1107

The failure to demonstrate a correlation between HbAI and malformation in some reports4 does not necessarily imply the absence of an association between them. A possible likely explanation is that in a group of well-controlled women the range of HbA1 is insufficient to demonstrate a graded relation. We agree with The Lancet’s view6 that: "the fact that absolute HbA1c concentrations cannot be used as a predictor of fetal abnormality in individual cases does not undermine the validity of the general association between high blood glucose in early pregnancy and an increased risk of fetal malformations". Finally, while it is possibly true that, as Gregory and Tattersall suggest, the perinatal mortality rate in diabetic pregnancy has fallen to less than 5% in most specialist centres in western Europe, there can be no doubt that worldwide a huge two-sided problem continues to exist-ie, how to get the treatment to the patient and the patient to the treatment. Nor is this situation confined to the third world.’ In this context we cannot emphasise too strongly that the value of pre-pregnancy care for diabetic women in the prevention of congenital abnormalities and perinatal deaths does not "remain controversial". If there is to be a talking-point it should concentrate on possible strategies to solve this worldwide problem.

JOYCE D. BAIRD

Metabolic Unit,

University Department of Medicine, Western General Hospital, Edinburgh EH4 2XU, UK

OTTO BELLMAN ULF ERIKSSON DAVID HADDEN BENGT PERSSON HAMISH SUTHERLAND GYULA TAMIAS, for the EASD Diabetic

Pregnancy Study Group

1. Persson B,

Björk O, Hanson U, Stangenberg M. Neonatal management 1983. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Edinburgh: Churchill Livingstone, 1984: 133-43. 2. Lucas MJ, Leveno KJ, Williams ML, et al. Early pregnancy glycosylated hemoglobin, severity of diabetes, and fetal malformations. Am J Obstet Gynecol 1989; 161: 426-31.

3. Pedersen JF, Mølsted-Pedersen L. Early growth delay predisposes the fetus in diabetic pregnancy to congenital malformation. Lancet 1982; i: 737. 4. Damm P, Mølsted-Pedersen L. Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women. Am J Obstet

Gynecol 1989; 161:

doxorubicin over 5 days, with ondansetron 15 mg, dexamethasone, and diphenhydramine. Ventricular arrhythmia and cardiac arrest occurred on day 3. After resuscitation, metoclopramide was used as an antiemetic without cardiovascular events. Case 5 (Male, aged 60, cytarabine/cisplatin/etoposide for metastatic carcinoma of colon). He received ondansetron 10 mg before chemotherapy and at 4 and 8 h after. He had severe chest pain on day 1. ECG showed sinus tachycardia. Ondansetron was stopped and chemotherapy was continued with other antiemetics without chest pain. Case 6 (Female, aged 75, carboplatin and etoposide for metastatic ovarian carcinoma, history of angina). Angina occurred during infusion of ondansetron 15 mg before and after chemotherapy. ECG was not done. She was switched to metoclopramide for this and subsequent courses, and the angina did not recur. She is now in remission, with angina on exertion. Case 7 (Male, aged 78, cyclophosphamide/doxorubicin/ vincristine/prednisolone for diffuse large cell lymphoma, two previous cardiac infarctions). Angina followed ondansetron 15 mg. Subsequent cycles with other anti-emetics were uneventful. We do not think that blood calcium in case 2 was high enough to be a cause of the chest pain. In case 3, the nausea and vomiting before ondansetron may have been a sign of the inferior myocardial infarction detected after ondansetron. Cases 4 and 7 received doxorubicin, which is cardiotoxic; and case 4 also received fluorouracil, which can cause arrhythmia. The associations we saw are not proof of a relation with ondansetron. But our observations in cases 1-4 prompted us to change our practice for cases 5-7, in whom we discontinued ondansetron after the first alert. We are intrigued that the US advertisement for ondansetron indicates that angina has been "rarely" reported as an adverse event whereas the UK advertisement lists no such side-effect. Department of Veterans Affairs Medical Center, 423 East 23rd Street, New York, NY 10010, USA Northern Westminster General Mount Kisco, New York

HAROLD S. BALLARD Hospital,

GINO BOTTINO

Our Lady of Mercy Hospital, Bronx, New York

JOSEPH BOTTINO

1163-67.

