Cardiac Arrhythmias in the Human Fetus

18 Pages·2004·0.39 MB·English

PediatrCardiol25:234–251,2004
DOI:10.1007/s00246-003-0589-x
Cardiac Arrhythmias in the Human Fetus
C.S. Kleinman,1 R.A. Nehgme2
1ProfessorofClinicalPediatricsinObstetrics&Gynecology,ColumbiaUniversityCollegeofPhysiciansandSurgeons,
WeillMedicalCollegeofCornellUniversity,DirectorofPediatricCardiacImaging,NewYork—PresbyterianHospital,
NewYork,NY,USA
2AssistantProfessorofPediatrics,JeffersonMedicalCollege,ActingChief,PediatricCardiology,NemoursCardiac
Center,A.I.duPontHospitalforChildren,Wilmington,DE,USA
Abstract. Fetal cardiac arrhythmias have been rec- Keywords: Fetalarrhythmias—Cardiacarrhythmias
ognized with increasing frequency during the past — Fetal physiology — Hydrops fetalis — Fetal
several years. Most fetal arrythmias are intermittent therapy — Fetal heart — Fetal cardiology
extrasystoles, often presenting as irregular pauses of
rhythm. These are significant only when they occur
Fetal cardiac rhythm irregularities often cause sig-
with appropriate timing to initiate sustained tachy-
nificant apprehension for prospective parents and
cardia, mediated by anatomic bypass pathways. The
their treating obstetricians. The concern raised by
most common important fetal arrhythmias are: 1)
these arrhythmias is often out of proportion to their
supraventricular tachycardias, and 2) severe brad-
physiologic and clinical significance. A review of our
yarrhythmias, associated with complete heart block.
clinical experience, amassed over a decade, indicates
Symptomatic fetal tachycardias are usually supra-
that approximately 50% of fetuses referred for eval-
ventricular in origin, and may be associated with the
uation of cardiac arrhythmias were in normal sinus
developmet of hydrops fetalis. These patients may
rhythm at the time of their initial visit to our labo-
respond to antiarrhythmic drug therapy, adminis-
ratory. The vast majority of the remaining patients
tered via maternal ingestion or via direct fetal injec-
were found to have isolated supraventricular ex-
tion.Suchtherapyshouldbeofferedwithcarefulfetal
trasystoles. Less than 10% of referrals for fetal ar-
and maternal monitoring, and must be based on a
rhythmia analysis were found to have sustained
logical, sequential analysis of the electrical mecha-
tachy- or bradyarrhythmias that were deemed to be
nismunderlyingthearrhythmia,andanappreciation
of clinical significance [27].
of the pharmacology and pharmacokinetics of the
Most referralsforfetalarrhythmiasoccurdue to
maternal, placental fetal system. Bradycardia from
the impression that the fetal heart is intermittently
complete heart block may either be associated with
‘‘skipping beats.’’ Although some of these patients
complex congential heart malformations involving
may, in fact, have low-grade second-degree heart
the atrioventricular junction of the heart, or may
block, with intermittent nonconducted sinus beats,
present in fetuses with normal cardiac structure, in
most of these cases represent extrasystoles. Doppler
motherswithautoimmuneconditionsassociatedwith
‘‘listening devices’’ detect the frequency shift associ-
hightitresofanti-SS-Aoranti-SS-Bantibody,which
ated with umbilical blood flow. In most cases the
cross the placenta to cause immune-related inflam-
perceived skipping of beats represents the pause fol-
matorydamagetothefetalatroventricularnode.This
lowing an extrasystole that has not reset the sinus
paper reviews experience with the analysis of fetal
node pacemaker. Alternatively, an extrasystole oc-
caridac rhythm, a detailed discussion of the patho-
curring with a very short coupling interval to the
physiologyofarrhythmiasandtheireffectonthefetal
preceding sinus beat may encounter the atrioven-
circulatorysystem,andoffersalogicalframeworkfor
tricular node while it is still refractory, resulting in a
the construction of treatment algorithms for fetuses
‘‘blocked’’ extrasystole. An extrasystole with a
at risk for circulatory compromise from fetal ar-
slightly longer coupling interval to the preceding si-
rhythmias.
nus beat may result in a ventricular contraction that
is so closely ‘‘coupled’’ to the preceding beat that
Correspondenceto:C.S.Kleinman,email:[email protected] diastolicfillingisinadequatetoresultinaventricular
KleinmanandNehgme:CardiacArrhythmiasintheHumanFetus 235
strokevolumeproducingdetectableumbilicalsystolic to the critical inflow pressure, at which lymphatic
blood flow. drainage abruptly declines [38].
Fetalrhythmdisturbanceswererarelyassociated In other words, due to the fine balance between
with congenital cardiac malformations. Supraven- hydrostatic and oncotic pressure, the intrinsic prop-
tricular tachycardia was not associated with congen- erties of the capillary wall and the interstitial space,
italheartdiseaseinanyofourpatients,whereasatrial and the susceptibility of lymphatic drainage to acute
flutter was associated with complex congenital heart obstruction in the face of increased systemic venous
disease in (cid:1)20% of cases. Two cases were found in pressure,thefetusfunctionsonarazor’sedgeoffluid
fetuses with Ebstein’s malformation of the tricuspid balance between normality and hydrops fetalis. The
valve, with right atrial dilation; two cases were as- limitationinpreloadandafterloadreserveofthefetal
sociated with critical pulmonary stenosis with tri- right, more than the left, ventricle increases the sus-
cuspid regurgitation and right atrial dilation; two ceptibilitytowardincreasedsystemicvenouspressure
cases were found with critical aortic stenosis, mitral in the face of acute changes in vascular dynamics.
