Risk Factor: A*
Fetal Risk Summary
Vitamin A (retinol; vitamin A1) is a fat-soluble essential nutrient that occurs naturally in a variety of foods. Vitamin A is required for the maintenance of normal epithelial tissue and for growth and bone development, vision, and reproduction (1). Two different daily intake recommendations for pregnant women in the United States have been made for vitamin A. The National Academy of Sciences’ recommended dietary allowance (RDA) for normal pregnant women, published in 1989, is 800 retinol equivalents/day (about 2700 IU/day of vitamin A) (1,2). The FDA’s RDA (i.e., U.S. RDA) for pregnant women, a recommendation made in 1976, is 8000 IU/day (3,4). The U.S. RDA of 8000 IU/day should be considered the maximum dose (4), although the difference between the two recommendations is probably not clinically significant.
The teratogenicity of vitamin A in animals is well known. Both high levels and deficiency of the vitamin have resulted in defects (5,6,7,8,9,10,11,12 and 13). In the past, various authors have speculated on the teratogenic effect of the vitamin in humans (5,14,15 and 16). A 1983 case report suggested that the vitamin A contained in a multivitamin product may have caused a cleft palate in one infant; however, the mother had a family history of cleft palate and had produced a previous infant with a malformation (16). Another case report, this one published in 1987, described an infant with multiple defects whose mother had consumed a vitamin preparation containing 2000 IU/day of vitamin A (17). The authors thought the phenotype of their patient was similar to the one observed with isotretinoin, but they could not exclude other causes of the defect, including a phenocopy of the isotretinoin syndrome (17). Therefore, in both cases, no definite association between the defects and vitamin A can be established, and the possibility that other causes were involved is high.
In response to the 1983 case report cited above, one investigator wrote in 1983 that there was no acceptable evidence of human vitamin A teratogenicity and none at all with doses less than 10,000 IU/day (18). Since that time, however, two synthetic isomers of vitamin A, isotretinoin and etretinate, have been shown to be powerful human teratogens (see Isotretinoin and Etretinate). In addition, recent studies have revealed that high doses of preformed vitamin A are human teratogens. These and the other reports are summarized below. Because of the combined animal and human data for vitamin A, and because of the human experience with isotretinoin and etretinate, large doses or severe deficiency of vitamin A must be viewed as harmful to the human fetus.
Severe human vitamin A deficiency has been cited as the cause of three malformed infants (19,20 and 21). In the first case, a mother with multiple vitamin deficiencies produced a baby with congenital xerophthalmia and bilateral cleft lip (19). The defects may have been caused by vitamin A deficiency because of their similarity to anomalies seen in animals deprived of this nutrient. The second report involved a malnourished pregnant woman with recent onset of blindness whose symptoms were the result of vitamin A deficiency (20). The mother gave birth to a premature male child with microcephaly and what appeared to be anophthalmia. The final case described a blind, mentally retarded girl with bilateral microphthalmia, coloboma of the iris and choroid, and retinal aplasia (21). During pregnancy, the mother was suspected of having vitamin A deficiency manifested by night blindness.
In 1986, investigators from the FDA reviewed 18 cases of suspected vitamin Ainduced teratogenicity (22). Some of these cases had been reviewed in previous communications by an FDA epidemiologist (23,24). Six of the cases (25,26,27,28,29 and 30) had been previously published and 12 represented unpublished reports. All of the cases except one involved long-term, high-dose (>25,000 IU/day) consumption continuing past conception. The exception involved a woman who accidentally consumed 500,000 IU, as a single dose, during the 2nd month of pregnancy (29). Twelve of the infants had malformations similar to those seen in animal and human retinoid syndromes (i.e., central nervous system and cardiovascular anomalies, microtia, and clefts) (22). The defects observed in the 18 infants were microtia (N=4), craniofacial (N=4), brain (N=4), facial palsy (N=1), micro/anophthalmia (N=2), facial clefts (N=4), cardio-aortic (N=2), limb reduction (N=4), gastrointestinal atresia (N=1), and urinary (N=4) (22).
The Centers for Disease Control and Prevention (CDC) reported in 1987 the results of an epidemiologic study conducted by the New York State Department of Health from April 1983 through February 1984 (3). The mothers of 492 live-born infants without congenital defects were interviewed to obtain their drug histories. Vitamin A supplements were taken by 81.1% (399 of 492) of the women. Of this group, 0.6% (3 of 492) took 25,000 IU/day or more, and 2.6% (13 of 492) consumed 15,00024,999 IU/day (3). In an editorial comment, the CDC noted that the excessive vitamin A consumption by some of the women was a public health concern (3).
