- Email: [email protected]
ENTERIC ADENOVIRUSES
1074 POSSIBLE RISK TO RECIPIENTS OF BLOOD FROM DONORS CARRYING SERUM MARKERS OF HUMAN T-CELL LEUKAEMIA VIRUS
SIR,-Newly developed testing procedures have detected protein antigens specific for a human T-cell leukaemia virus (HTLV) in about 1% of the sera of normal blood donors from the National Institutes of Health blood bank. HTLV is an exogenously acquired human type-C RNA tumour virus first isolated from U.S. cases of human leukaemia and lymphoma affecting mature T-cells. 1-3 More recently, Japanese investigators have also detected4and isolated5 from patients with adult T-cell leukaemia a virus which is closely related to HTLV by immunological and nucleic acid hybridisation
(Gallo et al.and Popovic M, et al., unpublished). Epidemiological studies on the distribution of serum antibodies to HTLV in the human population have revealed clusters of antibodypositive sera in groups of patients with acute T-cell leukaemialymphoma and some family members in certain regions ofJapan7,8 and the Caribbean basin9endemic for this type of disease. tests
While cell-free transmission has not been demonstrated in tissue culture for either virus, both viruses have been transmitted to human cord blood lymphocytes by co-cultivation(and M. Popovic et al., unpublished). Furthermore, both groups have found a low incidence among subjects from non-endemic regions and a higher incidence of seropositivity among’residents of Japanese endemic areas and relatives of seropositive patients 6,10 (and Popovic et al., unpublished), supporting the infectious nature of HTLV. Nevertheless, the mechanism of transmission of HTLV remains unproven. Since the incidence of HTLV seropositive T-cell leukaemia has so far been much lower and less is known about the occurrence of these viruses in the normal U.S. population or how they might be transmitted, we tested sera from N.I.H. blood donors for the presence of antibody to the HTLV virus, and for the presence of circulating HTLV structural proteins p24 and p 19. The assays used were newly developed enzyme linked immunoassays (ELISA) using either purified virus or viral antibodies immobilised in microtitre plate wells and monospecific peroxidase-labelled heteroantibody against the p248 or peroxidase-labelled monoclonal antibody against the p1911 proteins of HTLV. These assays are highly sensitive and require small serum samples, and it takes only 2.55 h to test large numbers of samples. The tests can be interpreted by the unaided eye and can be done very well in a clinical setting. BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC Detection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 1980, 77: 7415-19 Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC Isolation of a new type-C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukaemia. Nature 1981, 294: 268-71 Reitz MS, Poiesz BJ, Ruscetti FW, Gallo RC. Characterization and distribution of nucleic acid sequences of a novel type-C retrovirus isolated from neoptastic human T lymphocytes Proc Natl Acad Sci USA 1981; 78: 1887-91. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtaiki Y, Shiraishi Y, Hinuma Y Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemia T cells Nature 1981, 294: 770-71. Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease Proc Natl Acad Sci USA (in press). Gallo RC, Blattner WA, Reitz MS, Ito Y. HTLV the virus of adult T-cell leukaemia in Japan and elsewhere. Lancet 1982, i: 683. Robert-Guroff M, Nakao Y, Notake K, Ito Y, Sliski A, Gallo RC. Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia Science 1982, 295: 975-78. Kalyanaraman VS, Sarngadharan MG, Nakao Y, Ito Y, Aoki T, Gallo RC. Natural antibodies to the structural core protein (p24) of the human T-cell leukemia (lymphoma) retrovirus found in sera of leukemia patients in Japan Proc Natl Acad Sci USA 1982; 79: 1653-57. Catovsky D, Greaves MF, Rose M, Galton DAG, Goolden AWG, McCluskey DR, White JM, Lampert I, Bourikas G, Ireland R, Brownell AI, Bridges JM, Blattner WA, Gallo RC Adult T-cell lymphoma-leukaemia in Blacks from the West Indies. Lancet 1982, i: 639-42 Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, Shirakawa S, Miyoshi I Adult T-cell leukemia Antigen in an ATI. cell line and detection of antibodies to the antigen in human serum Proc Natl Acad Sci USA 1981, 78: 6476-80 Robert-Guroff M, Ruscetti FW, Posner LE, Poiesz BJ, Gallo RC Detection of the human T cell lymphoma virus p19 in cells of some patients with cutaneous T cell lymphoma and leukemia using a monoclonal antibody 7 Exp Med 1981, 154: 1957-64.
