The most award winning
healthcare information source.
TRUSTED FOR FOUR DECADES.
By Anthony R. Scialli, MD
Vitamin a and its precursors are popular sup- plements, usually taken in the hope of preventing cancer or cardiovascular disease. Preformed vitamin A, retinol (also called vitamin A1 or vitamin A alcohol), is found only in animal products; vegetables and fruits contain provitamin A compounds called carotenoids, the most common of which is beta-carotene. Beta-carotene is cleaved in the liver to retinol. Although excessive ingestion of vitamin A can cause hypervitaminosis, excessive ingestion of dietary or supplemental beta-carotene results in deposition of beta-carotene in skin and other tissues rather than hypervitaminosis A. Vitamin A supplements, however, contain retinyl esters, which are readily converted to retinol. Retinol, whether derived from dietary or supplemental sources, is metabolized to retinal, the form important in vision, and to all-trans retinoic acid (also called retinoic acid). All-trans retinoic acid can isomerize to 13-cis retinoic acid (isotretinoin).
For many years, teratologists have used all-trans retinoic acid as a positive control in experimental animal studies on birth defects, and therapeutic use of isotretinoin (marketed as Accutane) has been associated with spontaneous abortion and a syndrome of birth defects when taken by pregnant women. In experimental animals, retinoids and vitamin A produce structural malformations involving the central nervous system, limbs, and cardiovascular system.1-6 High-dose vitamin A treatment of pregnant rats produces behavioral abnormalities in offspring.7 Very high doses of vitamin A are needed to produce developmental abnormalities; for example, in monkey experiments, doses of 20,000 IU/kg were required to produce an effect.8 The comparable weight-adjusted dose in a pregnant woman would be 1.2 million IU, about 400 times the RDA.
Case reports document an association between high-dose supplemental vitamin A use by pregnant women and developmental abnormalities of the offspring.5,9-14 Urinary tract anomalies (hydroureter) were seen with daily maternal ingestion of 25,000 and 40,000 IU of vitamin A9,11 and central nervous system defects were seen with daily doses of 150,000 IU.5,14 Malformations involving the face, palate, heart, and ears have been reported with maternal vitamin A ingestion in doses of 25,000 IU/d and more.15,16 These abnormalities are similar to those reported after use of isotretinoin.
Mechanism of Action
The mechanism of abnormal embryo development with retinoid treatment is well characterized. As the neural folds elevate and fuse to form the neural tube, a separate population of cells just lateral to the folding tube, the neural crest cells, emerge and then migrate to positions elsewhere in the embryo, where they add to mesenchymal tissues. Neural crest cells contribute to some bony and connective tissue elements of the face, mela-nocytes, adrenal medulla, spinal and autonomic ganglia, and conotruncal portions of the heart. The abnormalities characteristic of isotretinoin embryopathy can be attributed to abnormal migration of neural crest cells of the cranial region of the embryo, and inhibition of neural crest cell migration has been documented in vitro and in experimental animals with retinoid exposure.
Epidemiologic studies have evaluated the association between cranial neural crest-related abnormalities in children and vitamin A intake during pregnancy. A widely reported study by Rothman et al in 1995 evaluated more than 22,000 women for vitamin A intake from food and supplements during pregnancy.17 When maternal intake was estimated at greater than 10,000 IU/d, an increased prevalence of congenital anomalies was identified in infants. The prevalence ratio for all birth defects in the group exposed to more than 10,000 IU/d compared to the group exposed to 5000 IU/d or less was 2.4 (95% confidence interval [CI] 1.3-4.4). For the group of anomalies associated with abnormal craniofacial and cardiac development, the prevalence ratio was 4.8 (95% CI 2.2-10.5). A computer-smoothed curve fit to data from this study was consistent with a threshold for increased risk of congenital anomalies at 10,000 IU/d. The authors estimated from their data that pregnant women who ingest this amount of vitamin A have a 1-2% chance of having a baby with a birth defect attributable to the vitamin.
This study was criticized because some malformations attributed to abnormalities of cranial neural crest cell origin did not involve cranial neural crest-derived structures. In addition, diverse single malformations identified among the offspring of the few women with high-dose exposure raise the possibility that the findings of the study were due to clustering, and that there is no actual causal relationship between lower doses of vitamin A and congenital malformations. In other words, a few babies exposed to high doses may have malformations by chance alone, but end up artifactually creating the high end of a presumed dose-response curve. The extrapolation of risk with low doses (in the range of 10,000 IU/d) is based on a dose-response curve that may have been unduly influenced by the clustering effect at high doses.15,18
Other epidemiological studies have failed to confirm the conclusions of the Rothman paper with regard to cranial neural crest-related abnormalities or, in one study, neural tube defects.19-23 Supplement use by women in these studies typically involved vitamin A doses near 10,000 IU, although some exposures to higher doses were included. Dietary sources of vitamin A were not assessed and would be expected to add to the vitamin A intake of the women.
