Perinatology. Fetal Congenital Complete Atrioventricu lar Block in a Mother with Isolated Serum Anti-SSA/Ro and Anti-SSB/La Antibodies

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1 pissn eissn Case report Vol. 27, No. 3, September, 2016 Chi-Won Mok, MD 1, Ju-Young Park, MD 1, Kyunghee Kim, MD 2, Suk-Joo Choi, MD, PhD 1, Soo-young Oh, MD, PhD 1, Cheong-Rae Roh, MD, PhD 1, Jong-Hwa Kim, MD, PhD 1 1 Department of Obstetrics and Gynecology, 2 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Fetal Congenital Complete Atrioventricu lar Block in a Mother with Isolated Serum Anti-SSA/Ro and Anti-SSB/La Antibodies Congenital atrioventricular block (AVB) is rare but carries a significant fetal or neonatal mortality and morbidity. In about half of the cases, it is associated with a congenital structural heart anomaly and often results from the transplacental transfer of maternal anti-ssa/ro and/or anti- SSB/La autoantibodies in women with autoimmune diseases. We report a case of an isolated congenital AVB with cardiomegaly and pericardial effusion in a woman who had both serum anti- SSA/Ro and anti-ssb/la antibodies, but had no clinical or laboratory evidence of autoimmune diseases. The mother was treated with oral dexamethasone for about 10 days antenatally until the fetal pericardial effusion regressed. AVB persisted without any fetal compromise throughout the remaining gestational period until elective cesarean delivery at term. A permanent pacemaker was implanted into the baby at 2 weeks after birth due to hypotension and aggravating heart failure. The baby did not develop any complications and was discharged from the hospital. Key words: Congenital Atrioventricular Block, Anti-SSA/Ro, Anti-SSB/La, Dexamethasone Received: 15 March 2016 Revised: 31 August 2016 Accepted: 10 September 2016 Correspondence to Suk-Joo Choi, MD, PhD Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gil 50 Irwon- Dong, Gangnam-Gu, Seoul 06351, Korea Tel: Fax: drmaxmix.choi@samsung. com Copyright 2016 by The Korean Society of This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License ( by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original work is properly cited. Introduction Congenital atrioventricular block (AVB) is a dysfunction of the conducting system and occurs in 1/15,000 to 1/20,000 live births. 1 About half of AVBs occur in association with structural heart diseases, such as atrioventricular septal defects, left atrial isomerism and abnormalities of the great arteries. 1,2 The other half is associated with the transplacental transfer of maternal circulatory antibodies against Ro/La antigens. 1,2 Anti-SSA/Ro and anti-ssb/la antibodies are closely associated with autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren syndrome, rheumatic arthritis, and systemic sclerosis, which occur frequently in women of child-bearing age. Autoimmune congenital AVB develops only in 1% to 2% of anti-ssa/ro and/or anti SSB/La positive pregnancies, but its recurrence rate is 12% to 20%. 3 Congenital AVB is related to significant morbidities such as dilated cardiomyopathy, fetal hydrops and neonatal heart failure. 1 The perinatal mortality rate of congenital AVB varies between studies with a 5.5% to 25% rate of intrauterine fetal demise and a 18% to 40% rate of neonatal mortality. 1 The fundamental treatment of congenital AVB is based on postnatal pacemaker implantation, while there are few options for antenatal management. Flurionated steroids, such as dexamethasone and betamethasone, have been used to diminish fetal cardiac inflammatory injuries and to increase the fetal heart rate, but some reports do not support their effectiveness. 4,5 We report a case of an isolated congenital AVB with cardiomegaly and pericardial effusion,

2 Mok CW, et al. Fetal Congenital Atrioventricular Block which were detected during a midtrimester screening ultrasound, in a woman who was found to have both serum anti-ssa/ro and anti-ssb/la antibodies, but had no clinical or laboratory evidence of autoimmune diseases. Case A 32-year-old nulliparous woman was referred to our institution at weeks of gestation for fetal arrhythmia, cardiomegaly and pericardial effusion detected by routine midtrimester screening ultrasound. A 3:1 AVB with an atrial rate of 150 bpm and a ventricular rate of 56 bpm was found in the fetal echocardiography (Fig. 1A). A mild cardiomegaly with a cardiac circumference/thoracic circumference ratio of 0.57 and a pericardial