HMJ, Porta M, Keen H, eds. Diabetes care and research in Europe: the St Vincent Declaration action programme: implementation document. Copenhagen: WHO Regional Office for Europe, 1992.

5. Krans

6. Editorial. Congenital abnormalities in infants of diabetic workers. Lancet 1988; i: 1313-15. 7. Landon MB, Gabbe SG, Sachs L. Management of diabetes mellitus and pregnancy: a survey of obstetricians and maternal-fetal specialists. Obstet Gynecol 1990; 75: 635-40.

Ondansetron and chest pain SIR,-We report associations between intravenous ondansetron and chest pain. Case 1 (Male, aged 73, vinblastine/cisplatin/methotrexate for metastatic bladder carcinoma, 3 1 hydration over 24 h, angina-free since cardiac bypass 10 years ago). Ondansetron 10 mg was given daily before and at 4 and 8 h after chemotherapy. Chest pain occurred on days 1, 3 (three episodes), and 4 (two episodes at rest). Nitroglycerin was efficacious except for one episode on day 3. The patient was still on chemotherapy on day 4. Previous chemotherapy without ondansetron had been unremarkable. Case 2 (Male, aged 61, history of arteriosclerotic heart disease, multiple myeloma). Nausea and vomiting following mithramycin given for hypercalcaemia. Ondansetron 10 mg every 8 h was given. Within 48 h, 4 episodes of chest pain at rest were successfully treated with nitroglycerin. A fifth episode included fatal cardiorespiratory arrest. Calcium the day before ondansetron was 95 mg/dl. Case 3 (Male, aged 65, squamous cell carcinoma and brain metastases). He had nausea and vomiting during whole-brain radiotherapy. 4 days after receiving three doses of ondansetron 30 mg, he became hypotensive and cardiac enzymes and changes in the electrocardiogram (ECG) showed inferior myocardial infarction, which was fatal. Case 4 (Female, aged 62, locally advanced pancreatic carcinoma, no history of cardiac disease). She received fluorouracil and

Who should receive

a

5-HT3 antagonist?

SIR,-The 5-hydroxytryptamine3 (5-HT3) receptor antagonists granisetron and ondansetron are at least as effective as, or better than, the best conventional antiemetic cocktails in controlling acute emesis (within 24 hours) of cytotoxic chemotherapy or breakthrough emesis in patients receiving moderately or highly emetogenic chemotherapy.1-5 Antiemetic control with the 5-HT3 antagonists may be further improved by the addition of dexamethasone.6 Furthermore, the frequency of adverse events with the new compounds is lower than that with conventional antiemetic regimens. In particular, extrapyramidal symptoms associated with high-dose metoclopramide and other dopaminereceptor antagonists have not been reported with granisetron, and there have been only anecdotal reports with ondansetron.’ In contrast to the benefits of these compounds in acute emesis, there is no evidence of clinical advantage for 5-HTg antagonists compared with conventional antiemetics for delayed nausea and vomiting (more than 24 hours after chemotherapy). For instance, in one study with oral ondansetron, only 15 % of patients had complete control of delayed emesis, a result equivalent to that previously achieved in placebo-treated individuals in that institution.8 In other trials in delayed vomiting, the efficacy of metoclopramide was equivalent to that of ondansetron during days 2-6 after cisplatin,9 while dexamethasone was equivalent to ondansetron during days 2-5 after moderately emetogenic chemotherapy.10 Moreover, in these studies, metoclopramide and dexamethasone were both significantly better than ondansetron in the control of delayed nausea, a potentially important result because patients may find nausea more distressing than vomiting. No data have yet been published on the use of granisetron in delayed emesis. Therefore, current data do not support the use of 5-HT3 antagonists for delayed nausea and vomiting.