1. Poiesz
2
3.
4.
5.
6. 7.
8.
9
10.
11
From a random group of 126 coded serum samples collected by the N.LH. blood bank in the first quarter of 1979 we found two samples (1 and 2) which showed presumptive positive antibody reactivity against the virus. In confirmation tests sample 1 was specifically competed for by purified virus while sample 2 was not. From this we conclude that while sample 1 was seropositive against HTLV, sample 2 may have been a false positive- or it may have contained antibody which binds with greater affinity to viral test antigen(s) in the hydrophobic solid phase than to competing viral antigen(s) in free solution. Of these, one of the sera (no. 1) also contained viral antigens detected by the ELISA tests. Age, sex, and demographic information are presently restricted because of the Privacy Act, but we are studying the effect of recipients of blood from seropositive donors., We were interested to learn that similar results of virus positivity from blood donors in "non-endemic" Kochi, Japan were obtained by culture of blood cells with phytohaemagglutinin for six days followed by immunofluorescence and electron microscopy. 12 We feel that the ELISA immunoassays described here may be much more practical for screening large numbers of donors in a clinical setting. At this time there may not be sufficient data accurately to determine the degree of public health risk for patients receiving blood from donors carrying the HTLV virus or who are simply seropositive against the virus, but we believe that there is sufficient reason to delineate high-risk recipient categories, such as pregnant women, and to establish schemes for prescreening blood or derived blood products for any high risk recipient categories that may exist. Laboratory of Tumor Cell National Cancer Institute,
Biology,
W. CARL SAXINGER
Bethesda, Maryland Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205, U.S A.
ROBERT C. GALLO
ENTERIC ADENOVIRUSES
SIR,—Adenoviruses, present in large quantities in stools of which fail to produce cytopathic effect in conventional cell cultures, have been referred to as "enteric adenoviruses". 1-4 The name implies that these viruses are restricted to the gastrointestinal tract, unlike conventional adenoviruses which also affect the respiratory tract. We have demonstrated that enteric adenovirus can be detected with good sensitivity by infecting human amnion cell cultures and staining by immunofluorescence for adenovirus.The pattern of immunofluorescence provided a preliminary diagnosis of enteric or non-enteric adenovirus infection. Using.this technique, we have examined paired nasopharyngeal secretions and stools of gastroenteritis patients, whose stools had been found to be positive for adenovirus by electron microscopy. Of 16 such paired specimens 8 stools resulted in characteristic enteric adenovirus staining pattern on immunofluorescence microscopy. No virus was detectable by this approach in the corresponding nasopharyngeal suctions. In contrast, stools from eight patients led to the development of immunofluorescent staining consistent with conventional adenoviruses. Five corresponding nasopharyngeal suctions manifested adenovirus by this technique: the adenoviruses isolated from these patients were types 1, 2, 5, and 7.
gastroenteritis patients,
12.
I
Miyoshi F, Fujishita M, Taguchi H, Ohtsuki Y, Akagi T, Morimoto YM, Nagasaki A. Caution against blood transfusion from donors to seropositive to adult T-cell leukaemia-associated antigens. Lancet 1982, i: 683-84. Flewett TH, Bryden AS, Davies H, Morris CA. Epidemic viral enteritis in a long-stay children’s ward Lancet 1975, i: 4-5.
2. Madeley CR Viruses in stools J Clin Pathol 1979; 32: 1-10 3. Middleton PJ, Szymanski MT, Petric M. Viruses associated with acute gastroenteritis in young children, Am J Dis Child 1977, 131: 733-36 4. Johansson ME, Wadell G, Jacobson PA, Svensson L. Preparation of specific antisera against adenoviruses by affinity bead immunization J Immunol Methods 1979, 26: 141-49. 5.
