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vitamin, folic acid, or iron preparations without consultation. Thewoman 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 missedmenstrual 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 ofspina bifida (the woman admits to having been haphazard in takingthe tablets, often forgetting); 14 women are still pregnant.E. M. S. has examined all the children bom: there was 1 with a smallcleft of the soft palate, 1 had pyloric stenosis, and 1 a dislocated hip.Obviously the recurrence rate for NTD was much less than thestandard 1 in 20 that used to be quoted before the introduction ofthis prophylaxis, and the rates of other complications were nohigher than expected. Many of these women were included in aletter to The Lancet in 19853 reporting 1080 women with 10recurrences on NTD, and were reported by Bernard et al. 4

In 10 years we and our patients have been very pleased with thereduction in NTD that has accompanied this regimen. Coupleshave certainly been encouraged to attempt further conception bypositive counselling about the ability of the vitamin/folic acidpreparation to reduce the recurrence likelihood. We are in closecontact with the group through B. M. who is regarded by thewomen as a friend, and we know of no further hidden lateside-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 feelhappy that it is as least as safe and effective as what we are doingnow. We work in a socially deprived area which further encouragesour stance, which has the sanction of Salford Maternity ServicesCommittee. The Salford Family Practitioner Committee has beennotified of our views. One reason for this letter is to invite commentsfrom those who criticise or support our decision.

Royal Manchester Children’s Hospital,University of Manchester School of Medicine,Pendlebury, Manchester M27 1HA, UK

MAURICE SUPERELIZABETH M. SUMMERSBERYL 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 neuraltube defects. Lancet 1985; i: 1392.

4. Bernard SH, Walsworth-Bell JP, Super M, et al. A survey of neural tube defectpregnancies in north-east England. Z Kinderchiro 1988; 43 (suppl II): 15-16.

Choriori villus samplingSIR,-In their comments on the Medical Research Council

(MRC) European trial of chorion villus sampling (CV S),1 Dr Sauraand colleagues and Dr Verma (Aug 17, pp 449-50) cite non-randomised studies of sampling at different gestational ages. Datafrom the European trial show that just delaying prenatal testingfrom 10 to 13 weeks (as suggested by Saura) would have halved thesubsequent rate of miscarriage. But this reflects ihe stage of

pregnancy at which testing is done, not the technique used, and itillustrates the importance of randomised controlled studies ratherthan comparisons based on observational data.

Another consideration is completeness of follow-up.2 The MRCEuropean trial achieved 99% ascertainment of outcome, and thiscompared favourably with ascertainment in the other largemulticentre randomised trial of CVS and amniocentesis and,almost certainly, with most non-randomised studies. Among thewomen allocated to CVS in the MRC European trial those whowere difficult to trace were more likely to have received a single testas allocated and to have a surviving infant, whereas the

corresponding group allocated amniocentesis were less likely tohave a single test and less likely to have a successful outcome ofpregnancy (table). Although the numbers are small and anyconclusions must therefore be tentative, these data suggest thatlosses to follow-up may introduce unpredictable bias. It would bewrong to assume that the MRC European trial results are a less

PREGNANCY OUTCOME* ACCORDING TO WHETHER OR NOTTRACING WAS DIFFICULT

*Women recruited in UK to MRC European trial

reliable indication of the true fetal loss rate than the Canadian figuredThe confidence intervals of these estimates overlap and the pooledestimate 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 applicablethan those from individual centres. A minimum level of experiencewas required of all operators in the European and Canadian trials,and secondary analyses of the European trial failed to demonstratethat performance improved during the study. We therefore doubtwhether inexperience is the explanation for the difference inoutcome in the two trials. Secondary analyses of the MRC

European data did indeed indicate that the risk of miscarriageincreased with the number of CVS needle insertions; however, therisk 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 positivediagnoses" in the European trial. As the report discusses, there aregood reasons to believe that the number of false positives was greaterafter CVS even though only one such case was confirmed from fetalmaterial.The report of the MRC European trial did not suggest, as

Smoleniec and James imply, that CVS should be abandoned infavour of early amniocentesis. The place of alternatives to

transcervical CVS for early prenatal diagnosis will be clarified byfurther large randomised trials. At least three such studies

comparing transabdominal with transcervical chorion CVS arenearing completion. We would argue that early amniocentesisshould not be introduced into clinical practice outside the context offurther randomised trials. Without such studies it will be impossibleto judge whose opinions about the safety and diagnostic accuracy ofthe procedure are correct.

