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Selenium in reproductive health


Hiten D. Mistry, PhD; Fiona Broughton Pipkin, DPhil, FRCOG ad eundem; Christopher W. G. Redman, MD, FCRP,
FRCOG; Lucilla Poston, PhD, FRCOG ad eundem

S elenium was first discovered in 1817


by Jns Jacob Berzelius when inves-
tigating the chemicals responsible for
Selenium is an essential trace element of importance to human biology and health.
Increasing evidence suggests that this mineral plays an important role in normal growth
outbreaks of ill health among workers in and reproduction in animals and humans, and selenium supplementation is now recom-
a Swedish sulphuric acid plant.1 The lo- mended as part of public health policy in geographical areas with severe selenium defi-
cal product contained a contaminant ciency in soil. This review addresses the biological functions of selenium followed by a
that he named Sele ne , after the detailed review of associations between selenium status and reproductive health. In many
Greek goddess of the moon.2 In 1957, countries, selenium dietary intake falls below the recommended nutrient intakes and is
3
Klaus Schwarz with Foltz proved that inadequate to support maximal expression of the selenoenzymes. Numerous reports im-
sele- nium is an essential nutrient plicate selenium deficiency in several reproductive and obstetric complications including
necessary for both normal growth and male and female infertility, miscarriage, preeclampsia, fetal growth restriction, preterm
reproduc- tion in animals. labor, gestational diabetes, and obstetric cholestasis. Currently, there is inadequate infor-
mation from the available small intervention studies to inform public health strategies.
Selenium, amino acids, Larger intervention trials are required to reinforce or refute a beneficial role of selenium
and selenoproteins supplementation in disorders of reproductive health.
Dietary selenium, initially taken up
Key words: antioxidant, pregnancy, reproduction, selenium
from the soil and concentrated by
plants, is ab- sorbed in the small
intestine and incor- porated into
proteins by complex mech-
anisms that remain unclear.4 Selenite then methylated, giving rise to methyl- tion and pregnancy are the 6 antioxidant
(SeO32 ; inorganic form of selenium) ated selenium derivatives that are ex- glutathione peroxidases (GPxs), which
crosses the plasma membrane and reacts 2012 Mosby, Inc. All rights creted in urine, expired air via the lungs,
reserved. doi: 5,6
with cytoplasmic thiols in the reduction and feces (Figure 1). The proportion
10.1016/j.ajog.2011.07.034
pathway; this forms selenide, which is of selenium intake excreted like this de-
pends on dietary intakes; when this is
high, urinary excretion will also be high
7-9
From the Maternal and Fetal Research Unit, and vice versa.
Division of Womens Health, Kings College Selenium is stored in the tissues in vary-
London, London, United Kingdom (Drs Mistry
ing density: 30% in the liver, 30% in mus-
and Poston); the School of Clinical Sciences,
Department of Obstetrics and Gynecology, cle, 15% in the kidney, 10% in the plasma,
University of Nottingham, Nottingham, and the remaining 15% throughout other
United Kingdom (Dr Broughton Pipkin); and organs.4,10 Concentrations of free sele-
Nuffield Department of Obstetrics and nium are greatest in the renal cortex and
Gynecology, University of Oxford, John
pituitary gland, followed by the thyroid
Radcliffe Hospital, Oxford, United Kingdom
(Dr Redman). gland, adrenals, testes, ovaries, liver,
11,12
Received April 6, 2011; revised July 12, 2011; spleen, and cerebral cortex.
accepted July 22, 2011. Selenium concentrations are typically
Part of the work cited in this manuscript was measured in plasma, serum, whole blood,
supported by Tommys Charity (registered amniotic fluid, and urine as well as hair
charity 1060508) as is H.D.M. and The and toenails (reflecting longer-term sele-
Biotechnology and Biological Sciences
Research Council (Biotechnology and
nium stores). The main methods used to
Biological Sciences Research Council, United be atomic absorption spectrometry; how-
Kingdom). ever, more recently inductively coupled
The authors report no conflict of interest. plasma-mass spectrometry has been used,
Reprints: Hiten D. Mistry, PhD, Maternal and which has improved the limits of detection
Fetal Research Unit, Division of Womens to 0.055 g/L.
Health, Kings College London, St Thomas Selenoproteins, coded by 25 seleno-
Hospital, Westminster Bridge Rd., London 13
SE1 protein genes in humans (Table 1), ex-
7EH, United Kingdom. ert multiple actions on endocrine, im-
14,15
hiten.mistry@kcl.ac.uk. mune, and inflammatory functions.
0002-9378/$36.00

