Treatment of fetal supraventricular tachyarrhythmias

J Clin Ultrasound 13:265-273, May 1985 Symposium Article

Treatment of Fetal Supraventricular Tachyarrhythmias

Charles S. Kleinman, MD, Joshua A. Copel, MD, Ellen M. Weinstein, MD, Thomas V. Santulli, Jr., MD, and John C. Hobbins, MD

Abstract: Supraventricular tachyarrhythmia has been encountered in 18 fetuses at the Yale-New Haven Medical Center during the past 4 years. Fourteen of these fetuses had supraventricular tachycardia and underwent in utero antiarrhythmic therapy with maternally administered digoxin either alone, or on combination with verapamil, propranolol, or procainamide. Thirteen of the 14 fetuses had successful in utero conversion of cardiac rhythm to normal sinus rhythm. The 14th patient underwent successful therapy after birth. All 14 fetuses survived despite severe fetal hydrops at the time of diagnosis in 13 of 14. The four remaining fetuses had either atrial flutter (3) or fibrillation. Two of the fetuses with atrial flutter died at birth, the 3rd survived after electrical cardioversion at birth. The fetus with atrial fibrillation converted to normal sinus rhythm and survived after maternal administration of digoxin. Using M-mode and pulsed Doppler echocardiography, the nature and electrophysiologic mechanism of the arrhythmia may be deduced. The latter information is reviewed along with the fetomaternal pharmacology of various antiarrhythmic agents to devise a rational antiarrhythmic treatment program. Indexing words: Fetal heart - Fetal arrhythmias * Fetal therapy * Fetal echocardiography

In recent years perinatologists have relied upon continuous-wave Doppler fetal heart rate monitoring to provide the means for evaluation of fetal well-being. While originally applied during labor, these techniques have been increasingly used during the last trimester of pregnancy, prior to the onset of uterine contractions.' The increased interest in fetal heart rate and rhythm has resulted in an increased awareness of the existence of fetal cardiac arrhythmias and has fostered interest in understanding the significance, mechanism, and potential for treatment of clinically sig- nificant fetal arrhythmias.

The use of two-dimensional, M-mode, and, more recently, pulsed Doppler echocardiography to document the presence and nature of fetal ar-

From the Departments of Pediatrics, Diagnostic Imaging, and Obstetrics and Gynecology, Yale University School of Medi- cine, New Haven, CT. This work was supported by Clinical Research Grant 6-225 of the March of Dimes Birth Defects Foundation, White Plains, New York. Manuscript received November 11, 1984. For reprints contact Charles S. Klein- man, MD, Section of Pediatric Cardiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

0 1985 by John Wiley & Sons, Inc. 0091 -2751/85/040265-09 $04.00

rhythmias has been described in a number of lab- and has been reviewed elsewhere in

this symposium. It is our purpose to discuss the use of fetal echo-

cardiographic techniques to direct and monitor the treatment of fetal supraventricular tachyarrhythmias. A rationale for transplacental drug therapy will be offered based upon an echocardiographic analysis of the electrophysiologic mecha- .nism of these arrhythmias, the fetomaternal pharmacology of various antiarrhythmic agents, and our understanding of fetal and newborn he- modynamics.

YALE EXPERIENCE WITH SUSTAINED FETAL TACHYARRHYTHMIAS

We have, during the past 4 years, encountered 18 cases of sustained supraventricular tachyarrhythmia (Table 1). Sixteen of these fetuses presented with edema, ascites, and maternal polyhydramnios. Fetal gestational ages ranged from 24-38 weeks.

Using two-dimensional imaging techniques, echocardiographic study documented the pres-

265

266 KLEINMAN ET AL.

TABLE 1 Fetal Supraventricular Tachyarrhythmias

(n = 18)

A. Supraventricular tachycardia Gestational age Hydrops fetalis In utero control Postnatal control Mortality

E . Atrial flutter Gestational age Hydrops fetalis In utero control Postnatal control Mortality

