Teratogenicity of high vitamin A intake

Authors: Rothman JK, Moore LL, Singer MR, Nguyen UDT, Mannin S, Milunsky A.
Source: New England Journal of Medicine. 333:1369-73. November 23, 1995.
Institutions: Boston University School of Medicine and University G. D'Annunzio, Chieti, Italy.
Financial support: National Institute of Neurological Disorders and Stroke; F. Hoffmann-LaRoche.



22,748 pregnant women originally recruited 1984-1987 for a study evaluating risk factors for neural-tube defects and enrolled mainly between weeks 15-20 of pregnancy (at time of plasma AFP measurement or amniocentesis).

Data on diet, dietary retinol intake and vitamin supplements were collected by telephone questionnaire, data on pregnancy outcome by questionnaires sent to obstetricians (77%) and mothers (23%) after delivery. For this study, defects were classified as: cranial-neural-crest (craniofacial, CNS except neural tube, thymic and heart), neural tube, musculoskeletal/urogenital, and other (GI and non-GI).


Among the 22,748 women, there were 339 births with birth defects, 121 of cranial-neural-crest origin. The prevalence of cranial-neural-crest defects among the 500 women who consumed >15,000 IU of retinol daily (dietary plus supplements) was 1.8%, compared with 0.51% among the 6410 women who consumed <5,000 IU (relative risk of 3.5). Looking at retinol from supplements alone, the prevalence of cranial-neural-crest defects among the 317 women consuming >10,000 IU daily was 2.21% vs. 0.46% among the 11,083 consuming < 5,000 IU daily (relative risk 4.8).

Dose-response curves suggested a threshold value of about 10,000 IU daily. Subgroup analysis suggests main effect occuring before week 7 of pregnancy. Consumption of over 10,000 IU of vitamin A daily would be expected to lead to a birth defect in one of every 57 births.


In an accompanying editorial G. Oakley and J. Erickson from the CDC point out that the potential toxicity from vitamin A should not be confused with the protective effect from folate (demonstrated from earlier results of this same study). They also feel that this study is well suited to show the safety of vitamin A intake below 10,000 IU daily. Whether the actual threshhold for increased risk is actually 10,000 is less sure, but prudence dictates recommending a multivitamin supplement with less than 8,000 IU of vitamin A and limiting the intake of liver and liver products.


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