Chapter 42 Neonatal Lupus: Clinical Perspectives
INTRODUCTION
Congenital heart block, absent structural abnormalities and detected in the second trimester, is almost universally associated with maternal autoantibodies reactive with the intracellular soluble ribonucleoproteins 48 kD SSB/La, 52 kD SSA/Ro, or 60 kD SSA/Ro.1,2 An erythematosus skin rash with a predilection for the scalp and periorbital region, most often apparent in the first 8 weeks after birth, is also strongly linked to these maternal antibodies as well as to antibodies against U1 RNP.2,3 Permanent cardiac and transient cutaneous disease are the most common manifestations of neonatal lupus, initially named because of the resemblance of the skin rash to subacute cutaneous lupus erythematosus (SCLE). Less often, abnormalities of the liver or blood affect newborns exposed in utero to maternal anti-SSA/Ro-SSB/La antibodies.4–7 Fetal and neonatal injury are presumed to result from the transplacental passage of IgG anti-Ro/La antibodies from the mother into the fetal circulation.8 Fetal/neonatal disease is independent of maternal disease; mothers may have systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) or other autoimmune symptoms, or may be entirely asymptomatic.9 The fetal heart appears to be uniquely vulnerable, since complete block has only been reported in a single mother,10 despite mothers’ exposure to identical circulating levels of the autoantibodies. CHB carries a significant mortality (15% to 30%, primarily fetal and neonatal) and morbidity (67% of surviving affected children require permanent pacing before adulthood).9 The recurrence rate of CHB in subsequent pregnancies is ∼19%11 (Table 42.1), or at least nine-fold greater than the risk for CHB in a primigravida with the candidate antibodies.10 Extensive work from several laboratories has resulted in the molecular characterization of the maternal autoantibody responses and the cloning of genes expressing the cognate antigens whose structural features suggest a role in transcriptional regulation. Anecdotal cases support the use of dexamethasone for the treatment of in utero effusions, hydrops, and incomplete block, but prospective evaluation of dexamethasone or other prophylactic therapy for the at-risk pregnancy remains to be reported.
TABLE 42.1 OUTCOME OF 100 PREGNANCIES IMMEDIATELY SUBSEQUENT TO BIRTH OF CHILD WITH CHBa
| Outcome | n | % |
|---|---|---|
| Healthy | 73 | 73 |
| Manifestations of Neonatal Lupus | ||
| CHB only | 15 | 15 |
| CHB + rash | 3 | 3 |
| Rash only | 7 | 7 |
| Fetal demise | 1 | 1 |
| Neonatal death (heart valve dysfunction and heart failure) | 1 | 1 |
CHB, congenital heart block.
a Data obtained from the Research Registry for Neonatal Lupus, September 15, 2005.
Bridging the gap from identification of the target antigens recognized by the maternal autoantibodies to the mechanism by which these antibodies result in tissue damage and overt clinical disease represents a major challenge. The necessity of anti-SSA/Ro-SSB/La antibodies is supported by their presence in more than 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart.1,2 However, when Brucato and colleagues10 prospectively evaluated 118 pregnancies in 100 patients with anti-SSA/Ro antibodies, the frequency of CHB in a fetus was only 1.7%. Gladman and colleagues12 reported no cases of CHB in 100 live births in 96 women with anti-SSA/Ro and/or anti-SSB/La antibodies and no history of a previous child with NL. This low frequency suggests that a fetal factor and/or the in utero environment are likely to amplify the effects of the antibody, which may be necessary but insufficient to cause fibrotic replacement of the atrioventricular (AV) node and in some cases cardiomyopathy. Notably, one mother in the series reported by Brucato and colleagues,10 who gave birth to two healthy children, developed complete heart block herself, raising the possibility that her heart had acquired “fetal factors.” Clearly, this is a unique situation and one that needs to be further studied, since it is likely to contribute important clues on pathogenesis.
CLINICAL OBSERVATIONS AND CONSIDERATIONS
Classification and Progression of Heart Block
To ascertain the spectrum of arrhythmias associated with maternal anti-SSA/Ro-SSB/La antibodies, Askanase and colleagues13 reviewed records of all children enrolled in the Research Registry for Neonatal Lupus (RRNL). Of 187 children with CHB whose mothers had anti-Ro/La antibodies, 9 had a prolonged PR interval on EKG at birth, 4 of whom progressed to more advanced AV block. A child whose younger sibling had third-degree block was diagnosed with first-degree block at age 10 years at the time of surgery for a broken wrist. Two children diagnosed in utero with second-degree block were treated with dexamethasone and reverted to normal sinus rhythm by birth, but ultimately progressed to third-degree block. Four children had second-degree block at birth: of these, two progressed to third-degree block. These data have important research and clinical implications. Perhaps many fetuses sustain mild inflammation, but resolution is variable, as suggested by the presence of incomplete AV block. Since subsequent progression of less-advanced degrees of block can occur, an EKG should be performed on all infants born to mothers with anti-Ro/La antibodies.
