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Nutritional suppliments in obstetrics and Gynaecology

    

Various nutritional supplements are today being studied in the management of a variety of conditions, like infertility, recurrent abortions, and pre-eclampsia. Controlled studies are not available about the efficacy of many of these products. They are marketed by various pharmaceutical companies, promising dramatic improvement. The dose of many of these nutritional supplements is still not known/standardized, as studies to prove their efficacy are still going on. What follows is an overview of the various nutritional supplements used in the field of Obstetrics and Gynaecology.
 

                                                                                        Anti-oxidants


Antioxidants are broadly substances which reduce the oxidative damage caused by reactive oxygen species, which are free radicals. Free radicals are molecules or atoms that contain unpaired electrons. These are extremely unstable and will almost instantly capture electrons from nearby molecules, destabilizing them. Free radicals are formed naturally in the body during metabolism.
Reactive oxygen species (ROS) are highly reactive oxidizing agents belonging to the class of free radicals. Free radicals are molecules or atoms that contain unpaired electrons. These are extremely unstable and will almost instantly capture electrons from nearby molecules, destabilizing them. They are formed naturally in the body during metabolism.
Free radicals in the form of ROS can modify cell functions; endanger cell survival, or both. Hence, ROS must be inactivated continuously to maintain only the small amount necessary to maintain normal cell function. Free radicals could have the following implications in the field of obstetrics and gynaecology:
1. The production of excessive amounts of ROS in semen can overwhelm the antioxidant defense mechanisms of spermatozoa and seminal plasma causing oxidative stress.
2. Preeclampsia has been associated with increases in lipid peroxidation and decreased concentrations of circulating antioxidants.
3. Reactive oxygen species (ROS) have been implicated in diabetic embryopathy.
4. Oxidative damage has been implicated in preterm premature rupture of membranes (PPROM).
5. Increases in oxidative stress have been associated with intrauterine growth restriction (IUGR).
6. A sharp peak in the expression of the markers of oxidative stress in the trophoblast was detected in normal pregnancies and this oxidative burst if excessive was speculated as a cause of early pregnancy loss.
Antioxidants are a broad group of compounds that destroy free radicals, in the body, thereby protecting against oxidative damage to cells.  Types of anti-oxidants:
While vitamins A, C, and E have been recognized for a long time for their antioxidant properties, there are others such as zinc, selenium, and bioflavonoids which directly or indirectly serve as free radical scavengers.

 

                                                                                     Vitamins E & C


Vitamin E, discovered in 1922, is the name given to a group of naturally occurring lipid-soluble antioxidants, the tocopherols and the tocotrienols, that are found in certain plant oils31. Vitamin E is the major, if not the only, chain-breaking antioxidant in membranes. The recommended dose of Vitamin E in human pregnancy is 22–30 mg/day.
In Preecclampsia: Two large, prospective, randomized trials involving more than 4000 low and high-risk subjects, respectively, compared vitamin C/E to placebo. There were no differences noted in the frequency of preeclampsia between groups 3. High doses of vitamin C(>500mg) and high doses of vitamin E(>400IU) have been known to be detrimental to pregnancy1.
In a randomized controlled study of 81 women who were at high risk for developing preeclampsia ( Women were identified as “at-risk” by a history of preeclampsia that required delivery before 37 weeks of gestation in the preceding pregnancy or by abnormal uterine artery Doppler FVW (resistance index of >=95th percentile for gestation or the presence of an early diastolic notch at 20 weeks of gestation)and who were taking vitamin C 1000mg and Vitamin E 400mg, Chapel LC et al concluded that administration of vitamin C and E from 16-22 weeks of pregnancy , was beneficial in preventing preeclampsia. However, in a similar study on1977 woman, In the Australian Collaborative Trial of Supplements (ACTS), did not find any difference between women who were treated with vitamins C & E and those who were not. The results of these 2 workers using vitamin E in the dose of 400mg and Vitamin C in the dose of 1000mg in preventing preeclampsia in high risk populations have conflicting results. However, the Indian gynaecologist would do well to note the dose of the vitamins used by these workers to achieve their ends. India also may boast of higher number of susceptible populations compared to our western counterparts. If any gynaecologist wants to try out these vitamins to prevent preeclampsia, they should probably be used in the same dose that these workers have used. It should also be remembered that vitamin E which was considered an innocuous drug so far should not be used in very high doses for long periods of time.

