- Email: [email protected]
Limb defects and gestational age at chorionic villus sampling
Based on *SAVE (thrice daily), tISIS-4 (twice daily), SOLVD (twice daily), §AIRE (twice daily), GtSS!-3 (once daily). Table: Cost of 28 days’ treatment with effective doses of ACE inhibitors used in myocardial infarction and left ventricular dysfunction clinical trials
dose of each ACE inhibitor (table). For comparison between drugs, no other analysis is possible
effective
RR=relative nsk; OR=odds ratio. *Rates (TLD cases/CVS procedures) calculated from reports of TLD cases in 5 CVSexposed cohorts m which data are presented by gestational aged test, p=0.04. tCompared with population-based TLD rate of 0.3 per 1000 births m Italy.’ These RR estimates are conservative, since population-based rates of TLD range from 0.15 to 0.3 per 1000 births in different studies. a
at
tNo CVS-exposed cases in Italian study at >76 days’ gestation. Table: Gestation-age-specific rates and relative risks/odds ratios for TLD in cohort and case-control studies of CVS
present. John
McMurray
Department of Cardiology,
Western General
Limb defects and villus sampling
Hospital, Edinburgh
gestational age
EH4
2XU, UK
at chorionic
SIR-Firth and colleagues’ analysis (April 30, p 1069) provides further evidence that chorionic villus sampling (CVS) can cause transverse limb deficiency (TLD). These findings contrast with your news item by Fishman (June 4, p 1420), describing WHO registry data presented by Froster in Israel in May. The WHO committee on CVS concluded that there is no increased risk for TLD if CVS is done after the 9th week of gestation (ie, 63 days). We fully agree with the suggestion that CVS can cause TLD, isolated or as part of the oromandibular-limb hypogenesis phenotype, at less than 9 weeks’. We would point out, however, that the findings of several studies have indicated that CVS done after the 9th week of gestation also results in an increased risk, albeit small, for some types of limb deficiency. Firth and co-workers classified less severe deficiencies as categories 3, 4, or 5 (through the carpus/tarsus or metacarpus/metatarsus, digits, or terminal phalanges, respectively). These defects occurred after CVS at a median gestational age of 67 days (range 56-89) for category 3 deficiencies, 69 (56-81) for category 4, and 72 (51-98) for category 5. Data from the Italian multicentre birth defects registry (IPIMC)’showed an increased risk for TLD at 10 weeks’ (70-76 days) gestation (odd ratio 14-3, 95% CI 3-2-47-2). Data from a USA case-control study’ suggest a threefold increase in risk for TLD after CVS at 10 weeks’ (70-76 days) gestation (table). Moreover, data from five cohort studies* that reported the timing of CVS procedures indicated that the TLD rate at 10 weeks’ (70-76 days) gestation was 0-95 per 1000, which is also a threefold increase over the population rate of 0-3 per thousand for similar defects.’‘ Although transverse deficiencies occur fairly infrequently after CVS, and the severity decreases with increasing gestation (as shown by Firth’s analysis of severity of deficiency), even "later" procedures (done at 9-10 weeks’ or 63-76 days gestation) have been associated with an increased risk for transverse digital or limb deficiencies. These observations are consistent with the proposed mechanism of vascular disruption, which can potentially operate throughout the first trimester. The discrepancies between data presented here and those reported from the WHO registry are still under discussion. Other investigators, with centre-specific spontaneous abortion data,’ have suggested that the inexperience of *List of references available from the authors
476
or
The Lancet,
on
request.
certain obstetricians undertaking CVS accounts for the high TLD rates in some centres. However, TLD data have not yet been adequately analysed to systematically test this hypothesis. In the meantime, we strongly suggest that couples considering CVS should be informed about the increased risk for TLD, at least up to 76 days’ gestation. Although the absolute risk for TLD after these later procedures may be perceived as small by some couples, it may be regarded as relevant by couples considering prenatal diagnosis solely because of maternal age-related risk. Richard S Olney, Muin J Khoury, Lorenzo D Botto, Pierpaolo Mastroiacovo Division of Birth Defects and Developmental Disabilities, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341. USA, and Birth Defects Unit, Department of Paediatrics, Catholic University, Rome, Italy
1
2
Mastroiacovo P, Botto LD. Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder. Am J Med Genet (in press). Olney RS, Khoury MJ, Alo CJ, et al. Increased risk for transverse digital deficiency after chorionic villus sampling (CVS): results of the US multistate case-control study, 1988-1992 (abstract). Teratology
1994; 49: 376. 3
Blakemore K, Filkins K, Luthy DA, et al. Cook obstetrics and gynecology catheter multicenter chorionic villus sampling trial: comparison of birth defects with expected rates. Am J Obstet Gynecol
1993; 169: 1022-26.
