- Email: [email protected]
ANENCEPHALY IN THE NETHERLANDS: A REMARKABLE DECLINE
64
WEEKS AFTER INOCULATION Chimpanzee (no. 1117) inoculated with cryoprecipitate prepared from plasma of a patient with chronic symptomless NANB hepatitis. AST, ALT= aspartate and alanine aminotransferase (IU/1). Liver histology +, - presence or absence of acute hepatitis in liver biopsy specimens stained with haematoxylin and eosin. =
detected in percutaneous liver biopsy samples obtained at weeks 8 and 14 after inoculation (figure). Level of serum alanine aminotransferase (ALT) were raised from weeks 15 to 20, with a peak of 105 IU/1 at week 17. The chimpanzee remained negative for all serological markers of hepatitis A and B when tested by
radioimmunoassay. This study shows that the NANB hepatitis agent transmitted by blood is not excluded from cryoprecipitate, and hence may also be present when cryoprecipitate is processed further into FVIII concentrate. The reconstituted cryoprecipitate had a concentration ten times that of the cryoprecipitate in the starting plasma; commercial preparations often have 100-fold concentration. The infectious titre of the agent in the cryoprecipitate was not
fig.
I-Incidence (per 1000 total
births) of anencephaly
in the
netherlands: 1950-80.
determined. Some evidence suggests an inverse relation between the concentration of this NANB hepatitis agent and the length of the incubation period.5 If so, the 8 week incubation period seen in this chimpanzee, compared with the 2-4 week range for incubation periods in chimpanzees inoculated with the starting plasma suggests that only some of the infectious agent was in the cryoprecipitate. Centrifugation alone, at the force used in this study, would not be expected to sediment this agent from the supernatant fluid to the cryoprecipitate.The infectivity of the supernatant fluid has not yet been evaluated. Sufficient infectivity was present in the cryoprecipitate, however, to transmit NANB heoatitis to this chimoanzee. Hepatitis Branch, Division of Blood and Blood Products and Division of Product Quality Control, National Center for Drugs and Biologics, Food and Drug Administration, Bethesda, Maryland 20205, U.S.A.
Blood Service Laboratories, American Red Cross,
EDWARD TABOR PHILIP SNOY ROBERT J. GERETY
Bethesda, Maryland
MILAN WICKERHAUSER DORIS MENACHE
V.A Medical Center, and Georgetown University School of Medicine, Washington, D.C.
LEONARD B. SEEFF
ANENCEPHALY IN THE NETHERLANDS: A REMARKABLE DECLINE
SIR,-We have studied the epidemiology of anencephaly in the Netherlands, using vital statistics and additional data obtained from the Central Bureau of Statistics, the Hague. From 1950 to 1980, 6699 children born with anencephaly (total number of births 6974 895) were registered in the Netherlands. Over these thirty-one years the incidence declined, with minor fluctuations, from about 15per 1000 total births in 1950 to 0 -4per 1000 in 1980 (fig. 1). As the incidence declined the sex ratio (male/female) of anencephalic children rose from 0-4-0-66 in the 1950s to 0-7-10in the 1970s. For the period 1951-68 a winter peak in the incidence of anencephaly was reported’ but over the years 1968-78 no obvious seasonal pattern emerged (fig. 2). E, Gerety RJ Inactivation of an agent of human non-A, non-B hepatitis by formalin. J Infect Dis 1980; 142: 767-70. Shih JW-K, Tabor E, Gerety RJ. Sedimentation of a non-A, non-B hepatitis agent. Hepatology 1982; 2: 681 (abstr).
5. Tabor 6.
Fig.
J FMAMJJASOND 2-Seasonal distribution of anencephaly in two time
periods.
