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Nutritional Models
Research Communication

A Theoretical Increase in Infants’ Hepatic Vitamin A Is Realized Using a Supplemented Lactating Sow Model

Integrated Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706

²To whom correspondence should be addressed. E-mail: sherry{at}nutrisci.wisc.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Vitamin A deficiency (VAD) is a public health problem affecting millions in developing nations. Supplementation for lactating women, whose needs are high, involves large oral doses of the preformed vitamin. The safety and efficacy of these doses has been inadequately studied. Lactating women typically receive 210 µmol of retinyl ester during early lactation, but 420 µmol has also been administered. If larger doses of vitamin A are not significantly more effective in preventing VAD in mothers and infants, then smaller doses would be recommended. We therefore examined the vitamin A concentration of milk from lactating sows (n = 15) that were provided two different doses of vitamin A (i.e., 1050 or 2100 µmol, n = 6/group) or corn oil (n = 3), corresponding to doses given women on the basis of body weight. Compared with controls, an overall significant treatment effect was found (P = 0.0019), but there was no difference in milk concentration between treatment groups. Theoretically, applying the mean milk vitamin A concentrations of the groups through 12 h and values to 48 h from 4 sows, we estimate that an infant of a supplemented mother could realize an increase of +0.08 or 0.16 µmol/g liver from the low or high dose, respectively.

KEY WORDS: • milk • retinyl ester • sows • vitamin A • vitamin A supplementation

Vitamin A (VA) supplementation programs began in the 1980s as a strategy for addressing vitamin A deficiency (VAD) sequelae. A major cause of blindness and morbidity, VAD is endemic in the developing world. Childhood infections cause a rapid depletion of hepatic VA, which makes children especially susceptible to VAD, ultimately leading to higher mortality (1 –4 ). The increased VA demands during pregnancy and lactation also make women susceptible (1 ,5 ,6 ).

VA programs are designed to provide large doses of preformed VA to groups at risk of VAD in an effort to improve stores. Doses to lactating women are typically 200,000 IU (210 µmol) of retinyl ester during early lactation, 8 wk postpartum, due to teratogenicity potential (1 ). However, up to 400,000 IU has been administered to women due to concerns that 200,000 IU was not effective (7 –9 ). These doses are 4.2–8.4 µmol VA/kg body weight (BW), assuming a body weight of 50 kg. Toxicity from large doses of preformed VA is a concern, especially after the deaths of children in India following a supplementation effort (10 ). In addition, the literature reports acute toxicity at intakes of 100 times the RDA, which is 70 and 90 mg retinol for women and men, respectively (11 ). Also of concern are recent observations that VA may interfere with the action of vitamin D and calcium absorption (12 ,13 ) and reports linking a high, chronic intake of preformed VA with increased hip fracture risk (14 –17 ).

Although VAD is a greater problem than toxicity, toxic effects from well-intentioned supplementation programs are undesirable. More research is required to determine safe and efficacious dosages, especially for lactating women, who may be able to conceive within weeks of parturition. If larger doses of VA provide marked improvement in stores of lactating women and nursing infants, the benefits may outweigh the potential of toxicity.

The pig is a good model for extrapolation to humans due to anatomic and physiologic similarity of the gastrointestinal tracts. The VA concentration of adult pig liver, 0.20–1.3 µmol/g, is close to that of humans (18 –21 ). In addition, the milk VA concentrations are similar (22 ,23 ). We therefore examined the VA concentration of milk from lactating sows that were provided two different doses of VA. We hypothesized that the two doses would result in significant differences in milk VA within 12 h of dosing. Subsequently, we used the data to predict the mean increase in VA liver reserves of breastfed infants from supplemented women for 48 h postdosing.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Animals and diet.

Approval for the experiment was obtained from the University of WI-Madison Research Animal Resources Center. Sows were housed at the Swine Research and Teaching Center (SRTC) in Arlington, WI, and the UW-Madison Livestock Laboratory. The sows, at 7–14 d of lactation, were a mix of purebreds and crossbreeds (Large White, Duroc and Landrace). Baseline characteristics and reproductive histories were obtained (Table 1 ). Before the experiment, pigs were fed a standard lactation diet (Table 2 ), which contained 5500 IU VA/kg. Approximately 12 h before dosing, the pigs were food restricted. Doses of retinyl acetate were dissolved in 4–5 mL of corn oil; 300-mg (1.05 mmol) and 600-mg (2.1 mmol) doses of retinyl acetate were provided to sows in each treatment group (n = 6/group) by mixing the oil with 500 g dry feed. The doses averaged slightly more VA/kg BW (4.7 and 9.4 µmol/kg) than is provided to lactating women to account for losses during feeding because food was invariably sloughed out of the trough. Each sow was observed to ascertain whether the meal was consumed. Three control sows were provided only corn oil.

