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Official Journal of the Society of Hospital Pharmacists of Australia

WOMEN'S AND CHILDREN'S THERAPEUTICS REVIEW

Vitamin and mineral supplementation in pregnancy: evidence to


practice
Rebecca L. Wilson, PhD1,2, Jason A. Gummow, PhD1, Dale McAninch, PhD1,2, Tina Bianco-Miotto, PhD1,3,
Claire T. Roberts, PhD1,2,*
1 Robinson Research Institute, University of Adelaide, Adelaide, Australia
2 Adelaide Medical School, University of Adelaide, Adelaide, Australia
3 School of Agriculture, Food and Wine, Waite Research Institute, University of Adelaide, Adelaide, Australia

Abstract
Pregnancy is a dynamic state that requires increased nutrient intakes in order to support the growing fetus, placenta and maternal
tissues, and hence a successful pregnancy outcome. Although maternal micronutrient deficiencies during pregnancy are often associ-
ated with pregnancy complications, as well as adverse fetal growth and development, evidence to support routine vitamin and min-
eral supplementation is relatively scarce. This review summarises existing evidence and special considerations regarding folic acid,
vitamin B12, vitamin D, calcium, zinc, iron, selenium and iodine supplementation on pregnancy outcomes. Current practice recom-
mendations are for routine supplementation of folic acid and iodine, but recommendations regarding other vitamins and minerals
are based on an individualised approach in pregnancy, with supplementation restricted to women with insufficient dietary intakes
or established deficiencies. This review aims to support pharmacists in evaluating the appropriateness of various individual and
multicomponent vitamin and mineral supplements and providing balanced and up-to-date information to women who are either
planning pregnancy or are already pregnant.

Keywords: supplements, pregnancy, pregnancy complications, micronutrients.

INTRODUCTION Pregnancy complications, including pre-eclampsia,


gestational hypertension, intrauterine growth restriction
Pregnancy is a dynamic state characterised by major (IUGR) and preterm birth, affect one in five first-preg-
changes to maternal physiology and anatomy in order nancies and predict lifelong morbidity and mortality for
to accommodate the growth of the fetus and placenta. both mother and child.3 The cause of many of these
Adjustments in nutrient metabolism are key to support- complications is largely unknown. However, there is
ing not only the fetus, but also the mother. It is impor- abundant literature looking at associations between
tant that pregnant women maintain adequate levels of pregnancy complications and deficiencies in vitamin D,
essential vitamins and minerals. Collectively known as folate, vitamin B12, iodine, iron, zinc and selenium.1 Sev-
micronutrients, these dietary components support virtu- ere micronutrient deficiencies are more common in
ally all aspects of cellular and metabolic activity, includ- developing countries,4 particularly in populations who
ing cell proliferation, apoptosis and differentiation, as avoid meat and/or dairy products, as well as those with
well as tissue growth and homeostasis.1 Deficiencies in diets high in unrefined grains and legumes that contain
certain micronutrients, either through reduced dietary phytates and polyphenols, which limit micronutrient
intake or impaired intestinal absorption or excretion, absorption.5 However, suboptimal micronutrient status
can have dire consequences on pregnancy outcome.2 may still affect the risk of adverse pregnancy outcomes
because many physiological pathways can be disrupted
by even the smallest perturbations in micronutrient
homeostasis. Thus, governing bodies like the Institute of
*Address for correspondence: Claire T. Roberts, University of Ade-
laide, Level 6, Adelaide Health and Medical Sciences Building, Ade-
Medicine5 and the National Health and Medical
laide, South Australia 5000, Australia. Research Council (NHMRC) of Australia6 recommend
E-mail: Claire.roberts@adelaide.edu.au

© 2018 The Society of Hospital Pharmacists of Australia Journal of Pharmacy Practice and Research (2018) 48, 186–192
doi: 10.1002/jppr.1438
Micronutrient supplementation in pregnancy 187