regurgitation, and left atrial dilation; and one fetus It is little wonder that acutely increased right
was encountered with left atrial isomerism, atrio- ventricular afterload, in the face of acute ductal
ventricularvalveregurgitation,completeheartblock, constriction or placental insufficiency, or acute right
andnonimmunehydropsfetalis.Fetalbradycardiais ventricular preloading, in the face of acute-onset tri-
frequently secondary to complete heart block. Al- cuspid regurgitation or acute ‘‘trapping’’ of systemic
most 50% of these fetuses have complex forms of venous return in the right heart secondary to im-
congenital heart disease, usually associated with ab- paired right-to-left shunting across the foramen
normalities of atrioventricular connection, including ovale, may result in hydrops fetalis. Similarly, it has
atrioventriculardiscordanceandleftatrialisomerism. become increasingly apparent that the fetuses who
We became aware of the proclivity of fetuses to deteriorate into a hydropic state in the face of sus-
develop anasarca as their primary manifestation of tained tachy- or bradyarrhythmias are usually mani-
cardiovascular failure very early in our clinical in- festing diastolic, rather than systolic, dysfunction.
vestigations [20, 41]. Rudolph [38] provides an ex- This should come as no surprise, since our under-
planation for this phenomenon. standing of the clinical manifestations of congestive
Consider that edema formation is determined by heart failure in themature cardiovascularsystem has
the reciprocal relationship between hydrostatic pres- turnedattentiontowardthediastolicdysfunctionthat
sure, with its tendency to ‘‘drive’’ fluid from the underlies most of the symptomatology of these pa-
vascular space into the interstitial space, and plasma tients.
oncotic pressure, with its tendency to ‘‘suck’’ inter- Thebaselinelimitationindiastolicrelaxationand
stitial fluid back into the vascular space. This fun- complianceofthefetalventricles[10]rendersthefetal
damental relationship is also influenced by the heart particularly susceptible to sustained tachycar-
intrinsic ‘‘leakiness’’ of the capillary wall (filtration diaorbradycardia.Severefetaltachycardiaresultsin
coefficient) to fluid as well as the permeability of the marked foreshortening of the diastolic filling period
capillary wall to protein (which determines the on- of the fetal ventricles. This shortening in diastolic
cotic gradient between the intravascular and inter- filling is particularly disadvantageous to a heart in
stitial spaces). In addition, the steady state of fluid which active myocardial relaxation is not facilitated
flux between the vascular and interstitial spaces will by rapid reuptake of Ca2+ by sarcoplasmic reticula
be determined, in part, by the Compliance of the in- [27], and in which diastolic compliance is impaired.
terstitial space, with regard to its ability to accom- Inadequate diastolic emptying results in increased
modatetheaddedvolumeofedemafluid.Theability end diastolic volume and pressure within the right
of thelymphatic system to‘‘scavenge’’fluid from the atrium and systemic veins and in augmented atrial
interstitial space and return it to the venous end of backflow in the systemic veins. The retrograde flow
the intravascular of space will be the final determi- pattern in the systemic veins is similar to the char-
nant of whether there is a net accumulation of fetal acteristic flow pattern in the hepatic and pulmonary
edema. Studies of fetal lymphatic flow suggest that veins of mature patients with restrictive cardiomy-
the characteristics of the fetalvascular system have a opathy. In the presence of fetal atrial flutter, the
significant baseline balance toward interstitial fluid ventricularresponserateisrapidbutusuallylessthan
accumulation that is swept dry by avid lymphatic the atrial rate. The venous flow pattern is perturbed
drainage. On the other hand, even a modest increase further by atrial contractions that occur against a
in systemic venous pressure will not only increase closed atrioventricular valve, resulting in more
hydrostaticpressure,increasingthetendencyforfluid prominent retrograde flow in the fetal inferior vena
extravasation, but also move venous pressure closer cava. These retrograde atrial pulsations result in in-
236 PediatricCardiologyVol.25,No.3,2004
creased atrial and venous mean diastolic pressure, most frequently encountered sustained fetal brady-
increased hydrostatic pressure, increased extravasa- cardia is congenital complete atrioventricular block.
tionofplasmaproteinintotheinterstitialspace,and, Previousstudieshavedemonstratedthatthesefetuses
ultimately, may result in passive hepatic congestion fall into two major categories (1) fetuses with con-
and impaired serum albumin production [32]. These genitalcompleteblockandassociatedcongenitalheart
factors all predispose the fetus with sustained tachy- disease. These fetuses usually have abnormalities of
cardia to the development of hydrops fetalis, inde- cardiacanatomyattheatrioventricularjunction[e.g.,
pendent of the impact of tachycardia on ventricular atrioventricular discordance (atrioventricular inver-
systolic performance. The latter may ultimately de- sion, or congenitally corrected transposition of the
teriorate but is not usually the immediate precursor great arteries) or visceral heterotaxy and left atrial
of hydrops fetalis in the tachycardic fetus. isomerism] or (2) fetuses with normal intracardiac
There is disagreement regarding the inherent anatomy, in whom maternal serum contains high
dangerofintermittenttachycardiatothehumanfetus concentrations of autoantibodies (anti-SS-A or anti-
andpredictingthedevelopmentofhydropsfetalisina SS-B) that may cross the placenta and cause autoim-
particular fetus with tachycardia [42, 43]. A realistic munedamagetothefetalatrioventricularconduction
risk/benefit analysis, which provides a necessary tissue. Such fetuses may also sustain autoimmune
foundation for the formulation of a rational treat- damagetocardiaccontractileelements,resultinginan
mentalgorithm,requiresthatoneidentifythefetusat autoimmunemyocarditis[16,40].
