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.
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
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
3. Reactive oxygen species (ROS) have been implicated in diabetic
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
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.
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
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
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
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.
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.
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 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
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
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
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
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
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.
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
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
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.
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
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
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
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
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
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 (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.
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.
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
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
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.
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.
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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