692 but
wasting of calories, and
no
hence
no
benefit
to
the obese
patient. Clinical Research Centre, Watford Road, Harrow, Middlesex HA1
3UJ
J. S. GARROW
WARFARIN AND FETAL ABNORMALITY
SiR,—Hypoplasia of nasal structures and mental retardation have been reported in the offspring of mothers who took warfarin throughout pregnancy.’ Chondrodysplasia punctata and brachydactyly have also been noted .23Haemorrhage and a high frequency of abortion have been demonstrated in laboratory animals treated with warfarin derivatives during
pregnancy.4 We have
seen a patient at the genetic clinic whose mother treated with warfarin (’Coumadin’) for the last six months of pregnancy. Our patient showed marked microcephaly with bifrontal narrowing, questionable blindness, and secondary findings of hypotonia and developmental retardation. Skeletal X-rays showed no epiphyseal stippling or other significant abnormality. Studies for rubella, cytomegalovirus, toxoplasma, and herpes virus were all negative. We wonder whether the baby’s abnormality might be due to the warfarin and invite any comment from others who may have noted abnormalities when warfarin derivatives were used late in pregnancy after the critical period of fetal morphowas
found 4 who had sufficient abnormalities to allow a diagnosis of fetal hydantoin syndrome. An additional 11 children each showed some features compatible with the prenatal effects of hydantoins, though the composite pattern was not sufficiently striking to allow a diagnosis of fetal hydantoin syndrome, Among these children, mental deficiency was the single feature warranting the most serious concern. Single malformations were relatively infrequent. Thus ascertainment by single major defects alone has, in our experience, been a less sensitive method of detecting seriously affected children. We have yet to see an infant with the composite pattern described whose mother had not taken one of the hydantoin anticonvulsants. On the other hand, we have seen several affected infants whose mothers were receiving a hydantoin only. For this reason, we believe hydantoin anticonvulsants do present a serious risk to the fetus over and any effect attributable to the convulsive disorder itself. We believe that women with convulsive disorders should be warned of the potential serious risks to the fetus related to hydantoin therapy. Sometimes it may be possible to stop hydantoin treatment. Whether other commonly used anticonvulsants present a serious teratogenic risk for man needs further investigation.
beyond
University of Washington Dysmorphology Unit, Department of Pediatrics, School of Medicine, Seattle, Washington 98195, U.S.A.
JAMES W. HANSON DAVID W. SMITH
genesis. Department of Pediatrics, University of California, San Francisco, California 94143, U.S.A.
SANDFORD SHERMAN BRYAN D. HALL
WHICH PROSTHETIC VALVE?
artificial heart valves (March 20, draw valid conclusions in this confused area. Unfortunately, it is both misleading and potentially hazardous, since simplistic conclusions have been drawn from inadequate data, which may encourage physicians to refer patients for valve surgery with a rider on the type of device that should be used. Valve replacement is a complex technique where the combinations and permutations are infinite; thus, it is highly unlikely that any two surgeons perform an identical operation, You have succumbed to the obvious temptation of correlating the mortality-rates from widely differing units with the device used to replace the abnormal valve, then attributing success or failure to this alone. Equally interesting data might have been obtained by correlating the results with the day of the week (i.e., with a particular surgeon). Starr’s1 3% operative-mortality rate in an unselected group indicates that some of the indifferent results cited are due to factors other than the hydraulic properties of the prosthesis. There is now abundant evidence 2-4 that a prime factor in the causation of operative deaths (generally from myocardial failure associated with dysrhythmias) is failure to protect the
SiR,—Your editorial
p. 619) is
FETAL HYDANTOIN SYNDROME
SIR,-Dr Shapiro and his colleagues (Feb. 7, p. 272) suggest that convulsive disorders per se rather than differences in drug therapy during pregnancy may account for the increased risk of malformation in the fetuses of epileptic women. Their conclusion is based upon an examination of rates of single malformations, and, as they point out, they did not consider characteristic patterns of abnormalities which might be associated with specific drugs. We have also examined the records of infants born to mothers with convulsive disorders treated with hydantoin anticonvulsants and a matched series of normal controls from the same Collaborative Perinatal Project. Besides minor differences in the choice of patients, our study design varied significantly from that of the Boston group. We attempted to determine the frequency of a specific pattern of abnormalities, the fetal hydantoin syndrome.5 We compared the frequencies of dysmorphic features and alterations of growth and performance characteristic of the total fetal hydantoin syndrome in the two groups. A full report will appear in the Journal of Pediatrics. 11% of children exposed prenatally to hydantoins displayed a broad pattern of altered growth, morphogenesis, and performance suggestive of the fetal hydantoin syndrome. No such children were found in the control group. There was also a significant difference in i.Q. scores between the groups at seven years of age, the hydantoin-exposed offspring having the lower scores. These results are similar to our experience in the Seattle area. Among a series of 35 children ascertained because of maternal treatment with hydantoins during pregnancy, we 1. Di Saia, P. J. Obstet. Gynec. 1966, 28, 469. 2. Becker, M. H., Genieser, N. B., Finegold, M., Miranda, D., Spackman, T. Am. J. Dis. Child. 1975, 129, 356. 3. Shaul, W. L., Emery, H., Hall, J. G. ibid. p. 360. 4. McCallion, D. J., Phelps, N. E., Hirsh, J., Cade, F. Teratology 1971, 4, 235 (abstr.) 5. Hanson, J. W., Smith, D. W.J. Pediat. 1975, 87, 285.