21 American Journal of Obstetrics & Gynecology JANUARY 2012 JANUARY 2012 American Journal of Obstetrics & Gynecology 21
www. AJOG.org Obstetrics Expert Reviews
play a pivotal role in reducing hydrogen man. 4,20
The content in food depends
peroxide (H2O2) and lipid peroxides to Dietary on the selenium content of the soil in
harmless products (water and alcohols; selenium which plants are grown or animals are
Figure 2), thereby dampening the prop- Plant foods are the major dietary raised. For example, the selenium
agation of damaging reactive oxygen sources of selenium in most content in the soil of the high plains of
16,17
species (ROS). As antioxidants, the countries.18,19 northern Nebraska and the Dakotas is
GPxs help maintain membrane integrity, Wheat is the most efficient selenium very high, and the inhabitants have the
protect prostacylin production, and ac- cumulator of the common highest selenium intakes in the United
limit the propagation of oxidative dam- cereals and is 1 of the most 21
States. Other foods make a substantial
age to lipids, lipoproteins, and deoxyri- important selenium sources for contribution to selenium intake in
17
bonucleic acid (DNA). northern Europe, particularly meat,
Of particular importance to reproduc- poultry, and fish (a total of about 36% in

22 American Journal of Obstetrics & Gynecology JANUARY 2012 JANUARY 2012 American Journal of Obstetrics & Gynecology 22
28
nancy and their lifetime. Dietary se-
FIGURE 1
lenium intake in most parts of Europe
Selenium metabolic pathway
Selenite is considerably lower than in the
General body proteins United States, mainly because of the
European soils providing a poorer
15,30
Selenoproteins source of selenium.
(as [Se]Cys/Sec) Assessments of requirements, ade-
GS-Se-SG
[Se]Met quacy, and intakes of selenium have
been reviewed previously in detail15,30
and summarized in Table 2. Selenium
Selenophosphate GS-SeH
intake appears on average to be at or
[Se]Cys/Sec
above the recommended dietary intakes
in the United States (60-220
19,31,32
H2Se g/d) or Canada (50-200
33,34
g/d). However, modest selenium
deficiency, in associa- tion with poor
CH3SeH diet, has been described in the United
States among the poor and obese,
which a recent review links pro-
(CH3)2Se Breath spectively to cardiovascular disease and
35
immune dysfunction. In the United
Kingdom, selenium dietary intake is
generally below the reference nutrient
+
intakes (30-40 g/d).22,36,37
(CH3)3Se Urine and Faeces
This diagram illustrates how selenoproteins can be produced in the body from a variety of selenium Selenium toxicity
sources. Glutathione (GSH) is considered to be the main component of the selenium metabolism There is also a moderate to high health
pathway, taking part in the first of a series of reduction reactions that convert selenite to hydrogen risk of selenium toxicity, first
selenide (H2Se), which is regarded as the precursor for supplying selenium in an active form for discovered in animals grazing in areas
synthesis of selenoproteins. The further metabolism of H2Se involves sequential methylation to methyl- with high se- lenium content in the
selenide (CH3SeH), dimethylselenide ([CH3]2Se), trimethylselenonium ion ((CH3)3Se ). soil.38 Chronic toxicity of selenium in
[Se]Met, selenomethionine; [Se]Cys, selenocysteine. humans results in selenosis, a
Adapted from other sources.5,6,158 condition characterized by brittleness
Mistry. Selenium in reproductive health. Am J Obstet Gynecol or loss of hair and nails,
2012. gastrointestinal problems, rashes, gar-
lic breath odor, and nervous system
39
abnormalities.
the United Kingdom).22 Thus, it has Selenium deficiency In China, it has been reported that
been predicted that vegetarians or veg- Selenium deficiency as assessed by di- sel- enosis occurs with increased
ans are at specific risk of selenium defi- etary intake and/or blood selenium con- frequency in people who consumed
4,23
ciency, but this claim is not fully centrations has been identified in selenium at levels above 850 g/d.40
substantiated. people inhabiting geographical regions The Institute of Medicine (United
Selenium incorporation into plants, notable for low soil selenium content, States) has set a toler- able upper
and then into animal tissues, depends on such as volcanic regions.15,25 Human intake level for selenium at
selenium 400 g/d for adults to prevent the risk of
not only soil selenium content or geo- developing selenosis.41 The European
deficiency diseases have been recognized Commission and the World Health Or-
chemistry but also soil pH, rainfall, in China and Tibet. 26,27 Keshan disease,
land ganization have proposed the lower daily
contour, and the use of high-sulphur fer-
However, in wetter regions, a reversible endemic cardiomyopathy, is
4,20
tilizers. Some bacteria can convert plexes.
insol- uble forms of selenium to soluble 4 characterised by focal myocardial necro-
rain leaches selenium from the soil.
forms, which can then be taken up by sis often associated with inflammatory
20,24
plants. Se- lenium tends to be infiltrates and calcification.
concentrated in the soils of the drier The disorder is exclusively endemic in
28
regions of the world, in which soil is selenium-deficient rural areas of China
usually more alkaline; in acidic poorly and supplementation with selenium
