"Functional foods," "nutraceuticals," "designer foods" and "medical foods" are terms that describe foods, and key ingredients isolated from foods, that have non-nutritive or tertiary functional properties. Researchers, healthcare practitioners, laypersons, and the popular media use these words interchangeably. The purpose of this article is to detail valid scientific information available on key lipophilic compounds found in wheat germ and chlorophyll-rich foods that may help to prevent neonatal intracranial hemorrhage, spontaneous abortion and miscarriage in at-risk women.

Key lipophilic compounds in chlorophyll-rich foods and wheat germ may function to prevent neonatal intracranial hemorrhage, spontaneous abortion and miscarriage in at-risk women.

Chlorophyll-Rich Foods

Green vegetables such as spinach, buckwheat, and kale contain a significant amount of chlorophyll, a porphyrin that comprises the primary photoreceptor pigment of plant photosynthesis. Of particular interest with respect to women at risk for spontaneous blood loss and fetal/neonate hemorrhage are the lipophilic side-chains of chlorophyll. The complete chlorophyll molecule (Figure 1) is made up of four ligated pyrrole rings (tetrapyrrole) that encircle a centrally located atom of magnesium.(1)

The fourth ring is esterified and contains a lipophilic side chain made up of one of the simplest diterpene molecules, phytol. This fat soluble fraction of chlorophyll may prove beneficial for women at risk for hemorrhaging during pregnancy, as well as for preventing hemorrhagic disease of the newborn. It contains the vegetable-derived blood-clotting factor, phylloquinone (K1), found in the vitamin K complex. A Danish scientist discovered this antihemorrhagic factor in 1935 who observed that newly hatched chickens developed a hemorrhagic disease, despite receiving a diet that contained all the known essential nutrients. He found the disease to be connected to a fall in prothrombin, a required substance for normal clotting of the blood, and thus named the missed nutrient Vitamin K (for "koagulations vitamin").

Vitamin K occurs in three forms, K1, K2, and K3. Phylloquinone (K1) and the menaquinones (K2) are the naturally occurring forms of vitamin K. Phylloquinone is found in green leafy vegetables, tomatoes, meat, egg yolks, cow's milk, and vegetable oils. Intestinal bacteria synthesize menaquinones (K2) and menadione (K3) is a synthetic vitamin K analog. Until recently, vitamin K1 was considered a less-important vitamin because it was believed that bacteria in the gut could synthesize enough of the related vitamin K2, also referred to as menaquinone. Furthermore, because vitamin K is involved with blood clotting, excessive bleeding was thought to be the only result of deficiency. Now researchers have confirmed that an imbalance in the bacterial composition of the colon dramatically reduces the presence of vitamin K2 in the blood stream. This is primarily caused when there is a relative increase in harmful gut bacteria and the vitamin K-producing beneficial bacteria decrease resulting in a vitamin K deficiency.(2) Phylloquinone absorption in the intestine is facilitated by the presence of bile and pancreatic juices. If there is an absence of the necessary gastric secretions, this vitamin will not be carried to the liver for further processing. If there is an absence of the necessary gastric secretions, this vitamin will not be carried to the liver for further processing. Collectively, these factors demonstrate the importance of addressing gastrointestinal issues prior to conception.

Research on a Lipophilic Factor Found in Chlorophyll: Vitamin K

Research suggests that maternal vitamin K supplementation may be as effective in preventing neonatal hemorrhaging as the common practice of vitamin K prophylaxis at birth.(3) In a study of 383 pregnant women in Japan, vitamin K appeared to cross the placental barrier and protection from hemorrhage was significantly improved for infants in the treatment group versus controls up to at least the fifth day of life. Despite a biological half-life of 2.0-2.8 hours for vitamin K1, plasma levels of the vitamin in treated mothers and infants remained high for 7-10 days after prenatal supplementation, supporting the notion that the vitamin is stored in the body (most likely in the liver) for at least this length of time.

