Withdrawal of loperamide drops

1603

It has been suggested that infusion of rIL-2 may yield valuable immunomodulatory effects, while having a lower frequency of toxicities than has rapid intravenous injection.1,2 Hamblin’ has claimed that the side-effects of rIL-2 given by infusion were "acceptable", citing the work of West et aL8 This group used non-protein formulated rIL-2 by continuous infusion but did not state

whether rIL-2

was

reconstituted with albumin. Therefore the

patients may not have received the intended dose. Our findings may partly explain the lower frequency of toxicity reported when rIL-2 is given by continuous infusion. The efficacy of infused IL-2 may also have been underestimated. Until syringes and infusion sets that do not bind cytokines substantially have been identified, we would recommend the routine use of a low concentration of albumin (eg, 2%) in 5% glucose when reconstituting non-protein formulated rIL-2 for infusion. We thank Dr Rose Gaines-Das (National Institute for and Control) for statistical assistance.

Biological

Standards

Cancer Research Fund (ICRF) Clinical Oncology Unit,

Imperial

Guy’s Hospital. London SE1 9RT, UK

DAVID W. MILES

National Institute for Biological Standards and Control (NIBSC), South Mimms

CHRISTOPHER R. BIRD MEENU WADHWA

ICRF Clinical

MAXWELL SUMMERHAYES

Oncology

Unit

Imperial Cancer Research Fund, London WC2

FRANCES R. BALKWILL

NIBSC

ROBIN THORPE

ICRF Clinical

Oncology

Unit

TIME TO CONCEPTION BY LEVEL OF COFFEE INTAKE

ROBERT D. RUBENS

1. Thompson JA, Lee DJ, Lindgren CG, et al. Influence of dose and duration of infusion of interleukin 2 on toxicity and immunomodulation. J Clin Oncol 1988; 6: 669-78. 2 Sondel PM, Kohler PC, Hank JA, et al Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res 1988; 48: 2561-67. 3 Rosenberg SA, Lotze MT, Mule JJ. New approaches to the immunotherapy of cancer using interleukin-2. Ann Intern Med 1988; 108: 853-64. 4. Gillis S, Smith KA. Long term culture of tumour-specific cytotoxic T cells. Nature

1977; 268: 154-56. S, Ferm MM, Ou W, Smith KA. T cell growth factor: parameters of production and a quantitative microassay for activity. Immunol 1978; 120: 2027-32. J 6. Gaines-Das RE, Tydeman MS. Iterative weighted regression analysis of logit a for of responses: computer program analysis bioassays and immunoassays. Comput Prog Biomed 1982; 15: 13-22. 7. Hamblin TJ. Interleukin 2. Side effects are acceptable. Br Med J 1990; 300: 275-76. 8. West WH, Tauer KW, Yannelli JR, et al. Constant-infusion recombinant interleukm 2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 5 Gillis

898-905.

intercourse, was estimated with multiple logistic regression. For all 3010 women the median time to conception was 2 47 months and the mean was 4 95 months; 10% took longer than 12 months to conceive. Times to conception were longest for the 129 women who drank four or more cups of coffee per day (table). Times for those drinking 3, 2, 1, or no cups of coffee were similar. Consumers of four or more cups of coffee were consistently less likely to become pregnant than women who did not drink coffee. The fecundability ratios for women drinking four or more cups as compared with those not drinking coffee were 0-87,0-84,0 85,0-77, 0-74, and 0 65 for the first six months, respectively. This ratio, adjusted for age, parity, weight for height, and alcohol, tobacco, and marijuana use, was 0-81 (95% confidence interval 0’67-0’97). About 10% of non-coffee drinkers took more than 12 months

conceive, compared with 17% of consumers of four or more

daily. The estimated relative risk of failure to conceive within one year (adjusted for age, parity, weight for height, welfare status, and tobacco and alcohol consumption) among consumers of four or more cups of coffee was 18 (95% CI 1 1-30) compared with non-coffee drinkers. These results support the findings of Wilcox and colleagues.1 Married women who planned their pregnancy, and who consumed four or more cups of coffee daily, were 81 % as likely to become pregnant per cycle as women who did not drink coffee. The risk of taking more than 12 months to conceive was 80% greater for high consumers of coffee than for non-coffee drinkers. Our exposure information is less precise than that of previous investigators,1,2,4 because we used coffee consumption during the first trimester as a proxy measurement for caffeine exposure during the time women were trying to conceive. If many women reduced their coffee intake during pregnancy,’ this misclassification of coffee consumption would underestimate the true risk of exposure to coffee while attempting to conceive.

Supported by the National

Foundation March of Dimes.