The Toronto registry group retrospectively analyzed the single-center outcome of children with isolated CHB presenting from 1965 to 1998, up to age 20 years.14 Cases were diagnosed from fetal life through childhood. There were a total of 102 cases, divided in three groups. Fetal presentation in 29 cases had 43% mortality rate; neonatal presentation in 33 cases had 6% mortality. There were no deaths in the 40 cases presenting in childhood, but it should be noted that 19 out of 20 tested had negative maternal antibody levels. Risk factors for death were a fetal diagnosis, the presence of hydrops, gestational age under 33 weeks, or the development of endocardial fibroelastosis (EFE) with ejection fraction of 40% of less. Three neonates who had been diagnosed before birth were treated with corticosteroids. Most of the cases (88 to 89%) were paced by age 20. Late cardiomyopathy occurred in 5% overall, but in the antibody-positive cases was 11%. There was progression noted also in the degree of heart block over time. Pacemaker insertions were associated with complications in 25% of cases, and there was a frequent need for pacemaker revisions.
The Toronto group also retrospectively reviewed the clinical history, echocardiography, and pathology of fetuses and children from five medical centers who had EFE associated with CHB and were born to mothers positive for anti-SSA/Ro or anti-SSB/La antibodies.15 Thirteen patients were identified, six with a prenatal and seven with a postnatal diagnosis. Severe ventricular dysfunction was seen in all fetal and postnatal cases. Four fetal and three postnatal cases had EFE at initial presentation. However, two fetal and four postnatal cases developed EFE 6 to 12 weeks and 7 months to 5 years from CHB diagnosis, respectively, even despite ventricular pacing in six postnatal cases. Eleven (85%) either died (n=9) or underwent cardiac transplantation (n=2) secondary to the EFE. Pathologic assessment of the explanted heart, available in 10 cases, revealed moderate to severe EFE in seven cases and mild EFE in three cases, predominantly involving the left ventricle. Immunohistochemistry in four cases (including three fetuses) demonstrated deposition of IgG in four, IgM in three, and T-cell infiltrates in three cases, suggesting an immune response by the affected fetus or child. The important conclusion from this study was that EFE occurs despite adequate ventricular pacing and is associated with significant mortality, whether developing in fetal or postnatal life.
Of interest, this same group of investigators also described a unique clinical series of three cases of isolated EFE (one fetus, two infants, all female) with antibody-positive mothers in the absence of CHB.16 Two died and one received a heart transplant. Histologic evaluation revealed EFE with diffuse IgG deposition and T-cell infiltration but, surprisingly, no detectable apoptosis. This latter observation is curious and remains unexplained.
Management of At-Risk Pregnancy and Congenital Heart Block Detected In Utero
All pregnant women with anti-SSA/Ro-SSB/La antibodies should have serial fetal echocardiography done by an experienced pediatric cardiologist weekly from 16 to 26 weeks, and every other week until about 34 weeks. Until recently, the in utero detection of first-degree block was not technically feasible. However, the EKG equivalent of the PR interval can now be measured by echocardiography.17 Using the gated-pulsed Doppler technique, time intervals from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole) within the same left ventricular cardiac cycle may be measured. This time interval represents the “mechanical” PR interval. Its validity was confirmed by neonatal electrocardiographic correlation to the pulsed Doppler mechanical PR interval.18 The normal mechanical PR interval in the fetus is 0.12 ±0.02 seconds (95% confidence interval, 0.10–0.14). A prospective National Institutes of Health–supported multicenter study, PR Interval and Dexamethasone Evaluation (PRIDE), in CHB is underway to examine the mechanical PR interval weekly in pregnant woman with anti-SSA/Ro and/or anti-SSB/La antibodies. One of the goals of this trial is to identify the prevalence of first-degree block and to determine whether it is a marker for more advanced destruction of the conducting system. Such information will provide the optimal opportunity for reversibility.
The initiation of dexamethasone or plasmapheresis as a preventive measure has been considered. With regard to prophylactic therapy of the high-risk mother (documentation of high-titer anti-SSA/Ro and SSB/La antibodies, anti-48kD SSB/La and 52kD SSA/Ro on immunoblot, and a previous child with NL), administration of prednisone, dexamethasone, or plasmapheresis is not justified at the present time. Maternal prednisone (at least in low and moderate doses) early in pregnancy does not prevent the development of CHB.19 This might be anticipated since prednisone given to the mother is not active in the fetus,20 and levels of anti-SSA/Ro and anti-SSB/La antibodies remain relatively constant during steroid therapy.