1108

We urge clinicians to view with caution recommendations

to use

5-HTantagonists in delayed emesis. Such use in the delayed phase may obscure or undermine the increasing evidence of the benefits that these compounds offer for acute emesis. Also, since antiemetics may be prescribed for several days in the delayed phase, such use of

the

may substantially burden drug budgets, a which cannot yet be clinically justified. Avoidance of their use in delayed emesis, at least outside clinical trials, will ensure that more funds are available for appropriate use for acute or rescue

5-HT3 antagonists

cost

Oncology Centre, Infirmary,

Glasgow G11 6NT,

Department of Haematology, London Hospital Medical College, London E1 2AD, UK

therapy. Beatson Western

systems detectable by PCR and being used or investigated for forensic work. For any particular VNTR system, therefore, it is important to know how many false negatives (failures to detect non-fathers) to expect, and how many false positives (arising because of single mutations in the chosen system), before assuming merely that a single VNTR marker, as implied by Le Roux et al, will detect all instances of non-paternity.

1.

S. B. KAYE

UK

Pierre and Marie Curie Paris 13, France

University,

DAVID KHAYAT

Clinique de Genolier, Genolier, Switzerland

M. AAPRO

Internal Medicine Clinic 1, University of Cologne, Germany

V. DIEHL

1. Chevallier B.

Efficacy and safety or granisetron compared to high dose metroclopramide plus dexamethasone in patients receiving high dose cisplatin in a single-blind study. Eur J Cancer 1990; 26: 33-36. 2. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5-hydroxytryptamine 3 (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816-21 3. Marty M. A comparative study of the use of granisetron, a selective 5-HT3 antagonist, versus a standard anti-emetic regimen of chlorpromazine plus dexamethasone in the treatment of cytostatic-induced emesis. Eur J Cancer 1990; 26: 28-32. 4. Schmoll HJ. The role of ondansetron in the treatment of emesis induced by non-cisplatin-containing chemotherapy regimens. Eur J Cancer Clin Oncol 1989; 25 (suppl): 535-39. 5. Warr D, Willan A, Fine S, et al. Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. J Natl Cancer Inst 1991; 83: 1169-73. 6. Smith DB, Newlands ES, Rustin GJS, et al. Comparison of ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet 1991; 338: 487-90. 7. Halperin JR, Murphy B. Extrapyramidal reaction to ondansetron. Cancer 1992; 69: 1275. 8. Kris MG, Tyson CB, Clark RA, Gralla RJ. Oral ondansetron for the control of delayed emesis after cisplatin. Cancer 1992; 70 (suppl): 1012-16. 9. De Mulder P, Seynaeve C, Vermoken J, et al. Ondansetron compared with high dose metoclopramide in prophylaxis of acute and delayed cisplatin induced nausea and vomiting. Ann Intern Med 1990; 113: 834-40. 10. Jones AL, Hill AS, Soukoup M, et al. Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet 1991; 338: 483-87.

Rates of

non-paternity

SIR,-Dr Le Roux and colleagues (Sept 5, p 607) describe their experience of Southern blot and polymerase chain reaction (PCR) with polymorphic DNA markers to detect and estimate the rate of non-paternity. Any such estimate ofnon-patemity rate depends not only on the population under consideration (and the true number of non-fathers that exists within it), but also the efficiency of the particular test system used to detect non-paternity. Any comparison of non-paternity rates reported from different studies should, therefore, take account of both these factors if it is to be meaningful. For instance, the section of the population specifically seeking confirmation of paternity may have a very different rate of non-paternity from that in the population at large; rates are also likely to vary between countries and within countries according to age or cultural group.’ Also, if, for example, studies were done with ABO grouping alone, this would be very inefficient at detecting non-paternity; less than 20% of the actual non-fathers in the sample would be located, and a substantial number of other conventional systems would need to be added to increase this figure to a useful