greatest risk of hemodynamic deterioration (e.g. In such fetuses, bradycardia causes prolonged
death or the development of hydrops fetalis) in ad- atrial and ventricular diastolic filling times, resulting
vance of such deterioration, in order to provide in increased filling volumes. Harkening back to the
timely treatment. It is not universally accepted, for initial studies of myocardial performance of fetal
example, that every fetus with intermittent, or even myocardium, the limited compliance of fetal ven-
sustained, tachycardia is in imminent danger of sud- tricular myocardium results in a higher diastolic
den death or the development of hydrops fetalis. pressure at any given diastolic volume. The atrio-
However, it is generally accepted that the hydropic ventricular dissociation between atrial and ventricu-
fetus is unlikely (but even this is not certain) to im- lar electrical activation and mechanical responses
provespontaneously.Itisalsowellestablishedthatin results in cannon waves, which are the product of
the presence of hydrops fetalis maternal absorption atrial contraction against a closed atrioventricular
and transplacental transfer of medications such as valve.Thesecannonwavesresultinafurtherincrease
digoxin are impaired [48, 50]. in mean right atrial and systemic venous pressure,
Inanefforttoidentifyclinicalfindingspredictive which predisposes to the development of fetal anas-
of early deterioration into hydrops fetalis in the arca.
tachycardic fetus, we identified the importance of
determining the atrial contraction sequence. In the
presence of tachycardia originating in the left, rather Supraventricular Tachycardia
than right, atrium (e.g., reentry tachycardia with a
left-sided bypass tract or atrial flutter arising within Supraventricular tachycardia (SVT) is the most
the left atrium), the onset of left atrial contraction, a common fetal cardiac arrhythmia that is associated
fraction of a second prior to right atrial contraction, with important clinical consequences. Although
resultsinatransientincreaseinleftatrialpressure[4]. SVT may result from a variety of underlying elec-
If left atrial pressure surpasses that in the right atri- trophysiological mechanisms, the most common of
um, the atrial septum primum, which represents the these is atrioventricular reentry, or reciprocating
flap valve that will ultimately appose the atrial sep- tachycardia, arising from a circus movement of
tum and close the foramen ovale postnatally, closes electrical energy between the atria and ventricles,
transiently in utero. Prenatal partial closure of the involving the atrioventricular node in one direction
foramen ovale in the fetal patient with atrial tachy- and an accessory connection in the other. The cir-
cardia arising in the left atrium may trap systemic cular wavefront alternately stimulates the atrium
venous return in the right atrium and inferior vena and ventricle to contract at a rate in excess of that
cava,resultinginadisproportionateincreaseinmean of the intrinsic sinus pacemaker. Therefore, there is
systemic venous pressure. This in turn renders this one atrial for each ventricular contraction. The
subgroup of tachycardic fetuses at highest risk for heart rate is dependent on the size of the reentry
early deterioration into a hydropic state [22, 39]. pathway and the intrinsic electric properties of the
Alternatively,fetuseswithseverebradycardiaare limbs of the circuit. In the human fetus with SVT,
susceptibletothedevelopmentofhydropsfetalis.The the characteristic heart rate is 240–260 beats/min.
KleinmanandNehgme:CardiacArrhythmiasintheHumanFetus 237
This electrophysiologic mechanism underlies more
than 90% of SVT encountered in fetuses and neo-
nates presenting with this arrhythmia. The other
mechanisms that may cause SVT are considerably
more rare and more difficult to control. These in-
clude automatic tachycardia (arising within an ir-
ritable ectopic atrial focus, above the bundle of
His), electrical reentry within the atrioventricular
junctional tissue [permanent junctional reciprocat-
ing tachycardia (PJRT)] and atrial flutter or fibril-
lation.
Atrioventricular reciprocating tachycardia re-
quires an anatomic substrate in the electrical con-
duction system, involving at least two discrete
pathways with differing conduction velocities and
recovery times. In this setting, an incidental extra-
systole or reentry (echo) beat, occurring with a criti-
cal timing (coupling interval) after the preceding
sinus beat, may encounter the atrioventricular junc- Fig. 1. In orthodromic reciprocating tachycardia (ORT) the
tion at a time when one of the available conduction rhythmissustainedbyacircularpathwayofelectricalenergythat
propogates in the atrial to ventricular direction through the
pathways has recovered its ability to conduct from
atrioventricularnode(AVN).Theelectricalenergyenterstheven-
atriumtoventricle.Atthesametime,thesecondlimb
tricles through the normal bundle branches and has a normal,
isstillunabletoconducttheimpulse,duetoitslonger
narrow, QRS morphology. The energy reenters the atria via the
recovery or refractory period. If the limb that con- accessoryconnection(AC),whichtypicallyconductsfasterthanthe
ducts activity to the ventricle conducts the impulse AVN.Therefore,theventriculoatrialreentrytime,isshorterthan
slowly enough (decremental conduction), the electri- the atrioventricular conduction time in ORT. In antidromic re-
cal impulse spreading through the ventricular muscle ciprocatingtachycardia(ART)thecircularpathwayisdirectedin
theoppositedirection,withatrioventricularconductionbywayof
may reach the ventricular end of the slowly recover-
theACandretrogradeactivationviatheslowlyconductingAVN.