Prenatal maternal vitamin K1 treatment has several advantages over prophylaxis at birth:

• Nearly all early neonatal hemorrhagic diseases are preventable, including those that do not respond to prophylaxis.
• Administration is simplified and avoids intramuscular or subcutaneous injection of newborns.
• The incidence and degree of intracranial hemorrhage in premature infants at birth is reduced by prenatal administration of vitamin K1.

Recently, Di Cintio et al.(4) performed a hospital-based case-control study to examine the association between dietary habits and the risk of spontaneous abortion in pregnant women. They found a significant inverse relationship between risk and the consumption of fruits, green vegetables, cheese, milk, fish, and eggs. Many of these foods are rich in carotenoids, folate, and vitamins, particularly vitamin K. However, the mechanism of action for the effects of these food groups in preventing spontaneous abortion was not elucidated in the study. A positive association was found between spontaneous abortion and a diet poor in these constituents but rich in major fats (butter and oils). In addition, spontaneous abortion cases, on average, drank more alcohol and coffee prior to pregnancy.

Risk of Neonatal Intracranial Hemorrhage Due to Vitamin K Deficiency

Vitamin K deficiency usually occurs as a result of one of the following:

• Poor utilization
• The presence of vitamin K antagonists (anticoagulant and anticonvulsant drugs), or
• Inadequate intake or absorption (in restricted diets, parenteral nutrition, or biliary obstruction)

Deficiency is a concern in the initial days of infancy because healthy neonates typically have vitamin K-dependent coagulation factor activities only 30-60% of that of normal adults, making them prone to excessive bleeding, especially in the brain. The risk of intracranial hemorrhage due to lack of coagulation factors is particularly high for premature neonates, affecting 35% to 45% of all neonates weighing under 1500 grams and causing death or severe motor and sensory impairment in those affected.(5) Hemorrhage often results from the use of medications by the pregnant mother that interfere with vitamin K synthesis in the fetus.(6) Vitamin K supplementation by women in the latter part of pregnancy results in significantly improved prothrombin levels and prothrombin times for infants.(7,8) This suggests that maternal vitamin K supplementation and/or consumption of a diet rich in natural sources of vitamin K (chlorophyll-rich vegetables such as spinach, buckwheat, and kale) may be beneficial in preventing in tracranial hemorrhage in newborns.

Chlorophyll as an Antagonist of Guanidine

Chlorophyll is also an antagonist of guanidine. Guanidine is a toxin released into the blood as a result of burns, trauma (including pregnancy-associated trauma to the uterine lining), or muscle fatigue in a natural attempt to eliminate dead or defective cell clusters. This is a beneficial and natural phenomenon to the extent that it eliminates "bad" cells. However, a pregnant woman with a history of miscarriage and/or threatened abortion may be predisposed to producing an excess of guanidine that can ultimately cause more damage than repair.(9-12)

Wheat Germ

Wheat germ is high in polyunsaturated fatty acids and is a natural source of Vitamin E.(13) The lipophilic fraction of wheat germ is extracted by cold-pressing the seed embryo of wheat in a filter press.

Known Medicinal Constituents of the Lipophilic Fraction of Wheat Germ

• Fatty oils: 60-75% triacylglycerols, linoleic acid, oleic acid, palmitic acid, and linolenic acid
• Phospholipids
• Steroids: 2.5-3% sterol esters, particularly beta-sitosterol and campesterol
• Tocopherols: 0.2-0.3% vitamin E, as alpha- beta- and gamma-tocopherol, alpha-tocotrienol, and beta-tocotrienol

The vitamin E complex, as it occurs naturally in the lipophilic fraction of wheat germ, was originally discovered by Evans and Bishop in 1932. Until then, it had been known that some component in vegetable oils was necessary for reproduction in rats. The unidentified "antisterility" vitamin was named vitamin E. Incidentally, the chemical name tocopherol comes from the Greek words tokos meaning "offspring" and phero meaning "to bring forth." Unfortunately, human studies did not support this notion when an isolated tocopherol (d-a-tocopherol) from wheat germ oil was researched by Evans and Bishop. This is probably because the isolate did not contain the entire vitamin E complex necessary to support fertility.(14)

Preeclampsia, Oxidative Stress, and Wheat Germ Oil

Preeclampsia is a disease of pregnant women that occurs in 4-6% of all deliveries.(15) It is an important cause of morbidity and mortality in expecting mothers and is believed to be related to a hyperoxidative state in which uteroplacental and systemic blood pressure becomes extremely high. It is correlated with vascular endothelial damage and lipid peroxidation may be involved in the process.