Retter M, Middleton PJ, Tam JS, Petric M Enteric adenoviruses: Detection, replication and significance. J Clin Microbiol 1979; 10: 574-78
1075 This small study suggests that while conventional adenoviruses may cause infection both in the nasopharyngeal and gastrointestinal tracts, the enteric adenoviruses are limited to the gastrointestinal tract alone- hence the name enteric adenovirus is very appropriate. M. PETRIC S. KRAJDEN N. DOWBNIA P. J. MIDDLETON
Department of Virology, Hospital for Sick Children, Toronto, Ontario, Canada
VITAMIN SUPPLEMENTS TO PREVENT NEURAL TUBE DEFECTS
SIR,-The letters from Professor Renwick and Dr Chalmers and Dr Sacks in the March 27 Lancet leave me with the impression that, there is
some
confusion about the strength of the nutritional
supplement used in the Smithells study of neural tube defects (NTD). Renwick points out that large dosages of vitamin D and pyridoxine are effective in various genetic diseases and then states that "the effectiveness of vitamin supplementation is not necessarily indicative by itself of inadequacy of dietary vitamin intake. A vitamin supplement could, for example, counter the teratogenic effect of some dietary toxin". Chalmers and Sacks write of "possibly unsuspected damage to the developing fetus by high doses of nutritional supplements" and speculate that this may result in a long term outcome similar to the stilboestrol The nutritional supplement used by Smithells et al. (’Pregnavite Forte F’) contains eleven nutrients. When taken daily as prescribed it provides these nutrients in quantities that approximate to or are less than the dietary allowance recommended for pregnant women by the Food and Nutrition Board of the U.S. National Academy of Sciences/National Research Council (1980). The accompanying table indicates this. Given the weak strength of this supplement I think it unlikely that its effect has a pharmacological basis, as Renwick implies, or that it will damage the fetus, which is what concerns Chalmers and Sacks. What seems most likely is that the supplement is simply partly correcting the effect of poor nutrition. The work of Laurence and associates supports this.They achieved results similar to those of Smithells study by using dietary counselling. There were three recurrences of NTD in the 103 counselled women and five recurrences in the 71 uncounselled. All 8 recurrences occurred among the 45 pregnancies of women taking poor diets (18%), whereas there were no recurrences among the 141 pregnancies of women taking moderate or good diets. The distinction between a high dose supplement and a supplement like pregnavite forte F is important for it has crucial implications for government policy. There are Federal budget cuts
traedy.
RW, Shepard 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 Child 1981; 56: 911-18. Laurence KM, James N, Miller M, Campbell H. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counselling. Br Med J 1980; 281: 1592-94.
1. Smithells
2
CONSTITUENTS OF DAILY PREGNAVITE FORTE F (THREE TABLETS DAILY) AND U.S. RECOMMENDED DIETARY ALLOWANCE (U.S. RDA) FOR
pending in the United States that could affect nutrition programmes such as the food stamp progamme and the special supplemental food programme for women, infants, and children. The purpose of these programmes is to supply needy individuals with a currently accepted level of adequate nutrition. The administration of pregnative forte F is compatible with this goal, and it should not be confused with an experimental treatment of uncertain value and safety-which is what the administration of a high dose supplement would represent. The investigations of Smithells, Laurence and their colleagues strikingly illustrate the potential consequences of curtailing these programmes, and these findings should be considered when funding for these programmes is discussed. Divisions of Biostatics and Epidemiology, School of Public Health, Columbia University,
J. D. KANOFSKY
New York, N.Y. 10032, U.S.A.