ing conduction pathway after an adequate delay to
Insuchcases,theventriculoatrialreentrytimeislongerthanthatin
allow the limb to recover its conductivity. This elec- ORT. Postnatally, ART can be distinguished from alternative
trical impulse may then conduct upward in the ven- causes of long ventriculoatrial reentry tachycardia, such as the
tricular-to-atrialdirection,thusestablishingacircular permanent form of junctional reciprocating tachycardia (PJRT),
movement of electrical energy that repetitively enters by the wide QRS complexes in ART that are explained by ven-
triculardepolarizationthroughtheventricularmuscle,ratherthan
and reenters the atrium and ventricle (Fig. 1). Thus,
bywayofthebundlebranches.InPJRTtheQRScomplexesare
reentry or reciprocating tachycardia refers to the
narrow.ThiscanbedistinguishedbypostnatalECGanalysisand,
unidirectional block of conduction over one of the
potentially, by magnetocardiography in the fetus, not by fetal
pathways, antegrade conduction over the second echocardiography. RA, Right atrium,RV, right ventricle. Repro-
pathway, and subsequent reentry over the initially ducedwithpermissionfromCreasyR,ResnickR(1999)Maternal–
refractory pathway. Such reciprocating tachycardia FetalMedicine,4thedn.Saunders,Philadelphia.
occurs most often in fetuses and neonates using an
accessory conduction (Kent) bundle, discretely sepa-
rate from the atrioventricular nodal tissue, which
electrically connects the atrium and ventricle across discrete accessory conduction pathways and AV re-
the fibrous atrioventricular junction, bypassing the entry tachycardia. The latter mechanism [AV nodal
normal electrical delay in the atrioventricular (AV) tachycardia (AVNRT)] is rare in fetuses, neonates,
node.ThisistheunderlyingmechanismoftheWolff– and in early childhood.
Parkinson–White (WPW) syndrome. Rarely, some In both forms of reciprocating SVT [AV reentry
neonates and fetuses have AV reentry within the re- (discrete accessory conduction bundle-mediated) and
gion of the AV node, where some of the electrically AV nodal reentry] the arrhythmia depends on a crit-
active tissues appear to have differing conduction ical relationship between conduction velocity and
velocities and refractory periods than neighboring refractory period in the two pathways to sustain the
tissue within the node. Such patients may present electrical circus movement. Therapeutic intervention
with reciprocating supraventricular tachycardia, is logically aimed at interrupting the delicate balance
which has the same physiologic, albeit slightly dif- in timing between the two electrical pathways that is
ferent anatomic, substrate as tthat of patients with required to sustain the tachycardia.
238 PediatricCardiologyVol.25,No.3,2004
Atrial Flutter
Atrial flutter is an arrhythmia that also arises due to
reentry of electrical impulses around a circular
pathway. In this case the reentry circuit involves
pathwayscompletelycontainedwithintheatrialwall.
The circus movement in atrial flutter occurs through
tissue with distinct electrophysiologic properties sep-
arated by electrically inactive tissue (usually fibrous
tissueorscar).TheAVnodeisnotpartofthecircuit
andservesonlytotransmit,withavariabledegreeof
slowing or block, the atrial flutter waves to the ven-
tricles (Fig. 2). Unlike reciprocating SVT, slowing or
blocking conduction through the AV node does not
terminate the arrhythmia, but decreases the ven-
tricular response rate to the atrial flutter. Fig.2. Inatrialflutterthesinuspacemakerisusurpedbyarapid
The atrial rate in atrial flutter in the neonate is circus movement of electrical energy in a circuit completely con-
typically300–400beats/minwhereasinthefetusatrial tainedwithinatrialtissue.Theatrialstimulationtypicallyoccursat
flutter rates up to 500 beats/min may be seen. The ratesbetween360and500beats/min.Thereisalwayssomedegree
ofatrioventricularblock(representedbytheboldlinethroughthe
varying degrees of AV block that may be associated
atrioventricular node (AVN), resulting in a regular or irregular
withatrialfluttermayresultinvaryingventricularre-
ventricularresponseratethatisslowerthanthemonotonous,very
sponseratesandrhythms[e.g.,dependingwhetherAV
rapid atrial rate. RA, Right atrium, RV, right ventricle. Repro-
blockisfixed(2:1;3:1;4:1)orvariable].Ineithercase, ducedwithpermissionfromCreasyR,ResnickR(1999)Maternal–
the fetal heart rate does not respond in a regular 1:1 FetalMedicine,4th,edn.Saunders,Philadelphia.
fashion to fetal atrial activity. Atrial flutter is an ar-
rhythmia seen in later life in patients who have pro-
gressivedilatationoftheatria(e.g.,incasesofchronic varying from 180 to more than 300 beats/min. Al-
mitralstenosisorinsufficiency).Inthefetuswithatrial though not invariably present, the finding of AV
flutter,theunderlyingsubstratemayalsoberelatedto dissociation, with ventricular rates in excess of those
atrialdilatation,asoccursinpatientswithrightatrial in the atria, without a fixed relationship between
dilatation with the Ebstein malformation of the tri- atrial and ventricular mechanical (and presumably
cuspid valve or right ventricular outlet obstruction electrical) activity, is highly suggestive of either ven-
with tricuspid regurgitation, or in fetuses with left tricular or a junctional origin of the arrhythmia. Al-
atrialdilationsecondarytomitralregurgitation. though ventricular tachycardia appears to be a more
common (albeit rare) fetal cardiac arrhythmia than
Atrial Fibrillation junctional ectopic tachycardia, distinguishing be-
tween these two arrhythmias is probably impossible
Atrial fibrillation isa less common arrhythmia in the using the echocardiographic techniques currently
fetus than atrial flutter. This arrhythmia results from available for analysis of fetal arrhythmias. The un-
an extremely rapid and disorganized electrical stim- derlying basis of this arrhythmia appears to be a re-
ulation of atrial muscle, resulting in a rapid writhing entrant electrical circuit that is contained within
motion. Atrioventricular conduction of atrial fibril- ventricular myocardium, with electrical circus move-
lationisblockedattheAVnode,resultinginvariable ment around an electrically inert area of muscle
ventricular response rates, with rhythms that are ir- (presumably fibrosis or scar). Such arrhythmias are
regular. One of the fundamental principles of anti- significantly more common among adults, who have
arrhythmictherapyistoavoidtheuseofmedications a propensity for the development of discrete areas of
that may inadvertently increase the ventricular re- ventricular scar relating to ischemic heart disease.
