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The importance of antioxidant micronutrients in pregnancy1

Hiten D. Mistry1 & Paula J. Williams2*2

1Division ofWomens Health, Maternal and Fetal Research Unit, St. Thomas Hospital , Kings College3

London, London, SE1 7UH, UK;4

2Human Genetics, School of Molecular and Medical Sciences, University of Nottingham, Queens Medical5

Centre, Nottingham, NG7 2UH, UK.6

7

*To whom correspondence should be addressed:8

Dr Paula J Williams9

Human Genetics,10

School of Molecular Medical Sciences,11

University of Nottingham,12

A Floor West Block,13

Queen's Medical Centre,14

Nottingham15

NG7 2UH16

E-mail: [email protected]

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Abstract25

Pregnancy places increased demands on the mother to provide adequate nutrition to the26

growing conceptus. A number of micronutrients function as essential cofactors for or27

themselves acting as antioxidants. Oxidative stress is generated during normal placental28

development however, when supply of antioxidant micronutrients is limited, exaggerated29

oxidative stress within both the placenta and maternal circulation occurs, resulting in30

adverse pregnancy outcomes. The present literature review summarises the current31

understanding of selected micronutrient antioxidants selenium, copper, zinc, manganese32

and vitamins C & E in pregnancy. To summarise antioxidant activity of selenium is via33

its incorporation into the glutathione peroxidase enzymes, levels of which have been34

shown to be reduced in miscarriage and pre-eclampsia. Copper, zinc and manganese are35

all essential cofactors for superoxide dismutases, which has reduced activity in36

pathological pregnancy. Larger intervention trials are required to reinforce or refute a37

beneficial role of micronutrient supplementation in disorders of pregnancies.38

39

Keywords: Pregnancy, antioxidants, micronutrients, vitamins.40

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Introduction48

Nutrition in Pregnancy49

The importance of proper nutrition prior to and throughout pregnancy has long been50

known for optimising the health and wellbeing of both mother and baby [1]. Pregnancy is51

a period of increased metabolic demands with changes in a womens physiology and the52

requirements of a growing fetus [2, 3]. Insufficient supplies of essential vitamins and53

micronutrients can lead to a state of biological competition between the mother and54

conceptus, which can be detrimental to the health status of both [4] Deficiency of trace55

elements during pregnancy is closely related to mortality and morbidity in the new born56

[5]. Deficiencies of specific antioxidant activities associated with the micronutrients57

selenium, copper, zinc and manganese can result in poor pregnancy outcomes, including58

fetal growth restriction [6], pre-eclampsia [7] and the associated increased risk of diseases59

in adulthood, including cardiovascular disease and type 2 diabetes [8-11].60

61

A large body of research has investigated the role of macronutrients in pregnancy and62

especially the effects of both maternal under and over nutrition on the long term health of63

the offspring [12, 13]. A number of hypotheses have been suggested to explain the64

contribution of maternal nutrition during the fetal and embryonic periods and the65

programming of the cardiovascular and metabolic system of the offspring [14, 15]. In66

addition to the contribution of macronutrition to successful pregnancy more recently67

studies have begun to focus on the role of essential specific micronutrients, so called68

because they are an absolute requirement and are required in only small amounts daily69

[16].70


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The pregnant mother must provide a source of nourishment and gaseous exchange to71

enable maximal embryonic and fetal growth to occur, whilst at the same time preparing72

her body for labour and parturition and the later demands of lactation. In addition a73

careful balance must be maintained between providing immune surveillance to protect the74

mother from infection, whilst at the same time allowing the implantation and survival of75

the semi-allogenic conceptus [17, 18]. The development and establishment of the76

placenta and its circulatory system is crucial in the successful maintenance of both77

maternal health and also enabling development of the embryo and growth of the fetus.78

79

The establishment of the feto-placental circulation requires the invasion of placental80

derived extravillous trophoblast from anchoring cytotrophoblast columns through the81

maternal decidua and into the maternal spiral arteries (Figure 1). During the first 8 weeks82

of pregnancy trophoblast plugs within the spiral arteries which exist to protect embryonic83

DNA from damage by oxidative stress [19], are released allowing the onset of placental84

circulation (Figure 1). The release of trophoblast plugs with flow of blood into the85

intervillous space leads to the generation of oxidative stress [20]. However, the placenta86

is armed with antioxidant defences, including the selenium-dependent glutathione87

peroxidases, thioredoxin reductases, selenoprotein-P and copper/zinc and manganese88

superoxide dismutases (Cu/Zn and Mn SODs) (Figure 2), which protect the placenta from89

any undue harm [21-24]. As the extravillous trophoblast cells migrate through the spiral90

artery wall they are involved in the process of physiological conversion, which serves to91

enlarge the vessel lumen thereby maximising blood supply to the intervillous space,92

enabling maximal perfusion of nutrients and gases through the placental93


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syncytiotrophoblast. Deficient extravillous trophoblast invasion is associated with94

reduced spiral artery remodelling leading to reduced blood flow and increased oxidative95

stress within the placenta and is known to be the primary defect occurring in pre-96

eclampsia [25, 26], fetal growth restriction [27, 28] and sporadic miscarriage [29].97

Additionally, pre-eclampsia has also been associated with reduced levels of antioxidant98

enzyme protection causing further placental damage [30-32].99

100

The pathogenesis of adverse pregnancy outcomes including pre-eclampsia and fetal101

growth restriction [33] and a number of neonatal outcomes [34] have been shown to be102

associated with oxidative stress. Pre-eclampsia (de novo proteinuric hypertension) is103

estimated to occur in ~3% of all pregnancies and is a leading cause of maternal and104

perinatal mortality and morbidity in the Western world [35, 36]; together with other105

hypertensive disorders of pregnancy, pre-eclampsia is responsible for approximately106

60,000 maternal deaths each year [37] and increases perinatal mortality five-fold [38].107

Optimal outcome for the mother and child often dictates that the infant is delivered early108

leading to increased preterm delivery and low infant birthweight rates. Placental and109

maternal systemic oxidative stress are components of the syndrome [39] and contribute to110

a generalised maternal systemic inflammatory activation [40]. Placental ischaemia-111

reperfusion injury has been implicated in excessive production of ROS, causing release of112

placental factors that mediate the inflammatory responses [41].113

114

Fetal growth restriction is associated with increased perinatal mortality and morbidity115

[42]. The mechanisms are still to be elucidated but a likely factor is placental116


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ischemia/hypoxia [43] but it is thought that ischemia-reperfusion injury may contribute to117

the oxidative stress and could result in the release of reactive oxygen species into the118

maternal circulation possibly resulting in oxidative DNA damage and may underlie119

development of fetal growth restriction [44].120

121

The current review focuses specifically on those micronutrients which are associated with122

antioxidant activity due to the importance of oxidative stress in both normal pregnancy123

and pathological pregnancy outcomes. However, it is important to highlight that other124

micronutrients are also important in pregnancy [16] but are outside the scope of the125

current review.126

127

Methods128

A number of micronutrients and vitamins are known to serve as antioxidants or be129

essential cofactors for antioxidant enzymes; these include, selenium, copper, zinc,130

manganese and vitamins C and E. The present literature review summarises current131

understanding of the importance of these micronutrient antioxidants in pregnancy. For132

this review, we included data and relevant information obtained through a search of the133