A similar decline has been noted in the U.K. (Merseyside)2 and in New York,3 both for anencephaly and spina bifida. Early termination of affected pregnancies is not a likely explanation because prenatal diagnosis of neural tube defects by measurement of amniotic fluid AFP was only introduced in the Netherlands in 1974, and more reliable ultrasonic techniques have been available only in recent years; the decrease apparently started much earlier. Moreover only a small proportion of all fetuses with neural tube defects are discovered by these methods in early pregnancy. Minor changes in the registration of early preterm anencephalic children cannot be discounted but the almost linear decline, with only minor fluctuations, since 1950 and the change in sex ratio make it unlikely that changes in registration are of major importance. Changes in food intake may have influenced the incidence of anencephaly. The decline has been most pronounced in those provinces in the north and east of the country where the incidence in the early 1950s was highest. Recently evidence has been produced 1. OverbekeAnencephahe in Nederland 1951-1969. Thesis, University of Leiden. 2. Owens JR, Harris F, AcAllister E, West L. 19-year incidence of neural tube defects in area under constant surveillance. Lancet 1981; ii: 1032-35. 3. Stein SC, Feldman JG, Friedlander M, Klein RJ. Is myelomeningocele a disappearing disease? Pediatrics 1982; 69: 511-514.
65 suggest that intake of vitamins before and after conception may prevent neural tube defects. 4,5 The declining incidence of anencephaly (and presumably of other neural tube defects) in the Netherlands is a remarkable epidemiological feature and will reduce the cost-effectiveness of a nationwide screening programme of serum AFP.
with a high incidence, if this high incidence has been caused environmental factors which are now changing.
Department of Obstetrics and Gynaecology, University Hospital Wilhelmina Gasthuis, Amsterdam, Netherlands
Department of Genetics, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
to
J. A. ROMIJN P. E. TREFFERS
INCIDENCE OF NEURAL TUBE DEFECTS IN VICTORIA, AUSTRALIA has SIR,-A decline in the incidence of neural tube defects been reported for two regions of the U.K. and for New York. To explore this trend the incidence of anencephaly and spina bifida in Victoria, Australia, was determined over the years 1976-81. Data were collected from perinatal mortality statistics, prenatal diagnostic centres, and hospital neonatal centres and the incidence per 1000 total (live and stillborn) births was compared with figures from the other three studies (table). The figures in parentheses show terminations of pregnancy after prenatal diagnosis. This incidence is likely to be slightly greater than that obtained at birth before the introduction of prenatal diagnosis, because some of the pregnancies might have aborted spontaneously before the stage of pregnancy necessary for classification as stillbirths. Owens et al.use the term "real incidence" to describe incidence figures that include terminations, but it would seem more logical to reserve this term for the frequency at conception, even though this cannot be measured. The Victorian figures do show an apparent decline in the combined incidence of NTD over the years under consideration. The Armitage linear test9was used to determine the significance of the trends in annual incidence of the two conditions and the combined incidence. The linear decline in incidence ofanencephaly was found to be significant at the 2 - 5% level (X2 = 5 - 26, df= 1) but not for spina bifida (o=0-12, df= 1), while the combined incidence ofNTDs shows a significant decline only at the 10% level (x20 3 -6, df=11). This finding is similar to that seen in other studies. The incidence of NTD in Victoria is considerably lower than that in Liverpool or in Northern Ireland and comparable with figures for New South Wales.’Larger declines might be expected in regions
(NTD)
=
We acknowledge the help of the Consultative Council on Maternity and Perinatal Mortality and thank colleagues at Queen Victoria Medical Centre, Royal Women’s Hospital, and paediatricians from other hospitals who provided data.
vitamin supplementation. Lancet 1980 i: 339-40. 5. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, Read AP, Fielding DW. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Childh 1981; 56: 911-18. 6. Owens JR, AcAllister E, Harris F, West L. 19-year incidence of neural tube defects in area under constant surveillance. Lancet 1981; ii: 1032-35. 7. Stein SC, Feldman JG, Friedlander M, Klein RJ. Is myelomeningocele a disappearing disease? Pediatrics 1982; 69: 511-14. 8. Nevin NC. Neural tube defects. Lancet 1981; ii: 1290-91. 9. Armitage P. Tests for linear trends in proportions and frequencies. Biometrics 1955; 11: 375-86. 10. Field B. Neural tube defects in New South Wales, Australia. J Med Genet 1978; 15: 329-38.