C. Atrial fibrillation Gestational age Hydrops fetalis In utero control Mortality

(n = 14) 24-28 weeks 13/14 cases 13/14 cases 1/14 cases

0

( n = 3) 30-38 weeks 313 cases 0/3 cases 113 cases 213 cases

(n = 1 ) 38 weeks

0 l/l 0

ence of normal fetal cardiac anatomy in all 18 cases. Using two-dimensional echocardiography to define the position of the m-mode sampling line, sequential (using an Advanced Technology Laboratories MK600 scanner) or simultaneous (using a Hewlett-Packard 77020 Phased Array Ultrasound scanner) M-mode echocardiographic recordings of cardiac motion were carried out. Us- ing the "dual M-mode" capability of the latter ap- paratus, simultaneous M-mode recordings of atrial and ventricular wall motion could be obtained, even when the fetal heart was oriented in a manner that did not allow simultaneous atrial and ventricular imaging with a single M-mode sample. Using a method similar to that described earlier in this symposium by Silverman and col- leagues, we attempted to relate atrial activity to the ventricular response. The hemodynamic con- sequences of these arrhythmias have, in our most recent case, also been studied using pulsed Dop- pler analysis of ventricular filling and great arte- rial flow characteristics (using the ATL MK600 instrument).

In all but one patient the nature of the cardiac arrhythmia was apparent at the time of initial echocardiographic examination. In the remaining patient a monotonous fetal tachycardia of 180 beatdminute was not recognized to be secondary to atrial flutter with 2 : l block until echocardiographic monitoring of transplacentally administered antiarrhythmic agents (digoxin and verapamil) increased the degree of atrioventricular block.

Fourteen of our 18 patients were diagnosed to have supraventricular tachycardia, with ventricular rates varying from 220 beatdminute to 280 beatslminute. Thirteen of these patients had evidence of hydrops fetalis at the time of diagnosis.

The 14th patient developed evidence of pleural and pericardial effusions during the first day of monitoring, prior to successful digitalis-induced conversion to normal sinus rhythm.

The remaining four patients were either in atrial flutter (three patients) or fibrillation (one patient) at the time of diagnosis. The three patients with atrial flutter were hydropic at the time of diagnosis and had variable degrees of atrioventricular block (varying from 2 : 1 in one patient to 7-8 : 1 in another) with atrial rates that ranged from 360 beatdminute to 420 beats/ minute. The fetus with atrial fibrillation was encountered in a severely hypertensive mother who underwent fetal nonstress testing within an hour of starting methyldopa therapy. An irregularly irregular fetal cardiac rhythm was noted and re- ferral to the Yale Fetal Cardiac Center was made. A diagnosis of fetal atrial fibrillation was subsequently made.

Supraventricular tachycardia

The 14 cases of supraventricular tachycardia underwent attempts at transplacental antiarrhythmic therapy. Sporadic case reports had noted the efficacy of a variety of agents in this setting, including dig~xin, ' ,~ propranolol," verapamil," and pr~ca inamide . '~ ,~~ The first two cases that we encountered responded within 48 hours of initiation of oral digoxin therapy to the mother.

One of these patients had gross fetal hydrops. The second patient had been assessed due to the presence of frequent atrial extrasystoles. This fetus had frequent (> 20/minute) atrial extrasystoles, which occurred at varying coupling inter- vals to the preceding normal beat with frequent self-limited episodes of supraventricular tachycardia (of 10-20 beat duration) of sudden onset and termination (Fig. 1). The mother was admitted for observation. During the first day of hospital- ization a sustained episode of supraventricular tachycardia at 240 beatdminute began. After 24- 36 hours the fetus began to accumulate pericardial and pleural effusions. Digoxin was administered in a dosage appropriate for maternal weight. A daily maintenance dosage of 0.50 mg was needed in order to attain a maternal digoxin serum level at the "upper end" of the therapeutic range (1.5-2.0 ng/ml). Within 48 hours of institu- tion of digoxin therapy the fetal cardiac rhythm converted to normal sinus rhythm. Both fetuses were maintained in normal sinus rhythm throughout the ensuing several weeks. The first patient delivered normally at term and was main-

JOURNAL OF CLINICAL ULTRASOUND

FETAL SUPRAVENTRICULAR TACHYARRHYTHMIAS 267

TABLE 2 Supraventricular Tachycardia in utero therapy

(n = 14)

Digoxin 6/14 cases Digoxin + verapamil 6,114 cases Digoxin + propranolol 2’114 cases

*One patient, initially controlled on digoxin + verapamil, was changed to a regimen of digoxin + propranolol due to maternal heart block following administration of verapamil.

tained on “prophylactic” digoxin therapy for 1 year after birth and was, thereafter, taken off digoxin without recurrent episodes of tachycardia. The second fetal patient was in sinus rhythm for approximately 1 month. At 38 weeks gestation a prenatal examination again detected fetal tachycardia. The mother admitted to having discontinued digoxin and refused further therapy. The infant was delivered by cesarean delivery due to uterine inertia and maternal fever and had supraventricular tachycardia that was ultimately controlled with digoxin and propranolol.