SIR,-Dr Meier (April 10, p. 859) suggests that well-controlled studies should be given high priority to substantiate Smithells and colleagues’ finding that maternal multivitamin supplementation may prevent neural tube defects (NTD). By "well controlled" I assume that Meier means double-blind, placebo-controlled studies. There are, however, great difficulties in using a placebo to investigate NTD. In the U.S.A., General Nutrition Corporation is sponsoring a nationwide NID nutrition study to repeat Smithells’ work. In designing the protocol, double-blindedness was much discussed. For ethical reasons, the American Spina Bifida Association and other cooperating groups would not endorse an NTD study if a placebo was used. Moreover, if informed of the possibility of receiving a placebo, many patients could simply purchase one of several commercial prenatal supplements which are similar to the test supplement. Consequently, the study will compare the sup-
plemented population against
an
unsupplemented population,
as
did Smithells et al. This is the second year of a five year study. Meier likens the use of multivitamin supplementation to early research on diethylstilboestrol (DES). The two are not comparable, however. In 1949, when Smith and Smith’ did their research, DES was known to be a toxic synthetic drug of unknown long-term effects. In contrast, the multivitamin formula used in Smithells’ study is a prenatal supplement of long established safety and nutritional benefit apart from its potential use to prevent NTD. The cost of supplementation is only 10 cents per day, not as much as Meier would have us believe. A whole year of supplementation would cost only$33 while the first year of medical treatment for a surviving NTD baby could reach$100 000. If Smithells is even partly correct and supplementation can prevent even a few NTD recurrences, the cost of multivitamin supplements for high risk mothers would be well justified. Research Department, General Nutrition Corporation, Fargo, North Dakota 58107, U.S A.
DAVID E. WALSH
ANTENATAL DIAGNOSIS OF SEVERE COMBINED IMMUNODEFICIENCY FROM FETAL CORD BLOOD
PREGNANT WOMEN
SIR,-Dr Durandy and colleagues (April 10, p. 852) reported on the antenatal diagnosis of severe combined immunodeficiency (SCID) using fetal cord blood obtained at fetoscopy. Even in the best hands fetoscopy carries a fatality rate of about 507o for the fetus.2 In several conditions where fetal cord blood has been used for prenatal diagnosis new methods have permitted diagnosis by analysis of amniotic fluid after amniocentesis, thus lessening the risk to the fetus. One example is antenatal diagnosis of sickle-cell anaemia where the technique of fetal blood sampling, requiring great
*1 =RE.
Depends on
source, source not known
1 Smith OW, Smith GV The influence ofdiethylstilbestrol on the progress and outcome of pregnancy as based on a comparison of treated with untreated primigravidas. Am J Obstet Gynecol 1949; 58: 994-1009. 2 Mahoney MJ, Hobbins JC Diagnosis of neural tube defects by direct fetoscopy. In: Proceedings of the First Scarborough Conference: Screening for neural tube defects in the United States Portland, Maine. Pilot Press, 1977: 108-20.
SIR,-Newly developed testing procedures have detected protein antigens specific for a human T-cell leukaemia virus (HTLV) in about 1% of the sera of normal blood donors from the National Institutes of Health blood bank. HTLV is an exogenously acquired human type-C RNA tumour virus first isolated from U.S. cases of human leukaemia and lymphoma affecting mature T-cells. 1-3 More recently, Japanese investigators have also detected4and isolated5 from patients with adult T-cell leukaemia a virus which is closely related to HTLV by immunological and nucleic acid hybridisation
(Gallo et al.and Popovic M, et al., unpublished). Epidemiological studies on the distribution of serum antibodies to HTLV in the human population have revealed clusters of antibodypositive sera in groups of patients with acute T-cell leukaemialymphoma and some family members in certain regions ofJapan7,8 and the Caribbean basin9endemic for this type of disease. tests
