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METHYLDOPA AND CHILD DEVELOPMENT
1076 obstetric skill, has been replaced by DNA analysis of amniotic fluid cells.3,4 Immunoglobulins produced by the fetus were, for many years, thought to be absent from amniotic fluid.s Newer, more sensitive methods, however, have demonstrated fetal IgM and IgA in the amniotic fluid throughout gestation. 6,Absence of fetally produced immunoglobulins could thus be used to confirm the diagnosis of SCID in a fetus at risk with little risk of accidentally aborting a normal fetus. The presence of these immunoglobulins in amniotic fluid would rule
out
SCID.
Department of Obstetrics and Gynecology, Cornell University Medical College, New York, N. Y. 10021, U.S.A.
LARS L. CEDERQVIST
METHYLDOPA AND CHILD DEVELOPMENT
SIR,-It would be regrettable if the Final Report of Study on Hypertension during Pregnancy by J. Cockburn and colleagues (March 20, p. 647) were the last to be heard of this topic. The painstaking work of this group has clearly demonstrated that methyldopa taken by the mother during the mid-trimester of pregnancy causes, in males at least, not only impaired brain growth but also impaired skeletal growth of an apparently permanent nature. This effect, from the use of a drug influencing the metabolism of dopamine, an important central neurotransmitter, surely invites further experimental study of the basic mechanisms involved. What part does dopamine play in the brain growth spurt which normally occurs in mid-pregnancy? Is the effect of methyldopa selective, or does it affect all forms of neuroblast multiplication? Is the impaired skeletal growth a primary effect, or is it secondary to the effect on brain growth? The answers to these questions might be found from further work in animals and could cast light on the central mechanisms regulating body growth, about which we know little. Gynaecological Pavilion, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW
PHILIP R. MYERSCOUGH Consultant
CALCIUM AND BLOOD PRESSURE
SIR,-Professor Kesteloot and Mr Geboers (April 10, p. 813) claim to have found only one previous report of an association between calcium and blood pressure. This topic has been investigated many times in the context of hyperparathyroidism. 1-9 In our 1977 studyl° of hypercalcaemic subjects in whom other causes of hypercalcaemia except hyperparathyroidism had been excluded the hypercalcaemia was verified by repeated tests. 66 nonthiazide-treated patients were detected in a health screening investigation of nearly 16 000 people in the Stockholm area. There were 55 females and 13 males aged 55 - 0±0 - 7 (SEM). On a pair basis these patients were compared with a series of 60 age and sex matched normocalcaemic subjects, selected from the health screening register. 5 subjects in each group were receiving medication for hypertension. Systolic and diastolic blood pressures were significantly higher in the hypercalcaemic subjects in the remaining fifty-eight pairs (p<0’001). This difference was unrelated to impaired renal filtration and other factors known to be associated with hypertension. It was concluded that hypercalcaemia and/or other effects of deranged parathyroid function per se may result in a blood pressure increase which need not necessarily attain the level of hypertension. A 10-year prospective follow-up study is now being done on these groups and blood pressure data before and after neck exploration in patients operated upon because of parathyroid adenomas are being evaluated. Department of Medicine, St Erik’s Hospital, S-11282 Stockholm, Sweden
TONY CHRISTENSSON
SIR,-Would the relation between calcium and blood pressure reported by Professor Kesteloot and Mr Geboers be sustained if they had used calcium adjusted for albumin in preference to total serum calcium? In men serum albumin falls by about 1 g/1 per decade. 11-16 The fall in total serum calcium of 0 - 05 mmol/1 between Kesteloot and Geboers’ youngest and oldest groups can be explained by a fall of about 2 - 5 g/1 in albumin. 17 In women, however, there is little change in albumin over the decades (and consequently in calcium adjusted for albumin) and this might explain the finding that in the women there was no significant relation between total J, Birke G, Edvall CA. Hypertension in hyperparathyroidism. Br J Urol 1958;30: 13-24. 2. Pyrah LN, Hodgkinson A, Anderson CK Primary hyperparathyroidism: Critical review. Br J Surg 1966; 53: 245-316. 3 Madhavan T, Frame B, Block MA Influence of surgical correction of primary hyperparathyroidism on associated hypertension. Arch Surg 1970, 100: 212-14 4. Rosenthal FD, Roy S. Hypertension and hyperparathyroidism. Br Med J 1972; iv. 1. Hellström
MEDIAN SURVIVAL TIME
SIR,-I thank Mr Wallemark (April 3. p. 802) and Dr Kirkham (March 6, p. 570) for their replies to my letter on the half-life principle in the interpretation of survival curves. They highlight an important source of confusion in the use of the term "median survival time". This term seems to be being used in two entirely different ways-first, and usually by statisticians, to indicate the time interval at which the survival rate drops to 50%, and, second, usually by clinicians, in the literal sense of the raw median of the survival times (i.e., the central observation when survival times are placed in rank order). The values for these two differ widely in the usual situation of a series of patients some of whom are alive and some of whom are dead, and the two observations can only coincide in a series where all patients are dead, a very unusual circumstance. Might I suggest that those who use the term define exactly what they mean by it. Would it also be reasonable to ask that future confusion be prevented by using a different term for one or the other. Perhaps "half-life" or to. 5 would be a clearer definition of the first usage. University Department of Oto-rhino-laryngology, Royal Liverpool Hospital, Liverpool L69 3BX
P. M. STELL
3 Kan YW, Dozy AM. Antenatal diagnosis of sickle-cell anaemia by DNA analysis of amniotic fluid cells. Lancet 1978; ii: 910-12. 4. Rothe OJ, Cederqvist LL, Zervoudakis IA, Fuchs F. Orgnaisation of ammocentesis for antenatal genetic diagnosis. Acta Obstet Gynaecol Scand 1978; 57: 7-11. 5 Wilfert CM, Alford CA. No IgM in amniotic fluid. J Infect Dis 1974; 129: 604-05. 6. Cederqvist LL, Litwin SD. Production of &agr; 1 and &agr;2 immunoglobulin heavy chains during fetal life. J Immunol 1974; 112: 1605-08. 7. Cederqvist LL, Ewool LC, Bonsnes RW, Litwin SD Detectability and pattern of
immunoglobulin
in
1978; 130: 220-24.
normal
amniotic
fluid
throughout gestation. J Obstet Gynecol
396-97. 5. 6. 7
8.
Johansson H, Thorén L, Werner I. Hyperparathyroidism. Clinical experiences from 208 cases. Upsala J Med Sci 1972; 77: 41-46. Romanus R, Heimann P, Nilsson O, Hansson G. Surgical treatment of hyperparathyroidism. Progr Surg 1973; 12: 22-76. Genant HK, Heck LL, Lanzl LH, Rossmann K, Van der Horst J, Paloyan E Primary hyperparathyroidism Radiology 1973; 109: 513-24. Mallette LE, Bilezikiam JP, Heath DA, Aurbách GD. Primary hyperparathyroidism.
clinical and biochemical features. Medicine 1974, 53: 127-46. hyperparathyreoidism: En studie av 160 patienter med särskild hänsyn till njurfunktion och stensjukdom efter operation. Academic thesis. Gothenburg: Uno Lundgren Tryckeri, 1975. 10 Christensson T, Hellström K, Wengle B. Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme. Europ J Clin Invest 1977; 7: 109-13. 11. Keating FR, Jr, Jones JD, Elveback LR, Randall RV.The relation of age and sex distribution of values in healthy adults of serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, total proteins, albumin and blood urea. J Lab Clin Med 1969; 73: 825-34. 12. O’Kell RT, Elliott JR Development of normal values for use in multitest biochemical screening of sera. Clin Chem 1970; 16: 161-5. 13 McPherson K, Healy MJR, Flynn FV, Piper KAJ, Garcia-Webb P. The effect of age, sex, and other factors on blood chemistry in health. Clin Chim Acta 1978; 84: 373-97. 14. Reed AH, Cannon DC, Winkelman JW, Bhasin YP, Henry RJ, Pileggi VJ. Estimation of normal ranges from a controlled sample survey I: Sex- and age-related influence on the SMA 12/60 screening group of tests. Clin Chem 1972; 18: 57-66. 15. Wilding P, Rollason JG, Robinson D. Patterns of change for various biochemical constituents detected in well population screening. Clin Chim Acta 1972, 41: 375-87. 16. Gardner MD, Scott R. Age and sex-related reference ranges for eight plasma constituents derived from randomly selected adults in a Scottish new town. J Clin Pathol 1980; 33: 380-85 17. Kennedy AC, Allam BF, Boyle IT, et al Abnormalities in mineral metabolism suggestive of parathyroid overactivity in rheumatoid arthritis. Curr Med Res Opin 1975; 3: 345-58. 9. Ohlsson L. Primär
out
SCID.
Department of Obstetrics and Gynecology, Cornell University Medical College, New York, N. Y. 10021, U.S.A.
LARS L. CEDERQVIST
METHYLDOPA AND CHILD DEVELOPMENT
SIR,-It would be regrettable if the Final Report of Study on Hypertension during Pregnancy by J. Cockburn and colleagues (March 20, p. 647) were the last to be heard of this topic. The painstaking work of this group has clearly demonstrated that methyldopa taken by the mother during the mid-trimester of pregnancy causes, in males at least, not only impaired brain growth but also impaired skeletal growth of an apparently permanent nature. This effect, from the use of a drug influencing the metabolism of dopamine, an important central neurotransmitter, surely invites further experimental study of the basic mechanisms involved. What part does dopamine play in the brain growth spurt which normally occurs in mid-pregnancy? Is the effect of methyldopa selective, or does it affect all forms of neuroblast multiplication? Is the impaired skeletal growth a primary effect, or is it secondary to the effect on brain growth? The answers to these questions might be found from further work in animals and could cast light on the central mechanisms regulating body growth, about which we know little. Gynaecological Pavilion, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW
PHILIP R. MYERSCOUGH Consultant
CALCIUM AND BLOOD PRESSURE
SIR,-Professor Kesteloot and Mr Geboers (April 10, p. 813) claim to have found only one previous report of an association between calcium and blood pressure. This topic has been investigated many times in the context of hyperparathyroidism. 1-9 In our 1977 studyl° of hypercalcaemic subjects in whom other causes of hypercalcaemia except hyperparathyroidism had been excluded the hypercalcaemia was verified by repeated tests. 66 nonthiazide-treated patients were detected in a health screening investigation of nearly 16 000 people in the Stockholm area. There were 55 females and 13 males aged 55 - 0±0 - 7 (SEM). On a pair basis these patients were compared with a series of 60 age and sex matched normocalcaemic subjects, selected from the health screening register. 5 subjects in each group were receiving medication for hypertension. Systolic and diastolic blood pressures were significantly higher in the hypercalcaemic subjects in the remaining fifty-eight pairs (p<0’001). This difference was unrelated to impaired renal filtration and other factors known to be associated with hypertension. It was concluded that hypercalcaemia and/or other effects of deranged parathyroid function per se may result in a blood pressure increase which need not necessarily attain the level of hypertension. A 10-year prospective follow-up study is now being done on these groups and blood pressure data before and after neck exploration in patients operated upon because of parathyroid adenomas are being evaluated. Department of Medicine, St Erik’s Hospital, S-11282 Stockholm, Sweden
TONY CHRISTENSSON
SIR,-Would the relation between calcium and blood pressure reported by Professor Kesteloot and Mr Geboers be sustained if they had used calcium adjusted for albumin in preference to total serum calcium? In men serum albumin falls by about 1 g/1 per decade. 11-16 The fall in total serum calcium of 0 - 05 mmol/1 between Kesteloot and Geboers’ youngest and oldest groups can be explained by a fall of about 2 - 5 g/1 in albumin. 17 In women, however, there is little change in albumin over the decades (and consequently in calcium adjusted for albumin) and this might explain the finding that in the women there was no significant relation between total J, Birke G, Edvall CA. Hypertension in hyperparathyroidism. Br J Urol 1958;30: 13-24. 2. Pyrah LN, Hodgkinson A, Anderson CK Primary hyperparathyroidism: Critical review. Br J Surg 1966; 53: 245-316. 3 Madhavan T, Frame B, Block MA Influence of surgical correction of primary hyperparathyroidism on associated hypertension. Arch Surg 1970, 100: 212-14 4. Rosenthal FD, Roy S. Hypertension and hyperparathyroidism. Br Med J 1972; iv. 1. Hellström
MEDIAN SURVIVAL TIME
SIR,-I thank Mr Wallemark (April 3. p. 802) and Dr Kirkham (March 6, p. 570) for their replies to my letter on the half-life principle in the interpretation of survival curves. They highlight an important source of confusion in the use of the term "median survival time". This term seems to be being used in two entirely different ways-first, and usually by statisticians, to indicate the time interval at which the survival rate drops to 50%, and, second, usually by clinicians, in the literal sense of the raw median of the survival times (i.e., the central observation when survival times are placed in rank order). The values for these two differ widely in the usual situation of a series of patients some of whom are alive and some of whom are dead, and the two observations can only coincide in a series where all patients are dead, a very unusual circumstance. Might I suggest that those who use the term define exactly what they mean by it. Would it also be reasonable to ask that future confusion be prevented by using a different term for one or the other. Perhaps "half-life" or to. 5 would be a clearer definition of the first usage. University Department of Oto-rhino-laryngology, Royal Liverpool Hospital, Liverpool L69 3BX
P. M. STELL
3 Kan YW, Dozy AM. Antenatal diagnosis of sickle-cell anaemia by DNA analysis of amniotic fluid cells. Lancet 1978; ii: 910-12. 4. Rothe OJ, Cederqvist LL, Zervoudakis IA, Fuchs F. Orgnaisation of ammocentesis for antenatal genetic diagnosis. Acta Obstet Gynaecol Scand 1978; 57: 7-11. 5 Wilfert CM, Alford CA. No IgM in amniotic fluid. J Infect Dis 1974; 129: 604-05. 6. Cederqvist LL, Litwin SD. Production of &agr; 1 and &agr;2 immunoglobulin heavy chains during fetal life. J Immunol 1974; 112: 1605-08. 7. Cederqvist LL, Ewool LC, Bonsnes RW, Litwin SD Detectability and pattern of
immunoglobulin
in
1978; 130: 220-24.
normal
amniotic
fluid
throughout gestation. J Obstet Gynecol
396-97. 5. 6. 7
8.
Johansson H, Thorén L, Werner I. Hyperparathyroidism. Clinical experiences from 208 cases. Upsala J Med Sci 1972; 77: 41-46. Romanus R, Heimann P, Nilsson O, Hansson G. Surgical treatment of hyperparathyroidism. Progr Surg 1973; 12: 22-76. Genant HK, Heck LL, Lanzl LH, Rossmann K, Van der Horst J, Paloyan E Primary hyperparathyroidism Radiology 1973; 109: 513-24. Mallette LE, Bilezikiam JP, Heath DA, Aurbách GD. Primary hyperparathyroidism.
clinical and biochemical features. Medicine 1974, 53: 127-46. hyperparathyreoidism: En studie av 160 patienter med särskild hänsyn till njurfunktion och stensjukdom efter operation. Academic thesis. Gothenburg: Uno Lundgren Tryckeri, 1975. 10 Christensson T, Hellström K, Wengle B. Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme. Europ J Clin Invest 1977; 7: 109-13. 11. Keating FR, Jr, Jones JD, Elveback LR, Randall RV.The relation of age and sex distribution of values in healthy adults of serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, total proteins, albumin and blood urea. J Lab Clin Med 1969; 73: 825-34. 12. O’Kell RT, Elliott JR Development of normal values for use in multitest biochemical screening of sera. Clin Chem 1970; 16: 161-5. 13 McPherson K, Healy MJR, Flynn FV, Piper KAJ, Garcia-Webb P. The effect of age, sex, and other factors on blood chemistry in health. Clin Chim Acta 1978; 84: 373-97. 14. Reed AH, Cannon DC, Winkelman JW, Bhasin YP, Henry RJ, Pileggi VJ. Estimation of normal ranges from a controlled sample survey I: Sex- and age-related influence on the SMA 12/60 screening group of tests. Clin Chem 1972; 18: 57-66. 15. Wilding P, Rollason JG, Robinson D. Patterns of change for various biochemical constituents detected in well population screening. Clin Chim Acta 1972, 41: 375-87. 16. Gardner MD, Scott R. Age and sex-related reference ranges for eight plasma constituents derived from randomly selected adults in a Scottish new town. J Clin Pathol 1980; 33: 380-85 17. Kennedy AC, Allam BF, Boyle IT, et al Abnormalities in mineral metabolism suggestive of parathyroid overactivity in rheumatoid arthritis. Curr Med Res Opin 1975; 3: 345-58. 9. Ohlsson L. Primär