PREGNANCY OUTCOME* ACCORDING TO WHETHER OR NOT TRACING WAS DIFFICULT
vitamin, folic acid, or iron preparations without consultation. The herself is also warned not to dose herself at the same time as receiving the tablets, given for a month before conception is attempted and then continously until the date of the second missed menstrual period. We have administered such courses to 208 women with a history of an NTD pregnancy. There have been 180 babies bom healthy, 10 miscarriages, 3 women lost to follow-up, and 1 recurrence of spina bifida (the woman admits to having been haphazard in taking the tablets, often forgetting); 14 women are still pregnant. E. M. S. has examined all the children bom: there was 1 with a small cleft of the soft palate, 1 had pyloric stenosis, and 1 a dislocated hip. Obviously the recurrence rate for NTD was much less than the standard 1 in 20 that used to be quoted before the introduction of this prophylaxis, and the rates of other complications were no higher than expected. Many of these women were included in a letter to The Lancet in 19853reporting 1080 women with 10 4 recurrences on NTD, and were reported by Bernard et al. In 10 years we and our patients have been very pleased with the reduction in NTD that has accompanied this regimen. Couples have certainly been encouraged to attempt further conception by positive counselling about the ability of the vitamin/folic acid preparation to reduce the recurrence likelihood. We are in close contact with the group through B. M. who is regarded by the women as a friend, and we know of no further hidden late side-effects. It is our intention to continue to use the same vitamin/relatively low folic acid preparation rather than the government recommended higher dose folic acid alone, until we feel happy that it is as least as safe and effective as what we are doing now. We work in a socially deprived area which further encourages our stance, which has the sanction of Salford Maternity Services Committee. The Salford Family Practitioner Committee has been notified of our views. One reason for this letter is to invite comments from those who criticise or support our decision. woman
Royal Manchester Children’s Hospital, University of Manchester School of Medicine, Pendlebury, Manchester M27 1HA, UK
MAURICE SUPER ELIZABETH M. SUMMERS BERYL MEYLAN
1. Smithells RW, Seller M, Hams R, et al. Further expenences of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983; i: 1027-31. 2. Smithells RW, Shephard S, Scorah CJ. Vitamin deficiencies and neural tube defects. Arch Dis Child 1976; 51: 944-49. 3. Seller MJ. Periconceptional vitamin supplementation to prevent recurrence of neural tube defects. Lancet 1985; i: 1392. 4. Bernard SH, Walsworth-Bell JP, Super M, et al. A survey of neural tube defect pregnancies in north-east England. Z Kinderchiro 1988; 43 (suppl II): 15-16.
SIR,-In their comments on the Medical Research Council (MRC) European trial of chorion villus sampling (CV S),1 Dr Saura and colleagues and Dr Verma (Aug 17, pp 449-50) cite nonrandomised studies of sampling at different gestational ages. Data from the European trial show that just delaying prenatal testing from 10 to 13 weeks (as suggested by Saura) would have halved the subsequent rate of miscarriage. But this reflects ihe stage of pregnancy at which testing is done, not the technique used, and it illustrates the importance of randomised controlled studies rather than comparisons based on observational data. Another consideration is completeness of follow-up.2 The MRC European trial achieved 99% ascertainment of outcome, and this compared favourably with ascertainment in the other large multicentre randomised trial of CVS and amniocentesisand, almost certainly, with most non-randomised studies. Among the women allocated to CVS in the MRC European trial those who were difficult to trace were more likely to have received a single test as allocated and to have a surviving infant, whereas the corresponding group allocated amniocentesis were less likely to have a single test and less likely to have a successful outcome of pregnancy (table). Although the numbers are small and any conclusions must therefore be tentative, these data suggest that losses to follow-up may introduce unpredictable bias. It would be wrong to assume that the MRC European trial results are a less
UK to MRC
reliable indication of the true fetal loss rate than the Canadian figured The confidence intervals of these estimates overlap and the pooled estimate of between 3% and 35% may be the most useful guide. The range of centres that collaborated in the European and Canadian trials provides data that are likely to be more applicable than those from individual centres. A minimum level of experience was required of all operators in the European and Canadian trials, and secondary analyses of the European trial failed to demonstrate that performance improved during the study. We therefore doubt whether inexperience is the explanation for the difference in outcome in the two trials. Secondary analyses of the MRC European data did indeed indicate that the risk of miscarriage increased with the number of CVS needle insertions; however, the risk was no higher after samplings that were reported as "difficult", or after a second prenatal test. We would urge Dr Smoleniec and Dr James (Aug 17, p 449) to be cautious in their interpretation of the data on "false positive diagnoses" in the European trial. As the report discusses, there are good reasons to believe that the number of false positives was greater after CVS even though only one such case was confirmed from fetal material. The report of the MRC European trial did not suggest, as Smoleniec and James imply, that CVS should be abandoned in favour of early amniocentesis. The place of alternatives to transcervical CVS for early prenatal diagnosis will be clarified by further large randomised trials. At least three such studies comparing transabdominal with transcervical chorion CVS are nearing completion. We would argue that early amniocentesis should not be introduced into clinical practice outside the context of further randomised trials. Without such studies it will be impossible to judge whose opinions about the safety and diagnostic accuracy of the procedure are correct. Perinatal Trials Service, Radcliffe Infirmary, Oxford OX2 6HE, UK
ADRIAN GRANT SARAH AYERS
MRC Human Genetics Unit, Western General Hospital,
MRC Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow
1. MRC Working Party on the evaluation of chorion villus sampling. Medical Research Council European Trial of chorion villus sampling. Lancet 1991; 337: 1491-99. 2. Halliday J, Sheffield L, Danks D, Lumley J. Complete follow-up in assessing fetal losses after chorion villus sampling. Lancet 1990; 335: 1156. 3. Canadian Collaborative CVS-Amniocentesis Clinical Trial Group. Multicentre randomised clinical trial of chorion villus sampling and amniocentesis. Lancet 1989; i: 1-6.