aerated soils, selenium is rel- atively tablets (such as sodium selenite) in
unavailable to plants because it is 29
pregnancy provides highly effective
present mainly as insoluble selenite com-
protection against its development in upper limit of 300 g/d for Selenium is essential for testosterone
susceptible women, both during preg- adults.
42,43 biosynthesis and the formation and nor-
44,45
mal development of spermatozoa.
Selenium in reproductive Testicular tissue contains high concen-
health trations of selenium, predominantly as
Male GPx4, and this provides the link
fertility between selenium, sperm quality, and
male fertil-
ity because GPx4 is a fundamental deter- TABLE 1
minant of the architecture of the sperma- Known mammalian selenoproteins that carry out functions
14,18
tozoan midpiece14,46 and is considered to of selenium (adapted from elsewhere )
shield developing sperm cells from oxida- Selenoprotein Proposed function
47,48
tive DNA damage. ROS have been GPx.....................................................................................................................................................................................................................................
implicated in male infertility because,
GPx1 Antioxidant in cell cytosol; Se store?
through attack of the spermatozoa mem- .....................................................................................................................................................................................................................................

brane, sperm viability is decreased. GPx2 Antioxidant in gastrointestinal tract


.....................................................................................................................................................................................................................................

Some evidence suggests that increas- GPx3 Antioxidant in extracellular space and plasma
.....................................................................................................................................................................................................................................
ing selenium dietary intake increases GPx4 Antioxidant in membranes; structural protein in sperm;
an- tioxidant GPx activity, thereby apoptosis?
.....................................................................................................................................................................................................................................
49
increas- ing male fertility. The study in GPx5 Unknown
.....................................................................................................................................................................................................................................
50
1984 by Bleau et al reported an GPx6 GPx1 homolog?
..............................................................................................................................................................................................................................................
optimal range between 50 and 60 Thioredoxin reductase (TR) Multiple roles including dithiol-disulphide oxoreductase.
g/mL in semen and a positive Detoxifies peroxides, reduces thioredoxin (control of cell
correlation between sperm count and growth); maintains redox state of transcription factors
.....................................................................................................................................................................................................................................
semen selenium concentra- tion in 125 TR1 Mainly cystosolic, ubiquitous
.....................................................................................................................................................................................................................................
men from couples being in- vestigated TR2 Expressed by testes
.....................................................................................................................................................................................................................................
for infertility. TR3 Mitochondrial, ubiquitous
In Scotland, a placebo-controlled ran- ..............................................................................................................................................................................................................................................
Iodothyronine deiodinases
domized control trial (RCT) of 64 men .....................................................................................................................................................................................................................................
Types D1 and D2 Converts thyroxine (T4) to bioactive 3,5,3-tri-iodothyronine
demonstrated that sperm quality and
fertility improved after selenium supple-
mentation.51 Other placebo-controlled
52 48
RCTs from Tunisia and Iran of infer-
(T3)
tile men demonstrated the beneficial ef- ...............................................................................................................................

