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Congenital heart block: Successful prophylactic treatment with intravenous gamma globulin and corticosteroid therapy
Volume 165 Number 5, Part I
tuitarism is an important nonosmotic stimulus for antidiuretic hormone secretion and can cause severe inappropriate secretion of antidiuretic hormone. In summary, we report a case of postpartum hypopituitarism that caused inappropriate secretion of antidiuretic hormone and hyponatremia. Replacement therapy with hydrocortisone increased sodium blood levels to normal. Even when appearing in the early
Inappropriate antidiuretic hormone in Sheehan's syndrome
postpartum period, severe hyponatremia can be the initial manifestation of Sheehan's syndrome. REFERENCES 1. Sidorov J, Mitnick P. Post partum hyponatremia. Am J Med 1987;83: 183-4. 2. Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989;321 :492-6.
Congenital heart block: Successful prophylactic treatment with intravenous gamma globulin and corticosteroid therapy Risto Kaaja, MD," Heikki Julkunen, MD," Pirkko Ammala, MD,a Anna-Maija Teppo, MSC,b and Pekka Kurki, MDc Helsinki, Finland In mothers with anti-Ro-positive antibodies whose previous pregnancies have ended in deliveries of infants with congenital heart block, prophylactic therapeutic strategies are used to try to diminish the production and passage into fetal circulation of autoantibodies. Intravenous gamma globulin was given at 14 and 18 weeks' gestation and prednisone was given from 14 weeks' gestation to a woman with Sjogren's syndrome. The pregnancy ended with delivery of an infant without congenital heart block. (AM J OSSTET GVNECOL 1991 ;165:1333-4.)
Key words: Intravenous gamma globulin, congenital heart block, anti-Ro antibodies Neonatal lupus syndrome and congenital heart block occur in infants whose mothers have antibodies to Ro (SS-A) and La (SS-B) autoantigens. The antibodies cross the placenta and may have a pathogenetic role in tissue damage in the fetus. Therefore therapeutic strategies such as plasmapheresis and corticosteroid therapy are used to diminish the autoantibody production and passage into the fetal circulation. The risk of congenital heart block is 1 in 20 pregnancies in which the mother has anti-Ro antibodies. If the mother has had an infant with congenital heart block, the risk in subsequent pregnancies is one in four. We report a high-risk pregnancy that was treated with intravenous gamma globulin and orally administered corticosteroids. From the Department of Obstetrics and Gynecolog;y" and the Fourth Department of Medicine,' Helsinki University Central Hospital, and the Department of Bacteriology and Immunology, University of Helsinki.' Received for publication December 18, 1990; revised Apri118, 1991 ; May 8,1991. Reprint requests: Risto Kaaja, MD, Department of Obstetrics and Gynecolog;y, Helsinki University Central Hospital, Haartmaninkatu 2, 00290 Helsinki 29, Finland. 611 /30967
Case report The patient was a 38-year-old woman with primary Sjogren's syndrome and hypothyroidism that began in 1978. Her first pregnancy was normal, and she was delivered of a healthy infant in 1974. During her second pregnancy 14 years later Sjogren's syndrome was inactive. At 22 weeks' gestation fetal bradycardia (60 beats/min) was observed and a diagnosis of congenital heart block was made with ultrasonography. Double immunodiffusion determined that anti-Ro-antibody titers were elevated (1 : 8), but no anti-La antibodies were found. She was delivered of an infant whose heart was structurally normal except for congenital heart block. A pacemaker was inserted. One year later during her third pregnancy the anti-Ro-antibody titer was 1: 1, but no anti-La antibodies were found. Intravenous gamma globulin (Sandoglobulin, Sandoz, Bern, Switzerland) was given at 14 and 18 weeks' gestation with a dose of 1 gm/kg during 16 hours of infusion. Prednisone was given at 14 weeks' gestation with an initial dose of 40 mg/day and tapered within 4 weeks to 10 mg/day until delivery. After the second infusion of gamma globulin, anti-Ro antibodies were not detectable by double-immunodiffusion technique (Fig. 1). Enzyme immunoassay was also used to detect non precipitating anti-Ro 1333
1334 Kaaja et al.
November 1991 Am J Obstet Gynecol
Fig. 1. Effect of intravenous gamma globulin on anti-Ro (SS-A) antibodies (I: I) measured with double-immunodiffusion technique.
antibodies. There was only a slight decrease in antibodies with solid-phase immunoassay. No signs of fetal bradycardia were observed, and a healthy child with normal heart function was born.
