Pillans, P. I.

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204 SAMJ VOL 73 20 FEB 1988
the creation of epidemiological posts at national and
regional level. We would hope that priority will be given
to the further development of such a service within the
Department of National Health and Population Develop-
ment.
A.J. Brink
BIBLIOGRAPHY
Brink AJ, Wicht CL. The need for training health professionals in epidemio-
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Emberron J. Strengthening the practice of epidemiology in the European com-
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Yach D, Botha JL. Epidemiological research methods: Parr VII. Epidemio-
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Dangers of large doses of vitamin A
during pregnancy
Vitamin A is an alcohol - retinol - which has profound
effects on cell differentiation and proliferation and is an
essential dietary nutrient for growth, vision, reproduction,
immunocompetence and the maintenance of differentiated
epithelia and mucus secretion. I Retinol metabolises to
an aldehyde form - retinal - and an acid form -
retinoic acid - both of which are members of a large
class of compounds, the retinoids. The average balanced
diet contains the recommended daily allowance (RDA)
for adults of approximately 4000 - 5 000 IU vitamin A.
The use of vitamin A and retinoids is increasing,2,3
perhaps encouraged by popular protagonists such as
Linus Pauling" and Adele Davis5 of megadose supple-
ments. Vitamin A tablets containing 25000 - 50000 IU
are freely available in health-food shops and pharmacies
in South Africa. Marketing data in the USA have shown
widespread high-dose vitamin A utilisation (IMS America
Ltd, Ambler, Pennsylvania, 1983) and the consumption
of megadose vitamin A appears to be encouraged by
health stores in the UK.2The toxic syndrome of hyper-
vitaminosis A can result from prolonged intake of doses
in excess of 10 - 20 times the RDA.6
Of particular concern is the use of excessive amounts
of vitamin A by women of childbearing age. Since the
original report of vitamin A teratogenicity in animals by
Cohlan,7 more than 100 studies have found various
analogues of vitamin A to be teratogenic in numerous
species.8 In humans, the teratogenic potential of the
synthetic retinoic acid derivatives, isotretinoin and
etretinate, used in the treatment of acne and psoriasis
are now well known, typically producing craniofacial
malformations such as microtia or anotia, agenesis or
marked stenosis of the external ear canal, maldevelopment
of skull and facial bones, micrognathia, heart defects,
thymic abnormalities and central nervous system mal-
formations such as hydrocephalus and microcephaly.9
The pattern of abnormalities is similar to that induced
by vitamin A if given during the same period of de-
velopment.8- 1O The first observations of human tera-
togenicity with isotretinoin were reported in 1983 by
Roche Laboratories. At this stage there were only 5
reports in the literature and 2 received by the Food and
Drug Administration (FDA) in the USA of human
birth defects associated with excessive maternal vitamin
A exposure. IO- IS In 1984 Hall l6 called vitamin A a
newly recognised human teratogen and suggested it was
a harbinger of things to come. Since 1984 10 more
unpublished case reports have been documented by the
FDA,IO and another has been documented in the litera-
ture. Twelve of the above cases had defects similar to
those seen in animals and in human retinoid syndromes,
such as microtia, cleft palate, and central nervous system
and cardiovascular abnormalities. The mothers of mal-
formed infants were exposed to supplements of 25000
IU vitamin A per day or more, and all but 1 of the 18
birth defects occurred with long-term exposure con-
tinuing after conception. IO Vitamin A levels are greatly
influenced by the duration of use - the vitamin is
cumulative because of its long half-life. 10, 18 In the mouse,
although the blastocyst appears to be resistant to the
teratogenic effects of vitamin A, we have found that a
large dose of the vitamin administered during the pre-
implantation period exerts its toxic effect during the
later more vulnerable embryonic period, which is in
keeping with a prolonged maternal elimination rate. 19
Patients are advised not .to become pregnant for several
months after discontinuing treatment with large doses of
vitamin A and the retinoic acid derivative, etretinate.8,20