fects of daily supplements of selenium Types D1 and D3 Converts T4 to bioinactive 3, 3, 5 reverse T3


..............................................................................................................................................................................................................................................
52
on improving sperm motility, semen Selenoprotein P Se transport protein; antioxidant in endothelium
..............................................................................................................................................................................................................................................
qual- ity including sperm count, Selenoprotein W Antioxidant in cardiac and skeletal muscle?
..............................................................................................................................................................................................................................................
concentration, morphology, and motility
as well as plasma
Selenophosphate synthetase Synthesis of selenophosphate for selenoprotein synthesis
and semen selenium
(SPS2)
concentrations.48
A recent study of 690 infertile Iranian ..............................................................................................................................................................................................................................................

men with idiopathic asthenoteratosper- 15 kDa selenoprotein (Sep 15) Protects against cancer?
..............................................................................................................................................................................................................................................

mia who received supplemental daily Selenoproteins H, I, K, M, N, Role largely unknown


se- lenium (200 g) in combination O, R, S, T, V
with vi- ..............................................................................................................................................................................................................................................
tamin E (400 U) for at least 100 days SE, selenoprotein.
observed a 52.6% total improvement in Mistry. Selenium in reproductive health. Am J Obstet Gynecol 2012.
sperm characteristics (362 cases), and
10.8% spontaneous pregnancies in com- such as these, in which basic selenium pleted a study of 135 follicular fluid
parison with no treatment (95% confi- intake, as in the United States is sam- ples collected from 115 patients
dence interval, 3.08 5.52).53 However, generally higher. during transvaginal oocyte retrieval;
this study was not a placebo-controlled Another point to note is that the par- patients with unexplained infertility
blinded RCT. ticipants in 2 of these studies were had signifi- cantly decreased follicular
Some studies have reported contrary healthy men with no fertility problems, selenium con- centrations compared
results in relation to selenium supple- so selenium supplementation may not with those with tubal infertility or a
mentation. Three small studies, from have had any effect. A recent review of known male-related cause of infertility.
Poland and the United States, supple- the effect of oral antioxidants (including
menting (200-300 mg/d) with selenite, A recent case-con- trolled study from
selenium) on male subfertility con- Turkey also found lower serum and
selenium-enriched yeast, or diets natu- cluded that supplementation could im-
rally high in selenium reported that, al- follicular fluid selenium concentrations
prove sperm quality and/or pregnancy in 30 women undergoing in vitro
though semen selenium concentrations rates but recommended that large ade-
increased, there were no positive fertilization treatment compared with 13
quately powered trials using individual
effects age-matched, nonpregnant con-
on sperm characteristics or activity.54-56 57 trol women.59 Women with unexplained
antioxidants are required.
Indeed, 1 reported decreased sperm mo-
56
tility. These studies highlight that the
dosage of supplementation needs to be Female fertility infertility or premature ovarian failure
carefully considered, especially studies Data regarding selenium and female fer- have significantly increased serum levels
tility are sparse. Paszkowski et al58 com- of the ovarian autoantibody protein,
60
selenium- binding protein-1.
The relationship between oxidative
FIGURE 2
stress, decreased female fertility, and
Major pathways of ROS generation and metabolism se- lenium deficiency is another
O2 association that warrants further
research activity.61
NAD(P)H Xanthine oxidase Selenium and normal pregnancy
NADPH oxidase The growing fetus requires selenium.
Mitochondrial Electron Transport Chain Se- lenium is transported across the
placenta by passive diffusion down a
NAD(P)+
concentration gradient.62 Decidual
-. selenium concentra- tions are higher
O2 63
than endometrial, whereas umbilical
SOD venous concentrations of selenium are
H
+ lower than maternal.64 In countries such
as Poland and Yugoslavia in which soil
Selenium-dependent
selenium content and dietary intake are
GPxs low, maternal selenium concen- trations
Catalase H 2O 2
and GPx activity fall during preg- nancy,
being the lowest at delivery com-
H 2O H2O pared with nonpregnant controls.65,66
In contrast, in areas of very high soil
sele- nium content (eg, South Dakota
2GSH GSSG and Southern Spain), it would appear
that there is no gestational trend in serum
sele- nium concentrations.67,68