sponse rate to atrial fibrillation (e.g., the use of dig- Fetuses and neonates with a predilection for seg-
oxin, which could decrease the effective refractory mental abnormalities of myocardial oxygen supply/
periodinaccessoryconductiontissueinpatientswith demand, such as those with severe ventricular
WPW syndrome and atrial fibrillation). hypertrophy secondary to semilunar valve stenosis,
hypertrophic cardiomyopathy, coronary artery dis-
Ventricular Tachycardia ease,orcardiactumors,maypresentwithventricular
tachycardia. Alternatively, fetuses with genetic ab-
Fetuses with ventricular tachycardia may present normalities of myocardial structure, such as those
with intermittent or incessant tachycardia at rates with arrhythmogenic right ventricular cardiomyopa-
KleinmanandNehgme:CardiacArrhythmiasintheHumanFetus 239
thyorthosewithinbornabnormalitiesofionchannel sinus rate. This results in fetal bradycardia. The pa-
function resulting in prolongation and dispersion of thology underlying this bradycardia doesnot involve
ventricular repolarization (e.g., prolongation of the anabnormalityoftheAVnode,andeachventricular
QTc interval), may present with ventricular tachy- contractionisprecededbyanatrialcontraction.This
cardia. rhythm can be distinguished from sinus bradycardia
and from second-degree AV block by the pattern of
Sinus Bradycardia atrial depolarization or atrial contraction (echocar-
diographically).Insinusbradycardiatheatrialrateis
Carotid sinus chemoreceptor activity has been as- slow,anditisequaltotheventricularrate.Insecond-
sumuedtobepresentduringmid-tolategestationin degree AV block the atrial rate is normal or some-
the human fetus. Physiologic studies in fetal lambs what above normal, with a regular atrial rhythm. In
have demonstrated that chemoreceptor stimulation this case, the ventricle does not respond to every
results in fetal bradycardia and hypertension. The atrial contraction. In the case of blocked atrial bige-
time course of the fetal lamb response to hypoxemia miny, or blocked atrial echo beats, the atrial con-
is rapid and suggests a chemoreceptor-mediated re- tractionpatternisirregular,withadistinctpairingof
flex, with a secondary endocrinologic response, me- atrial contractions and with a ventricular response
diated by circulating cortisol, catecholamines, occurring only after the first of the two paired atrial
arginine vasopressin, and angiotensin II. Fetal brad- beats. The significance of this pattern of contraction
ycardia may be encountered during labor, as normal relates to the potential for completion of a reentry
reflex responses to uterine contraction, or in patho- circuitinresponsetooneoftheectopicorechobeats,
logicpatterns,associatedwithplacentalinsufficiency. with the subsequent development of reciprocating
On the other hand, fetal heart rates that vary nor- SVT. The presence of echo beats establishes the
mally around a baseline heart rate less than 110–120 presence of an accessory conduction pathway, al-
beats/min may be encountered in otherwise normal lowing electrical impulses to be conducted in the
fetuses. In such situations, the potential for fetal hy- retrograde direction from ventricle to atrium. It does
pothyroidism should be considered. In some fetuses notnecessarilyfollowthattheelectricalpropertiesof
with structurally abnormal hearts, there may be an- the two pathways can support a completed circus
atomic abnormality of the sinus node. In such cases, pathway for development of sustained reciprocating
the heart rate will be determined by a lower and SVT.
slower, non-sinus pacemaker. Structural abnormali-
ties such as bilateral superior venae cavae, AV septal Atrioventricular Block
defect, and inferior vena caval interruption with
azygousorhemiazygouscontinuationtothesuperior Atrioventricular block represents a functional im-
vena cava should be sought in such patients to rule pairment in the conduction tissue between the sinus
out the presence of left atrial isomerism. Such pa- node and ventricular activation. The various degrees
tients may manifest nonsinus atrial or junctional of AV block vary in etiology and pathologic signifi-
rhythms with rates slightly slower than normal sinus cance.
rhythm, or they may present with complete heart
block, with more profound bradycardia.
First-Degree Atrioventricular Block
Blocked Atrial Bigeminy
First-degreeAVblockreferstoagreaterthannormal
Supraventricular extrasystolic beats may occur in a interval between the onset of sinus node activation
randomorinafixedrelationshipwiththeunderlying and the first activation of the ventricular muscle
sinus rhythm. In some cases, the extrasystolic beat (prolongedPRinterval).Structuralheartdiseasemay
may result from reentry of electrical energy from the contribute to first-degree heart block through dila-
ventricular depolarization of the previous sinus beat tation of the right atrium, through which atrial acti-
into the atrium. If such a reentry occurs before the vation must pass before reaching the AV node and
antegrade limb of the conduction system has recov- the bundle of His. However, in most patients first-
ered its ability to conduct the echo beat into the degree AV block results from prolonged conduction
ventricle,thebeatwillbeblocked,resultinginapause withintheAVnode.Althoughfirst-degreeblockmay
in the ventricular response rate. When such beats be diagnosed by measurement of the PR interval on
recur in a regular pattern [e.g., echo beats following the neonatal electrocardiogram (ECG), midtrimester
alternately after each sinus beat (bigeminal pattern)] fetus recordings of the fetal ECG do not provide
the result will be a ventricular response that is regu- high-quality recordings of atrial P waves. M-mode
lar, at a rate considerably lower than the intrinsic recordings of AV valve and semilunar valve motion,
240 PediatricCardiologyVol.25,No.3,2004
pulsed Doppler recordings of vena caval, aortic,
pulmonary venous, and pulmonary arterial flow
waveforms, Doppler tissue imaging, and magneto-
cardiography offer means of diagnosing AV con-
duction delay in the human fetus (Fig. 3).
