1327

Ovulation induction and neural tube defects SIR,-Pregnancy outcome after ovulation induction is important, because about 1% of pregnant women have undergone this induction. Six published case-reports and a case-control study by Cornel et all raised questions about an association between neural tube defects (NTD) and ovulation induction. Since 1972, a cumulative total of 368 birth defects associated with clomiphene ovulation induction have been reported to the US Food and Drug Administration (FDA). These include 35 NTDs. This represents only a small fraction of severe birth defects expected by chance. Because of incomplete reporting, the FDA has repeatedly reviewed the frequency of exposures in case-control studies and outcomes in defined exposure cohort studies. Published case-control data have lately been expanded by Dr Mills and colleagues (July 14, p 103), and cohort data have been reviewed by Cornel et all 3995 outcomes additional to the 1642 referenced by them are as follows: Series Listed by Cornel et al 19891 Merrell-National, 1966 (FDA Fertility and Maternity Drug

1642

NTD 1 M, 1 A, 1 E

2082 349

3 SB 2 SB, 1A

Sample

Advisory Group Sas, 1977 (Fortschr Med 95: 2122) Hack et al, 1979 (additional to those in Comel list (Pediatr Adolesc Endocrirwl5: 191) Karow and Payne, 1968 (Fertil Steril 19:351) Greenblatt et ai, 1969 (In: Inquilla, Greenblatt, eds. Endocrinologic and

240

hormone more efficiently than the oral synthetic progestins and with considerable saving (US$4 versus US$40 per month). Transdermal oestrogen (oestradiol patch) has been developed lately, but I have persisted in my use of conjugated oestrogen (’Premarin’) because of its oestrone content and the ease of dose adjustment. In my practice, transdermal oestradiol worked well for hot flushes but was attended by breast swelling and tenderness. Some workers have suggested that its use may correlate with an increased frequency of breast cancer.1 Dual photon absorptiometry (DPA) has become clinically available for the accurate measurement of bone density. Thus, monitoring of osteoporosis treatments can now be part of mainstream medical practice. I have followed postmenopausal patients at various stages of osteoporosis, receiving transdermal progesterone 330-500 mg per month, depending on bone density response. Some patients, those with hot flushes or vaginal dryness, were also supplemented with low-dose premarin (0-3-0-625 mg).2 The bone benefits found were unaffected by supplemental oestrogen. I believe that transdermal progesterone is far better than oestrogen in reversing postmenopausal osteoporosis and that this action is independent of oestrogen. This benefit is clearly independent of age or time from menopause and is proportional to the pretreatment osteoporotic bone loss. Serial DNA bone-matrix density (BMD) results in 63 patients over 3 years were: Lumbar BMD*

0

range 05-08 0-8-0-9 0.9-1.0 10-11 1-1-1-2 1-2-1-3

183

0

156

0

128

0

103 92 91

0 0 1 SB

morphologic correlations of the ovary, 261)

Scheumpflug,

1977

(Fortschr Med 95:

2515) Rutz-Valasco, 1976 (Clin Invest Gynecol Obstet 3: 343) Baron, 1975 (Endokrynol Pol 26: 537) Giustini, 1977 (W Va Medl 73: 47) Bettendorf and Lehman (WHO symposium, Moscow, 1976) Barrot, 1979 (7 GytMeo7 Obstet Biol Rep (Paris) 8: 333)

64

0

59

0

448

0

*g/sq

FRANZ ROSA

LP, Dukes MNG, et al. Ovulation induction and neural tube defects. Lancet 1989; i: 1386. 2. Cornel MC, Ten Kate LP, Te Meeran CJ. Ovulation induction, in vitro fertilization, and neural tube defects. Lancet 1989; ii: 1520.