D. M. DANKS
J. L. HALLIDAY
EPIDERMAL GROWTH FACTOR, SOMATOSTATIN, AND PSORIASIS
SIR,-Somatostatin has been tried in patients with psoriasis because ofasuggested phasic rise of growth hormone (GH) found in this disease.’Although somatostatin seems useful for these patients (80% improvement has been reported 2) no definitive GH rise has been demonstrated-nor has a clinical correlation between psoriasis and acromegaly been reported. In view of the wide action of somatostatin on hormones and peptides we wondered if the beneficial effects of somatostatin in psoriasis could be related to an acts on inhibitory effect on epidermal growth factor (EGF), which the proliferation and keratinisation of epidermal cells.3 Eight psoriatic patients with erythroderma were studied, two with severe arthropathy. All these patients, in whom conventional therapy was ineffective, were treated with continuous intravenous infusions of somatostatin (250 g/h for 4 days). A remarkable improvement in the epidermal lesions was obtained in every patient, with a complete remission in two. An improvement in pain was also noted in the patients with arthropathy. Plasma EGF values, measured by radioreceptor assay,4were 5’03±I’20 ng/ml under basal conditions and 3 -· 75±066 ng/ml after 4 days of somatostatin The normal treatment (Student t test for paired data, p<0-01). range is 4 -0-5 -5ng/ml (48:t0’9). These preliminary data show that somatostatin lowers plasma values of EGF in psoriatic patients, suggesting that EGF may play a part in the improvement in psoriasis seen in patients treated with somatostatin. G. GHIRLANDA L. UCCIOLI
4. Smithells
RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R. Read AP, Fielding DW. Possible prevention of neural tube defects by periconceptional
by
Institute of Special Medical Pathology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; and General Pathology II, University of Rome
F. PERRI L. ALTOMONTE A. BERTOLI R. MANNA L. FRATI A. V. GRECO
G, Klughardt G, Neidhardt M. Psoriasis and human growth hormone. Arch Dermatol Res 1981; 270: 361. 2 Weber G, Klughardt G, Neidhardt M, et al Treatment of psoriasis with somatostatin. Arch Dermatol Res 1982; 272: 31. 3 Cohen S, Taylor JM. Epidermal growth factor chemical and biological characterization Rec Prog Horm Res 1974; 30: 533 4. Frati L, Cenci G, Sbaraglia G, et al. Levels of epidermal growth factor in mice tissues measured by a specific radioreceptor assay Life Sci 1976, 18: 905. 1 Weber
INCIDENCE OF NEURAL TUBE DEFECTS/ 1000 TOTAL BIRTHS/YEAR IN FOUR SERIES
WEEKS AFTER INOCULATION Chimpanzee (no. 1117) inoculated with cryoprecipitate prepared from plasma of a patient with chronic symptomless NANB hepatitis. AST, ALT= aspartate and alanine aminotransferase (IU/1). Liver histology +, - presence or absence of acute hepatitis in liver biopsy specimens stained with haematoxylin and eosin. =
detected in percutaneous liver biopsy samples obtained at weeks 8 and 14 after inoculation (figure). Level of serum alanine aminotransferase (ALT) were raised from weeks 15 to 20, with a peak of 105 IU/1 at week 17. The chimpanzee remained negative for all serological markers of hepatitis A and B when tested by
radioimmunoassay. This study shows that the NANB hepatitis agent transmitted by blood is not excluded from cryoprecipitate, and hence may also be present when cryoprecipitate is processed further into FVIII concentrate. The reconstituted cryoprecipitate had a concentration ten times that of the cryoprecipitate in the starting plasma; commercial preparations often have 100-fold concentration. The infectious titre of the agent in the cryoprecipitate was not
fig.
I-Incidence (per 1000 total
births) of anencephaly
in the
netherlands: 1950-80.
determined. Some evidence suggests an inverse relation between the concentration of this NANB hepatitis agent and the length of the incubation period.5 If so, the 8 week incubation period seen in this chimpanzee, compared with the 2-4 week range for incubation periods in chimpanzees inoculated with the starting plasma suggests that only some of the infectious agent was in the cryoprecipitate. Centrifugation alone, at the force used in this study, would not be expected to sediment this agent from the supernatant fluid to the cryoprecipitate.The infectivity of the supernatant fluid has not yet been evaluated. Sufficient infectivity was present in the cryoprecipitate, however, to transmit NANB heoatitis to this chimoanzee. Hepatitis Branch, Division of Blood and Blood Products and Division of Product Quality Control, National Center for Drugs and Biologics, Food and Drug Administration, Bethesda, Maryland 20205, U.S.A.