The results of these 2 workers using vitamin E in the dose of 400mg and Vitamin C in the dose of 1000mg in preventing preeclampsia in high risk populations have conflicting results. However, the Indian gynaecologist would do well to note the dose of the vitamins used by these workers to achieve their ends. India also may boast of higher number of susceptible populations compared to our western counterparts. If any gynaecologist wants to try out these vitamins to prevent preeclampsia, they should probably be used in the same dose that these workers have used. It should also be remembered that vitamin E which was considered an innocuous drug so far should not be used in very high doses for long periods of time.

In Male infertility: Rolf et al performed a placebo controlled, double-blind study of high dose oral vitamins C(1000mg) and E(800mg) for 56 days in 31 infertile men with asthenozoospermia and a normal or only moderately decreased sperm concentration25. They concluded that combined high-dose antioxidative treatment with vitamins C and E did not improve conventional semen parameters or the 24-h sperm survival rate.
Since vitamin C and E in very high doses have been shown to have little or no effect on oligoasthenospermia, it probably is of no use in male infertility and certainly there may be no rationale in increasing the cost of a tablet by incorporating vitamin E or C in it in small doses with the hope of enhancing the role of the primary drug.

Female infertility: As oxidative stress results in luteolysis, antioxidant supplementation, for example vitamin C and vitamin E, has been shown to have beneficial effects in preventing luteal phase deficiency and resultant increased pregnancy rate and others have reported no value. Improved pregnancy rates were also reported with combination therapy with the antioxidants pentoxifylline and vitamin-E supplementation for 6 months in patients with thin endometria who were undergoing IVF with oocyte donation.


                                                                                        Zinc


Dietary studies typically estimate usual zinc intakes of pregnant women throughout the world to range from 5 to 15 mg/day, compared with a 1989 US Recommended Dietary Allowance of 15 mg/day during pregnancy2. Severe maternal zinc deficiency is associated with infertility, spontaneous abortion, and congenital malformations, including neural tube defects. Maternal zinc deficiency has been associated with low-birth-weight (LBW), intrauterine growth retardation (IUGR), and preterm delivery.
Daily zinc supplementation in women with relatively low plasma zinc concentrations in early pregnancy is associated with greater infant birth weights and head circumferences, with the effect occurring predominantly in women with a body mass index less than 26 kg/m2.8 However, Mahomed in a systematic review of 7 trials found no difference on small for gestational age fetuses (SGA) between the group receiving zinc and the placebo group. Similarly, there was no difference between groups on low birth weight LBW30. Thus routine zinc supplementation in pregnancy is not advocated. In zinc deficient women, it may be of use.
Male infertility:
Zinc in the dose of 66mg along with folic acid 5mg per day, was shown to increase sperm count in a randomized controlled study. The mode of action is not known, as hormone parameters were not altered. Biological zinc administration was shown to improve sperm count in patients with chronic prostatitis in another study.

Thus, zinc in the dose mentioned could be used as an adjunct along with other antioxidants in subfertile men.


                                                                                     Selenium


Selenium is important in the role of glutathione peroxidase pathway to remove damaged cellular peroxidases, hence antioxidant activity. Serum selenium concentrations are reduced in women with preeclampsia compared with normotensive pregnant controls. A group from Beijing randomized 52 women at high risk for developing preeclampsia to receive 1000 µg per day of liquid selenium or placebo for 6 to 8 weeks during late gestation. There was a decreased incidence of pregnancy-induced hypertension from 22.7% to 7.7% in the treatment group.
Male infertility: Scott et al concluded in a double blind placebo controlled study that men with low sperm motility could improve their sperm motility with selenium in the dose of 100umg/day or selenium with vitaminA1mg, with vitaminC10mg with vitaminD15mg for 3 months.
Thus selenium, in the dose of 1000umg/day in pregnant women at high risk for preeclampsia and in the dose of 100umg in male infertility could be useful . There are no studies on whether incorporating selenium in smaller doses in multivitamin tablets will achieve the same effect.