Second-Degree Atrioventricular Block
Periodic pauses in ventricular activation, in the
presence of regular atrial stimulation, occur when
there areoccasionalatrial electricalimpulses that are
Fig. 3. Simultaneous pulsed Doppler recordings of right pulmo-
nonconducted.Twopatternsofsuchintermittentloss naryarterial(abovebaseline)andrightupperpulmonaryveinflow
of conduction have been described. The first, de- waveforms. The time interval between the onset of the atrial un-
scribed at the turn of the 20th century by Wencke- dulationonthevenouswaveformandtheonsetofejectionintothe
bach, results when there is a progressive lengthening pulmonaryarteryrepresentsthea–Vinterval,whichisthepulsed
DopplersurrogateoftheelectrocardiographicPRinterval.Similar
ofthePRinterval,withprogressiveshorteningofthe
information is available if the Doppler sample gate overlaps the
RR interval, until there is a skipped beat. Although
ascendingaortaandsuperiorvenacavaortheinferiorvenacava
there are a number of potential explanations for
anddescendingaorta.ThisinformationmaybeusedtoassessPR
Wenckebach-type, or Mobitz type I, second-degree intervalinfetusessuspectedofhaving1(cid:1)AVblockorventricular
block, the frequent association of this conduction preexcitation in suspected Wolff–Parkinson–White syndrome.
abnormality among patients with increased vagal Similarly, recordings during supraventricular tachycardia may
tone suggests some involvement of the autonomic provide information concerning ventriculoatrial conduction time.
a,atrialundulation;s,systolicfillingwave;d,diastolicfillingwave;
nervous system.
v,pulmonaryarterialejection.
Mobitz type II AV block is the periodic loss of
AV conduction without a progressive lengthening of
the PR interval. This may be manifest as occasional
loss of AV conduction or, in the presence of high- high as 75% within the first 18 months of life. This
grade second-degree block, as several consecutive mortality rate is considerably higher than that re-
dropped beats. Although the former may be associ- portedinotherpediatricstudiesoftheprolongedQT
ated with wide swings in vagal tone, high-grade sec- interval.
ond-degree block is usually associated with
conduction system disease and may presage the de- Complete Heart Block
velopment of third degree, or complete, heart block.
High-grade second-degree heart block may be asso- In complete AV block, atrial electrical impulses are
ciatedwithStokes–Adamsattacksandsuddendeath. completely unable to propagate through the con-
Fetuses of mothers with high anti-SS-A anti-Ro) or ductionsystemtoactivatetheventricles.ThereisAV
anti-SS-Banti-La)titersmaymanifestMobitztypeII dissociation, with a regular atrial rate that is faster
second-degree block before progressing to complete thantheventricularrate,withoutafixedrelationship
heart block. between atrial and ventricular activation. This con-
In infants with marked prolongation of the QT duction abnormality is invariably associated with an
interval, repolarization of the ventricle may be so anatomic abnormality in the AV node, the penetrat-
prolongedthattheventricleremainsrefractorytothe ing bundle of His, or with extensive damage of the
electrical stimulation of the subsequent sinus beat, distal conduction system involving the AV node and
resulting in a slowing of ventricular rate, due to the the bundle branches.
presenceof2:1AVblock.Thisrepresentsanunusual In congenital complete heart block with con-
presentation of a rare, malignant, genetic syndrome. genital heart disease, the structural abnormalities
Many of these cases present sporadically and prob- involve abnormalities of AV connection, such as
ably represent isolated genetic mutations. The discordance or ambiguous connections. In fetuses
potential for the development of polymorphic ven- with normal cardiac morphology, complete heart
tricular tachycardia and sudden death, secondary to block is almost always attributable to immune com-
dispersion of ventricular repolarization, is exceed- plex-mediated inflammatory damage to the conduc-
ingly high in these neonates. Fetuses and neonates tionsystem.Themothersofthesepatientsoftenhave
presenting with 2:1 AV block as a manifestation of histories of symptoms consistent with Sjogren’s syn-
prolongedQTintervalsyndromehavemortalityrates dromeandusuallyhavehightitersofanti-SS-A(anti-
as high as 50% within the first months of life and as Ro) or anti-SS-B (anti-La).
KleinmanandNehgme:CardiacArrhythmiasintheHumanFetus 241
Fetal Antiarrhythmic Therapy AV nodal dysfunction. Digoxin toxicity may be as-
sociated with atrial tachycardia with variable block
The simple existence of techniques for the diagnosis or with junctional or ventricular tachycardia. Due to
and treatment of fetal cardiac arrhythmias is insuffi- prolongation of the QTc interval, type IA or III
cientjustificationtoexposeamotherandfetustothe agents, alone or in combination with medications
potential hazards of antiarrhythmic therapy. The that may interfere with drug metabolism involving
management schema for such patients should be the cytochrome P-450 pathway (e.g. tricyclic antide-
predicatedonanunderstandingofthenaturalhistory pressants, histamine blockers, erythromycin, clarith-
of the arrhythmia, a precise knowledge of the romycin, zithromycin, ketoconazole, quinolone
electrophysiologic perturbation underlying the ar- antibiotics, trimethoprim sulfamethoxazole, and cis-
rhythmia, and a detailed appreciation of the phar- apride), may be associated with torsade de pointes
macokinetics and pharmacology of antiarrhythmic polymorphic ventricular tachycardia. Uniform ven-
agentsinthefetus,mother,andplacenta.Thesemust tricular tachycardia resistant to resuscitation is a
befactoredintoacommonsenserisk-benefitanalysis. characteristic proarrhythmic response to class IC
Neonatal risk increases proportionately with the de- antiarrhythmic drugs, such as flecainide and propa-
gree of prematurity and lung immaturity at the time fenone.