Because the only known cure for preeclampsia is delivery, women with preeclampsia typically miscarry or deliver prematurely and have lower birthweight babies than women without the disorder.(15) Thus, any therapeutic protocol that reduces the incidence of the disease would be beneficial in preserving maternal and fetal health and reducing health care requirements during pregnancy.

Free radicals likely play a major role in the maternal vascular dysfunction associated with preeclampsia and foods naturally high in free radical scavengers may prove essential for preventing or reducing its occurrence. The level of free fatty acids (FFAs) in the blood is significantly higher in women with recurring miscarriages.(16,17) The relative increase in FFAs in the blood may be the result of a continuous discharge of catecholamines from autonomic nerve endings (a natural response to stress) that can also cause strong uterine vasoconstriction and placental isehemia, leading to symptoms of preeclampsia and eventual miscarriage. Further, abnormal catecholamine discharge causes a relative increase in reactive oxygen species, which can result in DNA damage and peroxidation of FFAs.(18,19)

The fat-soluble compounds naturally occurring in wheat germ suppress oxidative DNA damage that can contribute to abnormal uterine growth. Essentially, these compounds function to re-establish antioxidant levels in the blood that have been compromised due to stress-dependent catecholamine discharge.(20-22)

Research on a Lipophilic Factor Found in Wheat Germ: Vitamin E

Gratacos et al.(23) explored the relationship of plasma vitamin E and circulating and placental levels of lipid peroxides to chronic hypertension and preeclampsia during pregnancy in 36 healthy pregnant women, 34 previously healthy pregnant women diagnosed with preeclampsia, 20 pregnant women with uncomplicated chronic hypertension, and 11 pregnant women with chronic hypertension complicated by superimposed preeclampsia.

In women with primary and superimposed preeclampsia, lipid peroxides in serum and placental tissue were significantly increased and vitamin E levels in serum were significantly decreased, relative to controls (Table 1). Women with uncomplicated hypertension did not differ from controls on these criteria. As expected, preeclamptic women delivered earlier and had lower birthweight babies than controls and chronically hypertensive women (without preeclampsia).

Table 1

Plasma lipoperoxide and vitamin E levels in normal pregnant women versus pregnant women with preeclampsia, superimposed preeclampsia, or uncomplicated chronic hypertension.(23)

	Control (n=36)	Preeclampsia (n=34)
Lipid peroxide (nmol/L)	5.5[+ or -]0.8	7.1[+ or -]2.01
Vitamin E (mg/mL)	38.1[+ or -]9.1	32.11
Ratio of vitamin E/cholesterol	14.8[+ or -]3.4	13.1[+ or -]1.92
	Chronic Hypertension (n=20)	Superimposed Preeclampsia (n=11)
Lipid peroxide (nmol/L)	5.9[+ or -]0.9	7.6[+ or -]2.31
Vitamin E (mg/mL)	41.3[+ or -]8.1	29.2[+ or -]5.11
Ratio of vitamin E/cholesterol	15.1[+ or -]5.0	11.9[+ or -]1.73

1. p<0.001  2. p<0.05  3. p<0.01

These results support a role for lipid peroxides in the pathophysiology of preeclampsia that may be associated with reduced levels of circulating vitamin E.