While cell-free transmission has not been demonstrated in tissue culture for either virus, both viruses have been transmitted to human cord blood lymphocytes by co-cultivation(and M. Popovic et al., unpublished). Furthermore, both groups have found a low incidence among subjects from non-endemic regions and a higher incidence of seropositivity among’residents of Japanese endemic areas and relatives of seropositive patients 6,10 (and Popovic et al., unpublished), supporting the infectious nature of HTLV. Nevertheless, the mechanism of transmission of HTLV remains unproven. Since the incidence of HTLV seropositive T-cell leukaemia has so far been much lower and less is known about the occurrence of these viruses in the normal U.S. population or how they might be transmitted, we tested sera from N.I.H. blood donors for the presence of antibody to the HTLV virus, and for the presence of circulating HTLV structural proteins p24 and p 19. The assays used were newly developed enzyme linked immunoassays (ELISA) using either purified virus or viral antibodies immobilised in microtitre plate wells and monospecific peroxidase-labelled heteroantibody against the p248 or peroxidase-labelled monoclonal antibody against the p1911 proteins of HTLV. These assays are highly sensitive and require small serum samples, and it takes only 2.55 h to test large numbers of samples. The tests can be interpreted by the unaided eye and can be done very well in a clinical setting. BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC Detection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 1980, 77: 7415-19 Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC Isolation of a new type-C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukaemia. Nature 1981, 294: 268-71 Reitz MS, Poiesz BJ, Ruscetti FW, Gallo RC. Characterization and distribution of nucleic acid sequences of a novel type-C retrovirus isolated from neoptastic human T lymphocytes Proc Natl Acad Sci USA 1981; 78: 1887-91. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtaiki Y, Shiraishi Y, Hinuma Y Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemia T cells Nature 1981, 294: 770-71. Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease Proc Natl Acad Sci USA (in press). Gallo RC, Blattner WA, Reitz MS, Ito Y. HTLV the virus of adult T-cell leukaemia in Japan and elsewhere. Lancet 1982, i: 683. Robert-Guroff M, Nakao Y, Notake K, Ito Y, Sliski A, Gallo RC. Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia Science 1982, 295: 975-78. Kalyanaraman VS, Sarngadharan MG, Nakao Y, Ito Y, Aoki T, Gallo RC. Natural antibodies to the structural core protein (p24) of the human T-cell leukemia (lymphoma) retrovirus found in sera of leukemia patients in Japan Proc Natl Acad Sci USA 1982; 79: 1653-57. Catovsky D, Greaves MF, Rose M, Galton DAG, Goolden AWG, McCluskey DR, White JM, Lampert I, Bourikas G, Ireland R, Brownell AI, Bridges JM, Blattner WA, Gallo RC Adult T-cell lymphoma-leukaemia in Blacks from the West Indies. Lancet 1982, i: 639-42 Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, Shirakawa S, Miyoshi I Adult T-cell leukemia Antigen in an ATI. cell line and detection of antibodies to the antigen in human serum Proc Natl Acad Sci USA 1981, 78: 6476-80 Robert-Guroff M, Ruscetti FW, Posner LE, Poiesz BJ, Gallo RC Detection of the human T cell lymphoma virus p19 in cells of some patients with cutaneous T cell lymphoma and leukemia using a monoclonal antibody 7 Exp Med 1981, 154: 1957-64.
1. Poiesz
2
3.
4.
5.
6. 7.
8.
9
10.
11
From a random group of 126 coded serum samples collected by the N.LH. blood bank in the first quarter of 1979 we found two samples (1 and 2) which showed presumptive positive antibody reactivity against the virus. In confirmation tests sample 1 was specifically competed for by purified virus while sample 2 was not. From this we conclude that while sample 1 was seropositive against HTLV, sample 2 may have been a false positive- or it may have contained antibody which binds with greater affinity to viral test antigen(s) in the hydrophobic solid phase than to competing viral antigen(s) in free solution. Of these, one of the sera (no. 1) also contained viral antigens detected by the ELISA tests. Age, sex, and demographic information are presently restricted because of the Privacy Act, but we are studying the effect of recipients of blood from seropositive donors., We were interested to learn that similar results of virus positivity from blood donors in "non-endemic" Kochi, Japan were obtained by culture of blood cells with phytohaemagglutinin for six days followed by immunofluorescence and electron microscopy. 12 We feel that the ELISA immunoassays described here may be much more practical for screening large numbers of donors in a clinical setting. At this time there may not be sufficient data accurately to determine the degree of public health risk for patients receiving blood from donors carrying the HTLV virus or who are simply seropositive against the virus, but we believe that there is sufficient reason to delineate high-risk recipient categories, such as pregnant women, and to establish schemes for prescreening blood or derived blood products for any high risk recipient categories that may exist. Laboratory of Tumor Cell National Cancer Institute,
Biology,
W. CARL SAXINGER
Bethesda, Maryland Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205, U.S A.
