1128
M.S.) except s.s.p.E. No statistical differences between these groups in mean C.D.V. titres were observed. In contrast, all but one serum from patients with M.S. and both S.S.P.E. sera contained antibody to M.v. on titres 1/236 (the highest dilutions tested), whereas control M.v. titres, as a group, were signifi-
ease, and
Preliminary
EARLY PRENATAL DIAGNOSIS OF
cantly lower.
NEURAL-TUBE DEFECTS BY titres for titres for measles in M.s. pa-
However, ratios of group
mean
antibody
C.D.V. isolates versus mean tients and controls (normals plus non-M.s. neurological disease) revealed modest differences between groups in their responses to c.D.v. For M.s. patients C.D.V./M.V. ratios were 9.5 and 10.8 for R252-c.D.v. and Ond-c.D.v., respectively, Calculated ratios in the controls were 8 - 8 and 7-9.
the possible implication of causative agent of M.s. was tested serologically. Samples from 21 subjects (10 with M.S., 2 with S.S.P.E., end 9 normal or neurological controls) were examined for the presence of disteriper-virus and measlesvirus neutralising antibodies. The presence of antibody to C.D.V. in all subjects (M.s. and controls) and antibody to M.v. confirms previous studies. 13-15 It has been assumed that M.v. serum antibodies in the human population are acquired by intentional immunisation with M.v. or by spontaneous infection and that c.D.v. antibodies observed are cross-reactive with M. V.16 However, differences were noted when the ratios of C.D.v./M.v. antibody levels were compared in M.s. patients and controls. It was shown that M.v. titres as well as the ratio C.D.V./M.V. were higher in M.s. than in controls. If C.D.V. titres observed were attributable strictly to cross-reaction with M.v., higher levels of C.D.v. antibody in M.s. sera should have been obtained and c.D.v./M.v. ratios in both groups should have been equivalent. This was not so. The results tend to eliminate C.D.V. linkage to M.s. and further support the implication of M.v. in the setiology of M.S. Many dogs are immunised with attenuated M.v. to prevent c.D.v. infection, 17 and if M.v. as a cause of M.s. in man is confirmed, this vaccination practice may be a human health hazard. The possibility that dogs are a source of M.v. has not been investigated. The relatively high c.D.v. titres in the two S.S.P.E. patients deserve further attention, although it is well docu-
preliminary study,
C.D.v. as a
of its variants cause s.S.p.E.18 titres of antibody to c.D.v. in S.S.P.E. sera have been noted elsewhere.19 In that study, the possibility of superinfection of S.S.P.E. patients with c.D.v. was raised. The present study, in a small number of patients, failed to implicate c.D.v. in the aetiology of M.s. Studies in a larger series of patients at various stages of illness and appropriate viral-antigen absorption experiments are needed to exclude C.D.v. definitely as a cause of M.s. in man. mented that
M.v. or some
Inordinately high
We thank Ms Addajane L. Wallace for her excellent technical assistand Dr Wallace W. Tourtellotte, VA Wadsworth Hospital Center, Los Angeles, for providing serum samples and histories. This work was supported by grant no. ROI-Al-09022-08 from the Institute of Allergy and Infectious Diseases, National Institutes of Health. ance
Requests for reprints should be addressed to S. K., Coffey Road, Columbus, Ohio 43210, U.S.A. Ilc/crrrces at Juut cf ncxt culunru
tory, 1925
ULTRASOUND-GUIDED FETOSCOPY S. CAMPBELL
C. H. RODECK
Department of Obstetrics and Gynœcology, King’s College
Hospital, London SE5
Summary
In three fetuses with neural-tube defects
(N.T.D.S) the lesions were clearly seen by in the second trimester. In a fourth fetus, in which the diagnosis of N.T.D. was suspected because of raised amniotic-fluid alpha-fetoprotein, spina bifida was excluded by fetoscopic examination and a normal baby was delivered at term. Ultrasound-guided fetoscopy has a place in the diagnosis of N.T.D.S when the results of other investigations are conflicting or inconclusive, and may be useful in assessing the severity of a lesion.