In a large, double-blind, randomized, placebo-controlled trial, 283 pregnant women (160 in completed-study cohort) identified as being at increased risk for preeclampsia were randomly assigned to receive either vitamin C (1000 mg/day) and vitamin B (400 IU/day), or placebo from 16-22 weeks of gestation.(20) Every month until delivery, the women were tested for plasma markers of endothelial activation and placental dysfunction. Preeclampsia was indicated by the development of proteinuric hypertension. Based on intention-to-treat of the entire sample, preeclampsia occurred in 24(17%) of 142 women receiving placebo, but in only 11(8%) of 141 women in the vitamin group (p=0.02). This result was more pronounced in the sample that completed the study: 21 of 81 (26%) in the placebo group vs. 6 of 79 (8%) in the supplemental group. In those who completed the study (at successful delivery), the odds ratio for preeclampsia was 0.24 (0.08-0.70; p=0.002) for the supplemented group. With vitamin treatment, plasma ascorbi c acid concentration increased by 32% from baseline and plasma a-tocopherol increased by 54% from baseline. At 36 weeks gestation, plasma concentrations of these antioxidants were 34% and 41% higher, respectively, in the supplemented group versus the placebo group. Chapell's group also found that vitamin E significantly reduced endothelial cell activation and placental insufficiency in preeclamptic women. In this study, the vitamin E was from a natural source, in a form that appears to be particularly bioavailable, as the placenta delivers it much more efficiently to the fetus than it does the synthetic form.

More recently, similar results were obtained by Kharb(19) who examined 30 normotensive and 30 preeclamptic pregnant women for plasma levels of vitamins C and E. Compared to controls, the preeclamptic women had significantly lower plasma levels of vitamin C and vitamin E. This study concluded that consuming these vitamins, as supplements or as they naturally occur in whole foods, will attenuate free radical-mediated disturbances. Interestingly, it has also been shown that decreased glutathione levels are also associated with preeclampsia.(24,25)

Final thoughts about the use of chlorophyll-rich foods and wheat germ to prevent complications of pregnancy

General nutritional and herbal support to maintain hormonal balance and nourish female reproductive organs may prove helpful when managing a patient at risk of hemorrhage, threatened abortion and/or miscarriage. Before considering any herbal and/or nutritional protocol for these health challenges, the practitioner must rule out and/or address the following conditions:

• Balanced chromosomal translocations in the parents
• Uterine and cervical anomalies
• Infection
• Connective tissue disorders
• Hormonal abnormalities

When working with a patient with a history of miscarriage using complementary nutritional and herbal support, it is essential to do so at least 3 months before conception.(26) Additionally, it is essential that the practitioner address gastrointestinal and liver function to improve bioavailability of fat-soluble vitamins.

Summary

Lipophilic Factors in Chlorophyll:

• Supply blood-clotting factors to prevent abortion in women and hemorrhage in neonates
• Prevent toxicity reactions associated with miscarriage by functioning as antagonists to guanidine
• Maintain vascular integrity

Lipophilic Factors in Wheat Germ:

• Improve oxygen transport to maternal tissues
• Reduce endothelial activation and placental dysfunction
• Replace antioxidant-loss due to excess lipid peroxidation / free fatty acid production caused by stress-induced catecholamine response associated with uterine vasoconstriction
• Prevent preeclampsia in "at risk" women

Recommended Dosages

• Chlorophyll-rich foods: 6 servings of organic green vegetables (examples: spinach, kale, buckwheat and juiced wheatgrass) per day. Begin at least 3 months prior to attempts at conception if possible.
• Wheat germ oil: 1 tablespoon, 3 times per day.

Drug/Nutrient Interactions, Nutrient/Nutrient Interactions, and Drug/Nutrient Depletions