PubMed database using free text and Medical Subject Headings terms for all articles134

published in English from 1971 through 2011 which included the term selenium, zinc,135

copper, manganese, vitamin E and C and one of the following: pregnancy, pre-136

eclampsia or fetal growth restriction. We further included published and unpublished137

data from our own laboratories and an in-house library of relevant publications. The138

procedurewas concluded by the perusal of the reference sections of allrelevant studies or139


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reviews, a manual search of key journalsand abstracts from the major annual meetings in140

the field ofpregnancy and nutrition and contact with experts on the subject, in an effort to141

identify relevant unpublished data.142

143

Selenium144

Selenium is incorporated into proteins to make selenoproteins, including the glutathione145

peroxidase antioxidant enzymes, thioredoxin reductases and selenoprotein-P [45]. In146

addition, selenium is essential for the production of active thyroid hormones and is147

essential for normal thyroid function [46]. Maternal selenium concentrations and148

glutathione peroxidase activity fall during pregnancy (selenium concentrations in 1st149

trimester: 65 g/L; 3rdtrimester: 50 g/L) [47, 48]. Worldwide differences exist in150

assessment of selenium requirements, adequacy and intakes (Table 1). Most of these151

values have been determined from the intake believed necessary to maximise the activity152

of the antioxidant glutathione peroxidase in plasma [49, 50] and selenium, like vitamins153

C and E has received much attention in recent years. It has been observed that babies on154

average have lower selenium concentrations compared to the mother (Maternal selenium155

58.4 g/L; Umbilical cord selenium: 42.1 g/L) [32, 51], which is expected as selenium156

is transported via the placenta across a concentration gradient via an anion exchange157

pathway, shared with sulphate [52, 53].158

159

Recurrent early pregnancy loss has been associated with reduced serum selenium160

concentrations compared to healthy controls in two observational studies from UK (mean161

SD: 54 19 vs. 76 14 g/L respectively) [54] and Turkey (55 17 vs. 81 16 g/L162


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respectively) [55]. It has therefore been suggested that reduced selenium concentration163

results in reduced glutathione peroxidase activity culminating in reduced antioxidant164

protection of biological membranes and DNA during the early stages of embryonic165

development [54, 56]. Although speculative, and requiring larger placebo-controlled166

randomised trials, women with recurrent early pregnancy loss may benefit from167

optimisation of selenium status.168

169

Recently, our group and others have demonstrated through retrospective studies, the170

association between low serum selenium concentrations and reduced antioxidant function171

of the associated antioxidant glutathione peroxidase enzymes in women with pre-172

eclampsia (defined a de novo proteinuric hypertension) [32, 57, 58]. It has been suggested173

that adequate selenium status is important for antioxidant defence and may be a potential174

factor in women at risk of pre-eclampsia; this hypothesis has been further justified by the175

reduced expression and activities of glutathione peroxidase found in maternal, fetal and176

placental samples taken from 25 pre-eclamptic pregnancies, when compared to 27 normal177

controls in our recent cross-sectional retrospective study [32]. Dawson et al, also178

completed a retrospective study in the US and reported lower amniotic fluid selenium179

concentrations in 29 pre-eclamptics delivering between 33-36 weeks gestation compared180

to 48 gestation-matched controls (10 1 vs. 7 0.7 g/L respectively) [59].181

182

Fetal growth restriction or delivery of a small-for-gestational-age (SGA) is defined as an183

individualised birth weight ratio below the 10th percentile [42]. Reports of selenium184

concentrations with regards to fetal growth restriction are inconsistent. A retrospective185


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study had reported low placental selenium concentrations in 49 mothers affected by fetal186

growth restriction, compared to 36 healthy normal birth weight controls [60], whereas187

others have reported higher [61, 62] or unchanged concentrations [63]. Another188

retrospective study also demonstrated that in 81 SGA babies, infant plasma selenium189

concentrations to be significantly lower compared to controls [64]. A recent retrospective190

study by our group on an adolescent cohort [65] found lower maternal plasma selenium191

concentrations on 28 mothers who delivered SGA babies compared to 143 healthy192

controls [66]. Further studies are warranted to fully investigate the potential link between193

selenium deficiency and fetal growth restriction.194

195

Only a small number of selenium supplementation trials during pregnancy have been196

carried out to date. A prospective, randomised, placebo controlled study of selenium197

supplementation during and after pregnancy in pregnant women positive for thyroid198

peroxidase antibodies (TPOAb(+)) who are prone to develop postpartum thyroid199

dysfunction (PPTD) and permanent hypothyroidism found that supplementation with 200200

g/d selenomethionine significantly reduced the incidence of PPTD and permanent201

hypothyroidism [67]. The authors concluded that selenium supplementation during202

pregnancy and in the postpartum period reduced thyroid inflammatory activity and the203

incidence of hypothyroidism, possibly by increasing the selenoproteins glutathione204

peroxidase or iodothyronine deiodinase activities, thereby contributing in part, to205

counterbalance the postpartum immunological rebound [67].206

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To date there have been a couple of small placebo-controlled randomised control trials on208

selenium supplementation, reporting lower rates of pre-eclampsia and/or pregnancy209

induced hypertension in the supplemented groups [68-70]. It must be noted that neither of210

these studies adequately addressed the role of supplementation on the incidence of pre-211

eclampsia. Currently the Selenium in Pregnancy Intervention Trial (SPRINT) is212

underway in the UK, jointly by the University of Surrey and Oxford. This is a small213

randomised controlled trial of selenium supplementation (60 g a day). It is not powered214

to demonstrate clinical benefit but will provide insight into the impact of selenium215

supplements on laboratory measurements of circulating factors that are relevant to the216

development of pre-eclampsia. If this is successful a much larger multicentre trial will be217

needed to analyse clinical benefit.218

219

Copper220

Copper is an essential cofactor for a number of enzymes involved in metabolic reactions,221

angiogenesis, oxygen transport and antioxidant protection, including catalase, superoxide222

dismutase (SOD) (Figure 2) and cytochrome oxidase [71]. During pregnancy, plasma223

copper concentrations significantly increase, returning to normal non-pregnant values224

after delivery (Mean SD - 1st trimester: 147.6 34.6; 3rd trimester: 204.2 41.8 g/L)225

[72-74]. The increase in copper with progression of pregnancy could be partly related to226

synthesis of ceruloplasmin, a major copper binding protein, due to altered levels of227

oestrogen [74]. Approximately 96% of plasma copper is strongly bound to ceruloplasmin228

[75], a protein with antioxidant ferroxidase properties [75, 76]. The dietary intake of229

copper in women aged between 19-24 years is generally below the recommended levels230


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(Table 1) [77] which may cause problems during pregnancy when requirements increase231

[78].232

233

Copper is essential for embryonic development [79]. Maternal dietary deficiency can234

result in both short term consequences including early embryonic death and gross235

structural abnormalities, as well as long term consequences such as increased r isk of236

cardiovascular disease risk and reduced fertilisation rates [71, 80]; current237

recommendations on intakes are summarised in Table 1. Severe copper deficiency can238

lead to reproductive failure and early embryonic death [81], whereas mild or moderate239

deficiency has little effect on either the number of live births or neonatal weight [82].240

