atrioventricular block during fetal life

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Disclosure: Authors have nothing to disclose with regard to commercialsupport.

Received 22 April 2014; revised 27 June 2014; accepted 5 July 2014.Available online 10 July 2014

⇑ Corresponding author. Tel.: +44 20 7188 2308; fax: +44 20 7188 2307.
E-mail address: [email protected] (J.M. Simpson).
Atrioventricular block during fetal life

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URL: www.ksu.edu.sa

http://dx.doi.org/10.1016/j.jsha.2014.07.001 Production and hosting by Elsevier

Lindsey E. Hunter a, John M. Simpson a,⇑

a Fetal Cardiology Unit, Department of Congenital Heart Disease, Evelina London Children’s Hospital, London, UK

a Saudi Arabia

Congenital complete atrioventricular (AV) block occurs in approximately 1 in 20,000 live births and is known toresult in significant mortality and morbidity both during fetal life and postnatally. Complete AV block can occur as aresult of an immune or a non-immune mediated process. Immune mediated AV block is a multifactorial disease, but isassociated with the trans-placental passage of maternal autoantibodies (anti-Ro/SSA and/or anti-La/SSB). Theseautoantibodies attach to and subsequently damage the cardiomyocytes and conduction tissue in susceptible fetuses. Inthis report, we examine the evidence in reference to means of assessment, pathophysiology, and potential prenataltherapy of atrioventricular block.

� 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Keywords: Congenital heart disease, Fetal arrhythmia, Fetal echocardiography, Complete atrioventricular block,
Prenatal therapy
Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165Assessment of fetal atrioventricular block. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165Complete atrioventricular block associated with structural heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Complete atrioventricular block with normal cardiac connections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Treatment of complete AV block. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Complete atrioventricular block . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Second degree AV block . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170First degree AV block . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Prophylactic maternal therapy for complete AV block . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172Approach to management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Approach and policy at our centre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Treatment side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Fetal and neonatal outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

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Figure 1. Normal M mode. The cursor is aligned through the atrialand ventricular myocardium. This is a normal M mode recordingdemonstrating 1:1 AV conduction. AV, atrioventricular; A, atrial; V,ventricular.

Abbreviations

A atrialAA ascending aortaAV atrioventricularAVCTI atrioventricular contraction time intervalCTD connective tissue diseaseECG electrocardiogramEFE endocardial fibroelastosisIVC inferior vena cavaIV intravenousLA left atriumLAI left atrial isomerismLV left ventricleLVOT left ventricular outflow tractMCG magnetocardiographyMV mitral valveRA right atriumRPA right pulmonary arterySLE systemic lupus erythematosisSP spineSVC superior vena cavaTV tricuspid valveV ventricularVSD ventricular septal defect

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J Saudi Heart Assoc2015;27:164–178

HUNTER, SIMPSON 165ATRIOVENTRICULAR BLOCK DURING FETAL LIFE

Introduction

Congenital complete atrioventricular (AV)block is defined as the dissociation of atrial

and ventricular contractions which occurs inapproximately 1 in 20,000 live births [1–3]. Thiscauses a significant drop in the ventricular ratewhich may cause fetal cardiac failure, includingfetal hydrops. Complete AV block is associatedwith a risk of intrauterine or postnatal demiseand the optimal prenatal therapy for affectedfetuses has proven controversial. Congenitalcomplete AV block may result from either animmune or non-immune mediated process. Itcan be associated with underlying structural heartdisease or can develop in association with amultifactorial, autoimmune process, associatedwith the trans-placental transfer of maternalautoantibodies. These autoantibodies are directedagainst Ro/SSA and La/SSB antibodies expressedon the fetal cardiomyocytes of susceptible fetuses.Congenital complete AV block of either isassociated with significant prenatal mortality andpostnatal morbidity and thus remains an area ofmajor clinical interest [1,4–8]. The aims of thisreport are to review atrioventricular blockoccurring during fetal life, with particularreference to means of assessment, causation andprenatal therapy.

Assessment of fetal atrioventricular block

Postnatally, the 12 lead electrocardiogram (ECG)recording is the gold standard for assessment anddiagnosis of rhythm disturbance. During fetal lifeit is difficult to extract the fetal ECG because ofthe distance of the fetus to the maternal skin,possible insulating properties of vernix, and thesmall size of the fetus, all of which contribute tolow voltages. Fetal movement, interference fromthe maternal heart rate and maternal muscularcontraction further contribute to the difficultiesin extracting a fetal ECG [9]. Despite theselimitations, this method has been used toaccurately record the fetal ECG. An alternativetechnique, fetal magnetocardiography (MCG)has been used to detect the magnetic fields causedby electrical signals in the fetal heart. Thistechnique is used in a research setting andtypically depends on a magnetically-shieldedroom to be feasible [10–12].

Thus, echocardiography remains the principaltechnique for assessing AV synchrony or arrhyth-mias in the fetus. Mechanical assessment by Mmode infers electrical activity by demonstratingsequential contraction of the atrial and ventricularmyocardium by aligning the cursor simulta-neously through both myocardial walls [13](Fig. 1). The M mode technique can be used toconfirm normal sinus rhythm, tachycardia andfetal bradycardia, including complete AV block[14] (Fig. 2). Tissue Doppler and pulsed Dopplertechniques are also widely employed [15–17].

Figure 2. M mode – complete AV Block. This M mode recordingdemonstrates a slow ventricular rate and complete dissociationbetween atrial and ventricular contractions (CAVB). CAVB, completeatrioventricular block; A, atrial; V, ventricular.