                                                                               
           Fatty acids
                                                                                      Omega-3 fatty acids

Omega-3 fatty acids are essential polyunsaturated fatty acids (PUFA) necessary for human health, but are not made by the body and hence must be obtained from a person’s food. Docasohexanoic acid and Ecisopentanoic acid are two types of Omega-3 fatty acids. Omega-3 fatty acids are found primarily in cold-water fish (salmon, herring, and mackerel) and several nuts and seeds.
These essential fatty acids and their metabolites are important in cervical maturation, parturition, initiation of labour, rupture of membranes, and birth. If there are low levels of omega-3 fatty acids and high levels of omega-6 fatty acids, there is an increased incidence of inflammatory prostaglandins, which are associated with preterm labor and intrauterine growth retardation32. Three randomized placebo-controlled clinical trials supplemented with either 920 mg of DHA and 1.3 g of EPA per day (total n-3 fatty acid intake of 2.7 g per day) or DHA-enriched eggs (205 mg of DHA per day without any EPA), found fewer low-birth-weight infants (LBW), preterm infants, and, in the trial using eggs, fewer women with gestational diabetes.
Recommendations on DHA intake27:
DHA is recommended in the following doses by various organizations.
International society for the study of fats and lipids(ISSFAL): Adequate intake to be at least 300mg per day for pregnant and lactating women.
Committee on Medical Aspects of Food Policy (COMA): 1.5g EPA plus DHA per week (i.e. 214mg per day)
British Nutrition Foundation (BNF): 8g EPA plus DHA per week for women (i.e. 1145mg per day)
Expert Workshop of the European Academy of Nutrition Sciences held in 1997(EANS): 200mg EPA plus DHA daily.
Supplementation with Omega 3 fatty acids in pregnancy has also been shown to increase IQ and visual acuity in the offspring in a few studies. It is a moot point whether higher IQ is directly proportional to increased productivity in life. This is an era where emotional quotient is considered as important as intelligence quotient for success in life. Thus it has to be debated whether all pregnant women should routinely be supplemented with omega 3 fatty acids. In light of the placebo controlled studies using 920 mg of DHA and 1.3 g of EPA per day finding lower incidence of preeclampsia and low birth weight babies, omega 3 fatty acids could be used in susceptible women towards this end. However most organizations recommend 200-300 mg DHA and EPA per day.

                                                                                         
   Amino acids
                                                                                                  Arginine
Arginine is an essential amino acid and plays an important role in cell division, the healing of wounds, removing ammonia from the body, inimmune function, and the release of hormones.
It is the immediate precursor of nitric oxide. It has been found to improve uteroplacental blood flow because of its vasodilating effect.

Preeclampsia and IUGR:
Sieroszewski and colleagues in an ultrasound evaluation of the efficacy of L-arginine as a therapy for growth retardation found that the group treated with L-arginine 3g daily orally for 20 days had only 29% women with retarded babies as compared to 73% in the untreated group.
Some investigators have proposed the use of the nitric oxide test to identify pregnancies with Foetal growth restriction. The test consists of giving the mother 0.3 mg of glyceryl nitrate sublingually and then evaluating the uterine artery by Doppler velocimetry. Positive tests would select women who may benefit from treatment with nitric oxide donor agents like Arginine.
The average Indian practitioner may desist from performing too many tests on a patient and may benefit from supplementing a woman with Arginine in indicated cases where there is a bad obstetric history,uterine artery notching at 20 weeks or oligohydramnios and features of IUGR, etc. It is available in 3gm satchets. If it is given all at once in the day it can cause nausea. It should be given in 3 divided doses. Some patients find it difficult to tolerate even in divided doses.