Perhaps the most important negative study, published by the European Network of Teratology Information, evaluated pregnancy outcome among women who called a Teratology Information Service with a concern about vitamin A ingestion of 10,000 IU/d or more prior to nine weeks of pregnancy; 394 of the women were followed for outcome information.24 There was no increase in the incidence of congenital malformations among the 311 pregnancies evaluable for birth defects, compared to the offspring of 116 women who took vitamin A supplements after nine weeks of pregnancy or 679 women who had contacted the information service about an unrelated exposure judged not to be a pregnancy risk. Among 120 women who used more than 50,000 IU/d during early pregnancy, no congenital malformations were identified among their offspring.
A more recent study resurrects the question of whether supplementation at about 10,000 IU/d increases pregnancy risk. The Baltimore-Washington Heart Study, a large case-control study of possible risk factors associated with congenital heart disease, administered questionnaires to mothers of children with heart disease and a matched sample of children without birth defects.25 The questionnaires involved many possible exposures and other risk factors, leaving open the likelihood that many associations could be identified by chance.
In spite of the multiple comparison problem, the vitamin A analysis may be more reliable, because it was based on an a priori hypothesis that makes biologic sense. The comparison made in this study was between mothers of children with two kinds of cardiac outflow tract abnormalities: those involving transposition of the great vessels, and those involving normal great vessels. Why would this difference be important? The great vessels, the aorta, and the pulmonary artery arise from the growth of a septum in the truncus arteriosis. This septum arises from conotruncal swellings, which receive a contribution from the neural crest. Thus, the distinction in this study may be between neural crest-related and neural crest-unrelated cardiac outflow tract abnormalities.
Vitamin A intake in the Baltimore-Washington Heart Study was evaluated by reported maternal food preferences for the year prior to conception. Supplement use also was recorded. The study found that intake of 10,000 IU/d from supplements, but not from food, was associated with an odds ratio of 9.2 (95% CI 4.0-21.2) with respect to cardiac outflow tract defects that included transposition of the great vessels. There was no significant association between vitamin A intake and outflow tract defects with normal great vessels. The lack of relationship of high intake of vitamin A from food is curious, and may have been due to errors from the use of food preference recall for the year prior to pregnancy. After all, dietary preferences may change during pregnancy, a fact acknowledged by the authors. Vitamin A from food may be less bioavailable than vitamin A from supplements; serum retinol levels have been shown to be increased more by ingestion of a supplement than by ingestion of liver with comparable vitamin A content.26
So how much vitamin A is safe? Prior to the Rothman study, it was believed, based on case reports, that women who were pregnant or might become pregnant should consume less than 25,000 IU/d.5 Since the Rothman study, recommended vitamin A limits have decreased to less than 10,000 IU/d. Two small epidemiologic studies support the conclusion that less than 10,000 IU/d of vitamin A is not teratogenic.27,28 In 1987, the Teratology Society recommended that the intake of supplemental vitamin A during pregnancy not exceed the RDA of 8,000 IU/d.16 Since that time, the RDA has been lowered to 800 mcg/d of retinol (about 2,700 IU/d).29 Manufacturers of prenatal vitamins have decreased the vitamin A content from 8,000 to 5,000 IU per dose and many have replaced some or all of the retinyl esters with beta-carotene. The evidence for an adverse effect of supplemental vitamin A in doses less than 10,000 IU is weak, but there is no reason to use high-dose supplementation during pregnancy.
Some nutritional advice, however, may be warranted too. An average portion of liver contains between four and 12 times the RDA for vitamin A, and one nutritionist has suggested that the intake of liver and liver products (some sausages and patés) be limited to about 100 g (4 oz) per week during pregnancy.30 The U.K. Department of Health has recommended that liver consumption be avoided entirely in early pregnancy.31,32 Liver is an excellent source of nutrients (including B vitamins, iron, and vitamin D), and the bioavailability of vitamin A from liver may be less than that from supplements. There is concern that the U.K. warning might lead some women to avoid vitamin A-containing foods and thereby risk vitamin A deficiency during pregnancy.32
Alternative sources of retinol are full-fat dairy foods, egg yolks, and fatty fish (including herring, sardines, anchovies, salmon, mackerel, and bluefish). Other strategies include deriving most nutritional vitamin A from carotenoids in vegetables, and avoiding vitamin A supplements altogether.