Systemic lupus erythematosus in pregnancy SIR,-Your July 13 editorial
pregnancy in patients with systemic lupus erythematosus (SLE) are not
widely available. prospectively
followed twenty-five pregnancies in 18 with SLE and in 4 with subacute cutaneous lupus. Among the SLE group, 6 patients had renal disease, complicated in 2 by hypertension, and 5 patients had high values of andphospholipid antibodies (3 of these had already had pregnancy failures). All patients were started on aspirin (100 mg/day) during pregnancy. Steroid treatment given before pregnancy was women
continued and the dose was increased up to 40 mg/day if needed; azathioprine was added in 8 patients after 20 weeks’ gestation to avoid an increase in steroid dose;1 patients not receiving steroid before pregnancy were started with 10 mg or received no steroid (1 case) after clinical and serological assessment. Our policy includes treatment in the puerperium with the dose of steroid that was used at the end of the gestation period. The women were seen monthly in the clinical immunology outpatient clinic and the high-risk pregnancy clinic. Serological evaluations including routine and immunological blood tests were done monthly and fetal growth was investigated by ultrasonography (at 8, 20, and 32 weeks’), echocardiography (at 20 and 30 weeks’), and repeated doppler flow studies (starting at week 20). In 14 patients we recorded lupus relapses (joint, skin, or renal disease), which responded to slight adjustment of treatment. The relapse rate was 0-07 per patient-month (14 relapses in 203 patient-months), in fair agreement with another report.2 23 livebom babies were delivered and only a few obstetric and neonatal complications were seen (1 abrubtio placentae, 6 fetal distress, 1 pre-eclampsia); 6 of these babies were small for gestational age but had no sequelae, confirming that careful monitoring of maternofetal conditions substantially improves pregnancy outcome. We did not see any postpartum exacerbation, and in our series pregnancy did not worsen the long-term course of maternal disease (mean follow up 4 years). We thank Prof P. Cattaneo, Dr M. Braga, and L. Spatola from the Clinical Immunology Unit for sharing the care of the patients; Dr M. Tarantini, Dr A. Lojacono, and Dr P. Tanzi from the Obstetric and Gynaecology Department for their skilful assistance. Clinical Immunology Unit, Obstetric and Gynaecology Department, and Neonatal Intensive Care Unit, Ospedale Civile di Brescia, 25125 Brescia, Italy
ANGELA TINCANI GENESIO BALESTRIERI DAVID FADEN CARMELO DIMARIO
A, Cattaneo R, Martinelli M, et al. Antiphospholipid antibodies m recurrent fetal loss: only one side of the coin. Clin Exp Rheumatol 1987; 5: 390-91. 2. Wong KL, Chan FY, Lee CP. Outcome of pregnancy in patients with systemic lupus erythematosus. a prospective study. Arch Intern Med 1991; 151: 269-73. 1. Tincani
Guillain-Barré syndrome and
usually immunogenic, they could induce an immune response when complexed to serum or tissue proteins. Delayed-type hypersensitivity and sensitisation to gangliosides have been described,4,5 and T cells might participate in the response through non-major-histocompatibility-complex restricted interactions.6 The immune response was not restricted to Gi, since complement fixing anti-myelin antibodies were also present. Immune reactivity to GMl could have triggered a broader antineural response, or GBS could have been caused by less specific immune mechanisms, as can happen after surgery. There was no evidence for preceding infection with campylobacter. Serological tests for campylobacter infection in patients with anti-GMl antibodies could be falsely raised, because of crossreactivity of anti-GM, antibodies with Gal (Bl-3)GalNAc determinants shared by some strains of campylobacter.7 The occurrence of GBS after parenteral administration of gangliosides is probably rare, but investigations of the mechanisms responsible for the reaction might help to identify patients who are at risk and provide clues to the pathogenesis of GBS. Department of Neurology, Black Building (room 3-323), Columbia University, New York 10032, USA
Department of Neurology, University of Maryland, Baltimore
CAROL L. KOSKI
PATRICIA A. WALICKE
Sadiq SA, Thomas FP, Kildereas K,
et al. The spectrum of neurological disease associated with anti-GM1 antibodies. Neurology 1990; 40: 1067-72. 2. Koski CL, Humphrey R, Shin ML. Anti-petipheral myelin antibodies in patients with demyelinating neuropathy: quantitative and kinetic determination of serum antibody activity by complement component 1 fixation. Proc Natl Acad Sci USA
1985, 82: 905-09. Carpo M, Nobile-Orazio E, Meucci N, Scarlato G. Anti-GM1 IgG antibodies in Guillain-Barré syndrome. Clin Neuropathol 1991; 10: 146. 4. Offner H, Standage BA, Burger DR, Vandenbark AA. Delayed type hypersensitivity to gangliosides in the Lewis rat. J Neuroimmunol 1985; 9: 145-57. 5. Knorr-Held S, Brendel W, Kiefer H, et al. Sensitization against brain gangliosides after therapeutic swine brain implantation in a multiple sclerosis patient. J Neurol 3.
