Materials and Methods
The cohort consisted of 44 fetuses with structurally normal hearts presenting with nonsinus tachycardia (heart rate over 180 beats per minute) at seven institutions in the Chicago area between 1987 and 1999 (Prentice Woman's Hospital and Evanston Hospital 1987–1999, Rush-Presbyterian-St. Luke's Medical Center 1991–1996, Christ Hospital and Medical Center 1996–1999, Rockford Memorial Hospital 1996–1999, Lutheran General Hospital 1996–1999, and Illinois Masonic Medical Center 1994–1999). A tachycardia risk-assessment profile (derived from echocardiographic and ultrasound findings and the biophysical profile) was determined for each fetus at the initial evaluation (Table 1). Based on the profile result, the fetus was assigned to one of the three groups. Two-dimensional, Doppler, color-flow Doppler, and M-mode echocardiograms were recorded using either Acuson 28XP or Sequoia (Acuson, Mountain View, California) or Hewlett-Packard 1000 or 1500 (Hewlett-Packard, Andover, Massachusetts) echocardiography platforms to assess ventricular function, atrioventricular valve insufficiency, and degree of hydrops (if present). M-mode measurements of ventricular shortening fraction and wall thicknesses were made using ventricular short-axis view when obtainable. If views were not obtainable, ventricular function was assessed qualitatively and measured using two-dimensional imaging. Ventricular dysfunction was defined as mild to moderate, if shortening fraction was less than 28% but greater than 15% for either ventricle, and as severe if shortening fraction was less than 15%. The degree of atrioventricular valve insufficiency was based on standard echocardiographic criteria.17 Hydrops was defined as small if only one body cavity was involved and large if more than one cavity or more than a 1-cm rim of fluid was present in the pleural, peritoneal, or pericardial space. Fetal well-being was evaluated by observations of breathing, movement, and tone. The tachycardia duration, determined by continuous monitoring (or in the more immature fetuses by frequent Doppler auscultation), was either sustained (more than 12 consecutive hours) or interrupted. Tachycardia cycle length and likely mechanism were determined by M-mode and pulsed Doppler echocardiography. Atrial flutter was diagnosed when the atrial rate exceeded the ventricular rate, and atrioventricular-reciprocating tachycardia was diagnosed when one-to-one atrioventricular concordance was present.
Fetuses in group 1 had interrupted tachycardia with normal ventricular function. They were treated expectantly and did not receive antiarrhythmic therapy. Fetuses in group 2 (n = 14) had sustained tachycardia, mild-to-moderate heart failure, and a normal biophysical profile. They received transplacental antiarrhythmic therapy administered orally or intravenously to the mother. Fetuses in group 3 (n = 17) had sustained tachycardia and severe heart failure, with or without abnormal biophysical profiles. They were treated with transplacental antiarrhythmic agents and by ultrasound-guided direct intramuscular injection of antiarrhythmics into the fetal thigh. Two fetuses (28 and 29) initially in group 2 progressed to group 3 because of unsuccessful transplacental therapy.
The administration of secondary transplacental agents varied during the study period because of trends in antiarrhythmic therapy, varying availability of certain agents, and because of the number of institutions involved. The primary drug protocol consisted of administration of digoxin 1000–1500 μg intravenously to the mother, in three or four divided doses over 24 hours, with trough serum concentrations obtained after the initial loading dose. In group 3 coadministration of fetal intramuscular digoxin was 60–88 μg/kg of estimated fetal dry weight every 12 hours to a maximum of three injections. A second transplacental agent was added when tachycardia persisted despite high therapeutic digoxin levels (1.5–2.0 ng%). During the early phase of this study, the second agent was verapamil (80–120 mg orally every 8 hours), quinidine (325–400 mg orally every 6 hours), or flecainide (100 mg every 8 hours). However, because of low efficacy in our experience and reports of adverse effects with these second-line agents, amiodarone (1800–2400 mg/day loading dose over 2–5 days, followed by 400–800 mg/day) was used subsequently. Sotalol (120–180 mg every 12 hours) was used unsuccessfully in one patient with atrial flutter.