a
bold attempt
on
to
myocardium during cardiopulmonary ’bypass. Mitochondrial damage in particular can be diminished by continuous myocardial perfusion and/or hypothermia and avoidance, as far as possible, of induced electrical brillation and coronary air embolisation. 16, I have reportedthe effect of such measures to protect the myocardium. In a consecutive series of 71 unselected patients with a mean age of 50 years (range 20-68) only 1 patient died after mitral-valve replacement using either the Starr 6120 or track valves. 47% had previously undergone Bonchek, L. I., Starr, A. Am. J. Cardiol. 1975, 35, 843. Burdette, W. J., Ashford, T. P. J. thorac. cardiovasc. Surg. 1965, 50, 210 Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., Buckberg,G. ibid. 1973, 66, 742. 4. Isom, O. W., Kutin, N. D., Falk, E. A., Spencer, F. C. ibid. p. 705. 5. Stemmer, E., McCart, P., Stanton, W., Thibault, W., Dearden, L., Connolly, J. ibid. p. 754. 6. Becker, R., Shizgal, H., Dobell, A. Ann. thorac. Surg. 1973, 16, 228. 7. Rees, G. M. Paper read at a conference on Cardiac Surgery, held in Coventry in September, 1975. (In the press.) 1. 2. 3.
wasting of calories, and
no
hence
no
benefit
to
the obese
patient. Clinical Research Centre, Watford Road, Harrow, Middlesex HA1
3UJ
J. S. GARROW
WARFARIN AND FETAL ABNORMALITY
SiR,—Hypoplasia of nasal structures and mental retardation have been reported in the offspring of mothers who took warfarin throughout pregnancy.’ Chondrodysplasia punctata and brachydactyly have also been noted .23Haemorrhage and a high frequency of abortion have been demonstrated in laboratory animals treated with warfarin derivatives during
pregnancy.4 We have
seen a patient at the genetic clinic whose mother treated with warfarin (’Coumadin’) for the last six months of pregnancy. Our patient showed marked microcephaly with bifrontal narrowing, questionable blindness, and secondary findings of hypotonia and developmental retardation. Skeletal X-rays showed no epiphyseal stippling or other significant abnormality. Studies for rubella, cytomegalovirus, toxoplasma, and herpes virus were all negative. We wonder whether the baby’s abnormality might be due to the warfarin and invite any comment from others who may have noted abnormalities when warfarin derivatives were used late in pregnancy after the critical period of fetal morphowas
found 4 who had sufficient abnormalities to allow a diagnosis of fetal hydantoin syndrome. An additional 11 children each showed some features compatible with the prenatal effects of hydantoins, though the composite pattern was not sufficiently striking to allow a diagnosis of fetal hydantoin syndrome, Among these children, mental deficiency was the single feature warranting the most serious concern. Single malformations were relatively infrequent. Thus ascertainment by single major defects alone has, in our experience, been a less sensitive method of detecting seriously affected children. We have yet to see an infant with the composite pattern described whose mother had not taken one of the hydantoin anticonvulsants. On the other hand, we have seen several affected infants whose mothers were receiving a hydantoin only. For this reason, we believe hydantoin anticonvulsants do present a serious risk to the fetus over and any effect attributable to the convulsive disorder itself. We believe that women with convulsive disorders should be warned of the potential serious risks to the fetus related to hydantoin therapy. Sometimes it may be possible to stop hydantoin treatment. Whether other commonly used anticonvulsants present a serious teratogenic risk for man needs further investigation.
beyond
University of Washington Dysmorphology Unit, Department of Pediatrics, School of Medicine, Seattle, Washington 98195, U.S.A.
