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Atrioventricular conduction delay in the second trimester measured by fetal magnetocardiography.
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PMID:  24741622     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Introduction. Fetal AV block in SSA/Ro pregnancies is generally not seen before 18-week gestation and onset is rare after 28-week gestation. If complete AV block appears, it is believed to be irreversible. The purpose of the study was to evaluate precise electrophysiological AV conduction from 18-week gestation onwards. Patients and Methods. 21 fetuses of pregnant women with collagen vascular diseases were included in the study group and 59 healthy fetuses served as controls. In addition to fetal echocardiography, fetal magnetocardiography (fMCG) was used to investigate precise electrophysiological fetal cardiac time intervals (fCTIs). Results. The PR segment (isoelectric segment between the end of the P wave and the start of the QRS complex) was significantly prolonged (P < 0.036 2nd trimester, P < 0.023 3rd trimester) in both trimesters within the study group. In fetuses less than 23-week gestational age, a nearly complete separation was found, where a PR segment of 60 ms or greater completely excluded control fetuses. All other fCTIs did not differ significantly. None of the fetuses progressed to a more advanced heart block. Conclusion. Slight antibody effects in pregnancy, leading to PR segment prolongation, can already be seen from 18-week gestation onwards by fMCG. Serial fetal Doppler echocardiography and additional fMCG can be useful methods to measure early and precise AV conduction time, to achieve best surveillance for these high-risk pregnancies.
Authors:
Annette Wacker-Gussmann; Henrike Paulsen; Krunoslav Stingl; Johanna Braendle; Rangmar Goelz; Joerg Henes
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Type:  Journal Article     Date:  2014-01-16
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Title:  Journal of immunology research     Volume:  2014     ISSN:  2314-7156     ISO Abbreviation:  J Immunol Res     Publication Date:  2014  
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Created Date:  2014-04-17     Completed Date:  -     Revised Date:  -    
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Nlm Unique ID:  101627166     Medline TA:  J Immunol Res     Country:  United States    
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Languages:  eng     Pagination:  753953     Citation Subset:  IM    
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Journal ID (nlm-ta): J Immunol Res
Journal ID (iso-abbrev): J Immunol Res
Journal ID (publisher-id): JIR
ISSN: 2314-8861
ISSN: 2314-7156
Publisher: Hindawi Publishing Corporation
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Copyright © 2014 Annette Wacker-Gussmann et al.
open-access:
Received Day: 23 Month: 8 Year: 2013
Revision Received Day: 22 Month: 12 Year: 2013
Accepted Day: 24 Month: 12 Year: 2013
Print publication date: Year: 2014
Electronic publication date: Day: 16 Month: 1 Year: 2014
Volume: 2014E-location ID: 753953
PubMed Id: 24741622
ID: 3987975
DOI: 10.1155/2014/753953

Atrioventricular Conduction Delay in the Second Trimester Measured by Fetal Magnetocardiography
Annette Wacker-Gussmann12*
Henrike Paulsen1
Krunoslav Stingl12
Johanna Braendle3
Rangmar Goelz1
Joerg Henes4
1Department of Neonatology, University Children's Hospital Tuebingen, 72076 Tuebingen, Germany
2fMEG Center, University of Tuebingen, 72076 Tuebingen, Germany
3Department of Obstetrics and Gynecology, University Hospital, 72076 Tuebingen, Germany
4Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-Inflammatory Diseases and Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology, Pulmonology), University Hospital, 72076 Tuebingen, Germany
Correspondence: *Annette Wacker-Gussmann: annette.wacker@med.uni-tuebingen.de
[other] Academic Editor: Michael Mahler

1. Introduction

Substantial morbidity and mortality of fetuses in patients with anti-SSA/Ro antibodies in pregnancy are associated with the development of congenital heart block [14]. Fetal AV block in SSA/Ro pregnancies is generally not seen before 18-week gestation and onset is rare after 28-week gestation [5]. If complete congenital heart block in these fetuses occurs, it is believed to be irreversible. Nevertheless, intrauterine therapy might be possible, although it is empiric at the moment. The rationale for treatment strategies is to identify the heart block as early as possible and to diminish the inflammatory insult to the heart by lowering the maternal antibodies [6]. Immune-mediated AV block may benefit from in utero treatment with fluorinated steroids, IVIG, or both. Dexamethasone is believed to reduce inflammation [79]. Although no clear consensus exists, most clinicians use dexamethasone 4–8 mg/day to treat not only second-degree AV block and recent onset AV block but also severe cardiac dysfunction and hydrops.

