OBJECTIVES:To investigate the relationship between maternal disease, anti-rheumatic treatment, autoantibody levels and foetal atrioventricular (AV) conduction. METHODS:A total of 324 pregnancies from two groups of anti-Ro/La autoantibody-positive women were included. The Surveillance group consisted of pregnancies with known anti-Ro positivity followed from early pregnancy; n = 302, including nine with AV block (AVB), and the Bradycardia group with no prior knowledge of anti-Ro/La autoantibodies and referred upon detection of foetal bradycardia, with a subsequent AVB II-III diagnosis (n = 22). Foetal AV conduction and routine anti-Ro52, anti-Ro60 and anti-La autoantibody levels were analysed. RESULTS:Women with primary Sjögren disease (SjD) had longer foetal AV time intervals (130.5 ± 11.9 vs 125.8 ± 8.7 ms, P = 0.002) compared with autoantibody-positive women with neither SjD nor SLE. Notably, AZA, mostly used in women with SLE, was associated with shorter foetal AV time intervals compared with autoantibody-positive pregnancies without AZA treatment (122.5 ± 8.9 vs 128.7 ± 11.0 ms, P = 0.038). For antibody-based prediction, anti-Ro52, anti-Ro60 and anti-La antibody levels obtained from routine assays could identify nearly 20% of pregnancies as low risk, and high levels (≥8 U/ml) of anti-La antibodies were associated with an increased risk of AVB I-III (OR = 6.0, 1.26-28.5). However, the positive predictive value for AVB II-III of the three autoantibodies did not reach 5% for a sensitivity of 100%. CONCLUSION:This report, based on over 20 years of surveillance of anti-Ro positive pregnancies, identifies associations between maternal disease, their treatments and foetal AV conduction. Routine detection assays for anti-Ro/La antibodies had low performance in predicting AVB among an anti-Ro/La positive population.

INTRODUCTION:Fetal arrhythmias have been described with intrapartum hypoxemia; however, they cannot be accurately diagnosed with currently used fetal heart rate (FHR) monitoring systems due to low resolution and signal averaging. We used a Holter device to record electrocardiogram (ECG) at 250 Hz in term sheep fetuses that developed severe metabolic acidosis induced by intermittent umbilical cord occlusions (UCOs), mimicking human labor contractions. We hypothesized that UCOs leading to worsening fetal metabolic acidosis provoke distinct fetal arrhythmias that could indicate impending fetal death. MATERIAL AND METHODS:Thirteen pregnant sheep (gestational age 133-135/145 days) were instrumented under general anesthesia. Three electrodes were placed on the fetal chest and connected to a Holter device for continuous ECG recording at a sampling rate of 250 Hz. The fetal axillary artery was catheterized and an inflatable occluder was placed around the umbilical cord. After a 4-5 day recovery, complete UCOs were induced by inflating the occluder for 1 min, followed by deflation for 2 min, until the fetal arterial pH dropped <7.0 and/or base excess (BE) <-16. Thereafter, an emergency cesarean section was performed to deliver the fetus. RESULTS:Eight sheep fetuses were included in the final analysis. All fetuses had normal baseline arterial blood gases and lactate values. During the first two UCOs, all fetuses demonstrated isolated benign arrhythmias. Three fetuses that developed severe metabolic acidosis after five UCOs showed persistent atrioventricular (AV) conduction abnormalities during the last UCO and its release, requiring cardiopulmonary resuscitation (CPR) at birth. One fetus with third-degree AV block had no detectable QRS complexes at birth, developed ventricular tachycardia and fibrillation (VT/VF) during CPR, and was successfully defibrillated. Five fetuses tolerated ≥10 UCOs before developing severe metabolic acidosis, and none of these showed any persistent AV-conduction abnormalities, though one fetus died after developing VT/VF after the 10th UCO. CONCLUSIONS:Metabolic acidemia induced by intermittent UCOs in term sheep fetuses is associated with various arrhythmias, some of which may be life-threatening. Continuous intrapartum fetal ECG recording at a sample rate of ≥250 Hz coupled with a software capable of automatically detecting significant arrhythmias could enhance intrapartum fetal monitoring in the future.