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166 HUNTER, SIMPSONATRIOVENTRICULAR BLOCK DURING FETAL LIFE


Complete AV block can be easily detected usingconventional M mode tracing, but measuringand determining the presence of lower grade AVblock is challenging and Doppler methods areroutinely incorporated to make this assessment.It should be noted that echocardiographic tech-niques cannot be used to measure time intervalssuch as the QT interval, which can be evaluatedby magnetocardiography [12,18].

In an effort to detect lower grade AV block,attention has focused on the measurement of themechanical PR interval by Doppler techniques,including pulsed wave (PW) Doppler or tissueDoppler. This is of particular interest in fetusesat an increased risk of developing heart block.

Figure 3. Normal AVCTI. The AVCTI is a reflection of the postnatalelectrocardiographic PR interval. The cursor is aligned simulta-neously through the mitral inflow and left ventricular outflow. TheDoppler time interval between the onset of the A wave (atrial systole)and the onset of the ejection outflow Doppler (ventricular systole) ismeasured (ms). AVCTI, atrioventricular contraction time interval.

The time between atrial and ventricular systoleis known as the atrioventricular contraction timeinterval (AVCTI) and is a mechanical representa-tion of the traditional postnatal electrical PR inter-val (Fig. 3). Within the same cardiac cycle, theAVCTI is obtained by aligning the gated PWDoppler cursor simultaneously across an inflowand outflow, for example, left ventricular outflowtract (LVOT) and mitral valve. The Doppler timeinterval is measured between the onset of the Awave (atrial systole) and the onset of the ejectionoutflow Doppler (ventricular systole). Alternativemethods involve aligning the Doppler cursorthrough a pulmonary vein and right pulmonaryartery (RPA) or ascending aorta (AA) and superiorvena cava (SVC), and measuring the time intervalfrom the onset of the retrograde venous A wave tothe onset of the outflow Doppler [11,19]. Althoughuseful, AV time intervals are derived from flowand, as such, the accuracy of the measurementsare influenced by myocardial intrinsic properties,ventricular loading conditions, fetal heart rateand the speed of pulse wave propagation [16].Normative fetal mechanical PR interval referenceranges have been published. In addition, AVCTIvalues have been shown to be increasingly relatedto gestational age, and specifically, MV/LVOTtime intervals are influenced independently bythe fetal heart rate [16,20–23]. The various meth-ods of assessing the AVCTI prenatally have beencompared to the postnatal electrical PR interval.A study by Bergman et al. found the most accuratemeasurement when compared to the postnatalECG was the AA/SVC technique [24]. AlthoughAVCTIs are influenced by intrinsic myocardialproperties, studies have confirmed that in thehands of experienced fetal echocardiographersthere is minimal inter-operator variability [22]. Ithas been hypothesized that measuring the fetalmechanical PR interval by this method may allowfor surveillance and early recognition of fetuseswith lower degrees of AV block, and possible pro-gression to complete AV block. However, thisremains controversial [25].

Complete atrioventricular block associatedwith structural heart disease

Certain structural heart defects are known topredispose to the development of prenatal con-genital complete AV block. The most frequent car-diac lesions associated with complete AV blockare isomerism of the left atrial appendages (LAI)and discordant atrioventricular connections(Figs. 4 and 5). A retrospective study of 116 fetuses

Figure 4. Left atrial isomerism – situs. This fetal echocardiographicimage demonstrates cardiac situs in the presence of LAI. The spinelies posteriorly with one rib surrounding the fetal thorax. Thestomach lies to the left. The aorta lies anteriorly and to the same sideof the spine as the azygous vein. There is azygous continuation due tointerruption of the IVC. LAI, left atrial isomerism; IVC, inferior venacava.

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Figure 5. AV discordance. This demonstrates a traditional fourchamber echocardiographic view of the fetal heart. There is reversalof normal AV valve offsetting, indicating AV discordance. AV,atrioventricular; VA ventriculoarterial.



diagnosed with complete AV block, detected anassociated congenital structural heart defect inover 50%. Of these affected fetuses, greater than60% were associated with LAI [26].

LAI is a multisystem disorder of visceral lateral-ity, characterized by the presence of morphologi-cal, bilateral left atrial appendages. A spectrum ofcardiac abnormalities can occur in associationwith LAI, for example, isolated interruption ofthe inferior vena cava (IVC) with azygous continu-ation to the SVC, defects of the atrioventricular

junction and outflow tract abnormalities. Systemicmanifestations may include abnormal pulmonarylobar morphology with bilateral left bronchialanatomy, abnormally positioned abdominal vis-cera including malrotation of the bowel, biliaryatresia and polysplenia or, rarely, asplenia whichmay result in altered or suboptimal immune func-tion. In normal cardiac situs, the sinus node is amorphologically right atrial structure. Thus, in adiagnosis of LAI, the sinus node by definition isabnormally positioned, hypoplastic or absent,often resulting in a sinus bradycardia or completeAV block. The combination of LAI and completeAV block prenatally has a very poor prognosis,particularly in the presence of fetal hydrops, withmortality rates by term reported as high as 100%[26]. This is a condition with very few therapeuticoptions and the prognosis does not seem to beimproving with advances in fetal cardiology[4,6,8,27].

A diagnosis of discordant atrioventricular (AV)connections may be made during routine fetalechocardiography. The four chamber view ofthe heart is assessed in a cross sectional viewthrough the fetal thorax. This traditional fourchamber view demonstrates reversal of the nor-mal pattern of offsetting of the atrioventricularvalves (Fig. 5). Discordant AV connections canoccur in isolation or with associated intra-cardiacdefects, for example, ventricular septal defects(VSDs), and outflow tract obstruction. Morpho-logically, the atrial and inlet portion of the ven-tricular septum are maligned, disrupting thenormal conduction axis, potentially leading toprogressive AV block and subsequent completeAV block, pre or postnatally [28].

