Retinoic acid and vitamin A: Effect of low levels on outcome of pregnancy in Guinea Pigs

To study the effect of marginal vitamin A status during pregnancy on the health of guinea pig neonates the level of vitamin A required to produce viable offspring was determined. In previous work adult animals fed a vitamin A-deficient diet for one month before mating and throughout pregnancy delivered dead pups. In this experiment depletion was followed by supplementation with three levels of vitamin A after day 30 (d30) of pregnancy (gestation=68±2d). Young adult guinea pigs were fed a vitamin A-deficient diet for 1 mo prior to mating and throughout pregnancy. Because approximately 6 wk was required for all females to mate under our conditions, they were dosed with retinoic acid (RA) from the end of the one month depletion until day 30 of pregnancy. RA was given to spare the females' remaining stores of vitamin A to reduce differences that might arise between females that mated first and those that mated last. All-trans RA was given orally three times a week; the weekly dose approximated 1.5 mg/kg body weight. After d30 RA was discontinued, and females were dosed weekly with 0, 175, 350 or 1166 retinol equivalents (RE) as retinol palmitate. At delivery malformations were observed in 28 to 66 percent of the litters irrespective of vitamin A supplementation. No malformations occurred in litters of 11 females of the same age fed a commercial guinea pig diet. Because the occurrence of malformations complicated determination of the amount of vitamin A required to produce viable neonates, females continued to receive the same treatment they received from d30 of the first pregnancy through remating, a second pregnancy, and a 2 wk lactation. Malformations were observed in litters of only 2/28 pregnancies. Under these conditions guinea pigs required a minimum of 175 RE/wk (equivalent to 25 RE/d) to produce viable neonates. To maintain normal weight gains of pups through a 2 wk lactation females required at least 45 RE/kg body wt/d. Since the dose of RA used was much less than the teratogenic dose in other animals, the guinea pig may be unusually sensitive to RA, or prior depletion of vitamin A stores may have increased the teratogenicity of RA.