696
offspring. 1 child had an unspecified lower extremity anomaly. Such a diagnosis in Medicaid records may range from flat foot and metatarsus varus to club feet, knockknees, and suspected congenital hip dislocation. Since diagnoses were derived from billing records, it is likely that severe anomalies will be detected and recorded in this database. However, more subtle defects, developmental abnormalities, and retardations may not be present in the billing records. A diagnosis of oral cleft can be easily found from Medicaid invoices, with a frequency of 06/1000. Oral cleft has been previously associated with benzodiazepine exposure, however, this diagnosis was not found in any of the 1354 first trimester benzodiazepine exposures.
Discussion This survey used only computerised claims files to record exposures and diagnoses-ie, there was no direct medicalrecord validation.l3 The study took advantage of an existing file of 104 339 pregnancies, which avoided recall bias because prescriptions were recorded before pregnancy outcomes were known. A weakness of this type of study is that it does not detect benzodiazepines obtained outside Medicaid. However, the inclusion of only women who had had ten or more benzodiazepine prescriptions ensures that the offspring had had an exposure to benzodiazepines during fetal life sufficient to identify the developmental changes described by Laegreid et al.3 Only 6 of the 64 infant profiles with major benzodiazepine exposure and 2 additional infants had diagnoses consistent with developmental teratogenicity. 50 of the 64 infants’ records showed no developmental abnormalities despite several records that indicated large maternal benzodiazepine exposures up to term. These data suggest that most children had no major abnormality after such exposure. Thus this study suggests that the abnormalities reported by Laegreid et aP are not frequently seen in mothers exposed to benzodiazepines during pregnancy. The neurofunctional and heart-defect diagnoses were consistent with fetalalcohol syndrome, but could also be due to benzodiazepines or other congenital toxins, or postnatal causes.14 The effects of benzodiazepine abuse are often confounded by maternal alcoholism and therefore would sometimes be expected to show some of the sequelae of alcohol exposure. Finally, consistent with our findings, Laegreid et ahs recently published data showing mainly sedation and withdrawal in infants of mothers taking benzodiazepines up to term. Grants were provided by the Karolinska Institute and the Swedish of Medicine.
Society
REFERENCES 1. Weber LWD.
Benzodiazepines in pregnancy—academical debate or teratogenic risk? Biol Res Pregn 1985; 6: 151-67. 2. Dukes MNG. Neuroleptics and behavioural teratogenicity. In: Dukes MNG, Beeley L, eds. Side effects of drugs annual 10. Amsterdam: Elsevier, 1986: 50-52. 3. Laegreid L, Olegard R, Wahlström J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; i: 108-09. 4. Olegard R, Sabel K-G, Aronsson M, et al. Effects on the child of alcohol abuse during pregnancy. Acta Paediatr Scand 1979; 275 (suppl): 112-21. 5. Winter RM, Czeizel A, Lendvay A, Gerhardsson M, Alfredsson L. In-utero exposure to benzodiazepines. Lancet 1987; i: 627-28. 6. Barry WS, St Clair SM. Exposure to benzodiazepines in utero. Lancet 1987; i: 1436-37. 7. Laegreid L, Olegard R, Wahlström J, Conradi N, Sisfontes L. Benzodiazepine overconsumption in pregnancy. Lancet 1987; ii: 1405-06. 8. Laegreid L, Olegard R, Wahlstrom J, Conradi N. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 1989; 114: 126-31.
9.
Bergman U, Boethius G, Swartling PG, Isacson D, Smedby B. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr
1990; 116: 490-91. Bergman U. Pharmacoepidemiological perspectives on the teratogenic effects of benzodiazepines. Bratisl Lek Listy 1991; 92: 560-63. 11. Piper JM, Baum C, Kennedy DL. Prescription drug use before and during pregnancy in a Medicaid population. Am J Obstet Gynecol 1987; 10.
157: 148-56. 12. Strom BL, Carson
JL, Halpern AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991;
10: 565-76. 13. Faich GA, Stadel BV. The future of automated record linkage for postmarketing surveillance: a response to Shapiro. Clin Pharmacol Ther 1989; 46: 387-89. 14. Nelson LB, Ehrlich S, Calhoun JH, Matteucci T, Finnegan LP. Occurrence of strabismus in infants born to drug-dependent women. Am J Dis Child 1987; 141: 175-78. 15. Laegreid L, Hagberg G, Lundberg A. The effect of benzodiazepines on the fetus and the newborn. Neuropediatr 1992; 23: 18-23.