Objectives The objective of this study was to investigate the role of infections in the pathogenesis of Kawasaki disease.Methods The investigation was a nationwide epidemiological case-control study, comprising all cases of Kawasaki disease diagnosed in Sweden 1987–2018. Controls were randomly sampled from the general population, matched on sex, age, and area of residency. Data on infections were obtained from the Swedish National Patient Register, which prospectively collects data on all Swedish residents. Infections were classified by organ system, infectious agent and by temporal proximity to Kawasaki disease diagnosis date. Prescription of antibiotics and infections in family members were also considered in separate analyses.Results The study comprised n=1774 (61% male) cases and n=17 731 controls. Overall, a history of infections was associated with Kawasaki disease with an OR of 2.3 (95% CI 2.0 to 2.5). Respiratory, skin, urogenital and gastrointestinal tract infections were all associated with Kawasaki disease. Temporal stratification revealed a prominent clustering of infections during the weeks before a Kawasaki diagnosis, but also higher frequencies of infections several months preceding Kawasaki disease with OR ranging from 5.1 (95% CI 3.6 to 7.1) 15–28 days to 1.3 (95% CI 1.1 to 1.6) 181–365 days prior Kawasaki disease. A dose–response relationship was observed, with repeated infections associating with higher ORs of Kawasaki.Conclusions The findings suggest that infections are closely linked with Kawasaki disease, and with a wider temporal association than previously known. Further, the data imply that many different agents may induce the disease.

INTRODUCTION:We investigated the effects of timing of detection and transplacental fluorinated steroid treatment on ventricular heart rate (HR) and age at pacemaker implantation in fetal third-degree atrioventricular block (AVB). MATERIAL AND METHODS:Twenty-five of 31 fetuses diagnosed with Ro/SSA autoantibody-positive AVB II-III at our tertiary fetal cardiology center (2000-2020) and AVB III as final feto-neonatal outcome were reviewed. RESULTS:AVB was detected approximately 5 weeks earlier in pregnancy if followed in a surveillance program compared to cases referred from primary care for bradycardia (20.6 [2.3] [mean (SD)] vs. 25.4 [3.2] weeks, p = 0.001). AVB detected before 24 weeks had higher HR than those detected later in gestation (63.3 [6.9] vs. 57.2 [6.9] bpm, p = 0.042), with a larger proportion having HR >60 bpm (80% vs. 33%, p = 0.041). The 17/25 cases that received treatment with fluorinated steroid were diagnosed earlier in gestation, with higher HR at diagnosis (61.7 [7.1] vs. 54.7 [6.3] bpm, p = 0.026), 1-2 weeks after diagnosis/treatment start, and before birth (65.4 [12.4] vs. 54.9 [5.7] bpm, p = 0.030) than untreated cases. Overall, 11 cases were commenced on betamimetics: three at diagnosis and eight at or after the examination made 1-2 weeks after diagnosis/treatment start, without any HR improvement. Two of 24 surviving babies were born preterm, and 4/24 received a neonatal pacemaker. Age at pacemaker implantation correlated significantly with HR before birth (Spearman R 0.57, p = 0.004), and fetuses with HR >60 bpm had a higher rate of pacemaker-free survival at three (90% vs. 40%, p = 0.018) and 12 months of age (80% vs. 13%, p = 0.002). The same trend was observed in pacemaker-free survival at 3 months of age in fluorinated steroid-treated compared to untreated cases (71% vs. 38%, ns). CONCLUSIONS:Our data confirm that AVB III detected earlier in gestation have a higher HR, and suggest that this higher HR can be successfully maintained to the end of gestation in cases treated with fluorinated steroids. Fetuses with HR >60 bpm before birth had a lower rate of pacemaker implantation at 3 and 12 months of age.