At 1 h before collection, the nursing piglets were partitioned to ensure adequate milk. Milk was obtained by injecting the sow with 40 IU oxytocin, waiting for letdown, and manually expressing milk; 90 mL pooled fore- and hind-milk was considered adequate. Some of the milk was divided into 1-mL aliquots after collection to ensure sample homogeneity for analysis (24 ). Milk samples were collected at baseline, 1.5, 3, 6 and 12 h after dosing. In addition, 24- and 48-h samples were collected from four sows to help define the peak. Between 14 and 26 d postdosing, 2 controls and 3 sows from each group were killed to collect livers. All samples were placed on dry ice until taken to the laboratory for freezing at -80°C.

All analyses were conducted under yellow lights. Milk (0.5 mL) was placed into screw-top test tubes for saponification (24 ). 3,4-Didehydroretinyl acetate was used as internal standard. The samples were mixed with 0.75 mL ethanol (0.1% BHT) and vortexed; 0.40 mL KOH:H₂O (0.8 x volume) was added and kept at 45°C for 2 h with vortexing every 15 min. Samples were extracted with hexane (3 x 1 mL), vortexed and centrifuged at 1,380 x g for 30 s. The extracts were pooled, evaporated and reconstituted in 100 µL (50:50 methanol/dichloroethane). Then, 25 µL was injected into an HPLC, with the detector (SPD-10A UV-VIS; Shimadzu, Kyoto, Japan) set at 335 nm and the pump (110B; Beckman, Fullerton, CA) set at 1.2 mL/min. The column was a Phenomenex 15 cm, 5 µm, C-18 reversed-phase (Torrance, CA); the mobile phase was 89:11 methanol/water (0.1% triethylamine). A Shimadzu C-R7A was used to calculate peak areas.

Liver (500 mg) was ground with sodium sulfate and extracted with a total of 50 mL dichloromethane. Retinyl acetate was added to calculate extraction efficiency, and 500 µL was removed and dried with argon. The residue was reconstituted in 100 µL (50:50 methanol/dichloromethane) and 50 µL was injected onto the HPLC with a mobile phase of 82:18 acetonitrile/dichloroethane (0.1% triethylamine). The column was an Alltech 25 cm, C-18 reversed-phase column (Nicholasville, KY). The detector monitored at 325 nm and the pump was set at 1.0 mL/min. Hematoxylin and eosin staining of representative livers was done at histopathology, UW School of Veterinary Medicine.

Statistical analysis.

For the milk, a repeated-measures ANOVA with contrasts was applied, using SAS PROC MIXED (Version 8, SAS Institute, Cary, NC) to account for correlations among measurements within each sow. Baseline measurements were subtracted for each sow and the differences (plus a small constant) were log-transformed to stabilize the variance. Statistical evaluation of milk at the 24- and 48-h time points was precluded due to insufficient sample size. For the liver, a nonparametric Kruskal-Wallis test was used to test differences. Differences were considered significant with P < 0.05.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Total milk VA was determined at each collection and means calculated by group (Fig. 1 ). ANOVA revealed significant treatment (P = 0.0019) and time effects (P = 0.0001), and a borderline treatment-by-time interaction (P = 0.053). Tests for differences among VA treatments showed no evidence of an effect at 1.5 h (P = 0.61), marginal evidence at 3 h (P = 0.046) and strong evidence of difference at 6 and 12 h (P = 0.0014 and P < 0.0001, respectively). Interestingly, there was no difference between the high (HD) and low dose (LD) groups at any of the times at which an effect of treatment was found (P = 0.60 at 3 h; P = 0.57 at 6 h; and P = 0.14 at 12 h). At 12 h, milk VA concentration was 16 ± 0.2 and 30.0 ± 16 µmol/L for the LD and HD groups, respectively. At 24 h, milk total VA reached 18 µmol/L for the pigs given LD and 35 and 45 µmol/L for two pigs administered the HD. The variance in VA concentration was greatest in HD sows, especially at 6 and 12 h. This was in contrast with the low variance for the LD and control groups (Fig. 1) .