effusion of 3 mm depth were observed (Fig. 1B), but there was no evidence of fetal hydrops or other fetal structural abnormalities. Maternal serum anti-ssa/ro and anti-ssb/la tests were performed and both showed positive (anti-ssa/ro level of >200 IU/ml and anti-ssb/la level of 49.2 IU/mL). The patient had no symptoms of autoimmune diseases, such as skin rash, joint pain, photosensitivity, alopecia, and oral ulcers. A work up for autoimmune disease screening, including serum complement levels, and anti-ds- DNA were conducted, with the results returning normal. Oral dexamethasone (4 mg per day) treatment was started at weeks of gestation, but AVB with a ventricular rate of 57 to 60 bpm persisted. Oral dexamethasone was discontinued at weeks of gestation when the pericardial effusion and cardiomegaly improved (cardiac circumference/thoracic circumference ratio=0.52) despite persistent AVB (Fig. 1C). Until 34 weeks of gestation, we checked the fetal heart with ultrasonography weekly at the outpatient clinic. The ultrasonographic findings showed no significant changes. The patient was hospitalized at 34 weeks for fetal surveillance with a daily nonstress test and biophysical profile every other day. The results were reassuring, except for the persistent fetal bradycardia. An elective lower segment cesarean section was done due to breech presentation at weeks without any complication. The baby weighed 2.72 kg at birth, and the Apgar scores at 1 and 5 minutes were 7 and 9, respectively. On the day of birth, the baby s heart rate was measured to be 40 to 50 beats per minute on an electrocardiogram (ECG) (Fig. 2A). A chest X-ray showed significant cardiomegaly, but left ventricular contractility was preserved on echocardiography (left ventricular ejection fraction (LVEF)=59.05%) (Fig. 2B). Isoproterenol, a non-selective β-adrenergic agonist, was administered to maintain the target mean blood pressure of 40 Fig. 1. (A) Fetal echocardiogram at weeks of gestation showing 3:1 atrioventricular block with atrial rate of 150 bpm and ventricular rate of 56 bpm. (B) Pericardial effusion (arrowhead) at weeks of gestation. (C) Regression of pericardial effusion (arrowhead) at weeks of gestation

3 2016 September;27(3): mmhg. However, on the next day, the mean blood pressure fell to 20 mmhg, and several episodes of ventricular tachycardia were detected on ECG. A temporary pacemaker was inserted into the baby due to hypotension and aggravating heart failure (LVEF=45.36%) (Fig. 2C). With the pacemaker, the heart rate stabilized to between 120 and 130 bpm (Fig. 2D), and a mean blood pressure of 40 mmhg was maintained. After 2 weeks, a permanent pacemaker was implanted without any complication. The postoperative heart rate was around 130 bpm, and there was no sign of heart failure from then on. After four months, follow up echocardiography at an outpatient pediatric clinic showed good cardiac function (LVEF=65.9%). The parturient visited an outpatient rheumatology clinic for the detection of the possible development of autoimmune diseases. All results of laboratory tests were normal and follow up visits were scheduled every 6 months. Discussion We report a case of isolated congenital AVB associated in a mother with serum anti-ssa/ro and anti-ssb/la antibodies without any clinical or laboratory evidence of autoimmune disease. The mother was treated with oral dexamethasone antenatally to ameliorate poor fetal cardiac function. The treatment was discontinued when the pericardial effusion regressed, although AVB persisted. She gave birth to a girl weighing 2.72 kg at weeks of gestation by elective cesarean section. A permanent pacemaker was implanted into the baby, because of aggravating heart failure, and the baby s cardiac function recovered after the procedure. Congenital AVB is a very rare congenital anomaly, but carries significant fetal or neonatal mortality and morbidities. 1 Congenital AVB can be diagnosed in utero, at birth or within the neonatal period, 6 but it commonly develops during the 18 to 24 weeks of pregnancy. 6,7 Because of the rapid progression of the disease from 1st or incomplete block to 2nd and 3rd block, most of the cases are not detected until they develop complete AVB. 3,4 The first sign of our case was fetal bradycardia with a ventricular rate of 50 to 60 bpm and complete block at 23 weeks of gestation. This is the typical presentation of congenital AVB. Some predictive factors of poor outcomes are suggested, including the presence Fig. 1. (A) Neonatal electrocardiogram after birth showing atrioventricular dissociation. (B) Neonatal echocardiogram after birth showing left ventricular ejection fraction of 59%. (C) Neonatal echocardiogram at 3 days after birth when a temporary pacemaker insertion was performed (left ventricular ejection fraction of 45.36%). (D) Electrocardiogram after insertion of permanent pacemaker showing a regular heart rate of 130 beats per minute