• Lipase-inhibiting drugs such as orilstat, used to manage obesity, act by inhibiting fat absorption. Thus, they may inhibit the absorption of key nutrient factors found in chlorophyll and wheat germ and supplementation of these essential nutrients may be required.(27-29)
• Mineral Oil can inhibit the absorption of the fat-soluble fractions of chlorophyll and wheat germ.(30)
• Warfarin is a coumarin anticoagulant drug that acts by inhibiting the synthesis of vitamin K dependant clotting factors. Hence, supplementation with vitamin K, or a diet high in vitamin K will impact the effects of this and related medications and may affect the required dosage range for treatment. Monitor a client's PT/INR closely if introducing the fat-soluble fraction of chlorophyll into the protocol. (31,32)
• Antibiotics alter intestinal microflora that produce vitamin K2. Hence, antibiotic use may reduce the body's supply of the vitamin K complex. Supplementation with chlorophyll may be necessary.(33)
• Anticonvulsant medications such as phenytoin, fosphenytoin, and barbiturates have been shown to increase the degradation of vitamin K through oxidation, resulting in potential bleeding complications. Supplementation with chlorophyll may prove beneficial by increasing the availability of clotting factors in the blood.(34,35)
• Cholestyramine and colestipol are examples of bile acid sequestrants that have been shown to inhibit the absorption of the fat-soluble fractions of chlorophyll and wheat germ.(36)
• Fenofibrate and clofibrate may result in a significant decrease in the amount of vitamin E available in the liver due to their ability to increase the production of hydrogen peroxide in the body.(37)
• Gemfibrozil can result in a 40% decline in serum vitamin E levels in hypercholesterolemic men.(38)
• Chitosan may reduce the absorption of key lipophilic compounds found in chlorophyll and wheat germ.(39)
• High intake of polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6 fatty acids, can result in excess lipid peroxidation, which may be prevented with supplementation of wheat germ oil.(40)
• Haloperidol may cause a depletion of vitamin E factors due to its effect on monoamine metabolism.(41)

