Swine: Folic Acid

Various animal species differ markedly in their requirements for folic acid. The previous swine NRC (1988) publication suggests a dietary requirement of 0.3 mg per kg (0.14 mg per lb) for all classes of growing swine. However, based on new research information, the latest NRC (1998) recently increased their dietary folic acid requirement for gestating and lactating sows from 0.3 mg to 1.3 mg per kg (0.14 to 0.59 mg per lb).

Folic acid requirements for monogastric species would be dependent on degree of intestinal folic acid synthesis and utilization by the animal. Lutz and Stahly (1997) evaluated the folic acid requirement of high lean growth pigs (8.6 to 23 kg; 19 to 51 lbs body weight) and reported that 0.31 mg folic acid per kg (0.14 mg per lb) of feed was adequate to support optimal growth and body nutrient accretion. Animals that practice coprophagy, likewise, would have a lower dietary need for folic acid, as feces are a rich source of the vitamin (Abad and Gregory, 1987). It has been suggested that part of the pig's folic requirement could be met by coprophagy (Agricultural Research Council, 1981; McDowell, 2000); however, fecal ingestion has never been quantified in sows, but it is likely to be of minor importance since the folate status of pigs from five to 23 weeks of age remained similar regardless of whether or not access to feces was restricted (de Passille et al., 1989; Bilodeau et al., 1989). Additionally, increased use of flooring that reduces the animals' access to feces in commercial swine operations diminishes the importance of folic acid of fecal origin as a dietary source of the vitamin.

Even though deficiencies can be produced with special diets, it has generally been reported that corn, soybean meal and other common feedstuffs in a practical swine diet should provide ample folic acid under most conditions.

Self-synthesis of folic acid is dependent on dietary composition. For poultry, some research has indicated higher folic acid requirements for very high protein diets or when sucrose was the only source of carbohydrates (Scott et al., 1982). Keagy and Oace (1984) reported that dietary fiber had an effect on folic acid utilization; xylan, wheat bran and beans stimulated folic acid synthesis in the rat, reflected as higher fecal and liver folic acid. The levels of antibacterials added to the feed will affect microbial synthesis of folic acid. Sulfa drugs, which are commonly added to swine diets, are folic acid antagonists. In the chicken, sulfa drugs have been shown to increase the requirement (Scott et al., 1982) for this vitamin. Moldy feeds have also been shown to contain antagonists (i.e., mycotoxins) that inhibit microbial intestinal synthesis of folic acid in swine (Purser, 1981).

Folic acid requirements are dependent on the form in which it is fed and concentrations and interrelationships of other nutrients. Deficiencies of choline, vitamin B12, iron and vitamin C all have an effect on folic acid needs. Research by Johnson et al. (1950) revealed that baby pigs require both vitamin B12 and folic acid for hematopoiesis. Although most folic acid in feedstuffs for swine is present in the conjugated form, the young pig is fully capable of utilizing it. Folic acid requirements are related to type and level of production. The more rapid the growth or production rates, the greater the need for folic acid because of its role in nucleic acid synthesis. Given the rapid growth rate until weaning and the stressful and disruptive period immediately following weaning, Letendre et al. (1991) investigated whether folic acid injection to piglets might influence their folate status and growth performance. The authors concluded folic acid injections increase serum concentrations and hepatic reserves of folates. However, the effect on folate status was not associated with an increase in growth performance or an influence on hematologic indices in piglets from two to 10 weeks of age. Letendre et al. (1991) suggested that even though serum folates decrease following weaning of piglets, detrimental effects on growth performance are not apparent.

The folic acid content of feed ingredients commonly used in swine diets plus bacterial synthesis in the intestinal tract appears adequate to meet the needs of all classes of swine. However, numerous reports have shown the benefits of folic acid supplementation to increase fertility (Ensminger et al., 1951; Easter et al., 1983; Matte et al., 1984a, b; Tremblay et al., 1986; Lindemann and Kornegay, 1989; Tremblay et al., 1989; Matte et al., 1990a) and growth rate (Lindemann and Kornegay, 1986a) for swine consuming corn-soybean meal diets.

