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: [email protected] (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

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

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

function, blood vessel dynamics, nerve impulse transmission,
A non-systematic literature search in PubMed and the Cochrane secretion of hormones, blood coagulation, cell membrane
Databases was undertaken using search words ‘‘minerals’’ or functions, and skeletal development. Ca is required for normal
‘‘vitamins’’ associated with ‘‘pregnancy’’ or ‘‘supplementation’’. In blood coagulation, cell membrane functions, optimal Ca
addition, in-house literature databases were screened. Journals absorption and development of the skeleton. During pregnancy,
dedicated to nutrition were screened specifically. Observational a substantially increased demand for Ca occurs. This is met by a
studies, randomised controlled trials, and meta-analyses, and doubling of intestinal absorption and mobilisation from the
reviews were selected. The referred studies were chosen on an skeleton [7]. Deficiency is rare in pregnancy, but is associated
estimation of clinical and global importance. with pre-eclampsia, and may induce IUGR. An overall significant
17% risk reduction for LBW and significantly increased birth
3. Minerals weight occur after Ca supplementation, probably due to
prolonged gestation. An association of low birth weight and
3.1. Iron low intake of milk and vitamin D during pregnancy was
demonstrated [8]. However, in a recent Cochrane report of 21
Iron (Fe) is a micronutritient essential for haemoglobin randomised, controlled studies, including 16,602 women, no
synthesis and several organ functions. Fe deficiency is the most statistically significant improvement in terms of preterm births
widespread nutrient deficiency in the world, affecting more than and low birth weight, was demonstrated [9]. Results from a
50% of all pregnant women in developing countries and being large, multinational, randomised, non-stratified, placebo-con-
prevalent also in the industrialised parts of the world. It may lead trolled study showed that supplementation did not prevent pre-
to anaemia, intrauterine growth retardation (IUGR), and neonates eclampsia, but reduced its severity, the maternal morbidity, and
small for gestational age (SGA). The prevalence of moderate to the neonatal morbidity and mortality [10]. Thus, present data
severe sideropenic anaemia varies among pregnant women, being are conflicting; making evidence-based general recommenda-
4–5 times greater in Nepal (21%) than in Java (6%) and Peru (4%), tions uncertain.
 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132 129

3.3. Magnesium and adaptive immune system, maintenance of mucosal surfaces,

intestinal iron uptake, hematopoiesis, vision and reproduction.
Magnesium (Mg) is a widespread enzyme cofactor and While vitamin A deficiency is prevalent in the developing world,
activator. Hypomagnesemia in diabetic women may lead to both overdose rather than deficiency is common in developed countries,
maternal and fetal hypoparathyreoidism with secondary hypo- reflecting richness in food resources and modern emphasis on
magnesaemia and hypocalcemia. Gestational Mg deficiency may antioxidants and ‘‘healthy eating’’. Vitamin A is considered
interfere with fetal growth and development and may cause a teratogenic in high concentrations. The recommended upper limit
range of morbidity from hematological to teratogenic damage [11]. for retinol supplements is 5000 IU/day [20], but high doses (8000–
A Cochrane review including seven trials of Mg supplementation in 10,000 IU/day) have not been associated with increased risk of
pregnancy, most of them uncontrolled, showed a significant malformations. Vitamin A supplementation has been shown to
overall LBW risk reduction in supplemented individuals. Too few improve birth weight and growth among infants born to HIV-
controlled data are available for general recommendations [12]. infected pregnant women, possibly due to the enhancement of
immunity [21]. Vitamin A supplementation may thus be beneficial
3.4. Zinc in high-risk pregnancies, but otherwise pregnant women should
avoid excess supplementation with vitamin A [20].
