Glutathione (GSH) in Pregnancy

Copyright ® 2004 Priya Shah
Reproduction prohibited

► Glutathione and Fertility

► Glutathione and the Developing Fetus

Environmental Factors: Pollution, Toxins

• Radiation
• Pesticides and Persistent Organic Pollutants (POPs)
• Air pollution
• Heavy metal pollution (mercury, cadmium, arsenic)
• Vinyl chloride
• Acryonitrile
• Excessive Oxygen: Hyperoxia

Xenobiotics: Drugs and Metabolites

• Anti-psychotic and anti-epileptic drugs (AEDs)
• Thalidomide

Lifestyle factors: Smoking and Alcohol

• Cigarette smoke
• Alcohol (ethanol) consumption

► Glutathione and Pregnancy Complications

• Gestational Diabetes
• Pre-Eclampsia
• Infection and Inflammation
• Fetus with Cystic Fibrosis gene

► Glutathione During Labor and Birth

Summary

References

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Oxidative stress and free radical formation can cause birth defects, abortion and miscarriages in pregnancy. There is overwhelming evidence to show that supplementation with glutathione precursors and antioxidants protects the fetus and mother from the harmful effects of oxidative stress in fertility, pregnancy, prececlampsia, diabetic pregnancy, pregnancy complications, and preterm labor.

Normal pregnancy is associated with an increase in oxidative stress and lipid peroxidation, but antioxidant protection also increases. Several of the antioxidants, such as vitamin E, increase progressively with gestation, so there is a gradual favoring of antioxidant activity over oxidative stress and lipid peroxidation (LOOH) as normal pregnancy advances.

In the placenta, concentrations of the antioxidant enzymes, superoxide dismutase and catalase, increase as gestation progresses, but lipid peroxide concentrations decrease. Therefore, in normal pregnancy, there is a sufficient increase in antioxidants to offset the increase in peroxidation. (1)

Currently, the American College of Obstetrics and Gynecology advises all pregnant women to take a prenatal vitamin containing antioxidants. In addition, they advise eating lots of fresh fruits and vegetables, the best sources of antioxidant protection.

Antioxidants and glutathione status play an important role in the development and growth of the fetus, maintenance of a healthy pregnancy - and even before pregnancy, in fertility and conception.

GLUTATHIONE AND FERTILITY

The chance of a successful in vitro fertilization of the egg cell was shown to depend on the activity of the selenium-containing antioxidant enzyme GSHPx (glutathione peroxidase) in the follicular fluid. (2, 3)

Supplementation of the in vitro maturation (IVM) medium with Cysteamine and beta-mercaptoethanol was found to increase intracellular glutathione (GSH) content in oocytes, decrease in peroxide levels within oocytes and improve embryo development and quality. (4)

GLUTATHIONE AND THE DEVELOPING FETUS

The role of glutathione in the development of the foetus and placenta is crucial. Glutathione (GSH) can control cell differentiation, proliferation, and apoptosis - essential functions in the developing embryo. Glutathione plays an important role in the development of organs (organogenesis) and the embryo (embryogenesis).

Studies have clearly shown how chemicals (like 2-nitrosofluorene and acetaminophen) which modulate intracellular glutathione (GSH) and cysteine levels cause developmental abnormalities (dysmorphogenesis) in the fetus. (5,6,7)

This also explains why lower levels of glutathione activities (like those caused by drugs and increased oxygen levels) during organogenesis, may make the fetus more vulnerable to developmental damage. (8)

In the placenta, glutathione detoxifies pollutants before they reach the developing child. Most substances or factors which cause birth defects (teratogens) are known to exert their embryotoxic effects because they cause oxidative stress. (9)

The fetus is sensitive to the toxic and teratogenic effects of chemicals in the early embryonic stages, whereas it is sensitive to carcinogenic effects during late fetal stages.