Infertility:
Arginine by it’s’ vasodilating effect was found to improve endometrial flow and thereby increase the successful rate of implantation of embryos in ART cycles. Battaglia et al concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate28.
However, in a later study,Battaglia et al evaluating the role of L-arginine supplementation in controlled ovarian hyper stimulation, concluded that Arginine supplementation may be detrimental to embryo quality and pregnancy rate during controlled ovarian hyper stimulation cycles. In this study , arginine was used in very high doses (8gm/day) and we do not know if it is this high dose which caused the detrimental effect.
Arginine is found in chocolate, wheat germ and flour, buckwheat, granola, oatmeal, dairy products (cottage cheese (Paneer), ricotta, nonfat dry milk, skim yogurt), beef , pork , nuts (coconut, pecans, cashews, walnuts, almonds, Brazil nuts, hazel nuts, peanuts), seeds (pumpkin, sesame, sunflower), poultry, seafood (halibut, lobster, salmon, shrimp, snails, tuna in water), chick peas, and cooked soybeans.

Arginine in the dose of 3 gm per day could reduce intrauterine growth retardation. It is available in 3gm satchets. If it is given all at once in the day it can cause nausea. It should be given in 3 divided doses. Some patients find it difficult to tolerate even in divided doses.


                                                                                             Carnitine


Carnitine, also known as L-carnitine (levocarnitine) is a quaternary ammonium compound synthesized from the amino acids lysine and methionine and is responsible for the transport of fatty acids from the cytosol into the mitochondria. It has been speculated that during growth or pregnancy the requirement of carnitine could exceed its natural production. The major sources of carnitine in the human diet are meat, fish and dairy products.
In male infertility: L-Carnitine (LC) and acetyl-L-carnitine (ALC) are highly concentrated in the epididymis and play a crucial role in sperm metabolism and maturation. They are related to sperm motility and have antioxidant properties. Carnitine enhances sperm energy production and, therefore, motility. Carnitine also has an antioxidant capacity and it protects sperms from oxidative damage Garella et al in a study concluded that in the presence of normal mitochondrial function(patients with normal phospholipid hydroperoxide glutathione peroxidase (PHGPx) levels), carnitine, in the dose of 2 gm per day for 3 months improved sperm motility. Vicari et al proved that in patients with prostate-vesiculo-epididymitis, treatment with 1gm carnitine and 0.5gm acetyle carnitine twice a day increased sperm forward motility and viability. Treatment with carnitine in these patients would have better effect if they were pretreated with anti-inflammatory agents.
However, when Sigman et al randomly selected a group of men with idiopathic oligoasthenospermia, and treated a group with carnitine 2gm/day and acetyle carnitine 1gm/day for 24 weeks, the motility and count did not significantly improve as compared to the group he treated with placeboes29. In a multicenter study of 100 patients treated with 3 gm carnitine for 4 months significant improvement in sperm motility was reported by Lewin et al, particularly in patients with idiopathic asthenospermia.14

Treatment with Carnitine 2gm/day or 1gm Carnintine /day with 0.5gm Acetyle carnitine twice a day for 3 months could be useful in some patients with idiopathic oligospermia, although some studies have shown no effect.
The treatment is costly, specially when combined with many other anti-oxidants.


                                                                                       
 Enzymes


                                                                                        Coenzyme Q10


Coenzyme Q(10) (CoQ(10)) is the predominant form of ubiquinone in man. CoQ(10) functions as an electron carrier in the mitochondrial respiratory chain as well as serving as an important intracellular antioxidant. Balercia et al in an open uncontrolled study found that Coenzyme Q10 in the dose of 200mg twice a/day for 6 months improved men with defective sperm motility23. This is probably the result of its role in mitochondrial bioenergetics and its antioxidant properties.
Studies have proved that there is a significant decrease in plasma levels of coenzyme Q10 in preeclamptic women compared with normal pregnant women3 . No prospective, randomized trials of coenzyme Q supplementation in pregnant women have been published.
Coenzyme Q7, an analogue of Coenzyme Q10 was shown in the year 1967 to improve sperm motility significantly as reported by Tanimura J in Bull Osaka medical school journal . 35 years later, the only randomized controlled study on Co-enzyme Q10 comes from Balercia et al who used Co-enzyme Q10 in the dose of 200mg twice daily for 6 months in patients with sperm count >20mill/ml with forward motility <50%. Coenzyme Q10 is used in the dose of 20-50mg for other indications, e.g.: cardiovascular indications.