fetoscopy
Discussion In this
Communications
Goss Labora-
INTRODUCTION
NEURAL-TUBE defects (N.T.D.s) can be diagnosed either amniotic-fluid alpha-fetoprotein (A.F.P.) estimation’1 or by ultrasound scanning of the fetal spinel These two methods complement each other,2 but ultrasound scanning may miss low lesions and A.F.P. may be raised in the presence of a normal fetus3 or by other abnormalities;’-" conversely, it may be normal in the presence of closed defects." While early attempts with fetoscopy were not very encouraging,14 our recent experience with fetoscopy guided by real-time scanning (R.T.S.) suggests that this method provides a definitive diagnosis when the results of A.F.P. estimation and ultrasonography are not consistent or are inconclusive.
by
TECHNIQUE Direct inspection of the fetus is carried out with the ’Needlescope’ (Dyonics, Inc.),15 but ultrasound scanning is essential at every stage of the technique. Initial amniocentesis should be
DR
KRAKOWKA, DR KOESTNER: REFERENCES
Soll, R. W Postgrad. Med. 1972, 52 113. Adams, J. N., Imagawa, D. T. Proc. Soc. exp. Biol. Med. 1962, 111, 562. Pette, E., Kuwert, E. Arch. ges. Virusforsch. 1965, 16, 141. Salmi, A., Gollmar, Y., Norrby, E., Panellus, M. Acta path. microbiol. stand. 1973, 81, 627. 5. Raisne, C. S., Peineas, J. W., Sheppard, R. D., Bornstein, M. B., DuboisDalcq, M. J. neurol. Sci. 1977, 33, 13. 6. ter Muelen, V., Koprowski, H., Iwasaki, Y., Käckell, Y. M., Müller, D. Lancet, 1972, ii, 1. 7. Iwasaki, Y., Koprowski, H., Müller, M. D., ter Muelen, V., Käckell, Y. M. 1. 2. 3. 4.
Lab. Invest. 1973, 28, 494. Cook, S. D., Dowling, P. C. Lancet, 1977, i, 980. Appel, M. J. E., Gillespie, J. H. Virol. Monogr. 1972, 2, 1. McCullough, B., Krakowka, S., Koestner, A. Lab. Invest. 1974,31,216. Confer, A. W., Kahn, D. E., Koestner, A., Krakowka, S. Infect. Immun. 1975, 11, 835. 12. Reed, L. J., Muench, H. Am. J. Hyg. 1938, 27, 493. 13. Hopper, P. K. Acta pœdiat. scand. 1959, 48, 43. 14. Karzon, D. T. Pediatrics, Springfield, 1955, 16, 809. 15. Carlström, G. Acta pœdiat. scand. 1956, 45, 180. 16. Imagawa, D. T. Prog. med. Virol. 1968, 10, 1960. 17. Strating, A. J. Am. vet. med. Ass. 1975, 167, 59. 18. Johnson, R. T. J. infect. Dis. 1970, 121, 227. 19. Sato, T. A., Yamanouchi, K., Shishido, A. Arch. ges. Virusforsch. 1973, 42,
8. 9. 10. 11.
36.