241

Cu/Zn SOD is an important antioxidant known to be expressed in both maternal and fetal242

tissues [83]. Copper concentration has been shown to be higher in maternal plasma than243

in umbilical cord plasma [84-86]. It has been suggested that the placenta acts as a244

blockade in the transfer of copper from the mother to the fetus [86, 87]. A recent245

observational Turkish study on 61 placentae from healthy pregnancies between 37 and 40246

weeks gestat ion found that copper concentrations positively correlated with neonatal247

weight; the authors suggested that copper may have interactive connections in human248

placenta [88] and this requires further studies to fully elucidate its role. It is known that249

copper is transferred across the placenta via high affinity copper transporter (CTR1) and250

have been shown to be expressed early in pregnancy and it is also thought that placental251

copper transport is related to iron transport but the mechanism is unknown [78].252

253


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A small retrospective study in the 1980s reported increased placental copper254

concentrations in 8 pre-eclamptic women compared to 10 controls (53 vs. 124 g/Kg255

respectively), suggesting that this increase in pre-eclampsia maybe an exaggerated256

response of normal pregnancies [89]. Further retrospective studies from Turkey have257

shown elevation of maternal serum copper levels in pre-eclampsia after clinical onset of258

the disease compared to controls (mean SD: 159 38 vs. 194 52 g/L respectively)259

[90, 91]. Moreover, increased amniotic fluid copper concentration from 19 pre-eclamptic260

women compared to 53 controls has also been reported (mean SD: 19 5 vs. 29 3261

g/L respectively) [59]. It is thought that as copper is a redox-active transition metal and262

can participate in single electron reactions and catalyse the formation of free radicals,263

including undesirable hydroxyl radicals, it could contribute to oxidative stress264

characteristic of pre-eclampsia [90]. This illustrates that copper itself appears to act as a265

pro-oxidant, but when associated in Cu/Zn SOD functions as an antioxidant.266

Furthermore, studies have reported increased levels of serum ceruloplasmin in women267

with pre-eclampsia; this positively correlated with serum malondialdehyde, suggesting an268

increased production of this antioxidant protein in response to increased lipid269

peroxidation [90, 92, 93], although further studies are required to confirm this hypothesis.270

However, it must be remembered that concentrations early in pregnancy have yet to be271

determined and data on copper status in normal human pregnancies are sparse. This is272

further hampered by the fact that at present there is no reliable biomarker for copper273

status, so whether deficiency is a significant public health problem remains unclear [94].274

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Zinc277

Zinc is an essential constituent of over 200 metalloenzymes participating in carbohydrate278

and protein metabolism, nucleic acid synthesis, antioxidant functions (through Cu/Zn279

SOD; Fig. 2) and other vital functions such cellular division and differentiation, making it280

essential for successful embryogenesis. [72]. It was estimated in 2002 by the World281

Health Organisation that suboptimal zinc nutrition effected nearly half the worlds282

population [95]. During pregnancy, zinc is also used to assist the fetus to develop the283

brain and also to be an aid to the mother in labour [96]. It has been estimated that the total284

amount of zinc retained during pregnancy is ~ 100 mg [97]. The requirement of zinc285

during the third trimester is approximately twice as high as that in non-pregnant women286

[98]. Plasma zinc concentrations decline as pregnancy progresses (mean SD1st287

trimester: 71.3 12.9 g/L; 3rdtrimester: 58.5 11.5 g/L) [72, 74, 99, 100]. In addition,288

a nutrition analysis revealed that in pregnant women the everyday diet intakes includes289

not more than 50% of the daily requirement of zinc [101].290

291

Alteration in zinc homeostasis may have devastating effects on pregnancy outcome,292

including prolonged labour, fetal growth restriction, or embryonic or fetal death [102].293

Zinc is a trace element with a great importance for fetal growth restriction where it is294

used in order to improve fetal growth [72]. Goldenberg et al completed a randomised295

double-blind placebo-controlled trail of zinc supplementation (25 mg per day) during296

pregnancy from 19 weeks gestation in African-American women (294 in supplemented297

and 286 in placebo group). Those given zinc supplementation had a significantly greater298

birth weight and head circumference compared to the placebo group highlighting the299


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importance of adequate zinc supply during pregnancy [103]. A limitation of many of the300

randomised controlled trails of zinc supplementation and pregnancy outcome is that they301

lacked the sample sizes to detect differences [102].302

303

Many of the zinc supplementation studies have been conducted in developing countries304

where incidence of zinc deficiency is high and these women are often selected as they are305

less well nourished or have low plasma zinc levels [103, 104]; benefits of306

supplementation include reduced incidence of pregnancy-induced hypertension or low307

birth weights [103]. These studies do however suggest the benefits of zinc308

supplementation in developing countries where zinc deficiency is likely, although for309

developed countries there is conflicting data as to the benefits [105-108].310

311

Zinc deficiency has been associated with pre-eclampsia since the 1980s [59, 89, 109]312

including adolescent pregnancies [110]. Placental zinc concentration has also been shown313

to be lower in pre-eclampsia in cross-sectional retrospective studies with placental zinc314

values positively correlating with birth weights [89, 111, 112]. More recently lower315

serum concentrations of zinc in pre-eclampsia compared to controls have been shown in316

two relatively small retrospective studies from Turkey (mean SD: 10.6 4.4 vs. 12.7 317

4.1 g/L respectively) [91, 113]; the authors suggested that this may be useful for early318

diagnosis as lower plasma zinc concentrations have been associated with increased lipid319

peroxidation in rat studies [114]. Moreover, in a recent retrospective study in India320

reported reduced serum zinc concentrations in mild and severe pre-eclamptic mothers321

compared to controls; the authors suggest that the reduction could not only effect the322


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antioxidant protection but could also contribute to the rise in blood pressure [115]. The323

lower serum zinc concentrations in mothers who develop pre-eclampsia has been324

suggested to at least be partly due to reduced oestrogen and zinc binding-protein levels325

[116]. Zinc is transported across the placenta via active transport from the mother to the326

fetus [109]. Studies have shown that the fetus has notably higher zinc concentrations327

compared to the mother, even in cases of pre-eclampsia [109, 117], indicating that the328

fetus itself, can maintain adequate zinc homeostasis. Amniotic fluid zinc concentrations329

have also been reported to be decreased in pre-eclamptic women delivering preterm (33-330

36 weeks gestation) in a small retrospective cross-sectional study from the US [59]. It331

must be noted that as with all these micronutrients, the concentrations early in pregnancy332

in relation to the development of pregnancy complications remains to be established.333

334

Manganese335

Manganese is a free element in nature (often in combination with iron), furthermore336

manganese(II) ions function as cofactors for a number of enzymes; the element is thus a337

required trace mineral for all known living organisms. Manganese is also an important338

cofactor for a number of enzymes, including the antioxidant manganese superoxide339

dismutase (Mn-SOD; Figure 2) which may protect the placenta from oxidative stress by340

detoxifying superoxide anions [118]. Dietary manganese is the main source of exposure341

under normal circumstances; current requirements for manganese, although less studied342

compared to other micronutrients are shown in Table 1 and little is known about the343

effects of deficiency or excess of manganese on the developing human fetus or pregnancy344

outcome [119]. This is further hampered by the fact that at present sensitive biomarkers345