Our third patient with fetal supraventricular tachycardia presented with hydrops fetalis at 34 weeks gestation. The tachycardia was unresponsive to digoxin therapy. We then instituted propranolol therapy, initially starting with 40 mg orally every 6 hours, ultimately increasing the dose to 120 mg every 6 hours. When this proved unsuccessful and amniocentesis suggested lung maturity14 (lecithidsphingomyelin ratio > 1 : 5 ) the child was delivered by cesarean section and was treated intensively for respiratory distress complicated by pulmonary edema, ascites, edema, hypoproteinemia, and sustained supraventricular tachycardia. Management was punctuated by multiple attempts at electrical cardioversion and an episode of low cardiac output and profound bradycardia requiring calcium administration and cardiopulmonary resuscitation, following administration of intravenous verapamil. This infant survived, the arrhythmia being eventually controlled with digoxin and propranolol.

After this harrowing experience we became more determined to avoid premature delivery of hydropic infants if in utero control of the tachycardia is, at all, feasible.

Our next tachycardic fetus with severe hydrops fetalis and maternal polyhydramnios was encountered at 29 weeks gestation. Maternal digoxin administration did not result in conversion of fetal tachycardia to normal sinus rhythm. Ad- ministration of propranolol in gradually increasing doses attained a maternal serum level of 436 ng/ml and resulted in brief episodes of sinus rhythm, which started and terminated abruptly. VOL. 13, NO. 4, MAY 1985

These episodes became fewer and shorter lived, and soon the rhythm was again continually supraventricular tachycardia. Thereafter, propran- 0101 was withheld and procainamide administered intravenously, without fetal response (maternal serum level of procainamide + N-acetyl procainamide reached 6 kg/ml). We then withheld procainamide and administered verapamil intravenously to the mother, with conversion of fetal tachycardia to normal sinus rhythm. The latter was sustained for 20 minutes. Thereafter oral verapamil therapy was begun and normal sinus rhythm was sustained, with gradual resolution of fetal edema. A normal female infant was born at term.

Since that experience we have had occasion to use the combination of digoxin and verapamil on five occasions. We have used oral rather than intravenous verapamil and have effected conversion to sinus rhythm in all five cases. In all cases there were brief episodes of normal sinus rhythm, starting approximately 90 minutes after each verapamil dose. These episodes gradually increased in duration until sinus rhythm was sustained.

In one case the mother developed second degree atrioventricular block within an hour of verapamil dosage. Despite alterations in the drug regimen we were unable to obtain fetal sinus rhythm at a dose that did not result in maternal heart block. Verapamil was then discontinued and propranolol started, with fetal sinus rhythm and resolution of fetal edema within 3 days.

The mothers who received therapy with verapamil after maintenance on digoxin had increased digoxin serum levels (30-50%), neces- sitating alteration in digoxin dosage.

The fourteen patients with fetal supraventricular tachycardia had some degree of fetal edema, although the second patient in this series had a fetus that had only a small amount of pericardial and pleural fluid. Thirteen of the 14 patients had successful in utero conversion of supraventricular tachycardia to normal sinus rhythm (Table 2). Six patients have responded to maternal digoxin administration, one to combined maternal digoxin and propranolol therapy, ar,d six to a combination of digoxin and verapamil administration. One of the patients, initially “controlled” with digoxin and verapamil was switched suc- cessfully to digoxin and propranolol due to lack of maternal tolerance of verapamil. The fourteenth patient was delivered at 34 weeks gestation after an unsuccessful attempt at antiarrhythmic therapy with digoxin and propranolol.