Results of an epidemiologic case-control study conducted in Spain between 1976 and 1987 were reported in preliminary form in 1988 (31) and as a full report in 1990 (32). A total of 11,293 cases of malformed infants were compared with 11,193 normal controls. Sixteen of the case mothers (1.4/1000) used high doses of vitamin A either alone or in combination with other vitamins during their pregnancies, compared with 14 (1.3/1000) of the controls, an odds ratio (OR) of 1.1 (n.s.). Five of the case infants and 10 of the controls were exposed to doses less than 40,000 IU/day (OR 0.5, p=0.15). In contrast, 11 of the case infants and 4 controls were exposed to 40,000 IU (OR 2.7, p=0.06). The risk of congenital anomalies, although not significant, appeared to be related to gestational age as the highest risk in those pregnancies exposed to 40,000 IU/day occurred during the first 2 months (32). The data suggested a dose-effect relationship and provided support for earlier statements that doses lower than 10,000 IU were not teratogenic (31,32).
Data from a case-control study was used to assess the effects of vitamin A supplements (daily use for at least 7 days of vitamin A either alone or with vitamin D, or of fish oils) and vitamin A-containing multivitamin supplements (33). Cases were 2,658 infants with malformations derived, at least in part, from cranial neural crest cells (primarily craniofacial and cardiac anomalies). Controls were 2,609 infants with other malformations. Case mothers used vitamin A supplements in 15, 14, and 10 pregnancies during lunar months 1, 2, and 3, respectively, compared with 6 control mothers in each period (33). Although not significant, the OR in each period was 2.5 (95% confidence interval [CI] 1.06.2), 2.3 (95% CI 0.95.8), and 1.6 (95% CI 0.64.5), respectively. The authors cautioned that their data should be considered tentative because of the small numbers and lack of dosage and nutrition information (33). Even a small increased risk was excluded for vitamin Acontaining multivitamins (33).
A congenital malformation of the left eye was attributed to excessive vitamin A exposure during the 1st trimester in a 1991 report (34). The mother had ingested a combination of liver and vitamin supplements that provided an estimated 25,000 IU/day of vitamin A. The unusual eye defect consisted of an hourglass cornea and iris with a reduplicated lens.
A brief 1992 correspondence cited the experience in the Hungarian Family Planning Program with a prenatal vitamin preparation containing 6000 IU of vitamin A (35). Evaluating their 1989 database, the authors found no relationship, in comparison with a nonexposed control group, between the daily intake of the multivitamin at least 1 month before conception through the 12th week of gestation and any congenital malformation.
A study published in 1995 examined the effect of preformed vitamin A, consumed from vitamin supplements and food, on pregnancy outcomes (36). Vitamin A ingestion, from 3 months before through 12 weeks from the last menstrual period, was determined for 22,748 women. Most of the women were enrolled in the study between week 15 and week 20 of pregnancy. From the total group, 339 babies met the criteria for congenital anomalies established by the investigators. These criteria included malformations in four categories (number of defects of each type shown: cranialneural crest defects (craniofacial, central nervous system, and thymic, N=69; heart defects, N=52); neural tube defects (NTDs) (spina bifida, anencephaly, and encephalocele, N=48); musculoskeletal (N=58) and urogenital (N=42) defects; and other defects (gastrointestinal defects, N=24; agenesis or hypoplasia of the lungs, single umbilical artery, anomalies of the spleen, and cystic hygroma, N=46) (36). The 22,748 women were divided into four groups based on their total (supplement plus food) daily intake of vitamin A: 05,000 IU (N=6,410), 5,00110,000 IU (N=12,688), 10,00115,000 IU (N=3,150), and 15,001 IU (N=500). Analysis of this grouping revealed that the women who took 15,001 IU daily had a higher prevalence ratio for defects associated with cranialneural crest tissue compared with those in the lowest group, 3.5 (95% CI 1.77.3). A slightly higher ratio was found for musculoskeletal and urogenital defects, no increase for NTDs or other defects, and for all birth defects combined, a ratio of 2.2 (95% CI 1.33.8) (36). Analysis of three groups (05,000 IU, 5,00110,000 IU, and 10,001 IU) of vitamin A ingestion levels from food alone was hampered by the small number of women and, although some increased prevalence ratios were found in the highest groups, the small numbers made the estimates imprecise (36). A third analysis was then conducted based on four groups (05,000 IU, 5,0018000 IU, 8,00110,000 IU, and 10,001 IU) of vitamin A ingestion levels from supplements. Compared with the lowest group, the prevalence ratio for all birth defects in the highest group was 2.4 (95% CI 1.34.4) and for defects involving the cranialneural crest tissue, the ratio was 4.8 (95% CI 2.210.5). Of interest, the mean vitamin A intake in the highest group was 21,675 IU. Based on these data, the investigators concluded that following in utero exposure to more than 10,000 IU of vitamin A from supplements, about 1 infant in 57 (1.75%) had a vitamin Ainduced malformation.
