal adolescent population, and is associated with a lower body weight in IS patients with MVP than in IS patients without MVP. The persistent nature of MVP, even after corrective spinal surgery, may be related to factors other than geometric changes of the heart caused by abnormal thoracic curvature.

Coronary arteries are not normally visualized by fetal echocardiograms. Reversal of flow in the transverse aortic arch is most often seen in association with severe coarctation. We describe a case of a near-term fetus whose fetal echocardiogram showed very prominent coronary arteries and severe reversal of flow in the transverse aorta suggestive of a coarctation who was postnatally confirmed to have normal intracardiac and aortic anatomy. We discuss the pitfalls in clinical diagnosis in this case to alert pediatric cardiologists of transient perturbations in physiology masquerading as heart disease.

Midodrine, a peripheral α-adrenergic agonist, was evaluated in 7 female and 2 male patients with familial dysautonomia (FD), a disorder characterized by decreased sympathetic innervation. Prior to and after three months of midodrine treatment, each patient's response to postural change was assessed by arteriosonde readings of blood pressure and heart rate, corrected QT-interval measurements, Doppler evaluation of renal blood flow and circulating atrial natriuretic peptide (ANP) levels. The initial midodrine dose (2.5 mg three times daily) was raised until subjective symptoms improved. Doses were reduced if patients felt jittery or developed erect hypertension (systolic > 180 mmHg or diastolic > 110 mmHg). Midodrine, at an average dose of 0.25 mg/kg per day, improved subjective symptoms in all patients. With treatment, magnitude of blood pressure responses was variable. Although mean erect blood pressure did not increase significantly for the aggregate, it did increase in six of nine patients. In addition, the QTc interval normalized and erect renal perfusion improved. Changes in supine mean blood pressure and supine circulating ANP correlated directly. We judge midodrine to be useful in management of orthostatic hypotension in patients with familial dysautonomia.

ObjectiveAt the present time, there is a trend towards performing open heart surgery at a younger age. Myocardium of infants has been thought to be more vulnerable to cardiopulmonary bypass in comparison with adults. For this study, we evaluated the degree of myocardial injury by measurement of cardiac troponin levels in infants in comparison with older children for similar surgeries.MethodsSerum was collected before bypass, after bypass, and daily after surgery and serum cardiac troponin I level (micrograms per litre). The demographic data, cardiac diagnoses, types of surgery performed, and peri-operative parameters were collected.ResultsOf the 21 children enrolled consecutively, five were infants. Among the 21 patients, four patients had post-operative peak troponin values greater than 100 (three were infants) and all four patients survived and had normal left ventricular systolic function upon discharge echocardiogram. The five infants had peak troponin levels of 222.3, 202, 129, 26.7, and 82.3. The post-operative peak troponin levels were significantly higher in infants (mean 132.5 with a standard deviation of 81.6) than in the older children (mean 40.3 with a standard deviation of 33.4), although there was no significant difference in bypass time, bypass temperature, cross-clamp time, or the length of stay in the intensive care unit between the two age groups.ConclusionsHigher troponin release is seen in infants in comparison with older children after bypass for similar surgeries. A troponin level greater than 100 after bypass does not necessarily predict death or a severe cardiovascular event in the very young.

Objective. The autopsy and clinical information on children dying with anti-SSA/Ro-associated cardiac manifestations of neonatal lupus (cardiac NL) were examined to identify patterns of disease, gain insight into pathogenesis and enhance the search for biomarkers and preventive therapies. Methods. A retrospective analysis evaluating reports from 18 autopsies of cardiac NL cases and clinical data from the Research Registry for Neonatal Lupus was performed. Results. Of the 18 cases with autopsies, 15 had advanced heart block, including 3 who died in the second trimester, 9 in the third trimester and 3 post-natally. Three others died of cardiomyopathy without advanced block, including two dying pre-natally and one after birth. Pathological findings included fibrosis/calcification of the atrioventricular (AV) node, sinoatrial (SA) node and bundle of His, endocardial fibroelastosis (EFE), papillary muscle fibrosis, valvular disease, calcification of the atrial septum and mononuclear pancarditis. There was no association of pathology with the timing of death except that in the third-trimester deaths more valvular disease and/or extensive conduction system abnormalities were observed. Clinical rhythm did not always correlate with pathology of the conduction system, and the pre-mortem echocardiograms did not consistently detect the extent of pathology. Conclusion. Fibrosis of the AV node/distal conduction system is the most characteristic histopathological finding. Fibrosis of the SA node and bundle of His, EFE and valve damage are also part of the anti-Ro spectrum of injury. Discordance between echocardiograms and pathology findings should prompt the search for more sensitive methods to accurately study the phenotype of antibody damage.

The beta-sympathomimetic oral tocolytic ritodrine can cause maternal tachycardia and hypotension, and may cross the placenta. A new echocardiographic technique has been developed to explore fetal and placental ritodrine effects. Values in 76 healthy historic controls were compared to 18 studies in 16 patients performed while receiving stable oral ritodrine therapy, measured both at baseline and 30 minutes after a dose. Data collected included maternal pulse and blood pressure (BP), fetal cerebral and umbilical Doppler waveforms, and fetal heart rate. A new index of fetal myocardial contractility, combined ventricular shortening fraction, was derived from two-dimensionally directed M-mode. Maternal pulse and BP, fetal heart rate and heart size, and all Doppler indices were normal, without demonstrable dose-response effects. In the control subjects, combined ventricular shortening fraction fell with increasing gestational age (combined ventricular shortening fraction = -0.27 estimated gestational age + 49; r = 0.27; P < or = 0.02; standard error of the estimate, 11%). However, combined ventricular shortening fraction in ritodrine patients was abnormally decreased in 72% of cases. The mean index in normal subjects was 43 +/- 5%, but in ritodrine patients it was only 31%. We conclude that a history of premature labor or oral ritodrine, or both, is associated with reduced shortening fraction. Since there was no change in placental resistance, cerebral hypoxia, fetal heart rate, or heart size (preload), then low shortening fraction may be due to increased fetal systemic vascular resistance (BP) or decreased myocardial contractility.