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of manganese exposure and nutritional status are not available other than some estimates346

from blood concentrations [119].347

348

Circulating whole blood manganese concentrations have been shown to be lower in349

women with fetal growth restriction compared to healthy controls (mean SD: 16.7 4.8350

vs. 19.1 5.9 g/L respectively) indicating that this micronutrient may be important in351

maintaining fetal growth [120]. This study also found that manganese concentrations352

were higher in umbilical samples from fetal growth restriction cases compared to controls353

suggesting that manganese contributes to different effects on birth weight in healthy354

mothers [120]. Zota et al retrospective study in the US reported a non- linear relationship355

between manganese concentrations and birth weights in a cohort of 470 full term356

(delivered at > 37 weeks gestation) infant further indicating the potential affect on fetal357

growth [121]. A recent small retrospective study of African-American mothers reported358

reduced umbilical cord whole blood manganese concentrations in neonates born to359

mothers with pre-eclampsia compared to controls (mean [95% CI]: 2.2 [1.5, 3.2] vs. 3.7360

[3.2, 4.2] g/L respectively) [122]. Furthermore, this study found that like other361

micronutrients umbilical cord blood from smoking mothers had reduced manganese362

concentrations [122]. Than et al demonstrated increased fetal membrane MnSOD mRNA363

expression in women with pre-term labour [123]. Manganese is one of the least studied364

micronutrients and at present no supplementation trial has been published which may365

reflect the lack of data on manganese concentrations in pregnancy.366

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Vitamins C and E369

Vitamin C (ascorbic acid and dihydroascorbic acid) is an essential water-soluble vitamin370

found widely in fruit and vegetables; it has important roles in collagen synthesis, wound371

healing, prevention of anaemia and as an antioxidant as it can quench a variety of reactive372

oxygen species and reactive nitrogen species in aqueous environments [124]. Vitamin C373

is commonly included in low doses (


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multicentre double-blinded randomised trials of a combination of vitamin C and E [129,392

130] also found supplementation did not reduce the rate of pre-eclampsia or gestational393

hypertension and like the Vitamins In Pre-eclampsia trial in 2006 [131] increased the risk394

of fetal loss or perinatal death and preterm prelabour rupture of membranes. Another395

recent multicentre placebo-controlled trial of vitamin C and E in women with type-1396

diabetes in pregnancy (DAPIT) also reported no differences in the rates of pre-eclampsia397

between supplemented or placebo groups [132]. Further investigations are required as the398

concentrations of these vitamins remain significantly reduced in women with pre-399

eclampsia, but in the absence of further evidence, routine supplementation with higher400

dose vitamin C and E is not recommended as they can be potentially dangerous in high401

concentrations.402

403

Adolescent pregnancies404

Another factor to highlight is that pregnancy in adolescent women is a topic of increasing405

health concern in many countries [133]. Pregnant adolescents are of a greater nutritional406

risk as they themselves are undergoing an intense process of growth and development407

[134]. It has been suggested that there is competition for nutrients between a pregnant408

adolescent and her fetus, as both are in critical stages of growth during the gestational409

period [65, 135]. As mentioned throughout above, micronutrient deficiencies have been410

associated with adolescent pregnancies [66, 84, 110]. The recent About Teenage Eating411

study showed that teenage pregnancy in the UK is associated with decreased412

consumption of micronutrients and that this is associated with an increased risk of SGA413

infants [65].414


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Low micronutrient intake poses a health risk to successful pregnancy in the UK,415

especially in adolescence. Socioeconomic deprivation in the UK population has been416

shown to be an independent risk factor for eating less fruit and vegetables and also for417

increased smoking, which is known to cause further depletion of micronutrients [136].418

Although attempts are being made to persuade women of low socioeconomic status of the419

importance of a balanced diet, the central roles that fruit and vegetables have in this and420

that healthy food can be low cost and convenient this is often met with resistance [137].421

422

The increase in pregnancies in mothers of older ages highlights another subgro up at423

increased risk of pregnancy complications. We are not aware of any studies at present424

examining this important group and future investigations are required especially as some425

of these micronutrient concentrations decline with increasing age.426

427

Conclusions428

Increased knowledge about the importance of these specific antioxidant micronutrients429

and the crucial part that they have in maintaining successful pregnancy and determining430

both the long and short term health of both mother and baby needs to be addressed and431

made a key focus for future health strategies in improving pregnancy outcomes. This is432

particularly important with regards to pre-eclampsia and fetal growth restriction, where433

oxidative stress is an essential component to the aetiology of these conditions and so434

these specific antioxidant micronutrient deficiencies may play a contributing role. Only435

by fully understanding the requirements for micronutrients during pregnancy will we be436

able to evaluate the potential use of these dietary antioxidant supplements as a way of437


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preventing pathological pregnancy outcomes. However, it must also be remembered that438

these antioxidant and other micronutrients can be obtained via a healthy diet thereby439

negating the need for supplementation. Future strategies focussing on providing440

nutritional guidance specifically to pregnant women will be pivotal in helping to ensure441

optimal health of both mother and baby.442

443

Key Messages444

1) Further research is needed to accurately quantify levels of micronutrients in445pregnancy and how levels vary over the course of pregnancy.446

2) The actions of antioxidant micronutrients on maternal, fetal and placental health447needs to further elucidated.448

3) Prenatal guidance needs to be made clear to ensure that women and practioners449are aware of the nutritional requirements during pregnancy, and how healthy diet450

can prevent diseases of pregnancy.451

452

Conflict of Interest: None of the authors have any conflict of interest.453

454

Funding: H.D. Mistry was funded by Tommys Charity (Charity No. 3266897) and P.J.455

Williams was supported by the Nottingham University Hospitals Special Trustees Charity456

(RB17B3).457

458

459

460


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References461

[1] Allen LH. Multiple micronutrients in pregnancy and lactation: an overview. Am J462

Clin Nutr 2005;81:1206S.463

[2] Broughton Pipkin F. Maternal Physiology. In: Edmonds DK, editor. Dewhurst's464

textbook of Obstetrics and Gynaecology. Oxford: Blackwell Publishing, 2007.465

[3] Bader RA, Bader ME, Rose DF, Braunwald E. Hemodynamics at rest and during466

exercise in normal pregnancy as studies by cardiac catheterization. J Clin Invest467

1955;34:1524.468

[4] King JC. The risk of maternal nutritional depletion and poor outcomes increases469

in early or closely spaced pregnancies. J Nutr 2003;133:1732S.470

[5] Srivastava S, Mehrotra PK, Srivastava SP, Siddiqui MK. Some essential elements471

in maternal and cord blood in relation to birth weight and gestational age of the baby.472

Biol Trace Elem Res 2002;86:97.473

[6] Fall CH, Yajnik CS, Rao S, Davies AA, Brown N, Farrant HJ. Micronutrients and474

fetal growth. J Nutr 2003;133:1747S.475

[7] Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxidants for preventing pre-476

eclampsia. Cochrane Database Syst Rev 2008:CD004227.477

[8] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of478

cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ479

2007;335:974.480

[9] Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ.481

Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2482

diabetes mellitus in the mother. Hypertension 2009;53:944.483


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22

[10] Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and484

the risk of end-stage renal disease. N Engl J Med 2008;359:800.485

[11] Staff AC, Dechend R, Pijnenborg R. Learning From the Placenta. Acute Atherosis486

and Vascular Remodeling in Preeclampsia-Novel Aspects for Atherosclerosis and Future487

