European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Influence of mineral and vitamin supplements on pregnancy outcome

Nils Hovdenak a,*, Kjell Haram b
a
Department of Internal Medicine, Haukeland University Hospital, 5021 Bergen, Norway
b
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway

A R T I C L E I N F O A B S T R A C T

Article history: The literature was searched for publications on minerals and vitamins during pregnancy and the possible
Received 12 January 2012 influence of supplements on pregnancy outcome. Maternal iron (Fe) deficiency has a direct impact on
Received in revised form 27 May 2012 neonatal Fe stores and birth weight, and may cause cognitive and behavioural problems in childhood. Fe
Accepted 14 June 2012
supplementation is recommended to low-income pregnant women, to pregnant women in developing
countries, and in documented deficiency, but overtreatment should be avoided. Calcium (Ca) deficiency
Keywords: is associated with pre-eclampsia and intra-uterine growth restriction. Supplementation may reduce
Minerals
both the risk of low birth weight and the severity of pre-eclampsia. Gestational magnesium (Mg)
Vitamins
deficiency may cause hematological and teratogenic damage. A Cochrane review showed a significant
Deficiency
Adverse effects low birth weight risk reduction in Mg supplemented individuals. Intake of cereal-based diets rich in
Pregnancy phytate, high intakes of supplemental Fe, or any gastrointestinal disease, may interfere with zinc (Zn)
Pre-eclampsia absorption. Zn deficiency in pregnant animals may limit fetal growth. Supplemental Zn may be prudent
Eclampsia for women with poor gastrointestinal function, and in Zn deficient women, increasing birth weight and
head circumference, but no evidence was found for beneficial effects of general Zn supplementation
during pregnancy. Selenium (Se) is an antioxidant supporting humoral and cell-mediated immunity.
Low Se status is associated with recurrent abortion, pre-eclampsia and IUGR, and although beneficial
effects are suggested there is no evidence-based recommendation for supplementation.
An average of 20–30% of pregnant women suffer from any vitamin deficiency, and without
prophylaxis, about 75% of these would show a deficit of at least one vitamin. Vitamin B6 deficiency is
associated with pre-eclampsia, gestational carbohydrate intolerance, hyperemesis gravidarum, and
neurologic disease of infants. About 25% of pregnant women in India are folate deficient. Folate
deficiency may lead to congenital malformations (neural tube damage, orofacial clefts, cardiac
anomalies), anaemia and spontaneous abortions, and pre-eclampsia, IUGR and abruption placentae.
Pregestational supplementation of folate prevents neural tube defects. A daily supplemental dose of
400 mg/day of folate is recommended when planning pregnancy. In developing countries diets are
generally low in animal products and consequently in vitamin B12 content. An insufficient supply may
cause reduced fetal growth. In vegetarian women, supplementation of vitamin B12 may be needed.
Vitamin A deficiency is prevalent in the developing world, impairing Fe status and resistance to infections.
The recommended upper limit for retinol supplements is 3000 IU/day. Vitamin A supplementation
enhances birth weight and growth in infants born to HIV-infected women. Overdosing should be avoided.
Low concentrations of vitamin C seem to increase the development of pre-eclampsia, and supplementation
may be beneficial. Supplementation with vitamin D in the third trimester in vitamin D deficient women
seems to be beneficial. The use of vitamins E, although generally considered ‘‘healthy’’, may be harmful to
the pregnancy outcome by disrupting a physiologic oxidative gestational state and is consequently not
recommended to prevent pre-eclampsia. Further studies on specific substances are needed as the basis for
stratified, placebo-controlled analyses.
ß 2012 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

* Corresponding author. Tel.: +47 92020408; fax: +47 55972101.

E-mail address: nils.hovdenak@helse-bergen.no (N. Hovdenak).

