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PROPERDIN FACTOR B ALLELES IN PRE-ECLAMPSIA
1145 FETAL DEATH ASSOCIATED WITH SEVERE RITODRINE INDUCED KETOACIDOSIS
SiR,—The paper by Dr Giindogdu and othersi on the metabolic side effects of salbutamol in insulin-requiring diabetics prompted us to report a case of fetal death associated with ritodrine-induced metabolic acidosis during treatment of preterm labour in a diabetic patient.
28-year-old insulin-dependent diabetic (gravida 3, para 2) admitted to University Hospital at 28 weeks of pregnancy in preterm labour. Her two earlier pregnancies had ended in preterm delivery at 27 and 28 weeks and both infants had died soon after birth from severe respiratory distress. During her third pregnancy she had had a Shirodkar operation at 8 weeks. From 20 weeks until 28 weeks she was treated for mild contractions with 10 mg ritodrine daily. Her diabetes had been well controlled, insulin requirements gradually increasing to 44 units daily. In the 28th week she was admitted in preterm labour. Despite intravenous ritodrine by infusion pump at 6 mg/h, contractions persisted and she was transferred to this A
was
hospital. We continued the i.v. ritodrine at doses up to 18’ mg/h; at was controlled by repeated intramuscular insulin injections. Details of blood glucose concentration, insulin requirement, and blood pH are shown in the figure. After 26 h of treatment, during which mild contractions continued and cardiotocography showed a normal fetal heart rate pattern, the patient became progressively dyspnoeic and drowsy. Her blood glucose was 21.5mmol/l, arterial pH 6-97, pC02 1.56 kPa (11.7 mm Hg), base excess - 28-5mmoVI, and she had ketonuria. Chest X-ray and maternal ECG were normal.
first, blood glucose
The ritodrine infusion was discontinued; insulin was given by infusion pump (12 U/h), and the acidosis was corrected with i.v. bicarbonate. This resulted in clinical improvement within 3 h, the pH rising to 7.33 and blood glucose falling to 6.7mmol/l; ritodrine infusion was started again at 9 mg/h. While the mother’s condition had been deteriorating the fetus had been neglected and for 6 h no attempt had been made to record fetal heart rate. However, fetal heart activity was now undetectable, so the ritodrine infusion was discontinued and the Shirodkar ligature was removed. The patient was delivered of a still born fetus weighing 970 g. Necropsy showed bilateral cheilognathopalatoschisis but no other congenital malformations or fetal or placental abnormalities. From this observation we conclude that beta-sympathomimetics can cause a rapid deterioration of diabetic control with the development of serious ketoacidosis.
Beta-sympthomimetic agents raise the blood glucose; this frequently for salbutamol and also for ritodrine;2.3 a rise in plasma glycerol and free fatty acids has also been recorded for salbutamol.l,4 The stimulation by betasympathomimetics of adenylcyclase, which catalyses the formation of cyclic 3, 5-adenosine monophosphate (cAMP) from has been recorded
cAMP concentrations. The cAMP stimulates the transformation of glycogen into glucose and lactate. Especially in diabetic patients the lack of insulin response to an increasing plasma glucose could account for the rise in free fatty acid, glycerol, and ketone-body concentrations, inducing a severe metabolic acidosis.
ATP, raises
1.
M!Ot)!9M
Blood glucose, rine.
Noon
mianignt
Noon
Mlonignt
pH ,and insulin dosage during infusion of ritod-
Time of diagnosis of fetal death is indicated by t. For blood glucose 1 mmol/1= 18 mg/dl.