Glutathione reductase Selenium and disorders of pregnancy


Superoxide can be generated by specialized enzymes, such as the xanthine or nicotinamide adenine Miscarriage
dinucleotide phosphate oxidase (NADPH) oxidases or as a byproduct of cellular metabolism, partic- Miscarriage, a clinically detectable preg-
ularly the mitochondrial electron transport chain. Superoxide dismutase (SOD) then converts the nancy that fails to progress past 24
superoxide (O2 ) to hydrogen peroxide (H2O2), which has to be rapidly removed from the system. weeks gestation, occurs in 10-20% of
This is generally achieved by catalase or peroxidases, such as the selenium-dependent GPxs, which all preg- nancies.69 Genetic
use reduced glutathione (GSH) as the electron donor. (chromosomal) ab- normalities explain
GSSG, glutathione disulfide. at least half of all miscarriages.
Mistry. Selenium in reproductive health. Am J Obstet Gynecol Although anatomical, en- docrine,
2012.
immune, infective, and throm-
bophilic conditions are other possible
causes, most chromosomally normal
miscarriages remain unexplained or
70
idiopathic.
In humans, a UK observational study
reported significantly lower serum sele-
TABLE 2
nium concentrations in 40 women with
Requirement of micronutrient intakes for selenium
first-trimester miscarriage compared
Micronutrient Group Selenium, g/d with 40 age-matched nonpregnant and
RDA
a
Female adult 55 40 healthy gestation-matched women71;
............................................................................................................................................
Pregnancy 60 a similar finding was reported in
............................................................................................................................................
Upper limit 400 another observational study from
72
..............................................................................................................................................................................................................................................
b Turkey.
RNI Female adult 60
............................................................................................................................................ Red-cell73 and hair74 selenium con-
Pregnancy 75
..............................................................................................................................................................................................................................................
c
centrations are also reported to be
NR Female adult 30
............................................................................................................................................ lower in women with recurrent
Pregnancy miscarriage. Conversely, a retrospective
..............................................................................................................................................................................................................................................
NR, normative requirement estimate; RDA, recommended dietary allowance; RNI, reference nutrient intakes. case-control study of nonpregnant
a
Values taken from Institute of Medicine;159,160 b Values taken from Department of Health;161 c Values taken from World Health women found no differences in
Organization/UN Food and Agriculture Organization/International Atomic Energy Agency.43
selenium concentration in
Mistry. Selenium in reproductive health. Am J Obstet Gynecol 2012.
47 women with a history of recurrent
mis- carriage compared with 47
75
controls. It must be noted that unlike the aforemen- tioned studies, which were
women in early
pregnancy, these were nonpregnant, and stopped, although this needs to be in- eclamptic women and 27 healthy controls
89

no information on parity or interpreg- vestigated in relation to preeclampsia. as well as cord blood and placental tissue
64
nancy intervals are provided, which Selenoprotein S (also known as collected immediately after delivery. To-
could confound the results. Early SEPS1 or VIMP), which contains a Sec
pregnancy loss has been linked to residue at its active site, is an
reduced antioxidant protection of antiinflammatory protein that acts
biological membranes and DNA and primarily to limit the damaging
also to low concentrations of the GPx,76- consequences of endoplasmic reticulum
78 90
warranting further investiga- tions to stress. It has recently been suggested
establish whether women with re- current to contribute to the develop- ment of
pregnancy loss could potentially benefit 91
preeclampsia. A polymorphic variant
from the optimization of selenium status. in the SEPS1 locus has been asso- ciated
with increased cardiovascular dis- ease
Preeclampsia morbidity in Finnish females and a
92