Cardiovascular Health. Hypertension 2010.488

[12] Armitage JA, Khan IY, Taylor PD, Nathanielsz PW, Poston L. Developmental489

programming of the metabolic syndrome by maternal nutritional imbalance: how strong490

is the evidence from experimental models in mammals? J Physiol 2004;561:355.491

[13] Armitage JA, Taylor PD, Poston L. Experimental mode ls of developmental492

programming: consequences of exposure to an energy rich diet during development. J493

Physiol 2005;565:3.494

[14] Solomons NW. Developmental origins of hea lth and disease: concepts, caveats,495

and consequences for public health nutrition. Nutr Rev 2009;67 Suppl 1:S12.496

[15] Wells JC. The thrifty phenotype as an adaptive maternal effect. Biol Rev Camb497

Philos Soc 2007;82:143.498

[16] Cetin I, Berti C, Calabrese S. Role of micronutrients in the periconceptional499

period. Hum Reprod Update 2009.500

[17] Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF, 3rd, Petraglia F.501

Inflammation and pregnancy. Reprod Sci 2009;16:206.502

[18] Hanson LA, Silfverdal SA. The mother's immune system is a balanced threat to503

the foetus, turning to protection of the neonate. Acta Paediatr 2009;98:221.504

[19] Ornoy A. Embryonic oxidative stress as a mechanism of teratogenesis with505

special emphasis on diabetic embryopathy. Reprod Toxicol 2007;24:31.506


23/41

23

[20] Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of507

maternal arterial blood flow and placental oxidative stress. A possible factor in human508

early pregnancy failure. Am J Pathol 2000;157:2111.509

[21] Wang Y, Walsh SW. Antioxidant activities and mRNA expression of superoxide510

dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas. J511

Soc Gynecol Investig 1996;3:179.512

[22] Vanderlelie J, Venardos K, Clifton VL, Gude NM, Clarke FM, Perkins AV.513

Increased biological oxidation and reduced anti-oxidant enzyme activity in pre-eclamptic514

placentae. Placenta 2005;26:53.515

[23] Mistry HD, Kurlak LO, Williams PJ, Ramsay MM, Symonds ME, Broughton516

Pipkin F. Differential expression and distribution of placental glutathione peroxidases 1,517

3 and 4 in normal and preeclamptic pregnancy. Placenta 2010;31:401.518

[24] Rayman MP. Selenoproteins and human health: Insights from epidemiological519

data. Biochim Biophys Acta 2009.520

[25] Redman CW, Sargent IL. Placental debris, oxidative stress and pre-eclampsia.521

Placenta 2000;21:597.522

[26] Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to523

preeclampsia. J Soc Gynecol Investig 2004;11:342.524

[27] Brosens I, Dixon HG, Robertson WB. Fetal growth retardation and the arteries of525

the placental bed. Br J Obstet Gynaecol 1977;84:656.526

[28] Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the527

pathogenesis of preeclampsia. Obstet Gynecol Annu 1972;1:177.528


24/41

24

[29] Gupta S, Agarwal A, Banerjee J, Alvarez JG. The role of oxidative stress in529

spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol530

Surv 2007;62:335.531

[30] Perkins AV. Endogenous anti-oxidants in pregnancy and preeclampsia. Aust N Z532

J Obstet Gynaecol 2006;46:77.533

[31] Nakamura M, Sekizawa A, Purwosunu Y, Okazaki S, Farina A, Wibowo N,534

Shimizu H, Okai T. Cellular mRNA expressions of anti-oxidant factors in the blood of535

preeclamptic women. Prenat Diagn 2009;29:691.536

[32] Mistry HD, Wilson V, Ramsay MM, Symonds ME, Broughton Pipkin F. Reduced537

selenium concentrations and glutathione peroxidase activity in pre-eclamptic pregnancies.538

Hypertension 2008;52:881.539

[33] Myatt L, Cui X. Oxidative stress in the placenta. Histochem Cell Biol540

2004;122:369.541

[34] Saugstad OD. Update on oxygen radical disease in neonatology. Curr Opin Obstet542

Gynecol 2001;13:147.543

[35] Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet544

2010.545

[36] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785.546

[37] Broughton Pipkin F. Risk factors for preeclampsia. N Engl J Med 2001;344:925.547

[38] Roberts JM, Lain KY. Recent Insights into the pathogenesis of pre-eclampsia.548

Placenta 2002;23:359.549

[39] Poston L. The Role of Oxidative Stress. In: Critchley H, MacLean A, Poston L,550

Walker J, editors. Pre-eclampsia. London: RCOG Press, 2004.551


25/41

25

[40] Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic552

inflammatory response--a review. Placenta 2003;24 Suppl A:S21.553

[41] Hung TH, Burton GJ. Hypoxia and reoxygenation: a possible mechanism for554

placental oxidative stress in preeclampsia. Taiwan J Obstet Gynecol 2006;45:189.555

[42] Cetin I, Foidart JM, Miozzo M, Raun T, Jansson T, Tsatsaris V, Reik W, Cross J,556

Hauguel-de-Mouzon S, Illsley N, Kingdom J, Huppertz B. Fetal growth restriction: a557

workshop report. Placenta 2004;25:753.558

[43] Biri A, Bozkurt N, Turp A, Kavutcu M, Himmetoglu O, Durak I. Role of559

oxidative stress in intrauterine growth restriction. Gynecol Obstet Invest 2007;64:187.560

[44] Takagi Y, Nikaido T, Toki T, Kita N, Kanai M, Ashida T, Ohira S, Konishi I.561

Levels of oxidative stress and redox-related molecules in the placenta in preeclampsia562

and fetal growth restriction. Virchows Arch 2004;444:49.563

[45] Rayman MP. The importance of selenium to human health. Lancet 2000;356:233.564

[46] Beckett GJ, Arthur JR. Selenium and endocrine systems. J Endocrinol565

2005;184:455.566

[47] Zachara BA, Wardak C, Didkowski W, Maciag A, Marchaluk E. Changes in567

blood selenium and glutathione concentrations and glutathione peroxidase activity in568

human pregnancy. Gynecol Obstet Invest 1993;35:12.569

[48] Mihailovic M, Cvetkovic M, Ljubic A, Kosanovic M, Nedeljkovic S, Jovanovic I,570

Pesut O. Selenium and malondialdehyde content and glutathione peroxidase activity in571

maternal and umbilical cord blood and amniotic fluid. Biol Trace Elem Res 2000;73:47.572

[49] Thomson CD. Assessment of requirements for selenium and adequacy of573

selenium status: a review. Eur J Clin Nutr 2004;58:391.574


26/41

26

[50] Rayman MP. Food-chain selenium and human health: emphasis on intake. Br J575

Nutr 2008;100:254.576

[51] Gathwala G, Yadav OP, Singh I, Sangwan K. Maternal and cord plasma selenium577

levels in full- term neonates. Indian J Pediatr 2000;67:729.578

[52] Shennan DB. A study of selenate efflux from human placental microvillus579

membrane vesicles. Biosci Rep 1987;7:675.580

[53] Shennan DB. Selenium (selenate) transport by human placental brush border581

membrane vesicles. Br J Nutr 1988;59:13.582

[54] Barrington JW, Taylor M, Smith S, Bowen-Simpkins P. Selenium and recurrent583

miscarriage. J Obstet Gynaecol 1997;17:199.584

[55] Kocak I, Aksoy E, Ustun C. Recurrent spontaneous abortion and selenium585

deficiency. Int J Gynaecol Obstet 1999;65:79.586

[56] Zachara BA, Dobrzynski W, Trafikowska U, Szymanski W. Blood selenium and587

glutathione peroxidases in miscarriage. BJOG 2001;108:244.588

[57] Rayman MP, Bode P, Redman CW. Low selenium status is associated with the589

occurrence of the pregnancy disease preeclampsia in women from the United Kingdom.590

