Persistent Fetal Sinus Bradycardia Associated with Maternal Anti-SSA/Ro and Anti-SSB/La Antibodies

MATERIALS AND METHODS

Between 2000 and 2010, 98 fetuses with maternal antibody-associated cardiac conduction disease were followed in the 5 participating centers. We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with raised maternal anti-SSA/Ro and anti-SSB/La antibodies. A postnatally diagnosed case of SB is also reported here.

RESULTS

Isolated SB was diagnosed in 3 fetuses (Cases 1–3, Table 1). Mild right ventricular dilatation and dysfunction were observed in Case 1. During followup with serial fetal echocardiography, SB with normal atrioventricular conduction persisted. All 3 fetuses exhibited normal intrauterine growth and development, resulting in term deliveries. Postnatal cardiac evaluation with electrocardiogram (ECG), echocardiogram, and 24-hour ambulatory ECG (Holter) confirmed the fetal findings. The right ventricular dilatation and dysfunction seen in Case 1 resolved after birth. The mean 24-hour heart rate was 100, 84, and 81 bpm in the 3 cases at ages 3 months, 1 day, and 4 days of life, respectively, with Case 2 exhibiting atrial and junctional escape rhythm. This patient developed symptoms of reduced exercise tolerance at the age of 5 years when his ECG showed a low heart rate of 50 bpm with mainly junctional escape rhythm (Figure 1A). There was no evidence of hepatic or hematologic involvement in any of the patients. However, cutaneous lesions of neonatal lupus were observed in Case 1 during infancy.

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Figure 1.

A. Case 2 at age 5 years. Lead II of 12-lead ECG (standard calibration) showing low heart rate of 50 bpm with mainly junctional escape rhythm in a child with persistent sinus bradycardia. B. Case 7 at age 9 yrs. Lead II of 12-lead ECG (half-standard calibration) showing first-degree heart block and sinus arrest.

SB with severe myocardial involvement in the form of CCAVB and/or EFE with ventricular dysfunction was present in 3 fetuses (Cases 4–6, Table 1). Cases 4 and 5 succumbed in utero at 30 and 25 weeks of gestation, respectively, not responding to maternal treatment. Fetal demise of Case 6 occurred within 3 days of referral to the fetal cardiologist. Postmortem examination revealed a structurally normal heart with hypertrabecularization of the ventricular walls in Case 4, and the histopathology showed extensive fibrosis and calcification of the sinus and atrioventricular nodes with involvement of the entire conduction system (Figure 2).

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Figure 2.

Case 4 at 30 weeks’ gestation. Postmortem histopathologic examination of the fetal heart showing the area of atrioventricular node (AVN) in overview (A) and in enlargement (B) and the sinoatrial node (SAN) in overview (C) and in enlargement (D). Arrows indicate inflammatory cells. Dense blue area in B shows calcification due to the severe inflammatory process. RA: right atrium; Ep: epicardial surface; VS: ventricular septum; MV: mitral valve; LVOT: left ventricular outflow tract; SCV: superior caval vein. *Wall of the SAN artery.

A 7-year-old girl (Case 7, Table 1) was referred with irregular heartbeat detected during routine school examination. The ECG showed SB with a rate of 65 bpm, first-degree heart block (PR interval 382 ms), QRS duration 94 ms, and QTc 380 ms. Holter ECG revealed an irregular sinus rhythm with first-degree and intermittent second-degree heart block (Mobitz type 1). During followup, progressive sinus arrest and atrial and junctional escape rhythm developed by the age of 9 years (Figure 1B). A permanent pacemaker was implanted at age 10 years for progressive sinus node dysfunction.

DISCUSSION

Immune-mediated destruction of the fetal cardiac conduction system by maternal autoantibodies is well recognized. However, our study showed that SB is a definite and persistent manifestation of the disease, and may either be isolated or part of a more widespread conduction abnormality. A functional basis for SB associated with CCAVB in maternal antibody-induced fetal conduction defects was provided by Hu, et al³. An ionic mechanism of the negative chronotropic action of maternal autoantibodies was proposed by demonstration of a reduction in L-type and T-type Ca2+ currents in sinus nodal cells. Further biochemical and functional evidence for the autoimmune-associated SB was shown in humans by way of the “calcium channel hypothesis,” where the neuroendocrine α1D Ca channel, which is a component of the L-type Ca2+ channel, is also inhibited by positive IgG⁴. Histopathological findings in our study are consistent with reports on involvement of the sinus node in the inflammatory response^5,6. Beaufort-Krol, et al specifically studied the sinus node function in children with CCAVB and found it to be normal⁷. Menon, et al studied the chronotropic competence of the sinus node in cases of CCAVB and reported it was incompetent in 11% of the cases⁸.

Maternal autoantibody-associated fetal cardiac disease is a spectrum of manifestations including SB^9,10,11. In our centers, 98 fetuses with antibody-associated atrioventricular conduction abnormality were followed between 2000 and 2010. Isolated SB persisting after birth was present in 3% of cases and they all had a good prognosis. Regular fetal ECG monitoring would largely suffice in cases with isolated SB. The presence of CCAVB and/or EFE changes the management strategy and carries a relatively poor prognosis. Transient SB in the newborn has been reported^12,13. However, the 3 cases we describe had SB persisting at the ages of 15 months, 5 years, and 2 months, respectively. Postnatal progression of the disease is possible and hence close monitoring is warranted to detect clinical and ECG signs of worsening conduction defects. SB can also present in a previously healthy child, as reported here. This child’s mother was asymptomatic and had elevated anti-SSA/Ro and anti-SSB/La antibodies at the time of diagnosis. There is evidence supporting this persistence of antibody positivity in mothers well after initial detection during pregnancy¹⁴. The late presentation in the child may be explained by subclinical disease in prenatal and neonatal periods, with progression later.

The differential diagnoses of persistent SB in the fetus include congenital cardiac anomalies and congenital long QT syndrome. Thus evaluation should include fetal echocardiography and ECG. An ECG at birth should be a mandatory part of evaluation of neonates exposed to maternal anti-SSA/Ro and anti-SSB/La antibodies. As normal fetal echocardiography in fetuses exposed to maternal autoantibodies and normal ECG (and echocardiography) at birth has never been followed by a cardiac abnormality, parents could be reassured based on these findings. Qualitative antibody assays showed significantly elevated anti-SSA/Ro antibody levels in all our cases, consistent with previous findings¹⁵.

Fetal sinus bradycardia associated with maternal autoantibodies may be permanent, but carries a good prognosis in the absence of widespread cardiac involvement.