Folic acid deficiency in polytocous (giving birth to several offspring at one time) species such as the rat has been reported to decrease the weight of conceptuses, placentas, brain tissue and DNA concentration in the brain. Various researchers (Morgan and Winick, 1978; Thenen, 1979) have reported reduced litter size. Habibzadeh et al. (1986) reported that supplementation of folic acid to guinea pigs decreased embryo mortality and increased the number of live fetuses at 36 days of gestation.

Possible effects of folic acid on growth performance, attainment of puberty and reproductive capacity of gilts have been investigated (Matte et al., 1992). Long-term administration of folic acid did not affect age at puberty or reproductive capacity of gilts although there was some indication that 15 mg per kg of dietary folic acid influenced growth performance of gilts by the end of the growing period.

Tissue synthesis during gestation is both rapid and intense (Matte and Girard, 1990). An increased supply of nutrients, including folic acid, is essential for enhanced metabolism during gestation, including that required for growth and development of conceptuses and placental structures (Pond and Houpt, 1978) and increased uterine secretory activity. Harper et al. (1989) recently reported that the number of live fetuses and percentage of fetal survival increased with 2.0 mg supplemental folic acid per kg (0.91 mg per lb) of diet in gilts fed a corn-soybean meal diet. Fetal weight and length, placenta weight and length, empty uterine weight and amniotic and allantoic fluid volume, however, did not respond to folic acid supplementation.

Ensminger et al. (1951) observed that folic acid supplemented at the rate of 2.1 mg per kg (0.95 mg per lb) of diet improved reproductive performance in sows; no further improvement was noted with the addition of 211 mg per kg (96.0 mg per lb) PABA (a constituent of folic acid). Injection of folic acid at mating and nine days post-mating (Otel et al., 1972) was reported to have increased litter size from 8.3 to 10.0 pigs per litter. Easter et al. (1979; 1983) evaluated the addition of biotin, pyridoxine, thiamin and folic acid to corn-soybean meal gestating primiparous sow diets. Crossbred gilts received their respective treatment diets from three days post-mating until parturition, whereupon all gilts received a common lactation diet. Folic acid was supplemented to the basal diet at the rate of 0.2 mg per kg (0.09 mg per lb). Total pigs born per litter, pigs born alive per litter and pigs weaned per litter increased approximately 0.5 pig.

It has been shown that the folic acid requirement is elevated in pregnant women and that serum folates fluctuate during pregnancy. In humans, serum folates may reflect short-term dietary changes (Rothenberg et al., 1974). Matte et al. (1984a) measured post-weaning serum folate levels in sows throughout the reproductive cycle (weaning; mating; and day 15, day 30, day 60, day 90 and day 110 of gestation) to identify possible critical periods. These researchers observed a biphasic decrease in sow serum folate levels (Figure 1), first at mating and then at day 60 of gestation, suggestive of a possible mid-gestation folic acid deficiency. Natsuhori et al. (1994) compared the plasma concentrations of tetrahydrofolic acid (THF) versus N5-methyltetrahydrofolate (5MF) throughout the life cycle of pigs, including birth until two to four years of age and gestating and lactating sows. These authors indicated the principal component of plasma folates in newborn piglets is 5MF. However, the levels of 5MF dropped as the piglets nursed and grew, while the THF levels gradually increased. Conversely, during pregnancy, levels of THF declined while 5MF concentrations appeared to remain constant. They reported that during lactation THF levels increased but not to the same levels as were present before gestation. Their study verified the decrease in plasma folates during pregnancy. The authors indicated this decrease is mainly due to the decrease of THF concentrations and suggested the loss of maternal folate is a result of supply to fetuses via placenta. The decrease in serum folate concentration observed in normal human pregnancy (Hall et al., 1976) was suggested to be due to increased plasma volume; however, in sows the largest increase in plasma volume occurs during the last trimester of gestation.