In India, many pharmaceutical companies market this drug in the dose of 30-50 mg /day for asthenospermia. We still do not know if it is of any use, especially in this dose , for the majority of male patients who come to the infertility clinic, with the diagnosis of oligoasthenospermia, where both count and motility are affected.


                                                                                         Glutathione

 

Glutathione (L--glutamyl-L-cysteinylglycine; GSH) is the most abundant non-protein thiol in mammalian cells. It plays a key role in many biological processes, including the synthesis of proteins and DNA and the transport of amino acids, but notably, it plays a key role in protecting cells against oxidation: the sulphydryl (SH) group is a strong nucleophile, and confers protection against damage by oxidants, electrophiles and free radicals . Parenteral glutathione in the dose of 600mg IM on alternate days for a period of 2 months in a study by Lenzi et al resulted in significant improvements in overall motility, progressive motility, velocity, linearity, amplitude of lateral head displacement and beat cross frequency, together with a significant reduction in the proportion of forms with abnormal morphology. Although the magnitude of the improvements was not large, the increases in velocity, for example, were apparent within 30 days of starting treatment, and persisted for some time after the cessation of treatment, suggesting effects both on epididymal spermatozoa and on the seminiferous epithelium.

Injectable glutathione in light of the above studies, may be useful in male infertility, although some patients have side effects for this drug. Orally, Glutathione is of limited value.

 


                                                                                     
   Carotenoids
                                                                                              Lycopene


Lycopene is a dietary carotenoid with a potent antioxidant activity. It quenches singlet oxygen and scavenges peroxyl radicals.
In preeclampsia: Sharma et al conducted a prospective clinical trial which randomized 251 primigravida women to receive oral lycopene (2 mg twice daily beginning at 16-20 wks) or matched placebo. Women randomized to lycopene were less likely to develop preeclampsia (8.6% vs. 17.7%, P < 0.05) than those who received placebo.
In Male infertility:Palan and Naz measured seminal lycopene by high pressure liquid chromatography in 37 men and noted significantly lower lycopene in the seminal plasma of immuno-infertile men than in fertile men. Gupta and Kumar treated 30 infertile men with 4 mg lycopene for 3 months and found a significant improvement in sperm counts and motility with no significant changes in sperm morphology. A 20% pregnancy rate was seen during the course of the study.
Thus lycopene could be a useful drug both in the treatment of patients susceptible to develop preeclampsia and in patients with idiopathic male infertility, the dose being 4mg per day.
Vitamins
                                                                                Folic acid and Vitamin B6


Steegers-Theunissen et al and Wouters et al found an association between hyperhomocysteneimia and embryo toxicity, leading to neural tube defects or spontaneous abortion, or vascular toxicity, leading to placental infarcts or abruption placentae. Hyperhomocysteinemia during pregnancy is also risk factor for both development of preeclampsia and its complications Hyperhomocysteinemia can be corrected, with a combination of folic acid and vitamin B6.
Leeda et al studied 207 patients with PIH or IUGR and found 37 them to have hyperhomocysteinemia and were given folic acid 5mg and vitaminB6 250 mg supplementation. 14 of them became pregnant while on treatment and had improved pregnancy outcome in their subsequent pregnancy, thus encouraging the use of these agents in hyperhomocysteinemic patients to prevent adverse effects of preecclampsia and IUGR. The average Indian practitioner would rather give empiric treatment with folic acid 5mg and vitamin B6 250mg for all patients with history of pre-eclampsia and IUGR than let all of them undergo tests to detect hyperhomocysteinemia. For the academically inclined, hyperhomocysteinemia can be detected by doing the methionine loading test.
Unexplained infertility: Skillern et al in a small study stated that there appeared to be an association between recurrent pregnancy loss and unexplained infertility and mutation in the methylenetetrahydrofolate reductase (MTHFR) gene , independent of homocysteine levels. These patients benefited from folic acid supplementation.