Fetuses presenting with sustained tachycardia (groups 2 and 3) were treated with transplacental digoxin until delivery. If transplacental amiodarone was given, it was discontinued after the fetus had sustained sinus rhythm for 3 consecutive weeks.
Mothers of fetuses in groups 2 and 3 were hospitalized and monitored while loading doses of antiarrhythmic agents were administered. They were released when sustained sinus rhythm or rate control was established.
Monitoring treatment response was accomplished by following fetal heart rate (FHR) and rhythm, hepatic venous Doppler pattern, the degree of heart failure, fetal well-being, and amount of amniotic fluid (AF). These conditions were determined by daily echocardiogram and ultrasound until sinus rhythm was established for approximately 80% of the time, then biweekly until hydrops resolved, and monthly thereafter. Fetal heart rate auscultation was done daily by the mother using a hand-held Doppler monitor or by a home-monitoring nurse at frequent intervals between clinic visits. Rate control was considered an adequate endpoint for drug-resistant atrial flutter, but only sustained sinus rhythm (more than 80% of the time) was considered adequate for tachycardia with 1:1 conduction. In some cases, that required combination of second- and third-line drugs.
Maternal cardiac status was monitored by electrocardiography before and after each antiarrhythmic agent was introduced, periodically during follow-up, and by telemetry inpatient monitoring for more potent antiarrhythmic agents. Appropriate serum chemistries (thyroid, renal, and liver) and serum drug concentrations were obtained. Maternal calcium and magnesium levels were maintained in the normal range by oral or intravenous supplementation. Postnatal thyroid function tests were done at birth, 2 weeks, and monthly for 3 months on infants and mothers who received intrauterine amiodarone.
Because of small sample sizes, differences among the three groups in gestational age at presentation and delivery were analyzed using Kruskal-Wallis test. Post hoc comparisons were done with Tukey's test. Fetuses 28 and 29 were included in group 2 for analytic purposes, analogous to an intent-to-treat approach. An exact confidence interval (CI) was calculated for the mortality rate.
Table 2 shows patient characteristics. Fifteen fetuses had nonsustained tachycardia without heart failure; none progressed to sustained tachycardia, developed hydrops, or required in utero therapy (Table 3). The mean gestational age at presentation was significantly greater for this group than for patients in group 3 (P = .01).
Of the 29 fetuses with sustained tachycardia, 14 initially presented with mild-to-moderate congestive heart failure and hydrops (Table 4). Sustained cardio-version with transplacental therapy was successful in eight patients; three responded to digoxin alone and five to the additional transplacental antiarrhythmic agents quinidine (n = 1), verapamil (n = 3), and amiodarone (n = 1). Tachycardia persisted but at a lower rate after combination transplacental treatment in fetus 26, and hydrops did not develop. This fetus was delivered electively at 36 weeks. Time to conversion or progression in group 3 was 1 to 18 (mean 5.4) days.
Two fetuses with mild to moderate congestive heart failure initially did not convert to sustained sinus rhythm or rate control despite combination transplacental therapy. Fetuses 28 and 29 developed severe heart failure after 2 weeks of unsuccessful treatment, necessitating direct fetal treatment and reassignment to group 3. The remaining three fetuses (20, 25, and 27) presented at or near term and were delivered electively by cesarean at the parents' request without antenatal treatment. All three were cardioverted successfully within 12 hours of delivery.
In 17 fetuses (15 fetuses at initial presentation and fetuses 28 and 29), heart failure was severe, with or without an abnormal biophysical profile (excluding heart rate) (Table 5). Fetuses presenting with severe heart failure were significantly less mature than those in group 1 (P = .02). These fetuses were treated with direct intramuscular injections of digoxin (n = 16). Fetus 43 was given intramuscular procainamide in addition to intramuscular digoxin because of advanced hydrops, an abnormal biophysical profile, and severe ventricular dysfunction. We were not confident at this early point in our experience that only one agent given directly would cardiovert a compromised fetus receiving transplacental antiarrhythmic medications.
