Role of vitamin E in pregnant women

BACKGROUND

Vitamin E is the term used for eight naturally occurring fat-soluble nutrients called tocopherols or tocotrienols, dependently of the chemical structure. alpha-Tocopherol is essential, has the highest biological activity and is found in all lipoprotein fractions and is associated with very-low-density lipoprotein (VLDL). Vitamin E is the most important lipid soluble antioxidant and deficiency during pregnancy may cause miscarriage, preterm birth, preeclampsia and intrauterine growth restriction (IUGR).

OBJECTIVE

This review highlights recent findings that have led to a better understanding of vitamin E absorption, transport, bioavailability and its role in pregnant women. This new information may be helpful for the evaluation of the potential benefits of vitamin E supplementation in pregnant women.

INTRODUCTION

There are eight forms of this lipophilic antioxidant: alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. With respect to tocopherols, although gamma-tocopherol is the major form of dietary vitamin E, alpha-tocopherol is the most important vitamin E form found in human plasma and tissues. The natural form of alpha-tocopherol is found in the RRR configuration and the synthetic alpha-tocopherol (all rac alpha-tocopherol) consists of an equal racemic mixture of the eight stereoisomer (RRR, RSR, RRS, RSS, SRR, SSR, SRS and SSS). The capacity to increase alpha-tocopherol concentrations in plasma is limited because alpha-tocopherol is replaced by newly absorbed alpha-tocopherol, the surplus being excreted in bile.

ORIGIN AND METABOLISM OF VITAMIN E

A. Intestinal absorption and plasma transport of vitamin E

The digestion of vitamin E in the small intestinal lumen is similar to that of dietary fats. Upon entering the circulation via the thoracic lymph, chylomicron triglycerides are hydrolysed by endothelium-bound lipoprotein lipase (LPL) resulting in the production of chylomicron remnants. At this point, fatty acids as well as some vitamin E molecules are then transferred to peripheral tissues. On the other hand, chylomicron remnants, carrying vitamin E, are then taken up by hepatic endocytosis. Within the liver, vitamin E is either excreted into the bile, metabolised to carboxyethyl-hydroxychroman (CEHC) and excreted into urine, or secreted back to plasma within VLDL.

B. Hepatic metabolism of vitamin E

Before secretion into the circulation via the VLDL pathway, the hepatic -tocopherol form of vitamin E is selected by the alpha-tocopherol transfer protein (alpha-TTP), a small cytoplasmic hepatic protein with differential affinity for vitamin E forms, and thus having the capacity of biodiscrimination. This protein is not only expressed in the liver but also in human brain and placenta.

C. Bioavailability

Bioavailability can be defined as the fraction of a food substance placed at the disposal of tissues after ingestion. This availability is essential for biological activity since only this fraction has a physiological activity. Vitamin E bioavailability depends also on its dispersion in the intestinal lumen and the co-ingestion of other fat components, namely fatty acids and plant sterols. Indeed, vitamin E bioavailability is greatest when administered with food. Some studies have observed that maternal vitamin E levels increased significantly during pregnancy despite the marked increase in plasma volume during pregnancy, suggesting that bioavailability may be increased in pregnant women.

D. Role of alpha-tocopherol

For many years, alpha-tocopherol has primarily been noted for its capacity to protect lipids and lipoproteins against peroxidative. However, alpha-tocopherol has other important biological functions, such as altering gene expression, modulating of cell signalling and proliferation. The alpha-tocopherol isoform of vitamin E inhibits radical chain propagation within lipid domains by its own conversion into an oxidized product, alpha-tocopherylquinone. It is increasingly clear that the balance between vitamin E and other antioxidants may be crucial for in vivo antioxidant protection. Indeed, the original form can be regenerated by reduction by ascorbate (vitamin C). Without this compound, alpha-tocopherol remains oxidized and is able to function as a pro-oxidant, i.e. it will able to oxidize lipoprotein. These observations do not contest a role for alpha-tocopherol as an antioxidant in vivo, given that, co-antioxidants such as ascorbate and ubiquinol-10, must be present in the vascular environment to convert alpha-tocopherol from a pro-oxidant into an antioxidant.

E. Role of gamma-tocopherol

gamma-Tocopherol can decrease platelet aggregation, delay time to occlusive thrombus, decrease arterial superoxide anion generation, lipid peroxidation and LDL oxidation, and increase endogenous SOD activity. gamma-Tocopherol and its metabolite also can reduce PGE2 synthesis, which plays a key role in inflammation. In addition, gamma-tocopherol is superior to alpha-tocopherol in controlling damage caused by reactive nitrogen oxide species and in reducing oxidative DNA damage.

F. Interactions between alpha- and gamma-tocopherol

After high-dose alpha-tocopherol administration, several studies have observed a decrease in gamma-tocopherol and during gamma-tocopherol administration, plasma concentration of alpha-tocopherol decreased significantly and urinary excretion of alpha-CEHC tended to increase.