Osteoporosis reversal with transdermal progesterone colleagues’ report (Aug 4, p 265) of the equivalent anti-osteoporotic effects of transdermal versus oral hormone replacement therapy is welcome. Since both oestrogen and progesterone are lipophilic and well absorbed transdermally, I have always thought it sensible to use them that way and avoid the Stevenson and

first-pass liver loss of the oral route. Stevenson et al state, however, "we do not think that either agent would have had an independent effect on bone density at the low doses used". I have found that transdermal progesterone, with or without supplemental oestrogen,

effectively reverses postmenopausal osteoporosis. Since 1981 I have used ’ProGest’ (Professional &

Technical

plant-derived transdermal progesterone cream, for my patients rather than oral progestins in postmenopausal women with osteoporosis. This cream delivers the a

cm

JOHN R. LEE

Bergkvist L, Adami HO, Persson I, et al. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl JMed 1989; 321: 293-97. 2. Lee JR. Osteoporosis reversal: the role of progesterone. Int Clin Nutr Rev 1990; 10: 1.

1. Cornel MC, Ten Kate

Services, Portland, Oregon),

22-4 18.4 17-2 10-5 5-5 2.6

Sebastopol, California 95472, USA

exposure.

SIR,-Dr

% gain

0-911 0.992 1122 1-134 1-215 1-289

9620 Bodega Hwy,

M = menmgocele, A = anencephaly, E = encephalocele, SB = spma bifida. 10 NTDs have been observed in cohort studies totalling 5637 outcomes. This list excludes cohorts without mention of birth defects, or those with less than 25 outcomes. This expanded experience continues to show a risk of about 1 in 500 pregnancies, which is not significantly different from that expected without Food and Drug Administration, Rockville, Maryland 20857, USA

3-year (mean)

0.745 0-838 0957 1.026 1-152 1-256

Having found no other benefit from supplemental oestrogen, I now advise it only for hot flushes and/or vaginal dryness. The safety of supplemental progesterone is impressive.3 If any oestrogen is used by postmenopausal women, the protective effect of progesterone is, I believe, a necessity.

Twelve additional cohorts with 25-49 outcomes

Initial

384-91.

3. Hargrove JT, Maxon WS, Wentz AC, Burnett LS. Menopausal hormone replacement therapy with continuous oral micronized estradiol and progesterone. Obstet Gynecol 1989; 71: 606-12.

Bone

density screening for osteoporosis

SIR,-We have waited for enlightenment from your protracted correspondence on bone density screening in osteoporosis (Aug 25, p 502) but none has been forthcoming, and the latest contribution (Dr Van Hemert, Sept 29, p 818) is, we believe, misleading. Bone densitometry is probably better than most present or proposed health screening procedures in the prediction of risk of disease (in this case fracture) at a stage in life when the risk factor (ie, bone density) is still normal and the (fracture) risk very low. This is because, as Van Hemert points out, all postmenopausal women lose bone at more or less the same rate, such that the women who will be at greatest-risk of fracture in the future can be identified well before there is a substantial increase in risk. We have found a correlation coefficient of 0-95 between two bone-mass measurements five years apart in 320 untreated postmenopausal women (unpublished). Thus women with high values at the start of the study had almost as high values at the end, whereas in those with low values these fell even lower. After the menopause, when bone density falls and fracture rates rise strikinglyl,2 an inverse relation between bone density and fracture risk has been clearly established.3-8 The relative risk of fracture in women increases by a factor of about 15 for each SD decrease in bone density. Since future bone density can be largely predicted from a measurement at about the time of the menopause, bone densitometry screening in mid-life is a potentially very