In addition to LAI and discordant AV connec-tions, complete AV block can occur in associationwith more common structural heart defects,including tetralogy of Fallot, right ventricularhypoplasia, double inlet left ventricle, VSD, coarc-tation with VSD, and multiple rhabdomyomas [26].

Complete atrioventricular block with normalcardiac connections

In contrast to complete AV block associated withstructural heart disease, immune mediated com-plete AV block most commonly occurs with astructurally normal heart. Functional abnormali-ties may coexist, including cardiomegaly, ventric-ular hypertrophy, impaired ventricular function,and atrioventricular valve regurgitation whichcan contribute to pericardial effusions and, insevere cases, fetal hydrops. Immune mediated

Table 1. Complete atrioventricular block.

Authors Study design Inclusioncriteria

AV block Treatment Prenataloutcome

Postnataloutcome

Copel et al.[45]

Prospective Antibody +ven = 5

CAVB n = 4 Dexamethasone n = 4 – CAVB n = 4IntermittentCAVB andsecond degreeAV block n = 1

Dexamethasone n = 1 – CAVB at term,reverted tosecond degreeAV Blockpostnatally n = 1

Yamadaet al. [51]


CAVB n = 1 Prednisolone andDexamethasone

– CAVB n = 1

Friedmanet al. [38]‘PRIDE’

Prospective,multicenter,observational

Antibody +ven = 98 (prestudy maternalsteroidsexcluded)

CAVB n = 1 Dexamethasone Fetalhydrops –TOP

–

CAVB n = 1 Dexamethasone CAVB CAVB PacedCAVB n = 1 Dexamethasone Fetal

Hydrops –TOP

–

Jaeggi et al.[39] UOG

Case Study Antibody +ven = 1

CAVB at21 weeksgestation

Dexamethasone 22 weeksseconddegree AVblock24 weeksFirst degreeAV block32 weeksCAVB andEFE

CAVB notpaced

Jaeggi et al.[39] Circ

Retrospective Antibody +ven = 33

CAVB n = 33 Dexamethasone n = 12 IUD n = 1 CAVB n = 11Dexamethasone/bStimulation n = 8

TOP/IUDn = 2

CAVB n = 5 IFDn = 1

b Stimulation n = 1 – CAVB/NNDn = 1

Dexamethasone/IVIG n = 1 – CAVB n = 1Jaeggi et al.

[39] CircRetrospective Antibody �ve

n = 4CAVB n = 4 No therapy n = 2 – NND n = 1

CAVB n = 1(paced)

Dexamethasone/bStimulation n = 2

CAVB n = 2(paced)

Sonessonet al. [40]


CAVB n = 1(preceded byfirst degree AVblock)

Betamethasone n = 1 – CAVB n = 1

Lopes et al.[26]

Retrospective Antibody +ven = 42Antibody �ven = 15

CAVB n = 35CAVB(preceded bysecond degreeAV block) n = 9

Dexamethasone ± bStimulation n = 4 unspecifiedcases

IUD n = 5 Alive n = 52

Fesslovaet al. [42]

Multicenter,retrospective

Antibody +ven = 28

CAVB n = 28 Dexamethasone n = 18 IUD n = 1 CAVB n = 17Dexamethasone + bStimulation n = 2

– CAVB n = 1NND n = 1

Isoproterenol n = 1 – NND n = 1No therapy n = 7 IUD n = 1 CAVB n = 6

Eliassonet al. [47]

Multicenter,multinational,retrospective

n = 175 (80%Ro/La antibody+ve)

CAVB n = 146 Dexamethasone/Betamethasone n = 54

TOP n = 1IUD n = 6(therapy)

NND n = 3(therapy) n = 7(no therapy)Alive at 1 monthn = 53 (therapy)n = 85 (notherapy) 11 lostto f/u

No therapy n = 92 IUD n = 9(notherapy)

CAVB(precedingsecond degreeAV block)n = 14

Dexamethasone/Betamethasone n = 6

–

No therapy n = 8 –

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Table 1. (continued)


AV block Treatment Prenataloutcome

Postnataloutcome

Izmirly et al.[52]

Casecontrolledstudy

Antibody +ven = 201 cardiacmanifestationsn = 50

Second degreeAV block/CAVB n = 43(out of 50 withcardiacmanifestations)

Dexamethasone/betamethasone n = 48 of 50hydroxychloroquine n = 7 of50

– No outcomesdocumented

Tunks et al.[55]


CAVB n = 4(HCQprophylaxisn = 0)

Dexamethasone n = 4 CAVB n = 3 CAVB n = 4(Paced n = 3)CAVB

precededby 1st AVblock n = 1

Kaaja andJulkunen[57]


CAVB n = 1 IVIG – CAVB n = 1Sinus rhythmn = 7

IVIG/Steroids – Sinus rhythmn = 7

Pisoni et al.[58]

Multicenter,prospective,observational

Antibody +ven = 24

Sinus rhythmn = 24

IVIG/Hydrocortisoneprophylaxis n = 15

CAVB n = 3(TOP n = 2)

Alive n = 12CAVB n = 1

No prophylaxis n = 9 CAVB n = 1(TOP)

Alive n = 8

Friedmanet al. [29]

Multicenter,prospective,open-labelclinical trial

Antibody +ven = 20

Sinus rhythmn = 20

IVIG prophylaxis n = 20 CAVB n = 3(n = 1precededby 2nd AVblock)

CAVB n = 3(despiteadditionaldexamethasone)

Sinusrhythmn = 17

Sinus rhythmn = 17

Jaeggi et al.[3]


CAVB n = 35(sinus rhythmn = 3)

Steroids ± Salbutamol ± IVIGn = 25

IUD n = 1 IFD n = 2, Aliven = 22

No therapy n = 4 TOP n = 2IUD n = 1

Alive n = 1

Not documented n = 6 – Alive n = 6

AV, atrioventricular; CAVB, complete; AV, block; TOP, termination of pregnancy; EFE, endocardial fibroelastosis; IUD, intrauterine demise; IFD,infant death; NND, neonatal death; f/u, follow up; IVIG, intravenous immunoglobulin.