0301-2115/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2012.06.020
128 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132

3. Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

3.1. Iron . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
3.2. Calcium . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
3.3. Magnesium . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.4. Zinc . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.5. Selenium . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4. Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.1. Vitamin A . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.2. Vitamin B complex: B1 (thiamine), B6 (pyridoxine) and folate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.2.1. Vitamin B1 . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.2.2. Vitamin B6 . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.3. Folate. . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.4. Vitamin B12 . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4.5. Vitamins C and E . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4.6. Vitamin D . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
5. Multiple micronutrients . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6. Comments . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . ...................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

1. Introduction and approximately 20% in industrialised countries [2,3]. Fe

During pregnancy a series of continuous, physiological
adjustments affect nutrient metabolism and energy require-
ments, the pre-pregnancy nutritional status constituting a
critical factor for fetal growth and maternal health. The most
important determinants of restricted fetal growth in the
Western world are a low pre-pregnancy body mass index and
a low gestational weight gain. Malnourished women more likely
bear growth-restricted babies. Nutrition and supplementation of
minerals and vitamins are likely key factors in the prophylaxis
and management.
Pre-eclampsia–eclampsia is a multiorgan disease and a major
cause of morbidity and mortality in mother, fetus, and offspring,
most devastating in developing countries. Pre-eclampsia is
associated with low levels of certain vitamins and minerals [1].
Its causes and pathogenesis are still uncertain, and many
controversies exist concerning occurrence and management. Our
aim is to focus on pregnancy outcome in relation to nutritional
deficiencies in minerals and vitamins, and to study the indications
for nutritional support.
deficiency induces maternal and fetal stress, increasing cortioco-
tropin-releasing hormone (CRH), cortisol production, and oxida-
tive damage to fetal erythrocytes. This may inhibit fetal growth.
Maternal Fe status has a direct impact on neonatal Fe stores, and
birth weight seems dependent on the mother’s Fe status [4].
Maternal Fe deficiency during pregnancy may have long-term
effects and may cause cognitive and behavioural problems in
childhood. A controlled study of Fe supplements to 513 low-
income pregnant women, 48% of whom had low ferritin and
haemoglobin, showed a significantly higher mean birth weight, a
lower incidence of low birth weight (LBW) and a significantly
improved birth weight in the supplemented group [5]. Conflicting
results are presented on the routine iron supplementation during
pregnancy, however. Low haemoglobin and plasma ferritin are
good indicators for supplementation. Overtreatment should be
avoided as it may increase risks (preterm delivery, gestational
diabetes mellitus, IUGR) when maternal iron stores are normal or
overloaded [6].
3.2. Calcium

2. Methods Calcium (Ca) has important roles in mediating muscle

A non-systematic literature search in PubMed and the Cochrane
Databases was undertaken using search words ‘‘minerals’’ or
‘‘vitamins’’ associated with ‘‘pregnancy’’ or ‘‘supplementation’’. In
addition, in-house literature databases were screened. Journals
dedicated to nutrition were screened specifically. Observational
studies, randomised controlled trials, and meta-analyses, and
reviews were selected. The referred studies were chosen on an
estimation of clinical and global importance.
3. Minerals
3.1. Iron
Iron (Fe) is a micronutritient essential for haemoglobin
synthesis and several organ functions. Fe deficiency is the most
widespread nutrient deficiency in the world, affecting more than
50% of all pregnant women in developing countries and being
prevalent also in the industrialised parts of the world. It may lead
to anaemia, intrauterine growth retardation (IUGR), and neonates
small for gestational age (SGA). The prevalence of moderate to
severe sideropenic anaemia varies among pregnant women, being
4–5 times greater in Nepal (21%) than in Java (6%) and Peru (4%),
function, blood vessel dynamics, nerve impulse transmission,
secretion of hormones, blood coagulation, cell membrane
functions, and skeletal development. Ca is required for normal
blood coagulation, cell membrane functions, optimal Ca
absorption and development of the skeleton. During pregnancy,
a substantially increased demand for Ca occurs. This is met by a
doubling of intestinal absorption and mobilisation from the
skeleton [7]. Deficiency is rare in pregnancy, but is associated
with pre-eclampsia, and may induce IUGR. An overall significant
17% risk reduction for LBW and significantly increased birth
weight occur after Ca supplementation, probably due to
prolonged gestation. An association of low birth weight and
low intake of milk and vitamin D during pregnancy was
demonstrated [8]. However, in a recent Cochrane report of 21
randomised, controlled studies, including 16,602 women, no
statistically significant improvement in terms of preterm births
and low birth weight, was demonstrated [9]. Results from a
large, multinational, randomised, non-stratified, placebo-con-
trolled study showed that supplementation did not prevent pre-
eclampsia, but reduced its severity, the maternal morbidity, and
the neonatal morbidity and mortality [10]. Thus, present data
are conflicting; making evidence-based general recommenda-
tions uncertain.