The mechanism by which vitamin A and other
retinoids interfere with normal embryonic development
is not well understood. Retinoids may enter the cell,
bind to a specific cytoplasmic protein, and then be
transported to the nucleus where they may alter the
pattern of gene action. The involvement of ear, thymus,
heart and brain has raised speculation of a specific effect
on neural crest cells.2I-23 Other mechanisms that have
been advanced include a toxic effect on cell membranes,
abnormal differentiation, interference with muco!,oly-
saccharide metabolism and increased cell death. 12,24-26.-
The concern of the Teratology Society regarding excess
vitamin A use during pregnancy recently led to the
publication of the first position paper in 13 years. 3 Their
important recommendations are: (i) women in their
reproductive years should be informed that excessive
use of vitamin A before and during pregnancy could be
harmful to their babies; (it) supplementation of 8000 IU
vitamin A (as retinollretinyl esters) per day should be
considered the maximum before or during pregnancy;
(iiz) manufacturers should lower the maximum amount
of vitamin A per unit dosage to 5000 - 8000 ID and
identify the source of vitamin A (high dosages of vitamin
A as retinollretinyl esters (25000 ID or more) are not
recommended because these dosages are not necessary
as a nutrient supplement and may be teratogenic); since
carotene has not been associated with embryotoxic effects,
it is suggested that ,B-earotene be considered the primary
source of these vitamins for women in their reproductive
years; and (iv) labelling of products containing vitamin
A supplements (as retinollretinyl esters) should indicate
that consumption of excessive amounts of vitamin A
may be hazardous to the embryo/fetus when taken
during pregnancy and that women of childbearing
potential should consult their doctor before consuming
these products.
It remains to be seen whether the authorities and/or
industry take cognisance of these recommendations and
limit the maximal amount of vitamin A per unit dosage.
Doctors and pharmacists remain responsible not only
for ensuring that pregnant patients are not prescribed
megadoses of vitamin A, but that women in their repro-
ductive years are informed of the dangers of excessive
use of vitamin A shortly before and during pregnancy.
However, even if health professionals fulfil their role, if
control of dosage is not forthcoming, large outlets such
as those through health-food stores will remain
unchecked.
P. I. Pillans
I. Goodman DS. Vitamin A and retinoids in health and disease. N EnglJ Med
1984; 310: 1023-1031.
2. Evans CDH, Lacey JH. Toxiciry of vitamins: complications of a healrh
movement. Br MedJ 1986; 292: 509-510.
SAMT VOL 73 20 FEB 1988 205
3. Teratology Sociery Position Paper: Vitamin A during pregnancy: recom-
mendations for viramin A use during pregnancy. Tera!ology 1987; 35:
267-275.
4. Pauling L. How to Live Longer and Feel Beller. New York: SM Freeman,
1986.
5. Davis A. Let's Ea! Righc to Keep Fi!. Bergen Field, NJ: New American
Lihrary, 1970.
6. Davidson RA. Complications of megavitamin therapy. Sourh MedJ 1984;
77: 200-203.
7. Cohlan SQ. Excessive intake of vitamin A as a cause of congenital anomalies
in the rat. Science 1953; 117: 535-536.
8. Gee1an JAG. Hn'ervitaminosis A-induced teratogenesis. CRC Cri! Rev
Torico11979; 4: 351-375.
9.Lammer EJ, Chen DT, Hoar RM et al. Retinoic acid emhryopahry. N Engl
J Med 1985; 313: 837-841.
10. Rosa FW, Wild AL, Kelsey FO. Teratogen update: vitamin A congeners.
Tera!ology 1986; 33: 355-364.
11. Pilorti GA, Scorta A. lpervitaminosi A gravidica e malformazini neonatali
dell'appatato urinario. Minerva Ginecoll965; 17: llO~-II08.
12. Morris GM, Steel CE. The effecrs of excess vitamin A on the development
of rat emhryos in culture.J Embryol ExpMorphol1974; 32: 505-514.
13. Mounoud RL, Klein D, Weber F. Report of a case of Goldenhar's syndrome:
acute maternal intoxication hy vitamin A during pregnancy. J Gene! Hum
1975; 23:· 135-154.
14. Stange L, Carlstrom K, Eriksson M. Hypervitaminosis A in early human
pregnancy and malfortnations of the central nervous system. Acta Obsrec
Gynecol Scand 1978; 57: 289-291.
IS. Bemhardt IB, Dorsey DJ. Hypervitaminosis A-and congenital renal anomalies
in a human infant. Obsrec Gyneco11974; 43: 750-755.
16. Hall JG. Vitamin A: A newly recognised human teratogen: harbinger of
things to come? J Pediacr 1984; 105: 583-584.