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congenital complete AV block is a passivelyacquired, autoimmune disease associated withthe trans-placental passage of maternal autoanti-bodies to the developing fetus. In susceptiblefetuses, the autoantibodies attach to the ribonu-cleotide proteins (antibodies) which are expressedon cardiomyocytes of the fetal myocardium, inparticular: 52 kD Ro/SSA (Ro52); 60 kD Ro/SSA(Ro60) and 48 kD La/SSB (La48). This immuneprocess results in inflammation of the fetal con-duction tissue and myocardium with resultantprogressive and irreversible fibrosis. In severecases that result in intrauterine demise, post-mor-tem assessment has identified necrosis, fibrosis,and calcification of the fetal myocardium and con-duction tissue [29]. Long QT syndrome may resultin complete AV block within a structurally normalheart. The QT interval may be so prolonged thatatrial depolarisation occurs during the refractoryperiod of the ventricle so that the atrial impulsedoes not result in ventricular contraction. In this

clinical situation parental ECGs may be helpful.In contrast to the PR interval, the QT interval can-not be measured by fetal echocardiography, butcan be assessed by fetal MCG [12,18,30].

Anti-Ro/SSA and La/SSB antibodies are com-monly associated with maternal connective tissuedisease, but have been detected in the asymptom-atic, general population. Within the population ofwomen seropositive for anti-Ro/SSA or anti-La/SSB antibodies, it is estimated that only 2–3% ofoffspring will develop congenital AV block orabnormalities of the myocardium [9]. However, ifa previous child has been affected the recurrencerisk in subsequent pregnancies increases to 17–20% [1,31,32]. Thus, it can be hypothesized thatthe presence of autoantibodies may be associatedwith the disease process but is not the solitarycausative factor resulting in irreversible damageto the fetal heart. There are as yet unrecognizedfactors which may contribute to the pathogenesisof immune mediated complete AV block, and

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these may be genetic, maternal, fetal or externalenvironmental factors. This hypothesis is corrobo-rated by a study in which 85% of mothers withchildren with congenital complete AV block wereasymptomatic for connective tissue disease priorto conception. In addition, 98% of the women inwhom fetal complete AV block was detected hada previously healthy child with no evidence of aconduction disorder [3]. There are reports ofdelayed seroconversion in previously asymptom-atic women several years after delivering a childaffected by congenital complete AV block [26].This highlights the importance of appropriatecounselling of all women in whom a fetus isaffected by complete AV block, including referralfor assessment by specialists in connective tissuedisease.

Treatment of complete AV block

Although complex, the pathophysiology ofimmune mediated congenital complete AV blockinvolves an immune mediated inflammatory pro-cess which damages the conduction tissue andmyocardium of the developing heart. In order todirectly target and potentially halt this destructiveprocess, anti-inflammatory medications andimmune modulators have been utilized. Manystudies are anecdotal, retrospective with smallstudy numbers, and vary with respect to whetherthe aim is prevention of AV block in the fetus ortreatment of the fetus who has developed signsof complete or lesser degrees of AV block. Themost common therapies include maternal steroids,b stimulation with salbutamol, IV immunoglobulinand hydroxychloroquine. Other less commonmaternal therapies include: B cell depletion ther-apy [33], azathioprine [34], cyclophosphamide[35], and plasmapheresis [36,37], Treatment maybe subdivided according to the degree of AV block,and may be classed as prophylactic or therapeutic.

Complete atrioventricular block

There is no robust evidence to suggest all casesof complete AV block are preceded by lowerdegrees of AV block. In the presence of lowerdegrees of AV block, progression to complete AVblock can occur rapidly over a short period oftime, often within days [25,38–40]. Once thisimmune reaction has occurred, complete AV blockhas not been reported to shown signs of revers-ibility or evidence of spontaneous reversion tosinus rhythm despite maternal medical therapy[38,41–43]. Prednisolone, betamethasone and

dexamethasone have been used as therapy inmany women with a positive antibody status.Dexamethasone, a fluorinated steroid, may actby reducing the maternal autoantibody load, butdoes not directly act to protect the fetal myocar-dium and conduction tissue from the destructiveaction of the autoantibodies [44]. However, mater-nal steroids have been associated with resolutionof fetal hydrops when associated with completeAV block, which may be related to an acuteinflammatory process resulting in a myocarditis[42,45]. Table 1 summarizes studies of the treat-ment and outcome of prenatally detected com-plete AV block.

The indications for treatment of complete AVblock are controversial. Some data has suggesteda beneficial effect of dexamethasone and salbuta-mol on outcome [43]. However, this paper usedhistoric controls, and other groups have suggestedthat the apparent effect of therapy may be a timeera effect [46]. Recently, a European multinationalretrospective study confirmed that steroid therapywas used in 38% of affected cases but that this didnot have a positive impact on intrauterine sur-vival, postnatal survival or development of latecardiomyopathy [47]. Of mothers treated with ste-roids, 15% developed an adverse fetal or maternalside effect [47]. That study did not address theimpact of additional therapy with b stimulationand confirmed that choice of therapy was morerelated to the institution than the condition ofthe fetus [43]. Groves et al. demonstrated thatmaternal salbutamol therapy increased the fetalventricular rate and subsequently improved fetalmyocardial function [48]. Conversely, other stud-ies have suggested that b stimulation does notincrease the fetal heart rate significantly but whenthe baseline fetal heart rate was lower than thecontrols there was no further reduction in the ven-tricular rate [43]. Use of maternal salbutamol hasbeen associated with prolongation of gestation inaffected fetuses [49].