Background— Cardiac manifestations of neonatal lupus include conduction disease and, rarely, an isolated cardiomyopathy. This study was initiated to determine the mortality and morbidity of cardiac neonatal lupus and associated risk factors in a multi–racial/ethnic US-based registry to provide insights into the pathogenesis of antibody-mediated injury and data for counseling. Methods and Results— Three hundred twenty-five offspring exposed to maternal anti-SSA/Ro antibodies with cardiac neonatal lupus met entry criteria. Maternal, fetal echocardiographic, and neonatal risk factors were assessed for association with mortality. Fifty-seven (17.5%) died, 30% in utero. The probability of in utero death was 6%. The cumulative probability of survival at 10 years for a child born alive was 86%. Fetal echocardiographic risk factors associated with increased mortality in a multivariable analysis of all cases included hydrops and endocardial fibroelastosis. Significant predictors of in utero death were hydrops and earlier diagnosis, and of postnatal death were hydrops, endocardial fibroelastosis, and lower ventricular rate. Isolated heart block was associated with a 7.8% case fatality rate, whereas the concomitant presence of dilated cardiomyopathy or endocardial fibroelastosis quadrupled the case fatality rate. There was a significantly higher case fatality rate in minorities compared with whites, who were at a lower risk of hydrops and endocardial fibroelastosis. Pacing was required in 70%; cardiac transplantation was required in 4 children. Conclusion— Nearly one fifth of fetuses who develop cardiac neonatal lupus die of complications predicted by echocardiographic abnormalities consistent with antibody-associated disease beyond the atrioventricular node. The disparity in outcomes observed between minorities and whites warrants further investigation.

Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ∼18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies.Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.

Publisher Summary Neonatal lupus (NL) is the occurrence of systemic lupus erythematosus (SLE) symptoms in an infant born from a mother with SLE, most commonly presenting with a rash resembling discoid lupus erythematosus, and sometimes with systemic abnormalities such as heart block or hepatosplenomegaly. This chapter reviews the current understanding of NL. Fetal exposure to maternal antibodies reactive with several components of the SSA/Ro-SSB/La ribonucleoprotein complex is a requisite factor for the development of NL. Although NL is uncommon, its discussion is an integral part of all pregnancy counseling of women with SLE. Overall, studies suggest that there is unacceptable morbidity and mortality. A major clue to defining the pathogenesis of antibody-mediated damage is the selective vulnerability of the fetal heart. Vulnerability could relate to a direct or indirect antigen target differentially expressed in the developing human heart. Alternatively, biologic events operative during fetal life, such as apoptosis, could facilitate accessibility of intracellular antigens to the extracellular environment. Opsonization of apoptotic cardiocytes might promote an inflammatory/fibrosing cascade leading to tissue injury. A reproducible murine model of congenital heart block (CHB) would be a critical tool to define antibody pathogenicity at the histologic and molecular level with subsequent application for testing prophylactic and therapeutic interventions. The reporting of recurrence rates, mortality and morbidity, and maternal outcomes in a large number of patients has greatly facilitated family planning. The genetic contributions to disease may offer further insights.

Cardiovascular instability is a prominent manifestation of familial dysautonomia [FD] while renal insufficiency occurs in a large number of adult FD patients. To determine if there was a causative relationship, renal artery blood flow velocity using Doppler technology, was recorded and the ratio of the peak systolic velocity (point A) to the end diastolic velocity (point B) was calculated. The A/B ratio was assessed in response to change of position and exercise, and was correlated with renal function, heart rate and systemic blood pressure. Studies were performed in 54 FD patients with a mean age of 24 years +/- 9.8 years, and 20 controls, with a mean age of 24.7 +/- 7.6 years. In the supine position, the mean A/B ratios were not significantly different, but FD subjects had a significantly higher mean blood pressure and heart rate than controls. When erect and post exercise, the mean A/B ratios in FD subjects were significantly higher than controls, p = 0.0004 and p = 0.0001, respectively. In contrast to controls, when FD subjects were standing erect and post exercise, mean blood pressure decreased significantly without a significant change in heart rate. When FD subjects were divided into two groups based on their creatinine clearance value, the group with the lower creatinine clearances had a significantly greater fall in diastolic pressure when they moved from the supine to the erect position. Our results indicate that noninvasive Doppler techniques are helpful in detecting changes in renal blood flow in subjects with familial dysautonomia.(ABSTRACT TRUNCATED AT 250 WORDS)

The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment withor = 20 mg/day of prednisone, and12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

This paper describes the case of an 11 year old girl who presented with mixed connective tissue disease which was complicated by the development of pulmonary hypertension. This case is unique with respect to the young age of onset, the serial non-invasive method used to follow the disease process, and the favourable response to treatment with vasodilator and anti-inflammatory drugs.