1328

powerful (and indispensable) first step towards bringing the postmenopausal fracture epidemic under control. The second step is to ensure that appropriate preventive therapy is offered to women with low peak bone densities (below the 25th gentile9), the group most at

risk of future fractures unless further bone loss

can

be

prevented. The potential preventive treatments available consist of not only oestrogens but also progestagens, calcium, calcitriol, diphosphonates, calcitonin, thiazide diuretics, and salt restrictionalone or in combination. The efficacy of these treatments can be monitored by longitudinal densitometry in individuals. This straightforward programme need not be expensive, and certainly not as costly as treatment of fractures, even when follow-up costs are included. Prospective studies indicate that peripheral densitometry is as good as measurement at the vertebra or hip as a predictor of fractures of all types, which is equally apparent in retrospective studies.lO A forearm densitometer costing some c20 000 can easily measure 20 patients a day or 5000 a year. The unit cost, after allowance for capital outlay, staffing, and isotope source replacement, could probably be as low as ,E10 with an appointment system. More sophisticated equipment (costing three times as much) may well be appropriate for major centres, but forearm densitometry is certainly adequate for the screening programme

we

describe.

Institute of Medical and Veterinary Science, Adelaide, 5000 South Australia; and Royal Adelaide Hospital

B. E. C. NORDIN A. G. NEED B. E. CHATTERTON M. HOROWITZ D. B. CLEGHORN

1. Knowleden J, Buhr AJ, Dunbar O. Incidence of fractures m persons over 35 years of age. Br J Prev Soc Med 1964; 18: 130-41. 2. Miller SWM, Grimley Evans J Fractures of the distal forearm in Newcastle: an

epidemiological survey. Age Ageing 1985; 14: 155-58. 3. Wasnich RD, Ross PD, Davis JW, Vogel JM. A comparison of single and multi-site BMC measurements for assessment of spine fracture probability J Nucl Med 1989; 30: 1166-71. 4. Gardsell P, Johnell O, Nilsson BE. Predicting fractures in women by using forearm bone densitometry. Calcif Tissue Int 1989; 44: 235-42. 5. Hui SL, Slemenda CW, Johnston CC. Baseline measurement of bone mass predicts fracture in white women. Ann Intern Med 1989; 111: 355-61. 6. Browner WS, Cummings SR, Genant HK, et al. Bone mineral density and fractures of the wrist and humerus in elderly women: a prospective study. J Bon Min Res 1989; 4 (suppl 1): 213. 7. Cummings SR, Black D, Arnaud C, et al. Appendicular bone density and age predict hip fracture in women. JAMA 1990; 263: 665-68. 8. Cleghorn DB, Polley KJ, Bellon MJ, Chatterton J, Baghurst PA, Nordin BEC. Fracture rates as a function of forearm mineral density in normal postmenopausal women. Calcif Tissue Int (in press). 9. Nordin BEC, Need AG, Chatteron BE, Horowitz M. More on bone mineral screening for osteoporosis. N Engl J Med 1987; 317: 1538-39. 10. Need AG, Nordin BEC. Which bone to measure? Osteoporosis Int 1990; 1: 3-6.

Health risks of salmon sushi SiR,—In the continuing discussions on the safety of sushi and other seafood products, most have shown concern about the prevalence of anisakid nematodes in individual host speciesl,2 or the qualifications of sushi chefs and restaurants.3°’ Little is known. however, of the prevalence of nematodes in the product available to the consumer. We have investigated the parasite content of the seafood component of sushi and the microbiological quality of the rice. Salmon sushi (sake) was chosen for study because salmon is widely available in the USA and elsewhere and is very popular. The sushi is generally prepared from a cold-smoked salmon product. Samples of salmon sushi were ordered for take-out from 14 of the 50 or so restaurants that serve sushi in Seattle, Washington. A sample was also purchased from a speciality grocery store that supplies many restaurants with seafood. Collections from the restaurants generally consisted of 5-6 pieces of sushi, of which samples of rice from 4 pieces were examined microbiologically. The mean weight of the slices of salmon used was 11g (range 49-252), with a mean maximum thickness of 0-7 cm (range 03-12). On the assumption that the average weight of a dressed salmon (irrespective of species) is 2-27 kg, one such fish can provide about 1000 slices for sushi. Findings for individual host species can be misleading since if we raw