Faced with a diabetic woman in preterm labour the obstetrician has to weigh the risks of worsening diabetic control by
giving beta-sympathomimetic drugs (or corticosteroids) against the risks of respiratory distress in the premature baby. When prevention of preterm delivery is essential the mother’s blood glucose and acid base balance must be carefully balanced and insulin administration by continuous infusion should be con-
sidered. Department of Obstetrics and Gynæcology, University Hospital, 9713 EZ-Groningen, Netherlands
M. S. SCHILTHUIS J. G. AARNOUDSE
PROPERDIN FACTOR B ALLELES IN PRE-ECLAMPSIA
SIR,-Your editorial (March 22, p. 364) on the genetic control of pre-eclampsia (PE) asks if genetic markers of the major histocompatibility system, other than HLA, play a part in this condition. The Bf locus maps between HLA-B and HLA-DR’ and our preliminary data suggest that this locus may be relevant to the aetiology of pre-eclampsia. We have investigated the properdin factor B (Bf) allotypes of 55 women with mild or severe pre-eclampsia.2 The frequency of phenotype BfFS was increased in patients with pre-eclampsia, in comparison with a group of random normal women (see table); however, the increase was not significant even at the 10% level. We have temporarily exhausted our supply of patients; perhaps those with access to larger numbers will be able to get a clearer result. for the major Jenkins et awl. suggested that histocompatibility system between women and their spouses
compatibility
Gündogdu AS,
Brown PM, Juul S, Sachs L, Sönksen PH. Comparison of hormonal and metabolic effects of salbutamol infusion in normal subjects and insulin-requiring diabetics. Lancet 1979; ii: 1317-21. 2. Desir D, Coevorden A, Kirkpatrick C, Caufriez A. Ritodrine-induced acidosis in pregnancy. Br Med J 1978; ii: 1194. 3. Urban G, Baumgarten K, Baumung H, Beck A, Gruber W. The influence of ntrodine on glucose and insulin blood levels after oral glucose loading in the last three months of normal pregnancy. Europ J Obstet Gynecol Reprod Biol 1973; 3: 77-79. 4. Chapman MG. Salbutamol-induced acidosis in pregnant diabetics. Br Med
J 1977; i: 639.
1. Rittner C, Grosse-Wilde H, Rittner B, Netzel B, Scholz S, Lorenz H, Albert ED. Linkage group HL-A—MLC—Bf the site of the Bf locus at the immunogenetic linkage group on chromosome 6. Humangenetik 1975; 27: 173. 2. Baird D. Epidemiological aspects of hypertensive pregnancy. Clin Obstet 3.
Gynaecol 1977; 4: 531-48. Jenkins DM, Need JA, Scott JS, Morris H, Pepper M. Human leucocyte antigens and mixed lymphocyte reaction in severe pre-eclampsia. Br Med J 1978; i: 542-44.
1146 DISTRIBUTION OF
Bf PHENOTYPES
IN WOMEN WITH
PRE-ECLAMPSIA AND IN CONTROLS
to pre-eclampsia. Women heterozygous for the two common Bf alleles (BfF and BfS) will be compatible with most males. However, women who are BfS homozygous still have a high chance of choosing a compatible partner (71% of males in our control population are BfS). The increase of BfFS in the pre-eclamptic women suggests that BfFS may predispose to the pre-eclampsia possibly because of linkage disequilibrium between alleles of the Bf locus and putative Ir
might predispose
genes. Department of Medical Genetics, University of Manchester, St Mary’s Hospital, Manchester M13 0JH
N. P. I. ARMSTRONG P. A. DYER P. T. KLOUDA R. HARRIS
PLASMA EXCHANGE IN SLE
SiR,-Your March 29 editorial deals admirably with the value of plasmapheresis in the treatment of immune complex diseases. The rationale for this therapeutic approach is that tissue damage is secondary to immune complexes which are not cleared effectively from the blood, because of saturation of the reticuloendothelial system or blocking of the IgG receptors on mononuclear phagocytic cells. Whilst the blocking effect by excessive amounts of IgG complexes on monocytes may certainly play an important part, an alternative mechanism should be considered. This invokes the polymorphonuclear leucocytes (PMN) and blocking by IgA complexes binding to IgA-Fc receptors, which in turn may interfere with the IgG receptors. Indeed, PMN from the blood of patients with SLE contain inclusions, composed of immunoglobulin and complement, indicating in vivo immune complex phagocytosis by PMN.1,2 Furthermore, IgA myeloma protein can suppress chemotaxis and phagocytosis ofPMN. 3.4 In an investigation of chemotaxis in 54 patients with Behçet’s syndrome or recurrent oral ulcers we have observed a significant negative correlation between complement activated chemotactic response of PMN and the concentration of IgA, but not IgG or IgM, in cold precipitable immune complexes.5 Moreover, IgA complexes, with or without IgG or IgM, showed a dose-dependent depression of chemotaxis (figure). Neither IgG nor IgM alone induced such a depression. Defective phagocytosis by PMN has also been observed in patients with Beh4;et’s syndrome and recurrent oral ulcers.6 1.