Follow-up has varied from 8 to 47 months. All

268 KLEINMAN ET AL.

FIGURE 1. M-mode echocardiogram at the ventricular level in a fetus with reentrant supraventricular tachycardia. The horizontal axis represents time (note the one-second marker). Cardiac motion against time is presented, with motion toward the chest wall represented by motion toward the top of the figure. The atrioventricular valve undulations are seen (open arrow). Note the sudden onset of supraventricular tachycardia. Atrioventric- ular valve undulations suddenly increase to reflect the heart rate of 240 beatshninute. (Reproduced with permission of

infants have been maintained on antiarrhythmic prophylaxis for a year after birth. One patient, the second in our series, was maintained on digoxin and propranolol and was lost to follow-up after 9 months. One patient was maintained on digoxin and propranolol for 6 months and was weaned to digoxin alone for the next 6 months. The other patients have been maintained on digoxin alone. There have been no recurrences of supraventricular tachycardia in our patients and no mortality. None of the patients has had evidence of Wolff-Parkinson-White syndrome on postnatal electrocardiograms; none have under- gone invasive electrophysiologic testing.

Atrial flutterlfibrillation One patient, with atrial flutter and moderate fetal edema at 38 weeks gestation was delivered by cesarean section and electrically cardioverted at delivery. Another patient, with severe hydrops fetalis at 36 weeks gestation, was severely brady- cardic, due to atrial flutter with 7 and 8: 1 atrioventricular block. This patient had been referred for evaluation to our center due to severe fetal edema and “fetal tachycardia’, of uncertain rate. By the time our evaluation was performed, the high-grade atrioventricular block and resultant bradycardia necessitated cesarean delivery, with the intention of performing electrical cardioversion and/or transvenous pacemaker therapy. This infant was stillborn.

The third patient with fetal atrial flutter also died. This fetus was referred to our center at 30

weeks gestation. There had been only a single prenatal obstetrical visit, at 22 weeks gestation. That visit had detected no maternal or fetal ab- normalities. During the month prior to our initial evaluation the mother had noted a 20-pound weight gain and increased abdominal girth. This woman admitted to the ingestion of ampheta- mines and hallucinogens during the first trimester, but denied such ingestions during the second and third trimesters of the pregnancy. M-mode echocardiography demonstrated a monotonous tachycardia at 180 beatdminute. After administration of digoxin no change in cardiac rhythm was noted, while fetal ascites and maternal polyhydramnios were increasing. Oral verapamil was administered to the mother, initially at a dose of 80 mg every 8 hours and subsequently at a dose of 120 mg every 8 hours. Maternal serum levels of verapamil varied from 17.3 ng/ml to 28.6 ng/ ml. At the higher dose of verapamil M-mode echocardiography documented periods of high- grade fetal atrioventricular block (Fig. 2), with rapid diastolic atrioventricular valve undulation, reflecting an atrial flutter rate of approximately 360 beatdminute. Premature rupture of mem- branes was followed by stillbirth of a female infant.

Hence two of three fetuses encountered with atrial flutter and hydrops fetalis died. The sole survivor, diagnosed at term, was electrically cardioverted at birth.

The only patient with atrial fibrillation was not hydropic at presentation and responded with conversion to normal sinus rhythm after administration of digoxin to the mother.



TABLE 3 Transplacental Antiarrhythmic Agents

Digoxin Veraparnil Propranolol Procainarnide

Loading PO IV

PO Maintenance

IV Protein bound Eliminating organ Transplacental passage

(cordimaternal serum level)

Therapeutic plasma concentration

Comments

1.0-2.5 mg 0.5-2.0 mg

0.25-0.75 mgiday 0.25 mg 20% Kidney 0.8-1.0

0.5-2.0 ngiml

Level may increase when verapamil is added; fetus may tolerate (need?) higher level than adult

5.0-10.0 mg

80-120 mg q 6-8 hrs

90% Liver 0.3-0.4

50-100 ngiml

Extensive first pass metabolism: may cause heart block; negative inotropic agent: DO NOT give with propranolol

0.5 mg q 5 min

20-160 mg q 6-8 hrs

90-95% Liver 0.1-0.3

50-1000 ngiml

Extensive first pass metabolism; DO NOT give with verapamil; fetal bradycardia, hypoglycemia, growth retarda- tion; maternal broncho- spasm can occur

12 mgikg

6 mg/kg Q 4 hrs

15% Kidney 0.8- 1.3

4-14 mcgiml

Active metabolite, N- acetyl procainamide (NAPA); may accumulate in fetus or neonate; in atrial fibiflutter should treat first with digoxin or verapamil