4 Mok CW, et al. Fetal Congenital Atrioventricular Block of a congenital structural heart defect or fetal hydrops, and early gestational age at diagnosis. The prognosis of isolated AVB is much better than that of AVB associated with a congenital structural heart defect. An overall mortality of 11% to 45% for isolated AVB and up to 80% in AVB associated with congenital structural heart defect has been reported,1 but most of those who survive with isolated AVB require pacemakers. Congenital AVB without structural abnormalities implies the presence of maternal anti-ssa/ro and/or anti-ssb/la antibodies in more than 85% of cases. 7 Hence, women who have affected babies are recommended to have a test for these antibodies. Immunopositive mothers should be evaluated for any underlying autoimmune diseases, and prospectively followed up by specialists. About half of the mothers are asymptomatic at the time of identification of AVB and others have SLE, unidentified autoimmune syndrome, or Sjögren syndrome. 2 Half of initially asymptomatic mothers develop symptoms of rheumatic disease and the mean time for the development of symptoms is 2.6 years after the affected birth. These symptoms are most commonly arthralgias and xerophthalmia, but few develop lupus nephritis. 8, 9 The parturient had a work up for SLE after delivery during her first visit to an outpatient clinic. The results were negative. The follow up visits are scheduled every 6 months. Anti-SSA/Ro and anti-ssb/la antibodies also affect skin, liver, and blood cells of neonates, and these are now categorized in neonatal lupus syndromes. 8 These non-cardiac manifestations are reversible and spontaneously disappear, so they do not require any treatment. 7 Our case did not have any symptoms or signs of neonatal lupus syndrome. Anti-SSA/Ro and anti-ssb/la antibodies do not affect other pregnancy outcomes, such as preterm birth, preeclampsia, and fetal growth restriction. 8 Congenital AVB in mothers with anti SSA/Ro and/or anti-ssb/la antibodies recurs in 12% to 20%. Therefore, serial fetal echocardiograms and obstetric ultrasonography should be performed at least every 1-2 weeks beginning at 16 weeks of gestation to detect early fetal abnormalities. If PR interval prolongation was found, follow-up ultrasonography of 1 to 3 days interval may be helpful for early detection of high degree AVB. There is no consensus on the prevention and antenatal treatment of congenital AVB, and complete AVB is known to be irreversible. Some reports support the effectiveness of intravenous immunoglobulin (IVIG) for the treatment and prevention of congenital AVB in a mother with anti-ssa/ro and anti-ssb/la.9 But a recent study showed no benefits of low dose IVIG (400 mg/kg) for the prevention of the recurrence of congenital heart block or for the reduction of maternal antibody titers, and subsequent investigations on high dose IVIG (1 g/kg) are warranted. And also, studies on the efficacy and safety of hydroxychloroquine for treatment of congenital AVB are needed. 10 β-agonists also have been used to increase fetal heart rate in utero, but their effects are in question. 11 Maternal dexamethasone treatment has been used to treat congenital AVB. In a multicenter prospective nonrandomized study, dexamethasone treatment did not effectively reverse the 3rd degree blocks but had benefits in reversing 1st and 2nd degree blocks in rare patients. 4 Generally, however, 1st and 2nd degree blocks often disappear spontaneously and do not require treatment. On the other hand, dexamethasone treatment is recommended in 3rd degree block in spite of the sparse evidence. Flurionated steroids, such as dexamethasone and betamethasone, are not metabolized by the placenta and are available to the fetus in an active form. Although complete heart block is not curable, incomplete AVB, myocardial dysfunction, and pericardial effusion can be ameliorated by dexamethasone therapy and it is recommended to start therapy as soon as congenital heart block is detected. 