ofinitialdiagnosis,andthismust befactored against The frequent association of hydrops fetalis with
the degree of cardiovascular compromise accompa- sustained SVTs and the dismal prognosis for such
nying the arrhythmia. In the absence of extreme fetusesandneonatesprobablyjustifyvigorousefforts
prematurity, and without evidence of severe hemo- at in utero therapy in such fetuses, if such treatment
dynamic compromise of the fetus such as hydrops can be offered with a reasonable expectation of suc-
fetalis, fetal intervention is difficult to justify. cess at a tolerably low risk to the mother. Even a
IfthediagnosisofSVTwithouthydropsfetalisis moderate risk to the fetus would be justifiable in this
made at a gestational age when pulmonary maturity setting,inlightofthepoorprognosisfortheneonate
ofthefetusislikely(oratanearlieragebutwithlung ifthearrhythmiaandhydropsfetalisareunremitting.
maturity documented by amniocentesis), delivery Therapy with potent antiarrhythmics should be
with postnatal treatment is advisable. At extreme initiated in an inpatient setting with low doses of the
levels of prematurity, immediate delivery may not be antiarrhythmic agents. If drug dosages are escalated,
aviableoption.Inthissetting,thedecisionregarding such increases should be made incrementally, with
the administration of in utero therapy should con- careful monitoring of fetal and maternal drug re-
sider (1) the fetal hemodynamic state (e.g., is there sponses. Special care should be taken to avoid po-
evidence of hydrops fetalis? (2) the potential risks to tentially hazardous drug combinations, either
motherandfetusinherentinantiarrhythmictherapy, purposelyadministeredorinadvertentlycombined,as
and (3) issues such as the ability to provide adequate is the case when second- or third-line agents are ini-
monitoring of mother and fetus and maternal will- tiated prior to adequate clearance of drugs that were
ingness to submit to such treatment. included during the earlier phases of therapy.
Itisimportanttonotethatmanyantiarrhythmic Prior to initiation of antiarrhythmic drug thera-
drugs have a narrow therapeutic margin between se- py,thetherapeuticgoaloftherapyshouldbedefined.
rumlevelsthataretherapeuticandthosethatmaybe Incertaincircumstances,ratecontrolmayprovidean
associated with significant toxicity. In addition, al- adequate opportunity for recovery of fetal cardio-
though these agents are administered with the hope vascular function, whereas in some situations more
of suppressingcardiacrhythm disturbances, virtually completecontrolofthearrhythmiamaybenecessary.
all have proarrhythmic potential to provoke new or Venous Doppler flow studies of human fetuses
to exacerbate existing arrhythmias. They may occur withSVThavedemonstratedthattheonsetofSVTis
early during the course of therapy and may range associated with marked retrograde pulsation in the
from minor disturbances to potentially lethal ven- vena cavae and pulmonary veins, consistent with rel-
tricular arrhythmias. Among the agents that have ative restriction to diastolic filling of the fetal ven-
been used for fetal antiarrhythmic therapy, only the tricular myocardium, which has been (cid:1)unmasked(cid:2) by
class II (b-blocking) agents appear to lack the po- the inadequate duration of diastolic filling associated
tential for late proarrhythmic mortality. Due to the with the tachycardia. These pulsations may be trans-
unique situation when treating a fetus by way of mittedthroughtheductusvenosusandmaybemani-
maternaldrugingestion,wedealwithamortalityrisk fest in the umbilical veins. Diastolic notching in the
as high as 200%. umbilicalveinsisconsideredtobeanominousfinding,
Digitalis glycosides and Vaughn–Williams class frequentlyassociatedwithhydropsfetalisofdiffering
I–IV antiarrhythmic agents can cause severe sinus or etiologies [35]. This finding is frequently associated
242 PediatricCardiologyVol.25,No.3,2004
withfetalhypoalbuminemia,presumablysecondaryto
impaired hepatic protein synthesis. The resulting de-
crease in serum oncotic pressure, associated with the
increased hydrostatic pressure that is associated with
retrogradeatrialpulsations,leadstothedevelopment
offetaledemaandeffusions.TheseretrogradeAwaves
may resolve immediately upon cessation of SVT of
limited duration. On the other hand, persistence of
suchretrogradepulsationsfordaystoweekshasbeen
citedasevidenceofthedevelopmentofalong-lasting
tachycardia-inducedcardiomyopathyinsomefetuses.
This has been associated with persistent tricuspid re-
gurgitation(Fig.4)[26].