Several investigators have reported a transient prolongation of AV conduction time by echocardiography during midtrimester, which was still present on postnatal electrocardiograms (ECG) in 50% of the subjects. The long-term prognosis in these studies was reported as being excellent [10, 11]. These findings might indicate a time frame, where reversal of incomplete block without treatment can be seen.

The methods used are mainly Doppler techniques which measure the mechanical rather than the electrophysiological events to obtain AV intervals. Fetal magnetocardiography (fMCG) might fill in this gap. This innovative method is more precise in detecting fetal conduction and arrhythmias [1214]. However, fMCG generally captures each of the cardiac time intervals (P wave, QRS complex, and T waves, RR-, PR-, and QT intervals) in fetuses over 24-week gestation; in fetuses below 24-week gestation, which is the most important time frame in the development of AV conduction delay, only QRS and RR intervals can be reliably measured in most fetuses [15, 16]. In consequence, a new analyzing method was investigated. We have previously reported PR segment prolongation, relative to controls, in sixteen 3rd trimester fetuses [17], however, analysis of fMCG intervals at younger gestations was difficult until a new method of signal extraction based on a combination of orthogonal projection and independent component analysis was developed. With the help of this new method, measurements of fCTIs were possible from 18-week gestation onwards [17]. The aim of this study was to investigate precise electrophysiological fetal cardiac time intervals in these high-risk fetuses from 18-week gestation onwards by fMCG. This might help to understand the pathophysiology of reverse AV prolongation.


2. Patients and Methods
2.1. Patient Population

Baseline characteristics of all 80 patients for this observational study were evaluated with regard to medical history, previous pregnancy outcomes, and medication intake.

21 fetuses of pregnant women with collagen vascular diseases such as systemic lupus erythematosus or Sjogren's syndrome were included in the study group.

At study entry, all patients of the study group fulfilled the following inclusion criteria: presence of anti-SSA/Ro and/or anti-SSB/La antibodies tested by an enzyme linked immunosorbent assay (ELISA) and/or an immunofluorescence test, an immunodiffusion test, and dot blots by a commercial laboratory. Rheumatologic disease was diagnosed by a rheumatologist according to defined criteria [18, 19]. There was no limit concerning the duration of medication intake. Pregnancies over 18-week of gestation with a normal heart beat and a structural normal heart were included.

Exclusion criteria for all neonates were chromosomal abnormalities, malformations, and congenital infections.

Data of the study group were compared to already established norm values of healthy women with uncomplicated pregnancies and normally developing fetuses. Neonatal outcomes defined as normal AV conduction by physical exam and established normative cardiac time intervals for age were assessed by a paediatrician by clinical routine examination, fetal heart rate monitoring, and neonatal ECG.

The study was approved by the ethics review board of the University Hospital Tuebingen. Informed written consent was obtained from each subject.

2.2. Methods

At the beginning of the study, conventional echocardiography was performed in the study group to evaluate structural cardiac abnormalities, myocardial function, and fetal heart rate, in addition to regular ultrasound examinations.

fMCG measurements were performed in the study group and in the control group.

Prior to the beginning of each fMCG measurement, ultrasound was performed in all patients to check the fetal position and to localize the fetal heart. Furthermore, cardiotocography was performed over a 20-minute period to obtain complete information about the health of the fetus.

2.2.1. Data Acquisition

The fMCG recordings were acquired using a 156-channel biomagnetic system with channels arranged in a curved array that matched the shape of the gravid abdomen (SARA system, VSM Med Tech Ltd., Port Coquitlam, Canada). All of the measurements were recorded with a sampling rate of 1220.7 Hz in a magnetically shielded room (Vakuumschmelze, Hanau, Germany). The length of the recordings ranged from nine to 35 minutes. Data collection was performed between 18 and 38 weeks gestation, focusing primarily on second trimester.

2.2.2. Data Processing

The analysis of the fetal heart signals was performed according to our previously published work [17]. An automated algorithm using orthogonal projection and independent component analysis was applied to reconstruct the fetal heart signal [2023]. fCTI evaluation was performed using a custom-made MATLAB program (R2008b, Mathworks, Natick, MA, USA).

The time points identified were used to calculate the duration of the CTI as follows.