Background Neonatal lupus, including autoimmune congenital heart block, is a passively acquired autoimmune condition dependent on placental transfer of maternal Ro/La autoantibodies to the fetus. The mothers are commonly diagnosed with Sjögren’s syndrome or systemic lupus erythematosus, and present with elevated plasma interferon (IFN) levels and signs of immune activation. Recent studies demonstrate both a correlation between the maternal and neonatal IFN-scores, as well as elevated plasma IFNα levels in the neonates. Whether IFNα can be produced by the fetus or whether it originates from the mother is not known. Objectives To characterize immune cells in Ro/La autoantibody-exposed neonates with regard to phenotypes, effector functions and cytokine production. Methods We used full spectrum multi-color flow cytometry staining for an array of cell phenotype, activation and proliferation markers combined with intracellular cytokine staining to cover the most important innate and adaptive immune cell populations in cord blood cells of anti-Ro/La-exposed (n=12) and non-exposed (n=6) newborns. Results We confirmed an increased surface expression of Sialic acid-binding Ig-like lectin-1 (Siglec-1) on CD14+ monocytes and further show increased Siglec-1 expression also on CD14-CD16+ non-classical monocytes and conventional dendritic cells in anti-Ro/La-exposed compared to healthy control neonates. We did not observe any major differences in general populations such as CD4+, CD8+ or gamma delta T cells. However, we found a decreased frequency of regulatory CD4+ FoxP3+ T cells in the autoantibody-exposed newborns. In line with this, we observed an increase in conventional CD4+ FoxP3- T cells and that these cells have less of a naïve phenotype with significantly lower frequency of CD62L+ and more CD69-expressing cells in the CD4+ FoxP3- population. Interestingly, Ro/La-exposed newborns also had less CD5-expressing CD19+ B cells compared to healthy newborns, while the frequency of CD19+ CD5- B cells was not affected. Further, we noted a decreased surface expression of CD19 and CD11b on both these CD19+ subpopulations. Interestingly, for neonates born to mothers with high levels of all three of Ro52, Ro60 and La autoantibodies, we also found intracellular cytokine IFNα and TNFα production in B cell, dendritic cell, and monocyte populations. Conclusion Together, our data provide valuable insight into the effects of Ro/La autoantibody exposure in utero on immune activation of both innate and adaptive immune cell populations in exposed fetuses, enhancing our understanding of the immunological basis of neonatal lupus. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared.

Objective Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function. Methods A genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography. Results We identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals. Conclusions Our study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.

Objective Congenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations. Methods In total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma. Results Similar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56dimCD16hi NK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8+ and CD4+ T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma. Conclusion Our study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.

Autoimmune congenital heart block (CHB) may develop in foetuses of women carrying anti‐Ro/SSA and La/SSB autoantibodies and is characterized by disruption of signal conduction at the atrioventricular (AV) node, resulting in partial or complete AV block. If not fatal in utero , complete CHB typically requires lifelong cardiac pacing. No treatment has so far been unequivocally demonstrated to prevent or treat autoimmune CHB, and the relatively low incidence (1%‐5%) and recurrence (12%‐16%) rates of second/third‐degree AV block add to the complexity of managing pregnancies in women with anti‐Ro/La antibodies. Altogether, a better understanding of events leading to development of autoimmune CHB is needed to improve surveillance and treatment strategies. In the past decade, studies have started to look beyond the role of maternal autoantibodies in disease pathogenesis to assess other contributing factors such as foetal genetics and, more recently, immune responses in foetuses and neonates of anti‐Ro/La antibody‐positive women. In this review, we provide an update on the epidemiology, clinical presentation and current treatment approaches of autoimmune CHB, summarize the previously proposed pathogenic mechanisms implicating maternal autoantibodies, and discuss the recent findings of type I interferon (IFN) and innate immune activation in foetuses with autoimmune CHB and in neonates of anti‐Ro/La antibody‐positive mothers, and how these may contribute to autoimmune CHB pathogenesis.