Vaughan JH, Barnett EV, Sobel MV, Jacox RF. Intracytoplasmic inclusions of immunoglobulins in rheumatoid arthritis and other disease. Arthr
Rheum 1968; 11: 125-34. 2. Cats A, Lafeber GJM, Klein F. Immunoglobulin phagocytosis by granulocytes from sera and synovial fluids in various rheumatoid and nonrheumatoid diseases. Ann Rheum Dis 1975; 34: 146-55. 3. Van Epps DE, Williams RC Jr. Suppression of leukocyte chemotaxis by human IgA myeloma components. J Exp Med 1976; 144: 1227-42. 4. Wilton JMA. Suppression by IgA of IgG-mediated phagocytosis by human polymorphonuclear leucocytes. Clin Exp Immunol 1978; 34: 423-8. 5. Abdulla YH, Lehner T. The effect of immune complexes on chemotaxis in Behçet’s syndrome and recurrent oral ulcers. In: Lehner T, Barnes CG, ed. Behçet’s syndrome: Clinical and immunological features. London: Academic Press, 1979: 55-66. 6. Wilton JMA, Lehner T. Defective polymorphonuclear leukocyte phagocytosis in patients with Behçet’s syndrome and recurrent oral ulcers. In: Lehner T, Barnes CG eds. Behçet’s syndrome: Clinical and immunological features. London: Academic Press, 1979: 67-75.
Effect
IgG,
on or
chemotaxis of pretreatment of normal PMN with IgA,
IgM complexes.
Cold precipitable complexes were tested in doses of 0, 1, 2, 4, and 6 fLI, and concentrations of immunoglobulins in each of four complexes are
given.
Most of the assays used for immune complexes do not detect IgA complexes, so that IgA has not been often considered in the pathogenesis of immune complex disease. However, IgA cold precipitable complexes (cryoglobulins),7,8 and IgA complexes inhibiting agglutination of IgA coated latex particles by anti-IgA9 have been found in a variety of immune complex diseases, so that they might be involved in blocking the clearance mechanism of phagocytes for IgG complexes. It would be of considerable interest to determine the relative avidity of IgA and IgG complexes for phagocytes and the differential effect of normal plasma on displacement of IgA and IgG complexes from phagocytes. Departments of Oral Immunology and Microbiology and of Pathology, Medical and Dental Schools,
Guy’s Hospital, London SE1 9RT
THOMAS LEHNER Y. H. ABDULLA
POSITIVE EHRLICHIA CANIS SEROLOGY IN KAWASAKI DISEASE
SIR,-Kawasaki disease (mucocutaneous lymph node syndrome, MLNS) is known in France and has been a special interest of two of us (B.L. and J.J.B.). However, we have not 7.
McIntosh RM, Griswold WR, Chernack WB, Williams G, Strauss J, Kaufman DB, Koss MN, McIntosh JR, Cohen R, Weil R III. Cryoglobulins III Further studies on the nature, incidence, clinical, diagnostic, prognostic
and immunopathologic significance of cryoproteins in renal disease. Quart J Med 1975; 44: 285-307. 8. Lehner T, Losito A, Gwyn Williams D. Cryoglobulins in Behçet’s syndrome and recurrent oral ulceration: Assay by laser nephelometry. Clin Exp Immunol 1979; 38: 436-44. 9. Levinsky RJ, Paganelli R, Lehner T. Immune complexes and their characterization in Behçet’s syndrome and recurrent oral ulcers. In: Lehar T, Barnes CG, eds: Behçet’s syndrome: Clinical and Immunological Features. London: Academic Press, 1979: 33-44. 1. Hamashimay, Kishi K, Tasaka K. Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph-node syndrome. Lancet 1973; ii: 42.