12,13 There is no consensus on optimal time to quit treatment and the majority of practitioners continue treatment until delivery. 14,15 Considering potential for fetal adverse effects of long-term steroid therapy, including neurodevelopmental and growth abnormalities, further studies on the best time to discontinue treatment is warranted. 7 When we first noticed the fetal pericardial effusion, we started oral dexamethasone treatment. Although the AVB persisted despite the treatment, the pericardial effusion did regress in 10 days. The treatment was discontinued for fear of possible side effects. The definite treatment of congenital AVB is postnatal pacemaker insertion. Frequently, a temporary pacemaker is implanted in the neonatal period depending on the clinical conditions, but the majority of patients need permanent pacing. 7 The implantation of pacemaker is indicated when symptoms develop from congestive heart failure in infants with advanced 2nd degree block or complete AVB. In summary, autoimmune congenital AVB is a dysfunction of the fetal conduction system, and is associated with maternal autoantibodies. The efficacy and safety of in utero therapy repre

5 2016 September;27(3): sented by flurionated steroid are questionable, but steroid treatment is recommended in higher degree blocks. The practitioners need to be alert for the deterioration of fetal/neonatal heart function and should not miss the appropriate time for intervention. We report a case of an isolated congenital heart block which treated with oral dexamethasone. This case is differentiated from the case which has been published in Korea, by its use of steroid. In spite of its lack of strong evidence, we decided to admit oral steroid because of aggravating cardiomegaly and pericardial effusion. Though the baby needed pacemaker implantation due to heart failure after birth, we regard steroid therapy to be effective in ameliorating signs of heart failure in utero. References 1) Kuleva M, Le Bidois J, Decaudin A, Villain E, Costedoat-Chalumeau N, Lemercier D, et al. Clinical course and outcome of antenatally detected atrioventricular block: experience of a single tertiary centre and review of the literature. Prenat Diagn 2015;35: ) Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med 1994;120: ) Ambrosi A, Wahren-Herlenius M. Congenital heart block: evidence for a pathogenic role of maternal autoantibodies. Arthritis Res Ther 2012; 14:208. 4) Friedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon JP. Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study. Am J Cardiol 2009;103: ) Lee JY, Hur SE, Lee SK. Prevention of anti-ssa/ro and anti-ssb/la antibodies-mediated congenital heart block in pregnant woman with systemic lupus erythematosus: A case report. Korean J Obstet Gynecol 2012;55: ) Brucato A, Jonzon A, Friedman D, Allan LD, Vignati G, Gasparini M, et al. Proposal for a new definition of congenital complete atrioventricular block. Lupus 2003;12: ) Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-ro/ssa antibodies. Clin Rev Allergy Immunol 2011;40: ) Brucato A, Doria A, Frassi M, Castellino G, Franceschini F, Faden D, et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-ro/ssa antibodies: a prospective controlled study. Lupus 2002; 11: ) Tonello M, Ruffatti A, Marson P, Tison T, Marozio L, Hoxha A, et al. Plasma exchange effectively removes 52- and 60-kDa anti-ro/ssa and anti-la/ssb antibodies in pregnant women with congenital heart block. Transfusion 2015;55: ) Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, et al. 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 Rheum 2010;62: ) Saxena A, Izmirly PM, Mendez B, Buyon JP, Friedman DM. Prevention and treatment in utero of autoimmune-associated congenital heart block. Cardiol Rev 2014;22: ) Iozza I, Cianci S, Di Natale A, Garofalo G, Giacobbe AM, Giorgio E, et al. Update on systemic lupus erythematosus pregnancy. J Prenat Med 2010;4: ) Hutter D, Silverman ED, Jaeggi ET. The benefits of transplacental treatment of isolated congenital complete heart block associated with maternal anti-ro/ssa antibodies: a review. Scand J Immunol 2010;72: ) Fesslova V, Vignati G, Brucato A, De Sanctis M, Butera G, Pisoni MP, et al. The impact of treatment of the fetus by maternal therapy on the fetal and postnatal outcomes for fetuses diagnosed with isolated complete atrioventricular block. Cardiol Young 2009;19: ) Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004;110: