370 of females in all groups,
must
be the
subject of further investi-
gation. Medicines Evaluation and
Monitoring Group, Royal Infirmary, Aberdeen AB9 2ZB
DOROTHY C. MOIR
DEATH FROM ACUTE PANCREATITIS
SIR The M.R.C. multicentre study’ compared glucagon and trasylol with placebo on a double-blind basis. Of 257 patients 123 received placebo, 68 were treated with glucagon, and 66 with trasylol. The mortality-rate for all patients was 10 - 7%; 11% for placebo, 12% for glucagon, and 9% for trasy-. lol. It was thus concluded that both drug treatments were ineffective. But the statistical design and the results of the M.R.C. study raise serious questions about the validity of this conclusion. Trapnell et al.2 found that trasylol reduced the mortality-rate by 70% compared with non-treated patients. To confirm these results, or even to demonstrate a reduction of mortality-rate of only 3% with trasylol, the M.R.C. study would have had to have at least 200 patients per experimental group--i.e., more than twice the number of patients. To demonstrate a mortality reduction of 5% (a clinically remarkable effect in this condition) would have demanded at least 428 patients per experimental group. This patient number would have satisfied the known relationship between the expected frequency of a result (mortality-rate) and the expected statistical difference between two patient groups. Such a study probably could not have been done since it would have lasted for years. The stringent selection of criteria for inclusion of patients in Trapnell’s study allowed for a reduction of the number of patients required for statistical evaluation. While the severity and the number of patients in the M.R.C. study raise questions about the conclusions, the data still show some support for Trapnell’s conclusion. A series of 25 severe cases were reported separately, patients who, for therapeutic or diagnostic reasons, had to have surgery. 10 of these (40%) died, a mortality-rate probably reflecting the severity of the disease.’ Classified according to therapy, the mortality-rate in each group is as follows : placebo group, 5 of 11 (45%); glucagon group, 4 of 8 (50%); trasylol group, 1 of 6 (17%). Thus, statistically, the trasylol data do not differ significantly from those obtained by Trapnell since in both studies, evaluating only severe pancreatitis cases, trasylol treatment resulted in equivalent reduction of mortality. Department of Biochemical Pharmacology, State University of New York at Buffalo, New York 14260, U.S.A.
NATHAN BACK
INTRAUTERINE HYPOTHYROIDISM DUE TO ANTITHYROID-DRUG THERAPY FOR THYROTOXICOSIS DURING PREGNANCY
SIR,-Antithyroid drugs can cross the placenta and impair thyroid function in fetus, leading to goitre formation with or without hypothyroidism.3 Neonatal goitres in infants born to mothers who have taken antithyroid drugs during pregnancy for thyrotoxicosis probably result from increased secretion of fetal thyroid-stimulating hormone (T.S.H.) in response
the
the depressed fetal thyroid-hormone output induced by the placental transfer of these drugs. Increased T.S.H. levels in the cord blood have been reported in infants who have druginduced goitres.4 However, little is known about thyroid hormone or T.s.H. levels in the neonatal period in infants who are to
.
1. M.R.C. Multicentre Trial. Lancet, 1977, ii, 632. 2. Trapnell, J. E., Rigby, C. C., Talbot, C. H., Duncan, E. H. L.
1974, 61, 177. 3. Burrow, G. N.J. clin. Endocr. Metab. 1965, 25, 403. 4. Refetoff, S., and others. J. Pediat. 1974, 85, 240.
DAYS POST-PARTUM
Thyroid biochemistry post partum. to antithyroid drugs in utero and who have no goitre clinical evidence of hypothyroidism.s We have information on two such infants during the first three weeks of life. Both infants were delivered spontaneously at term and appeared clinically euthyroid and without thyroid enlargement. The mother of baby A was thyrotoxic and taking 40 mg carbimazole and 80 µg triiodothyronine daily when she first came to our clinic at 24 weeks’ gestation. The drugs were stopped but had to be restarted at 34 weeks because of recurrence of symptoms, and carbimazole 30 mg/day with 60 µg of triiodothyronine was continued until delivery. The mother of baby M received carbimazole alone 15-30 mg/day throughout pregnancy, and she was on 30 mg at the time of delivery. The thyroid biochemistry of the mothers at the time of delivery was:
exposed
or
Mother of A Mother of M Normal range (in non-pregnant patients)
T4
T3
Binding capacity
(nmol//)
(nmol/l)
(%)
175 4-7 140 1.9 55-144
0.9-2.8
133 129 ..
The serum thyroxine (T4), triiodothyronine (T3), and T.S.H. in the neonatal period of these two infants are shown in the figure. The serum-T.S.H. was high in cord blood and at 6 h and 24 h but it returned to near normal within 72 h after delivery. High cord-blood T.S.H. can be caused by extreme parturition stress and hypoxia6 but in their absence the likely cause of the raised T.S.H. levels in these two infants is maternal antithyroid drug therapy. The rise in T4 at about 24 h after delivery induced by the surge of T.S.H. secretion shortly after birth’ was not observed in these two infants. The effect of placentally transferred antithyroid drugs on the fetal pituitary-thyroid axis seems transient, with recovery within 72 h after withdrawal of exposure. These data are consistent with a state of relative hypothyroidism, and presumably this existed in utero throughout the time the mother was receiving antithyroid drugs during her pregnancy. The first case (A) shows that this state is not prevented by simultaneous administration of amounts of triiodothyronine sufficient to raise the circulating maternal level. Can relative hypothy-
Br. J. Surg. 5. 6. 7.
