Therapeutic Trial of Sympathomimetics in Three Cases of Complete Heart Block in the Fetus
Background A total of 36 fetuses with isolated congenital complete heart block and structurally normal hearts have been seen in the department of fetal echocardiography since 1980. Although the prognosis is good in the majority of cases, those who develop intrauterine cardiac failure have a high mortality. The aim of this study was to investigate the contribution to management of sympathomimetic therapy by comparing two possible agents administered to the mothers.
Methods and Results The effect of two sympathomimetic agents, isoprenaline and salbutamol, was compared in three patients with isolated complete heart block. Fetal heart rate and indexes of cardiac function were monitored during therapy. Maternal cardiovascular status was also regularly assessed. Dosage of isoprenaline increased from 1 to 12 μg/min, and salbutamol increased from 4 to 64 μg/min during the trial. No significant change was detected with isoprenaline therapy, but all fetuses showed an increase in heart rate and improvement in ventricular function with salbutamol. Salbutamol was maintained until delivery in one case with evidence of cardiac failure, with resolution of fetal hydrops. All three delivered in good condition close to term. Two of three required pacing in the neonatal period.
Conclusions We conclude that salbutamol can be effective in the treatment of fetal complete heart block and should be considered in patients with this condition where there is evidence of deteriorating cardiac function.
Echocardiography has become established as the method for the detection, analysis, and monitoring of fetal arrhythmias.1 The association between fetal isolated complete heart block and maternal connective tissue disease was described in 1966, and heart block has since been causally related to the presence of circulating maternal anti-Ro antibodies, even in the absence of clinical disease.2 In this condition, histology of the conducting tissue of the affected offspring shows fibrous replacement of the atrioventricular node.
Our previous published experience included 16 fetuses with isolated complete heart block.3 In this series the outcome of those pregnancies with isolated complete heart block was favorable (19%), compared with a high mortality (85%) in the 21 cases with structural malformation. It has since become evident that intrauterine cardiac failure and subsequent death can also occur in isolated complete heart block, with 12 deaths from a total of 33 continuing pregnancies, not including the 3 patients studied. These observations have been confirmed4 and have generated therapeutic interventions during pregnancy, including prophylactic plasmapheresis with or without prenatal steroid therapy,5 premature delivery,6 or even direct fetal pacing.7
Sympathomimetic agents have been noted to cause fetal tachycardia as a side effect during use as tocolytic agents.8 These drugs have been used previously to increase the heart rate in cases of fetal complete heart block without significant clinical improvement.6 7 The aim of this study was to investigate the use of sympathomimetic drugs in the management of isolated complete heart block in utero.
Since 1980, congenital complete heart block without structural abnormality has been detected in 36 fetuses. All but 2 were referred after detection of fetal bradycardia. The fetal cardiac structure was assessed by using an Advanced Technical Laboratories Mark 4 or a Hewlett Packard 77020A ultrasound scanner. Cross-sectional, M-mode studies of the left ventricle and Doppler studies of the outflow velocities in the ascending aorta and pulmonary artery were performed to establish the diagnosis and evaluate cardiac function. Evidence of intrauterine cardiac failure, such as skin edema, ascites, and pericardial or pleural effusion, was sought and noted if present.
Trial of Sympathomimetics
Three mothers had a therapeutic trial of sympathomimetics. All were anti-Ro antibody positive with titers of more than 1 in 64, and 1 of the 3 had systemic lupus erythematosus. Prior to treatment, all were assessed clinically by 12-lead ECG and by echocardiography. All patients and families gave informed verbal consent to the procedure. There were no signs of placental insufficiency in any of the fetuses recruited for the trial. Maternal electrolyte status and glucose tolerance were regularly monitored.
Initial treatment was with 10 mg isoprenaline diluted in 1 L 5% dextrose. The intravenous infusion began at 1 μg/min and increased stepwise every 20 minutes until the patients were symptomatic, the maternal heart rate exceeded 160 beats per minute (bpm), or the dose had reached the maximum of 12 μg/min. The patient returned to the ward overnight, and on the following day the salbutamol regime was begun. An infusion of 80 mg salbutamol in 1 L dextrose 4%, saline 0.18% was begun at 4 μg/min (3 mL/h) and increased by 4 μg at a time to a total of 64 μg/min. Maternal blood pressure and heart rate and rhythm were monitored continuously during both infusions. The fetal heart rate was measured every 15 minutes, with any change noted on sonocardiographic auscultation confirmed by ultrasound examination. Peak ascending aortic and pulmonary Doppler velocities and left ventricular M-mode recordings were performed before and concurrent with the maximal dosage of each drug.
Results obtained were subjected to χ2 analysis, and a value of P<.05 was taken as significant.
This patient had systemic lupus erythematosus diagnosed after two previous stillbirths, at 28 and 35 weeks’ gestation. Fetal bradycardia was detected at 22 weeks’ gestation in her fourth pregnancy, and she was referred to our center having had maintenance steroid therapy before conception; therapy was continued. Ultrasound examination showed normal cardiac connections but with cardiomegaly and a ventricular rate of 60 bpm. The ventricular walls were echogenic and function was reduced. By 26 weeks’ gestation, cardiomegaly had increased and hydrops had developed in the form of abdominal wall edema and a pericardial effusion. Fetal movements had decreased. On review at 29 weeks’ gestation, there was a further deterioration in cardiac functional parameters. The mother was therefore admitted for a trial of intravenous inotropes. She had no clinical or ECG evidence of cardiovascular involvement from her connective tissue disease. An echocardiogram demonstrated a small unsuspected pericardial effusion with normal left ventricular function.
There was no significant response to the isoprenaline infusion protocol, but a significant improvement in fetal heart rate and cardiac function was evident on salbutamol (Table⇓). The intravenous regime was changed to an oral slow-release preparation, ultimately 16 mg TDS, which was continued until delivery. There was resolution of the hydrops after 4 weeks of salbutamol therapy, which was well tolerated with only mild maternal glucose intolerance responsive to diet.
A female infant, weighing 2.2 kg, was delivered by cesarean section (in view of previous section) at 35 weeks’ gestation in good condition with no evidence of cardiac failure. A postnatal echocardiogram confirmed normal cardiac connections with complete heart block. On postnatal cardiac monitoring, the heart rate did not drop below 50 bpm, and the infant showed no signs of congestive cardiac failure. She was discharged home at 10 days and has remained healthy and has not required a pacemaker at follow-up to date.
This patient was referred with isolated complete heart block in a previous pregnancy resulting in perinatal death despite steroid therapy, delivery at 33 weeks, and immediate pacing. In her second pregnancy, the fetus was in sinus rhythm at 18 weeks’ gestation. By 24 weeks the fetus had developed complete heart block. The mother was admitted for a trial of inotropes at 26 weeks to assess the effect on the fetal heart rate. The fetus did not respond to isoprenaline but showed a good response to intravenous salbutamol (see the Table⇑). The mother was discharged on no treatment. On close monitoring throughout the pregnancy, the fetal heart rate remained between 50 and 56 bpm, functional measurements were unchanged, and hydrops did not develop. Delivery of a healthy male weighing 3.6 kg was by elective cesarean section, in view of previous section, at 38 weeks. An endocardial pacemaker was implanted in view of a long corrected QT interval and a minimal/maximal heart rate of 37/42 bpm on postnatal Holter recording.
This primigravida was referred for assessment of fetal bradycardia noted at routine ultrasound. Isolated complete heart block was found with a ventricular rate of 58 bpm at 24 weeks. There was mild cardiomegaly but no evidence of cardiac compromise. The patient was admitted at 26 weeks’ gestation for a trial of inotropes. The fetus showed a good heart rate response to salbutamol (Table⇑). Regular assessment throughout the rest of the pregnancy showed that the heart rate fell to 43 bpm at the time of induction at 38 weeks but with no evidence of increasing cardiomegaly, fall in arterial Doppler velocities, or fetal hydrops. A normal delivery resulted in a female infant in good condition weighing 2.7 kg. Observation for the first 4 days of postnatal life revealed a good cardiac output despite a ventricular rate of 43 bpm. However, left ventricular function deteriorated, and an isoprenaline infusion was used in the first instance to increase the cardiac output and heart rate, which reached 55 bpm. A permanent endocardial pacemaker was inserted at 6 days of age, and the infant was stable at discharge at 2 weeks.