ROBERT C. GALLO
ENTERIC ADENOVIRUSES
SIR,—Adenoviruses, present in large quantities in stools of which fail to produce cytopathic effect in conventional cell cultures, have been referred to as "enteric adenoviruses". 1-4 The name implies that these viruses are restricted to the gastrointestinal tract, unlike conventional adenoviruses which also affect the respiratory tract. We have demonstrated that enteric adenovirus can be detected with good sensitivity by infecting human amnion cell cultures and staining by immunofluorescence for adenovirus.The pattern of immunofluorescence provided a preliminary diagnosis of enteric or non-enteric adenovirus infection. Using.this technique, we have examined paired nasopharyngeal secretions and stools of gastroenteritis patients, whose stools had been found to be positive for adenovirus by electron microscopy. Of 16 such paired specimens 8 stools resulted in characteristic enteric adenovirus staining pattern on immunofluorescence microscopy. No virus was detectable by this approach in the corresponding nasopharyngeal suctions. In contrast, stools from eight patients led to the development of immunofluorescent staining consistent with conventional adenoviruses. Five corresponding nasopharyngeal suctions manifested adenovirus by this technique: the adenoviruses isolated from these patients were types 1, 2, 5, and 7.
gastroenteritis patients,
12.
I
Miyoshi F, Fujishita M, Taguchi H, Ohtsuki Y, Akagi T, Morimoto YM, Nagasaki A. Caution against blood transfusion from donors to seropositive to adult T-cell leukaemia-associated antigens. Lancet 1982, i: 683-84. Flewett TH, Bryden AS, Davies H, Morris CA. Epidemic viral enteritis in a long-stay children’s ward Lancet 1975, i: 4-5.
2. Madeley CR Viruses in stools J Clin Pathol 1979; 32: 1-10 3. Middleton PJ, Szymanski MT, Petric M. Viruses associated with acute gastroenteritis in young children, Am J Dis Child 1977, 131: 733-36 4. Johansson ME, Wadell G, Jacobson PA, Svensson L. Preparation of specific antisera against adenoviruses by affinity bead immunization J Immunol Methods 1979, 26: 141-49. 5.
Retter M, Middleton PJ, Tam JS, Petric M Enteric adenoviruses: Detection, replication and significance. J Clin Microbiol 1979; 10: 574-78
1075 This small study suggests that while conventional adenoviruses may cause infection both in the nasopharyngeal and gastrointestinal tracts, the enteric adenoviruses are limited to the gastrointestinal tract alone- hence the name enteric adenovirus is very appropriate. M. PETRIC S. KRAJDEN N. DOWBNIA P. J. MIDDLETON
Department of Virology, Hospital for Sick Children, Toronto, Ontario, Canada
VITAMIN SUPPLEMENTS TO PREVENT NEURAL TUBE DEFECTS
SIR,-The letters from Professor Renwick and Dr Chalmers and Dr Sacks in the March 27 Lancet leave me with the impression that, there is
some
confusion about the strength of the nutritional
supplement used in the Smithells study of neural tube defects (NTD). Renwick points out that large dosages of vitamin D and pyridoxine are effective in various genetic diseases and then states that "the effectiveness of vitamin supplementation is not necessarily indicative by itself of inadequacy of dietary vitamin intake. A vitamin supplement could, for example, counter the teratogenic effect of some dietary toxin". Chalmers and Sacks write of "possibly unsuspected damage to the developing fetus by high doses of nutritional supplements" and speculate that this may result in a long term outcome similar to the stilboestrol The nutritional supplement used by Smithells et al. (’Pregnavite Forte F’) contains eleven nutrients. When taken daily as prescribed it provides these nutrients in quantities that approximate to or are less than the dietary allowance recommended for pregnant women by the Food and Nutrition Board of the U.S. National Academy of Sciences/National Research Council (1980). The accompanying table indicates this. Given the weak strength of this supplement I think it unlikely that its effect has a pharmacological basis, as Renwick implies, or that it will damage the fetus, which is what concerns Chalmers and Sacks. What seems most likely is that the supplement is simply partly correcting the effect of poor nutrition. The work of Laurence and associates supports this.They achieved results similar to those of Smithells study by using dietary counselling. There were three recurrences of NTD in the 103 counselled women and five recurrences in the 71 uncounselled. All 8 recurrences occurred among the 45 pregnancies of women taking poor diets (18%), whereas there were no recurrences among the 141 pregnancies of women taking moderate or good diets. The distinction between a high dose supplement and a supplement like pregnavite forte F is important for it has crucial implications for government policy. There are Federal budget cuts
traedy.
