Postnatal Progression of Autoimmune-Associated CHB

Age 2 wk -NSR

20 wk gestation -2:1 HB

•Atrial beat

•Ventricular beat

Dexamethasone 4mg

Age 4 yr -PR interval prolonged for age

3°block 2° 1°block 2°

Age 5 yr -Variable degrees of high-grade block

Fig. 24.2 Heart involvement in NLS. In the upper left panel is an in utero echocardiogram demonstrating second-degree block, 2:1. In red is the atrial beat and in blue the ventricular beat. The mother was treated with dexamethasone at 4 mg. At 2 weeks after birth the EKG showed normal sinus rhythm. However, over time the block progressed and at the age of 4 years a prolonged PR interval was noticed (middle panel). By the age of 5 years, the Holter showed variable degrees of high-grade block (lower panel) (This figure was kindly provided by Dr. Jill Buyon)

NLS included isolated endomyocardial elastosis with subsequent mitral and tricuspid avulsion, dysfunction of the sinus or sino-atrial nodes, conduction disturbances below the His bundle, and atrial flutter [32].

24.3.2Maternal and Fetal Outcomes in NLS

Several studies assessed the clinical picture and long-term outcome of mothers who have given birth to children with NLS and/or CHB (Table 24.2). At least 50% of mothers whose offspring develop NLS or CHB are themselves entirely asymptomatic and have no idea that they possess antibodies to the Ro/SSA or La/SSB antigens. The true figure may be 80% [33–35]. The remaining 30–50% are known to have SLE, SS, or an undifferentiated autoimmune syndrome. Approximately half of women who are asymptomatic at the time of giving birth to a child with NLS will

CHB. One study employed gated, pulsed Doppler ultrasound to the mechanical PR interval in 98 pregnancies in 95 anti-Ro/SSA-positive mothers. The study detected three newborns with complete CHB, of whom none had a preceding prolonged PR interval [31].

In another study of 24 women with anti-Ro/SSA antibodies, the delay between atrial and ventricular depolarization was estimated by two Doppler echocardiographic methods [38]. Eight fetus in that study were found to have first-degree AV block, but only one progressed to complete CHB. Another fetus converted from second-degree heart block to first-degree heart block after treatment with betamethasone. In the remaining six babies, spontaneous normalization of the heart rhythm occurred.

Finally, fetal kinetocardiogram aiming to detect first-degree AV block was performed in 70 fetuses of 56 mothers with anti-Ro/SSA antibodies. Six fetuses had first-degree AV block, but all six recovered normal cardiac conduction features following treatment with dexamethasone [39].

In summary, several studies to date support the utility of a variety of echocardiographic methods in detecting fetal conduction defects. Further research is needed to establish their role to optimal approach this problem.

24.3.4Risk Factors

The first clinical study addressing the risk of CHB in newborns of anti-Ro/SSA antibody-positive mothers was conducted by Brucato et al. [40]. In that study, 100 anti-Ro/SSA antibody-positive women with a history of an underlying connective tissue disease were followed before and after pregnancy. The risk of delivering an infant with complete CHB was found to be 2%. Since then, several other studies have confirmed that the risk of CHB in an anti-Ro/SSA pregnant woman ranges between 1% and 2.7% [20, 30, 31]. Other studies have reported even lower estimates [41, 42].

The presence of anti-La/SSB autoantibodies appears to increase the risk of CHB. In one study, the presence of anti-La/SSB autoantibodies increased the risk of CHB to 3.1%, compared to 0.9% for women without anti-La/SSB autoantibodies [43]. The likelihood of having a second child with CHB is at least twoto threefold higher in women with a previous pregnancy complicated by fetal CHB compared with the risk of who never had an affected child. The risk of recurrence may be as high as 15–20% (Table 24.3). Llanos et al. have shown that the recurrence rate of cardiac disease in 161 pregnancies of 129 anti-Ro/SSA-positive mothers was 17.4% (95% confidence intervals 11.1–23.6%) [44]. Another study estimated the risk of women CHB following the birth of an earlier child with cutaneous NLS to be 12.8% [45].

Hypothyroidism may also be a risk factor for CHB. Spence et al. showed that women with hypothyroidism and anti-Ro/SSA antibodies had a ninefold increased risk for delivering a child with complete CHB compared to women with antibodies but normal thyroid function [46].