Comment There are several mechanisms by which the combined corticosteroid and intravenous immunoglobulin therapy could be beneficial in an antibody-mediated disease. In addition to the simple antiinflammatory effect of corticosteroids and the dilution effect of intravenous immunoglobulin infusion , we can conjecture that there is a blockade of the transplacental pathway of antibodies. Corticosteroids will also slowly diminish antibody productions. Jerne's theory of an idiotype-antiidiotype regulation of the immune system I has gained strong experimental support. The antiidiotypes of normal human serum are able to interfere with autoantibodies present in a patient'S sera. Such antiidiotypes are present in the intravenous immunoglobulin used in our case. Thus it is possible that antiidiotypes are partly responsible for the decrease in the anti-Ro titer in the immunodiffusion test. This elimination may take place on the cellular (production) level or in the circulation (elimination). It is also possible that the antiidiotypes interfere in the immunodiffusion test used for the antiRo assay. Interestingly, the therapy did not have a similar impact on the anti-Ro levels as measured with a solidphase enzyme immunoassay. It is obvious that the immunodiffusion test and the solid-phase immunoassay detect different autoantibody populations. Most moth-
ers who have anti-Ro-positive antibodies give birth to normal children. Therefore it is possible that there is a pathogenetic subgroup of anti-Ro or other antibodies that are sensitive to immunomodulation by intravenous immunoglobulin. The timing of therapeutic intervention is important in the prophylaxis of congenital heart block. There are no reports of successful outcome if the treatment has been started after fetal bradycardia is observed (usually > 22 weeks' gestation). There are two reports in which a reduction of anti-Ro-antibody titers was achieved after steroid therapy and plasmapheresis and led to delivery of a healthy child. In these cases the treatment was given before 20 weeks' gestation. 2 Our report of successful early prophylactic therapy is in agreement with these reports. Experimental prophylactic therapies should be restricted to high-risk pregnancies under research protocols with informed consent until controlled data are available. It is not clear that the good outcome of this case was related to the infusion of gamma globulin; it may be that the outcome was unrelated to the therapy. However, we think that intravenous immunoglobulin infusion is a good substitute for more laborious and hazardous techniques such as plasmapheresis. The immunoglobulin should be infused before the onset of bradycardia, which is an indicator of cardiac damage. REFERENCES 1. Jerne NK. Towards a network theory of immune system. Ann Immunol (Paris) 1974;125C : 373~89. 2. Petri M, Watson R, Hochberg MC. Anti-Ro antibodies and neonatal lupus. Rheum Dis Clin North Am 1989; 15:33559.
tuitarism is an important nonosmotic stimulus for antidiuretic hormone secretion and can cause severe inappropriate secretion of antidiuretic hormone. In summary, we report a case of postpartum hypopituitarism that caused inappropriate secretion of antidiuretic hormone and hyponatremia. Replacement therapy with hydrocortisone increased sodium blood levels to normal. Even when appearing in the early
Inappropriate antidiuretic hormone in Sheehan's syndrome
postpartum period, severe hyponatremia can be the initial manifestation of Sheehan's syndrome. REFERENCES 1. Sidorov J, Mitnick P. Post partum hyponatremia. Am J Med 1987;83: 183-4. 2. Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989;321 :492-6.
Congenital heart block: Successful prophylactic treatment with intravenous gamma globulin and corticosteroid therapy Risto Kaaja, MD," Heikki Julkunen, MD," Pirkko Ammala, MD,a Anna-Maija Teppo, MSC,b and Pekka Kurki, MDc Helsinki, Finland In mothers with anti-Ro-positive antibodies whose previous pregnancies have ended in deliveries of infants with congenital heart block, prophylactic therapeutic strategies are used to try to diminish the production and passage into fetal circulation of autoantibodies. Intravenous gamma globulin was given at 14 and 18 weeks' gestation and prednisone was given from 14 weeks' gestation to a woman with Sjogren's syndrome. The pregnancy ended with delivery of an infant without congenital heart block. (AM J OSSTET GVNECOL 1991 ;165:1333-4.)