Hayek, A., Brooks, M. ibid. 1975,87,446. Walfish, P. G. Lancet, 1976,i, 1208. Erenberg, A., and others. Pediatrics, 1974, 53, 211.
must
be the
subject of further investi-
gation. Medicines Evaluation and
Monitoring Group, Royal Infirmary, Aberdeen AB9 2ZB
DOROTHY C. MOIR
DEATH FROM ACUTE PANCREATITIS
SIR The M.R.C. multicentre study’ compared glucagon and trasylol with placebo on a double-blind basis. Of 257 patients 123 received placebo, 68 were treated with glucagon, and 66 with trasylol. The mortality-rate for all patients was 10 - 7%; 11% for placebo, 12% for glucagon, and 9% for trasy-. lol. It was thus concluded that both drug treatments were ineffective. But the statistical design and the results of the M.R.C. study raise serious questions about the validity of this conclusion. Trapnell et al.2 found that trasylol reduced the mortality-rate by 70% compared with non-treated patients. To confirm these results, or even to demonstrate a reduction of mortality-rate of only 3% with trasylol, the M.R.C. study would have had to have at least 200 patients per experimental group--i.e., more than twice the number of patients. To demonstrate a mortality reduction of 5% (a clinically remarkable effect in this condition) would have demanded at least 428 patients per experimental group. This patient number would have satisfied the known relationship between the expected frequency of a result (mortality-rate) and the expected statistical difference between two patient groups. Such a study probably could not have been done since it would have lasted for years. The stringent selection of criteria for inclusion of patients in Trapnell’s study allowed for a reduction of the number of patients required for statistical evaluation. While the severity and the number of patients in the M.R.C. study raise questions about the conclusions, the data still show some support for Trapnell’s conclusion. A series of 25 severe cases were reported separately, patients who, for therapeutic or diagnostic reasons, had to have surgery. 10 of these (40%) died, a mortality-rate probably reflecting the severity of the disease.’ Classified according to therapy, the mortality-rate in each group is as follows : placebo group, 5 of 11 (45%); glucagon group, 4 of 8 (50%); trasylol group, 1 of 6 (17%). Thus, statistically, the trasylol data do not differ significantly from those obtained by Trapnell since in both studies, evaluating only severe pancreatitis cases, trasylol treatment resulted in equivalent reduction of mortality. Department of Biochemical Pharmacology, State University of New York at Buffalo, New York 14260, U.S.A.
NATHAN BACK
INTRAUTERINE HYPOTHYROIDISM DUE TO ANTITHYROID-DRUG THERAPY FOR THYROTOXICOSIS DURING PREGNANCY
SIR,-Antithyroid drugs can cross the placenta and impair thyroid function in fetus, leading to goitre formation with or without hypothyroidism.3 Neonatal goitres in infants born to mothers who have taken antithyroid drugs during pregnancy for thyrotoxicosis probably result from increased secretion of fetal thyroid-stimulating hormone (T.S.H.) in response
the
the depressed fetal thyroid-hormone output induced by the placental transfer of these drugs. Increased T.S.H. levels in the cord blood have been reported in infants who have druginduced goitres.4 However, little is known about thyroid hormone or T.s.H. levels in the neonatal period in infants who are to
.
1. M.R.C. Multicentre Trial. Lancet, 1977, ii, 632. 2. Trapnell, J. E., Rigby, C. C., Talbot, C. H., Duncan, E. H. L.
1974, 61, 177. 3. Burrow, G. N.J. clin. Endocr. Metab. 1965, 25, 403. 4. Refetoff, S., and others. J. Pediat. 1974, 85, 240.
DAYS POST-PARTUM
Thyroid biochemistry post partum. to antithyroid drugs in utero and who have no goitre clinical evidence of hypothyroidism.s We have information on two such infants during the first three weeks of life. Both infants were delivered spontaneously at term and appeared clinically euthyroid and without thyroid enlargement. The mother of baby A was thyrotoxic and taking 40 mg carbimazole and 80 µg triiodothyronine daily when she first came to our clinic at 24 weeks’ gestation. The drugs were stopped but had to be restarted at 34 weeks because of recurrence of symptoms, and carbimazole 30 mg/day with 60 µg of triiodothyronine was continued until delivery. The mother of baby M received carbimazole alone 15-30 mg/day throughout pregnancy, and she was on 30 mg at the time of delivery. The thyroid biochemistry of the mothers at the time of delivery was:
exposed
or
Mother of A Mother of M Normal range (in non-pregnant patients)
T4
T3
Binding capacity
(nmol//)
(nmol/l)
(%)
175 4-7 140 1.9 55-144
0.9-2.8
133 129 ..
The serum thyroxine (T4), triiodothyronine (T3), and T.S.H. in the neonatal period of these two infants are shown in the figure. The serum-T.S.H. was high in cord blood and at 6 h and 24 h but it returned to near normal within 72 h after delivery. High cord-blood T.S.H. can be caused by extreme parturition stress and hypoxia6 but in their absence the likely cause of the raised T.S.H. levels in these two infants is maternal antithyroid drug therapy. The rise in T4 at about 24 h after delivery induced by the surge of T.S.H. secretion shortly after birth’ was not observed in these two infants. The effect of placentally transferred antithyroid drugs on the fetal pituitary-thyroid axis seems transient, with recovery within 72 h after withdrawal of exposure. These data are consistent with a state of relative hypothyroidism, and presumably this existed in utero throughout the time the mother was receiving antithyroid drugs during her pregnancy. The first case (A) shows that this state is not prevented by simultaneous administration of amounts of triiodothyronine sufficient to raise the circulating maternal level. Can relative hypothy-
Br. J. Surg. 5. 6. 7.
Hayek, A., Brooks, M. ibid. 1975,87,446. Walfish, P. G. Lancet, 1976,i, 1208. Erenberg, A., and others. Pediatrics, 1974, 53, 211.