Clearly, the resolution or even partial resolution
of fetal SVT in a nonhydropic fetus may prevent the
destabilization of the delicate balance between fetal
hydrostatic and oncotic pressure, filtration coeffi-
cient, capillary permeability to albumin, interstitial
tissue turgor, and lymphatic drainage that results in
progressive fetal edema. On the other hand, once the
fetus has developed significant hydrops fetalis re-
versal of the situation appears to require total, or
subtotal, control of the rhythm disturbance. This
probably relates to the limitation in myocardial re-
serve in the fetus. We surmise that circulating levels
of catecholamines are elevated in these stressed fe-
tuses. The frequency with which one observes ex-
trasystoles in fetuses going in and out of tachycardia
provides an opportunity to observe whether the fetal
heart has retained its ability to manifest postextr-
asystolic potentiation. In fetuses with intermittent
tachycardia, without manifestations of hydrops fe-
talis, postextrasystolic potentiation is routinely ob-
served,whereasinfetuseswithseverehydropsfetalis,
intermittent episodes of sinus rhythm, with extrasy-
stoles or echo beats interposed, postextrasystolic
potentiation is rarely seen. We have interpreted this
asevidencethatthestressedmyocardiumhaslittleor
nofurthercontractilereserve.Theseobservationsare
c
Fig. 4. Sequence of three inferior vena caval pulsed Doppler
waveforms in a fetus with hydrops fetalis and supraventricular
tachycardia.(A)Thereisbidirectionalflowintheinferiorveracava
during supraventricular tachycardia. Flow below the baseline is
towardtherightatrium,withflowabovethebaselinerepresenting
prominent retrograde flow toward the liver associated with atrial
systole(Awavereversal).(B)Obtainedlessthan5minutesafterthe
rhythmconvertedtonormalsinus,thenormalbiphasicantegrade
flow pattern toward the right atrium has been reestablished. The
initialantegradeundulationisassociatedwiththedownwardmo-
tion of the AV junction, associated with ventricular systole. This
wave is associated with descent of the cardiac base, due to ven-
tricularsystole.Thiscreatesa‘‘suction’’thatenhancesvenousre-
turn.Thereisstillprominenta-wavereversal.(C)Obtained20–30
minutes later, a-wave reversal has almost resolved. Protracted
a-wave reversal that has been attributed to tachycardia-induced
cardiomyopathy.
KleinmanandNehgme:CardiacArrhythmiasintheHumanFetus 243
consistentwiththefindingthatfetallambsexposedto
infusions of isoproterenol do not demonstrate pos-
textrasystolic potentiation, due to the fact that their
myocardium is functioning along a curve represent-
ing maximal contractility [2]. Such fetuses cannot be
expected to recover myocardial reserve without
complete resolution of arrhythmia. The predilection
forrecurrenceoffetaltachycardiamakesitlikelythat
any fetus treated for sustained tachycardia will re-
quire chronic therapy to prevent recurrence.
Although acute intravenous treatment with an
agent such as adenosine may provide valuable diag-
nostic information concerning the underlying elec-
Fig.5. DevelopmentalchangesindrugclearancefortheCYP1A2
trophysiologyofthearrhythmia (e.g. breaking ofthe
isoformofcytochromeP450,usingcaffeineasamodelsubstrate.
tachycardia with adenosine-induced AV node block- Reproduced with permission from Goodman and Gilman’s The
ade confirms the underlying reentry mechanism in- Pharmacological Basis of Therapeutics, 10th, edn. McGraw-Hill,
volving the AV node as one of the limbs of the NewYork,2001.
electricalcircuit),itisveryunlikelythatsuchtherapy
will result in a long-lastingresolution of tachycardia.
The need for chronic antiarrhythmic therapy may
increase the potential risks of such treatment. addingadditionalantiarrhythmicagents,since useof
A report from Great Britain of a neonate who antiarrhythmic medications often involves use of
hadbeentreatedinuterowithflecainideforSVT,and drugs with narrow therapeutic margins. Attaining a
whopresentedwithflecainidetoxicityandaflecainide steady state level of medication, consistently above
serumlevelwellabovethatofthemother,givespause the therapeutic threshold and below the toxic
for some alarm [34]. Certainly, some medications threshold, may be difficult or impossible considering
may accumulate in the fetus. Previous data do not the marked difference between the fetus and mother.
suggest that this is the case for flecainide. Other an- If one administers a medication at intervals equal to
tiarrhythmicmedicationsinwhichfetalaccumulation theeliminationhalf-lifeofthemedication,itwilltake
in excess of the mother’s serum level has been re- approximately four half-lives to attain a steady-state
ported include procainamide; there is a single case concentration. This is based upon a one-compart-
report of such accumulation in a patient receiving mentmodel.Weareunawareofanypharmacokinetic
sotalol during pregnancy. In the report of unexpect- study of steady-state kinetics for fetal levels of the
edly high flecainide levels in the neonate, it was antiarrhythmic agents that have been used for the
speculated that the maternal flecainide level might treatment of fetal arrhythmias. It is clear that oral
haveincreasedatterm.Itisunclearwhetherthedose absorption of digoxin is significantly impaired in the
administered to the mother had been escalated or pregnant woman and is further impaired in the
whether there was a change in fetal or maternal presenceofhydropsfetalis.Inaddition,themarkedly
hemodynamics that might have accounted for a increased volume of distribution in the presence of
sudden increase in absorption. polyhydramniosandhydropsfetalismakesitdifficult
The distributionofdruginthepregnantwoman, to be certain of the blood level of this medication.
placenta, and fetus is dependent on several factors, This accounts for the disappointing results in the
including drug absorption, lipid solubility, albumin treatment of SVT and hydrops fetalis with digoxin
binding,drugpKa,maternalandfetalplasmapH,he- orally administered to the pregnant woman. It is
paticandrenalfunction,maturityoftheenzyme and unsoundtoescalatedrugdosagesatintervalsthatare
cytochromesystemsinvolvedindrugmetabolismand less than four elimination half-lives, unless one is
alsopotentialgeneticdifferencesbetweenmotherand resigned toovershootingdesireddrugconcentrations
fetus(Fig.5).Thevolumeofdistributionofdrugmay (Figs. 6 and 7). On the other hand, it is potentially
varygreatly,especiallyinfetuseswithhydropsfetalis dangerous to change drug regimens without consid-
withmaternalpolyhydramnios,placentaledema,fetal ering thatthesame foureliminationhalf-lives should
hypoalbuminemia,andascites.Insuchcases,itmaybe elapse between discontinuation of a medication and
difficultorimpossibletoanticipatethedegreeofdrug addition of a new medication, unless one has ascer-
absorptionandtheeliminationhalf-lifeofmedications. tained that the two medications in combination are
It is essential to at least consider such issues, not exposing the mother or her fetus to untoward
before considering escalation of drug dosage, and/or danger.