pregnant women increase their daily intake of most VITAMIN D


micronutrients (Table 1).
This review summarises a number of recent meta- Vitamin D synthesis, metabolism and action are pivotal
analyses of the use of supplements taken during preg- in numerous biological pathways, including bone miner-
nancy containing specific micronutrients, namely folic alisation, immune function and disease prevention.12
acid, vitamin D, calcium and trace minerals iron, iodine, Vitamin D plays an important role in regulating calcium
zinc and selenium, for the prevention of pregnancy com- and phosphate serum concentrations and demonstrates
plications. Most of these micronutrients are included in a complex relationship with other micronutrients, such
the leading Australian pregnancy multivitamin formula- as magnesium.13 Dietary and supplemental sources of
tions (Table 2). Thus, there is increased interest in deter- vitamin D include ergocalciferol (D2) and colecalciferol
mining their utility in improving pregnancy outcome. (D3),6 but the major natural source of vitamin D is the
synthesis of colecalciferol in the skin. Each of these
forms of vitamin D is biologically inactive and requires
FOLIC ACID enzymatic conversion in the liver and kidneys to form
calcitriol. Dietary recommendations for vitamin D are
Folic acid is synthetic vitamin B9 that is converted to largely based on oral intake alone because sun exposure
folate in the body. Its metabolism is essential in numer- in the population is highly variable and thus recommen-
ous biological pathways, including the 1-carbon meta- dations assume average sun exposure.6 In terms of preg-
bolic pathway, in which it, together with vitamin B12, nancy, there are many reports on possible clinical
facilitates the transfer of a methyl group for numerous consequences of diminished maternal vitamin D levels.
biosynthetic reactions.7 It has long been known that Vitamin D deficiency is associated with an increased
supplementation with folic acid in the periconceptional risk of pregnancy complications, including pre-eclamp-
and gestational periods prevents the development of a sia,14,15 preterm birth16 and low birth weight.17,18 Fur-
number of major congenital malformations, particularly thermore, maternal vitamin D deficiency in pregnancy
neural tube defects (NTD) because folate is critically has been associated with the onset of diseases later in
important during periods of rapid growth.8,9 Most nota- life, including autoimmune diseases,19 asthma20 and
bly, folic acid administration prior to and during early type 1 diabetes.21 Despite such findings from observa-
pregnancy has been demonstrated to significantly tional studies, a recent meta-analysis of randomised con-
reduce the risk of NTD (Risk Ratio (RR) 0.31; 95% confi- trolled trials investigating vitamin D determined that
dence interval (CI) 0.17–0.58).10 For this reason, it is rec- evidence to date is insufficient to guide clinical or policy
ommended that all women should take at least 0.4 mg recommendations regarding supplementation in preg-
daily for a minimum of 1 month before conception and nancy.22 Despite no high-quality evidence supporting a
for the first 12 weeks of pregnancy.6 Special considera- reduction in adverse pregnancy outcomes following
tions and recommendations for higher doses of folic
acid are provided in Table 3. Given not all pregnancies
are planned, many women may not even realise that Table 1 National Health and Medical Research Council recom-
they are pregnant until late in the first trimester. In an mended daily intake of key micronutrients for non-pregnant,
effort to reduce the risk of folate deficiencies among pregnant and lactating women6
women of childbearing age, all wheat flour used for
Non-pregnant
making bread in Australia has been fortified with folic
women Pregnant Lactating
acid since September 2009. (≤50 years) women women
Despite benefits with regard to congenital malforma-
tions, a meta-analysis of 31 trials of folic acid supple- Folic acid 400 600 500
(micrograms)
mentation throughout pregnancy found no conclusive
Vitamin B12 2.4 2.6 2.8
evidence of benefit with respect to any pregnancy out- (micrograms)
comes.11 This was despite the fact that supplementation Vitamin D 5 5 5
with folic acid improves predelivery maternal folate (micrograms)
levels (RR 0.38; 95% CI 0.25–0.59).11 None of the studies Calcium (mg) 1000 1000–1300 1000–1300
included in that analysis assessed pre-eclampsia or Iron (mg) 18 27 9–10
hypertensive disorders of pregnancy as key outcomes, Iodine (micrograms) 150 220 270
Zinc (mg) 8 10–11 11–12
and thus further trials are required to determine the
Selenium 60 65 75
effects of folic acid supplementation throughout preg- (micrograms)
nancy on other prevalent pregnancy complications.

© 2018 The Society of Hospital Pharmacists of Australia Journal of Pharmacy Practice and Research (2018) 48, 186–192
188 R. L. Wilson et al.