P  wave = Pend − Ponset, QRS  complex = QRSend − QRSonset. The QT interval was defined as Tend − QRSonset. The PR interval was determined as P wave + PR segment, whereas PR segment was defined as Pend to QRSonset. The PR segment may more accurately reflect the AV conduction as the PR interval, because it eliminates any intra-atrial conduction delay reflected by the P wave duration measurement. All fMCG recordings were reviewed by at least one physician who has extended experience in pediatric cardiology.

2.3. Statistical Analysis

Statistical analysis was performed using SPSS 20.0 (IBM) for Windows. Normal distribution was tested using Kolmogorov-Smirnov Test. ANCOVA was used for data analysis and the influence of age, gender, and birth weight was tested. P < 0.05 was regarded as statistically significant.


3. Results
3.1. Patient Population
3.1.1. Study Population

21 mothers were included in the study group. The median age of the mothers with systemic lupus erythematosus (n = 15 patients) or Sjogren's syndrome (n = 6 patients) was 31 years (range 21–46 years) (Table 1). The maternal suppressive therapies in these 21 patients were low-dose prednisolone (n = 13), high-dose prednisolone (n = 1), hydroxychloroquine (n = 12), cyclosporine (n = 1), and azathioprine (n = 6). Most of the patients received more than one medication.

21 fetuses were measured with a median gestational age of 28 weeks (range 18–38 weeks). Six neonates were too small for gestational age.

3.1.2. Control Population

59 pregnant women were included in the control group. Mean age of the women was 33 years (range 25–50 years). All women were healthy except for one with gestational diabetes. Chronic diseases were found in the following patients: thalassaemia minor (two patients), Crohn's disease (one patient), and factor V Leiden mutation (one patient). Twelve women had a previous history of hypothyroidism but were euthyroid at time of measurement.

59 fetuses were measured with a median gestational age of 32 weeks (range 19–38 weeks). Neonatal outcome revealed 59 healthy newborns. Four fetuses were born prematurely (>32 and <37 weeks of gestation). One newborn was small for gestational age whereas three newborns were large for gestational age.

3.2. Fetal Cardiac Time Intervals

Altogether 36 measurements in 21 patients were included in the study group and 63 measurements in 59 subjects were included in the control group. The measurements included measurements >24 weeks gestation of the previous study.

The fCTIs for all patients are shown in Tables 2 and 3. Table 2 focuses on second trimester (18–26 weeks of gestation), whereas Table 3 has its impact on late gestational ages (27–38 weeks of gestation). As the mean birth weight (shown in Table 1) was significantly smaller (P = 0.013) in the study group compared to the control group, P values were adjusted for this parameter. In addition, P values were adjusted for age and gender.

The PR segment (isoelectric segment between the end of the P wave and the start of the QRS complex) was significantly prolonged in both trimesters within the study group (P < 0.036 2nd trimester, P < 0.023 3rd trimester). All other CTIs did not differ significantly. Available postnatal ECGs in the study group did not show first-, second- or third-degree AV block.


4. Discussion

The main finding in this study was that the PR segment (PR  interval − P  wave), measured by fMCG, was significantly prolonged in the study group not only in the third but also in the second trimester when compared to controls. Four of the study subjects and only one of the control subjects had PR segment measurements equal to or exceeding 75 ms. In fetuses less than 23-week gestational age, a nearly complete separation was found, where a PR segment of 60 ms or greater completely excluded control fetuses (see Figure 1). All other fCTIs did not differ significantly and none of the fetuses progressed to second- or third-degree heart block.

These findings support the concept that mild AV conduction delays may not progress. In a large multicenter study, first-degree AV block did not predict development of advanced AV block, whereas tricuspid regurgitation of moderate or severe degree, and endocardial fibroelastosis, was associated with subsequent onset of 2nd or 3rd degree AV block.

Van Leeuwen and colleagues and Stinstra and colleagues, both, have reported dependency of fCTIs (also the PR segment duration) on gestational age and gender [16, 24, 25]. Additionally, subjects in the study group had a lower weight at birth than those of the control group [26]. However, significant PR segment prolongation was found in the study group, relative to the control group, even after adjusting for all these possible confounding factors.

The new analyzing method improved signal detection and reconstruction in early gestational ages. In consequence, a total of 99 measurements (in 80 patients) could be achieved, 18 under 24-week gestational age. In this study, PR segment prolongation was additionally found in the second trimester (from 18-week gestation onwards) by fMCG. None of the fetuses developed AV block. The prolongation of the PR segment duration might indicate antibody effects already present in the second trimester of pregnancy.