Second degree AV block

Traditional M mode assessment may detectsecond degree AV block. In particular, type 2 seconddegree AV block can be detected by demonstratingtwo atrial contractions to every ventricular contrac-tion with a fixed relationship between atrial andventricular beats. However, differentiating seconddegree and complete AV block by M Mode assess-ment can be extremely difficult. Alternatively,Doppler techniques can be used to determine thetime intervals between atrial and ventricular con-tractions including a Wenckebach pattern [50].

Table 2. Second degree atrioventricular block.


AV block Treatment Postnatal outcome

Copelet al.[45]


Second degree AVblock n = 1

Dexamethasone Sinus rhythm n = 1

Second degree AVblock andintermittent CAVBn = 1

Dexamethasone CAVB with subsequentsecond degree AV block(not paced) n = 1

Yamadaet al.[51]



Prednisolone andDexamethasone

Second degree AVblock at term n = 1

Sonessonet al.[40]



Betamethasone First degree AV block atterm n = 1

Lopeset al.[26]

Retrospective Antibody +ven = 42Antibody �ve

n = 15


No therapy Sinus rhythm n = 4Second degree AVblock n = 9CAVB n = 9

Eliassonet al.[47]

Multicenter,retrospective

n = 175 Second degree AVblock n = 29

Dexamethasone/betamethasone n = 13

Outcome see CAVBtable*

No therapy n = 16Izmirly

et al.[52]

Case controlledstudy

Antibody +ven = 201Cardiac

Manifestationsn = 50

Second degree AVblock (or CAVB)n = 43 of 50

Dexamethasone n = 26Betamethasone n = 22Hydroxychloroquine n = 7

No outcomesdocumented*

Friedmanet al.[29]

Multicenter,Prospective,Open-LabelClinical Trial

Antibody +ven = 20


Prophylaxis IVIG/hydrocortisone Treatmentwith dexamethasone

CAVB n = 1

AV, atrioventricular; SR, sinus rhythm; CAVB, complete atrioventricular block; IVIG, intravenous immunoglobulin.* See CAVB Table.

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In contrast to complete AV block, there is someevidence that second degree AV block may poten-tially be reversible (Table 2) and some cases ofsecond degree AV block may not progress to com-plete AV block [40,45,51]. Lopes et al. retrospec-tively identified 22 fetuses affected by seconddegree AV block. None of the mothers receivedmedical therapy and subsequently, nine fetusesremained in second degree AV block; fourreverted to sinus rhythm, and a further nine pro-gressed to complete AV block by term [26]. Otherstudies include very small numbers of fetusesaffected by second degree AV block. Thus, theefficacy of maternal steroid therapy for the treat-ment of second degree AV block remains contro-versial [38,45,51–54]. Table 2 summarizes studiesreviewing the treatment and outcomes of prena-tally detected second degree AV block.

First degree AV block

It is reported that approximately 30% of womenwho are seropositive for anti-Ro/SSA 52 Kd exhibittransient first degree AV block in the fetus, without

progression to higher degrees of AV block [40].Screening high risk pregnancies by measuring thefetal AVCTI (mechanical PR interval) has been pro-posed to allow early recognition and potentialintervention for first degree AV block. Normalranges, using a variety of techniques have beenpublished [11,22]. The fundamental clinical deci-sion is whether treatment will be initiated followingdetection of prolongation of the AVCTI or whetherthe fetus will be observed to check that the AVCTIspontaneously normalizes. The approach in stud-ies has varied between observation [40] and activetherapy including dexamethasone, hydroxychloro-quine and IV immunoglobulin [3,52,55]. Even thelarger studies had a sample size of less than tenfetuses. Tunks et al. treated five antibody positivewomen, in whom the fetus demonstrated firstdegree AV block, with a combination of dexameth-asone, IV immunoglobulin or hydroxychloroquine.Their results showed that one fetus progressed tocomplete AV block while the other four remainedin first degree AV block or reverted to sinus rhythm[55]. Table 3 summarizes studies reviewing thetreatment and outcomes of prenatally detectedcomplete AV block.

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Table 3. First degree atrioventricular block.

Authors Study Design InclusionCriteria

AV Block Treatment PrenatalOutcome

PostnatalOutcome

Sonessonet al.[40]


First degree AVblock n = 8

Nil – Sinus rhythmn = 5 Firstdegree AV blockn = 3

First degree AVblock at 22 weeksgestation n = 1

Dexamethasone Sinus rhythmwithin 2 days oftherapy n = 1

Sinus rhythmn = 1

Normal prenatalPR interval n = 1

– – First degree AVblock (preterm32 weeks) n = 1

Izmirlyet al.[52]

Case controlstudy

Antibody +ven = 201Cardiac

manifestationsn = 50


Dexamethasone n = 2 Sinus rhythmn = 2

Sinus rhythmn = 2

No therapy n = 1 – First degree AVblock n = 1

Tunkset al.[55]



Dexamethasone n = 1 CAVB n = 1 CAVBDexamethasone/IVIG n = 1

Alternate firstand seconddegree AV blockn = 1

First degree AVblock

Hydroxychloroquine/dexamethasone n = 1


Sinus rhythm orfirst degree AVblockDexamethasone n = 2 First degree AV

block n = 2Jaeggi

et al. [3]Prospective Antibody +ve

n = 40First degree AVblock n = 2

Steroids/IVIG n = 1 – AliveNo therapy n = 1 – Alive

AV, atrioventricular; IVIG, intravenous immunoglobulin; CAVB, complete atrioventricular block.