1129 but a low N.T.D. could not be excluded. The cells of further sample of amniotic fluid were studied (Dr C. Gosden, Medical Research Council Clinical and Population Cytogenetics Unit, Edinburgh); although the percentage of viable rapidly adhering cells" was normal, their morphology was suggestive of an N.T.D. After full discussion of the diagnostic problem, the patient agreed to fetoscopy and no abnormality was seen. The pregnancy was allowed to continue and at 41 weeks’ gestation a healthy normal girl was delivered spon-
scanning a
taneously. DISCUSSION
clearly recognised by fetoscopy in 3 cases. views of the N.T.D.s were obtained despite the facts that in all gestation was beyond 18 weeks and that conditions were less than ideal. This experience was then used to establish a negative diagnosis in a fourth fetus in which there were strong grounds for suspecting an N.T.D., and an unnecessary abortion was avoided There was some agreement between the fetoscopic and the necropsy findings, and with more experience, fetoscopy may be of prognostic value. This is likely to be crude, however. Other less invasive methods are also being used to diagnose N.T.D.S-e.g., study of the rapidly adhering cells from amniotic fluid I? and amniography’-—but fetoscopy has the advantage that an immediate diagnosis can be made by direct visualisation and abortifacients can be instilled intra-amniotic ally at once if a lesion is found. Recent evidence19 from several centres in the world suggests that the spontaneous abortion-rate after fetoscopy is between 3 and 4%. The use of R.T.S. should make fetoscopy even safer, and the greater accuracy of the combined technique increases its diagnostic power. We have also used it to examine fetuses at high risk of cleft lip and palate and limb deformities, and to sample fetal blood. We believe, therefore, that its use is justified in high-risk patients if the diagnosis of N.T.D. is in doubt. Such cases will probably become more common with the increasing use of maternal serum A.F.P. as a screening test for N.T.D.s. N.T.D.s were
Convincing
spine (Sp.) and fetoscope (F) as dfsplayed on screen of R.T.S. ; fetoscope is pointing towards the sacral region.
Fetal
,
performed under ultrasound control to avoid intra-amniotic bleeding, which can obscure vision even if fetoscopy is postponed tor 2 weeks." Early ultrasonic fetal measurements will ensure that fetoscopy is performed at the optimum gestational age, namely between 16 and 18 weeks. R.T.S. immediately before the fetoscopy is used to determine the fetal position and placental site and enables the operator to predict whether or not the fetal area of interest is accessible to the needlescope. If not, the procedure is delayed and failed fetoscopy avoided. If conditions are favourable, the most suitable entry site is selected so that the placenta is not damaged. This is usually possible when the fetal back is to be examined because the fetus tends to face its placenta. Intravenous sedation or general anxsthesia are then induced and these diminish fetal movements, permitting more careful scrutiny of the area. In the unusual event of the placenta covering all the accessible parts of the uterus, gentle pressure on one side will rotate the contralateral side of the uterus forwards so that the fetoscope can be safely introduced lateral to the placental edge. Once the tip is inside the amniotic cavity, orientation may be difficult, particularly as the fetal back is featureless. Furthermore, it is essential to examine thoroughly the lower lumbar and sacral region. These problems can be overcome by simultaneous R.T.S. to guide the fetoscope (see accompanying figure).
We thank Mr M. E. Setchell of St. Bartholomew’s Hospital and Mr R. E. Robinson of Cambridge for permission to report on their patients.
Requests for reprints should be addressed to C. H. R. REFERENCES
PATIENTS
Three fetuses were known to have N.T.D.S on the basis of raised amniotic-fluid A.F.P. and positive ultrasound findings. The lesions were clearly recognised at fetoscopy, and in all 3 cases the appearance was similar. They were yellow-grey, devoid of hair, and there was a superficial network of small blood-vessels. The junction with normal skin was sharply defined although the skin margin was ragged. Normal skin was white, covered with fine hair, and blood-vessels were inconspicuous. The lesion in the first case was judged to be small and at the base of the spine; in the second, a large dorsolumbar defect was observed, while in the third a complete rachischisis was identified in association with anencephaly. Abortion was immediately induced by intra-amniotic instillation of prostaglandin E, and hypertonic saline. The above findings were confirmed by pathological examination. A fourth fetus was at risk of having a N.T.D. because the mother had had a previous anencephalic child and A.F.P. was raised in a clear sample of amniotic fluid. The fetal cerebral ventricles and spine down to L4 were normal on ultrasound
1. 2. 3.