Am J Obstet Gynecol 2003;189:1343.591

[58] Maleki A, Fard MK, Zadeh DH, Mamegani MA, Abasaizadeh S, Mazloomzadeh592

S. The Relationship between Plasma Level of Se and Preeclampsia. Hypertens Pregnancy593

2010.594

[59] Dawson EB, Evans DR, Nosovitch J. Third-trimester amniotic fluid metal levels595

associated with preeclampsia. Arch Environ Health 1999;54:412.596


27/41

27

[60] Klapec T, Cavar S, Kasac Z, Rucevic S, Popinjac A. Selenium in placenta597

predicts birth weight in normal but not intrauterine growth restriction pregnancy. J Trace598

Elem Med Biol 2008;22:54.599

[61] Osada H, Watanabe Y, Nishimura Y, Yukawa M, Seki K, Sekiya S. Profile of600

trace element concentrations in the feto-placental unit in relation to fetal growth. Acta601

Obstet Gynecol Scand 2002;81:931.602

[62] Zadrozna M, Gawlik M, Nowak B, Marcinek A, Mrowiec H, Walas S, Wietecha-603

Posluszny R, Zagrodzki P. Antioxidants activities and concentration of selenium, zinc604

and copper in preterm and IUGR human placentas. J Trace Elem Med Biol 2009;23:144.605

[63] Llanos MN, Ronco AM. Fetal growth restrict ion is related to placental levels of606

cadmium, lead and arsenic but not with antioxidant activities. Reprod Toxicol607

2009;27:88.608

[64] Strambi M, Longini M, Vezzosi P, Berni S, Buoni S. Selenium status, birth609

weight, and breast-feeding: pattern in the first month. Biol Trace Elem Res 2004;99:71.610

[65] Baker PN, Wheeler SJ, Sanders TA, Thomas JE, Hutchinson CJ, Clarke K, Berry611

JL, Jones RL, Seed PT, Poston L. A prospective study of micronutrient status in612

adolescent pregnancy. Am J Clin Nutr 2009;89:1114.613

[66] Mistry HD, Kurlak LO, Young SY, Briley AL, Broughton Pipkin F, Poston L.614

Reduced plasma selenium in adolescent mothers with small for gestational age infants;615

impact of smoking and ethnicity. Society for Gynecologic Investigation. Orlando:616

Reproductive Sciences, 2010.617


28/41

28

[67] Negro R, Greco G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. The influence618

of selenium supplementation on postpartum thyroid status in pregnant women with619

thyroid peroxidase autoantibodies. J Clin Endocrinol Metab 2007;92:1263.620

[68] Han L, Zhou SM. Selenium supplement in the prevention of pregnancy induced621

hypertension. Chin Med J (Engl) 1994;107:870.622

[69] Rumiris D, Purwosunu Y, Wibowo N, Farina A, Sekizawa A. Lower rate of623

preeclampsia after antioxidant supplementation in pregnant women with low antioxidant624

status. Hypertens Pregnancy 2006;25:241.625

[70] Tara F, Rayman MP, Boskabadi H, Ghayour-Mobarhan M, Sahebkar A, Yazarlu626

O, Ouladan S, Tavallaie S, Azimi-Nezhad M, Shakeri MT, Teymoori MS, Razavi BS,627

Oladi M, Ferns G. Selenium supplementation and premature (pre-labour) rupture of628

membranes: a randomised double-blind placebo-controlled trial. J Obstet Gynaecol629

2010;30:30.630

[71] Gambling L, Andersen HS, McArdle HJ. Iron and copper, and their interactions631

during development. Biochem Soc Trans 2008;36:1258.632

[72] Izquierdo Alvarez S, Castanon SG, Ruata ML, Aragues EF, Terraz PB, Irazabal633

YG, Gonzalez EG, Rodriguez BG. Updating of normal levels of copper, zinc and634

selenium in serum of pregnant women. J Trace Elem Med Biol 2007;21 Suppl 1:49.635

[73] Huang HM, Leung PL, Sun DZ, Zhu MG. Hair and serum calcium, iron, copper,636

and zinc levels during normal pregnancy at three trimesters. Biol Trace Elem Res637

1999;69:111.638


29/41

29

[74] Liu J, Yang H, Shi H, Shen C, Zhou W, Dai Q, Jiang Y. Blood copper, zinc,639

calcium, and magnesium levels during different duration of pregnancy in Chinese. Biol640

Trace Elem Res 2010;135:31.641

[75] Fattah MM, Ibrahim FK, Ramadan MA, Sammour MB. Ceruloplasmin and642

copper level in maternal and cord blood and in the placenta in normal pregnancy and in643

pre-eclampsia. Acta Obstet Gynecol Scand 1976;55:383.644

[76] Shakour-Shahabi L, Abbasali-Zadeh S, Rashtchi-Zadeh N. Serum level and645

antioxidant activity of ceruloplasmin in preeclampsia. Pakistan Journal of biological646

Sciences 2010;13:321.647

[77] Institute of Medcine. Dietary Reference Intakes for Vitamin A, Vitamin K,648

Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel,649

Silicon, Vanadium, and Zinc.: National Academy Press, 2001.650

[78] McArdle HJ, Andersen HS, Jones H, Gambling L. Copper and iron transport651

across the placenta: regulation and interactions. J Neuroendocrinol 2008;20:427.652

[79] Kambe T, Weaver BP, Andrews GK. The genetics of essential metal homeostasis653

during development. Genesis 2008;46:spcone.654

[80] Keen CL, Hanna LA, Lanoue L, Uriu-Adams JY, Rucker RB, Clegg MS.655

Developmental consequences of trace mineral deficiencies in rodents: acute and long-656

term effects. J Nutr 2003;133:1477S.657

[81] Prohaska JR, Brokate B. The timing of perinata l copper deficiency in mice658

influences offspring survival. J Nutr 2002;132:3142.659

[82] Masters DG, Keen CL, Lonnerdal B, Hurley LS. Comparative aspects of dietary660

copper and zinc deficiencies in pregnant rats. J Nutr 1983;113:1448.661


30/41

30

[83] Ali Akbar S, Nicolaides KH, Brown PR. Measurement of Cu/Zn SOD in placenta,662

cultured cells, various fetal tissues, decidua and semen by ELISA. J Obstet Gynaecol663

1998;18:331.664

[84] de Moraes ML, de Faria Barbosa R, Santo RE, da Silva Santos F, de Jesus EF,665

Sardinha FL, Tavares do Carmo MD. Maternal-Fetal Distribution of Calcium, Iron,666

Copper, and Zinc in Pregnant Teenagers and Adults. Biol Trace Elem Res 2010.667

[85] McArdle HJ, Ashworth CJ. Micronutrients in fetal growth and development. Br668

Med Bull 1999;55:499.669

[86] Krachler M, Rossipal E, Micetic-Turk D. Trace element transfer from the mother670

to the newborn--investigations on triplets of colostrum, maternal and umbilical cord sera.671