Carcinogens administered to the mother can be transferred through the placenta and induce cancer in the fetus. Many potential carcinogens tend to act as abortifacients and teratogens as well. Many carcinogens are much more active in the fetus than in adults. (10,11)

Increasing evidence points to potential risks of delayed effects upon prenatal exposure to chemicals. In fact, several systems (e.g., nervous, excretory) show important developmental processes well after the organogenetic period, up to the postnatal phase. So these would also be sensitive to developmental toxicants.

ENVIRONMENTAL FACTORS: POLLUTION AND TOXINS

A large number of substances in the environment are known to be toxic to the growing fetus. It is impossible to completely eliminate exposure to many of them, because we inhale or ingest them through polluted food, air and water.

Many of these compounds exert their damaging effects through the production of free radicals that lower glutathione levels. Glutathione, as the master-antioxidant, plays an important protective role role in detoxifying these chemicals and reducing their damaging effects on the body.

1. Radiation

Placental glutathione status is sensitive to environmental pollution - as a study of placental detoxifying activity in chemically polluted or radioactively contaminated regions like the Ukraine has shown.

The decreased activity of glutathione transferase activity in the placenta correlated with the increased frequency of complications during the pregnancy and the delivery and with the worsening status of newborns. (12,13)

2. Pesticides and Persistent organic pollutants (POPs)

Pesticides, like lindane, deplete cysteine (CYS) and embryonic GSH, indicating that the glutathione redox cycle plays a role in lindane embryotoxicity in early organogenesis. (14)

In utero exposure to a mixture of pesticides and polychlorinated biphenyls, or persistent organic pollutants (POPs) - similar to those present in the diet of Inuit people - was found to alter hepatic (liver) gene expression in the mother and the fetus. These changes may have functional implications during pregnancy. (15)

3. Air pollution

Studies have found that increased exposure to nitrogen-oxidizing compounds (NOx - a component of air pollutants) in polluted areas, was related to significant rises in the levels of methemoglobin. (16)

Methemoglobin may lead to hypoxia and hypoxemia in pregnant women. It has an important influence on maternal health and placental and fetal development and may lead to conditions like anemia, threatened abortion/premature labor, and signs of preeclampsia, compared with normal pregnancies. (17)

This suggests that maternal exposure to environmental oxidants can increase the risk of pregnancy complications by stimulating the formation of cell-damaging lipid peroxides and decreasing maternal antioxidant reserves.

4. Heavy metal (mercury, cadmium, arsenic) pollution

Exposure to high levels of methylmercury (MeHg) a known teratogen, has been found to compromise fetal glutathione redox status. (23)

The combined exposures of smoking and arsenic exposure (as a result of living in a smelter area) have been associated with lower levels of reduced glutathione and higher concentrations of lipid peroxides in maternal blood, cord blood and placenta. (18)

Cadmium exposure during critical stages of development has been associated with exencephaly (a neural tube defect) and gross facial and limb abnormalities. (19,20,21,22)

Glutathione is an important defense against oxidative stress and heavy metal toxicity. Removal of heavy metals (mercury, lead, cadmium) from the body requires glutathione.

Treatment with the glutathione precursor, N-Acetyl-L-cysteine (NAC) during the period of organogenesis can drastically reduce the severe embryolethality induced by methyl mercuric chloride (MMC). (24)

5. Vinyl Chloride

The primary constituent in the manufacture of polyvinyl chloride (PVC) products, vinyl chloride is known to have genotoxic and carcinogenic effects. (25)

Vinyl chloride is detoxified in the liver, where it is conjugated to glutathione and excreted in the urine. Chronic exposure to vinyl chloride may significantly deplete the glutathione pool and reduce the defensive mechanisms of the body against subsequent attacks by oxidative metabolites. (26,27)

6. Acrylonitrile

Low glutathione (GSH) levels have been shown to significantly enhance the embryotoxic effects of acrylonitrile. (28)

7. Excessive Oxygen: Hyperoxia

Oxygen may be essential for life but a sudden rush during the early weeks of pregnancy could spell death for a foetus. The amount of oxygen foetuses receive triples between the eighth and 15th week of pregnancy.