Preeclampsia (de novo proteinuric hy- 105G A promoter polymorphism as-


pertension) is estimated to occur in ap- sociated with reduced function has been
proximately 3% of all pregnancies and defined and is significantly but not
is a leading cause of maternal and strongly associated with preeclampsia.
93

perinatal mortality and morbidity in the Preeclampsia has a familial compo-


79,80
Western world ; together with other nent.94-96 A high prevalence of these
hyperten- sive disorders of pregnancy, poly- morphisms could, together with
preeclamp- sia is responsible for selenium deficiency, be a major
approximately determinant of im- paired antioxidant
60,000 maternal deaths each year81 and defense in this disorder, through altered
increases perinatal mortality 5-fold.82 selenoprotein activity, and thereby
Placental and maternal systemic oxida- contribute to development of the disease
tive stress are components of the syn- through nutrigenomic pathways.
drome83 and contribute to a generalized In the United Kingdom, where sele-
maternal systemic inflammatory activa- nium dietary intake is low, our group
84
tion. Placental ischemia-reperfusion and others have reported selenium con-
injury has been implicated in excessive centrations in preeclamptic pregnancies
production of ROS, causing release of to be reduced in sera from the
placental factors that mediate the in- mother
64,97,98
and fetus64 as well as in
85
flammatory responses. amniotic fluid99 and in toenails100 when
In light of the association between compared with normal pregnant controls.
ox- idative stress and the prevalence of Conversely, others have shown no
low dietary selenium status worldwide, 101
differences, and in 1 study from the
sev- eral studies have suggested that United States, higher sera selenium
selenium deficiency may be linked to concentrations have been reported in
preeclamp- sia. The recent appreciation women with preeclampsia.
102
that nutri- ent-gene interactions may However, a reported lack of sensitivity of
play a major role in manifestation of the assays used,101 or dependence of
hereditary dis- ease traits86 could be of the maternal leucocyte selenium content
relevance to the association between in es- timation of selenium status,
102