Kaaja and Julkunen21 recently reported their experience using intravenous immunoglobulin (IVIG) and corticosteroids in highest-risk mothers (those with anti-SSA/Ro antibodies and a previous child with CHB). Conclusions are limited by the small number of treated patients (n=8) and the absence of a control group. The one mother who did have a second baby with CHB received only IVIG and no corticosteroids. Effectiveness of treatment is difficult to assess in this study. To formally evaluate the efficacy of treatment, a randomized, placebo-controlled trial would need to be conducted, and probably only include mothers who had a previous child with CHB. An example of a power analysis follows: if one accepts a clinically meaningful outcome as a reduction of the recurrence rate of CHB from 19 to 10%, 261 mothers will be needed in each group; and from 19 to 5%, 97 mothers would be needed (α=80%).
The mechanism of potential efficacy is unknown, but effective decrease of circulating antibody in the fetus might involve idiotype/anti-idiotype regulation, a decrease in placental transport, or perhaps induction of surface expression of the inhibitory Fc receptor, FcγRIIB, on macrophages.22 Precedent for decrease of anti-Ro/La transport has been provided by a murine model.23,24 Modulation of inhibitory signaling could be a potent therapeutic strategy for attenuating autoantibody-triggered inflammatory diseases.
The rationale for treatment of identified heart block and prevention of potential heart block is to diminish a generalized inflammatory insult and reduce or eliminate maternal autoantibodies. Accordingly, several intrauterine therapeutic regimens have been tried including dexamethasone, which is not metabolized by the placenta and is available to the fetus in an active form. In the largest retrospective study published to date, it was observed that fluorinated glucocorticoids ameliorated incomplete AV block and hydropic changes in autoimmune-associated congenital heart block but did not reverse established third-degree block.25 Maternal risks of dexamethasone are similar to any glucocorticoid and include infection, osteoporosis, osteonecrosis, diabetes, hypertension, and pre-eclampsia. Fetal risks include oligohydramnios, intrauterine growth retardation, and adrenal suppression. Intervention with glucocorticoids might decrease acute inflammation but not necessarily prevent subsequent fibrosis. A second goal of the PRIDE trial, noted above, is to assess the efficacy of maternal oral dexamethasone (4 mg/d) in reversing or preventing the progression of AV block newly detected in utero. Under the PRIDE protocol, if third-degree block has remained present with no improvement through 6 weeks of dexamethasone therapy, the drug is tapered and discontinued. (Continued use of dexamethasone is warranted in such a case only if hydropic changes are present.)
A case report in which ritodrine was given intravenously to the mother to increase the heart rate of a 28-week fetus with CHB and a ventricular rate of 54 beats per minute reminds us that nonimmunosuppressive approaches may have a role in therapy (sympathomimetics can transiently increase fetal heart rate, although they do not restore coordination of AV conduction on which the heart is dependent for adequate filling).26
Current treatment recommendations for CHB diagnosed in utero are summarized in Table 42.2. Figure 42.1 provides an overview of the translational approach to prevention and therapy, including both current and investigational strategies.
TABLE 42.2 THERAPEUTIC APPROACHES TO CONGENITAL HEART BLOCK DIAGNOSED IN UTERO
| Situation (Degree of Block at Presentation) | Treatment |
|---|---|
| 3rd degree (>2 weeks from detection) | Evaluation by serial echos; no therapy |
| 3rd degree (<2 weeks from detection) | 4 mg p.o. dexamethasone daily for 6 weeks. If improvement to 2nd degree or better, continue until delivery |
| Alternating 2nd degree/3rd degree 2nd degree | 4 mg dexamethasone to delivery, unless block progresses to 3rd degree and remains so for 6 weeks (then taper and withdraw) |
| Prolonged mechanical PR interval (1st degree) | |
| Block associated with signs of myocarditis, congestive heart failure and/or hydropic changes | 4 mg dexamethasone until improvement |
| Severely hydropic fetus | 4 mg dexamethasone plus apheresis to rapidly remove maternal antibodies |
Fig. 42.1 Translational approach to congenital heart block. This schematic outlines monitoring and treatment options for pregnancy and birth in women with anti-Ro/La antibodies, including both recommended practice as well as approaches under investigation. Current recommendations include weekly echocardiograms between 16 and 32 weeks of gestation, treatment with 4 mg dexamethasone to the mother (see Table 42.2), and an EKG at birth (any conduction abnormality at birth should be followed by a cardiologist, but no later conduction abnormalities have been reported to date in an infant with normal sinus rhythm at birth). Treatment of the mother with intravenous immune globulin (IVIG) to reduce transplacental transport of anti-Ro/La antibodies is currently being evaluated. Recent laboratory findings point to inhibition of transforming growth factor (TGF)-β production as a promising therapeutic target to forestall fibrosis in the fetus with third-degree block in utero.
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