First, we want to thank Dr Bijoy Balakrishnan, Department of Fetal Medicine, Cimar Fertility Center, Cochin, India, for recently making us aware of a typographical error in our article published in AOGS.1 When discussing ventricular rhythms with a shorter time interval between two consecutive ventricular contractions (VV-interval) that systematically alternated with a longer interval (bigeminal ventricular rhythms), we wrote that this pattern could be seen in 3:1 atrioventricular block (AVB), which will result in a slow regular rhythm, instead of writing 3:2 AVB. Secondly, we would like to share the experience we have accumulated in recent years, as we believe this may improve the diagnosis and management of fetuses with bigeminal ventricular rhythms. As discussed in our article, we recommend starting by establishing whether the longer VV-interval corresponds to a heart rate >100 bpm, suggesting that every second beat is a premature extrasystole (in bigeminy), or <90 bpm, suggesting that every third atrial beat is blocked. Ventricular extrasystoles will not affect the atrial rhythm, which will remain regular (Figure 1A). Conducted atrial extrasystoles in bigeminy will also affect the atrial rhythm, but are rarely diagnosed in the fetus. In our recent experience, not only blocked atrial extrasystoles in trigeminy (BAT) but also 3:2 second-degree AVB results in a ventricular rhythm with a long VV-interval that is only 70%-80% of twice the short VV-interval (Figure 1B-F), and will be difficult to differentiate by analyzing the ventricular rhythm. That a premature blocked atrial extrasystole will result in an incomplete compensatory pause is easy to understand, as it resets the sinus node.1 In addition, a delayed ventricular beat will lead to an increased diastolic filling period that will improve systolic performance and shorten the time lag from atrial to ventricular ejection.2 This is illustrated in Figure 1B, where the time interval between events related to atrial and ventricular contractions is shorter during a longer than a shorter VV-interval (100 vs 125 ms), even though these two beats have the same electrical delay in the atrioventricular node. This effect will make the longer VV-interval shorter. In our cases with 3:2 AVB there is also a progressive lengthening of atrioventricular conduction between the two beats preceding the non-conducted beat (Wenckebach or Mobitz type I block, Figure 1E,F), which makes the shorter VV-interval significantly longer and the compensatory pause incomplete. The atrial rhythm consequently needs to be clarified in cases where every third atrial beat is blocked. It is trigeminal in BAT and regular in 3:2 AVB with or without (Mobitz II) Wenckebach conduction. This can be demonstrated by using Doppler recordings where both atrial and ventricular depolarizations can be identified by their hemodynamic consequences. Besides showing a closer “resemblance” to an electrocardiogram, these recordings also allow us to estimate mechanical time intervals, used as an indirect measure of atrioventricular conduction.3 As illustrated, these intervals increase from approximately 145 ms (+4 SD) to 225-250 ms between the two conducted beats, and confirm Wenckebach conduction in our fetuses with 2:3 AVB (Figure 1E,F). The clinical management of these arrhythmias differs markedly. Ventricular extrasystoles usually disappear spontaneously within a few weeks. Fetuses with blocked atrial beats in bigeminy and trigeminy have a 6%-14% risk of developing supraventricular tachycardia.4 The risk may be even higher when extrasystoles occur as couplets (Figure 1D). Fetuses with incomplete AVB might benefit from transplacental treatment with fluorinated steroids.5 In conclusion, we recommend that fetuses with bigeminal rhythms should be diagnosed by someone who can record and interpret Doppler recordings, where the timing of both atrial and ventricular depolarizations can be recognized.