View larger version (23K): [in this window] [in a new window]   FIGURE 1 The time course of vitamin A concentrations in milk of lactating sows fed two different doses of retinyl ester shows no difference at baseline from control with an increase at 3 h and a peak between 12 and 24 h. *Different from control (P < 0.05) but not between dose groups. Values are means ± SD, n = 6 or 3 (controls). Some SD are not visible. Predicted values (–––) are based on 4 sows.

View larger version (103K): [in this window] [in a new window]   FIGURE 2 Liver histology of lactating sows provided either corn oil (left) or a vitamin A supplement (600 mg, right), viewed and photographed under 400X magnification. Neither liver shows hypertrophy and hyperplasia of Ito cells as expected in vitamin A toxicity.

Using data generated from the groups and 24- and 48-h values from 4 sows, we applied these data theoretically to humans. From the control group data, a nursing infant would consume 710 µg VA over 48 h from an unsupplemented mother (assuming an average milk intake of 700 mL/d). This would barely meet the infant’s needs, according to VA recommendations of the WHO (350 µg/d) and the U.S. (400–500 µg/d) (25 ). By dividing the mean concentration curves from the supplemented groups into 0.5-h intervals over 48 h and using an estimated intake of 14.6 mL/0.5 h (700 mL/d), our data suggest that during the 48 h immediately after the low or high dose, a nursing infant would consume 5250 or 10,750 µg VA, respectively. Assuming an infant weight of 3 kg, an estimated liver size of 120 g and a 50% hepatic storage factor for VA intake (26 ), an increase of 0.08 µmol/g for the LD and 0.16 µmol/g for the HD could be realized within 48 h. Therefore, the potential accrual and storage of VA by infants during this time could be sufficient to elevate their VA status from poor to adequate, which is defined as 0.07 µmol VA/g liver (27 ).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In this study, we evaluated the effects of a high dose of retinyl ester on VA concentrations in milk and liver of lactating sows. The doses provided, 1.05 and 2.1 mmol retinyl acetate, were calculated to emulate the 200,000 and 400,000 IU VA supplements provided to lactating women in developing countries on a BW basis (4.0 and 8.0 µmol/kg BW). The data presented here show that retinyl ester supplementation increased sows’ hepatic VA stores in a dose-dependent manner. Milk VA rose until 12–24 h, at which point it declined toward baseline. Although there was a treatment effect with both doses of VA compared with control, the difference in milk VA concentration between the two groups was not significant.

Considering that VAD is defined as 0.07 µmol/g liver (27 ), the LD, which could result in an increase of 0.08 µmol VA/g liver in an infant breastfed by a supplemented mother, appears effective in elevating liver status above deficiency, assuming optimal intake during the 48 h after dosing. However, the HD, if adequately absorbed, could provide an increase in infant hepatic stores of 0.16 µmol VA/g liver. This would appear to provide a buffer in the event of low dietary VA intake by the mother and/or illness in the infant causing rapid VA depletion (3 ,4 ). This assumes that other factors do not affect the infant’s intake or VA absorption during the 48 h postdosing when VA concentration is highest. If the infant was sick, for example, or did not otherwise consume an optimum volume of milk after the dose, his/her VA intake would be lower. Our data also suggest that some infants of mothers receiving the HD would not be able to achieve a level any higher than that in infants of mothers given the LD due to the lack of significant difference between the groups. The variance in milk data for sows administered the LD was small, i.e., 16 ± 0.2 µmol/L at 12 h. Thus, the sows uniformly absorbed the dose. However, the variance in the HD group was high, i.e., 30.0 ± 16 µmol/L, yielding no significant difference from the LD group. Therefore, it seems plausible that splitting the dose over 2 or 3 d would sustain enhanced milk VA for a longer time, further enhancing infant status.

Despite theoretical gains in milk VA, there are concerns about high dose supplements. First is the well-accepted risk of teratogenicity should a woman become pregnant while lactating when the dose is given in close proximity to conception (28 ,29 ). Although results of human studies on VA and its putative contribution to teratogenicity appear inconclusive (29 ), it would seem prudent to avoid extremely high doses of VA while there is a chance of pregnancy. As an alternative, it may be advisable to administer multiple doses during the 6 wk immediately after delivery or pursue a multifactorial approach that includes enhanced access to high VA foods as well as periodic supplementation (25 ).