With direct plus transplacental therapy, 15 fetuses converted to sinus rhythm in 0.25–21 days (mean 4.3 days). In six fetuses, cardioversion occurred 3–24 hours after intramuscular therapy was initiated. Time to resolution of hydrops was 2–56 days. Two immature fetuses were delivered at 33 weeks after spontaneous rupture of membranes. Fetus 44 had partial sinus rhythm with resolving hydrops, and fetus 33 had sustained sinus rhythm with resolved hydrops. Neither required intubation or oxygen therapy.
There was no difference in mean gestational age at delivery among groups. In addition to the two fetuses delivered at 33 weeks after ruptured membranes, six were delivered before 36 weeks (five for obstetric reasons and one because of a restrictive patent foramen ovale and persistent ascites). No fetus required intubation after 24 hours; none had central nervous system or respiratory sequelae of prematurity.
Atrioventricular-reciprocating tachycardia with rates of 220–300 beats per minute was the sole mechanism in 30 fetuses. Ten fetuses had atrial flutter with predominantly 2:1 conduction, one had ventricular tachycardia, and three had more than one type of tachycardia (two atrial flutter plus atrioventricular-reciprocating tachycardia, one atrial flutter plus ventricular tachycardia).
One death occurred for a mortality rate of 2.2% (95% CI 0.06%, 12.0%). A severely hydropic 34-week-old fetus died 80 hours after successful transplacental and direct fetal digoxin therapy. Even with sinus rhythm, this fetus had poor heart rate variability with decreased fetal movement and tone. In contrast to the surviving fetuses that had normal hepatic venous flow pattern within hours of cardioversion, this fetus continued to have reversal of hepatic vein Doppler flow for several days despite sinus rhythm. Maternal viral titers and AF cultures were negative, but postmortem examination of the fetal heart showed lymphocytic infiltrates suggestive of myocarditis. A second major adverse reaction occurred during flecainide treatment, when a slower but incessant fetal tachycardia developed (160–180 beats per minute) and persisted for 3 weeks with progression of hydrops. This condition resolved after flecainide was discontinued.
Minor fetal and maternal adverse reactions resolved after medication reduction or discontinuation. One complication unrelated to treatment occurred in fetus 36, which was delivered at 36 weeks because of persistent ascites despite sustained cardioversion. Necrotizing enterocolitis developed at 1 week of age, but the infant recovered after a prolonged hospitalization and is currently doing well. One mother with normal thyroid function throughout treatment and for 6 months postpartum subsequently developed clinical hypothyroidism. It is not known whether such delayed onset of thyroid dysfunction was attributable to amiodarone therapy. Two fetuses had transient elevation in TSH postnatally without hypothyroidism.
The safe delivery of a full-term, nonhydropic infant with sinus rhythm is the desired outcome of a pregnancy complicated by fetal tachycardia. To achieve this outcome, our management strategy has the following goals: to limit exposure to potent antiarrhythmic agents to fetuses that have or are likely to develop heart failure and, in fetuses with heart failure, to distinguish those for which the risk of direct treatment outweighs the need from those that risk significant morbidity and mortality without direct treatment.