VITAMIN E SUPPLEMENTATION

Vitamin E supplementation results in variable increases in plasma alpha-tocopherol concentrations. Such variations may result from differences in, alpha-TTP activity, metabolic rate, lipid content and composition, the status of other micronutrients that recycle alpha-tocopherol, and environmental conditions. Vitamin E supplementation has been reported to be safe for most adults in amounts less than 1600 IU and to prevent oxidative stress which is associated with many diseases such as injury, trauma, sepsis, ischemia, or severe inflammation. However, two studies have suggested that more than 400 IU/day of vitamin E may increase the risk of all-cause mortality and heart failure, whereas Bjelakovic et al have reported that antioxidant supplements for primary and secondary prevention of several diseases, including atherosclerosis, may increase mortality. On the other hand, Chappell et al reported that antioxidant supplementation in women who were at risk of preeclampsia was associated with improvement in biochemical indices of the disease.

VITAMIN E AND PREGNANCY

As an antioxidant, vitamin E contributes to limit oxidative stress but this vitamin is also an indispensable nutrient for reproduction. Indeed, female rats fed on a vitamin E free diet are sterile, and impaired fertility is also observed in animals lacking the alpha-TTP, suggesting that vitamin E may play an important role in human reproduction. Furthermore, it is suggested that alpha-TTP plays a major role in supplying the placenta and consecutively the foetus with alpha-tocopherol during pregnancy. During normal pregnancy, the plasma alpha-tocopherol concentration increases but in abnormal pregnancies, blood alpha-tocopherol concentrations are lower than those in normal pregnancies at a corresponding gestational age.

VITAMIN E SUPPLEMENTATION AND PREECLAMPSIA

Theoretically, supplements of vitamins C and E might prevent diseases such as preeclampsia because of their multiple actions in addition to prevention of lipid peroxidation. However, this effect has not been validated in clinical practice. While Chappell et al found some beneficial effects, Poston et al failed to confirm such a protective role of vitamin supplementation in a larger study. Furthermore, an increase in low birth weight babies was observed among pregnancies exposed to vitamin supplementation. Similarly, Beazley et al and Rumbold et al, no reduction in preeclampsia risk was noted with vitamin E supplementation. Rodrigo et al have suggested that the failure to observe a protective effect may be due to the fact that the initiation of the treatment was after the critical phase of placentation (14 and 22 weeks of gestation). Polyzos et al have concluded that the available evidence does support the use of combined vitamin C and E supplementation during pregnancy for the prevention of preeclampsia, whereas the safety of such supplementation vis-à-vis infant outcome is at least questionable. Differences in observations and conclusions may be due to the vitamin E bioavailability which differs between women or other factors such as the form of vitamin E used in supplementation. Indeed, when alpha-tocopherol administration increased, studies have observed a decrease in gamma-tocopherol and the later may be superior to alpha-tocopherol to controlling oxidation. Moreover, many studies have not determined vitamin E levels by HPLC analysis. Because vitamin E bioavailability change depending many factors and because we don’t really know if women took the pill everyday, it’s essential to measure the real plasmatic concentration of vitamin E before concluding.

NEW KNOWLEDGE AND CHALLENGES REMAIN TO BE ADDRESSED

While vitamin E is essential for reproduction, the optimal dose has not been determined. In order to study the effects of exposure to vitamin E, studies that correlate plasma and tissue levels to physiological indicators are required. It is possible that vitamin E supplementation would be necessary only when the bioavailability is decreased. Further research is needed for vitamin E supplementation either alone or in combination with supplements during pregnancy will be beneficial or not for the maternal and infant health. Several recent studies evaluating alpha-tocopherol supplementation have failed to show a protective effect and, in some studies, adverse effects were observed. Also, it has been noted that supplementation with alpha-tocopherol decreases the levels of gamma-tocopherol. Now that we know physiological effects associated with the gamma- form, it is suggest that the supplementation with alpha-tocopherol is not appropriate. Moreover, it is possible that alpha-tocopherol supplementation could result in pro-oxidant effects, especially if alpha-tocopherol concentration were already high. Further studies are required to answer these questions.

TRANSDISCIPLINARY APPROACH/TRANSFER KNOWLEDGE

This review will be very useful for scientists in several fields. Indeed, the biochemical aspect is discussed when the metabolism of vitamin E is explained. As for the clinical aspects, it will be very useful for health professionals which to know a little more about vitamin E supplements. Finally, the epidemiological aspect is very important because it allows us to make an analysis of previous studies to verify the efficiency of vitamin E and it permits to design further research. This review has been accepted for publication in the Journal of Obstetrics and Gynaecology Canada.

QUESTIONS
-What is your opinion about vitamin E supplementation in pregnant women?
-Do you have any ideas about future studies to be done to answer questions regarding the gamma-tocopherol form?