Cells called cytotrophoblasts, which anchor the placenta in the womb and invade the blood vessels to limit oxygen intake, dissipate at about eight to 10 weeks, allowing more of the gas in. In pregnant women who about to miscarry at that time, there is an excessive and early onset of maternal blood flow.

The relative resistance to oxygen toxicity in newborn animals of some species has been associated with a rapid increase in antioxidants in lung tissue. The failure to maintain sustained high levels of total glutathione during hyperoxia might suggest that glutathione depletion is a factor in the timing of death from oxygen toxicity in these animals. (29)

According to researchers, diet rich in antioxidant vitamins such as vitamins C and E could help protect the foetus from this sudden change in their environment. (30)

XENOBIOTICS: DRUGS AND METABOLITES

The human placenta possesses a significant amount of glutathione S-transferase (GST) capable of detoxification or activation of xenobiotics during the critical organogenesis period in the fetus. (31)

Aminoglycosides, angiotensin-converting enzyme inhibitors, indomethacin affect the functional maturation of the kidney, while anticonvulsivants, antiretroviral compounds, and benzodiazepines affect the brain on exposure in utero. (32)

Some drugs are known to cause birth defects in the growing fetus by generating free radicals, and depleting GSH stores.

1. Anti-Psychotic and Anti-Epileptic Drugs (AEDs)

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk.

Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. (33)

AEDs are commonly used in women of childbearing age for epilepsy and other indications, but studies have shown marked detrimental effects of in utero AED exposure on behavioral neurodevelopment. Free radicals and epoxides are thought to play a role in these congenital malformations. (34)

Chlorpromazine (CPZ), cyclophosphamide, sodium valproate, phenobarbital, vigabatrin, are all known to have teratogenic effects. (35,36,37,38,39,40)

The tripeptide glutathione is able to detoxify a number of reactive metabolites. The FDA'S Division of Reproductive and Developmental Toxicology (DRDT) plans to develop methods to measure embryonic concentrations of glutathione and to test additional scavenging compounds to determine if they are able to decrease carbamazepine-induced embryotoxicity. (41)

2. Thalidomide

Thalidomide is a teratogen that causes stunted limb growth (dysmelia) during human embryogenesis.

There is direct evidence to suggest that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules. Studies have confirmed that thalidomide-induced oxidative stress in utero leads to phocomelia (flipper-like limbs). (42)

Thalidomide inhibits the formation of new blood vessels (angiogenesis) in the growing embryo by generating of toxic hydroxyl radicals. (43)

Thalidomide has been shown to cause species-specific GSH depletion in rat and rabbit embryos treated in culture. Rabbit conceptuses displayed lower GSH and cysteine levels and a greater propensity for thalidomide-induced GSH depletion than in rat conceptuses, consistent with the greater sensitivity of the rabbit to thalidomide teratogenicity. (44,45)

LIFESTYLE FACTORS: SMOKING AND ALCOHOL

Smoking and alcohol intake are avoidable substances that are known teratogens in humans. Both are known to affect GSH stores adversely.

1. Cigarette smoke

Smoking during pregnancy has been linked to a variety of adverse pregnancy outcomes, including low birthweight, spontaneous abortion, and infant death. Maternal exposure to environmental tobacco smoke (ETS) negatively affects neonatal birth weight. (46)

Smoking during the first months of pregnancy induces morphologic changes in the placenta, because of the acute sensitivity of the outer layer of the first trimester placenta to oxygen-mediated damage. (47,48)

Research has shown that a having a certain genotype of the enzyme, glutathione-S-transferase, could affect the outcome of maternal exposure to ETS on neonatal birth weight. (49)

Studies have shown that components of tobacco smoke can reach the fetus, and that human fetal tissues are capable of activating carcinogens similar to those in tobacco smoke. This suggests that prenatal exposure to maternal smoking could cause transplacental carcinogenesis in humans, and that resulting tumours could occur in adulthood. (50,51,52)

Tumours that are most often found associated with maternal smoking in pregnancy or ETS exposure, are childhood brain tumours and leukaemia-lymphoma, with risks up to two or greater. (53)

Although stopping smoking is the primary goal in pregnancy, chemoprevention provides a complementary approach applicable to high risk individuals such as current smokers and ex-smokers. Glutathione is known to detoxify the nicotine and free-radicals contained in cigarette smoke - even second hand smoke.