SiR,—The paper by Dr Giindogdu and othersi on the metabolic side effects of salbutamol in insulin-requiring diabetics prompted us to report a case of fetal death associated with ritodrine-induced metabolic acidosis during treatment of preterm labour in a diabetic patient.
28-year-old insulin-dependent diabetic (gravida 3, para 2) admitted to University Hospital at 28 weeks of pregnancy in preterm labour. Her two earlier pregnancies had ended in preterm delivery at 27 and 28 weeks and both infants had died soon after birth from severe respiratory distress. During her third pregnancy she had had a Shirodkar operation at 8 weeks. From 20 weeks until 28 weeks she was treated for mild contractions with 10 mg ritodrine daily. Her diabetes had been well controlled, insulin requirements gradually increasing to 44 units daily. In the 28th week she was admitted in preterm labour. Despite intravenous ritodrine by infusion pump at 6 mg/h, contractions persisted and she was transferred to this A
was
hospital. We continued the i.v. ritodrine at doses up to 18’ mg/h; at was controlled by repeated intramuscular insulin injections. Details of blood glucose concentration, insulin requirement, and blood pH are shown in the figure. After 26 h of treatment, during which mild contractions continued and cardiotocography showed a normal fetal heart rate pattern, the patient became progressively dyspnoeic and drowsy. Her blood glucose was 21.5mmol/l, arterial pH 6-97, pC02 1.56 kPa (11.7 mm Hg), base excess - 28-5mmoVI, and she had ketonuria. Chest X-ray and maternal ECG were normal.
first, blood glucose
The ritodrine infusion was discontinued; insulin was given by infusion pump (12 U/h), and the acidosis was corrected with i.v. bicarbonate. This resulted in clinical improvement within 3 h, the pH rising to 7.33 and blood glucose falling to 6.7mmol/l; ritodrine infusion was started again at 9 mg/h. While the mother’s condition had been deteriorating the fetus had been neglected and for 6 h no attempt had been made to record fetal heart rate. However, fetal heart activity was now undetectable, so the ritodrine infusion was discontinued and the Shirodkar ligature was removed. The patient was delivered of a still born fetus weighing 970 g. Necropsy showed bilateral cheilognathopalatoschisis but no other congenital malformations or fetal or placental abnormalities. From this observation we conclude that beta-sympathomimetics can cause a rapid deterioration of diabetic control with the development of serious ketoacidosis.
Beta-sympthomimetic agents raise the blood glucose; this frequently for salbutamol and also for ritodrine;2.3 a rise in plasma glycerol and free fatty acids has also been recorded for salbutamol.l,4 The stimulation by betasympathomimetics of adenylcyclase, which catalyses the formation of cyclic 3, 5-adenosine monophosphate (cAMP) from has been recorded
cAMP concentrations. The cAMP stimulates the transformation of glycogen into glucose and lactate. Especially in diabetic patients the lack of insulin response to an increasing plasma glucose could account for the rise in free fatty acid, glycerol, and ketone-body concentrations, inducing a severe metabolic acidosis.
ATP, raises
1.
M!Ot)!9M
Blood glucose, rine.
Noon
mianignt
Noon
Mlonignt
pH ,and insulin dosage during infusion of ritod-
Time of diagnosis of fetal death is indicated by t. For blood glucose 1 mmol/1= 18 mg/dl.