selenium status and preeclampsia. may con- found the interpretation of


Several genes that encode selenopro- these studies.
teins demonstrate functional polymor- GPx activities in both maternal and
phisms. Examples include GPx3, func- cord plasma have also been shown to be
tional polymorphisms that decrease lower in preeclamptic pregnancies.
transcriptional activation, gene expres- Several retrospective studies from
87,88
sion, and plasma protein activities. Turkey,
97,103,104
the United States,105,106
A single nucleotide polymorphism
and Australia107 of maternal plasma or
within the 3 untranslated region of the
placental tissue col- lected from normal
GPx4 gene (GPx4c718t) affects GPx
pregnancy and pre- eclampsia report a
protein concentration and activity but
reduction in GPx activ- ity in
also has differential effects on GPx3
preeclampsia. Our group recently
and GPx1 when selenium
conducted a retrospective cross-sectional
supplementation is
study in the United Kingdom of 25 pre-
tal GPx activity in plasma and in were random- ized to selenium (100 trimester (100 g selenium per day) in
placental tissue were significantly g/d) or placebo for a small pi- lot RCT and concluded that
64
reduced in pre- eclampsia. Further 6-8 weeks during late pregnancy. supplemen- tation may be associated
prospective, longitu- dinal studies are Maternal and umbilical serum selenium with a lower fre- quency of
required to elucidate a cause-or-effect rose signif- icantly, and the incidence preeclampsia, although this just failed
relationship. of PIH report- edly decreased.108 to reach statistical significance. There is
If selenium deficiency is confirmed in Another very small, prospective, no current consensus on the optimal
women suffering from preeclampsia and dou- ble-blind, placebo-controlled dietary selenium supplement for use
this continues to be linked with GPx in- RCT in In- donesia also reported in clinical supplementation be- cause
adequacy, adequately powered selenium lower rates of pre- eclampsia and/or bioavailability and effects on ex-
supplementation trials in pregnancy PIH in women who were at increased pression of the various selenoproteins
may be of benefit in prevention or ame- risk of developing these conditions depend on the form of selenium
30
lioration of preeclampsia. after supplementation with a range of product used. A small UK-based
Some small studies have attempted to antioxidants and cofactors in- cluding RCT of sele- nium supplementation
assess the influence of selenium supple- selenium (100 g).109 Neither study (selenium in pregnancy; Systolic
mentation on the incidence of pregnan- adequately addressed the role of Blood Pressure In- tervention Trial) is
cy-related hypertensive disorders. Beijing supplementation on the incidence of ongoing. Although not powered to
has a high incidence of both selenium preeclampsia. demonstrate clinical benefit, this study
de- ficiency and pregnancy-induced Recently, however, Tara et al110 inves- is designed to assess
hyperten- sion (PIH). One hundred tigated selenium supplementation
women with known risk factors for PIH of Iranian women in their first
the impact of selenium supplements on A potential association with selenium premature delivery and fetal distress and
preeclampsia-related biomarkers. If suc- has been highlighted through a recent is believed to be an important cause of
133
cessful, a larger multicenter RCT ade- small, prospective, double blind, stillbirth.
quately powered to detect differences in placebo-con- trolled RCT in Iran, Kauppila et al134 first demonstrated in
the rates of preeclampsia will be needed which randomized 1987 that serum selenium concentra-
to assess the potential clinical benefit.166 primigravid pregnant women in the tions and GPx activities were signifi-
first trimester of pregnancy to receive cantly lower in 12 Finnish women with
Preterm labor 100 OC when compared with 12 normal
Preterm labor (labor 37 weeks gesta- g/d selenium or placebo until pregnancies during the last trimester
tion) is a major cause of perinatal mor- delivery.123 and postpartum. These initial results
bidity and mortality occurring in 6-7% The supplemented group demonstrated a were confirmed and extended in a study
pregnancies in the developed world and significant increase in the mean serum se- in Chile, also showing that the decrease
up to 25% in undeveloped countries111 lenium concentration and a reduction in in prevalence of OC in Chile during the
and is likely to be of complex origin. A the incidence of PPROM.123 last decade coincided with an
few studies have investigated selenium increase in plasma selenium
135
and preterm labor. Cross-sectional stud- concentrations.
Small for gestation
ies in India,112 Holland,113 Germany,114 age Thus, it has been hypothesized that
115
and Iran all reported lower plasma se- inad- equate antioxidant protection
A small-for-gestational-age (SGA) in-
may lead
fant is defined as an individualized
to hepatocyte oxidative damage and re-
birth- weight ratio below the 10th
percentile and is associated with
increased perinatal
mortality and morbidity. 124 A recent pa-
lenium concentrations in women deliv- duce excretion of bile.136
ering preterm as compared with women per from North Dakota State University
delivering at term. suggests some protective effect of high Gestational diabetes mellitus
Another study from Poland reported selenium intake in nutrient-restricted Gestational diabetes mellitus (GDM) is
lower maternal selenium concentrations pregnant ewes on fetal birthweight and one of the commoner diseases in preg-
125
placental development. Some studies
and reduced maternal and cord plasma nancy and is an increasing problem with
GPx activities in 46 women who deliv- of SGA deliveries report reduced placen- 137
126 an incidence of 7.6%. GDM is defined
ered preterm compared with 42 women tal selenium concentrations, whereas as a deficient insulin supply relative to
127,128
delivering at term. The low selenium others report higher or unchanged
116
129 130 the increased demands that are charac-
concentrations and GPx activities in the concentrations. Strambi et al dem- 138
teristic of pregnancy. GDM is associ-
blood of the preterm infants may con- onstrated that in 81 SGA (both term and ated with birthweight above the 90th
tribute to their susceptibility to sepsis preterm) retrospective subjects from Italy, centile, increased levels of primary cesar-
and other prematurity-related condi- infant plasma selenium concentrations ean deliveries, and neonatal
tions. A study from the United States were significantly lower compared with
116
hypoglyce- mia if left untreated or
of 13 preterm and 15 term infants also adequate- for-gestational-age (AGA)
undiagnosed.
139

reported that preterm infants had lower infants.