Second, questions remain about the hepatic storage and release of VA and its availability for milk synthesis during times of low dietary intake. We found a dose-dependent increase in hepatic VA. Presumably, this enhanced liver reserve could be used for milk during periods of low VA intake. However, evidence suggests that VA-deficient animals accumulate hepatic VA less readily than VA-sufficient animals, such as the sows in this experiment, due to less cellular retinol binding protein (RBP) in stellate (VA storing) cells (30 ). Whether women whose VA status is marginal would be able to store VA as effectively as well-fed sows after a single high dose remains a question. Furthermore, although it has been generally assumed that liver VA stores are made equally available to peripheral tissues, derived from the retinol-RBP complex (31 ,32 ), the efficiency with which liver stores are mobilized to mammary tissue is unknown. Earlier, Vahlquist and Nilsson concluded that plasma RBP was the most important source of milk VA in rhesus monkeys (31 ). However, VA was injected intravenously, and the dietary intake was uniformly high (90,000 IU VA/d) throughout the study. The effect on milk of low dietary VA was not examined. More recently, chylomicron delivery of VA has been suggested as a primary contributor to milk (32 ,33 ), with higher milk concentrations of VA associated with higher intakes. Additionally, others have shown that the ester form as delivered by chylomicrons is more readily available for milk than is the alcohol form, such as that which follows endogenous mobilization of VA from liver (34 ). These observations suggest that dietary VA may be the most important contributor to milk and that liver stores are mobilized primarily to maintain serum levels.

Third, there is increasing acceptance for potential, long-term detrimental effects of preformed VA at much smaller doses than previously thought, e.g., 1.5–2 mg/d, specifically regarding bone density and hip fracture risk (14 –17 ). Although this may seem an unimportant consideration among a population whose intake of preformed VA is suboptimal, unintended detrimental consequences of supplementation should be avoided. If VA-deficient women do not store VA in the liver as effectively as those with higher intakes, as suggested earlier (30 ), then presumably there is more circulating retinol in serum after the intake of mega-doses. Higher circulating retinol could, in turn, interfere with the action of vitamin D (12 ), decreasing calcium absorption (13 ), or induce bone resorption by direct effects on bone osteoclasts and osteoblasts (35 ,36 ). For young women who may still be building bone mass, this potential disturbance in calcium absorption, coupled with the increased physiologic demands of pregnancy and lactation, should be examined more closely.

Important caveats of this study are that inadequate numbers of samples were collected beyond 12 h because we anticipated an earlier peak on the basis of chylomicron uptake. Also, the baseline nutriture of the sows used in this study was likely better than that of lactating women recipients of VA supplementation. Thus, further evaluation in women whose dietary intake of VA may not be as plentiful and whose health may otherwise be compromised due to infection or other micronutrient deficiencies (25 ) should be made. Finally, we report that one sow from each VA group died after receiving the dose. However, information available to us from the postmortem evaluation does not support a connection between the deaths and treatment. A more likely explanation is that the two sows had other health problems.

In conclusion, we observed no difference in milk VA concentration between the two groups and the increase was transient. Given this short window of opportunity for a nursing infant to obtain much needed VA, other supplementation strategies may be more beneficial, such as smaller doses provided to women over time, increased access to fortified foods and direct supplementation of infants. For example, the current practice in Ghana (37 ) of splitting the 400,000 IU dose over 2 d should increase infant liver stores by lengthening the time of exposure to enhanced VA in breast milk.

	ACKNOWLEDGMENTS

 
Tom Crenshaw, UW-Madison professor and director of SRTC, provided exceptional guidance and technical expertise. Kevin Gross, UW College of Agriculture Statistical Consulting Service, performed statistical calculations. Jordan Mills and Sara Augustine were valuable team members. Melissa Glenn and John Kane, SRTC staff, provided excellent support.

	FOOTNOTES

 
¹ Presented in part at Experimental Biology 2002, April 2002, New Orleans, LA [Penniston, K. L. & Tanumihardjo, S. A. (2002) Vitamin A profiles of serum and milk in supplemented lactating sows. FASEB J. 16: A744 (abs.).]

² Supported by Hatch-Wisconsin Agricultural Experiment station number WIS04389, the University of Wisconsin Graduate School, and National Institutes of Health grant DK61973–01.

⁴ Abbreviations used: BW, body weight; HD, high dose (600 mg retinyl acetate) group; LD, low dose (300 mg retinyl acetate) group; RBP, retinol binding protein; SRTC, Swine Research and Teaching Center; VA, vitamin A; VAD, vitamin A deficiency.

Manuscript received 11 October 2002. Initial review completed 15 November 2002. Revision accepted 18 December 2002.

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