SHORT REPORTS Stereoselective release of (S)-atenolol from adrenergic nerve endings at exercise
In-vitro studies have shown that atenolol, a beta-blocking agent, is stereoselectively taken up by and released from adrenergic nerve endings by membrane depolarisation. To investigate the potential importance of these findings, blood samples were taken at rest and after exercise testing from 10 patients (mean [SE] age 60 [3] years) receiving long-term treatment with racemic atenolol. At rest, mean plasma concentration of (R)-atenolol was higher than that of (S)-atenolol (ratio 1·14, but after exercise there was a p
offspring. 1 child had an unspecified lower extremity anomaly. Such a diagnosis in Medicaid records may range from flat foot and metatarsus varus to club feet, knockknees, and suspected congenital hip dislocation. Since diagnoses were derived from billing records, it is likely that severe anomalies will be detected and recorded in this database. However, more subtle defects, developmental abnormalities, and retardations may not be present in the billing records. A diagnosis of oral cleft can be easily found from Medicaid invoices, with a frequency of 06/1000. Oral cleft has been previously associated with benzodiazepine exposure, however, this diagnosis was not found in any of the 1354 first trimester benzodiazepine exposures.
Discussion This survey used only computerised claims files to record exposures and diagnoses-ie, there was no direct medicalrecord validation.l3 The study took advantage of an existing file of 104 339 pregnancies, which avoided recall bias because prescriptions were recorded before pregnancy outcomes were known. A weakness of this type of study is that it does not detect benzodiazepines obtained outside Medicaid. However, the inclusion of only women who had had ten or more benzodiazepine prescriptions ensures that the offspring had had an exposure to benzodiazepines during fetal life sufficient to identify the developmental changes described by Laegreid et al.3 Only 6 of the 64 infant profiles with major benzodiazepine exposure and 2 additional infants had diagnoses consistent with developmental teratogenicity. 50 of the 64 infants’ records showed no developmental abnormalities despite several records that indicated large maternal benzodiazepine exposures up to term. These data suggest that most children had no major abnormality after such exposure. Thus this study suggests that the abnormalities reported by Laegreid et aP are not frequently seen in mothers exposed to benzodiazepines during pregnancy. The neurofunctional and heart-defect diagnoses were consistent with fetalalcohol syndrome, but could also be due to benzodiazepines or other congenital toxins, or postnatal causes.14 The effects of benzodiazepine abuse are often confounded by maternal alcoholism and therefore would sometimes be expected to show some of the sequelae of alcohol exposure. Finally, consistent with our findings, Laegreid et ahs recently published data showing mainly sedation and withdrawal in infants of mothers taking benzodiazepines up to term. Grants were provided by the Karolinska Institute and the Swedish of Medicine.
Society
REFERENCES 1. Weber LWD.
Benzodiazepines in pregnancy—academical debate or teratogenic risk? Biol Res Pregn 1985; 6: 151-67. 2. Dukes MNG. Neuroleptics and behavioural teratogenicity. In: Dukes MNG, Beeley L, eds. Side effects of drugs annual 10. Amsterdam: Elsevier, 1986: 50-52. 3. Laegreid L, Olegard R, Wahlström J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; i: 108-09. 4. Olegard R, Sabel K-G, Aronsson M, et al. Effects on the child of alcohol abuse during pregnancy. Acta Paediatr Scand 1979; 275 (suppl): 112-21. 5. Winter RM, Czeizel A, Lendvay A, Gerhardsson M, Alfredsson L. In-utero exposure to benzodiazepines. Lancet 1987; i: 627-28. 6. Barry WS, St Clair SM. Exposure to benzodiazepines in utero. Lancet 1987; i: 1436-37. 7. Laegreid L, Olegard R, Wahlström J, Conradi N, Sisfontes L. Benzodiazepine overconsumption in pregnancy. Lancet 1987; ii: 1405-06. 8. Laegreid L, Olegard R, Wahlstrom J, Conradi N. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 1989; 114: 126-31.
9.
Bergman U, Boethius G, Swartling PG, Isacson D, Smedby B. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr
1990; 116: 490-91. Bergman U. Pharmacoepidemiological perspectives on the teratogenic effects of benzodiazepines. Bratisl Lek Listy 1991; 92: 560-63. 11. Piper JM, Baum C, Kennedy DL. Prescription drug use before and during pregnancy in a Medicaid population. Am J Obstet Gynecol 1987; 10.
157: 148-56. 12. Strom BL, Carson
JL, Halpern AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991;
10: 565-76. 13. Faich GA, Stadel BV. The future of automated record linkage for postmarketing surveillance: a response to Shapiro. Clin Pharmacol Ther 1989; 46: 387-89. 14. Nelson LB, Ehrlich S, Calhoun JH, Matteucci T, Finnegan LP. Occurrence of strabismus in infants born to drug-dependent women. Am J Dis Child 1987; 141: 175-78. 15. Laegreid L, Hagberg G, Lundberg A. The effect of benzodiazepines on the fetus and the newborn. Neuropediatr 1992; 23: 18-23.
SHORT REPORTS Stereoselective release of (S)-atenolol from adrenergic nerve endings at exercise
In-vitro studies have shown that atenolol, a beta-blocking agent, is stereoselectively taken up by and released from adrenergic nerve endings by membrane depolarisation. To investigate the potential importance of these findings, blood samples were taken at rest and after exercise testing from 10 patients (mean [SE] age 60 [3] years) receiving long-term treatment with racemic atenolol. At rest, mean plasma concentration of (R)-atenolol was higher than that of (S)-atenolol (ratio 1·14, but after exercise there was a p