A number of studies have proved that N-Acetylcysteine (NAC), a precursor of glutathione, has anti-genotoxic and anti-carcinogenic properties. NAC protects from the genotoxicity of cigarette smoke and its constituents. (54,55)

N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to cigarette smoke and atmospheric pollutants, which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. (56)

Treatment with NAC enhances detoxification mechanisms, either by stimulating enzyme activities promoting glutathione formation or by reacting with direct-acting mutagens and with the genotoxic metabolites of procarcinogens. (57)

2. Alcohol (Ethanol) consumption

The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal alcohol syndrome is characterized by pre and postnatal growth retardation, mental retardation, behavioral deficits, and facial deformities.

Acute doses of alcohol during critical stages of neural tube development are harmful to both the central nervous system (CNS) and axial skeleton formation in the fetus. Fetuses exposed in utero to ethanol have an increased incidence of cleft lip and cleft palate. (58,59)

Administration of alcohol to adult rats is known to decrease liver glutathione (GSH) levels. In utero administration of alcohol has also been shown to produce a decrease in GSH levels, as well as prenatal growth retardation, and intrauterine death. (60)

The biochemical mechanism(s) by which alcohol produces teratogenic effects on the developing fetus are not well understood, but there is increasing evidence that alcohol-induced liver damage may be associated with increased oxidative stress.

Although ethanol depletes GSH and cysteine earlier in utero than in vitro, maternal protective mechanisms allow embryos exposed in utero to respond rapidly to chemical-induced oxidative stress. (61)

Ethanol-induced liver damage is associated with oxidative stress, but co-administration of N-acetylcysteine (NAC) - a precursor of glutathione - effectively provides protection from toxic liver damage by elevating intracellular glutathione concentrations. (62)

GLUTATHIONE AND PREGNANCY COMPLICATIONS

Many pregnancy complications and birth defects have been linked to oxidative stress and free radical damage to the mother and fetus. Increased lipid peroxidation and reduced antioxidant activity are associated with pregnancy complications.

The glutathione antioxidant system has been shown to play an important protective role in reducing the effects of oxidative stress in pregnancy and childbirth. Several complications during pregnancy have been linked to poor glutathione levels. (63)

Women with habitual abortion (HA) are found to have significantly lower levels of antioxidants like GSH, vitamin A, E and beta carotene and higher levels of lipid peroxidation. (64,65)

Some disease conditions like diabetes are known to cause birth defects, and others like preeclampsia, cause complications in pregnancy. There is evidence of decreased detoxifying or free radical scavenging capacity in pregnancies complicated by preeclampsia and diabetes.

In preeclampsia, maternal total glutathione levels are found to be lower than in normal pregnancy. Also, diabetic preeclamptics showed low total glutathione levels as compared to preeclampsia and control. (66)

1. Gestational Diabetes

Diabetes in pregnant women is a known teratogen. Fetal malformations (embryopathy) resulting from maternal type 1 or type 2 diabetes is a well-established phenomenon, with the risk of a birth defect in a diabetic pregnancy being at least two and as much as six times higher than normal. (67)

Maternal diabetes has the potential to adversely affect the development of multiple organ systems, resulting in a wide range of congenital malformations. Generally, the birth defects most commonly associated with maternal diabetes are caudal regression, situs inversus, kidney malformations, cardiac anomalies, and neural tube defects (NTDs). (68,69,70)

Diabetes in pregnancy is also known to cause deficits in learning and memory in the offspring. (71)

A diabetic maternal environment produces irreversible developmental retardation in the embryo very early in gestation. More common congenital malformations in infants of diabetic mothers occur before the seventh week of gestation.