Eur J Clin Nutr 1999;53:486.672

[87] Rossipal E, Krachler M, Li F, Micetic-Turk D. Investigation of the transport of673

trace elements across barriers in humans: studies of placental and mammary transfer.674

Acta Paediatr 2000;89:1190.675

[88] Ozdemir Y, Borekci B, Levet A, Kurudirek M. Assessment of trace element676

concentration distribution in human placenta by wavelength dispersive X-ray677

fluorescence: effect of neonate weight and maternal age. Appl Radiat Isot 2009;67:1790.678

[89] Brophy MH, Harris NF, Crawford IL. Elevated copper and lowered zinc in the679

placentae of pre-eclamptics. Clin Chim Acta 1985;145:107.680

[90] Serdar Z, Gur E, Develioglu O. Serum iron and copper status and oxidative stress681

in severe and mild preeclampsia. Cell Biochem Funct 2006;24:209.682


31/41

31

[91] Kolusari A, Kurdoglu M, Yildizhan R, Adali E, Edirne T, Cebi A, Demir H,683

Yoruk IH. Catalase activity, serum trace element and heavy metal concentrations, and684

vitamin A, D and E levels in pre-eclampsia. J Int Med Res 2008;36:1335.685

[92] Aksoy H, Taysi S, Altinkaynak K, Bakan E, Bakan N, Kumtepe Y. Antioxidant686

potential and transferrin, ceruloplasmin, and lipid peroxidation levels in women with687

preeclampsia. J Investig Med 2003;51:284.688

[93] Vitoratos N, Salamalekis E, Dalamaga N, Kassanos D, Creatsas G. Defective689

antioxidant mechanisms via changes in serum ceruloplasmin and total iron binding690

capacity of serum in women with pre-eclampsia. Eur J Obstet Gynecol Reprod Biol691

1999;84:63.692

[94] Arredondo M, Nunez MT. Iron and copper metabolism. Mol Aspects Med693

2005;26:313.694

[95] WHO. The World Health Report 2002: Reducing risks, promoting healthy life.695

Geneva: World Health Organisation, 2002.696

[96] Uriu-Adams JY, Keen CL. Zinc and reproduction: effects of zinc deficiency on697

prenatal and early postnatal development. Birth Defects Res B Dev Reprod Toxicol698

2010;89:313.699

[97] Swanson CA, King JC. Zinc and pregnancy outcome. Am J Clin Nutr700

1987;46:763.701

[98] WHO/FAO/IAEA. Trace Elements in Human Nutrition and Health. Geneva:702

World Health Organisation, 1996.703


32/41

32

[99] Ilhan N, Ilhan N, Simsek M. The changes of trace elements, malondialdehyde704

levels and superoxide dismutase activities in pregnancy with or without preeclampsia.705

Clin Biochem 2002;35:393.706

[100] Groenen PM, Roes EM, Peer PG, Merkus HM, Steegers EA, Steegers-Theunissen707

RP. Myo-inositol, glucose and zinc concentrations determined in the preconceptional708

period, during and after pregnancy. Eur J Obstet Gynecol Reprod Biol 2006;127:50.709

[101] Harley K, Eskenazi B, Block G. The association of time in the US and diet during710

pregnancy in low-income women of Mexican descent. Paediatr Perinat Epidemiol711

2005;19:125.712

[102] King JC. Determinants of maternal zinc status during pregnancy. Am J Clin Nutr713

2000;71:1334S.714

[103] Goldenberg RL, Tamura T, Neggers Y, Copper RL, Johnston KE, DuBard MB,715

Hauth JC. The effect of zinc supplementation on pregnancy outcome. JAMA716

1995;274:463.717

[104] Black RE. Micronutrients in pregnancy. Br J Nutr 2001;85 Suppl 2:S193.718

[105] Garg HK, Singhal KC, Arshad Z. A study of the effect of oral zinc719

supplementation during pregnancy on pregnancy outcome. Indian J Physiol Pharmacol720

1993;37:276.721

[106] Caulfield LE, Zavaleta N, Figueroa A, Leon Z. Maternal zinc supplementation722

does not affect size at birth or pregnancy duration in Peru. J Nutr 1999;129:1563.723

[107] Osendarp SJ, van Raaij JM, Arifeen SE, Wahed M, Baqui AH, Fuchs GJ. A724

randomized, placebo-controlled trial of the effect of zinc supplementation during725


33/41

33

pregnancy on pregnancy outcome in Bangladeshi urban poor. Am J Clin Nutr726

2000;71:114.727

[108] Jonsson B, Hauge B, Larsen MF, Hald F. Zinc supplementation during pregnancy:728

a double blind randomised controlled trial. Acta Obstet Gynecol Scand 1996;75:725.729

[109] Kiilholma P, Paul R, Pakarinen P, Gronroos M. Copper and zinc in pre-eclampsia.730

Acta Obstet Gynecol Scand 1984;63:629.731

[110] Cherry FF, Bennett EA, Bazzano GS, Johnson LK, Fosmire GJ, Batson HK.732

Plasma zinc in hypertension/toxemia and other reproductive variables in adolescent733

pregnancy. Am J Clin Nutr 1981;34:2367.734

[111] Diaz E, Halhali A, Luna C, Diaz L, Avila E, Larrea F. Newborn birth weight735

correlates with placental zinc, umbilical insulin-like growth factor I, and leptin levels in736

preeclampsia. Arch Med Res 2002;33:40.737

[112] Acikgoz S, Harma M, Mungan G, Can M, Demirtas S. Comparison of738

angiotensin-converting enzyme, malonaldehyde, zinc, and copper levels in preeclampsia.739

Biol Trace Elem Res 2006;113:1.740

[113] Kumru S, Aydin S, Simsek M, Sahin K, Yaman M, Ay G. Comparison of serum741

copper, zinc, calcium, and magnesium levels in preeclamptic and healthy pregnant742

women. Biol Trace Elem Res 2003;94:105.743

[114] Yousef MI, El-Hendy HA, El-Demerdash FM, Elagamy EI. Dietary zinc744

deficiency induced-changes in the activity of enzymes and the levels of free radicals,745

lipids and protein electrophoretic behavior in growing rats. Toxicology 2002;175:223.746

[115] Jain S, Sharma P, Kulshreshtha S, Mohan G, Singh S. The role of calcium,747

magnesium, and zinc in pre-eclampsia. Biol Trace Elem Res 2010;133:162.748


34/41

34

[116] Bassiouni BA, Foda AI, Rafei AA. Maternal and fetal plasma zinc in pre-749

eclampsia. Eur J Obstet Gynecol Reprod Biol 1979;9:75.750

[117] Kiilholma P, Gronroos M, Erkkola R, Pakarinen P, Nanto V. The role of calcium,751

copper, iron and zinc in preterm delivery and premature rupture of fetal membranes.752

Gynecol Obstet Invest 1984;17:194.753

[118] Ademuyiwa O, Odusoga OL, Adebawo OO, Ugbaja RN. Endogenous antioxidant754

defences in plasma and erythrocytes of pregnant women during different trimesters of755

pregnancy. Acta Obstet Gynecol Scand 2007:1.756

[119] Wood RJ. Manganese and birth outcome. Nutr Rev 2009;67:416.757

[120] Vigeh M, Yokoyama K, Ramezanzadeh F, Dahaghin M, Fakhriazad E,758

Seyedaghamiri Z, Araki S. Blood manganese concentrations and intrauterine growth759

restriction. Reprod Toxicol 2008;25:219.760

[121] Zota AR, Ettinger AS, Bouchard M, Amarasiriwardena CJ, Schwartz J, Hu H,761