Zinc (Zn) is essential for the activity of approximately 100
enzymes. In addition to antioxidant functions, Zn supports the 4.2. Vitamin B complex: B1 (thiamine), B6 (pyridoxine) and folate
immune system. It is essential for embryogenesis and important
for normal fetal growth and growth during childhood and 4.2.1. Vitamin B1
adolescence. Zn deficiency in pregnant experimental animals Vitamin B1 (thiamine) is a water-soluble vitamin acting as a
limits fetal growth and is, if severe, teratogenic. General coenzyme, being essential in energy metabolism, and lipid and
physiological adjustments in intestinal Zn absorption meet fetal nucleotide synthesis enzymes, especially in the developing brain.
demands, but transfer of sufficient Zn to the fetus is dependent on Deficiency may impair brain development. Specific active placen-
maintenance of normal maternal serum Zn concentrations. Intake tal transport systems for vitamin B1 and riboflavin cause higher
of cereal-based diets rich in phytate, high intakes of supplemental concentrations in the fetus than in maternal blood. Vitamin B1
Fe, or any gastrointestinal dysfunction, may interfere with Zn deficiency is common in developing countries, especially during
absorption. Supplemental Zn may be prudent in any of these pregnancy, and may impair fetal growth. There is, however, a
conditions during pregnancy [13]. Zn supplementation was paucity of articles on the role of vitamin B1 supplementation in
associated with significantly higher birth weight and head pregnancy.
circumference in a 1995 randomised study of 580 African-
American pregnant women with low plasma Zn levels [14]. 4.2.2. Vitamin B6
However, a review of 17 randomised controlled trials, involving Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) is a
9000 women showed no evidence for beneficial effects of general water-soluble vitamin, important as co-enzymes in protein
Zn supplementation during pregnancy. Most randomised, con- metabolism in development of the central nervous system. Poultry,
trolled trials were too small and not uniformly designed to detect fish, pork, eggs, liver, kidney, soya beans, peanuts and walnuts are
effects on pregnancy outcome [15]. rich sources. Vitamin B6 deficiency rarely occurs alone, but is often
associated with deficiencies in several B-complex vitamins.
3.5. Selenium Vitamin B6 deficiency is associated with pre-eclampsia, gestation-
al carbohydrate intolerance, hyperemesis gravidarum, and neuro-
Selenium (Se) is an antioxidant supporting humoral and cell logic disease of infants. There is, however, no appropriate evidence
mediated immunity, important for reproduction. Low Se status is to detect clinical benefits of vitamin B6 supplementation in
associated with recurrent abortions, pre-eclampsia and IUGR pregnancy and/or labour other than one trial suggesting protection
[16,17]. A study suggested beneficial effects of Se supplementation against dental decay [22].
in the development of pre-eclampsia in Iranian women [18].
Presently, however, no evidence-based recommendations can be 4.3. Folate
given as to supplementation. Prospective trials are awaited.
Folate is a water-soluble B vitamin that plays a major co-
4. Vitamins enzymatic role in carbon metabolism and in the synthesis of DNA,
RNA and certain amino acids. Dietary folate deficiency is prevalent
Vitamins are fat- or water-soluble organic compounds, essen- in developing countries, about 25% of pregnant women in India
tial in small amounts for support of normal physiologic functions, being folate deficient. Deficiency may lead to congenital mal-
that cannot generally be biosynthesised quickly enough to meet formations (neural tube damage, orofacial clefts, cardial anoma-
the needs of the body. An average 20–30% of pregnant women lies), anaemia and certain complications during pregnancy
suffer from a vitamin deficiency; and without prophylaxis, about (spontaneous abortions, bleeding, pre-eclampsia, IUGR and
75% would show a deficit of at least one vitamin. In a study it was abruptio placentae) [23]. Low folate status may also cause
observed that despite vitamin supplementation, a high percent of hyperhomocystemia, hypercoagulability and venous thrombosis.
vitamin A, B6, niacin, thiamin and B12 hypovitaminemia was noted To reduce risk of congenital malformations and pregnancy
during all pregnancy trimesters. An especially high percentage of complications a daily supplemental dose of 400 mg/day of folate is
niacin deficiency was seen during the 1st trimester, and it recommended when planning pregnancy [24]. Increased risk of
worsened in later trimesters; B-12 deficits increased during the fetal neural tube defects is seen in several conditions: obesity,
late trimester [19]. personal or family history of neural tube defects, pregestational
diabetes, and epilepsy. A higher dose (5 mg) is recommended in
4.1. Vitamin A these situations [25].
A systematic review and a meta-analysis (92 studies identified,
Vitamin A (retinoids) is a fat-soluble vitamin essential for gene 41 evaluated) concluded that maternal consumption of folic acid-
regulation, cell differentiation, proliferation and growth, innate 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 Results from vitamin C supplementation are conflicting,
[26]. A large randomised controlled trial including 2928 women, however. Even given in high doses, the vitamin may not achieve
demonstrated no difference in mean birth weight, placental weight sustained serum levels to provide effective antioxidant activity.