Brock, D. J. H., Sutcliffe, R. G. Lancet, 1972, ii, 197. Campbell, S. Clin. Obstet. Gynaec. 1977, 20, 351. Kjessler, B., Hemmingsson, A., Nillson, B. A., Johansson, S. G. Acta obstet. gynec. scand. 1977, suppl. 69, p. 83. 4. Ward, A. M., Stewart, C. R. Lancet, 1974, ii, 345. 5. Seppälä, M., Ruoslahti, E. ibid. 1973, i, 155. 6. De Bruijn, H. W. A., Huisjes, H. ibid. 1975, i, 525. 7. Seppälä, M., Laes, E., Harvo-Noponen, M. J. Obstet. Gynœc. Br. Commonw. 1974, 81, 827. 8. Weinberg, A. G., Milunsky, A., Harrod, M. J. Lancet, 1975, ii, 496. 9. Kjessler, B., Serhman, M., Johansson, S. G. O., Gustavson, K-H., Hultquist, G. ibid. 1975, i, 432. 10. Schmid, W., Muhlethaler, J. P. Humangenetik, 1975, 25, 353. 1. Seller, M. J., Creasy, M. R , Alberman, E D. Br. med J. 1974, ii, 22 12. Jandial, V., Thom, H., Gibson, J. ibid. 1976, ii, 22. 13. Brock, D. J. H. Br. med. Bull. 1976, 32, 16. 14. Scrimgeour, J. B. in Intrauterine Fetal Visualisation (edited by M. M. Kaback and C. Valenti); p. 150. Amsterdam, 1976. 15. Hobbins, J. C., Mahoney, M. J., Goldstein, L. A. Am. J. Obstet. Gynec. 1974, 118, 1069. 16. Rodeck, C. H., Campbell, S. Unpublished. 17. Gosden, C. M., Brock, D. J. H. Lancet, 1977, i, 919. 18. Weiss, R. R., Macri, J. N., Balsam, D. ibid. 1978, i, 717.
Meeting on Perinatal Detection of Haemoglobinopathies, Angeles, February, 1978.
19. N.I.H.
Los
I
M.S.) except s.s.p.E. No statistical differences between these groups in mean C.D.V. titres were observed. In contrast, all but one serum from patients with M.S. and both S.S.P.E. sera contained antibody to M.v. on titres 1/236 (the highest dilutions tested), whereas control M.v. titres, as a group, were signifi-
ease, and
Preliminary
EARLY PRENATAL DIAGNOSIS OF
cantly lower.
NEURAL-TUBE DEFECTS BY titres for titres for measles in M.s. pa-
However, ratios of group
mean
antibody
C.D.V. isolates versus mean tients and controls (normals plus non-M.s. neurological disease) revealed modest differences between groups in their responses to c.D.v. For M.s. patients C.D.V./M.V. ratios were 9.5 and 10.8 for R252-c.D.v. and Ond-c.D.v., respectively, Calculated ratios in the controls were 8 - 8 and 7-9.