Background Fetal anemia is associated with a hyperdynamic circulation and cardiac remodeling. Rapid intrauterine transfusion (IUT) of blood with high hematocrit and viscosity into the umbilical vein used to treat this condition can temporarily further affect fetal heart function. The aim of this study was to evaluate the short-term changes in fetal myocardial function caused by IUT using automated analysis of cine-loops of the fetal heart obtained by color tissue Doppler imaging (cTDI). Methods Fetal echocardiography was performed before and after IUT. cTDI recordings were obtained in a four-chamber view and regions of interest were placed at the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls. Myocardial velocities were analyzed by an automated analysis software to obtain peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm), rapid ventricular filling (Em) and Em/Am ratio was calculated. Myocardial velocities were converted to z-scores using published reference ranges. Delta z-scores (after minus before IUT) were calculated. Correlations were assessed between variables and hemoglobin before IUT. Results Thirty-two fetuses underwent 70 IUTs. Fourteen were first time transfusions. In the LV and septal walls, all myocardial velocities were significantly increased compared to normal values, whereas in the RV only Sm was increased before IUT (z-scores 0.26–0.52). In first time IUTs, there was a negative correlation between LV Em (rho = − 0.61, p = 0.036) and LV Em/Am (rho = − 0.82, p = 0.001) z-scores and hemoglobin before IUT. The peak myocardial velocities that were increased before IUT decreased, whereas LV Em/Am increased significantly after IUT. Conclusions This study showed that peak myocardial velocities assessed by cTDI are increased in fetuses before IUT reflecting the physiology of hyperdynamic circulation. In these fetuses, the fetal heart is able to adapt and efficiently handle the volume load caused by IUT by altering its myocardial function.

We thank Marie Wahren-Herlenius and Sven-Erik Sonesson for their comments. We acknowledge that in our first Correspondence1Costedoat-Chalumeau N Morel N Surveillance of congenital heart block in highly specialised care – Authors' reply.Lancet Rheumatol. 2020; 2: e204-e205Summary Full Text Full Text PDF Scopus (2) Google Scholar we should have compared overall mortality in the three studies, and we apologise for this error.2Sonesson S Wahren-Herlenius M Surveillance of congenital heart block in highly specialised care.Lancet Rheumatol. 2020; 2: e203-e204Summary Full Text Full Text PDF Scopus (6) Google Scholar, 3Morel N Levesque K Maltret A et al.Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus.Int J Cardiol. 2017; 248: 263-269Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Izmirly PM Saxena A Kim MY et al.Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.Circulation. 2011; 124: 1927-1935Crossref PubMed Scopus (194) Google Scholar, 5Levesque K Morel N Maltret A et al.Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome.Autoimmun Rev. 2015; 14: 1154-1160Crossref PubMed Scopus (94) Google Scholar When we did this comparison, mortality became 3·8% for the Stockholm cohort (one of 26 patients died; a median follow-up 7·5 years [range 1–19])2Sonesson S Wahren-Herlenius M Surveillance of congenital heart block in highly specialised care.Lancet Rheumatol. 2020; 2: e203-e204Summary Full Text Full Text PDF Scopus (6) Google Scholar versus 21·4% in the French registry5Levesque K Morel N Maltret A et al.Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome.Autoimmun Rev. 2015; 14: 1154-1160Crossref PubMed Scopus (94) Google Scholar (45 of 210 patients died; median follow-up 7 years [birth to 36 years]) and 17·5% in the US registry4Izmirly PM Saxena A Kim MY et al.Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.Circulation. 2011; 124: 1927-1935Crossref PubMed Scopus (194) Google Scholar (57 of 325 patients died; follow-up period unknown). When we combined the US4Izmirly PM Saxena A Kim MY et al.Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.Circulation. 2011; 124: 1927-1935Crossref PubMed Scopus (194) Google Scholar and French5Levesque K Morel N Maltret A et al.Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome.Autoimmun Rev. 2015; 14: 1154-1160Crossref PubMed Scopus (94) Google Scholar registries (a total of 102 [19%] of 535 patients died) and compare the mortality with the Swedish series the difference is almost statistically significant (p=0·06).2Sonesson S Wahren-Herlenius M Surveillance of congenital heart block in highly specialised care.Lancet Rheumatol. 2020; 2: e203-e204Summary Full Text Full Text PDF Scopus (6) Google Scholar, 4Izmirly PM Saxena A Kim MY et al.Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.Circulation. 2011; 124: 1927-1935Crossref PubMed Scopus (194) Google Scholar, 5Levesque K Morel N Maltret A et al.Description of 214 cases of autoimmune congenital heart block: results of the French neonatal lupus syndrome.Autoimmun Rev. 2015; 14: 1154-1160Crossref PubMed Scopus (94) Google Scholar In the appendix of their Correspondence, Wahren-Herlenius and Sonesson reported that fetuses treated with fluorinated steroids had better outcomes at their centre compared with those reported in the French and Italian registries. However, because all fetuses at their centre were treated with fluorinated steroids, this analysis does not prove the efficacy of fluorinated steroids. The difference in mortality might be because the oldest case in the Stockholm cohort dates back to 2000, compared with 1976 in the French registry (personal communication), 1969 in the Italian registry,6Fredi M Andreoli L Bacco B et al.First report of the Italian registry on immune-mediated congenital heart block (Lu.Ne Registry).Front Cardiovasc Med. 2019; 6: 11Crossref PubMed Scopus (29) Google Scholar and 1963 in the US registry.4Izmirly PM Saxena A Kim MY et al.Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus.Circulation. 2011; 124: 1927-1935Crossref PubMed Scopus (194) Google Scholar The difference in mortality might also be attributable to better management in the expert Swedish centre, including for pacemaker implantation. Consistent with this observation, we encourage physicians who are confronted with a case of congenital heart block to refer the pregnant woman to an expert centre, as done in France. Nevertheless, although management in expert centres is certainly better, we stand by our conclusion that the efficacy of fluorinated steroids is not supported by analysis of the literature, questioning the need for routine screening of pregnant women who test positive for anti-SSA antibodies. We also continue to believe that more research is needed in this area, research that is better done in centres of excellence. We declare no competing interests. Surveillance of congenital heart block in highly specialised careA complete third-degree atrioventricular (AV) block can develop in the fetus in the absence of major heart malformation when the mother carries Ro/SSA and La/SSB autoantibodies.1 This life-threatening condition is often referred to as congenital heart block. Incomplete blocks might precede congenital heart block, and treatment with fluorinated steroids has been suggested to prevent this progression or even revert an incomplete block to normal sinus rhythm. This observation has been the rationale for establishing echocardiographic surveillance programmes for weeks 18–24 of pregnancy, when congenital heart block usually develops, enabling treatment to be administered in a timely fashion. Full-Text PDF Mortality in congenital heart blockWe read with interest the comparison of mortality in congenital heart block between different studies put forward by Nathalie Costedoat-Chalumeau and Nathalie Morel.1 However, we noted that they compared overall mortality from one study with postnatal mortality of another study and with overall mortality in a third study that included fetuses without second-degree or third-degree atrioventricular block,2–4 leading to incorrect conclusions. To examine mortality in fetuses with second-degree or third-degree atrioventricular block in published studies, we structured and analysed the available data from similar reports (appendix p 1). Full-Text PDF