                                                                                         Vitamin B12


A series of articles in the Japanese journal Hinyokika koyo published between 1984 and 1988 have found methylecobalamin in the dose of 1500mg/day to be useful in increasing sperm concentration. Isoyama et al in 1986 in a study studied the effect of Methylcobalamin CH3-B12 + Clomid (CH3-B12: 1,500 micrograms/day, daily and Clomid: 25 mg/day for 25 days followed by a 5-day rest period, for 12 to 24 weeks in men with counts above 10million/ml and found that sperm counts increased significantly in this population of patients compared to methylcobalamin alone or clomiphene citrate alone.

Hyperhomocysteinemia could be managed with folic acid alone or with the addition of vitaminB6. If vitamin B12 is useful for this purpose, the exact dose is not known.


                                                                     Miscellaneous

                                                                                         Phytoestrogens

Phytoestrogens are molecules with estrogenic activity that are found in plants: 'phyto' = plant; 'estrogen' comes from 'estrus' (period of fertility for female mammals; derived from the name of an ancient Anglo-Saxon fertility goddess, Oestre) + 'gen,' to initiate, generate. Three major types of known phytoestrogens are coumestans, isoflavones, and lignans .
Phytoestrogen supplements containing isoflavones derived mostly from soya are very popular as an alternative therapy for menopause in India. Isoflavonoids are phytoestrogens present in soybeans concomitantly with soy protein, and they structurally and functionally resemble estradiol. Consumption of as little as 30 mg soy isoflavones, in soy protein or as an extract, reduces vasomotor menopausal symptoms by 30–50%. Isoflavonoids may reduce ghrelin levels and thus hunger and weight;(ghrelin is a recently detected hormone synthesized in the stomach in response to insulin-induced hypoglycemia and is capable of increasing appetite by stimulating hunger).There are no effects of isolated isoflavonoids(114mg) on lipids, lipoproteins, or insulin sensitivity in postmenopausal women, implying no vascular benefit. It also has no proven benefit on genitourinary symptoms, or osteoporosis.
Breast cancer is a common concern while using standard estrogens, and isoflavones are thought to be an attractive alternative to them, particularly in breast cancer survivors, and in those women at high risk for breast cancer. In a double blind study of breast cancer survivors, by Mc Gregor et al, there was no difference in menopausal symptoms in breast cancer survivors, between two groups, one taking placebo and the other soy supplements. However, in Asian countries, where soy is being used since childhood in diet, it does seem to offer some sort of decrease in breast cancer rate. This effect possibly cannot be emulated by concentrated soy supplements used for a short time later in life as in clinical trials.

Practitioners using soy suppliments would do well to give realistic expectations to their menopausal patients. It may decrease hot flushes to some extent, though not as effectively as traditional HRT. Its other benefits for menopausal patients other than hot flushes remain controversial. Again, cancer prevention going by the decreased cancer incidence in the soy consuming nations, may not work out too well in populations who start these suppliments late in life for short periods of life.

Conclusion:
Research in new molecules usually requires a lot of stringent studies and they can be available for clinical use only after they have been approved by drug controllers. However, nutritional supplements need not always need these approvals before they are available for use; hence the widely prevalent use of these substances in clinical practice for indications, for which there are still no remarkable breakthroughs by way of therapy.
The presence of several mechanisms to counteract oxidative stress leads to the need for multiple antioxidants as defence against reactive oxygen species radicals. Antioxidants should be used in correct dose to achieve desired results. Overdose should be avoided as in high doses it may decrease the level of free oxygen radicals to less than what is needed for physiological functions.

These drugs used judiciously, could be a boon to many patients with bad obstetric history, male infertility and unexplained infertility.

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Does folic acid and zinc sulphate intervention affect endocrine parameters and sperm characteristics in men?
Int, J. Andrology 29 (2), 339–345.
































 

 

 

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