 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132
3.3. Magnesium
Magnesium (Mg) is a widespread enzyme cofactor and
activator. Hypomagnesemia in diabetic women may lead to both
maternal and fetal hypoparathyreoidism with secondary hypo-
magnesaemia and hypocalcemia. Gestational Mg deficiency may
interfere with fetal growth and development and may cause a
range of morbidity from hematological to teratogenic damage [11].
A Cochrane review including seven trials of Mg supplementation in
pregnancy, most of them uncontrolled, showed a significant
overall LBW risk reduction in supplemented individuals. Too few
controlled data are available for general recommendations [12].
3.4. Zinc
Zinc (Zn) is essential for the activity of approximately 100
enzymes. In addition to antioxidant functions, Zn supports the
immune system. It is essential for embryogenesis and important
for normal fetal growth and growth during childhood and
adolescence. Zn deficiency in pregnant experimental animals
limits fetal growth and is, if severe, teratogenic. General
physiological adjustments in intestinal Zn absorption meet fetal
demands, but transfer of sufficient Zn to the fetus is dependent on
maintenance of normal maternal serum Zn concentrations. Intake
of cereal-based diets rich in phytate, high intakes of supplemental
Fe, or any gastrointestinal dysfunction, may interfere with Zn
absorption. Supplemental Zn may be prudent in any of these
conditions during pregnancy [13]. Zn supplementation was
associated with significantly higher birth weight and head
circumference in a 1995 randomised study of 580 African-
American pregnant women with low plasma Zn levels [14].
However, a review of 17 randomised controlled trials, involving
9000 women showed no evidence for beneficial effects of general
Zn supplementation during pregnancy. Most randomised, con-
trolled trials were too small and not uniformly designed to detect
effects on pregnancy outcome [15].
3.5. Selenium
Selenium (Se) is an antioxidant supporting humoral and cell
mediated immunity, important for reproduction. Low Se status is
associated with recurrent abortions, pre-eclampsia and IUGR
[16,17]. A study suggested beneficial effects of Se supplementation
in the development of pre-eclampsia in Iranian women [18].
Presently, however, no evidence-based recommendations can be
given as to supplementation. Prospective trials are awaited.
4. Vitamins
Vitamins are fat- or water-soluble organic compounds, essen-
tial in small amounts for support of normal physiologic functions,
that cannot generally be biosynthesised quickly enough to meet
the needs of the body. An average 20–30% of pregnant women
suffer from a vitamin deficiency; and without prophylaxis, about
75% would show a deficit of at least one vitamin. In a study it was
observed that despite vitamin supplementation, a high percent of
vitamin A, B6, niacin, thiamin and B12 hypovitaminemia was noted
during all pregnancy trimesters. An especially high percentage of
niacin deficiency was seen during the 1st trimester, and it
worsened in later trimesters; B-12 deficits increased during the
late trimester [19].
4.1. Vitamin A
Vitamin A (retinoids) is a fat-soluble vitamin essential for gene
regulation, cell differentiation, proliferation and growth, innate
129
and adaptive immune system, maintenance of mucosal surfaces,
intestinal iron uptake, hematopoiesis, vision and reproduction.
While vitamin A deficiency is prevalent in the developing world,
overdose rather than deficiency is common in developed countries,
reflecting richness in food resources and modern emphasis on
antioxidants and ‘‘healthy eating’’. Vitamin A is considered
teratogenic in high concentrations. The recommended upper limit
for retinol supplements is 5000 IU/day [20], but high doses (8000–
10,000 IU/day) have not been associated with increased risk of
malformations. Vitamin A supplementation has been shown to
improve birth weight and growth among infants born to HIV-
infected pregnant women, possibly due to the enhancement of
immunity [21]. Vitamin A supplementation may thus be beneficial
in high-risk pregnancies, but otherwise pregnant women should
avoid excess supplementation with vitamin A [20].