MICHELLE A. WILLIAMS RICHARD R. MONSON MARLENE B. GOLDMAN ROBERT MITTENDORF

Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 021 15, USA

Coffee and delayed conception SIR,- The Lancet has published two studies on fecundability (the probability of becoming clinically pregnant in each menstrual cycle) and caffeine-containing beverages.1,2 Prompted by these conflicting examined data from a large cross-sectional study done between August, 1977, and March, 1980,3 in which post-partum were women asked about sociodemographic characteristics, reproductive and medical history, and lifestyle factors, including consumption of coffee during the first trimester. There were 3010 non-diabetic married women who planned their pregnancy and who were delivered of a single baby after 20 or more gestational weeks. Women with a history of infertility of assisted conception were excluded. We examined times to conception for different levels of daily coffee intake. We assessed population differences in fecundability by calculating the per-cycle probability of pregnancy for exposed and unexposed groups, expressing the results as fecundability ratios.l The ratio was adjusted for confounders by Cox proportional hazards models. We also used a dichotomous variable based on the clinical definition of infertility (failure to achieve pregnancy within one year of unprotected intercourse). An adjusted odds ratio, as a measure of the association between coffee consumption and conception only after 12 or more months of unprotected

results,

we

to

cups

Department of Obstetrics

and Harvard Medical School and Brigham and Women’s

Gynecology, Hospital,

Boston

KENNETH

J. RYAN

1. Wilcox A, Weinberg C, Baird D. Caffeinated beverages and decreased fertility. Lancet 1988; ii: 1453-56 2. Joesoef MR, Beral V, Rolfs RT, Aral SO, Cramer DW. Are caffeinated beverages risk factors for delayed conception? Lancet 1990; 335: 136-37. 3 Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. No association between coffee consumption and adverse outcomes of pregnancy. N Engl J Med 1982; 306: 141-45. 4. Christianson RE, Oechsli FW, van den Berg BJ. Caffeinated beverages and decreased fertility. Lancet 1989; i 378. 5. Aldridge A, Arana JV, Neims MD Caffeine metabolism in the newborn. Clin Pharmacol Therap 1979; 25: 447-53.

Withdrawal of

loperamide drops

SIR,- This letter responds your June 9 note (p 1394) on the misuse of ’Imodium’ (loperamide) drops in Pakistan and the actions of our company. Our voluntary withdrawal of loperamide drops from Pakistan, following Prof Tariq Bhutta’s reports of fatalities from its misuse to treat diarrhoea in infants, has indeed been a prolonged and difficult process. We have been doing our utmost to to

1604

accomplish this through letters, personal visits and incentives to chemists and distributors, newspaper advertising appeals and Government notices, and warnings against further illegal dispensing. Having completed additional on-site inspections, we are now confident that the product has been virtually eliminated from the Pakistani market. We have also withdrawn the drops in other developing countries and have halted sale worldwide. We are also voluntarily withdrawing imodium syrup in countries where the World Health Organisation has a programme for control of diarrhoeal diseases. We think that imodium syrup is valuable in treating acute diarrhoea. The formulation has one-tenth the potency of the drops. However, the risk of overdosing cannot be excluded in developing countries where illiteracy and inadequate medical supervision could result in misuse in infants. Tablets and capsules will remain available in those countries. In developed countries, where control of distribution and proper use exist, tablets, capsules, and the syrup will continue to be available. The safety and efficacy of imodium used properly is not at issue. The issue is misuse and abuse of the product in infants. We have reported our actions to Professor Bhutta and thanked him for bringing misuse of the product to our attention. Johnson & Johnson, New Brunswick, New

Jersey 08933,

USA

ROBERT Z. GUSSIN, Corporate vice president, science and technology

Does breast cancer originate in utero? SIR,-Professor Trichopoulos (April 21, p 939) suggests that breast has its origins in utero. I propose a further "natural experiment" which may be of relevance to both the prenatal and, more probably, postnatal causes of breast cancer, and perhaps other * oestrogen-dependent conditions. There are many women who conceive dizygotic twins, they have a sufficiently unusual level of exposure to oestrogen to warrant attention, and they are easily identified. They fall into two groups-those who conceive dizygotic twins "naturally" and those who conceive after ovulation induction (10-20% of dizygotic twin births in England). Women who naturally conceive dizygotic twins probably have higher average levels of gonadotropins and oestrogen per menstrual cycle throughout their lifetime than fertile women who do not have twins.2 During twin pregnancy they and their babies are also exposed to higher levels of endogenous oestrogen than in singleton pregnancies, albeit for a gestational period shortened by about 2-3 weeks.3 In contrast to Trichopoulos’ assertion, during a pregnancy twins may therefore be exposed to a higher cumulative oestrogen dose than singleton babies However,

association with age-standardised cross-sectional mortality in the 1970s and 80s (unpublished observations). These results should be interpreted with caution; but if women who have had dizygotic twins have an essentially unaltered profile of disease despite having increased exposure to endogenous free oestrogen, surely they and their babies offer an important test of the unopposed oestrogen model of disease aetiology? University of Oxford Department of Public Health and Primary Care, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, UK

MIKE MURPHY

F, Elwood JM. A study of the influence of ovulation stimulants and oral contraception on twin births in England. Acta Genet Med Gemellol 1985; 34:

1. Webster

105-08. 2. Short RV. Testis size, ovulation rate and breast cancer. Chapter 3. In: Ryder OA, Byrd ML, eds. One medicine. Berlin: Springer-Verlag, 1984: 32-44. 3. Tamby Raja RL, Ratnam SS. Plasma steroid changes in twin pregnancies. In: Gedda L, Parisi P, Nance W, eds. Twin research 3: twin biology and multiple pregnancey, progress in clinical and biological research. Vol 69A. New York: Alan R. Liss, 1981: 189-95. 4. Coulam CB, Annegers JF, Kranz JS. Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 1983; 61: 403-07. 5. Murphy M, Key T, Wang D, Moore J, Clark G, Allen D. Multiple births and maternal risk of breast cancer. Am J Epidemiol (in press). 6. Wyshak G. Reproduction and menstrual characteristics of mothers of multiple births and mothers of singletons only: a discriminant analysis. In: Gedda L, Parisi P, Nance W, eds. Twin research 3: twin biology and multiple pregnancy, progress in clinical and biological research. Vol 69A. New York: Alan R. Liss, 1981: 95-105. 7. Jacobson HI, Thompson WD, Janerich DT. Multiple births and maternal risk of breast cancer. Am J Epidemiol 1989; 29: 865-73. 8. Wyshak G, Honeyman MS, Flannery JT, Beck AS. Cancer in mothers of dizygotic twins. J Natl Cancer Inst 1983; 70: 593-99.

cancer

the group who receive ovulation stimulation do so for various conditions. Those successfully treated for polycystic ovarian syndrome may have higher unopposed cumulative oestrogen exposure throughout the month than average and increased rates of disease,4but most probably have below average or normal levels throughout their lives, apart from when receiving ovulatory stimulants and during twin pregnancies. Hence women who naturally conceived dizygotic twins, and populations with high rates of dizygotic twinning before the widespread use of ovulation induction in the 1970s, should represent groups with higher than average hormone levels. If the oestrogen hypothesis is correct, their expectation of breast cancer should be altered if their unbound hormones are proportionally higher (this could be determined5); factors such as age at menarche and menopause and other aspects of obstetric history may also be implicated.6 Because the prevalence of twinning is low, only large case-control studies of breast cancer would have sufficient power to detect an effect of twinning on risk; indeed, the largest such study reported a protective effect of last twin birth.’ The one cohort study reporting subsequent disease in women who were successfully delivered of a dizygotic twin pregnancy found only an increased risk of pancreatic cancer.8 I correlated the age-standardised total twinning rates (dominated by the dizygotic component) throughout Europe in the 1940s and 1950s (before the striking decline in dizygotic twinning) with subsequent mortality from breast, endometrial, and ovarian cancer, and found no significant

SIR,—Professor Trichopoulos postulates that exposure levels of oestrogens in utero

to high predisposes female offspring to breast

cancer.

He suggests that women with breast cancer are less likely to be twins because the truncation of multiple pregnancy would shorten this exposure. However, mothers of twins have high levels of gonadotropins,1,2 so exposure might well be greater. Also, breast cancer incidence3 and the risk of twinning4 are both associated with increased stature in women. A possible explanation is that evolutionary selection pressure reduced twinning in short women because of the high related perinatal mortality. This could have been mediated through lower pituitary gonadotropins and, as a secondary consequence, breast cancer was reduced in short women.5 This approach is consistent with the empirical data Trichopoulos discusses and explains part of the previously unaccounted interpopulation variability. Food and Agriculture Organisation of the United Nations, Via delle Terme di Caracalla, 00100 Rome, Italy

JOHN DOHERTY

1. Martin NG, Beaini JL, Olsen ME, Bhatnagar AS, Macourt D. Gondadotropin levels in mothers who have had two sets of DZ twins. Acta Genet Med Gemellol 1984; 33: 131-39. 2. Nylander PPS. Pituitary gonadotropins and multiple births in Nigeria. Acta Genet Med Gemellol 1974; suppl 22: 198-201. 3. Gray GE, Pike MC, Henderson BE. Breast cancer incidence and mortality rates in different countries in realtion to known risk factors and dietary practices. Br J Cancer 1979; 39: 1-7. 4. Corney G, Seedburgh D, Thompson B, Campbell DM, MacGillivray I, Timlin D. Ann Hum Genet 1979; 43: 55-59. 5. Doherty JDH. Height of women, twinning and breast cancer. epidemiological evidence of a relationship. Acta Genet Med Gemellol 1988; 37: 263-75.

CORRECTIONS Serum creatinine in cyclosporin-induced remission of steroid-resistant nephrotic syndrome In this letter by Mrs C. Miller and colleagues (June 2, p 1352) the table legend should have read "Serum creatinine in cyclosporininduced remission of steroid-resistant nephrotic syndrome" and the total number of children should have been 20. L-carnitine. In this letter by Prof Noris Siliprandi (May 19, p 1215) line 12 ". should have read "significant decrease in ...