This suggests that any therapeutic intervention aimed at decreasing the incidence of congenital malformations must be instituted during the critical early period. (72)

Mothers with diabetes have abnormally high blood sugar levels, which means their embryos also have high blood sugar levels. This excess blood sugar produces damaging free radicals in the blood faster than antioxidants can eliminate them in the underdeveloped embryo - a process known as oxidative stress.

Even mild oxidative stress can cause birth defects. Oxidative stress also disrupts the expression of specific genes in the embryo, and may be a more common cause of birth defects in the babies of women with and without diabetes than is currently appreciated.

Oxidative stress in the fetus can lead to inhibition of the Pax-3 gene. Embryos of mothers with diabetes have low levels of this gene and three times more neural tube defects. This may explain the genetic basis for neural tube defects that occur in diabetic pregnancies. (73)

Hyperglycemia-induced embryonic malformations have been linked to an increase in free radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. An excess of reactive oxygen species (ROS) has been associated with the increased rate of congenital malformations in experimental diabetic pregnancy.

Numerous studies have associated fetal birth defects (dysmorphogenesis) and embryonic death (abortion/miscarriage) in diabetic pregnancies with an increase in maternal and embryonic oxygen-free radicals and oxidative stress. (76,77) The oxidation of embryonic proteins by free radicals may be an important factor in causing birth defects in diabetic pregnancies.

The effect of dietary fat intake on glutathione peroxidase (GPx) activity also suggests a potential link among diet, insulin resistance, and antioxidant status during pregnancy. These factors may contribute to the increased levels of lipid peroxidation and oxidative stress during pregnancy as well. (87)

GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes. (74)

Diabetic conditions in the mother damage the yolk sac endodermal cells and alter GSH transport to the fetus. Embryonic GSH is reduced as a result. This could reduce fetal protection against oxidative stress in diabetic mothers. (75)

Since the free radical eliminating system of the embryo is immature, it may be particularly vulnerable to oxidative stress. Even with good control of diabetes, the risk for neural tube and other birth defects among women with diabetes is two to five times higher than those without diabetes.

Antioxidants may, hence, be critical to preventing birth defects in babies of women with diabetes. (78)

Oxygen radicals-scavenging enzymes can reduce the embryotoxic effects induced by diabetic conditions. Previous in vitro and in vivo studies show that antioxidants can protect the embryonic development in a diabetic environment. (79)

Glutathione is the main defense against free radicals in embryonic tissues, as it is in adult tissues (80). Treatment with dietary GSH has a protective affect on kidney function in diabetics, and suggests that dietary GSH treatment may reduce diabetic complications (81).

The use of multivitamin supplements during pregnancy may also reduce the risk for birth defects among offspring of mothers with diabetes (82). Vitamin C supplementation of the maternal diet can reduce the rate of malformation in the offspring of diabetic rats. (83)

Combined antioxidative treatment with vitamins E and C has also been shown to decrease fetal malformation rate and improve the oucome of the pregnancy by reducing oxygen radical-related tissue damage. (84,85,86)

2. Preeclampsia

Pre-eclampsia is a serious condition in pregnancy characterized by high blood pressure, swelling in the hands and face, and protein in the urine. It is considered a key cause of death in pregnant women, as well as premature delivery.

The major pathophysiologic changes observed in preeclampsia suggest that endothelial cell (the cells that form the lining of blood vessels) dysfunction plays an important role in this disorder. The cause and development of preeclampsia is thought to be related to increased oxidative stress and increased vasoconstriction (narrowing of blood vessels).

In contrast to women with uncomplicated pregnancies, women with preeclampsia have antioxidant activity that is markedly reduced by late gestation. Maternal blood levels and placental tissue levels, of lipid peroxides, and the production rates of lipid peroxides, are even further increased in preeclampsia as compared with normal pregnancy. (88)

With so many deficiencies of antioxidants, the preeclamptic woman is not able to effectively control her increase in oxidative stress and lipid peroxidation. For women with preeclampsia, this could potentially cause oxidative damage to the endothelial cells in blood vessels.