4.2. Vitamin B complex: B1 (thiamine), B6 (pyridoxine) and folate
4.2.1. Vitamin B1
Vitamin B1 (thiamine) is a water-soluble vitamin acting as a
coenzyme, being essential in energy metabolism, and lipid and
nucleotide synthesis enzymes, especially in the developing brain.
Deficiency may impair brain development. Specific active placen-
tal transport systems for vitamin B1 and riboflavin cause higher
concentrations in the fetus than in maternal blood. Vitamin B1
deficiency is common in developing countries, especially during
pregnancy, and may impair fetal growth. There is, however, a
paucity of articles on the role of vitamin B1 supplementation in
pregnancy.
4.2.2. Vitamin B6
Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) is a
water-soluble vitamin, important as co-enzymes in protein
metabolism in development of the central nervous system. Poultry,
fish, pork, eggs, liver, kidney, soya beans, peanuts and walnuts are
rich sources. Vitamin B6 deficiency rarely occurs alone, but is often
associated with deficiencies in several B-complex vitamins.
Vitamin B6 deficiency is associated with pre-eclampsia, gestation-
al carbohydrate intolerance, hyperemesis gravidarum, and neuro-
logic disease of infants. There is, however, no appropriate evidence
to detect clinical benefits of vitamin B6 supplementation in
pregnancy and/or labour other than one trial suggesting protection
against dental decay [22].
4.3. Folate
Folate is a water-soluble B vitamin that plays a major co-
enzymatic role in carbon metabolism and in the synthesis of DNA,
RNA and certain amino acids. Dietary folate deficiency is prevalent
in developing countries, about 25% of pregnant women in India
being folate deficient. Deficiency may lead to congenital mal-
formations (neural tube damage, orofacial clefts, cardial anoma-
lies), anaemia and certain complications during pregnancy
(spontaneous abortions, bleeding, pre-eclampsia, IUGR and
abruptio placentae) [23]. Low folate status may also cause
hyperhomocystemia, hypercoagulability and venous thrombosis.
To reduce risk of congenital malformations and pregnancy
complications a daily supplemental dose of 400 mg/day of folate is
recommended when planning pregnancy [24]. Increased risk of
fetal neural tube defects is seen in several conditions: obesity,
personal or family history of neural tube defects, pregestational
diabetes, and epilepsy. A higher dose (5 mg) is recommended in
these situations [25].
A systematic review and a meta-analysis (92 studies identified,
41 evaluated) concluded that maternal consumption of folic acid-
containing prenatal multivitamins is associated with decreased
130 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132
risk of several congenital anomalies, not only neural tube defects
[26]. A large randomised controlled trial including 2928 women,
demonstrated no difference in mean birth weight, placental weight
or gestational age. Folic acid in high doses, however, was
associated with significantly reduced risk of LBW [27]. The effect
of folic acid taken throughout pregnancy is still unclear, but
evidence may support a beneficial effect on fetal growth.
4.4. Vitamin B12
Vitamin B12 (cobalamin) is a member of the vitamin B complex,
an important support for erythropoiesis, found primarily in meat,
eggs and dairy products. There is a global increased prevalence of
low plasma vitamin B12 concentrations during pregnancy. In
developing countries diets are generally low in animal products
and consequently in vitamin B12 content. Pregnant women
consuming a long-term, predominantly vegetarian diet, have an
increased risk of vitamin B12 deficiency [28].
A decline in plasma cobalamin is common also in pregnant
women consuming an adequate diet, explained by alterations in
haptocorrin-bound cobalamin, while intestinal absorption is
unimpaired [29]. The significance of low plasma cobalamin is
uncertain, although a negative fetal outcome has been reported
[30]. A strong association between maternal and infant plasma
vitamin B12 concentrations at delivery has been demonstrated,
indicating that maternal B12 status affects the fetal vitamin status
at birth. Low maternal concentrations are associated with multiple
clinical symptoms and reduced fetal growth [31]. Sanchez et al.