In response to the above study, a note of caution was sounded by two authors from the CDC (37). Citing results from previous studies, these authors concluded that without more data, they could not recommend use of the dose-response curve developed in the above study for advising pregnant women of the specific risk of anomalies that might arise from the ingestion of excessive vitamin A. Although they agreed that very large doses of vitamin A might be teratogenic, the question of how large a dose remained (37). A number of correspondences followed publication of the above study, all describing perceived methodologic discrepancies that may have affected the conclusions (38,39,40,41 and 42) with a reply by the authors supporting their findings (43).
Using case-control study data from California, a paper published in 1997 examined the relationship between maternal vitamin A ingestion and the risk of NTDs in singleton live-born infants and aborted fetuses (44). Although the number of cases was small, only 16 exposed to 10,000 IU/day and 6 to 15,000 IU/day, the investigators did not find a relationship between these levels of exposure and NTDs.
Referring to the question on the teratogenic level of vitamin A, a 1997 abstract reported the effects of increasing doses of the vitamin in the cynomolgus monkey, a species that is a well-documented model for isotretinoin-induced teratogenicity (45). Four groups of monkeys were administered increasing doses of vitamin A (7,50080,000 IU/kg) in early gestation (day 1627). A dose-related increase in abortions and typical congenital malformations was observed in the offspring. The NOAEL (no observed adverse effect level) was 7,500 IU/kg, or 30,000 IU/day based on an average 4-kg animal. A human NOAEL extrapolated from the monkey NOAEL would correspond to >300,000 IU/day (45).
A brief 1995 report described the outcomes of 7 of 22 women who had taken very large doses of vitamin A during pregnancy, 20 of whom had taken the vitamin during the 1st trimester (46). The mean daily dose was 70,000 IU (range 25,00090,000 IU) for a mean of 44 days (range 7180 days). None of the offspring of the 7 patients available at follow-up had congenital malformations. Data on the other 15 women were not available.
Two abstracts published in 1996 examined the issue of vitamin A supplementation in women enrolled in studies in Atlanta, Georgia, and in California, both during the 1980s (47,48). In the first abstract, no increase in the incidence of all congenital defects or those classified as involving cranialneural crest derived was found for doses
Using data collected between 1985 and 1987 in California and Illinois by the National Institute of Child Health and Human Development Neural Tube Defects Study, a case-control study published in 1997 examined whether periconceptional vitamin A exposure was related to NTDs or other major congential malformations (49). Three study groups of offspring were formed shortly after the pregnancy outcome was known (prenatally and postnatally): those with NTDs (N=548), those with other major malformations (N=387), and normal controls (N=573). The latter two groups were matched to the NTDs group. A subgroup, formed from those with other major malformations, involved those with cranialneural crest malformations (N=89), consisting mainly of conotruncal defects of the heart and great vessels, including ventricular septal defects, and defects of the ear and face (49). The vitamin A (supplements and fortified cereals) exposure rates by group for those ingesting a mean >8,000 IU/day or >10,000 IU/day were NTDs (3.3% and 2.0%), other major malformations (3.6% and 1.6%), cranialneural crest malformations (3.4% and 2.2%), and controls (4.5% and 2.1%), respectively. None of the values were statistically significant, thus no association between moderate consumption of vitamin A and the defect groups was found (49).