ANTIARRHYTHMIC DRUGS (Table 3)

Experience postnatally with neonatal supraventricular tachycardia suggests that the most com- monly encountered electrophysiologic mechanism for this arrhythmia is atrioventricular reentry.15 When M-mode or pulsed Doppler fetal echocardiography demonstrates sudden onset (Fig. 1) and termination of tachycardia with induction of the arrhythmia by extrasystoles, we have interpreted this as evidence for a reentrant basis for the ar-

rhythmia. Onset and termination of the arrhythmia may not be noted until after a therapeutic trial of antiarrhythmic medication is begun. If, as noted in one of our cases of atrial flutter (Fig 2), antiarrhythmic therapy results in second degree atrioventricular block without termination of the arrhythmia, one can rule out atrioventricular reentry as the mechanism of the arrhythmia, and further attempts at therapy should be based on this information.

RGURE 2. M-mode echocardiograrn at the ventricular level in 3 30-week fetus who presented with an incessant tachycardia of 180 beatsiminute. The one-second marker is seen at the bottom. After digoxin and verapamil were administered second degree atrioventricular block was induced. This figure demonstrates slowed undulations of the ventricular posterior wall due to the block in the atrioventricular node (curved open arrows). The undulations on the mitral valve, within the left ventricle (LV), are labelled with vertical arrows. During the episodes of atrioventricular block the mitral valve undulations reflect continued atrial flutter, at a rate of 360-380 beatdrninute. The continued atrial tachyarrhythimia, in face of atrioventricular block, rules out atrioventricular reentrant tachycardia. (Reproduced with permission of Journai of the American College of Cardio/ogy.26)

VOL. 13, NO. 4, MAY 1985

KLEINMAN ET AL. 270

Dig oxin

Digoxin was chosen as our drug of choice for treatment of in utero fetal supraventricular tachycardia. Our experience has suggested that maternal and “cord” serum levels of digoxin are similar (cord level 90-100% maternal level). While it has been suggested that neonates may tolerate and even require higher serum levels of digoxin than adults,16 we are, of course, limited in transplacental therapy by maternal tolerance. For this reason we prefer to “push” digoxin levels in the mother toward the upper end of the therapeutic range for our laboratory (2 ng/ml). In order to attain these levels we have had to employ rather large oral doses to the mother (between 0.50-0.75 mg/day). Limited oral absorption of digoxin has been documented in the gravid state. Administration of digoxin for treatment of supraventricular tachycardia of infancy is a policy undergoing reexamination in many centers. This reassessment is due to the high incidence of Wolff-Parkinson- White syndrome that has been found in infants with supraventricular tachycardia, and documentation of digitalis-induced short- ening of the effective refractory period within the accessory conduction pathways of some of these children. The latter has been implicated as the underlying cause of the sporadic reports of sudden death in children with Wolff-Parkinson-White syndrome who are maintained on digitalis therapy. We have not yet documented evidence of preexcitation in any of our 14 fetal patients with supraventricular tachycardia.

Verapamil

Verapamil was initially added to our antiarrhythmic protocol after a futile effort to control supraventricular tachycardia in a 29-week fetus with severe hydrops fetalis (after digoxin, propranolol, and procainamide had failed). As a drug that blocks slow inward calcium and sodium cur- rents, verapamil is a potent agent for blocking atrioventricular nodal conduction.17 Verapamil is, therefore, useful for treatment of reentrant tachycardias involving atrioventricular node conduction (either antegrade or retrograde) as one limb of the reentrant circuit. An extensive experience has been accumulated in Europe over the past several years using intravenous verapamil infusions during the third trimester of pregnancy as part of the “tocolytic cocktail” for control of premature labor.18 Verapamil is included as a means of prophylaxis against the cardiovascular