Objective In utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment. Methods Blood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays. Results We observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14 + monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma. Conclusions Ro/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.

Background: Norwood surgery has been available in Sweden since 1993. In this national cohort study, we analysed transplantation-free survival after Norwood surgery for hypoplastic left heart syndrome with aortic atresia. Methods: Patients were identified from the complete national cohort of live-born with hypoplastic left heart syndrome/aortic atresia 1993-2010. Analysis of survival after surgery was performed using Cox proportional hazards models for the total cohort and for birth period and gender separately. Thirty-day mortality and inter-stage mortality were analysed. Patients were followed until September 2016. Results: The 1993-2010 cohort consisted of 208 live-born infants. Norwood surgery was performed in 121/208 (58%). The overall transplantation-free survival was 61/121 (50%). The survival was higher in the late period (10-year survival 63%) than in the early period (10-year survival 40%) (p = 0.010) and lower for female (10-year survival 34%) than for male patients (10-year survival 59%) (p = 0.002). Inter-stage mortality between stages I and II decreased from 23 to 8% (p = 0.008). For male patients, low birthweight in relation to gestational age was a factor associated with poor outcome. Conclusion: The survival after Norwood surgery for hypoplastic left heart syndrome/aortic atresia improved by era of surgery, mainly explained by improved survival between stages I and II. Female gender was a significant risk factor for death or transplantation. For male patients, there was an increased risk of death when birthweight was lower than expected in relation to gestational age.

