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- Ambrosi, Aurelie, et al.
(author)
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Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern
- 2012
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In: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:3, s. 334-340
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Journal article (peer-reviewed)abstract
- Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. less thanbrgreater than less thanbrgreater thanMethods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. less thanbrgreater than less thanbrgreater thanResults There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (pandlt;0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (pandlt;0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. less thanbrgreater than less thanbrgreater thanConclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.
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- Hedlund, Malin, et al.
(author)
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Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero
- 2020
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In: RMD Open. - : BMJ. - 2056-5933. ; 6:1
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Journal article (peer-reviewed)abstract
- 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.
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- Herling, Lotta, et al.
(author)
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Fetal cardiac function at intrauterine transfusion assessed by automated analysis of color tissue Doppler recordings
- 2020
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In: Cardiovascular Ultrasound. - : Springer Nature. - 1476-7120. ; 18:1
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Journal article (peer-reviewed)abstract
- 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.
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- Meisgen, Sabrina, et al.
(author)
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The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence
- 2014
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:6, s. 640-651
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block.SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases, and 95 unaffected siblings).RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n=1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of p<2.59×10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (p<0.03 and p<0.05, respectively), while HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (p<0.04 and p<0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (p<0.02).CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, while DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.
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- Salomonsson, Stina, et al.
(author)
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Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block
- 2005
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 201:1, s. 11-17
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Journal article (peer-reviewed)abstract
- Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.
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- Speier, Maximilian, et al.
(author)
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Fundamental Research of Ferrofluids
- 2022
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In: IAC 2022 Congress Proceedings, 73<sup>rd</sup> International Astronautical Congress (IAC), Paris, France. - : International Astronautical Federation, IAF.
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Conference paper (peer-reviewed)
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- Tingström, Joanna, et al.
(author)
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Anti-Ro/SSA autoantibody-positive women's experience of information given on the risk of congenital heart block.
- 2016
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In: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 25:5, s. 536-542
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Congenital heart block (CHB) may develop in fetuses of women with anti-Ro/SSA autoantibodies, and carries substantial morbidity and mortality. The aim was to evaluate how information on CHB is imparted and identify areas of improvement.METHODS: A questionnaire was distributed to anti-Ro/SSA antibody-positive women who had either participated in a surveillance programme but whose expected child did not develop CHB (n = 100, denoted Doppler-Assessed Pregnancies (DAP) group) or given birth to a child with CHB (n = 88, denoted CHB-Affected Pregnancies (CAP) group).RESULTS: The response rate was 83% (157/188). Most women received the information on CHB when they were already pregnant (DAP group 60%, CAP group 83%). However, a majority of them would have wanted the information before pregnancy (DAP group 52%, CAP group 56%), and most stated that it would not have influenced their decision to have a child (DAP group 77%, CAP group 58%). The ability to both understand the information and to perceive the information as sufficient were significantly higher when someone trained in paediatric cardiology gave the information.CONCLUSIONS: Our findings indicate that information on CHB should be given to women before pregnancy. The data further highlight the importance of having specific knowledge for giving relevant and understandable, yet sufficient information.
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- Tingström, Joanna, et al.
(author)
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Ro/SSA autoantibody-positive pregnancy : reactions to serial fetal Doppler echocardiographic surveillance
- 2015
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In: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 24:14, s. 1540-1545
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The risk for congenital heart block (CHB) associated with maternal Ro/SSA autoantibodies is low, but the possibility of treating early stages of disease has seen the introduction of Doppler echocardiographic surveillance programs with serial examinations during the CHB susceptibility weeks of pregnancy. The aim of the present study was to understand how Ro/SSA autoantibody-positive women having undergone Doppler echocardiographic surveillance programs and giving birth to children without CHB experienced their pregnancy and frequent ultrasound examinations.METHODS: A validated questionnaire based on data from an interview-study was distributed to Ro/SSA-positive women supervised with Doppler examinations during their pregnancy (n = 100).RESULTS: The response rate was 79%. The majority of the women (61%) reported that the increased number of ultrasound examinations influenced their pregnancy, but in a positive way, with qualified information and additional support from health care personnel in conjunction with the examinations. Further, the visits to the clinic provided opportunities to see the ultrasound picture of the expected infant. However, one-third of the women also reported stress in relation to the examinations.CONCLUSIONS: Fetal echocardiographic surveillance holds many and predominantly positive effects for Ro/SSA-positive women during pregnancy in addition to the medical advantages.