side effects of the beta agonists used for control of uterine contraction. This experience has documented the safety of administration of verapamil, both for mother and fetus, during the third trimester of pregnancy. Studies of verapamil action on the normal heart suggest that despite the potential for a negative inotropic effect associated with calcium channel blockade, the drug is well tol- erated by the normal heart. Cardiac output has re- mained in the normal range, the negative inotropic effects apparently countered by the afterload reduction related to vasodilation induced by the medication.lg In a report by Wolff et a1.l’ oral verapamil resulted in cardioversion of fetal supraventricular tachycardia. In that report verapamil was started simultaneously with the oral administration of digoxin. The time course of response (5 days after initiation of therapy) raises some doubt about which agent was responsible for the therapeutic effect. Transplacental transfer of verapamil was documented in this report, with a ratio of maternal to cord serum levels of verapamil of 4: 1 to 6: 1, and no verapamil was detected in cord blood 3 hours after a single 80-mg oral dose of verapamil was administered to the mother during labor. Our experiences with verapamil suggest that oral absorption of this medication may vary markedly [levels of 155-210 ng/ml attained in one patient on the same dose (120 mg orally every 8 hours) that attained levels of only 17-29 ng/ml in a woman with similar body habitus]. Our data suggest that at “steady state,” after 6-12 weeks of therapy, levels of verapamil and nonverapamil in cord serum approximate 35-40% of maternal serum levels 6-8 hours after the last dose of oral verapamil. Oral absorption and first-pass metabolism of verapamil may be impaired during active labor. The earlier report noted above” must be interpreted in light of the probable absence of a “steady state” and ques- tionable drug absorption during active labor. Our first administration of verapamil, as an intravenous medication, convinced us of the potential for the use of this medication for control of fetal supraventricular tachycardia. We have since used oral verapamil, both for initial conversion and for chronic antiarrhythmic maintenance therapy. Caution is, of course, in order when considering verapamil administration, due to the possibility of precipitating severe bradycardia and depression of cardiac function when this drug is administered in a setting of severe cardiac failure. In the presence of severe fetal heart failure in the late second or early third trimester, with associated pulmonary immaturity, we believe that risk/ benefit considerations indicate a role for



verapamil treatment. Informed parental consent is obtained before such treatment is instituted and continuous hemodynamic monitoring of mother and fetus is essential.

While we have not encountered dysfunctional labor or postpartum hemorrhage attributable to a verapamil-induced impairment of uterine contraction, we have routinely discontinued oral verapamil administration at the onset of labor. Because concomitant administration of intravenous verapamil and propranolol can have severe negative inotropic effects and can induce high- grade atrioventricular block, we recommend verapamil therapy after initial administration of digoxin, before considering administration of propranolol. One must be aware of the potential for digoxin accumulation due to impaired excre- tion when verapamil therapy is started, even after a digoxin steady-state has been reached. The “quinidine-like” effect on digoxin clearance has been described by others,” and has required a 33% decrease in digoxin dosage in the cases in which this drug combination has been employed.

Propranolol We have had limited success with the combination of digoxin and the beta-blocking agent, propranolol. Transplacental transfer of propranolol has been demonstrated in the past, although the degree of transfer has been disputed.21 The broad therapeutic index of propranolol has allowed us to increase maternal dosage markedly without de- velopment of untoward maternal effects, while at- tempting to attain “therapeutic” fetal drug levels. The risks of maternal propranolol therapy have been well-described and the potential for causing low birth weight, hypoglycemia, and sinus node depression must be weighed against the therapeutic goal of conversion of in utero tachycardia when considering use of this d r ~ g . ’ ~ , ~ ~

Procainamide

Procainamide is a “Type I” antiarrhythmic agent that blocks the sodium current responsible for the rapid phase 0 of the action potential and de- creases conduction velocity in atrial, ventricular, His-Purkinje, and accessory conduction tissue.24 It also prolongs action potential duration and refractory periods of these tissues, and may therefore be useful for therapy of reentrant tachycardias mediated by conduction through these tissues. Procainamide has not been useful for treatment of supraventricular tachycardia due to ab- normal automaticity. This medication is consid- VOL. 13, NO. 4, MAY 1985