Faced with a diabetic woman in preterm labour the obstetrician has to weigh the risks of worsening diabetic control by
giving beta-sympathomimetic drugs (or corticosteroids) against the risks of respiratory distress in the premature baby. When prevention of preterm delivery is essential the mother’s blood glucose and acid base balance must be carefully balanced and insulin administration by continuous infusion should be con-
sidered. Department of Obstetrics and Gynæcology, University Hospital, 9713 EZ-Groningen, Netherlands
M. S. SCHILTHUIS J. G. AARNOUDSE
PROPERDIN FACTOR B ALLELES IN PRE-ECLAMPSIA
SIR,-Your editorial (March 22, p. 364) on the genetic control of pre-eclampsia (PE) asks if genetic markers of the major histocompatibility system, other than HLA, play a part in this condition. The Bf locus maps between HLA-B and HLA-DR’ and our preliminary data suggest that this locus may be relevant to the aetiology of pre-eclampsia. We have investigated the properdin factor B (Bf) allotypes of 55 women with mild or severe pre-eclampsia.2 The frequency of phenotype BfFS was increased in patients with pre-eclampsia, in comparison with a group of random normal women (see table); however, the increase was not significant even at the 10% level. We have temporarily exhausted our supply of patients; perhaps those with access to larger numbers will be able to get a clearer result. for the major Jenkins et awl. suggested that histocompatibility system between women and their spouses
compatibility
Gündogdu AS,
Brown PM, Juul S, Sachs L, Sönksen PH. Comparison of hormonal and metabolic effects of salbutamol infusion in normal subjects and insulin-requiring diabetics. Lancet 1979; ii: 1317-21. 2. Desir D, Coevorden A, Kirkpatrick C, Caufriez A. Ritodrine-induced acidosis in pregnancy. Br Med J 1978; ii: 1194. 3. Urban G, Baumgarten K, Baumung H, Beck A, Gruber W. The influence of ntrodine on glucose and insulin blood levels after oral glucose loading in the last three months of normal pregnancy. Europ J Obstet Gynecol Reprod Biol 1973; 3: 77-79. 4. Chapman MG. Salbutamol-induced acidosis in pregnant diabetics. Br Med
J 1977; i: 639.
1. Rittner C, Grosse-Wilde H, Rittner B, Netzel B, Scholz S, Lorenz H, Albert ED. Linkage group HL-A—MLC—Bf the site of the Bf locus at the immunogenetic linkage group on chromosome 6. Humangenetik 1975; 27: 173. 2. Baird D. Epidemiological aspects of hypertensive pregnancy. Clin Obstet 3.
Gynaecol 1977; 4: 531-48. Jenkins DM, Need JA, Scott JS, Morris H, Pepper M. Human leucocyte antigens and mixed lymphocyte reaction in severe pre-eclampsia. Br Med J 1978; i: 542-44.
1146 DISTRIBUTION OF
Bf PHENOTYPES
IN WOMEN WITH
PRE-ECLAMPSIA AND IN CONTROLS
to pre-eclampsia. Women heterozygous for the two common Bf alleles (BfF and BfS) will be compatible with most males. However, women who are BfS homozygous still have a high chance of choosing a compatible partner (71% of males in our control population are BfS). The increase of BfFS in the pre-eclamptic women suggests that BfFS may predispose to the pre-eclampsia possibly because of linkage disequilibrium between alleles of the Bf locus and putative Ir
might predispose
genes. Department of Medical Genetics, University of Manchester, St Mary’s Hospital, Manchester M13 0JH
N. P. I. ARMSTRONG P. A. DYER P. T. KLOUDA R. HARRIS
PLASMA EXCHANGE IN SLE
SiR,-Your March 29 editorial deals admirably with the value of plasmapheresis in the treatment of immune complex diseases. The rationale for this therapeutic approach is that tissue damage is secondary to immune complexes which are not cleared effectively from the blood, because of saturation of the reticuloendothelial system or blocking of the IgG receptors on mononuclear phagocytic cells. Whilst the blocking effect by excessive amounts of IgG complexes on monocytes may certainly play an important part, an alternative mechanism should be considered. This invokes the polymorphonuclear leucocytes (PMN) and blocking by IgA complexes binding to IgA-Fc receptors, which in turn may interfere with the IgG receptors. Indeed, PMN from the blood of patients with SLE contain inclusions, composed of immunoglobulin and complement, indicating in vivo immune complex phagocytosis by PMN.1,2 Furthermore, IgA myeloma protein can suppress chemotaxis and phagocytosis ofPMN. 3.4 In an investigation of chemotaxis in 54 patients with Behçet’s syndrome or recurrent oral ulcers we have observed a significant negative correlation between complement activated chemotactic response of PMN and the concentration of IgA, but not IgG or IgM, in cold precipitable immune complexes.5 Moreover, IgA complexes, with or without IgG or IgM, showed a dose-dependent depression of chemotaxis (figure). Neither IgG nor IgM alone induced such a depression. Defective phagocytosis by PMN has also been observed in patients with Beh4;et’s syndrome and recurrent oral ulcers.6 1.