Wright RO. Maternal blood manganese levels and infant birth weight. Epidemiology762

2009;20:367.763

[122] Jones EA, Wright JM, Rice G, Buckley BT, Magsumbol MS, Barr DB, Williams764

BL. Metal exposures in an inner-city neonatal population. Environ Int 2010;36:649.765

[123] Than NG, Romero R, Tarca AL, Draghici S, Erez O, Chaiworapongsa T, Kim766

YM, Kim SK, Vaisbuch E, Tromp G. Mitochondrial manganese superoxide dismutase767

mRNA expression in human chorioamniotic membranes and its association with labor,768

inflammation, and infection. J Matern Fetal Neonatal Med 2009;22:1000.769

[124] Buettner GR. The pecking order of free radicals and antioxidants: lipid770

peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 1993;300:535.771


35/41

35

[125] Poston L, Chappell LC, Seed P, Shennan A. Biomarkers for oxidative stress in772

pre-eclampsia. Pregnancy Hypertension 2011;1:22.773

[126] Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E,774

Selenium, and Carotenoids. National Academy Press, 2000. p.284.775

[127] Packer JE, Slater TF, Willson RL. Direct observation of a free radical interaction776

between vitamin E and vitamin C. Nature 1979;278:737.777

[128] Burton GW, Foster DO, Perly B, Slater TF, Smith IC, Ingold KU. Biological778

antioxidants. Philos Trans R Soc Lond B Biol Sci 1985;311:565.779

[129] Xu H, Perez-Cuevas R, Xiong X, Reyes H, Roy C, Julien P, Smith G, von780

Dadelszen P, Leduc L, Audibert F, Moutquin JM, Piedboeuf B, Shatenstein B, Parra-781

Cabrera S, Choquette P, Winsor S, Wood S, Benjamin A, Walker M, Helewa M, Dube J,782

Tawagi G, Seaward G, Ohlsson A, Magee LA, Olatunbosun F, Gratton R, Shear R,783

Demianczuk N, Collet JP, Wei S, Fraser WD. An international trial of antioxidants in the784

prevention of preeclampsia (INTAPP). Am J Obstet Gynecol 2010;202:239 e1.785

[130] Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, Pearson GD,786

Wapner RJ, Varner MW, Thorp JM, Jr., Mercer BM, Peaceman AM, Ramin SM,787

Carpenter MW, Samuels P, Sciscione A, Harper M, Smith WJ, Saade G, Sorokin Y,788

Anderson GB. Vitamins C and E to prevent complications of pregnancy-associated789

hypertension. N Engl J Med 2010;362:1282.790

[131] Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E791

in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled792

trial. Lancet 2006;367:1145.793


36/41

36

[132] McCance DR, Holmes VA, Maresh MJ, Patterson CC, Walker JD, Pearson DW,794

Young IS. Vitamins C and E for prevention of pre-eclampsia in women with type 1795

diabetes (DAPIT): a randomised placebo-controlled trial. Lancet 2010;376:259.796

[133] Maia PA, Figueiredo RC, Anastacio AS, Porto da Silveira CL, Donangelo CM.797

Zinc and copper metabolism in pregnancy and lactation of adolescent women. Nutrition798

2007;23:248.799

[134] American Dietetic Association. Position of the American Dietetic Association:800

nutrition management of adolescent pregnancy. J Am Diet Assoc 1989;89:104.801

[135] Naeye RL. Teenaged and pre-teenaged pregnancies: consequences of the fetal-802

maternal competition for nutrients. Pediatrics 1981;67:146.803

[136] Amuzu A, Carson C, Watt HC, Lawlor DA, Ebrahim S. Influence of area and804

individual lifecourse deprivation on health behaviours: findings from the British805

Women's Heart and Health Study. Eur J Cardiovasc Prev Rehabil 2009;16:169.806

[137] Hampson SE, Martin J, Jorgensen J, Barker M. A social marketing approach to807

improving the nutrition of low-income women and children: an initial focus group study.808

Public Health Nutr 2009;12:1563.809

[138] Department of Health. Dietary reference values for foodenergy and nutrients for810

the United Kingdom. Report on Social Subjects no. 41. London, 1991.811

812

813

814

815

816


37/41

37

Table 1: Requirement of micronutrient intakes for selenium, copper, zinc, manganese,817

vitamin C and vitamin E. RDA: Recommended Dietary Allowance; RNI:818

Reference Nutrient Intakes and NR: Normative Requirement Estimate. Values819

taken from 1Institute of Medicine [77, 126], 2Department of Health [138] and820

3WHO/FAO/IAEA [98]821

822

Selenium

(g/d)

Copper

(g/d)

Zinc

(mg/d)

Manganese

(mg/d)

Vitamin C

(mg/d)

Vitamin E

(g/d)

RDA1

Female

Adult 55 900 8 1.8 75 15

Pregnancy 60 1,000 11 2 85 15

Upper

limit 400 10,000 40 2,000 1,000

RNI

2

Female

Adult 60 1,200 7 1.4 40 -

Pregnancy 75 1,500 7 - 50 -

- - -

NR3

Female

Adult 30 1,350 1 - - -

Pregnancy - 1,150 2 -

823

824

825

826

827


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38

Figure Legends828

829

Figure 1: Diagram of the maternal fetal interface in early pregnancy. Extravillous830

cytotrophoblast cells migrate away from the cell column of the anchoring villus and831

invade through the maternal deciduas and inner third of the myometrium in o rder to gain832

access to maternal blood supply via maternal spiral arteries. Transformation of the833

maternal spiral arteries occurs as endovascular trophoblast help convert the endothelial834

cells lining the arteries into an amorphous fibrinoid matrix which is unresponsive to835

vasoactive stimuli, and serves to enlarge the vascular lumen maximising blood supply to836

the intervillous space.837

838

Figure 2: Major pathways of reactive oxygen species generation and metabolism.839

Superoxide can be generated by specialised enzymes, such as the xanthine or NADPH840

oxidases, or as a byproduct of cellular metabolism, particularly the mitochondrial electron841

transport chain. Superoxide dismutase (SOD), both Cu/Zn and Mn SOD then converts the842

superoxide to hydrogen peroxide (H2O2) which has to be rapidly removed from the843

system. This is generally achieved by catalase or peroxidases, such as the selenium844

dependent glutathione peroxidases (GPxs) which use reduced glutathione (GSH) as the845

electron donor.846

847

Figure 3: Synergistic mechanisms ofvitamin C (ascorbate) and vitamin E (-tocopherol)848

to prevent lipid peroxidation. O2.oxygen free radical.849

850


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Figure 1.851852

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Figure 2.866867

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H+

O2

O2-.

H2O2

H2O H2O

GSSG

2GSH

Cu/Zn & Mn SOD

NAD(P)H

NAD(P)+

Se GPxsCatalase

Glutathione reductase

Xanthine oxidase

NADPH oxidase

Mitochondrial Electron Transport Chain


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Figure 3.903904

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Ascorbate

Ascorbate

Hydrophilic

-tocopherol

-tocopherol

Lipophilic

Plasma membrane protein

Lipid peroxide

O2

OM Un Grutnieciba

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