Prophylactic maternal therapy for completeAV block

Studies have been published on the use of ther-apies to prevent development of AV block in highrisk pregnancies. The treatments used includehydroxychloroquine, IV immunoglobulin, plasma-pheresis, azathioprine, and B cell depletion. Mostdata relates to the use of hydroxychloroquineand IV immunoglobulin. Hydroxychloroquine(Plaquenil) is an immune modulator with anti-inflammatory effects. A retrospective, case con-trolled study demonstrated a trend towards alower incidence of rhythm or functional cardiaccomplications in fetuses exposed to hydroxychlo-roquine compared to those who were not. Thestudy defined exposure to hydroxychloroquine asmaternal therapy P200 mg per day. This studydid not reach statistical significance but the overallOR was 0.44 (95% CI 0.19–1.03; p = 0.06) [52]. Thiswas corroborated by a single center, retrospectivestudy by Tunks et al. (n = 33) [55], which suggestedthat exposure to hydroxychloroquine in the pre-conception phase or during pregnancy, mayreduce the incidence of complete AV block in highrisk fetuses. Of the fetuses who did not developany degree of AV block (n = 25), thirteen were

exposed to hydroxychloroquine during the preg-nancy. In the cohort of fetuses who developedAV block (n = 8) only one was exposed to hydroxy-chloroquine. All fetuses who developed completeAV block were treated with dexamethasone, butthere was no reversion to lower degrees of AVblock. A significant proportion of the mothersreceiving hydroxychloroquine in this study wasconcurrently treated with low dose prednisolone,thus carrying implications for the interpretationof the results [55]. Both studies included womenwho were seropositive for anti-Ro/SSA or La/SSB, proven to be affected by systemic lupuserythematosus (SLE) or had a previous childaffected by congenital complete AV block, thusrepresenting a high risk population [52,55].

Murine models have hypothesized that IVimmunoglobulin may prevent trans-placental pas-sage of anti-Ro/SSA and anti-La/SSB antibodiesby non-specifically blocking placental Fc receptors,and therefore preventing the detrimental antibodyeffects on the developing fetal myocardium[56]. Kaaja and Julkunen [57] prophylacticallyadministered a combination of IV immunoglobu-lin and prednisolone to women (n = 7) in whom aprevious pregnancy was affected by complete AVblock. The fetuses of women treated with combina-

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tion therapy remained in sinus rhythm at term.Conversely, the single fetus whose mother wasadministered IV immunoglobulin in isolation(patient declined prednisolone) developed com-plete AV block [57]. However, more recent pro-spective studies have not confirmed benefit. In aprospective, multicenter trial by Pisoni et al. [58]a cohort of antibody-positive women (n = 15) weretreated prophylactically with hydrocortisone andIV immunoglobulin. In the treatment cohort, threefetuses developed complete AV block, and two outof the three pregnancies were interrupted. How-ever, in the non-treatment cohort (n = 9) only onefetus developed complete AV block. They con-cluded that the dose and frequency of IV immuno-globulin was insufficient to prevent AV block inthe fetus [58]. This was corroborated by a secondmulticenter, prospective study by Friedman et al.[29] who prescribed low dose immunoglobulin tomothers who were positive for anti-Ro/SSA anti-bodies. This failed to prevent the development ofcomplete AV block in high-risk fetuses or reducethe level of maternal antibody titres. The trialwas stopped early due to the development of com-plete AV block in three of the first 19 patientsrecruited. The study speculated that a higher doseof IV immunoglobulin might be more effective at

Table 4. Prophylaxis for AV block.

Authors Study design InclusionCriteria

Prophylaxis

Izmirlyet al. [52]

Case controlledstudy

Antibody+ve n = 50

DexamethasoneBetamethasone nHydroxychloroqu

Tunks et al.[55]

Retrospective Antibody+ve n = 33

Hydroxychloroquprednisolone n =

No therapy n = 1

Kaaja andJulkunen[57]

Prospective Antibody+ve n = 8

IVIG n = 1IVIG/Steroids n =

Pisoni et al.[58]

Multicenter,prospective,observational

Antibody+ve n = 24

IVIG/Hydrocortisprophylaxis n = 1No prophylaxis n

Friedmanet al. [29]

Multicenter,Prospective,Open–LabelClinical Trial

Antibody+ve n = 20

IVIG prophylaxis

AV, atrioventricular; IVIG, intravenous immunoglobulin; CAVB, complete a* See CAVB Table.

preventing complete AV block [29]. These studiesare summarized in Table 4.

In a further attempt to provide more accuraterisk stratification for the development of congeni-tal complete AV block, the assessment of plasmalevels of maternal anti-Ro/SSA and anti-La/SSBhave been studied. Jaeggi et al. [3] described anassociation between high levels of anti-Ro/SSA(>100U/ml) and the development of complete AVblock [3]. No fetuses prenatally exposed to mater-nal anti-Ro/SSA levels <50 U/ml developed com-plete AV block. Levels of maternal anti-La/SSBshowed no association with AV block. However,57% of neonates with prenatal exposure to mater-nal anti-La/SSB levels P100 U/ml developed signsof non-cardiac neonatal lupus [3]. These findingswere not corroborated by Tunks et al. [55] whosestudy suggested there was no correlation betweenprenatal exposure to high levels of maternal anti-Ro/SSA antibody titres and the development ofcomplete AV block. However, they suggested pre-natal exposure to elevated levels of anti-La/SSBwas pathognomonic of developing complete AVblock [55]. It is difficult to compare these twostudies as the demographics and inclusion criteriaof the two studies vary significantly. Despiteconflicting opinions, there are proposals that all