Conflict of Interest Statement: In the year after the Rothman study appeared, I was recruited by Hoffman-LaRoche, a manufacturer of vitamin A, to serve on a panel charged with considering the experimental and epidemiology data on the developmental effects of supplements. The meeting was held in Boston and included tickets to an absolutely superb performance by the Boston Symphony. Although this experience may be interpreted as having produced a biased point of view, as of this writing, Hoffman-LaRoche has not paid the honorarium that was promised, producing at least as strong a potential bias in the opposite direction, the Boston Symphony notwithstanding.
1. Cohlan SQ. Congenital anomalies in the rat produced by the excessive intake of vitamin A during pregnancy. Pediatrics 1954;13:556-559.
2. Geelen JA. Hypervitaminosis A induced teratogenesis. CRC Crit Rev Toxicol 1979;6:351-375.
3. Fantel AG, et al. Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina). I. General features. Teratology 1977;15:65-71.
4. Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982;6:652-659.
5. Rosa FW, et al. Teratogen update: Vitamin A congeners. Teratology 1986;33:355-364.
6. DiGiacomo RF, et al. Hypervitaminosis A and reproductive disorders in rabbits. Lab Anim Sci 1992;42: 250-254.
7. Saillenfait AM, Vannier B. Methodological proposal in behavioural teratologenicity testing: Assessment of propoxyphene, chlorpromazine, and vitamin A as positive controls. Teratology 1988;37:185-199.
8. Hendrickx AG, et al. Vitamin A teratogenicity and risk assessment in the cynomolgus monkey. Teratology 1997;55:68.
9. Bernhardt IB, Dorsey DJ. Hypervitaminosis A and congenital renal anomalies in a human infant. Obstet Gynecol 1974;43:750-755.
10. Rosa FW. Retinoic acid embryopathy. N Engl J Med 1986;315:262.
11. Pilotti G, Scorta A. Hypervitaminosis A in pregnancy and neonatal malformations of the urinary tract [in Italian]. Minerva Ginecol 1965;17:1103-1108.
12. Stange L, et al. Hypervitaminosis A in early human pregnancy and malformations of the central nervous system. Acta Obstet Gynecol Scand 1978;57:289-291.
13. Von Lennep E, et al. A case of partial sirenomelia and possible vitamin A teratogenesis. Prenat Diagn 1985; 5:35-40.
14. Evans K, Hickey-Dwyer MU. Cleft anterior segment with maternal hypervitaminosis A. Br J Ophthalmol 1991;75:691-692.
15. Various authors. Teratogenicity of high vitamin A intake (letters). N Engl J Med 1996;334:1195-1197.
16. Teratology Society position paper: Recommendations for vitamin A use during pregnancy. Teratology 1987; 35:269-275.
17. Rothman KJ, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-1373.
18. Oakley GP Jr, Erickson JD. Vitamin A and birth defects. Continuing caution is needed. N Engl J Med 1995;333:1414-1415.
19. Shaw GM, et al. High maternal vitamin A intake and risk of anomalies of structures with a cranial neural crest cell contribution. Lancet 1996;347:899-900.
20. Werler MM, et al. Maternal vitamin A supplementation in relation to selected birth defects. Teratology 1990;42:497-503.
21. Shaw GM, et al. Periconceptional intake of vitamin A among women and risk of neural tube defect-affected pregnancies. Teratology 1997;55:132-133.
22. Mills JL, et al. Vitamin A and birth defects. Am J Obstet Gynecol 1997;177:31-36.
23. Khoury MJ, et al. Vitamin A and birth defects (letter). Lancet 1996:347:322.
24. Mastroiacovo P, et al. High vitamin A intake in early pregnancy and major malformations: A multicenter prospective controlled study. Teratology 1999;59:7-11.
25. Botto LD, et al. Vitamin A and cardiac outflow tract defects. Epidemiology 2001;12:491-496.
26. Buss NE, et al. The teratogenic metabolites of vitamin A in women following supplements and liver. Hum Exp Toxicol 1994;13:33-43.
27. Martinez-Frias ML, Salvador J. Epidemiological aspects of prenatal exposure to high doses of vitamin A in Spain. Eur J Epidemiol 1990;6:118-123.
28. Dudas I, Czeizel AE. Use of 6,000 IU vitamin A during early pregnancy without teratogenic effect. Teratology 1992;45:335-336.
29. National Research Council. Recommended Daily Allowances. 10th ed. Washington, DC: National Academy Press; 1989.
30. Nelson M. Vitamin A, liver consumption, and risk of birth defects. BMJ 1990;301:1176.
31. Acheson D, Poole A. Letter from the Department of Health to all doctors, nursing officers and public health officers. October 1990. Department of Health, London. PL/CLMO(90)11;PL/CMO (90)10.
32. Sanders TA. Vitamin A and pregnancy. Lancet 1990; 336:1375.