Table 2 Key micronutrient content of four leading pregnancy multivitamins available in Australia

Elevit (Bayer), Pregnancy and Breastfeeding Pregnancy Platinum Pregnancy Ultivite


Australia Gold (Blackmores), Australia (Natures Own), Australia (Swisse), Australia

Dose (tablets/day) 1 2 1 1
Micronutrient content
Folic acid (micrograms) 800 250 500 500
Vitamin B12 (micrograms) 2.6 1.3 0 2.6
Vitamin D3 (colecalciferol; micrograms) 5 12.5 5 15
Calcium (mg) 125 50 20 20
Iron (mg) 60 5 5 5
Iodine (micrograms) 220 75 250 250
Zinc (mg) 11 5.5 12 11
Selenium (micrograms) 50 32.5 16.25 65

Values represent the amount of each micronutrient found in one tablet.

vitamin D supplementation in pregnancy, there is evi- and 15 470 women, predominantly from countries
dence to support a reduction in the risk of offspring where calcium intake is predicted to be lower. Indeed,
wheeze by age 3 years (RR 0.81; 95% CI 0.67–0.98).22 the greatest effect was seen in trials undertaken among
Furthermore, low maternal serum vitamin D concentra- women with low-calcium diets (eight trials, 10 678
tions are correlated with low neonatal levels. This is women; RR 0.36; 95% CI 0.20–0.65). Furthermore, high-
important because vitamin D deficiency in the neonate dose calcium supplementation compared with placebo
and the infant has been associated with impaired skele- significantly reduces the risk of preterm birth (11 trials,
tal development and an increased incidence of hypocal- 15 275 women; RR 0.76; 95% CI 0.60–0.97), but does not
caemic seizures.23 Although routine screening and appear to affect the risk of delivering a small-for-gesta-
supplementation with vitamin D is not currently recom- tional age infant (four trials, 13 615 women; RR 1.05;
mended, women should be assessed for vitamin D defi- 95% CI 0.86–1.29).35
ciency based on established risk factors (Table 3) and
offered treatment as appropriate.
IRON

CALCIUM Anaemia, as a result of iron deficiency, is highly preva-


lent in women worldwide.36 Iron is required by numer-
During pregnancy, maternal calcium homeostasis is inte- ous proteins that participate in many cellular functions,
gral to supporting fetal bone health and development.25 including oxygen transport, antioxidant defences and
This is largely dependent on maternal vitamin D status DNA synthesis.37 Thus, reducing the incidence of iron
and the vitamin D metabolic pathway, which, during deficiency in pregnant women is a key goal for many
pregnancy, maintains adequate transfer of calcium to health organisations. Iron deficiency in pregnancy has
the growing fetus.26 Currently, it is recommended that been associated with increasing perinatal morbidity and
pregnant women consume >1000 mg calcium in order mortality36,38 and it is recommended that pregnant
to meet increased fetal calcium requirements.6 Hypocal- women increase their daily iron intake to support
ciuria (reduced calcium in the urine) has been associated increased requirements.6 However, routine supplementa-
with pre-eclampsia,27–29 and measuring urinary calcium tion of iron is not recommended and no clear benefit for
to creatinine ratio in early pregnancy has been sug- a reduction in adverse perinatal outcomes has been
gested as a possible predictor of pre-eclampsia.30 For observed,39 despite iron supplementation reducing the
this reason, calcium supplementation is recommended risk of maternal anaemia and the development of iron
as a preventative measure for pre-eclampsia, particularly deficiency. There is evidence for possible reductions in
in groups of women who avoid dairy products the risk of preterm birth or delivering a low birth
(Table 3).31–34 A recent meta-analysis on the use of high- weight infant in settings where nutritional intake is poor
dose (>1 g/day) calcium supplementation compared and the risk of anaemia or adverse perinatal outcomes
with placebo found a reduced risk of pre-eclampsia (RR is much higher, such as in developing nations.40 There-
0.45; 95% CI 0.31–0.65).35 That study included 13 trials fore, the relevance of these findings and potential

Journal of Pharmacy Practice and Research (2018) 48, 186–192 © 2018 The Society of Hospital Pharmacists of Australia
Micronutrient supplementation in pregnancy 189

Table 3 Summary of current recommendations regarding vitamin and mineral supplementation in pregnancy (adapted from The Royal
Australian and New Zealand College of Obstetricians and Gynaecologists24)

Vitamin or mineral General recommendations Special considerations

Folic acid All women should take at least 0.4 mg A higher daily dose of 5 mg should be recommended for women
daily for a minimum of 1 month at increased risk of NTD:
before conception and for the • Pre-existing diabetes mellitus
first 12 weeks of pregnancy • Family history of NTD or women with a child with NTD
• Women taking folate antagonists
(e.g. carbamazepine, valproic acid)
• Increased BMI (>30 kg/m2)
• Malabsorption syndrome (e.g. inflammatory bowel disease)