[32] found no evidence of an increased risk of pre-eclampsia.
Vitamin B12 deficiency may cause defective DNA synthesis,
megaloblastic anaemia and neurological abnormalities. The role
of vitamin B12 supplementation in pregnancy is uncertain. Special
care should be noted. Supplementation may be especially needed
in women at nutritional risk, by vegetarian women, in malabsorp-
tion disorders and in communities or countries where under-
nutrition is prevalent.
4.5. Vitamins C and E
Oxidative stress is an important pathogenic factor for develop-
ment of pre-eclampsia. Plasma oxidative stress markers are
elevated in women with pre-eclampsia [33]. Recently, much
interest has been focused on the water-soluble vitamin C (ascorbic
acid) and the fat-soluble vitamin E (alpha-tocopherol being the
most active form), which are powerful antioxidants for the
prevention and treatment of pre-eclampsia. Supplementation
treatment would appear a logical approach. Both vitamin C and
vitamin E concentrations are reduced in pre-eclampsia, parallel
with an increase in oxidative stress markers [33]. Zhang et al.
observed an increased risk of pre-eclampsia among women with
an intake below 85 mg vitamin C [34]. Oxidative stress was
proposed as a key factor involved in the development of pre-
eclampsia. Supplementing women with antioxidants during
pregnancy seemed feasible to counteract oxidative stress and
thereby prevent or delay the onset of pre-eclampsia. Biochemical
indices of pre-eclampsia were normalised in a placebo-controlled
study in high-risk women receiving combined vitamin C and E
[35]. A Cochrane report (7 trials; 6082 women) on the preventive
use of antioxidants (any antioxidant) versus placebo during
pregnancy showed a significant 39% reduction in the risk of pre-
eclampsia. The effect on other outcomes was modest [36]. Two
similar studies showed no effect of vitamin C [37] and vitamin E,
respectively [38], and a meta-analysis concluded that combined
vitamin C and E supplementation during pregnancy does not
reduce the risk of pre-eclampsia, fetal or neonatal loss, small for
gestational age infant, or preterm birth [39].
Results from vitamin C supplementation are conflicting,
however. Even given in high doses, the vitamin may not achieve
sustained serum levels to provide effective antioxidant activity.
Further clinical trials are therefore suggested to be postponed until
‘‘further rigorous research is undertaken’’ [25].
The safety of vitamin E prophylaxis against pre-eclampsia has
been questioned. A prospective Danish cohort study reported an
increased incidence of severe pre-eclampsia/eclampsia and HELLP
syndrome in women consuming high amounts of vitamin E. For
vitamin E intake aggregated from diet and supplementation
(n = 49,373), with an intake of 10.5–13.5 mg/day as a reference, the
‘‘severe pre-eclampsia/eclampsia/HELLP’’ odds ratio (OR) was 1.46
(95% confidence interval (CI) 1.02–209) [1]. Other studies have also
given rise to some concern about vitamin C and E supplementation
because of risk of gestational hypertension and LBW. Combined
vitamin C and E supplementation not only have no potential
benefit in improvement of maternal and neonatal outcome but
increase the risk of gestational hypertension in women at risk of
pre-eclampsia and low birth weight [40,41].
During pregnancy, a physiologic placental inflammation of type
1 is dominant, with production of pro-inflammatory Th1 cytokines,
while type 2 (Th2) cytokines, which are anti-inflammatory, are
suppressed. In pre-eclampsia, type 1 inflammation is dominant
[42]. The formation of reactive oxygen species (ROS) in macro-
phages in the placenta may damage endothelial cells, causing
placental ischemia, eventually insufficiency and consequently
IUGR [43] as part of down-regulated immunoregulatory system
where the T-cell function is reduced [44]. The prime antioxidant
component of vitamin E (a-tocopherol) might enhance the Th1
induction and prevent the early-to-late Th1 to Th2 switch in
normal human pregnancy [42]. In addition to its antioxidative
properties vitamin E also has a variety of non-antioxidative
pleiotropic effects on redox-regulated transcription [45], cell cycle
[46], and cytokine signalling [47]. Vitamin E could also be a
potential interferon-gamma (IFN-gamma) mimic, facilitating
persistent proinflammatory reactions at the fetal–maternal inter-
face [48]. The clinical significance of these actions is unclear. It
follows that supplementation of vitamin C may be advantageous
and that vitamin E in pregnancy is possibly dangerous, and may not
be recommended.