or gestational age. Folic acid in high doses, however, was Further clinical trials are therefore suggested to be postponed until
associated with significantly reduced risk of LBW [27]. The effect ‘‘further rigorous research is undertaken’’ [25].
of folic acid taken throughout pregnancy is still unclear, but The safety of vitamin E prophylaxis against pre-eclampsia has
evidence may support a beneficial effect on fetal growth. been questioned. A prospective Danish cohort study reported an
increased incidence of severe pre-eclampsia/eclampsia and HELLP
4.4. Vitamin B12 syndrome in women consuming high amounts of vitamin E. For
vitamin E intake aggregated from diet and supplementation
Vitamin B12 (cobalamin) is a member of the vitamin B complex, (n = 49,373), with an intake of 10.5–13.5 mg/day as a reference, the
an important support for erythropoiesis, found primarily in meat, ‘‘severe pre-eclampsia/eclampsia/HELLP’’ odds ratio (OR) was 1.46
eggs and dairy products. There is a global increased prevalence of (95% confidence interval (CI) 1.02–209) [1]. Other studies have also
low plasma vitamin B12 concentrations during pregnancy. In given rise to some concern about vitamin C and E supplementation
developing countries diets are generally low in animal products because of risk of gestational hypertension and LBW. Combined
and consequently in vitamin B12 content. Pregnant women vitamin C and E supplementation not only have no potential
consuming a long-term, predominantly vegetarian diet, have an benefit in improvement of maternal and neonatal outcome but
increased risk of vitamin B12 deficiency [28]. increase the risk of gestational hypertension in women at risk of
A decline in plasma cobalamin is common also in pregnant pre-eclampsia and low birth weight [40,41].
women consuming an adequate diet, explained by alterations in During pregnancy, a physiologic placental inflammation of type
haptocorrin-bound cobalamin, while intestinal absorption is 1 is dominant, with production of pro-inflammatory Th1 cytokines,
unimpaired [29]. The significance of low plasma cobalamin is while type 2 (Th2) cytokines, which are anti-inflammatory, are
uncertain, although a negative fetal outcome has been reported suppressed. In pre-eclampsia, type 1 inflammation is dominant
[30]. A strong association between maternal and infant plasma [42]. The formation of reactive oxygen species (ROS) in macro-
vitamin B12 concentrations at delivery has been demonstrated, phages in the placenta may damage endothelial cells, causing
indicating that maternal B12 status affects the fetal vitamin status placental ischemia, eventually insufficiency and consequently
at birth. Low maternal concentrations are associated with multiple IUGR [43] as part of down-regulated immunoregulatory system
clinical symptoms and reduced fetal growth [31]. Sanchez et al. where the T-cell function is reduced [44]. The prime antioxidant
[32] found no evidence of an increased risk of pre-eclampsia. component of vitamin E (a-tocopherol) might enhance the Th1
Vitamin B12 deficiency may cause defective DNA synthesis, induction and prevent the early-to-late Th1 to Th2 switch in
megaloblastic anaemia and neurological abnormalities. The role normal human pregnancy [42]. In addition to its antioxidative
of vitamin B12 supplementation in pregnancy is uncertain. Special properties vitamin E also has a variety of non-antioxidative
care should be noted. Supplementation may be especially needed pleiotropic effects on redox-regulated transcription [45], cell cycle
in women at nutritional risk, by vegetarian women, in malabsorp- [46], and cytokine signalling [47]. Vitamin E could also be a
tion disorders and in communities or countries where under- potential interferon-gamma (IFN-gamma) mimic, facilitating
nutrition is prevalent. persistent proinflammatory reactions at the fetal–maternal inter-
face [48]. The clinical significance of these actions is unclear. It
4.5. Vitamins C and E follows that supplementation of vitamin C may be advantageous
and that vitamin E in pregnancy is possibly dangerous, and may not
Oxidative stress is an important pathogenic factor for develop- be recommended.