level. The DNA polymorphisms usually selected for investigation of doubtful parentage have been chosen for their high efficiency in the detection of non-patemity and for their low mutation rates. For example, four single-locus VNTR probes routinely used in our laboratory have each been shown, by construction of false families, to have the ability to exclude between 85% and 95% of non-fathers,2 but the use of more than one such VNTR locus is needed to exclude virtually all (over 99%) non-fathers. Not all DNA polymorphisms will necessarily be equally effective in the detection ofnon-patemity, and this is certainly true of some of the

P. J. LINCOLN D. SYNDERCOMBE COURT

MacIntyre S, Sooman A. Non-paternity and prenatal genetic screening. Lancet 1991;

338: 869-71. 2. Lincoln PJ, Phillips CP, Syndercombe Court D, et al. Application of conventional polymorphisms and single locus DNA probes in cases of disputed paternity. In: Rittner C, Schneider P, eds. Advances m forensic haemogenetics 4 (14th Congress of the International Society for Forensic Haemogenetics, Mainz, Sept 18-21, 1991). Berlin Heidelberg: Springer Verlag, 1992; 225: 173-74.

Absence of local suppression in incestuous pregnancy understand fetomaternal interactions better, we are SiR,—To interested in studying lymphocytes that infiltrate the decidual tissue. Decidua is obtained after termination of pregnancy.

Decidua-infiltrating lymphocytes (DIL) are prepared by enzyme dissociation and filtration through sieves, and lymphocytes are obtained by density gradient. Functional studies of DIL showed that they can suppress lymphoblastogenesis after mitogen stimulation as well as the mixed lymphocyte reaction. This activity in vitro could occur in vivo to regulate trophoblast invasion and the maternal immune response against the fetus. This local suppression could be genetically programmed, since the same type of lymphocytes are observed in the endometrium before pregnancy,! and also initiated by a hormonal cascade at fertilisation. We favour an immunological mechanism based on local suppression. This suppression would be initiated as down-regulation by maternal T lymphocytes that are stimulated by paternal antigens to induce and maintain tolerance to the fetus. Of course, there may be coexistence of several mechanisms. We analysed 26 deciduas and observed suppressive activity in 25. In 1 case, however, suppression was weak. This sample was obtained after termination of an incestuous pregnancy. In this case, the mother and the fetus could be genetically identical, at least in a main part of the major histocompatibility complex. Consequently, maternal T lymphocytes would not be stimulated and suppression not initiated. The weak suppression that still occurred could be mediated by a second mechanism to control the trophoblast invasion. This observation highlights the importance of the recognition of the fetus as non-self by the maternal immune system, a necessary event to initiation of active tolerance during pregnancy via specific down-regulation. We wonder whether the chance of success of consanguinous pregnancies would decline because of the absence of stimulation of maternal immune system or, to the contrary, would increase because the fetus is regarded as self. Reproduction Immunology Laboratory, Centre of Perinatal Haematology, 75015 Paris;

Gynecology-Obstetrics Service, Hôpital St Antoine, Paris, and Hôpital Saint Louis, Paris, France

I. MANSOUR M. A. JARRAYA A. NETTER L. MARPEAU M. F. REZNIKOFF-ETIEVANT

1. Bulmer JN, Lunny DP, Hagin SV. Immunohistochemical characterization of stromal leucocytes in nonpregnant human endometrium. Am J Reprod Immunol 1988; 17: 83-90.

First singleton term birth after ovarian superovulation with rhFSH SIR,-Earlier this year we reported’ the first pregnancy achieved after controlled ovarian superovulation with pure recombinant human follicle stimulating hormone (rhFSH; Org 32489; Organon International) in a patient undergoing in-vitro fertilisation and embryo transfer. This pregnancy was established in an open study evaluating the efficacy of rhFSH alone and of rhFSH in association