Women with preeclampsia have significantly increased levels of serum iron when compared with normally pregnant women, probably due to the decrease in the iron-binding capacity of the blood and peroxide-stimulated release of iron from hemoglobin.

Transition metals, such as iron (Fe++, Fe+++) react with superoxide, hydrogen peroxide, and lipid peroxides to produce strong oxidizing oxygen radicals that produce oxidative damage and initiate lipid peroxidation. (89)

A number of studies have indicated that enhanced superoxide generation and impaired glutathione metabolism may be involved in the cause and outcome of preeclampsia. (93)

Significantly lower ratios of free to oxidized cysteine, homocysteine, and cysteinylglycine - indicative of oxidative stress - are found in women with preeclampsia (90,91)

Homocysteine and cysteine levels, are normally lowered in pregnant women with normal blood pressure. But in women with preeclampsia they were comparable to levels in non-pregnant women, whereas glutathione levels are lower.

These results suggest that in women with preeclampsia, glutathione use is higher or its synthesis is disturbed. Glutathione might, hence, affect the disease process and outcome of preeclampsia. (92)

Decreased total glutathione levels in maternal whole blood are found in pregnancies complicated by preeclampsia and diabetes. In preeclampsia, maternal total glutathione levels are lower than in normal pregnancy. Also, diabetic preeclamptics showed low total glutathione levels as compared to preeclampsia and control. (94)

This indicates that detoxiftying or free radical scavenging capacity is decreased - in pregnancies complicated by preeclampsia, or the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. (95)

Preeclamptic and diabetic preeclamptic women also show a significant fall in vitamin E levels, suggesting that lipid peroxidation plays a role in the pathogenesis of preeclampsia (97).

Uncontrolled lipid peroxidation may play an important role in the preeclampsia because of its potential to causing vascular endothelial cell dysfunction (96).

There is also compelling evidence that women with low levels of carotenoids in their blood and placenta are much likelier to develop preeclampsia than women whose levels were normal. Carotenoids are natural pigments that act like antioxidants in protecting cells against free-radical oxygen damage. (98)

Tumor necrosis factor alpha (TNF-), a cytokine produced by macrophages and many other cell types, is significantly increased in preeclampsia and has been shown to induce oxidative stress and cause secretion of vasoconstrictors in human endothelial cells. (99)

A number of studies have found that supplementation with antioxidants is beneficial in prevention of pre-eclampsia. Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease.

In a study published in the the Lancet, British researchers found that pregnant women who took 1000 mg vitamin C and 400 IU vitamin E reduced their risk of pre-eclampsia by 76%. (100,101,102,103)

3. Infection and Inflammation

Intrauterine and maternal systemic infections are proposed causes of preterm labor. The resulting prematurity is associated with 75% of infant mortality and 50% of long-term neurologic handicaps.

Free radicals generated in large quantities during an inflammatory response are associated with maternal and fetal GSH depletion, compromising the fetus. Oxidative stress damages the fetus independent of prematurity.

Selective inactivation of free radicals with N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursors, has been found to improve the outcome of preterm deliveries associated with inflammation. (104)

4. Fetus with Cystic Fibrosis gene

Researchers have shown that the chronic and excessive inflammation that characterizes cystic fibrosis (CF) begins in utero.

This inflammatory state directly damages the tissues of the body, which in turn primes the body for bacterial colonization as well as eventual immunodeficiency. If one could lessen or even shut off the very start of that inflammation which begins in utero, the CF infant should have a better start in life.

GSH is the most important antioxidant in the body and a powerful mucolytic. Glutathione is also an important regulator of inflammation. The CFTR channel, which is missing or defective in CF persons, is the main efflux route of cellularly-produced GSH.

This is very important, as the redox state of GSH in immune system cells is the primary trigger of inflammation in the body. If GSH becomes depleted in immune system cells, inflammation begins. This is precisely what begins to happen in the CF body, and this is what is hypothesized to be happening in utero.