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- Tingström, Joanna, et al.
(author)
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Ro52 autoantibody-positive women's experience of being pregnant and giving birth to a child with congenital heart block
- 2013
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In: Midwifery. - : Elsevier. - 0266-6138 .- 1532-3099. ; 29:1, s. 18-23
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Journal article (peer-reviewed)abstract
- OBJECTIVE: congenital heart block may develop in the fetus of women with Ro/SSA autoantibodies. The aim of this study was to investigate how women expecting a child with congenital heart block (CHB) experienced their pregnancy and post-partum period.DESIGN, SETTING AND PARTICIPANTS: women giving birth to a child with CHB in Sweden during 2000-2009 were identified in a population-based manner and individually interviewed post-pregnancy using a semi-structured interview guide. The interviews (n=21) were audiotaped, transcribed verbatim and analysed by qualitative content analysis.FINDINGS: three categories emerged from the responses: learning, suspense and facing. Learning contained both learning about the child's heart block, but frequently also about autoantibody-positivity and a potential rheumatic diagnosis in the mother (16/21). The medical procedures and information differed considerably depending on the area of residence and who was encountered in the health-care system. In many cases, ignorance about this rare condition caused a delay in treatment and surveillance. Suspense described the women's struggle to cope with the feeling of guilt and that the child had a serious heart condition and might not survive the pregnancy. Facing included the post-partum period, leaving the hospital and adjusting to everyday life. The women had tended to put their pregnancies 'on hold', and some described that they needed prolonged time to bond with their newborn child.CONCLUSION: increased awareness and knowledge of CHB are needed to provide adequate care. Offering psychological support by a health-care professional to facilitate early bonding with the child should be considered.IMPLICATIONS FOR PRACTICE: there is a need for structured programs for surveillance of the pregnancies. Such programme should implement guidelines for the involved personnel in the chain of care and make relevant information accessible for the women and families.
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- Tingström, Joanna, et al.
(author)
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The experiences of pregnancy in women with SSA/Ro52 autoantibodies
- 2010
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In: Musculoskeletal Care. - : John Wiley & Sons. - 1478-2189 .- 1557-0681. ; 8:4, s. 215-223
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Congenital heart block may develop in the foetus during pregnancy in SSA/Ro52 autoantibody-positive women. The aim of this study was to investigate how women with SSA/Ro52 autoantibodies experience their pregnancy in terms of the risk of developing foetal heart block, and in undergoing serial ultrasound Doppler echocardiography to detect early signs of congenital heart block.METHODS: Data were collected through individual semi-structured interviews with SSA/Ro52-positive women post-pregnancy (n = 14). The interviews were audio-taped, transcribed verbatim and analysed according to qualitative content analysis.RESULTS: Three categories emerged from the responses: information, emotional response and support. The information received prior to and during early pregnancy was focused on the need for attending a specialized antenatal clinic, and information on the risk for congenital heart block was scarce or missing. During gestational weeks 18-24, when the ultrasound/Doppler examinations were performed, all women described increased stress. However, the interaction with the caregivers made the women feel more safe and secure. Several women also said that they did not emotionally acknowledge the pregnancy until after gestational week 24. None had been offered psychological support.CONCLUSION: There is a need for structured information and organized programmes for the surveillance of women who are SSA/Ro52 positive during their pregnancy. Further, offering psychological support to the women and their families to manage the stress and to facilitate the early attachment to the child should be considered.
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- Öhman, Annika, et al.
(author)
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Changing Epidemiology of Hypoplastic Left Heart Syndrome : Results of a National Swedish Cohort Study
- 2019
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In: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 8:2
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Journal article (peer-reviewed)abstract
- 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.
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- Öhman, Annika, et al.
(author)
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Transplantation-free survival after Norwood surgery for hypoplastic left heart syndrome with aortic atresia : A Swedish national cohort study
- 2020
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In: Cardiology in the Young. - : Cambridge University Press. - 1047-9511 .- 1467-1107. ; 30:3, s. 353-360
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Journal article (peer-reviewed)abstract
- 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.
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