Jaeggi and colleagues reported similar findings by echocardiography from 15 untreated fetuses either with AV prolongation between 2 and 6 z-scores or with type one second-degree block. None of the fetuses developed progressive heart block [27].

In addition Sonesson and colleagues reported eight of 24 fetuses who had signs of first-degree block in their study. These AV blocks, measured by Doppler echocardiography, mainly reverted spontaneously. One of these fetuses had progression to complete block, another showed recovery from second-degree to first-degree block with treatment [28]. The lack of progression of first-degree AV block to more severe block makes treatment on the basis of first-degree AV block unnecessary, except perhaps in the most severe prolongation. Rein and colleagues have reported treating patients with dexamethasone for first-degree AV block and attributed the lack of progression as a sign that steroids were effective [29].

Mechanical measurements by Doppler echocardiography and electrophysiological measurements by fMCG, both, show AV prolongation. Stable but also progressive AV prolongation was described in different studies. Therefore serial fetal Doppler echocardiography and additional fMCG measurements of AV time intervals are proposed as a useful method to measure early and precise AV conduction time to achieve best surveillance of these high-risk pregnancies.

In summary, antibody in pregnancy patients might have an effect on the fetal atrioventricular conduction already from early second trimester onwards. But this effect can be reversible and does not consecutively lead to congenital heart block.

To develop new management strategies, fMCG measurements in addition to Doppler echocardiography might be helpful. However, a higher number of these high-risk patients in multicenter studies of this rare condition are probably necessary.


Acknowledgments

The authors thank JF Strasburger (MD), Professor of Pediatrics, Division of Cardiology, Children's Hospital of Wisconsin-Milwaukee and Fox Valley, USA, for her great advice and review of the paper. They thank J. Muenssinger (MSc), H. Preissl (PhD), and I. Kiefer-Schmidt (MD) (fMEG Center and Department of Obstetrics and Gynecology, University of Tuebingen) for the support of the study. The study was supported by AKF 307-0-0, TUEFF Application 2156-0-0, University of Tuebingen and “Deutsche Stiftung für Herzforschung” F02/11. The installation of the fMEG device was supported by the “Deutsche Forschungsgemeinschaft” (BI 195-50) and the “Landesstiftung Baden-Wuerttemberg.”

Conflict of Interests

The authors declare that there is no conflict of interests.