Additionally, Matte et al. (1984b) and Matte and Girard (1989) reported that sow serum folate levels were responsive to intramuscular injection of 15 mg folic acid administered at weaning, first day of behavioral estrus, weekly during the first four weeks of gestation and every two weeks for the following eight weeks. This injection schedule maintained serum folate levels at day 60 of gestation, whereas folate concentrations decreased approximately 50% in sows that did not receive an injection. An improvement in reproductive performance (i.e., increased numbers of pigs born per litter and pigs born alive per litter) was observed in sows receiving the injectable folic acid compared with controls. This improvement was most pronounced for sows fed a flushing level (ad libitum intake) of feed compared with those fed a normal level of feed per day (1.8 kg or 4.0 lb) from weaning to mating and approximately the same to both groups thereafter. These results (Matte et al., 1984b) may suggest that folic acid was involved in a reduction of embryo mortality induced by a flushing treatment. Bazer et al. (1968) reported that flushing, although able to increase ovulation rate, is often associated with elevated embryo mortality with the subsequent benefit of prolificacy at parturition unrealized (Etienne et al., 1976). In another study utilizing injection of folic acid, when 25 mg was injected at the time of breeding and at one week later, the authors indicated that the benefits of folic acid were realized at a time when the sows' serum folate levels were low and the requirements for folic acid would be high for the rapidly developing embryos (Friendship and Wilson, 1991). If only parities 3 to 5 were analyzed, the litter size was improved by one pig per litter over that of the control sows.

Tremblay et al. (1986) observed that sow serum folate concentrations could be maintained by dietary folic acid to the same degree as those observed in sows injected with folic acid (Matte et al., 1984a). It was determined by regression analysis that about 4.3 mg supplemental folic acid per kg (1.95 mg per lb) of diet was necessary. Matte et al. (1990a) reported that sow serum folate concentration increased linearly when sows were supplemented with either 5 or 15 mg folic acid per kg (2.3 or 6.8 mg per lb) of diet. A level of 15 mg per kg (6.8 mg per lb) of dietary folic acid was necessary to maintain serum folate concentrations at eight weeks of gestation to those levels observed at mating. Additionally, litter size at weaning was greater in sows supplemented with 15 mg folic acid per kg (6.8 mg per lb) of diet.

Tremblay et al. (1989) reported that the addition of 5 mg folic acid per kg (2.3 mg per lb) of diet increased survival rate of fetuses during early gestation and tended to increase the number of fetuses presumably living at day 30 of gestation when associated with high ovulation rates. Sows were assigned at weaning to two levels of folic acid (0 or 5 mg per kg) and three treatments to stimulate ovulation (restricted feed intake, ad libitum feed intake or pregnant mare serum gonadotropin [PMSG] injection).