JAMES W. HANSON DAVID W. SMITH
genesis. Department of Pediatrics, University of California, San Francisco, California 94143, U.S.A.
SANDFORD SHERMAN BRYAN D. HALL
WHICH PROSTHETIC VALVE?
artificial heart valves (March 20, draw valid conclusions in this confused area. Unfortunately, it is both misleading and potentially hazardous, since simplistic conclusions have been drawn from inadequate data, which may encourage physicians to refer patients for valve surgery with a rider on the type of device that should be used. Valve replacement is a complex technique where the combinations and permutations are infinite; thus, it is highly unlikely that any two surgeons perform an identical operation, You have succumbed to the obvious temptation of correlating the mortality-rates from widely differing units with the device used to replace the abnormal valve, then attributing success or failure to this alone. Equally interesting data might have been obtained by correlating the results with the day of the week (i.e., with a particular surgeon). Starr’s1 3% operative-mortality rate in an unselected group indicates that some of the indifferent results cited are due to factors other than the hydraulic properties of the prosthesis. There is now abundant evidence 2-4 that a prime factor in the causation of operative deaths (generally from myocardial failure associated with dysrhythmias) is failure to protect the
SiR,—Your editorial
p. 619) is
FETAL HYDANTOIN SYNDROME
SIR,-Dr Shapiro and his colleagues (Feb. 7, p. 272) suggest that convulsive disorders per se rather than differences in drug therapy during pregnancy may account for the increased risk of malformation in the fetuses of epileptic women. Their conclusion is based upon an examination of rates of single malformations, and, as they point out, they did not consider characteristic patterns of abnormalities which might be associated with specific drugs. We have also examined the records of infants born to mothers with convulsive disorders treated with hydantoin anticonvulsants and a matched series of normal controls from the same Collaborative Perinatal Project. Besides minor differences in the choice of patients, our study design varied significantly from that of the Boston group. We attempted to determine the frequency of a specific pattern of abnormalities, the fetal hydantoin syndrome.5 We compared the frequencies of dysmorphic features and alterations of growth and performance characteristic of the total fetal hydantoin syndrome in the two groups. A full report will appear in the Journal of Pediatrics. 11% of children exposed prenatally to hydantoins displayed a broad pattern of altered growth, morphogenesis, and performance suggestive of the fetal hydantoin syndrome. No such children were found in the control group. There was also a significant difference in i.Q. scores between the groups at seven years of age, the hydantoin-exposed offspring having the lower scores. These results are similar to our experience in the Seattle area. Among a series of 35 children ascertained because of maternal treatment with hydantoins during pregnancy, we 1. Di Saia, P. J. Obstet. Gynec. 1966, 28, 469. 2. Becker, M. H., Genieser, N. B., Finegold, M., Miranda, D., Spackman, T. Am. J. Dis. Child. 1975, 129, 356. 3. Shaul, W. L., Emery, H., Hall, J. G. ibid. p. 360. 4. McCallion, D. J., Phelps, N. E., Hirsh, J., Cade, F. Teratology 1971, 4, 235 (abstr.) 5. Hanson, J. W., Smith, D. W.J. Pediat. 1975, 87, 285.
a
bold attempt
on
to
myocardium during cardiopulmonary ’bypass. Mitochondrial damage in particular can be diminished by continuous myocardial perfusion and/or hypothermia and avoidance, as far as possible, of induced electrical brillation and coronary air embolisation. 16, I have reportedthe effect of such measures to protect the myocardium. In a consecutive series of 71 unselected patients with a mean age of 50 years (range 20-68) only 1 patient died after mitral-valve replacement using either the Starr 6120 or track valves. 47% had previously undergone Bonchek, L. I., Starr, A. Am. J. Cardiol. 1975, 35, 843. Burdette, W. J., Ashford, T. P. J. thorac. cardiovasc. Surg. 1965, 50, 210 Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., Buckberg,G. ibid. 1973, 66, 742. 4. Isom, O. W., Kutin, N. D., Falk, E. A., Spencer, F. C. ibid. p. 705. 5. Stemmer, E., McCart, P., Stanton, W., Thibault, W., Dearden, L., Connolly, J. ibid. p. 754. 6. Becker, R., Shizgal, H., Dobell, A. Ann. thorac. Surg. 1973, 16, 228. 7. Rees, G. M. Paper read at a conference on Cardiac Surgery, held in Coventry in September, 1975. (In the press.) 1. 2. 3.