The causes are not known but are
selenium concentrations compared with A recent investigation by our group
closely related to a constitutional risk
in a cohort of poor adolescent
of type 2 diabetes in later life and
pregnant
strongly associ-
women from 2 UK inner cities131 found
term infants, although maternal concen- ated with obesity.140-142
trations were not significantly differ- lower plasma selenium concentrations In diabetes protein glycosylation and
ent. As might be anticipated, the daily in mothers who delivered SGA infants
117
glucose autooxidation can lead to the
dietary selenium intake was 2-3 times compared with mothers who delivered
formation of free radicals, possibly in-
AGA infants.132 Again, geographical dif-
higher (96-134 g) than in the subjects ducing lipid peroxidation.143 An impor-
reported in the Polish population.116 mortality.
118,119
Increased generation of ferences may explain the difference be-
Population selenium intake may explain ROS as well as antioxidant deficiency tween the selenium status in the different
some variation between studies. may play an important role in the studies. We are not aware of any ongoing
Preterm premature rupture of mem- pathophysiology of PPROM, which has studies investigating maternal and fetal
branes before the onset of labor been associated with enhancement of selenium status in relation to fetal
(PPROM) is a major initiating factor in collagen degradation and subsequent growth restriction.
120-
preterm labor and affects 10-12% of damage to fetal membrane integrity.
all pregnancies. PPROM is associated 122
Obstetric cholestasis
worldwide with in- creased rates of Obstetric cholestasis (OC) is a serious
neonatal and maternal morbidity and complication of pregnancy and affects
approximately 4500 women per year in tant factor responsible for the GDM.146-149 Bo et al150 completed a ret-
the United Kingdom. Affected women develop- ment of oxidative stress rospective study investigating selenium
develop itching, otherwise-unexplained and ROS is hyperglycemia that intakes through dietary questionnaires
elevation of plasma liver enzymes and se- occurs in diabetic pregnancy.
144,145 in 504 pregnant women (210 with
rum bile acids and occasionally jaundice. Several studies from China, hyper- glycemia and 294 healthy
OC is associated with an increased risk of Kuwait, Turkey, and the United controls) as well as measuring serum
States have shown a decrease in concentrations in a second cohort (71
maternal plasma se- lenium hyperglycemic and 123 control women).
concentrations in women with A lower dietary
intake of selenium was observed in the ducted, further work is required on selenium supplementation with or with-
hyperglycemic group, and in the second op- timizing the timings, dosage, and out other antioxidants to ensure the best
cohort, the selenium concentrations were type of possible chances of positive outcomes.
significantly lower in the women who Only when such issues have been exam-
had impaired glucose tolerance; both ined and confirmed can a powered, care-
dietary intakes and selenium fully conducted, blinded, placebo-con-
concentration were negatively associated trolled RCT of selenium supplementation
with gestational hyper- glycemia in a both in relation to infertility and preg-
multiple regression model (odds ratio, nancy be completed in multiple centers in
0.97 and 0.92, respectively).150 areas of known selenium deficiency.
An inverse relationship between In conclusion, although persuasive ev-
selenium concentrations and blood idence already exists to suggest that ad-
glucose concen- trations has also been ditional selenium would be beneficial in
observed146-148 with- out changes in some of these disorders in selenium-in-
147
insulin, suggesting that selenium may sufficient women, results from interven-
affect glucose metabolism downstream tion trials underway or planned have the
from insulin or possibly through potential to reinforce or refute the argu-
independent energy-regulating ment for increasing selenium intake. f
147
pathways such as thyroid hormones.
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