Pharazyn and Aherne (1987) reported that supplementation of 0.45 mg folic acid per kg (0.20 mg per lb) to a complex diet containing an estimated 0.45 mg folic acid per kg (0.20 mg per lb) fed solely from day 109 of gestation throughout lactation produced no difference in litter size or litter weights either at birth or at weaning at day 28. Similarly, Gannon and Leibholz (1988) reported no significant difference in litter size or birth weight of pigs from sows supplemented with 1.0 mg folic acid per kg (0.45 mg per lb) of diet. The supplemental folic acid was fed for six weeks before mating and throughout gestation. Lindemann and Kornegay (1989), however, reported an increase in pigs born and weaned and a possible improved conception rate in a three-parity study in which sows received either 0 or 1.0 mg supplemental folic acid per kg (0.45 mg per lb) of diet. An interaction between folic acid supplementation and parity was observed indicating that the response to folic acid may have increased with each successive parity, from parity one to three. This is in agreement with O'Connor et al. (1989) who suggested that 0.6 mg of folic acid per kg (0.28 mg per lb) of diet may be insufficient for gestating sows. Thaler et al. (1989) observed an increase in litter size at parturition following the addition of 1.7 or 6.6 mg of dietary folic acid per kg (0.77 or 3.0 mg per lb). These authors reported a much greater improvement in litter size at birth and day 21 for sows fed the lower level of folic acid during the course of this two-parity study; however, reproductive potential of sows was relatively low in this study (7.8 pigs per litter in control sows), possibly masking the effect of the higher supplementation level. In contrast, a large study involving five different universities failed to show a benefit in reproductive performance when folic acid was fed throughout gestation at levels up to 4 ppm (Harper et al., 1994). However, in a Fuchs et al. (1995) study, with litter size ranging from 10.2 to 11.2 pigs per litter and when 3 and 5 mg of folic acid per kg were supplied in the feed to pregnant sows, embryo mortality and the number of stillborn piglets were decreased. Matte et al. (1992) investigated the folic acid requirements of gestating and lactating gilts. As expected, during gestation and lactation, addition of folic acid increased concentrations of serum folate. Although numerically higher in gilts receiving 15 mg per kg, litter size at parturition and weaning was not affected by folic acid addition. Growth of piglets and total litter weight from birth to eight weeks of age increased linearly with the level of folic acid (0, 5 or 15 mg per kg) in the gestation diet. The authors concluded that 15 mg per kg of folic acid was necessary to avoid the drop in concentration of serum folate in gestating sows and influenced some performance traits such as total litter weight up to eight weeks post-parturition. There was no effect of folic acid supplementation during lactation on reproductive performance. However, supplementation during both gestation and lactation maximized piglet growth. The authors concluded that greater than 5 mg of folic acid is required for maximum sow reproductive performance but were not sure if 15 mg was too much or too little for reproducing swine.

Although the specific action of folic acid's involvement in enhancing various reproductive parameters is unknown, it has been suggested (Scherf and Scott, 1989) that folic acid may act through its influence on the transfer of single-carbon units, which is necessary for purine and pyrimidine base synthesis and hence nucleic acid synthesis. The rate of cell proliferation during fetal development is great and the concentration of intracellular ribonucleic acid is highly correlated with embryonic survival. Although number of live fetuses at day 45 + 3 of gestation was not affected by supplying 2 ppm of dietary supplemental folic acid, Harper et al. (1996) determined that fetal pig weight, length, protein and RNA content were increased over controls. The authors suggested that these effects, which took place by day 45 of gestation and are associated with placental and fetal growth, may promote improved litter size at birth. The response to folic acid supplementation on the RNA and DNA contents of 25-day embryos is influenced by the breed of sows studied (Guay et al., 1998).

Matte et al. (1986) have also suggested that folic acid may be involved with an embryo growth factor. Matte et al. (1993) indicated that maternal folic acid can be transferred to fetuses in utero. In addition, Matte et al. (1996) reported a significant increase in total uterine prostaglandin E2 (PGE2) on day 12 and day 15 and a numerical (60%) increase in PGF2 for sows fed 15 mg folic acid from two weeks prior to estrus through either 12 or 15 days after mating. Although a more precise mechanism remains to be elucidated, Matte et al. (1996) concluded that the influence of folic acid during early gestation appears to be partially related to modifying the uterine environment. In particular, folic acid may affect the exocrine secretions of prostaglandins, which may reduce the maternal immune response to conceptuses and improve their chances of survival. Giguere et al. (1999) reported that the frequency of sows having elevated allantoic PGE2 was higher in nulliparous sows that received 15 ppm of supplemental folic acid. For a more thorough discussion of the role of prostaglandins during gestation, see Bazer et al. (1991; 1992; 1994).

More research is needed to determine folic acid requirements for swine and the conditions that elicit the greatest response.

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