Key words: Intravenous gamma globulin, congenital heart block, anti-Ro antibodies Neonatal lupus syndrome and congenital heart block occur in infants whose mothers have antibodies to Ro (SS-A) and La (SS-B) autoantigens. The antibodies cross the placenta and may have a pathogenetic role in tissue damage in the fetus. Therefore therapeutic strategies such as plasmapheresis and corticosteroid therapy are used to diminish the autoantibody production and passage into the fetal circulation. The risk of congenital heart block is 1 in 20 pregnancies in which the mother has anti-Ro antibodies. If the mother has had an infant with congenital heart block, the risk in subsequent pregnancies is one in four. We report a high-risk pregnancy that was treated with intravenous gamma globulin and orally administered corticosteroids. From the Department of Obstetrics and Gynecolog;y" and the Fourth Department of Medicine,' Helsinki University Central Hospital, and the Department of Bacteriology and Immunology, University of Helsinki.' Received for publication December 18, 1990; revised Apri118, 1991 ; May 8,1991. Reprint requests: Risto Kaaja, MD, Department of Obstetrics and Gynecolog;y, Helsinki University Central Hospital, Haartmaninkatu 2, 00290 Helsinki 29, Finland. 611 /30967
Case report The patient was a 38-year-old woman with primary Sjogren's syndrome and hypothyroidism that began in 1978. Her first pregnancy was normal, and she was delivered of a healthy infant in 1974. During her second pregnancy 14 years later Sjogren's syndrome was inactive. At 22 weeks' gestation fetal bradycardia (60 beats/min) was observed and a diagnosis of congenital heart block was made with ultrasonography. Double immunodiffusion determined that anti-Ro-antibody titers were elevated (1 : 8), but no anti-La antibodies were found. She was delivered of an infant whose heart was structurally normal except for congenital heart block. A pacemaker was inserted. One year later during her third pregnancy the anti-Ro-antibody titer was 1: 1, but no anti-La antibodies were found. Intravenous gamma globulin (Sandoglobulin, Sandoz, Bern, Switzerland) was given at 14 and 18 weeks' gestation with a dose of 1 gm/kg during 16 hours of infusion. Prednisone was given at 14 weeks' gestation with an initial dose of 40 mg/day and tapered within 4 weeks to 10 mg/day until delivery. After the second infusion of gamma globulin, anti-Ro antibodies were not detectable by double-immunodiffusion technique (Fig. 1). Enzyme immunoassay was also used to detect non precipitating anti-Ro 1333
1334 Kaaja et al.
November 1991 Am J Obstet Gynecol
Fig. 1. Effect of intravenous gamma globulin on anti-Ro (SS-A) antibodies (I: I) measured with double-immunodiffusion technique.
antibodies. There was only a slight decrease in antibodies with solid-phase immunoassay. No signs of fetal bradycardia were observed, and a healthy child with normal heart function was born.
Comment There are several mechanisms by which the combined corticosteroid and intravenous immunoglobulin therapy could be beneficial in an antibody-mediated disease. In addition to the simple antiinflammatory effect of corticosteroids and the dilution effect of intravenous immunoglobulin infusion , we can conjecture that there is a blockade of the transplacental pathway of antibodies. Corticosteroids will also slowly diminish antibody productions. Jerne's theory of an idiotype-antiidiotype regulation of the immune system I has gained strong experimental support. The antiidiotypes of normal human serum are able to interfere with autoantibodies present in a patient'S sera. Such antiidiotypes are present in the intravenous immunoglobulin used in our case. Thus it is possible that antiidiotypes are partly responsible for the decrease in the anti-Ro titer in the immunodiffusion test. This elimination may take place on the cellular (production) level or in the circulation (elimination). It is also possible that the antiidiotypes interfere in the immunodiffusion test used for the antiRo assay. Interestingly, the therapy did not have a similar impact on the anti-Ro levels as measured with a solidphase enzyme immunoassay. It is obvious that the immunodiffusion test and the solid-phase immunoassay detect different autoantibody populations. Most moth-
ers who have anti-Ro-positive antibodies give birth to normal children. Therefore it is possible that there is a pathogenetic subgroup of anti-Ro or other antibodies that are sensitive to immunomodulation by intravenous immunoglobulin. The timing of therapeutic intervention is important in the prophylaxis of congenital heart block. There are no reports of successful outcome if the treatment has been started after fetal bradycardia is observed (usually > 22 weeks' gestation). There are two reports in which a reduction of anti-Ro-antibody titers was achieved after steroid therapy and plasmapheresis and led to delivery of a healthy child. In these cases the treatment was given before 20 weeks' gestation. 2 Our report of successful early prophylactic therapy is in agreement with these reports. Experimental prophylactic therapies should be restricted to high-risk pregnancies under research protocols with informed consent until controlled data are available. It is not clear that the good outcome of this case was related to the infusion of gamma globulin; it may be that the outcome was unrelated to the therapy. However, we think that intravenous immunoglobulin infusion is a good substitute for more laborious and hazardous techniques such as plasmapheresis. The immunoglobulin should be infused before the onset of bradycardia, which is an indicator of cardiac damage. REFERENCES 1. Jerne NK. Towards a network theory of immune system. Ann Immunol (Paris) 1974;125C : 373~89. 2. Petri M, Watson R, Hochberg MC. Anti-Ro antibodies and neonatal lupus. Rheum Dis Clin North Am 1989; 15:33559.