Fetal bradycardia

Fetal Bradycardia

1. What every clinician should know

Clinical features

Fetal arrhythmias affect over 2% of pregnancies and include irregularities of the cardiac rhythm, rate or a combination of both. Fetal bradycardia is defined as a sustained fetal heart rate less than 110 beats per minute. Once fetal bradycardia is noted, a quick ultrasound examination of the remainder of the fetus should be performed to confirm normal fetal movement, tone, and amniotic fluid. This will help assess for fetuses in distress requiring urgent delivery.

There are various types of fetal bradycardia, including sinus bradycardia, blocked atrial ectopic beats and atrioventricular (AV) heart block. The diagnosis of the specific bradycardia depends on particular echocardiogram findings and AV conduction patterns.

Sinus bradycardia: atria and ventricles beat at the same rate with electrical impulses originating in the sinus node.

• Transient sinus bradycardia refers to brief episodes of bradycardia of less than 1-2 minutes duration that are usually physiologic and due to increased vagal stimulation. This phenomenon is usually seen during the second trimester when the sympathetic nervous system is immature and unable to sufficiently respond to the vagal response of the parasympathetic system.

• New-onset sinus bradycardia can be a sign of fetal distress and/or severe hypoxia and may be an indication for urgent delivery. This finding may be associated with placental abruption, uterine rupture, prolapsed umbilical cord and fetal hemorrhage. Depending on the clinical situation, delivery may be indicated.

• Sinus node dysfunction is often due to an abnormally positioned sinus node that functions at a slower rate, usually varying between 80-120 beats per minute (bpm). Structural heart diseases that disturb the location of the sinus node include heterotaxy syndrome, interrupted inferior vena cava, and single ventricle heart physiology.

• Long QT syndrome (LQTS) includes a diverse group of disorders of myocardial repolarization that can lead to life-threatening polymorphic ventricular tachycardia (torsade de pointes). On electrocardiogram (ECG), it is characterized by a prolonged QT interval. When sustained fetal bradycardia is identified and congenital heart block is ruled out, the diagnosis of LQTS should be considered and can usually only be ruled out by a postnatal ECG. Multiple mutations have been identified in congenital LQTS. Given the genetic predisposition, a detailed family history is vital in evaluating fetal bradycardia. Two clinical phenotypes of LQTS have been described:

  Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder that is associated with profound sensorineural hearing loss. Mutations in the KCNE1 and KCNQ1 genes interfere with the normal structure and function of potassium channels found within the cardiac muscle and inner ear.

  Romano-Ward syndrome is an autosomal dominant form of long QT syndrome without extracardiac abnormalities. Mutations in the KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes are responsible for causing Romano-Ward syndrome. Proteins derived from these genes are vital in providing normally functioning sodium and ion channels in cardiac tissue. The ANK2 gene, another gene thought to play a role in this syndrome, provides instructions for proteins that are inserted within cell membranes. Disruptions in proteins derived from the above genes interfere with the normal rhythm of the heart.

Blocked premature atrial contractions: arrhythmias caused by ectopic beats arising prematurely from a site other than the sinus node. The non-conducted atrial ectopic beats result in “missed” beats manifesting as fetal bradycardia. The diagnosis is challenging if the ectopic beats occur with regularity and give rise to a regularly irregular rhythm. Atrial bigeminy results from ectopic beats that alternate with sinus beats and the lack of conduction of the ectopic beats are physiologic and not indicative of conduction abnormalities.

It is essential to differentiate blocked premature beats from AV block because of prognostic and therapeutic implications. The time intervals between consecutive atrial impulses remain relatively constant in AV block versus shortened atrial impulses on every second or third beat in bigeminy or trigeminy.

Congenital heart block: refers to delay or interruption in electric conduction within the AV node, bundle of His or bundle branches. Congenital AV block occurs in approximately 1 in 15,000 live births, 40% of which occur in the setting of underlying structural heart disease (e.g. heterotaxy, corrected transposition of the great arteries). The remaining 60% are caused by immune-mediated connective tissue disorders due to the presence of anti-Ro (SSA) or anti-La (SSB) antibodies. 1-2% of pregnancies with anti-Ro (SSA) or anti-La (SSB) antibodies will be affected by heart block among women who have never had an affected child, with a recurrence risk of about 15% for those who have had a prior affected child.

• First degree block refers to a prolonged AV interval with a 1:1 conduction pattern between the atria and ventricles. Although the resulting fetal heart rate is normal, first degree block may be a precursor for 2nd and 3rd degree block.

• Second degree block allows some but not all atrial impulses to penetrate the AV node and bundle of His. The atrial rate remains regular.

  Mobitz type I involves progressive lengthening of the AV interval followed by a blocked impulse resulting in an irregular ventricular rate. This is usually due to a conduction abnormality of the AV node.

  Mobitz type II refers to a normal AV interval with intermittently nonconducted impulses resulting in a slow irregular ventricular rate. This signifies disease within the bundle of His and may progress to third degree heart block.

• Third degree block occurs when there is complete interruption of the AV conduction and the atria and ventricles beat independently. This is usually due to dysfunction of the AV node and/or bundle of His. Ventricular contractions are dependent on the underlying escape rhythm intrinsic to the ventricles. The resulting ventricular rhythm is usually slower with rates between 40-90 bpm. Third degree block, commonly known as complete heart block, may occur in association with structural heart diseases such as heterotaxy and AV discordance.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

The diagnosis of fetal bradycardia is established by fetal echocardiogram. Evaluation of the conduction pattern is required to diagnose the particular type of fetal bradycardia. It is also important to obtain certain laboratory studies when working up congenital AV block that may be due to immune-mediated maternal connective tissue diseases.

Imaging studies

• Fetal echocardiogram is performed to assess the structure of the fetal heart and diagnose any structural anomalies.

• M-mode demonstrates cardiac and valvular wall motion and the relationship of atrial to ventricular contractions.

• Pulsed wave Doppler velocimetry also helps to characterize the relative timing of cardiac events and is used to measure the P-R interval. The mechanical P-R interval is very similar to the P-R interval on ECG but is measured using Doppler timing. The ability of that, or any test, to predict fetuses at risk for heart block in pregnancies with anti-Ro (SSA) and anti-La (SSB) antibodies remains unproven. The normal fetal mechanical PR interval is 0.12 +/- 0.02 seconds when measured in the area of the mitral/aortic valves. (Figure 1) We offer women with positive antibodies weekly ultrasound testing for the PR interval from 16-24 weeks and biweekly testing from 24-34 weeks. Tricuspid regurgitation, echogenicity of the atria and decreased cardiac function may be other potential predictors of heart block.

Figure 1.

Conduction patterns

• Sinus bradycardia: one-to-one AV conduction with a normal AV interval and a slow atrial rate.

• Blocked premature contractions/atrial bigeminy or trigeminy: the time interval between consecutive atrial impulses is not constant and the atrial rate is higher than the ventricular rate. The atrial impulse is shortened on every second beat in bigeminy and on every third beat in trigeminy.

• Congenital AV block

  First degree: one-to-one AV conduction with a prolonged AV interval and a normal heart rate.

  Second degree:

  Mobitz type I: progressive lengthening of the AV interval with a subsequently blocked impulse resulting in an irregular heart rate.

  Mobitz type II: normal AV interval with intermittently blocked impulses. If there is a 2:1 conduction pattern, the heart rate will be slow and regular. If the conduction pattern is not fixed (e.g. 2:1 or 3:1 pattern), the heart rate may be irregular.

  Third degree: the atria and ventricles beat independently due to complete AV conduction interruption. Contractions of the ventricles are usually a result of an underlying escape rhythm resulting in a slow, regular ventricular rate.

Laboratory studies

• anti-Ro (SSA) antibody testing.

• anti-La (SSB) antibody testing.

The above laboratory tests are important in diagnosing congenital AV block due to maternal connective tissue disorders, such as systemic lupus erythematosus and Sjogren’s syndrome. Over 90% of patients with fetuses with immune-mediated congenital heart block will test positive for these antibodies. Only a small minority of these women will actually carry a preexisting diagnosis of connective tissue disease. In rare cases of congenital heart block, maternal antibodies are not identified but may be found years later, and in the remainder of cases the cause is unknown and possibly familial.

Differential diagnosis

• Sinus bradycardia due to vagal stimulation.

• Sinus bradycardia due to fetal distress and/or hypoxia.

• Sinus bradycardia due to sinus node dysfunction.

• Sinus bradycardia due to long QT syndrome.

• Blocked premature atrial contractions.

• Atrial bigeminy.

• Atrial trigeminy.

• Congenital heart block (first, second or third degree) due to structural heart disease.

• Congenital heart block (first, second or third degree) due to maternal autoimmune antibodies anti-Ro (SSA) and anti-La (SSB).

3. Management

Antepartum

The antepartum management must be targeted towards the particular type of fetal bradycardia.

• Sinus bradycardia: no fetal therapy is necessary unless the bradycardia is a result of fetal distress or hypoxia and urgent delivery is clinically indicated. Fetal sinus bradycardia that persists after birth should be comprehensively evaluated by pediatric cardiology. Infants with sick sinus syndrome may require pacemakers. Beta-blockers, pacemakers and/or defibrillators are possible treatments for children with long QT syndrome.

• Blocked atrial premature contractions: no fetal therapy is necessary as these premature atrial contractions are not pathologic.

• Congenital heart block: in the setting of structural heart disease, heart block cannot be treated in utero. Immune-mediated congenital heart block may improve with certain therapies. Multiple studies have evaluated various therapeutic strategies, including steroids, intravenous immunoglobulin, and more recently hydroxychloroquine. It is well established, though, that third degree block is irreversible and therefore treatment is primarily expectant.

• Fluorinated steroids (dexamethasone 4mg/day). We offer this to women with prolonged mechanical PR intervals in an attempt to prevent progression to complete heart block, although the data supporting this are not definitive. First and second AV block may have brief windows of reversibility. Steroids are thought to play a role in diminishing the autoimmune response and cardiac inflammatory injury and perhaps preventing progression of first and second degree AV block.

• Intravenous immunoglobulin (IVIG) (400 mg/kg). IVIG has also been studied as a potential prophylactic therapy but current data does not demonstrate its efficacy in preventing recurrent congenital heart block. Additionally, it is extremely expensive and requires prolonged weekly infusions.

• Beta-sympathomimetic drugs. These drugs have been used to increase the fetal heart rate in cases of complete heart block. Although acute therapy results in short-term increases in the fetal heart rate, the effect is brief due to fetal tolerance which develops over time. Therefore, increasing doses, which are unlikely to be tolerated by the mother, are required to achieve a long-lasting response and are not standard of care. Additionally, beta-sympathomimetics do not reverse AV block, which is at the root of the cardiac dysfunction.

• Hydroxychloroquine. A recent case-control study suggests that in mothers with lupus and anti-Ro (SSA) or anti-La (SSB) antibodies hydroxychloroquine may reduce the risk of fetal cardiac injury of neonatal lupus. Larger prospective studies are being performed to confirm these findings.

• Fetal pacing has previously been described in isolated case reports, although outcomes were poor. Work is in progress to develop devices and leads to improve outcomes with fetal pacing.

Intrapartum

If workup reveals that the fetal bradycardia is a sinus bradycardia due to fetal distress, urgent delivery may be indicated.

Postpartum

Any medical therapy that had been initiated to target the fetus should be discontinued in the postpartum period. Women with underlying connective tissue diseases should follow-up with their primary care physicians or rheumatologists postpartum for the remainder of their medical care.

4. Complications

Complications of fetal bradycardia

• Hydrops fetalis: In the setting of fetal hydrops, prognosis is extremely poor and, in the presence of AV block, it is almost universally fatal. A course of fluorinated steroids may be administered in an attempt to improve the underlying condition (myocarditis). If fetal hydrops occurs early in the pregnancy, termination of pregnancy may be considered.

• Low ventricular rate: A low ventricular rate (less than 55 bpm) along with a nonreactive fetal heart rate are associated with an increased risk of hydrops fetalis, neonatal cardiac failure and need for neonatal pacing.

Complications due to management of fetal bradycardia

Long-term steroid use during pregnancy may increase the risk of gestational diabetes, while beta-sympathomimetic drugs may cause maternal tachycardia.

5. Prognosis and outcome

Maternal and fetal/neonatal outcomes

The prognosis depends on the underlying etiology of the fetal bradycardia, the clinical situation, gestational age and associated structural heart defects. Specifically, the prognosis of heart block is extremely poor when there are major structural cardiac anomalies and/or fetal hydrops. These conditions are associated with an increased risk of intrauterine fetal demise and neonatal demise. Additional predictors of adverse neonatal outcomes include low ventricular rates, cardiac dilatation, tricuspid regurgitation and pericardial effusions. The prognosis for immune-mediated heart block without hydrops is better but children are at risk of requiring pacemakers after birth or later in life.

Impact on maternal long-term health

A patient diagnosed with fetal bradycardia in the setting of a connective tissue disorder is at risk for the long-term complications of these autoimmune disorders, including chronic renal insufficiency, cardiovascular diseases, and neurological problems.

6. What is the evidence for specific management and treatment recommendations

Abuhamad, A, Chaoui, R. “A Practical Guide to Fetal Echocardiography: Normal and Abnormal Hearts”. Lippincott Williams and Wilkins. 2010. (This textbook reviews the practical aspects of fetal echocardiography as well as the interpretation of findings in normal and abnormal hearts. The final chapter on Fetal Arrhythmias includes a section on diagnosis and management of fetal bradyarrhythmias.)

Askanase, AD, Friedman, DM, Copel, J. “Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies”. Lupus.. vol. 11. 2002. pp. 145-51. (The authors examined records from children enrolled in the Research Registry for Neonatal Lupus and described the various conduction abnormalities in infants born to mothers with anti-Ro (SSA) and/or anti-La (SSB) antibodies. They described findings on fetal echocardiogram and postnatal electrocardiogram. They noted that resolution of incomplete AV block was variable and that progression of incomplete block could occur postnatally.)

Brucato, A, Frassi, M, Franceschini, F. “Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women”. Arthritis rheumatism. vol. 44. 2001. pp. 1832-35. (Brucato et al performed a prospective study of 100 women with anti-Ro (SSA) antibodies and connective tissue disease to determine the prevalence of congenital complete heart block. They calculated a prevalence of 2%.)

Buyon, JP, Hiebert, R, Copel, J. “Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry”. J Am Coll Cardiol.. vol. 31. 1998. pp. 1658-1666. (Using information from the National Neonatal Lupus Registry, this study found that immune-mediated congenital heart block was most often diagnosed in the late second trimester and was associated with substantial morbidity and mortality in the neonatal period. The recurrence rate of congenital heart block was 2-3 times higher than in those women with previously unaffected children. The authors support close monitoring with fetal echocardiography in subsequent pregnancies of patients with prior pregnancies complicated by congenital heart block.)

Friedman, D, Kim, M, Copel, J. “Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study”. Circulation. vol. 117. 2008. pp. 485-93. (The authors performed a prospective study evaluating 98 pregnancies in 95 women with anti-Ro (SSA) antibodies in an attempt to identify early markers and effective therapy for third-degree congenital heart block. They found that prolongation of the PR interval did not precede more advanced block and that third-degree block and cardiomyopathy could occur within a week of a normal echocardiogram and prior to 24 weeks gestation. Therefore, the authors concluded that it was appropriate to perform intense fetal echocardiographic monitoring between 16 and 24 weeks.)

Friedman, D, Kim, M, Copel, J, Llanos, C, Davis, C. “Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study”. Am J Cardiol. vol. 103. 2009. pp. 1102-6. (The study was a multicenter, open-label, nonrandomized trial that evaluated the efficacy of dexamethasone in 30 pregnancies involving fetuses with congenital heart block in the setting of anti-Ro (SSA) exposure. The study concluded that complete congenital heart block was irreversible and that the progression of second to third degree heart block occurred despite the use of dexamethasone. The authors considered the potential benefit of steroids in reversing first or second degree block in rare cases but also noted the potential adverse effects of prolonged steroid use.)

Friedman, D, Llanos, C, Izmirly, P. “Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial”. Arthritis rheumatism. vol. 62. 2010. pp. 1138-46. (The study involved a multicenter, prospective, open-label clinical trial to determine the efficacy of intravenous immunoglobulin (IVIG) as preventive therapy for congenital heart block. Twenty pregnancies were included in the trial. The authors found that IVIG at low doses did not prevent the recurrence of congenital heart block or reduce maternal antibody titers.)

Izmirly, P, Kim, M, Llanos, C. “Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine”. Ann Rheum Dis. vol. 69. 2010. pp. 1827-30. (This case-control study evaluated the risk of cardiac neonatal lupus in fetuses in women with systemic lupus erythematosus exposed to hydroxychloroquine. Using multivariate analysis, the group found that the risk of congenital heart block was lower in fetuses in mothers with lupus and hydroxychloroquine exposure [OR 0.46, 95% CI 0.18-1.18; p=0.10].)

Saleeb, S, Copel, J, Friedman, D, Buyon, JP. “Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus”. Arthritis rheumatism.. vol. 42. 1999. pp. 2335-45. (The group of authors performed a retrospective review of the Neonatal Lupus Research Registry to compare outcomes with fluorinated steroid treatment versus untreated congenital heart block with respect to conduction abnormalities, pleural effusions, ascites, fetal hydrops and the requirement of a pacemaker. Reviewing 50 pregnancies, the data suggested that fluorinated steroids could improve outcomes in fetuses with incomplete heart block or hydrops.)

Zhao, H, Cuneo, B, Strasburger, J, Huhta, J, Gotteiner, N. “Electrophysiological characteristics of fetal atrioventricular block”. J Am Coll Cardiol. vol. 51. 2008. pp. 77-84. (The authors described the complex fetal electrophysiological characteristics of congenital heart block by evaluating 28 fetuses with fetal magnetocardiography. Fetuses with second degree or isolated third degree block did better than those fetuses with structural cardiac anomalies and third degree block.)

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