the possible implication of causative agent of M.s. was tested serologically. Samples from 21 subjects (10 with M.S., 2 with S.S.P.E., end 9 normal or neurological controls) were examined for the presence of disteriper-virus and measlesvirus neutralising antibodies. The presence of antibody to C.D.V. in all subjects (M.s. and controls) and antibody to M.v. confirms previous studies. 13-15 It has been assumed that M.v. serum antibodies in the human population are acquired by intentional immunisation with M.v. or by spontaneous infection and that c.D.v. antibodies observed are cross-reactive with M. V.16 However, differences were noted when the ratios of C.D.v./M.v. antibody levels were compared in M.s. patients and controls. It was shown that M.v. titres as well as the ratio C.D.V./M.V. were higher in M.s. than in controls. If C.D.V. titres observed were attributable strictly to cross-reaction with M.v., higher levels of C.D.v. antibody in M.s. sera should have been obtained and c.D.v./M.v. ratios in both groups should have been equivalent. This was not so. The results tend to eliminate C.D.V. linkage to M.s. and further support the implication of M.v. in the setiology of M.S. Many dogs are immunised with attenuated M.v. to prevent c.D.v. infection, 17 and if M.v. as a cause of M.s. in man is confirmed, this vaccination practice may be a human health hazard. The possibility that dogs are a source of M.v. has not been investigated. The relatively high c.D.v. titres in the two S.S.P.E. patients deserve further attention, although it is well docu-
preliminary study,
C.D.v. as a
of its variants cause s.S.p.E.18 titres of antibody to c.D.v. in S.S.P.E. sera have been noted elsewhere.19 In that study, the possibility of superinfection of S.S.P.E. patients with c.D.v. was raised. The present study, in a small number of patients, failed to implicate c.D.v. in the aetiology of M.s. Studies in a larger series of patients at various stages of illness and appropriate viral-antigen absorption experiments are needed to exclude C.D.v. definitely as a cause of M.s. in man. mented that
M.v. or some
Inordinately high
We thank Ms Addajane L. Wallace for her excellent technical assistand Dr Wallace W. Tourtellotte, VA Wadsworth Hospital Center, Los Angeles, for providing serum samples and histories. This work was supported by grant no. ROI-Al-09022-08 from the Institute of Allergy and Infectious Diseases, National Institutes of Health. ance
Requests for reprints should be addressed to S. K., Coffey Road, Columbus, Ohio 43210, U.S.A. Ilc/crrrces at Juut cf ncxt culunru
tory, 1925
ULTRASOUND-GUIDED FETOSCOPY S. CAMPBELL
C. H. RODECK
Department of Obstetrics and Gynœcology, King’s College
Hospital, London SE5
Summary
In three fetuses with neural-tube defects
(N.T.D.S) the lesions were clearly seen by in the second trimester. In a fourth fetus, in which the diagnosis of N.T.D. was suspected because of raised amniotic-fluid alpha-fetoprotein, spina bifida was excluded by fetoscopic examination and a normal baby was delivered at term. Ultrasound-guided fetoscopy has a place in the diagnosis of N.T.D.S when the results of other investigations are conflicting or inconclusive, and may be useful in assessing the severity of a lesion.
fetoscopy
Discussion In this
Communications
Goss Labora-
INTRODUCTION
NEURAL-TUBE defects (N.T.D.s) can be diagnosed either amniotic-fluid alpha-fetoprotein (A.F.P.) estimation’1 or by ultrasound scanning of the fetal spinel These two methods complement each other,2 but ultrasound scanning may miss low lesions and A.F.P. may be raised in the presence of a normal fetus3 or by other abnormalities;’-" conversely, it may be normal in the presence of closed defects." While early attempts with fetoscopy were not very encouraging,14 our recent experience with fetoscopy guided by real-time scanning (R.T.S.) suggests that this method provides a definitive diagnosis when the results of A.F.P. estimation and ultrasonography are not consistent or are inconclusive.
by
TECHNIQUE Direct inspection of the fetus is carried out with the ’Needlescope’ (Dyonics, Inc.),15 but ultrasound scanning is essential at every stage of the technique. Initial amniocentesis should be
DR
KRAKOWKA, DR KOESTNER: REFERENCES
Soll, R. W Postgrad. Med. 1972, 52 113. Adams, J. N., Imagawa, D. T. Proc. Soc. exp. Biol. Med. 1962, 111, 562. Pette, E., Kuwert, E. Arch. ges. Virusforsch. 1965, 16, 141. Salmi, A., Gollmar, Y., Norrby, E., Panellus, M. Acta path. microbiol. stand. 1973, 81, 627. 5. Raisne, C. S., Peineas, J. W., Sheppard, R. D., Bornstein, M. B., DuboisDalcq, M. J. neurol. Sci. 1977, 33, 13. 6. ter Muelen, V., Koprowski, H., Iwasaki, Y., Käckell, Y. M., Müller, D. Lancet, 1972, ii, 1. 7. Iwasaki, Y., Koprowski, H., Müller, M. D., ter Muelen, V., Käckell, Y. M. 1. 2. 3. 4.