Blood Service Laboratories, American Red Cross,
EDWARD TABOR PHILIP SNOY ROBERT J. GERETY
Bethesda, Maryland
MILAN WICKERHAUSER DORIS MENACHE
V.A Medical Center, and Georgetown University School of Medicine, Washington, D.C.
LEONARD B. SEEFF
ANENCEPHALY IN THE NETHERLANDS: A REMARKABLE DECLINE
SIR,-We have studied the epidemiology of anencephaly in the Netherlands, using vital statistics and additional data obtained from the Central Bureau of Statistics, the Hague. From 1950 to 1980, 6699 children born with anencephaly (total number of births 6974 895) were registered in the Netherlands. Over these thirty-one years the incidence declined, with minor fluctuations, from about 15per 1000 total births in 1950 to 0 -4per 1000 in 1980 (fig. 1). As the incidence declined the sex ratio (male/female) of anencephalic children rose from 0-4-0-66 in the 1950s to 0-7-10in the 1970s. For the period 1951-68 a winter peak in the incidence of anencephaly was reported’ but over the years 1968-78 no obvious seasonal pattern emerged (fig. 2). E, Gerety RJ Inactivation of an agent of human non-A, non-B hepatitis by formalin. J Infect Dis 1980; 142: 767-70. Shih JW-K, Tabor E, Gerety RJ. Sedimentation of a non-A, non-B hepatitis agent. Hepatology 1982; 2: 681 (abstr).
5. Tabor 6.
Fig.
J FMAMJJASOND 2-Seasonal distribution of anencephaly in two time
periods.
A similar decline has been noted in the U.K. (Merseyside)2 and in New York,3 both for anencephaly and spina bifida. Early termination of affected pregnancies is not a likely explanation because prenatal diagnosis of neural tube defects by measurement of amniotic fluid AFP was only introduced in the Netherlands in 1974, and more reliable ultrasonic techniques have been available only in recent years; the decrease apparently started much earlier. Moreover only a small proportion of all fetuses with neural tube defects are discovered by these methods in early pregnancy. Minor changes in the registration of early preterm anencephalic children cannot be discounted but the almost linear decline, with only minor fluctuations, since 1950 and the change in sex ratio make it unlikely that changes in registration are of major importance. Changes in food intake may have influenced the incidence of anencephaly. The decline has been most pronounced in those provinces in the north and east of the country where the incidence in the early 1950s was highest. Recently evidence has been produced 1. OverbekeAnencephahe in Nederland 1951-1969. Thesis, University of Leiden. 2. Owens JR, Harris F, AcAllister E, West L. 19-year incidence of neural tube defects in area under constant surveillance. Lancet 1981; ii: 1032-35. 3. Stein SC, Feldman JG, Friedlander M, Klein RJ. Is myelomeningocele a disappearing disease? Pediatrics 1982; 69: 511-514.
65 suggest that intake of vitamins before and after conception may prevent neural tube defects. 4,5 The declining incidence of anencephaly (and presumably of other neural tube defects) in the Netherlands is a remarkable epidemiological feature and will reduce the cost-effectiveness of a nationwide screening programme of serum AFP.
with a high incidence, if this high incidence has been caused environmental factors which are now changing.
Department of Obstetrics and Gynaecology, University Hospital Wilhelmina Gasthuis, Amsterdam, Netherlands
Department of Genetics, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
to
J. A. ROMIJN P. E. TREFFERS
INCIDENCE OF NEURAL TUBE DEFECTS IN VICTORIA, AUSTRALIA has SIR,-A decline in the incidence of neural tube defects been reported for two regions of the U.K. and for New York. To explore this trend the incidence of anencephaly and spina bifida in Victoria, Australia, was determined over the years 1976-81. Data were collected from perinatal mortality statistics, prenatal diagnostic centres, and hospital neonatal centres and the incidence per 1000 total (live and stillborn) births was compared with figures from the other three studies (table). The figures in parentheses show terminations of pregnancy after prenatal diagnosis. This incidence is likely to be slightly greater than that obtained at birth before the introduction of prenatal diagnosis, because some of the pregnancies might have aborted spontaneously before the stage of pregnancy necessary for classification as stillbirths. Owens et al.use the term "real incidence" to describe incidence figures that include terminations, but it would seem more logical to reserve this term for the frequency at conception, even though this cannot be measured. The Victorian figures do show an apparent decline in the combined incidence of NTD over the years under consideration. The Armitage linear test9was used to determine the significance of the trends in annual incidence of the two conditions and the combined incidence. The linear decline in incidence ofanencephaly was found to be significant at the 2 - 5% level (X2 = 5 - 26, df= 1) but not for spina bifida (o=0-12, df= 1), while the combined incidence ofNTDs shows a significant decline only at the 10% level (x20 3 -6, df=11). This finding is similar to that seen in other studies. The incidence of NTD in Victoria is considerably lower than that in Liverpool or in Northern Ireland and comparable with figures for New South Wales.’Larger declines might be expected in regions
(NTD)
=
We acknowledge the help of the Consultative Council on Maternity and Perinatal Mortality and thank colleagues at Queen Victoria Medical Centre, Royal Women’s Hospital, and paediatricians from other hospitals who provided data.