RW, Shepard 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 Child 1981; 56: 911-18. Laurence KM, James N, Miller M, Campbell H. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counselling. Br Med J 1980; 281: 1592-94.
1. Smithells
2
CONSTITUENTS OF DAILY PREGNAVITE FORTE F (THREE TABLETS DAILY) AND U.S. RECOMMENDED DIETARY ALLOWANCE (U.S. RDA) FOR
pending in the United States that could affect nutrition programmes such as the food stamp progamme and the special supplemental food programme for women, infants, and children. The purpose of these programmes is to supply needy individuals with a currently accepted level of adequate nutrition. The administration of pregnative forte F is compatible with this goal, and it should not be confused with an experimental treatment of uncertain value and safety-which is what the administration of a high dose supplement would represent. The investigations of Smithells, Laurence and their colleagues strikingly illustrate the potential consequences of curtailing these programmes, and these findings should be considered when funding for these programmes is discussed. Divisions of Biostatics and Epidemiology, School of Public Health, Columbia University,
J. D. KANOFSKY
New York, N.Y. 10032, U.S.A.
SIR,-Dr Meier (April 10, p. 859) suggests that well-controlled studies should be given high priority to substantiate Smithells and colleagues’ finding that maternal multivitamin supplementation may prevent neural tube defects (NTD). By "well controlled" I assume that Meier means double-blind, placebo-controlled studies. There are, however, great difficulties in using a placebo to investigate NTD. In the U.S.A., General Nutrition Corporation is sponsoring a nationwide NID nutrition study to repeat Smithells’ work. In designing the protocol, double-blindedness was much discussed. For ethical reasons, the American Spina Bifida Association and other cooperating groups would not endorse an NTD study if a placebo was used. Moreover, if informed of the possibility of receiving a placebo, many patients could simply purchase one of several commercial prenatal supplements which are similar to the test supplement. Consequently, the study will compare the sup-
plemented population against
an
unsupplemented population,
as
did Smithells et al. This is the second year of a five year study. Meier likens the use of multivitamin supplementation to early research on diethylstilboestrol (DES). The two are not comparable, however. In 1949, when Smith and Smith’ did their research, DES was known to be a toxic synthetic drug of unknown long-term effects. In contrast, the multivitamin formula used in Smithells’ study is a prenatal supplement of long established safety and nutritional benefit apart from its potential use to prevent NTD. The cost of supplementation is only 10 cents per day, not as much as Meier would have us believe. A whole year of supplementation would cost only$33 while the first year of medical treatment for a surviving NTD baby could reach$100 000. If Smithells is even partly correct and supplementation can prevent even a few NTD recurrences, the cost of multivitamin supplements for high risk mothers would be well justified. Research Department, General Nutrition Corporation, Fargo, North Dakota 58107, U.S A.
DAVID E. WALSH
ANTENATAL DIAGNOSIS OF SEVERE COMBINED IMMUNODEFICIENCY FROM FETAL CORD BLOOD
PREGNANT WOMEN
SIR,-Dr Durandy and colleagues (April 10, p. 852) reported on the antenatal diagnosis of severe combined immunodeficiency (SCID) using fetal cord blood obtained at fetoscopy. Even in the best hands fetoscopy carries a fatality rate of about 507o for the fetus.2 In several conditions where fetal cord blood has been used for prenatal diagnosis new methods have permitted diagnosis by analysis of amniotic fluid after amniocentesis, thus lessening the risk to the fetus. One example is antenatal diagnosis of sickle-cell anaemia where the technique of fetal blood sampling, requiring great
*1 =RE.
Depends on
source, source not known
1 Smith OW, Smith GV The influence ofdiethylstilbestrol on the progress and outcome of pregnancy as based on a comparison of treated with untreated primigravidas. Am J Obstet Gynecol 1949; 58: 994-1009. 2 Mahoney MJ, Hobbins JC Diagnosis of neural tube defects by direct fetoscopy. In: Proceedings of the First Scarborough Conference: Screening for neural tube defects in the United States Portland, Maine. Pilot Press, 1977: 108-20.