Lab. Invest. 1973, 28, 494. Cook, S. D., Dowling, P. C. Lancet, 1977, i, 980. Appel, M. J. E., Gillespie, J. H. Virol. Monogr. 1972, 2, 1. McCullough, B., Krakowka, S., Koestner, A. Lab. Invest. 1974,31,216. Confer, A. W., Kahn, D. E., Koestner, A., Krakowka, S. Infect. Immun. 1975, 11, 835. 12. Reed, L. J., Muench, H. Am. J. Hyg. 1938, 27, 493. 13. Hopper, P. K. Acta pœdiat. scand. 1959, 48, 43. 14. Karzon, D. T. Pediatrics, Springfield, 1955, 16, 809. 15. Carlström, G. Acta pœdiat. scand. 1956, 45, 180. 16. Imagawa, D. T. Prog. med. Virol. 1968, 10, 1960. 17. Strating, A. J. Am. vet. med. Ass. 1975, 167, 59. 18. Johnson, R. T. J. infect. Dis. 1970, 121, 227. 19. Sato, T. A., Yamanouchi, K., Shishido, A. Arch. ges. Virusforsch. 1973, 42,
8. 9. 10. 11.
36.
1129 but a low N.T.D. could not be excluded. The cells of further sample of amniotic fluid were studied (Dr C. Gosden, Medical Research Council Clinical and Population Cytogenetics Unit, Edinburgh); although the percentage of viable rapidly adhering cells" was normal, their morphology was suggestive of an N.T.D. After full discussion of the diagnostic problem, the patient agreed to fetoscopy and no abnormality was seen. The pregnancy was allowed to continue and at 41 weeks’ gestation a healthy normal girl was delivered spon-
scanning a
taneously. DISCUSSION
clearly recognised by fetoscopy in 3 cases. views of the N.T.D.s were obtained despite the facts that in all gestation was beyond 18 weeks and that conditions were less than ideal. This experience was then used to establish a negative diagnosis in a fourth fetus in which there were strong grounds for suspecting an N.T.D., and an unnecessary abortion was avoided There was some agreement between the fetoscopic and the necropsy findings, and with more experience, fetoscopy may be of prognostic value. This is likely to be crude, however. Other less invasive methods are also being used to diagnose N.T.D.S-e.g., study of the rapidly adhering cells from amniotic fluid I? and amniography’-—but fetoscopy has the advantage that an immediate diagnosis can be made by direct visualisation and abortifacients can be instilled intra-amniotic ally at once if a lesion is found. Recent evidence19 from several centres in the world suggests that the spontaneous abortion-rate after fetoscopy is between 3 and 4%. The use of R.T.S. should make fetoscopy even safer, and the greater accuracy of the combined technique increases its diagnostic power. We have also used it to examine fetuses at high risk of cleft lip and palate and limb deformities, and to sample fetal blood. We believe, therefore, that its use is justified in high-risk patients if the diagnosis of N.T.D. is in doubt. Such cases will probably become more common with the increasing use of maternal serum A.F.P. as a screening test for N.T.D.s. N.T.D.s were
Convincing
spine (Sp.) and fetoscope (F) as dfsplayed on screen of R.T.S. ; fetoscope is pointing towards the sacral region.
Fetal
,
performed under ultrasound control to avoid intra-amniotic bleeding, which can obscure vision even if fetoscopy is postponed tor 2 weeks." Early ultrasonic fetal measurements will ensure that fetoscopy is performed at the optimum gestational age, namely between 16 and 18 weeks. R.T.S. immediately before the fetoscopy is used to determine the fetal position and placental site and enables the operator to predict whether or not the fetal area of interest is accessible to the needlescope. If not, the procedure is delayed and failed fetoscopy avoided. If conditions are favourable, the most suitable entry site is selected so that the placenta is not damaged. This is usually possible when the fetal back is to be examined because the fetus tends to face its placenta. Intravenous sedation or general anxsthesia are then induced and these diminish fetal movements, permitting more careful scrutiny of the area. In the unusual event of the placenta covering all the accessible parts of the uterus, gentle pressure on one side will rotate the contralateral side of the uterus forwards so that the fetoscope can be safely introduced lateral to the placental edge. Once the tip is inside the amniotic cavity, orientation may be difficult, particularly as the fetal back is featureless. Furthermore, it is essential to examine thoroughly the lower lumbar and sacral region. These problems can be overcome by simultaneous R.T.S. to guide the fetoscope (see accompanying figure).