This suggests that supplementation of the mother with GSH may tend to rectify any GSH deficit that may start to develop in the immune system cells of her fetus. This should serve to lessen or even shut off the origin of fetal inflammation.

Thus, in addition to all of the usual vitamins and minerals a pregnant woman is asked to take, a woman who is pregnant with a fetus that she knows or suspects to have CF might also consider supplementation with both DHA and GSH.

Supplementation with two nutritional supplements - DHA and GSH - may lessen or even prevent the manifestations of CF that begin even in utero. (105)

GLUTATHIONE DURING LABOR AND BIRTH

A number of studies have shown that glutathione (GSH ) is crucial in preventing or minimising the oxidative stress that occurs during labor and the birth process.

Oxidative stress is implicated in diseases that are associated with prematurity (such as retinopathy, cerebral palsy, intraventricular hemorrhage, and necrotizing enterocolitis). Nonenzymatic antioxidant reserve is the first line of defense against free radicals.

In pregnant women who deliver at full term, the process of labor triggers a compensatory increase of the nonenzymatic antioxidant reserve in fetal red blood cells. This may act to protect against the relative hyperoxia (excess oxygen exposure) that is experienced by the full-term newborn infant at birth.

In contrast, decreased fetal nonenzymatic antioxidant reserve in preterm labor and delivery, would enhance the vulnerability to free radical damage of the preterm neonate. (106)

Perinatal or birth asphyxia/hypoxia (deprivation of oxygen supply to the brain) in preterm deliveries and labor can lead to cerebral palsy, respiratory distress syndrome, irreversible brain injury, and permanent neurological and intellectual handicaps.

Postnatally a rapid change occurs from a relatively hypoxic to a relatively hyperoxic environment, especially during artificial ventilation, with all the risks of ROS-formation. In the fetal-to-neonatal transition, important circulatory and respiratory changes ensue which lead to oxidative stress evidenced by changes in glutathione status. (107)

The close correlation found between the antioxidant capacity of the mothers and babies, suggests that supplementation with sulfur-containing amino acids (methionine, cysteine) during pregnancy would improve the antioxidant capacity of prematures.

Animal studies have found that oral administration of N-Acetyl-Cysteine (NAC), a glutathione precursor, to the pregnant mother partially prevents the oxidative stress and change in hepatic GSSG that occurs in the fetal-neonatal transition. (108)

GSH supplementation is found to maintain normal lavage and lung tissue GSH levels in preterm animals exposed to hyperoxia and prevents the changes in lung mechanics associated with oxygen-induced lung injury. (109)

Vitamin E treatment of "any retinopathy" infants seemed to have a positive effect against the development of Retinopathy of Prematurity. An antioxidant cocktail (selenium + vitamin E) given to the high-risk mothers (advanced age, smoking, pregnancy-induced hypertension) before delivery might be useful in prevention of Retinopathy of Prematurity. (110)

SUMMARY:

Overwhelming evidence indicates that antioxidants like Glutathione, Vitamin C, and E are crucial to all stages of pregancy - from pre-conception to fetal growth and development, to labor and post-natal development.

They help to protect the fetus from the damaging effects of pollutants, carcinogens and teratogens, and provide protection against the oxidative stress that is known to cause congenital malformations, abortion and miscarriage.

Numerous studies have shown that glutathione and other antioxidants are crucial in preventing oxidative stress in in pregnant women with inflammation or disease conditions like diabetes and pre-eclampsia, or in fetuses at risk for developing cystic fibrosis.

GSH and antioxidant supplementation can decrease the incidence of birth defects and protect both mothers and the fetus from the damaging and possibly fatal consequences of pregnancy complications.

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Warning: Pregnant women and nursing mothers should avoid the use of supplementary glutathione. Pregnant women must always consult their healthcare provider before initiating any course of supplementation. Women who are pregnant or nursing should discontinue all supplements except as directed by their healthcare providers.

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