Isolated complete congenital heart block in the fetus is well described and increasingly recognized. Association with maternal anti-Ro antibody is also well documented.2 The risk of complete heart block is 5% for mothers with anti-Ro antibody but increases to around 25% in those with a previously affected child.9 In one of our patients with known anti-Ro antibodies, the fetus was in sinus rhythm at initial scans at 12 and 18 weeks but developed heart block by rescan at 22 weeks’ gestation. This indicates the need for sequential examination in mothers known to carry the antibody.7
Since our previous publication on this condition, it has become evident that this condition can result in intrauterine cardiac failure leading to fetal or neonatal loss. In our total series of 36 cases, 9 losses occurred of 34 continuing pregnancies. Eight of these 9 showed evidence of cardiac failure. Hydrops affected 4 of 26 cases in a combined report from 3 centers, with none surviving.4 Therapeutic interventions that have been advocated include prophylactic plasmapheresis, steroid therapy,5 premature delivery, and fetal pacing.7 Our own experience of delivering hydropic fetuses prematurely for immediate pacing has not been as favorable as that of other authors.6 Maternal administration of sympathomimetic therapy has also been advocated.6 7 Schmidt et al4 reported an increase in fetal heart rate of 15% to 50% in 4 fetuses treated with terbutaline, ritodrine, or isoprenaline, but only 1 survived to delivery. In view of the lack of success so far, transabdominal intrauterine pacing was suggested6 and attempted7 and was technically successful for some hours before fetal demise. Potential problems with this treatment include the premature labor or infection secondary to the implantation of a foreign body, or dislodgement of or limb damage from the pacing wire.
None of our three fetuses responded to isoprenaline infusion. However, the third baby showed a normal response to isoprenaline postnatally, indicating poor placental transfer rather than end-organ insensitivity as the basis of failure of response.11 When we used a higher dose than has been used previously, an increase in both heart rate and cardiac function indexes was achieved with salbutamol. In one fetus, therapy was associated with resolution of fetal hydrops, a finding not previously demonstrated. In the other two, a response to salbutamol was proved, and maintenance treatment could have been instituted had fetal compromise occurred.
The regimen used for the salbutamol infusion was based on that used in preterm labor.8 The only contraindication to this high-dose salbutamol therapy is placental insufficiency.10 The pharmacokinetics of infused salbutamol are not well documented in pregnancy, but it appears that the elimination half-life is in the region of 2 to 6 hours with a mean of 3.86 hours in most studies.10 11 It may be that the stepwise increment of infusion rate, based on obstetric usage, could be slower to ascertain more clearly the minimal levels of the drug required for this purpose. None of the mothers were symptomatic during treatment, including the mother maintained on long-term salbutamol therapy although she developed a mild degree of glucose intolerance. After 4 weeks of therapy, she had postprandial glucose levels of 10 mmol/L, but fructosamine levels remained within the normal range and response to diet was satisfactory. This side effect may have been exacerbated by concomitant steroid therapy for systemic lupus erythematosus.
Our study demonstrates the significant effect of a β-agonist on heart rate and function in complete heart block in the fetus. Although in only one case was it clinically necessary to continue therapy, placental transfer and response were demonstrated in the other two fetuses. This drug, therefore, would have been a therapeutic option had either fetus shown evidence of decompensation. In the case with hydrops, resolution and safe delivery of the fetus close to term was an outcome that would have been highly unlikely without the intervention. Thus, we would recommend sequential examination of known anti-Ro–positive mothers, especially if there has been a previous child with complete heart block; sequential examination of the rate, cardiothoracic ratio, shortening fraction of the left ventricle, and arterial Doppler velocities, perhaps monthly; regular search for fetal fluid collections and a trial of sympathomimetic therapy in cases showing deterioration in more than one measured parameter. The dose should be higher than that used for treating premature labor, and treatment should be considered before intrauterine pacing is attempted or premature delivery considered.
We would like to acknowledge the assistance of Susanna Gilmour-White of the Drug Information Centre at Guys Hospital and Dr P.T. McCarthy of the Guys Poison’s Unit.
- Received July 6, 1995.
- Revision received September 21, 1995.
- Accepted September 24, 1995.
- Copyright © 1995 by American Heart Association
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