For the compromised fetus with severe heart failure and hydrops, the mortality rate is high (8%–27%).1–8,10 The alternative—delivery of an immature, hydropic infant—has equally unacceptable morbidity and mortality. The combination of direct intramuscular digoxin therapy and short-term transplacental treatment with amiodarone achieved cardioversion or rate control and averted preterm delivery. Because transplacental drug delivery is markedly impaired in the presence of hydrops, direct intramuscular therapy achieves therapeutic drug effect more rapidly, often resulting in short-term cardioversion.6,15 The use of intramuscular digoxin for treatment of supraventricular tachycardia in hydropic fetuses is well established.6,18,19 Other investigators have used intracordal digoxin,7 amiodarone,20 verapamil,7 adenosine (Blanch G, Walkinshaw SA, Walsch K. Cardioversion of fetal tachyarrhythmia with adenosine [letter]. Lancet 1994;44:1646), but there is an inherent risk of fetal death.21,22 Brief conversion of fetal tachycardia can be achieved after cordal drug administration, but recurrence of tachycardia because of atrial ectopy is frequent.4 We, therefore, recommend intramuscular administration of digoxin in conjunction with maternal digoxin because of its safety and superior efficacy in eliminating recurrences when used alone or in tandem with maternal amiodarone therapy.
Amiodarone is highly effective in achieving rapid and sustained conversion (Strasburger JF, Cuneo BF, Naheed Z, Gotteiner N, Duffy E, Deal S, et al. Cardiovascular disease in the young: Short-term amiodarone for refractory fetal tachycardia with hydrops fetalis [abstract]. Circulation 1995;92(Suppl 1)I-764.),23–26 but clinical and biochemical fetal hypothyroidism and possible growth restriction have been reported after long-term exposure during the second and third trimesters.27–29 These consequences have led some investigators to use other transplacental second-line agents, such as verapamil,1,7 quinidine,30 flecainide,31 or sotalol (Eric J. Meijboom, MD, PhD, University Medical Center, Utrecht, The Netherlands, personal communication). However, those agents are not without risk. Fetal death has been reported with flecainide12,14; in addition, concerns about proarrhythmias in other studies32 and in this series have led us to abandon flecainide in favor of amiodarone. Reports of fetal death with verapamil11 and the negative inotropic effects of calcium channel blocking agents in severe congestive heart failure have prompted us to restrict its use to fetuses with no or mild congestive heart failure. We know of no reports of fetal death after transplacental amiodarone therapy. Because these are potent antiarrhythmic agents, however, close supervision by an electrophysiologist is advised for both mother and fetus.
Approximately 75–85% of fetuses with sustained tachycardia and mild heart failure respond to transplacental antiarrhythmic therapy.6,8,10 It is difficult to predict which fetuses will progress to severe heart failure. We have found that it does not depend on tachycardia mechanism or rate but appears to be related to sustained duration of tachycardia and young gestational age.18 Fetal myocardial reserve, status of the placental vascular bed, and other factors might have contributory effects. Most fetuses that cardioverted did so within 24 hours of maternal drug effect, measured either by high serum concentrations (digoxin, procainamide, quinidine, flecainide) or maternal electrocardiographic effects (verapamil, amiodarone, sotalol). Therapeutic options when initial transplacental therapy fails include direct intramuscular digoxin therapy, alternate transplacental drug therapy, or combination transplacental drug therapy. However, if conversion is delayed beyond 1 week, heart failure is likely to progress and hydrops to worsen.
Our results support the findings that fetuses with intermittent tachycardia are at low risk for progression to sustained tachycardia and development of heart failure.8,10,16 However, heart failure has been reported in three of 16 fetuses and in one of nine fetuses with intermittent tachycardia.10,16 There might be a relationship between gestational age and duration of tachycardia. Similar to those in other reports, fetuses with intermittent tachycardia in our series were more mature than those with sustained tachycardia.16 Further investigation is necessary to determine whether the less mature fetus is at greater risk for arrhythmia progression. For this reason, we recommend vigilant fetal heart rate and ultrasound monitoring to allow for early intervention should tachycardia progress and heart failure develop.
Vigilant monitoring must be continued for the remainder of the pregnancy, even after sustained conversion. Phasic forward flow has been seen in the hepatic vein almost immediately after cardioversion even in severe congestive heart failure.33,34 The findings of significant reversed flow many hours after sustained sinus rhythm and persistently poor fetal movement are poor prognostic signs, as seen in the fetus that died in our series. Although this strategy resulted in low morbidity and mortality rates, the study was limited by a small sample size.
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