ment of pre-eclampsia. Plasma oxidative stress markers are
elevated in women with pre-eclampsia [33]. Recently, much 4.6. Vitamin D
interest has been focused on the water-soluble vitamin C (ascorbic
acid) and the fat-soluble vitamin E (alpha-tocopherol being the Vitamin D is a fat-soluble vitamin which plays an important
most active form), which are powerful antioxidants for the role in immune function, cell differentiation, bone growth and the
prevention and treatment of pre-eclampsia. Supplementation reduction of inflammation. Vitamin D is essential for Ca
treatment would appear a logical approach. Both vitamin C and homeostasis and in reducing the risk of chronic diseases. It is
vitamin E concentrations are reduced in pre-eclampsia, parallel biologically inactive and must be metabolized to its biologically
with an increase in oxidative stress markers [33]. Zhang et al. active forms. It enters the circulation from the gut or skin and is
observed an increased risk of pre-eclampsia among women with transported to the liver, where it is hydroxylated to 25-
an intake below 85 mg vitamin C [34]. Oxidative stress was hydroxyvitamin D 25(OH)D, the major circulating form of
proposed as a key factor involved in the development of pre- vitamin D.
eclampsia. Supplementing women with antioxidants during Vitamin D deficiency is variable in adolescents. About 40% of
pregnancy seemed feasible to counteract oxidative stress and African American and 4% of Caucasian-non-Hispanic women have
thereby prevent or delay the onset of pre-eclampsia. Biochemical low plasma concentrations. Vitamin D status in pregnant women
indices of pre-eclampsia were normalised in a placebo-controlled should be of concern even in industrialised countries. Even
study in high-risk women receiving combined vitamin C and E moderately decreased levels of 25-hydroxyvitamin D at the end
[35]. A Cochrane report (7 trials; 6082 women) on the preventive of winter were associated with poor fetal and infant skeletal
use of antioxidants (any antioxidant) versus placebo during growth and tooth mineralisation [49].
pregnancy showed a significant 39% reduction in the risk of pre- Vitamin D deficiency is a risk factor in fetal growth, bone
eclampsia. The effect on other outcomes was modest [36]. Two metabolism, and fetal immune system development. Increased
similar studies showed no effect of vitamin C [37] and vitamin E, availability of 1,25-dihydroxyvitamin D may improve immune
respectively [38], and a meta-analysis concluded that combined regulation, after correction of inadequate Ca intake, contributing to
vitamin C and E supplementation during pregnancy does not the observed benefit [50].
reduce the risk of pre-eclampsia, fetal or neonatal loss, small for Osteomalacia is a well-recognised pregnancy complication in
gestational age infant, or preterm birth [39]. Asians living in the United Kingdom. Asian immigrants to Europe
 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132 131

are at particular risk of vitamin D deficiency during pregnancy, may therefore be insufficient to obtain a clinical response, and a
with dietary inadequacy being an important factor. A higher multiple micronutrient supplementation may contain unnecessary
incidence of severe deficiency in vegetarians indicates that oral and even harmful overdoses. In addition, nutrient interactions are
intake is important. Recently the role of vitamin D in the numerous. However, valuable data emerge from non-interven-
prevention of pre-eclampsia has been debated, but associations tional, population studies. Although not stratified, these studies
between maternal vitamin D levels and fetal growth were not usually recruit patients from areas and cultures with generally
demonstrated in a Norwegian study, where supplementation in known dietary shortcomings. Findings from these studies may be
the third trimester in subjects on a vitamin D deficient diet applied in controlled interventional studies where corresponding
significantly increased birth weights and crown-heel-lengths [51]. deficiencies can be objectively detected, e.g. vitamin B12 in
Other studies showed only slight or no effects of vitamin D vegetarians [28].
supplementation. Overall, vitamin D supplementation in at-risk Pre-eclampsia is an important cause of impaired fetal health
populations leads to improved neonatal handling of Ca. There is no and development, and naturally, much of the literature on
evidence of benefit of general supplementation during pregnancy pregnancy outcome relates to this condition. New insights in
beyond the amounts routinely required to prevent vitamin D the immunology of pregnancy have shed some light on the basis of
deficiency [52]. treatment and prophylaxis of pre-eclampsia. As reported, placental
oxidative stress has been demonstrated, and up to now, antioxi-
5. Multiple micronutrients dant agents have been advocated as a logical approach to both
prophylaxis and treatment. Several vitamins have antioxidative
Micronutrient deficiencies often appear in combination, properties. During the early stages of placental development an
especially in developing countries, due to a range of causes, such oxidative drive may, however, be a physiological phenomenon
as insufficient availability of adequate food quality, cultural governing the further maturation of the placenta. An immunologi-
differences, seasonal variations, poverty, and infections in the cal switch from the pro-inflammatory type Th1 cytokine response
population. This is often the case in developing countries [53]. towards the anti-inflammatory Th2 occurs towards the later part
Results from several randomised, controlled studies show signifi- of the pregnancy. This switch may be of importance, both for fetal
cant improvements in pregnancy outcomes (increase in birth development and neonatal and child health. Supplementation with
weight; reduction in low birth weight) after introduction of vitamins C and E may negatively affect this switch, resulting in
multiple micronutrient (MMN) supplementation [54,55]. Avail- complications.
