MEGADOSE VITAMIN A AND TERATOGENICITY

236

settings. Congenital defects of colour the colour sense defects seem to be dose-dependent and were detected in three females, whereas colour blindness is usually caused by sex-linked recessive mutations. No patient complained about altered colour vision before and during etretinate therapy. Disturbances of retinal function by synthetic retinoids might be explained by interference with 11-cM-retinal/opsin binding. Differences in binding affinities of particular retinoids to various opsins might explain the diversities of retinal side effects. Until the full extent of possible adverse retinal reactions of etretinate is known, it seems reasonable to suggest that ophthalmological examinations of patients on long-term etretinate should be done, special attention being paid to colour vision and dark adaptation. Patients with pre-existing colour sense defects or with degenerative or dystrophic retinal diseases should be more carefully monitored-or even excluded from etretinate therapy. revealed deuteroanomalous

vision

CASE-CONTROL STUDY OF TWO LEVELS OF EXPOSURE TO VITAMIN A DURING PREGNANCY*

unlikely;

are most

Departments of Ophthalmology, Dermatology, and Pharmacology, University of Dusseldorf, D-4000 Dusseldorf, West Germany

*2

cases

of Down

Syndrome not considered

in the

analysis.

interviewed about the prenatal, obstetric, and family histories and about exposures during pregnancy. From April, 1976, to March, 1987, the study collected 12 315 cases with specific data about the use of drugs during pregnancy and 12 206 controls. Among the cases 19 mothers used vitamin A during pregnancy (1’5 5 per 1000) and 14 among the controls (1’1 per 1000), for an odds ratio (OR) of 1-4 with a confidence interval (CI) of 0-6-2.9, not significant. For products with vitamin A alone we found 10 exposed cases and 1 exposed control (OR 9 9, CI =1 4430-3; p = 0 006), while for combined vitamin A there were 7 exposed cases and 12 exposed controls (OR 0-6, CI 02—1 -6). A major difference between these two kinds of product is the amount of vitamin A, this being 66 700 (SD 24 200) IU (n == 12) for vitamin A alone and 19 600 (16 170) (n = 20) for combined vitamin A, (p < 0,00 1). This suggests a dose-effect relationship. Although it is difficult to define a level of exposure during pregnancy (sometimes we only knew the range of dose), to study dose and risk we used the minimum dose of exposure when necessary. The OR values for two levels of exposure (less and more than 40 000 IU) suggest the same dose-effect relationship (table). Our results, albeit preliminary, are, as far as we know, the first from an epidemiological case-control study on human prenatal exposure to vitamin A. They show that a teratogenic effect could exist for exposures to high doses of vitamin A. Our results are in complete agreement with Smithells’ opinion6 that there is no evidence that doses lower than 10 000 IU can produce a teratogenic effect. They provide epidemiological support for the recommendations of the American Teratology Society.7 A full account will be published elsewhere. are

U. WEBER B. MELNIK G. GOERZ L. MICHAELIS

=

=

FT, La Braico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol 1985, 100: 534-37. Hazen PG, Carney JM, Langston RHS, Meisler DM. Corneal effect of isotretinoin: Possible exacerbation of neovascularization in a patient with the keratitis, ichthyosis, deafness ("KID") syndrome. J Am Acad Dermatol 1986; 14: 141-42. Weleber RG, Denman ST, Hanifin JM, Cunningham WJ. Abnormal retinal function associated with isotretinoin therapy for acne Arch Ophthalmol 1986, 104: 831-37. Kaiser-Kupfer MI, Peck GL, Caruso RC, Jaffe MJ, DiGiovanna JJ, Gross EG. Abnormal retinal function associated with fenretimde, a synthetic retinoid. Arch Ophthalmol 1986; 104: 69-70. Verriest G, v Laethem J, Uvijls A. A new assessment of the normal ranges of the Farnworth-Munsell 100 hue test scores Am J Ophthalmol 1982; 93: 635-42