take the average number of worms per salmon to be 46 (as reported by Deardorff and Throm’) there is only a 1 in 22 chance of encountering an anisakid larva. In 92 individual pieces of salmon from sushi we showed a chance of 1 in 13, with the possibility of ingesting up to 3 larvae from a single slice. Larvae were not visible by eye before artificial digestion by pepsin. The discrepancy between our fmdings and those of Deardorff and Throms can probably be explained by the higher concentration of larvae in the front end of the fish than in the tail (W. G. Schwien, Seattle Food and Drug Administration, unpublished data). The front of the fish is preferred for sushi. All the larvae recovered during this study were dead. The salmon proved to have been frozen after the cold-smoking process (larvae are not killed by cold-smoking). Live larvae might be recovered if fresh cold-smoked salmon were used in season. Our results lend support to the US FDA’s recommendation that fish served raw or undercooked should be properly frozen before consumption6 With respect to rice used in sushi, the Seattle-King county health department requires that rice is not left at room temperature for more than 1 h and that the pH is kept at a low level to retard the growth of bacteria. This is especially important with respect to its use at room temperature and the handling required during sushi preparation. The pH of the rice from the fourteen restaurants sampled ranged from 40 to 46, well within the public health guidelines (Yuene GA, Seattle-King county health department, personal communication). To establish the numbers of bacteria present, aerobic plate counts were done on 59 samples of rice (mean 20’g per sample, range 10-36) from these restaurants, with counts ranging from 103 to 107 per g rice. 55 samples from thirteen restaurants were tested for both Staphylococcus aureus and Bacillus cereus. S aureus was selected as an indicator of improper handling and poor sanitation during sushi preparationThree of the restaurants had positive samples (more than 3 organisms per g rice) for S aureus with a range of 4-9 organisms per g rice. B cereus is naturally present in rice and other grains, and can form a toxin pathogenic to man 8 Samples from three restaurants tested positive for this organism, with a range of 4-93 organisms per g rice. Although some samples were positive for these two organisms, the levels reported generally are notjudged of public health importance. Seafood Products Research Center, US Food and Drug Administration, PO Box 3012, 22201 23rd Dr S.E Bothell, Washington 98041-3012, USA

A. A. ADAMS J. L. BEEH M. M. WEKELL

1 Kliks MM. Human anisakiasis: an update. JAMA 1986; 255: 2605. 2. Myers BJ. Anisakine nematodes in fresh commercial fish from waters along the Washington, Oregon and California coasts. J Food Protect 1979; 42: 380-84. 3. Kure K, Yokoi M. Safe sushi. N Engl J Med 1989; 321: 900-01. 4. Wittner M, Tanowitz HB, Ash LR. Safe sushi. N Engl J Med 1989; 321: 901. 5. Deardorff TL, Throm R. Commerical blast-freezing of third-stage Anisakis simplex larvae encapsulated in salmon and rockfish. J Parasitol 1988; 74: 600-03. 6. Jackson GJ, Bier JW, Schwarz TL. More on making sushi safe. N Engl J Med 1990; 322: 1011. 7. Newsome RL. Staphylococcus aureus. In: Oblinger JL, ed. Bacteria associated with foodborne diseases. Scientific status summary, Institute of Food Technologists. Food Tech 1988; 42: 181-200. 8. Johnson KM. Bacillus cereus foodbome illness: an update. J Food Protect 1984; 47: 145-53.

HIV seroprevalence in

a

defined London

population SIR,-In the UK data from the national reporting of HIV infection’ specific studies on the prevalence of HIV infection2-S cannot be translated into estimates of prevalence in a locality, such as a health district. Data from national anonymous seroprevalence studies6 will be of limited use unless they can be related to geographically defined populations. Without information on district/area prevalence, HIV prevention strategies will be unable to focus on the target population and their efficacy will be difficult to assess. In Riverside health district in south-west London, a study of HIV infection by the public health department established that by December, 1989, the prevalence of HIV infection in the Riverside population was at least 279 per 100 000. For males aged 20-50 it was more than 1 in 100. These will probably be underestimates because or