vitamin supplementation. Lancet 1980 i: 339-40. 5. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, Read AP, Fielding DW. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Childh 1981; 56: 911-18. 6. Owens JR, AcAllister E, Harris F, West L. 19-year incidence of neural tube defects in area under constant surveillance. Lancet 1981; ii: 1032-35. 7. Stein SC, Feldman JG, Friedlander M, Klein RJ. Is myelomeningocele a disappearing disease? Pediatrics 1982; 69: 511-14. 8. Nevin NC. Neural tube defects. Lancet 1981; ii: 1290-91. 9. Armitage P. Tests for linear trends in proportions and frequencies. Biometrics 1955; 11: 375-86. 10. Field B. Neural tube defects in New South Wales, Australia. J Med Genet 1978; 15: 329-38.
D. M. DANKS
J. L. HALLIDAY
EPIDERMAL GROWTH FACTOR, SOMATOSTATIN, AND PSORIASIS
SIR,-Somatostatin has been tried in patients with psoriasis because ofasuggested phasic rise of growth hormone (GH) found in this disease.’Although somatostatin seems useful for these patients (80% improvement has been reported 2) no definitive GH rise has been demonstrated-nor has a clinical correlation between psoriasis and acromegaly been reported. In view of the wide action of somatostatin on hormones and peptides we wondered if the beneficial effects of somatostatin in psoriasis could be related to an acts on inhibitory effect on epidermal growth factor (EGF), which the proliferation and keratinisation of epidermal cells.3 Eight psoriatic patients with erythroderma were studied, two with severe arthropathy. All these patients, in whom conventional therapy was ineffective, were treated with continuous intravenous infusions of somatostatin (250 g/h for 4 days). A remarkable improvement in the epidermal lesions was obtained in every patient, with a complete remission in two. An improvement in pain was also noted in the patients with arthropathy. Plasma EGF values, measured by radioreceptor assay,4were 5’03±I’20 ng/ml under basal conditions and 3 -· 75±066 ng/ml after 4 days of somatostatin The normal treatment (Student t test for paired data, p<0-01). range is 4 -0-5 -5ng/ml (48:t0’9). These preliminary data show that somatostatin lowers plasma values of EGF in psoriatic patients, suggesting that EGF may play a part in the improvement in psoriasis seen in patients treated with somatostatin. G. GHIRLANDA L. UCCIOLI
4. Smithells
RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R. Read AP, Fielding DW. Possible prevention of neural tube defects by periconceptional
by
Institute of Special Medical Pathology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; and General Pathology II, University of Rome
F. PERRI L. ALTOMONTE A. BERTOLI R. MANNA L. FRATI A. V. GRECO
G, Klughardt G, Neidhardt M. Psoriasis and human growth hormone. Arch Dermatol Res 1981; 270: 361. 2 Weber G, Klughardt G, Neidhardt M, et al Treatment of psoriasis with somatostatin. Arch Dermatol Res 1982; 272: 31. 3 Cohen S, Taylor JM. Epidermal growth factor chemical and biological characterization Rec Prog Horm Res 1974; 30: 533 4. Frati L, Cenci G, Sbaraglia G, et al. Levels of epidermal growth factor in mice tissues measured by a specific radioreceptor assay Life Sci 1976, 18: 905. 1 Weber
INCIDENCE OF NEURAL TUBE DEFECTS/ 1000 TOTAL BIRTHS/YEAR IN FOUR SERIES