ered one of the drugs of choice for control of rapid ventricular response to atrial fibrillation/flutter in the presence of an atrioventricular bypass tract and should be considered for early inclusion in the treatment protocol when M-mode echocardiography demonstrates atrial flutter or fibrillation. In this setting digoxin, propranolol, or verapamil should be administered first, in order to prevent the rapid ventricular response that may occur if the atrial refractory period is increased. When reentrant supraventricular tachycardia is suspected, we would use this agent only if digoxin and/or verapamil has been unsuccessful and if the hydrops remains unchanged or appears to worsen. Our single trial of procainamide was unsuccessful but this may have been related to the “low therapeutic” levels of procainamide plus N-acetyl procainamide that were attained despite a high intravenous infusion rate. The report of Dumesic et a1.l’ documented a maternal procainamide level of 15.6 pg/ml with a neonatal level of 4.3 pg/ml (levels of the active metabolite N-acetyl procainamide were not reported). These data suggest the possibility that we did not attain a therapeutic fetal serum level of this medication. These data are in dispute with the pharmaco- kinetic data of Lima et al.,25 who documented levels of procainamide and N-acetyl procainamide in neonatal serum 8 hours after birth ex- ceeding those levels in maternal and cord blood. Explanation of this phenomenon includes a phar- macokinetic model in which the fetus represents a “deeper compartment” than the mother. In this model the drug enters the fetus slowly but because maternal clearance is fzister than fetal clearance, a fetal drug concentration higher than maternal concentration may eventually be reached. An alternate explanation related the usual differential between maternal and fetal plasma pH (maternal pH usually 0.10-0.15 units higher) to alterations in ionization of the weak bases of procainamide and N-acetylated procainamide (pKa 9.4 and 9.8, respectively). This would account for a fetal/maternal concentration ratio of 1.4, if one assumes that diffusion of lipid soluble nonionized drug accounts for fetal uptake. In the setting of sustained fetal tachycardia and hydrops fetalis, a degree of fetal acidosis can be expected. This could account for an even larger fetallmaternal concentration ratio. The report of Given et al.I3 demonstrated a ratio of cord maternal serum level of procainamide + N-acetyl procainamide of 1.3 (12 pglmU9.3 pgfml). Caution should, therefore, be exercised in the administration of this medication to the pregnant woman, due to the potential for fetal and neonatal toxicity

272 KLEINMAN ET AL.

secondary to accumulation of drug and active metabolite in the fetus and the slow rate of elimi- nation of these compounds by the neonate. The apparent discrepancies between these two reports re-emphasize the need for further study of fetomaternal pharmacokinetics of procainamide before this drug is routinely included in the fetal treatment protocol. Concern over potential toxicity from this medication makes us reluctant to include procainamide as a drug for treatment of fetal supraventricular tachycardia, unless the condition of the fetus is severe enough to necessi- tate cardioversion and the degree of prematurity and amniotic fluid studies contraindicate premature delivery (in a fetus whose arrhythmia has been unresponsive to therapy with digoxin, verapamil, andlor propranolol).

On the basis of our high fetal wastage with atrial flutter, we now consider fetal hydrops in the presence of this arrhythmia to have a poor enough prognosis to warrant therapy with procainamide early in the treatment protocol.

CONCLUSION

Fetal tachycardia is a medical emergency that should be treated aggressively. Because the fetus is not dependent upon pulmonary gas exchange, and because of the difficulties inherent in treat- ing a premature infant with arrhythmias in a setting of pulmonary edema, hyaline membrane disease, and hydrops fetalis, we believe that in utero therapy of these arrhythmias is preferable to premature delivery, especially in the presence of an unfavorable lecithidsphingomyelin ratio. We re- sort to premature delivery only if transplacental therapy (following a systematic, sequential administration of medications) is unsuccessful in the face of persistent or worsening fetal hydrops. On the basis of our previous experience with supraventricular tachycardia and atrial flutter/ fibrillation, our “threshold” for recommending premature delivery is lower for the latter arrhythmias.

M-mode echocardiography and pulsed Doppler analysis of fetal supraventricular tachyarrhythmias provide valuable information concerning the nature and electrophysiologic mechanism of the tachyarrhythmia. This information should be used to direct efforts at transplacental therapy. A variety of medications are useful for transplacental management of supraventricular tachyarrhythmias. Basing therapy on electrophysiologic principles allows a more logical and safer ap- proach to the management of these potentially life-threatening arrhythmias and allows the car-

diologist and perinatologist to place the varied medications in their proper perspective. Docu- mentation of the nature of a rhythm is essential for directing appropriate therapy. Administra- tion of potent drugs to the fetus via the mother requires close hernodynamic monitoring of both members of the fetomaternal “biologic unit.” Car- diac ultrasound evaluation of the fetal heart may provide both diagnostic and monitoring data of value in this setting.

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VOL. 13, NO. 4, MAY 1985

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Treatment of fetal supraventricular tachyarrhythmias