17. Von Lennep E, El Khazen N, De Pierreux G, Amy" JJ, Rodesch F, Van
Regemorter N. A case of partial sirenomelia and possible vitamin A tera-
togenesis. Prenac Diagn 1985; 5: 35-40.
18. Rosa FW, WiIk AL, Joshi SR, Kelsey FO, Troendle G. Teratology of
hypervitaminosis A. ADR Highlights 1984; No 84-1.
19. Pillans PI, Folb PI, Ponzi SF. The effects of in vitro administration of
teratongenic doses of vitamin A during the pre-implantation period in the
mouse. Teratology 1988 (in press).
20. Grote W, Harmse D, Janig V, Kietzmann H, Ravens U, Schwarze 1.
Malfortnation of fetus conceived four months after termination of maternal
etretinate treatment. Lance! 1985; i: 1276.
21. Dencker L. Accumulation of retinoids in embryonic neural and neuronal
crest cells as part of the mechanism ofteratogene5"is. UpsJ Med Sci 1986; 91:
295-298.
22. Goulding EH, Pran RM. Isotretinoin teratogeniciry in mouse whole embryo
culture.. J Craniofac Gene! Dev Bioi 1986; 6: 99-112.
23. Webster WS, JohnslOn MC, Lammer EJ, SuIik KK. Isotretinoin embryo-
pathy and the cranial neural crest: an in vivo and in virro study. J Craniofac
Gene! Dev Bioi 1986; 6: 211-222.
24. Dingle JT, Lucy JA. Vitamin A, carotenoids and biological cell function.
Bioi Rev 1965; 40: 422-461.
25. Kochar DM, Larsson KS, Bostrom H. Embryonic uptake of S35-sulphate:
change in level following treatment with some teratogenic agents. Bioi
Neonare 1968; 12: 41-53.
26. Nawar NNY, Sakla FB, Mahran ZY. Effect of maternal administration of
endoxan, vitamin A and vitamin B12 on the development of the fetal spinal
cord of the albino mouse. Appl Neurophysiol1979; 42: 203-211.
Nuus en Kommentaar/News and Comment
Autotransfusion
Concern about AIDS virus transmission by blood transfusion has
led to increased interest in autotransfusion, the transfer of the
patient's blood back into the body. An anicle by Dale er al. (Ann R
Coll Surg Engl 1986; 68: 296) discusses the use of autotransfusion
with a centrifugal cell washer in a series of 76 cases, 54 of which
involved liver transplantation. The procedures were commonly
accompanied by major blood loss and the apparatus used was the
Haemonetics Cell Saver, which 1J.lters the blood and performs the
centrifugal separation and cell washing. It has an efficient suction
apparatus which provides immediate effective anticoagulation. One
snag is the cost, about R60 000.
All the patients involved were at risk for excessive haemorrhage,
but only 2 died of continued haemorrhage, I being an elderly
patient with a ruptured aneurysm who developed disseminated
intravascular coagulation. On average in these cases 64% of the
estimated total blood loss was collected and about 45% of collected
blood was actually processed, representing 27% of total blood loss.
The authors estimate the use of this apparatus reduced the
amount of blood needed in these 74 cases by about 604 units.
Malnutrition and misleading advertising
Intellectual ability and the higher education should not necessarily
be equated with common sense, as a case repon in the Canadian
Medical AssociarionJournal points out (MUll A, Kalnins D, 1987;
136: 1274). A 6!tS-month-old boy was admitted to hospital with a
I-day history of increasing lethargy, vomiting and a bulging
anterior fontanelle. He was the child of university-educated vegans
and weighed 2 580 g at binh. At 6 weeks maternal anxiety resulted
in a change from breast milk to a soya-based substitute claimed in
advenisements to be a 'quality substitute' for breast milk. The
product was obtained from a health food store, and the general
practitioner presumably did not scrutinise the accompanying
brochure too closely. The result of feeding with this formula was
that the child was eventually admitted to hospital with all the
signs of deficiency of vitamins A and D together with marasmus.
A more onhodox formula together with supplies of vitamins A
and D rapidly dealt with the condition. This bears out the old
adage that the best place to peddle phoney wares is among the
highly educated.


Dangers of large doses of vitamin-A during pregnancy

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Dangers of large doses of vitamin-A during pregnancy

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