AV Block PrenatalOutcome

PostnatalOutcome

n = 26= 22ine n = 7

1st AV Block n = 32nd AV block (orCAVB) n = 43

– No outcomesdocumented⁄

ine or16

1st AV Block n = 1 – Sinus rhythmn = 251st AV Blockn = 1

7 CAVB n = 4 – CAVB n = 41st AV Block n = 3 1st AV Block

n = 3CAVB n = 1 – CAVB n = 1

7 Sinus rhythmn = 7

– Sinus rhythmn = 7

one5

CAVB n = 3 TOPn = 2

CAVB n = 1 Aliven = 12

= 9 CAVB n = 1 TOPn = 1

Alive n = 8

n = 20 CAVB n = 3 (n = 1preceded by 2ndAV block)

– CAVB n = 3(despiteadditionaldexamethasone)

Sinus rhythmn = 17

– Sinus rhythmn = 17

trioventricular block; TOP, termination of pregnancy.

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pregnant women should be screened in the firsttrimester for the presence of autoantibodies andwith particular emphasis on anti-Ro/SSA andanti-LA/SSB levels [27].

Approach to management

Due to the low incidence of complete AV blockin the general population, studies are mainlyobservational, retrospective and involve smallcohorts of patients. The team from Toronto SickChildren’s Hospital have published their guid-ance for the management of varying degrees ofcongenital AV block. In their protocol, Jaeggiet al. [43] advise no therapy in the presence of iso-lated first degree AV block, but in the presence ofsecond degree AV block or complete AV block, acourse of maternal steroids is recommended. Ifthe fetal ventricular escape rate is 655 bpm,supplementary maternal salbutamol therapy isconsidered. In the presence of isolated fetal myo-cardial endocardial fibroelastosis (EFE), maternalIV immunoglobulin is administered at two tothree weekly intervals prenatally. Postnatally, theaffected child would also be treated with a courseof IV immunoglobulin [43].

Approach and policy at our centre

In our institution, Evelina London, we do notcurrently recommend cardiac referral of motherswith connective tissue disease (CTD) whose

P

Yes (17% Risk)

Referral to Fetal Cardiology

2D Echo, Function, AVCTI, M mode, EFE

PreviouChild CA

Increased AVCTI

Anti Ro/Status

Normal: 4 weekly r/v

2:1 AV Bl

Consider Dexamethasone

No treatment - observe

D

Figure 6. Fetal cardiology assessment

anti-Ro/La antibody status is negative, unlessthere is evidence of fetal heart block on the obstet-ric anomaly scan. Some mothers with CTD arereferred with unknown antibody status. In this sit-uation, anti-Ro/SSA and La/SSB titres are checkedand, if negative, coupled with a normal echocar-diogram, then no further cardiac review is under-taken. For mothers who are known to be anti-Roand/or anti-La positive, fetal echocardiography isundertaken at 18–24 weeks gestational age,including 2D imaging to confirm structural nor-mality, pulsed wave Doppler, color flow Dopplerand M mode assessment to confirm AV syn-chrony. To identify first degree AV block, theAVCTI (ms) is measured by pulsed wave Dopplerand compared to normative values. The presenceof maternal anti-Ro/SSA and La/SSB antibodiesis recorded in a bid to provide prognostication,and we recently introduced measurement ofantibody titres. Tissue Doppler imaging is notroutinely used in our assessment. In the presenceof a structurally normal fetal heart and an AVCTIwithin normal limits for gestational age, two fur-ther assessments are arranged at regular intervals(Fig. 6). The detection of first degree AV blockwould warrant closer follow-up to assess for pro-gression to higher degrees of AV block or rever-sion to a normal AVCTI. It is not our policy totreat isolated first degree AV block. Detection ofsecond degree AV block would merit consider-ation of maternal dexamethasone therapy (4 mgdaily initially, followed by a tapering regimen) to

Negative

ositive

No (2% Risk)

2D Echo, Function, AVCTI, M mode, EFE

sVB

Normal: 4-6 weekly r/v

Check Anti Ro/La Titres

La ReassurePatient

ock Complete AV

Block

Fetal Hydrops No Fetal Hydrops

ExpectantManagement

Considerexamethasone + Salbutamol

of maternal autoimmune disease.

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gauge whether this is associated with reversion toa lower degree of AV block. Depending on thefetal response, this dose is tapered with the aimof minimizing potential side effects of dexametha-sone for the fetus and mother.

If there is complete AV block, then the decisionto give therapy depends on additional findings. Ifthere is no evidence of fetal hydrops, good ven-tricular function and no echogenicity of the ven-tricular myocardium, then our policy is for closereview without initiation of therapy. If, however,there is hydrops, subjective evidence of reducedventricular function and/or echogenicity of themyocardium (which may suggest endocardialfibroelastosis) then maternal dexamethasonewould be seriously considered. Fetal hydropswould be an indication for active therapy whichwould include dexamethasone coupled with sal-butamol, particularly if the fetal ventricular rateis very low. Slow release salbutamol is adminis-tered orally, with baseline monitoring of maternalelectrolytes prior to therapy. Whether treatment isgiven or not, close fetal cardiological and obstetricreview is warranted to monitor fetal cardiac func-tion, fetal ventricular rate and signs of hydrops.Within our unit, we would not recommendextreme preterm delivery due to its associationwith poorer neonatal outcomes [59]. Each case isconsidered individually within our multidisciplin-ary team, ensuring delivery occurs at an optimaltime, in an effort to minimize neonatal morbidityand mortality.