In vitro studies have shown that following ingestion of apoptotic cardiomyocytes, the macrophages become activated and secrete TNF-a [51] and TGF-b [52]. TGF-b is a pivotal cytokine involved in the fibrotic process, leading ultimately to injury of the conductive system. Exposure of cardiac fibroblasts to supernatants derived from macrophage cultures, after incubation with autoantibody-coated apoptotic cells, shifts their phenotype toward scar promotion. This process is mediated by TGF-b and inhibited specifically by anti-TGF-b monoclonal antibodies. Studying the role of clearance of apoptotic cells in the heart, Clancy et al. showed that the proliferating cardiomyocytes can eliminate the neighboring apoptotic cardiomyocytes. This process was inhibited by the presence of anti-Ro/SSA antibodies, suggesting that autoantibodies bound to apoptotic cells delay their clearance, leading eventually to their accumulation and contributing further to inflammation and fibrosis [53].

Genetics appear also to be involved in the pathogenesis of CHB. One study evaluated codons 10 and 25 of the TGF-b gene in 40 children with CHB, 17 children with NLS-related rash, 31 unaffected siblings, and 74 mothers who had at least one child with NLS [54]. The investigators found that the Leu10 TGF-b polymorphism was higher among CHB with CHB compared to both unaffected offspring and controls, implying that this specific polymorphism is associated with increased expression of TGF-b by macrophages [54]. Genome-wide association studies to address the genetic profile of these patients are pending.

24.3.6Management of Pregnancy in Women with Anti-Ro/La Autoantibodies

The risk of an anti-Ro/SSA- or anti-La/SSB-antibody-positive mother with no history of a previous CHB delivery giving birth to a newborn with CHB does not exceed 3%. These pregnancies are viewed as low risk compared with those of a woman whose previous pregnancy was complicated by NLS or CHB, in whom the risk of having a child with CHB may be as high as 20%. These individuals comprise the high-risk group.

Low-risk patients require close monitoring to detect cardiac involvement as early as possible. Glucocorticoids are the cornerstone of therapy for CHB. Once CHB has become established, glucocorticoids cannot revert the disease but may improve the overall prognosis [55], probably through their effects on inflammation-related manifestations such as hydrops and pleural effusions [56, 57]. Because fluorinated glucocorticoids are not metabolized by the placenta, these preparations (e.g., betamethasone and dexamethasone) are the medications of choice in this setting. Glucocorticoid treatment has been reported in some studies to revert firstand second-degree AV block [38, 42, 56], but other studies have not confirmed these observations [58, 59]. Treatment complications observed in mothers treated with glucocorticoids include diabetes mellitus, infections, and osteoporosis. In fetuses, oligohydroamnios and intrauterine growth retardation may occur. A recent study on 13 children with CHB who were exposed to a high dose of dexamethasone demonstrated no adverse effects on neuropsycological development [60].

Brucato et al. suggested that betamethasone or dexamethasone of 4 mg daily should be administered to mothers if fetal heart block is incomplete or recent, or if heart block is complicated by myocarditis, heart failure, and hydropic changes [8]. The dexamethasone dose should be tapered and discontinued if no changes are evident within several weeks. In contrast, if the heart block is complete and known to be present for more than 2 weeks, a watchful waiting with serial echocardiography is recommended [8].

IVIG administration has been also proposed to prevent CHB in high-risk pregnancies [61, 62]. The possible mechanisms by which IVIG could prevent the development of CHB include elimination of maternal anti-Ro/SSA and La/SSB autoantibodies through anti-idiotypic antibodies, decreased transplacental transport of pathogenetic autoantibodies, and inhibition of macrophage activation. The value of IVIG at a dose of 400 mg/kg administered at 12, 15, 18, 21, and 24 weeks of high-risk pregnancies was recently addressed by two double-blind studies [63, 64]. Both failed to demonstrate a beneficial effect of IVIG, since CHB developed in 15% [66] of fetuses on one study and 20% of those in another, figures similar to those observed in the control groups. More specific immunotherapies, aimed at providing high-affinity blocking anti-idiotypic antibodies, are worthy of study in this disorder. In both studies the reasons of IVIG treatment failure could be attributed to: i) the chosen dose was low, ii) IVIG might not be effective in preventing transplacental passage of pathogenetic autoantibodies because it contains a small amount of specific anti-idiotypic antibodies with low affinity or iii) other, still undetermined, environmental factors are also involved.

Beta 2 adrenergic agonists such as salbutamol or ritodrine could also be administrated to the mothers in order to increase fetal heart rate and improve ventricular function [8, 65]. For newborns with CHB, the cornerstone of therapy is implantation of a permanent pacemaker [8]. Isopreterenol can be used to control bradycardia. In Table 24.4, the management of CHB proposed by Brucato et al. is shown. In regard to low-risk pregnancies, the administration of hydroxychloroquine is a therapeutic option, since exposure of SLE mothers with anti-Ro/SSA and/or antiLa/SSB antibodies to hydroxychloroquine has been found to decrease the risk of CHB [67].