Pitfalls in
scanning for phaeochromocytoma
SIR-’3’I_m-iodobenzylguanidine (’3’I-MIBG) scan is known its specificity for phaeochromocytomas and other tumours of neural crest origin. We describe a case with uptake of "’I-MIBG in a non-functioning adrenocortical for
adenoma. A 42-year-old woman without symptoms was investigated because of an incidental finding of a right adrenal mass by echography during a medical check-up. The nodule was 3 cm in diameter, heterogeneous but with well-defined margins, and moderately enhanced on computed tomography scan. Plasma and urine concentrations of catecholamines and their metabolites were almost within normal range, and no endocrinological abnormalities were observed. Provocation tests with metoclopramide and glucagon were negative. However, marked uptake of ’3’I_MIBG was observed at the site of the tumour and right adrenalectomy was performed with the diagnosis of symptomless phaeochromocytoma. However, further
pathological investigation including immunological staining revealed that this
adrenocortical adenoma, of clear cells. The residual cortex and consisting mainly medulla of the specimen were normal, and postoperative reexamination by ‘3’I-MIBG scan showed disappearance of the former abnormal uptake. tumour was an
dose of each ACE inhibitor (table). For comparison between drugs, no other analysis is possible
effective
RR=relative nsk; OR=odds ratio. *Rates (TLD cases/CVS procedures) calculated from reports of TLD cases in 5 CVSexposed cohorts m which data are presented by gestational aged test, p=0.04. tCompared with population-based TLD rate of 0.3 per 1000 births m Italy.’ These RR estimates are conservative, since population-based rates of TLD range from 0.15 to 0.3 per 1000 births in different studies. a
at
tNo CVS-exposed cases in Italian study at >76 days’ gestation. Table: Gestation-age-specific rates and relative risks/odds ratios for TLD in cohort and case-control studies of CVS
present. John
McMurray
Department of Cardiology,
Western General
Limb defects and villus sampling
Hospital, Edinburgh
gestational age
EH4
2XU, UK
at chorionic
SIR-Firth and colleagues’ analysis (April 30, p 1069) provides further evidence that chorionic villus sampling (CVS) can cause transverse limb deficiency (TLD). These findings contrast with your news item by Fishman (June 4, p 1420), describing WHO registry data presented by Froster in Israel in May. The WHO committee on CVS concluded that there is no increased risk for TLD if CVS is done after the 9th week of gestation (ie, 63 days). We fully agree with the suggestion that CVS can cause TLD, isolated or as part of the oromandibular-limb hypogenesis phenotype, at less than 9 weeks’. We would point out, however, that the findings of several studies have indicated that CVS done after the 9th week of gestation also results in an increased risk, albeit small, for some types of limb deficiency. Firth and co-workers classified less severe deficiencies as categories 3, 4, or 5 (through the carpus/tarsus or metacarpus/metatarsus, digits, or terminal phalanges, respectively). These defects occurred after CVS at a median gestational age of 67 days (range 56-89) for category 3 deficiencies, 69 (56-81) for category 4, and 72 (51-98) for category 5. Data from the Italian multicentre birth defects registry (IPIMC)’showed an increased risk for TLD at 10 weeks’ (70-76 days) gestation (odd ratio 14-3, 95% CI 3-2-47-2). Data from a USA case-control study’ suggest a threefold increase in risk for TLD after CVS at 10 weeks’ (70-76 days) gestation (table). Moreover, data from five cohort studies* that reported the timing of CVS procedures indicated that the TLD rate at 10 weeks’ (70-76 days) gestation was 0-95 per 1000, which is also a threefold increase over the population rate of 0-3 per thousand for similar defects.’‘ Although transverse deficiencies occur fairly infrequently after CVS, and the severity decreases with increasing gestation (as shown by Firth’s analysis of severity of deficiency), even "later" procedures (done at 9-10 weeks’ or 63-76 days gestation) have been associated with an increased risk for transverse digital or limb deficiencies. These observations are consistent with the proposed mechanism of vascular disruption, which can potentially operate throughout the first trimester. The discrepancies between data presented here and those reported from the WHO registry are still under discussion. Other investigators, with centre-specific spontaneous abortion data,’ have suggested that the inexperience of *List of references available from the authors
476
or
The Lancet,
on
request.
certain obstetricians undertaking CVS accounts for the high TLD rates in some centres. However, TLD data have not yet been adequately analysed to systematically test this hypothesis. In the meantime, we strongly suggest that couples considering CVS should be informed about the increased risk for TLD, at least up to 76 days’ gestation. Although the absolute risk for TLD after these later procedures may be perceived as small by some couples, it may be regarded as relevant by couples considering prenatal diagnosis solely because of maternal age-related risk. Richard S Olney, Muin J Khoury, Lorenzo D Botto, Pierpaolo Mastroiacovo Division of Birth Defects and Developmental Disabilities, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341. USA, and Birth Defects Unit, Department of Paediatrics, Catholic University, Rome, Italy
1
2
Mastroiacovo P, Botto LD. Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder. Am J Med Genet (in press). Olney RS, Khoury MJ, Alo CJ, et al. Increased risk for transverse digital deficiency after chorionic villus sampling (CVS): results of the US multistate case-control study, 1988-1992 (abstract). Teratology
1994; 49: 376. 3
Blakemore K, Filkins K, Luthy DA, et al. Cook obstetrics and gynecology catheter multicenter chorionic villus sampling trial: comparison of birth defects with expected rates. Am J Obstet Gynecol
1993; 169: 1022-26.
Pitfalls in
scanning for phaeochromocytoma
SIR-’3’I_m-iodobenzylguanidine (’3’I-MIBG) scan is known its specificity for phaeochromocytomas and other tumours of neural crest origin. We describe a case with uptake of "’I-MIBG in a non-functioning adrenocortical for
adenoma. A 42-year-old woman without symptoms was investigated because of an incidental finding of a right adrenal mass by echography during a medical check-up. The nodule was 3 cm in diameter, heterogeneous but with well-defined margins, and moderately enhanced on computed tomography scan. Plasma and urine concentrations of catecholamines and their metabolites were almost within normal range, and no endocrinological abnormalities were observed. Provocation tests with metoclopramide and glucagon were negative. However, marked uptake of ’3’I_MIBG was observed at the site of the tumour and right adrenalectomy was performed with the diagnosis of symptomless phaeochromocytoma. However, further
pathological investigation including immunological staining revealed that this
adrenocortical adenoma, of clear cells. The residual cortex and consisting mainly medulla of the specimen were normal, and postoperative reexamination by ‘3’I-MIBG scan showed disappearance of the former abnormal uptake. tumour was an