Vaughan JH, Barnett EV, Sobel MV, Jacox RF. Intracytoplasmic inclusions of immunoglobulins in rheumatoid arthritis and other disease. Arthr
Rheum 1968; 11: 125-34. 2. Cats A, Lafeber GJM, Klein F. Immunoglobulin phagocytosis by granulocytes from sera and synovial fluids in various rheumatoid and nonrheumatoid diseases. Ann Rheum Dis 1975; 34: 146-55. 3. Van Epps DE, Williams RC Jr. Suppression of leukocyte chemotaxis by human IgA myeloma components. J Exp Med 1976; 144: 1227-42. 4. Wilton JMA. Suppression by IgA of IgG-mediated phagocytosis by human polymorphonuclear leucocytes. Clin Exp Immunol 1978; 34: 423-8. 5. Abdulla YH, Lehner T. The effect of immune complexes on chemotaxis in Behçet’s syndrome and recurrent oral ulcers. In: Lehner T, Barnes CG, ed. Behçet’s syndrome: Clinical and immunological features. London: Academic Press, 1979: 55-66. 6. Wilton JMA, Lehner T. Defective polymorphonuclear leukocyte phagocytosis in patients with Behçet’s syndrome and recurrent oral ulcers. In: Lehner T, Barnes CG eds. Behçet’s syndrome: Clinical and immunological features. London: Academic Press, 1979: 67-75.
Effect
IgG,
on or
chemotaxis of pretreatment of normal PMN with IgA,
IgM complexes.
Cold precipitable complexes were tested in doses of 0, 1, 2, 4, and 6 fLI, and concentrations of immunoglobulins in each of four complexes are
given.
Most of the assays used for immune complexes do not detect IgA complexes, so that IgA has not been often considered in the pathogenesis of immune complex disease. However, IgA cold precipitable complexes (cryoglobulins),7,8 and IgA complexes inhibiting agglutination of IgA coated latex particles by anti-IgA9 have been found in a variety of immune complex diseases, so that they might be involved in blocking the clearance mechanism of phagocytes for IgG complexes. It would be of considerable interest to determine the relative avidity of IgA and IgG complexes for phagocytes and the differential effect of normal plasma on displacement of IgA and IgG complexes from phagocytes. Departments of Oral Immunology and Microbiology and of Pathology, Medical and Dental Schools,
Guy’s Hospital, London SE1 9RT
THOMAS LEHNER Y. H. ABDULLA
POSITIVE EHRLICHIA CANIS SEROLOGY IN KAWASAKI DISEASE
SIR,-Kawasaki disease (mucocutaneous lymph node syndrome, MLNS) is known in France and has been a special interest of two of us (B.L. and J.J.B.). However, we have not 7.
McIntosh RM, Griswold WR, Chernack WB, Williams G, Strauss J, Kaufman DB, Koss MN, McIntosh JR, Cohen R, Weil R III. Cryoglobulins III Further studies on the nature, incidence, clinical, diagnostic, prognostic
and immunopathologic significance of cryoproteins in renal disease. Quart J Med 1975; 44: 285-307. 8. Lehner T, Losito A, Gwyn Williams D. Cryoglobulins in Behçet’s syndrome and recurrent oral ulceration: Assay by laser nephelometry. Clin Exp Immunol 1979; 38: 436-44. 9. Levinsky RJ, Paganelli R, Lehner T. Immune complexes and their characterization in Behçet’s syndrome and recurrent oral ulcers. In: Lehar T, Barnes CG, eds: Behçet’s syndrome: Clinical and Immunological Features. London: Academic Press, 1979: 33-44. 1. Hamashimay, Kishi K, Tasaka K. Rickettsia-like bodies in infantile acute febrile mucocutaneous lymph-node syndrome. Lancet 1973; ii: 42.