4.6. Vitamin D
Vitamin D is a fat-soluble vitamin which plays an important
role in immune function, cell differentiation, bone growth and the
reduction of inflammation. Vitamin D is essential for Ca
homeostasis and in reducing the risk of chronic diseases. It is
biologically inactive and must be metabolized to its biologically
active forms. It enters the circulation from the gut or skin and is
transported to the liver, where it is hydroxylated to 25-
hydroxyvitamin D 25(OH)D, the major circulating form of
vitamin D.
Vitamin D deficiency is variable in adolescents. About 40% of
African American and 4% of Caucasian-non-Hispanic women have
low plasma concentrations. Vitamin D status in pregnant women
should be of concern even in industrialised countries. Even
moderately decreased levels of 25-hydroxyvitamin D at the end
of winter were associated with poor fetal and infant skeletal
growth and tooth mineralisation [49].
Vitamin D deficiency is a risk factor in fetal growth, bone
metabolism, and fetal immune system development. Increased
availability of 1,25-dihydroxyvitamin D may improve immune
regulation, after correction of inadequate Ca intake, contributing to
the observed benefit [50].
Osteomalacia is a well-recognised pregnancy complication in
Asians living in the United Kingdom. Asian immigrants to Europe
 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132
are at particular risk of vitamin D deficiency during pregnancy,
with dietary inadequacy being an important factor. A higher
incidence of severe deficiency in vegetarians indicates that oral
intake is important. Recently the role of vitamin D in the
prevention of pre-eclampsia has been debated, but associations
between maternal vitamin D levels and fetal growth were not
demonstrated in a Norwegian study, where supplementation in
the third trimester in subjects on a vitamin D deficient diet
significantly increased birth weights and crown-heel-lengths [51].
Other studies showed only slight or no effects of vitamin D
supplementation. Overall, vitamin D supplementation in at-risk
populations leads to improved neonatal handling of Ca. There is no
evidence of benefit of general supplementation during pregnancy
beyond the amounts routinely required to prevent vitamin D
deficiency [52].
5. Multiple micronutrients
Micronutrient deficiencies often appear in combination,
especially in developing countries, due to a range of causes, such
as insufficient availability of adequate food quality, cultural
differences, seasonal variations, poverty, and infections in the
population. This is often the case in developing countries [53].
Results from several randomised, controlled studies show signifi-
cant improvements in pregnancy outcomes (increase in birth
weight; reduction in low birth weight) after introduction of
multiple micronutrient (MMN) supplementation [54,55]. Avail-
ability of large scale blood tests in these communities is scarce, and
little is therefore known about the range and extent of nutrient
deficiencies, and no data exist on the optimal composition of MMN.
Overall, however, there is evidence that outcomes are better when
providing a minimum of three components [56]. The most
prevalent deficiencies in developing countries are iron, Ca, vitamin
D, vitamin A, Zn, and folate. Even in developed countries selected
groups are micronutrient deficient, e.g. pregnant adolescents,
possibly calling for MMN treatment [57].
MMN can be implemented in a large-scale programme and
should be well suited for developing countries, where medical
and economic resources are limited. Production and distribution
are not very costly, and the application fairly simple. In addition,
and rather a sine qua non, improvements in ante-natal health
services and securing of adequate food supplies must have
priority.
6. Comments
For many decades vitamin supplements have been regarded as
solely health-promoting. Deficiencies may result in significant
morbidity, where vitamin treatment is curative. Increased
demands may ensue during pregnancy, with negative conse-
quences to the fetus and child health. However, the effect of
vitamin supplements in non-deficient pregnant individuals is
poorly understood.