Perinatal Trials Service,Radcliffe Infirmary,Oxford OX2 6HE, UK

ADRIAN GRANTSARAH AYERS

MRC Human Genetics Unit,Western General Hospital,Edinburgh CHRISTINE GOSDEN

MRC Epidemiologyand Medical Care Unit,

Northwick Park Hospital, Harrow TOM MEADE

1. MRC Working Party on the evaluation of chorion villus sampling. Medical ResearchCouncil 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 fetallosses after chorion villus sampling. Lancet 1990; 335: 1156.

3. Canadian Collaborative CVS-Amniocentesis Clinical Trial Group. Multicentrerandomised clinical trial of chorion villus sampling and amniocentesis. Lancet 1989;i: 1-6.

Systemic lupus erythematosus in pregnancySIR,-Your July 13 editorial notes that precise data about

pregnancy in patients with systemic lupus erythematosus (SLE) arenot widely available.We have prospectively followed twenty-five pregnancies in 18

women with SLE and in 4 with subacute cutaneous lupus. Amongthe SLE group, 6 patients had renal disease, complicated in 2 byhypertension, and 5 patients had high values of andphospholipidantibodies (3 of these had already had pregnancy failures).

All patients were started on aspirin (100 mg/day) duringpregnancy. Steroid treatment given before pregnancy was

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continued and the dose was increased up to 40 mg/day if needed;azathioprine was added in 8 patients after 20 weeks’ gestation toavoid an increase in steroid dose;1 patients not receiving steroidbefore pregnancy were started with 10 mg or received no steroid (1case) after clinical and serological assessment. Our policy includestreatment in the puerperium with the dose of steroid that was usedat the end of the gestation period.The women were seen monthly in the clinical immunology

outpatient clinic and the high-risk pregnancy clinic. Serologicalevaluations including routine and immunological blood tests weredone 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 renaldisease), which responded to slight adjustment of treatment. Therelapse rate was 0-07 per patient-month (14 relapses in 203

patient-months), in fair agreement with another report.2 23 livebombabies were delivered and only a few obstetric and neonatalcomplications were seen (1 abrubtio placentae, 6 fetal distress, 1

pre-eclampsia); 6 of these babies were small for gestational age buthad no sequelae, confirming that careful monitoring of maternofetalconditions 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 Departmentfor their skilful assistance.

Clinical Immunology Unit,Obstetric and Gynaecology Department,and Neonatal Intensive Care Unit,

Ospedale Civile di Brescia,25125 Brescia, Italy

ANGELA TINCANIGENESIO BALESTRIERIDAVID FADENCARMELO DIMARIO

1. Tincani A, Cattaneo R, Martinelli M, et al. Antiphospholipid antibodies m recurrentfetal 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 lupuserythematosus. a prospective study. Arch Intern Med 1991; 151: 269-73.

Guillain-Barré syndrome and parenteralgangliosides

SIR,-Dr Yuki and colleagues (May 4, p 1109) report a patient inwhom a reversible motoneuron disease syndrome developed withanti-GM2 ganglioside antibodies after treatment with an injectablepreparation of brain gangliosides. Professor Scarlato and DrNobile-Orazio (Aug 3, p 314) suggest that the patient may have hada form of Guillain-Barre syndrome (GBS). However, Dr Callergaroand colleagues (March 30, p 789) argue that gangliosides are notimmunogenic, although anti-GMl ganglioside antibodies are seen inGBS after campylobacter infection. We report a patient in whomGBS developed with increased titres of anti-GMl antibodies aftertreatment 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 ofbrain gangliosides (’Cronnasial’), which she continued after

returning home. On the 10th day of treatment she became weak andwas admitted to a local hospital with the diagnosis of GBS. Over thenext few days the weakness progressed to quadrapareses andareflexia. Electrophysiological studies were initially normal, butlater showed F-wave and H-reflex delays in the legs, with normalconduction velocities, low amplitude motor latencies, and dispersedpotentials. On the 5th day in hospital, anti-GMi and asialo-GMiantibodies were increased at titres 3200 and 25 600, respectively(normal 800 or less and 3200 or less, respectively).l Antiperipheralmyelin antibodies, as measured by the Clq transfer and fixationassay were increased to 70 (normal 25 or less) On the 9th day inhospital, her strength began to improve, and she made a slow butcomplete recovery.The onset of GBS 10 days after initiation of ganglioside injections