OBJECTIVES:Assuming that autoimmune congenital heart block (CHB) is a progressive disease amenable to therapeutic modulation, we introduced a surveillance program for at-risk pregnancies with the dual aim of investigating if fetal atrioventricular block (AVB) could be detected and treated before becoming complete and irreversible, and to establish the incidence of AVB I, II and III in a large prospective cohort. METHODS:This was a prospective study of 212 anti-Ro52 antibody-exposed pregnancies at risk of fetal AVB that were followed weekly between 18 and 24 weeks' gestation at our tertiary fetal cardiology center from 2000 to 2015. A 12-lead electrocardiogram (ECG) was recorded within 1 week after birth. Fetal Doppler atrioventricular (AV) intervals were converted to Z-scores using reference standard values derived from normal pregnancies. Each fetus was represented by the average value of the two recordings, obtained at two consecutive visits, which resulted in the longest AV interval. AV interval values were classified into normal AV conduction (Z-score ≤ 2.0) and three levels of delayed AV conduction: Z-score > 2.0 and ≤ 3.0, Z-score > 3.0 and ≤ 4.0, and Z-score > 4.0. RESULTS:AVB II or III developed in 6/204 (2.9%) pregnancies without a CHB history and 1/8 (12.5%) of those with a CHB history. AV intervals > 2 and ≤ 3, > 3 and ≤ 4, and > 4 were detected in 16.0%, 7.5% and 2.8% of cases, respectively, and were related to the PR interval on 185 available ECGs. Three of the five cases with AVB III and one of two cases with 2:1 AVB II developed within 1 week of AV interval Z-score of 1.0, 1.9, 2.8 and 1.9, respectively. Transplacental treatment with betamethasone was associated with restoration of 1:1 AV conduction in the two fetuses with AVB II, with a better long-term result (normal ECG vs AVB I or II) observed in the case in which treatment was started within 1 week after AVB developed. Betamethasone treatment did not reverse AVB III, although a temporary effect on AV conduction was observed in 1/5 cases. Notably, the three cases in which treatment was started within 1 week after AVB III development responded with a higher ventricular rate than the other two cases and did not require pacemaker implantation until a later age (2-5 years vs 1.5-2 months). CONCLUSION:Fetal AV interval is a poor predictor of CHB progression, but CHB surveillance still allows detection of fetuses with AVB II or III shortly after its development, allowing for timely treatment initiation and potentially better outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Background Norwood surgery provides a palliative surgical option for hypoplastic left heart syndrome and has been available in Sweden since 1993. The practice of prenatal ultrasound screening was gradually implemented in the same era, resulting in an increased prenatal detection rate. Our primary aims were to study changes in the incidence of live births, prenatal detection rate, and the termination of pregnancies over time. The secondary aims were to study the proportion of live‐borns undergoing surgery and to identify factors that influenced whether surgery was or was not performed. Methods and Results Neonates with hypoplastic left heart syndrome with aortic atresia born 1990‐2010 were identified through national databases, surgical files, and medical records. The fetal incidence was estimated from the period when prenatal screening was rudimentary. The study period was divided into the presurgical, early surgical, and late surgical periods. The incidence was calculated as the overall yearly incidence for each time period and sex separately. Factors influencing whether surgery was performed were analyzed using Cox‐logistic regression. The incidence at live birth decreased from 15.4 to 8.4 per 100 000. The prenatal detection rate increased from 27% to 63%, and terminations increased from 19% to 56%. The odds of having surgery was higher in the late period and higher in the group with prenatal diagnosis. Conclusions We observed a decrease in incidence of live‐borns with hypoplastic left heart syndrome aortic atresia. There was in increase in prenatal detection rate and an increase in termination of pregnancy. The proportion of live‐borns who underwent surgery increased between time periods.