We thank Mr M. E. Setchell of St. Bartholomew’s Hospital and Mr R. E. Robinson of Cambridge for permission to report on their patients.
Requests for reprints should be addressed to C. H. R. REFERENCES
PATIENTS
Three fetuses were known to have N.T.D.S on the basis of raised amniotic-fluid A.F.P. and positive ultrasound findings. The lesions were clearly recognised at fetoscopy, and in all 3 cases the appearance was similar. They were yellow-grey, devoid of hair, and there was a superficial network of small blood-vessels. The junction with normal skin was sharply defined although the skin margin was ragged. Normal skin was white, covered with fine hair, and blood-vessels were inconspicuous. The lesion in the first case was judged to be small and at the base of the spine; in the second, a large dorsolumbar defect was observed, while in the third a complete rachischisis was identified in association with anencephaly. Abortion was immediately induced by intra-amniotic instillation of prostaglandin E, and hypertonic saline. The above findings were confirmed by pathological examination. A fourth fetus was at risk of having a N.T.D. because the mother had had a previous anencephalic child and A.F.P. was raised in a clear sample of amniotic fluid. The fetal cerebral ventricles and spine down to L4 were normal on ultrasound
1. 2. 3.
Brock, D. J. H., Sutcliffe, R. G. Lancet, 1972, ii, 197. Campbell, S. Clin. Obstet. Gynaec. 1977, 20, 351. Kjessler, B., Hemmingsson, A., Nillson, B. A., Johansson, S. G. Acta obstet. gynec. scand. 1977, suppl. 69, p. 83. 4. Ward, A. M., Stewart, C. R. Lancet, 1974, ii, 345. 5. Seppälä, M., Ruoslahti, E. ibid. 1973, i, 155. 6. De Bruijn, H. W. A., Huisjes, H. ibid. 1975, i, 525. 7. Seppälä, M., Laes, E., Harvo-Noponen, M. J. Obstet. Gynœc. Br. Commonw. 1974, 81, 827. 8. Weinberg, A. G., Milunsky, A., Harrod, M. J. Lancet, 1975, ii, 496. 9. Kjessler, B., Serhman, M., Johansson, S. G. O., Gustavson, K-H., Hultquist, G. ibid. 1975, i, 432. 10. Schmid, W., Muhlethaler, J. P. Humangenetik, 1975, 25, 353. 1. Seller, M. J., Creasy, M. R , Alberman, E D. Br. med J. 1974, ii, 22 12. Jandial, V., Thom, H., Gibson, J. ibid. 1976, ii, 22. 13. Brock, D. J. H. Br. med. Bull. 1976, 32, 16. 14. Scrimgeour, J. B. in Intrauterine Fetal Visualisation (edited by M. M. Kaback and C. Valenti); p. 150. Amsterdam, 1976. 15. Hobbins, J. C., Mahoney, M. J., Goldstein, L. A. Am. J. Obstet. Gynec. 1974, 118, 1069. 16. Rodeck, C. H., Campbell, S. Unpublished. 17. Gosden, C. M., Brock, D. J. H. Lancet, 1977, i, 919. 18. Weiss, R. R., Macri, J. N., Balsam, D. ibid. 1978, i, 717.
Meeting on Perinatal Detection of Haemoglobinopathies, Angeles, February, 1978.
19. N.I.H.
Los
I