Considerable problems arise in the interpretation of dietary
studies and in determining the consequences on pregnancy and
fetal growth. There is a paucity of well designed, controlled studies.
Isolated deficiencies of dietary components rarely appear, and the
quantification of individual food components, e.g. vitamins, as well
as the estimation of food intake, are difficult and unreliable.
Furthermore, the populations studied are often non-homogenous
and poorly defined. The inclusion of large numbers of individuals is
necessary to allow statistically reliable analyses. These studies are
usually not stratified in terms of defined deficiencies, demographic
background, etc. In intervention studies from populations where
under-nutrition is prevalent the diets are usually deficient in
several food components. Supplementation of single components
131
may therefore be insufficient to obtain a clinical response, and a
multiple micronutrient supplementation may contain unnecessary
and even harmful overdoses. In addition, nutrient interactions are
numerous. However, valuable data emerge from non-interven-
tional, population studies. Although not stratified, these studies
usually recruit patients from areas and cultures with generally
known dietary shortcomings. Findings from these studies may be
applied in controlled interventional studies where corresponding
deficiencies can be objectively detected, e.g. vitamin B12 in
vegetarians [28].
Pre-eclampsia is an important cause of impaired fetal health
and development, and naturally, much of the literature on
pregnancy outcome relates to this condition. New insights in
the immunology of pregnancy have shed some light on the basis of
treatment and prophylaxis of pre-eclampsia. As reported, placental
oxidative stress has been demonstrated, and up to now, antioxi-
dant agents have been advocated as a logical approach to both
prophylaxis and treatment. Several vitamins have antioxidative
properties. During the early stages of placental development an
oxidative drive may, however, be a physiological phenomenon
governing the further maturation of the placenta. An immunologi-
cal switch from the pro-inflammatory type Th1 cytokine response
towards the anti-inflammatory Th2 occurs towards the later part
of the pregnancy. This switch may be of importance, both for fetal
development and neonatal and child health. Supplementation with
vitamins C and E may negatively affect this switch, resulting in
complications.
Normal mineral and vitamin metabolism is important for
successful pregnancies, but when it comes to practical implica-
tions, very few evidence-based, general recommendations on
prophylactic measures can be derived from the literature.
Micronutritients of particular importance for prevention of
adverse pregnancy outcomes are folic acid, Zn, and Fe [19]. Pre-
pregnancy and early pregnancy folate supplementation is now
firmly established. Fe treatment in iron deficiency seems to have a
beneficial effect on pregnancy outcome. Most other intervention
studies large enough to allow statistically reliable analysis,
however, include mixed populations which are not stratified
according to single or multiple deficiencies. Therefore, numbers
needed to treat are unknown and unnecessary treatment may
carry risks. Studies from areas with high prevalence of specific
nutrient defects are important, however, showing that supple-
mentation prophylaxis works. The ideal prospective trial is
therefore awaited, including individuals with a pre-gestational,
biochemically and physiologically defined nutritional status as the
basis for a stratified, placebo-controlled analysis. In the meantime,
individual evaluation is necessary if feasible.
In conclusion, substitution therapy and supplementation may
be beneficial during pregnancy, but specific deficiencies should be
sought. Pre-pregnancy and early pregnancy folate supplementa-
tion is now firmly established, and iron treatment in iron
deficiency seems to have a beneficial effect on pregnancy outcome.
Pregnant women consuming a long-term, predominantly vegetar-
ian diet, have an increased risk of vitamin B12 deficiency and
supplementation with B12 may be needed. Asian immigrants to
Europe are at particular risk of vitamin D deficiency during
pregnancy, with dietary inadequacy being an important factor.
Vitamin D may be beneficial against development of pre-
eclampsia. Supplementation with vitamins C may be beneficial.
Supplementation with vitamin E is not presently recommended,
and may even be hampered by untoward effects.
Authors’ contributions
Both authors were equally involved in literature studies and
writing.
132 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132
Conflict of interest statement
None.
Funding
None.
Ethical approval
Approval by the Medical Ethics Committee was not considered
necessary. The Committee was not contacted.
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