could have been a coincidence, but similar reactions have beennoted in two other patients,3 and the presence of anti-GMlantibodies suggests otherwise. Although gangliosides are not

usually immunogenic, they could induce an immune response whencomplexed to serum or tissue proteins. Delayed-typehypersensitivity and sensitisation to gangliosides have been

described,4,5 and T cells might participate in the response throughnon-major-histocompatibility-complex restricted interactions.6The immune response was not restricted to Gi, since complementfixing anti-myelin antibodies were also present. Immune reactivityto GMl could have triggered a broader antineural response, or GBScould have been caused by less specific immune mechanisms, as canhappen after surgery.There was no evidence for preceding infection with

campylobacter. Serological tests for campylobacter infection inpatients with anti-GMl antibodies could be falsely raised, because ofcrossreactivity of anti-GM, antibodies with Gal (Bl-3)GalNAcdeterminants shared by some strains of campylobacter .7The occurrence of GBS after parenteral administration of

gangliosides is probably rare, but investigations of the mechanismsresponsible for the reaction might help to identify patients who areat risk and provide clues to the pathogenesis of GBS.

Department of Neurology,Black Building (room 3-323),Columbia University, New York 10032, USA NORMAN LATOV

Department of Neurology,University of Maryland, Baltimore CAROL L. KOSKI

Atlanta, Georgia PATRICIA A. WALICKE

1. Sadiq SA, Thomas FP, Kildereas K, et al. The spectrum of neurological diseaseassociated with anti-GM1 antibodies. Neurology 1990; 40: 1067-72.

2. Koski CL, Humphrey R, Shin ML. Anti-petipheral myelin antibodies in patientswith demyelinating neuropathy: quantitative and kinetic determination of serumantibody activity by complement component 1 fixation. Proc Natl Acad Sci USA1985, 82: 905-09.

3. Carpo M, Nobile-Orazio E, Meucci N, Scarlato G. Anti-GM1 IgG antibodies inGuillain-Barré syndrome. Clin Neuropathol 1991; 10: 146.

4. Offner H, Standage BA, Burger DR, Vandenbark AA. Delayed type hypersensitivityto gangliosides in the Lewis rat. J Neuroimmunol 1985; 9: 145-57.

5. Knorr-Held S, Brendel W, Kiefer H, et al. Sensitization against brain gangliosidesafter therapeutic swine brain implantation in a multiple sclerosis patient. J Neurol1986; 233: 54-56.

6. Strommger JL. The T cell receptor and class Ib MHC-related proteins: enigmaticmolecules 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.

SIR,-Dr Yuki and colleagues (May 4 and Aug 3, p 314) describea patient in whom progressive weakness and wasting developedduring treatment with gangliosides.A similar ganglioside preparation from bovine brain

(’Cronassial’) was introduced into the German market in 1986. Thedrug was approved by the Federal Health Office against the vote ofthe advisory committee. It was greeted by a drug bulletin with theprediction that it was likely to cause Guillain-Barre syndrome(GBS).1 Berlit2 reported 5 patients with symptoms of GBS oramyotrophic 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 drugwas 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 treatedwith the ganglioside preparation, 4 of whom died. Additionally, thenetwork received a further report of a 62-year-old patient in whoman immunogenic reaction with fever, shock, and rapidly progressingtetraparesis developed 3 days after treatment with GMl gangliosidewas started.3 This case occurred during a small clinical trial, and thepatient died.

These data argue for a causal link between treatment with

gangliosides and GBS or ALS.

Institute of Clinical Pharmacology,Zentralkrankenhaus St-Jurgen-Strasse,D-2800 Bremen, Germany PETER S. SCHÖNHÖFER

1. Anon. Cronassial, ein zweiter Fall Carnivora? Arznei-telegramm 1985; v: 33-34.2. Berlit P. Cronassial. Tagl Praxis 1989; 30: 358-60.3. Anon. Kompliltationen mit Todesfolge nach Rinderhirngangliosid GM 1 (SYGEN).

Arznei-telegramm 1991; i: 8.