Treatment side effects

When considering prenatal therapy it is impor-tant to consider the risks and benefits for boththe mother and the developing fetus. Some unitshave strongly advocated the use of dexametha-sone, given the observation of better outcome[43]. Dexamethasone is associated with maternalcomplications such as hypertension, gestationaldiabetes and fetal complications, for example, oli-gohydramnios and detrimental effects on growthand development [42,47,60,61]. A single dose ofsteroids is commonly administered to promotelung maturation in the preterm infant with threa-tened preterm labor, but concerns have beenraised regarding the effects of multiple steroiddoses, in particular, the effect on the developingfetal brain. The National Institute of Healthreleased a consensus statement, stating there areno substantiated reports of adverse effects froma single dose of prenatal steroids, but advised thatmultiple courses of steroids should only be

administered within clinical trials [61]. This washighlighted in the PRIDE study, which advisedthat the potential benefits of maternal steroidtherapy must be carefully balanced against thepotential detrimental effects on fetal growth [38].Regarding neurodevelopment, Brucato et al. [62]retrospectively examined a cohort (n = 16) ofinfants with congenital complete AV block whohad been exposed to high levels of dexametha-sone in utero. They found no significant intellec-tual deficiencies in preschool or school agechildren [62]. As with dexamethasone therapy,maternal safety when prescribing salbutamol isfundamental. In our own unit, therefore, mothersare admitted for observation during initiation ofsalbutamol therapy and a baseline 12 lead ECG,plasma urea and electrolytes are undertaken.The ECG and electrolytes are assessed at regularintervals during the treatment period.

Fetal and neonatal outcome

When assessing the rate of intra-uterine death,the live birth rate and one year survival, studieshave indicated no statistical difference betweencohorts prenatally exposed to maternal dexameth-asone when compared to those who received noprenatal therapy [26,47]. In one study, bothcohorts had similar rates of fetal hydrops, fetalventricular escape rates and ventricular dysfunc-tion [47]. Risk factors predicting a poorer outcomein a fetus with congenital complete AV block havebeen identified. These include a ventricularescape rate 650 bpm, gestation at diagnosis<20 weeks, fetal hydrops, and impaired left ven-tricular function [6]. In the presence of such riskfactors, the risk of intrauterine death is 22%, andneonatal mortality 18% in comparison to 2% and3%, respectively in the absence of any risk factors[47]. A report by Moak et al. [63] described 16 chil-dren with congenital complete AV block whodeveloped late onset dilated left ventricular car-diomyopathy despite adequate pacing. Threequarters developed cardiac failure within the firsttwo years of life, myocardial histology demon-strated fibrosis in eleven cases, and myocytedegeneration in two cases. This study highlightsthe importance of careful long term monitoringof cardiac function even in children receivingappropriate pacing for complete AV block [63].

In relation to fetal growth and development, aEuropean study suggested that fetuses of motherswith anti-Ro/SSA 52 Kd antibodies and evidenceof second degree AV block or complete AV blockhad a birth weight which was lower than those

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with first degree AV block or normal conduction[64]. There was no statistical difference in the ges-tational age of both cohorts. In addition, thefetuses with second or complete AV block showedno evidence of catch up growth during early child-hood. In contrast, those with first degree AV blockor normal conduction demonstrated catch upgrowth within the first two months of life. Noneof the infants with a lower birth weight demon-strated any gross cognitive impairment [64].

In neonatal lupus syndrome, the autoimmuneprocess not only affects the fetal conduction tis-sue, but also the myocardium, papillary musclesand valvular tissue, resulting in endocardial fibro-elastosis (EFE). It should be noted that not allfetuses affected by immune mediated completeAV block have EFE and the converse is also true.Immunohistochemical staining of EFE in completeAV block demonstrates autoantibody deposition[65]. Previously, EFE in this condition wasassumed to be a result of prolonged bradycardiain utero, but has now been described as a separateentity which may develop in both pre and postna-tal periods. The postnatal prognosis must remainguarded due to the potential development of latecongestive cardiac failure. Thus, neonatal lupuserythematosis can present as EFE or completeAV block, and these should probably be regardedas separate disease entities [65].

Future directions

New advances are being made in the form ofin vitro studies. Preliminary studies have identi-fied a potential protective mechanism in the formof b2-glycoprotein I. This glycoprotein is closelyassociated with anti-phospholipid antibodies,binding to Ro-60 on the surface of apoptotic cells.Further study is require to assess the efficacy ofthis potential therapy in a clinical setting [66–68].

Conclusion

The general consensus within the scientific andmedical community is that the development ofimmune mediated complete AV block is a multi-factorial, autoimmune process. Clinicians are inagreement that the presence of anti-Ro/SSA andLa/SSB are contributing factors to the develop-ment of the disease but only as part of a morecomplex autoimmune process. Screening for pre-natal complete AV block remains a challenge asthe majority of women have no pre-existing clini-cal features of connective tissue disease or a previ-ous child with complete AV block. In summary,

there is insufficient robust evidence to suggestthat prophylactic maternal therapy alters the inci-dence or recurrence rate of congenital completeAV block in the high risk population [69]. Further-more, despite an increased incidence of completeAV block in asymptomatic women, until morerobust scientific evidence is available, most clini-cians will continue to refer women with antibodypositive connective tissue disease for fetal cardiol-ogy surveillance during the second trimester tomonitor for the development and progression ofAV block. A further understanding of the patho-physiology of complete AV block, in particulardisease progression, will guide therapy for lowerdegrees of AV block, complete AV block and pre-conception therapy. This will allow clinicians tocounsel parents more accurately and provide bet-ter prognostication. There is consensus that multi-center, prospective trials are required to answerthese questions.

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atrioventricular block during fetal life

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