Several investigators have studied maternal and fetal vitamin A levels during various stages of gestation (5,50,51,52,53,54,55,56,57,58,59,60 and 61). Transport to the fetus is by passive diffusion (61). Maternal vitamin A concentrations are slightly greater than those found in either premature or term infants (50,51 and 52). In women with normal levels of vitamin A, maternal and newborn levels were 270 and 220 ng/mL, respectively (51). In 41 women not given supplements of vitamin A, a third of whom had laboratory evidence of hypovitaminemia A, mean maternal levels exceeded those in the newborn by almost a 2:1 ratio (51). In two reports, maternal serum levels were dependent on the length of gestation with concentrations decreasing during the 1st trimester, then increasing during the remainder of pregnancy until about the 38th week when they began to decrease again (5,53). A more recent study found no difference in serum levels between 10 and 33 weeks’ gestation, even though amniotic fluid vitamin A levels at 20 weeks onward were significantly greater than at 1618 weeks (54). Premature infants (36 weeks or less) have significantly lower serum retinol and retinol-binding protein concentrations than do term neonates (50,55,56 and 57).
Mild to moderate deficiency is common during pregnancy (51,58). A 1984 report concluded that vitamin A deficiency in poorly nourished mothers was one of the features associated with an increased incidence of prematurity and intrauterine growth retardation (50). An earlier study, however, found no difference in vitamin A levels between low-birth-weight (2500 g) infants (52). Maternal vitamin A concentrations of the low-birth-weight group were lower than those of normals, 211 vs 273 ng/mL, but not significantly. An investigation in premature infants revealed that infants developing bronchopulmonary dysplasia had significantly lower serum retinol levels as compared with infants who did not develop this disease (57).
Relatively high liver vitamin A stores were found in the fetuses of women younger than 18 and older than 40 years of age, two groups that produce a high incidence of fetal anomalies (5). Low fetal liver concentrations were measured in 2 infants with hydrocephalus and high levels in 14 infants with NTDs (5). In another report relating to NTDs, a high liver concentration occurred in an anencephalic infant (59). Significantly higher vitamin A amniotic fluid concentrations were discovered in 12 pregnancies from which infants with NTDs were delivered as compared with 94 normal pregnancies (60). However, attempts to use this measurement as an indicator of anencephaly or other fetal anomalies failed because the values for abnormal and normal fetuses overlapped (54,60).
The effect of stopping oral contraceptives shortly before conception on vitamin A levels has been studied (61). Because oral contraceptives had been shown to increase serum levels of vitamin A, it was postulated that early conception might involve a risk of teratogenicity. However, no difference was found in early pregnancy vitamin A levels between users and nonusers. The results of this study have been challenged based on the methods used to measure vitamin A (63).
Vitamin A is known to affect the immune system (64). Three recent studies (65,66 and 67) and an editorial (68) have described or commented on the effect that maternal vitamin A deficiency has on the maternal-fetal transmission of human immunodeficiency virus (HIV). In each of the studies, a low maternal level of vitamin A was associated with HIV transmission to the infant. In the one study conducted in the United States, severe maternal vitamin A deficiency (
In summary, excessive doses of preformed vitamin A are teratogenic, as may be marked maternal deficiency. In addition, recent evidence has demonstrated that severe maternal vitamin A deficiency may increase the risk of mother-to-child HIV transmission and reduced infant growth during the first year. b-Carotene, a vitamin A precursor, has not been associated with either human or animal toxicity (see b-Carotene). Doses exceeding the U.S. RDA (8,000 IU/day) should be avoided by women who are, or who may become, pregnant. Moreover, the U.S. RDA established by the FDA should be considered the maximum dose (4). Although the minimum teratogenic dose has not yet been defined, doses of 25,000 IU/day or more, in the form of retinol or retinyl esters, should be considered potentially teratogenic (3,4,22), but based on one study, smaller doses than this may be teratogenic (36). One of the recommendations of the Teratology Society, published in a 1987 position paper, states: Women in their reproductive years should be informed that the excessive use of vitamin A shortly before and during pregnancy could be harmful to their babies (4). The Teratology Society also noted that the average balanced diet contains approximately 7,0008,000 IU of vitamin A from various sources, and this should be considered prior to additional supplementation (4).
[*Risk Factor X if used in doses above the U.S. RDA.]
Breast Feeding Summary
Vitamin A is a natural constituent of breast milk. Deficiency of this vitamin in breast-fed infants is rare (70). The RDA of vitamin A during lactation is approximately 4000 IU (1). It is not known whether high maternal doses of vitamin A represent a danger to the nursing infant or whether they reduce HIV transmission via the milk.
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