© COPYRIGHT 2006 Dr. Gina L. Nick

References

1. Wettstein, D. est al. 1995. Chlorophyll biosynthesis. The Plant Cell 7: 1027-1038.
2. Igarashi, O. 1993. Vitamin K. Nippon Rinsho 51(4): 910-918.
3. Takanobu, A. et al. 1993. Can prenatal vitamin K1 (phylloquinone) supplementation replace prophylaxis at birth? Obstet Gynecol 81(2): 251-254.
4. Di Cinito E. et al. 2001. Dietary factors and risk of spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 95(1): 132-136.
5. Morales, W. J. et al. 1988. The use of antenatal vitamin K in the prevention of early neonatal intraventricular hemorrhage. Am J Obstet Gynecol 159(3): 774-779.
6. Thorp. J. A. et al., 1995. Current concepts and controversies in the use of vitamin K. Drugs 49(3): 376-387.
7. Owen, G. M. et al. 1967. Use of vitamin K1 in pregnancy. Am J Obstet Gynecol 99: 368-373.
8. Deblay, M. F. et al. 1982. Transplacental vitamin K prevents hemorrhagic disease of infant of epileptic mother. Lancet 1: 1247.
9. Rairigh RL, et al. 2001. Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus. Circ Res 13;88(7):721-6.
10. Nakatsuka M, et al. 2000. Nafamostat mesilate. a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts. Life Sci 67(10):1243-50.
11. Farina M, et a]. 2000. IL lalpha augments prostaglandin synthesis in pregnant rat uteri by a nitric oxide mediated mechanism. Prostaglandins Leukot Essent Fatty Acids 62(4):243-7.
12. Athanassakis, I. et al. 1999. Inhibition of nitric oxide production rescues LPS-induced fetal abortion in mice. Nitric Oxide 3(3): 210-224.
13. Fleming, T. (Ed.). 2000. PDR for Herbal Medicines, 2nd ed. Montvale, NJ: Medical Economics Company. 656-657.
14. Kotarski, J. 1979. The vitamin E concentration in the trophoblast and blood serum of women in the course of an abortion. Ann Univ Mariae Curie Sklodowska 34: 403-413.
15. Poston, L. and L. C. Chappell. 2001. Is oxidative stress involved in the aetiology of preeclampsia? Acta paediatr Suppl 90(436): 3-5.
16. Nicotra, M. et al, 1994. Blood levels of lipids, lipoperoxides, vitamin E and glutathione peroxidase in women with habitual abortion. Gynecol Obstet Invest 38(4): 223-226.
17. Svetlova, K. et al. 1971. Some clinical-physiological indices in children born of mothers with habitual abortion. Vopr Okkr Materin Vet 16(5): 64-70.
18. Simsek, M. et al. 1998. Blood plasma levels of lipoperoxides, glutathione peroxidase, beta carotene, vitamin A and E in women with habitual abortion. Cell Biochem Funct. 16(4): 227-231.
19. Kharb, S. 2000a. Vitamin E and C in preeclampsia. Eur J Obstet Gynecol Reprod Biol 93(1): 37-39.
20. Chappell, L. C. et al, 1999. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial. Lancet 334(9181): 810.816.
21. Kukushkina IP, Dmitrieva NV. 1991 Evaluation of the effect of vitamin E on the fetus and newborn baby. Pediatriia (5):13-6
22. Davidov LIa, et al. 1979. Content of vitamin S in blood and estriol excretion in women with threatened abortion. Pediatr Ginckol. 1:33-5.
23. Gratacas, M.D. et al. 1999. Serum and placental lipid peroxides in chronic hypertension during pregnancy with and without superimposed preeclampsia. Hypertens Pregnancy 18(2): 139-146.
24. Knapen, M. F. et al. 1998. Low whole blood glutathione levels in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets syndrome. Obstet Gynecol 92(6): 1012-1015.
25. Kharb, S. et al. 2000b. Superoxide anion formation and glutathione levels in patients with preeclampsia. Gynecol Obstet Invest 49(1): 28-30.
26. Veal L.1998. Complementary therapy and infertility: an Icelandic perspective. Complement Ther Nurs Midwifery 4(1):3-6.
27. Heck, A. M. et al. 2000. Orlistat: A new lipase inhibitor for the management of obesity. Pharmacotherapy 20(3): 270-279.
28. Finer, N. et al. 2000. One-year treatment of obesity: A randomized double-blind, placebo-controlled, multicentre study of Orlistat, a gastrointestinal lipase inhibitor. lot J Obey Relat Metab Disord 24(3): 306-313.
29. Melia, A. T. et a]. 1996. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol 36(7): 647-653.
30. Becker G. L. 1952. The Case Against Mineral Oil. Am J Dig Dis 19: 344.
31. Bell, H. G. 1978. Metabolism of Vitamin K and Prothrombin Synthesis: Anticeagulants and the Vitamin K-Expoxide Cycle. Fed Proc 37(12): 2599-2604.
32. DuPont Pharma. 2001. Coumadin (warfariis): Product Prescribing Information. Wilmington, Delaware: Dupont Pharma Corp.
33. Cummings, J. H. et al. 1997. Role of intestinal bacteria in nutrient metabolism. J Parenter Enteral Nutr 21(6): 357-365.
34. Keith, D. A. and P. M. Gallop. 1979. Phenytoin, Hemorrhage, Skeletal Defects and Vitamin K in the Newborn. Med Hypotheses 5(12): 1347-1351.
35. Keith, D.A. et al. 1983. Vitamin K-dependent Proteins and Anticonvulsant Medication, Clin Pharmacot Ther 34(4): 529-532.
36. Knodel, L. C. at al. 1987. Adverse Effects of Hypolipidoemic Drugs. Med Toxicol 2(1): 10-32.
37. Lores Arnaiz, S. at al. 1997. Chemiluminescence and Antioxidant Levels During Peroxisome Proliferation by Fenotibrate. Bieelsim Biaphys Acfa 1360(3): 222-228.
38. Aberg, F. at al. 1998. Gemflbrozil-induced Decrease in Serum Ubiquinone and Alpha- and Gamma-tocopherol Levels in Men with Combined Hyperlipidaentia. Eur J Clin Invest 28(3): 235-242.
39. Deuchi, K. at al. 1995. Continuous and Massive Intake of Chitesan Affects Mineral and Fat-soluble Vitamin Status in Rats Fed On a High-fat Diet. Biosci Biotechnol Biochem 59(7): 1211-1216.
40. Weber, P. at al. 1997. Vitamin E and human health: rationale for determining recommended intake levels. Nutrition 13(5): 450-460.
41. Von Voigtlander, P. F. at al. 1990. Effects of Chronic Haloperidol on Vitamin E Levels and Monoamine Metabolism in Rats Fed Normal and Vitamin H Deficient Diets. Res Cammun Chem Pathol Pharmacol 68(3): 343-352.