1. Fraunfelder 2.

3 4

5

ISOTRETINOIN DOSE AND TERATOGENICITY

SIR,-Dr Rosa (Nov 14, p 1154) raises the question of a dose relationship in isotretinoin teratogenicity. This is plausible and possible. However, other factors may be important in explaining the absence of isotretinoin teratogenicity in France. The usual dose here does not appear to be significantly lower than what is used in the US. The usual starting dose is 0-5 mg/kg, increased after two months to 1-0 mg/kg if necessary. Because of teratogenicity, dermatologists are very reluctant to prescribe this drug for females of childbearing age, and when prescribed, an oral contraceptive is taken

Supported in part by a grant from Direccion General de Farmacia y Productos Sanitarios, Plan Espanot de Farmacovigilancia, Ministerio de Sanidad y Consumo; by a grant from Direccion General de Planificación Sanitaria, Ministerio de Sanidad y Consumo; and by the Spain-USA Committee for Scientific and Technological Cooperation.

time. Indicated uses are further limited to severe the cost reimbursable by the French national social insurance system: if a drug is largely prescribed for mild cases, it is considered a "comfort drug" and is refundable at a lower rate or not at

cases, to

at

the

same

keep

ECEMC, Department of Anatomy II, Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain

all, suppressing widespread use.

Insritut Européen des 69005 Lyon, France

=

M. L. MARTÍNEZ-FRÍAS J. SALVADOR

Génomutations,

ELISABETH ROBERT

1. Lammer

EJ, Hoor RM,

et

al Retinoic acid

embryopathy. N Engl J Med 1985; 313:

837-41

EJ, Flannery DB, Barr M Does isotretinoin cause limb reduction defects? Lancet 1985; ii: 328. 3. Rosa FW. Teratogenicity of isotretinoin. Lancet 1983; ii: 513. 4. Rosa FW, Wilk AL, Kelsey FO. Teratogen update. Vitamin A congeners. Teratology

MEGADOSE VITAMIN A AND TERATOGENICITY

2. Lammer

SIR,-Since 1982, when isotretinoin was marketed in the USA treatment of severe acne (followed by etretinate for psoriasis) several birth defects have been reported in babies born to for oral

1986; 33: 355-64. ML, Salvador J, Prieto L, Zaplana J Epidemiological study of gastroschisis and omphalocele in Spain. Teratology 1984; 29: 377-82. 6. Smithells RW. Spina bifida and vitamins. Br Med J 1983; 286: 388-89. 7. Teratology Society Position paper: Recommendations for vitamin A use during pregnancy. Teratology 1987; 35: 269-75. 5. Martinez-Frias

mothers treated with these vitamin A derivatives.l The human teratogenicity of synthetic retinoids is now well accepted, prompting concern about the potential teratogenicity of megadoses of vitamin A. However, there are no epidemiological studies of this point. We have done an epidemiological study on prenatal exposure to vitamin A alone or in combination with other vitamins such as B, C, D, and E. We excluded multivitamins specifically used during’ pregnancy and other products containing low doses of vitamin A. We used data from the Spanish collaborative study of congenital malformations (ECEMCS), a hospital-based case-control study and surveillance system. Malformed infants are ascertained in each hospital by examination of all liveborn babies by a participating physician during the first three days of life. For each malformed infant, the next non-malfonned baby of the same sex and born in the same hospital is selected as a control. Mothers of cases and controls °

RENAL AUTOTRANSPLANTATION FOR SEVERE SICKLE CELL MAEMATURIA

SIR,-Gross haematuria secondary to sickle cell disease is a major therapeutic challenge.1 The pathogenesis is unknown. One possibility is that the renal medulla, being hypertonic, acidotic, and hypoxic (conditions known to precipitate sickling) is thereby at risk of obstruction of blood flow, congestion, loss of vascular integrity, and hence haematuria. However, not all cases of haematuria in patients with sickle cell haemoglobin abnormalities are related to sickling itself, and infection, malignancy, and primary coagulation