References
1. Eliasson H,Sonesson S,Sharland G,et al. Isolated atrioventricular block in the fetus: a retrospective, multinational, multicenter study of 175 patientsCirculationYear: 201112418191919262-s2.0-8015515586021986286
2. Jaeggi ET,Hamilton RM,Silverman ED,Zamora SA,Hornberger LK. Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block: a single institution’s experience of 30 yearsJournal of the American College of CardiologyYear: 20023911301372-s2.0-003700578411755298
3. Izmirly 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 lupusCirculationYear: 201112418192719352-s2.0-8025513821121969015
4. Buyon JP,Hiebert R,Copel J,et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registryJournal of the American College of CardiologyYear: 1998317165816662-s2.0-00317459679626848
5. Buyon JR. Neonatal lupusCurrent Opinion in RheumatologyYear: 1996854854902-s2.0-00298380028941454
6. Buyon JP,Nelson JL,Lockshin MD. The effects of pregnancy on autoimmune diseasesClinical Immunology and ImmunopathologyYear: 1996782991042-s2.0-00299156528625564
7. Trucco SM,Jaeggi E,Cuneo B,et al. Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathyJournal of the American College of CardiologyYear: 20115767157232-s2.0-7955155148721292131
8. Jaeggi ET,Fouron J,Silverman ED,Ryan G,Smallhorn J,Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart diseaseCirculationYear: 200411012154215482-s2.0-464428664515353508
9. Cuneo BF,Lee M,Roberson D,et al. A management strategy for fetal immune-mediated atrioventricular blockJournal of Maternal-Fetal and Neonatal MedicineYear: 20102312140014052-s2.0-7824923353420384469
10. Bergman G,Wahren-Herlenius M,Sonesson SE. Diagnostic precision of Doppler flow echocardiography in fetuses at risk for atrioventricular blockUltrasound in Obstetrics and GynecologyYear: 20103655615662-s2.0-7834923627220069676
11. Bergman G,Eliasson H,Mohlkert L,Wahren-Herlenius M,Sonesson S. Progression to first-degree heart block in preschool children exposed in utero to maternal anti-SSA/Ro52 autoantibodiesActa PaediatricaYear: 201210154884932-s2.0-8485958778722175870
12. Zhao H,Cuneo BF,Strasburger JF,Huhta JC,Gotteiner NL,Wakai RT. Electrophysiological characteristics of fetal atrioventricular blockJournal of the American College of CardiologyYear: 200851177842-s2.0-3744902930718174041
13. Strasburger JF,Cheulkar B,Wakai RT. Magnetocardiography for fetal arrhythmiasHeart RhythmYear: 200857107310762-s2.0-4584915169718486565
14. Strasburger JF,Wakai RT. Fetal cardiac arrhythmia detection and in utero therapyNature Reviews CardiologyYear: 2010752772902-s2.0-77951735572
15. Leuthold A,Wakai RT,Martin CB. Noninvasive in utero assessment of PR and QRS intervals from the fetal magnetocardiogramEarly Human DevelopmentYear: 19995432352432-s2.0-003300518110321790
16. Van Leeuwen P,Schiermeier S,Lange S,et al. Gender-related changes in magnetocardiographically determined fetal cardiac time intervals in intrauterine growth retardationPediatric ResearchYear: 20065968208242-s2.0-3374656800916641208
17. Stingl K,Paulsen H,Weiss M,et al. Development and application of an automated extraction algorithm for fetal magnetocardiography—normal data and arrhythmia detectionJournal of Perinatal MedicineYear: 201341672573423828424
18. Tan EM,Cohen AS,Fries JF. The 1982 revised criteria for the classification of systemic lupus erythrematosusArthritis and RheumatismYear: 19822511127112772-s2.0-00204366897138600
19. Fox RI,Robinson CA,Curd JG. Sjogren’s syndrome. Proposed criteria for classificationArthritis and RheumatismYear: 19862955775852-s2.0-00225555253718551
20. McCubbin J,Robinson SE,Cropp R,et al. Optimal reduction of MCG in fetal MEG recordingsIEEE Transactions on Biomedical EngineeringYear: 2006538172017242-s2.0-3374661370116916111
21. Vrba J,Robinson SE,McCubbin J,et al. Fetal MEG redistribution by projection operatorsIEEE Transactions on Biomedical EngineeringYear: 2004517120712182-s2.0-294270004315248537
22. Jung TP,Makeig S,Mckeown MJ,et al. Imaging brain dynamics using independent component analysisProceedings of the IEEEYear: 20018971107112220824156
23. Delorme A,Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysisJournal of Neuroscience MethodsYear: 200413419212-s2.0-124228394115102499
24. Stinstra J,Golbach E,van Leeuwen P,et al. Multicentre study of fetal cardiac time intervals using magnetocardiographyBJOGYear: 200210911123512432-s2.0-003687692912452461
25. van Leeuwen P,Lange S,Klein A,Geue D,Grönemeyer DHW. Dependency of magnetocardiographically determined fetal cardiac time intervals on gestational age, gender and postnatal biometrics in healthy pregnanciesBMC Pregnancy and ChildbirthYear: 20044, article 62-s2.0-2642568537
26. Yasmeen S,Wilkins EE,Field NT,Sheikh RA,Gilbert WM. Pregnancy outcomes in women with systemic lupus erythematosusJournal of Maternal-Fetal MedicineYear: 200110291962-s2.0-003570273511392599
27. Jaeggi ET,Silverman ED,Laskin C,Kingdom J,Golding F,Weber R. Prolongation of the atrioventricular conduction in fetuses exposed to maternal Anti-Ro/SSA and Anti-La/SSB antibodies did not predict progressive heart block: a prospective observational study on the effects of maternal antibodies on 165 fetusesJournal of the American College of CardiologyYear: 20115713148714922-s2.0-7995292047321435519
28. Sonesson S,Salomonsson S,Jacobsson L,Bremme K,Wahren-Herlenius M. Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodiesArthritis and RheumatismYear: 2004504125312612-s2.0-184278376215077309
29. Rein AJJT,Mevorach D,Perles Z,et al. Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti-SSA/Ro-SSB/La antibodies a prospective, observational, fetal kinetocardiogram-based studyCirculationYear: 200911914186718722-s2.0-6554913295119332471

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