ability of large scale blood tests in these communities is scarce, and Normal mineral and vitamin metabolism is important for
little is therefore known about the range and extent of nutrient successful pregnancies, but when it comes to practical implica-
deficiencies, and no data exist on the optimal composition of MMN. tions, very few evidence-based, general recommendations on
Overall, however, there is evidence that outcomes are better when prophylactic measures can be derived from the literature.
providing a minimum of three components [56]. The most Micronutritients of particular importance for prevention of
prevalent deficiencies in developing countries are iron, Ca, vitamin adverse pregnancy outcomes are folic acid, Zn, and Fe [19]. Pre-
D, vitamin A, Zn, and folate. Even in developed countries selected pregnancy and early pregnancy folate supplementation is now
groups are micronutrient deficient, e.g. pregnant adolescents, firmly established. Fe treatment in iron deficiency seems to have a
possibly calling for MMN treatment [57]. beneficial effect on pregnancy outcome. Most other intervention
MMN can be implemented in a large-scale programme and studies large enough to allow statistically reliable analysis,
should be well suited for developing countries, where medical however, include mixed populations which are not stratified
and economic resources are limited. Production and distribution according to single or multiple deficiencies. Therefore, numbers
are not very costly, and the application fairly simple. In addition, needed to treat are unknown and unnecessary treatment may
and rather a sine qua non, improvements in ante-natal health carry risks. Studies from areas with high prevalence of specific
services and securing of adequate food supplies must have nutrient defects are important, however, showing that supple-
priority. mentation prophylaxis works. The ideal prospective trial is
therefore awaited, including individuals with a pre-gestational,
6. Comments biochemically and physiologically defined nutritional status as the
basis for a stratified, placebo-controlled analysis. In the meantime,
For many decades vitamin supplements have been regarded as individual evaluation is necessary if feasible.
solely health-promoting. Deficiencies may result in significant In conclusion, substitution therapy and supplementation may
morbidity, where vitamin treatment is curative. Increased be beneficial during pregnancy, but specific deficiencies should be
demands may ensue during pregnancy, with negative conse- sought. Pre-pregnancy and early pregnancy folate supplementa-
quences to the fetus and child health. However, the effect of tion is now firmly established, and iron treatment in iron
vitamin supplements in non-deficient pregnant individuals is deficiency seems to have a beneficial effect on pregnancy outcome.
poorly understood. Pregnant women consuming a long-term, predominantly vegetar-
Considerable problems arise in the interpretation of dietary ian diet, have an increased risk of vitamin B12 deficiency and
studies and in determining the consequences on pregnancy and supplementation with B12 may be needed. Asian immigrants to
fetal growth. There is a paucity of well designed, controlled studies. Europe are at particular risk of vitamin D deficiency during
Isolated deficiencies of dietary components rarely appear, and the pregnancy, with dietary inadequacy being an important factor.
quantification of individual food components, e.g. vitamins, as well Vitamin D may be beneficial against development of pre-
as the estimation of food intake, are difficult and unreliable. eclampsia. Supplementation with vitamins C may be beneficial.
Furthermore, the populations studied are often non-homogenous Supplementation with vitamin E is not presently recommended,
and poorly defined. The inclusion of large numbers of individuals is and may even be hampered by untoward effects.
necessary to allow statistically reliable analyses. These studies are
usually not stratified in terms of defined deficiencies, demographic Authors’ contributions
background, etc. In intervention studies from populations where
under-nutrition is prevalent the diets are usually deficient in Both authors were equally involved in literature studies and
several food components. Supplementation of single components writing.
132 N. Hovdenak, K. Haram / European Journal of Obstetrics & Gynecology and Reproductive Biology 164 (2012) 127–132

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