1986; 233: 54-56. The T cell receptor and class Ib MHC-related proteins: enigmatic molecules of immune recognition. Cell 1989; 57: 895-98. 7. O’Sullivan N, Benjamin J, Skirrow MB. Lectin typing of Campylobacter isolates. J Clin Pathol 1990; 43: 856-59.
gangliosides SIR,-Dr Yuki and colleagues (May 4, p 1109) report a patient in a reversible motoneuron disease syndrome developed with anti-GM2 ganglioside antibodies after treatment with an injectable
of brain gangliosides. Professor Scarlato and Dr Nobile-Orazio (Aug 3, p 314) suggest that the patient may have had a form of Guillain-Barre syndrome (GBS). However, Dr Callergaro and colleagues (March 30, p 789) argue that gangliosides are not immunogenic, although anti-GMl ganglioside antibodies are seen in GBS after campylobacter infection. We report a patient in whom GBS developed with increased titres of anti-GMl antibodies after treatment with parenteral gangliosides. A 70-year-old woman had symptoms of an L-5 radiculopathy, and visited a health spa in Italy. She received daily injections of brain gangliosides (’Cronnasial’), which she continued after returning home. On the 10th day of treatment she became weak and was admitted to a local hospital with the diagnosis of GBS. Over the next few days the weakness progressed to quadrapareses and areflexia. Electrophysiological studies were initially normal, but later showed F-wave and H-reflex delays in the legs, with normal conduction velocities, low amplitude motor latencies, and dispersed potentials. On the 5th day in hospital, anti-GMi and asialo-GMi antibodies were increased at titres 3200 and 25 600, respectively (normal 800 or less and 3200 or less, respectively).l Antiperipheral myelin antibodies, as measured by the Clq transfer and fixation assay were increased to 70 (normal 25 or less)On the 9th day in hospital, her strength began to improve, and she made a slow but
SIR,-Dr Yuki and colleagues (May 4 and Aug 3, p 314) describe patient in whom progressive weakness and wasting developed during treatment with gangliosides. A similar ganglioside preparation from bovine brain (’Cronassial’) was introduced into the German market in 1986. The drug was approved by the Federal Health Office against the vote of the advisory committee. It was greeted by a drug bulletin with the prediction that it was likely to cause Guillain-Barre syndrome (GBS).1 Berlit2 reported 5 patients with symptoms of GBS or amyotrophic lateral sclerosis (ALS) during treatment with cronassial, out of a total of 14 000 patients exposed to the drug. Further investigations revealed an additional 6 cases, and the drug was banned on July 27, 1989. The network of mutual information run by the Arznei-telegramm has data for 19 patients with GBS or ALS who had been treated with the ganglioside preparation, 4 of whom died. Additionally, the network received a further report of a 62-year-old patient in whom an immunogenic reaction with fever, shock, and rapidly progressing tetraparesis developed 3 days after treatment with GMl ganglioside was started.3 This case occurred during a small clinical trial, and the patient died.
These data argue for a causal link between gangliosides and GBS or ALS. Institute of Clinical Pharmacology, Zentralkrankenhaus St-Jurgen-Strasse, D-2800 Bremen, Germany
PETER S. SCHÖNHÖFER
complete recovery. The onset of GBS 10 days after initiation of ganglioside injections could have been a coincidence, but similar reactions have been noted in two other patients,3and the presence of anti-GMl antibodies suggests otherwise. Although gangliosides are not
zweiter Fall Carnivora? Arznei-telegramm 1985; v: Tagl Praxis 1989; 30: 358-60.
1. Anon. Cronassial, ein 2. Berlit P. Cronassial.
Kompliltationen mit Todesfolge nach Rinderhirngangliosid GM 1 (SYGEN).
Arznei-telegramm 1991; i: 8.