Iodine All women who are pregnant, breast-feeding, Mandatory in areas of regional deficiency
or considering pregnancy should
take 150 micrograms/day
Vitamin B12 Routine supplementation not recommended Consider supplementation in pregnancy and lactation for women
who are vegetarian or vegan
Vitamin D Routine screening and supplementation of Offer vitamin D screening to women with limited exposure to
vitamin D is not currently recommended sunlight (e.g. because they are predominantly indoors or
usually protected from the sun when outdoors), or those who
have dark skin or a prepregnancy BMI >30 kg/m2
Calcium Routine supplementation not recommended Supplementation (≥1000 mg/day) is recommended for women
who avoid dairy in their usual diet and do not consume
alternative high-calcium foods (e.g. calcium-enriched soya milk)
Iron Routine supplementation is not recommended. Risk factors for iron deficiency include:
All women should have their haemoglobin • Previous anaemia or iron deficiency
assessed at the first antenatal visit and • Multiparity (para >2)
again around 28 weeks gestation • Consecutive pregnancy <1 year following delivery

Women who are identified as anaemic should • Vegetarians


be appropriately investigated and treated • Teenage pregnancies
• Aboriginal or Torres Strait Islander women
• Recent history of bleeding
• Inflammatory bowel disease
• Bariatric surgery

Zinc, selenium and Routine supplementation is not recommended N/A


other minerals
Vitamin E Routine supplementation is not recommended N/A
Vitamin K Routine supplementation is not recommended Should be administered in late pregnancy to women with
proven obstetric cholestasis, due to reduced vitamin K absorption

BMI = body mass index; N/A = not applicable; NTD = neural tube defects.

benefits of routine iron supplementation in a developed 28 weeks gestation. Women who are identified as anae-
setting are unclear. Of interest is that studies have mic should be appropriately investigated and treated
demonstrated that intermittent (i.e. two or three times a with iron supplements if iron deficiency is the identified
week on non-consecutive days) supplementation regi- cause. Specific risk factors for iron deficiency are out-
mens produced similar maternal and infant outcomes as lined in Table 3 and can be used to guide screening
daily supplementation, but with a reduction in associ- practices. Specific guidelines for the management of
ated side effects and a lower risk of high levels of hae- anaemia in pregnancy have been published elsewhere.41
moglobin in mid- and late pregnancy.38 Therefore,
intermittent regimens have been proposed as a feasible
alternative to daily iron supplementation. Despite uncer- IODINE
tain evidence surrounding routine iron supplementation,
all women should have their haemoglobin and ferritin Iodine is an essential component of thyroid hormones,
assessed at the first antenatal visit and again around which are necessary for brain development in utero.42

© 2018 The Society of Hospital Pharmacists of Australia Journal of Pharmacy Practice and Research (2018) 48, 186–192
190 R. L. Wilson et al.

Since the implementation of universal fortification of salt USE OF MULTIVITAMINS


with iodine in bread making, severe iodine deficiency is
rare. However, mild to moderate deficiency still per- In an effort to address potential individual micronutrient
sists.43 Irreversible damage to a child’s normal physical deficiencies, many women take complex pregnancy mul-
growth and mental development can be attributed to tivitamins. Despite high-frequency use and widespread
maternal iodine deficiency during pregnancy, as well as marketing and promotion, there is a lack of evidence that
iodine deficiency in early childhood. Thus, iodine sup- routine supplementation with multivitamins or supple-
plementation with 150 micrograms daily is recom- ments containing multiple micronutrients either in pre- or
mended for both pregnant and lactating women and periconception is beneficial to pregnancy outcome.57,58 In
mandatory in areas of regional deficiency (Table 3).6 many cases, supplementation with such multivitamins
Despite consistent reports that iodine is integral to sup- may provide amounts of various vitamins and minerals
porting fetal neurodevelopment, there is inconclusive above what is actually needed. Such supplements may
evidence to show any beneficial support to pregnancy not be completely without harm. For example, although
complications, primarily due to a lack of randomised supplementation with vitamin C alone does not appear to
controlled trails that have assessed outcomes such as be beneficial,59 supplementation with combined vitamins
preterm birth or pre-eclampsia.44 These trials have lar- C and E from 12 to 18 weeks gestation has been shown to
gely focused on neurodevelopment, so there is still no increase the risk of fetal loss or perinatal death.60 Further-
understanding of the effects of supplementation on birth more, vitamin A is a teratogen, with high intake during
weight or prematurity. pregnancy being associated with an increased risk of con-
genital malformations.61,62 Therefore, limits to the
amount of vitamin A pregnant women should take are
ZINC AND SELENIUM advised. A lack of high-quality, large, randomised con-
trolled trials significantly limits our ability to evaluate the
Trace minerals including zinc and selenium are present in benefits, or potential harms, of routine vitamin and
minute amounts within the body but are integral to cellu- mineral supplementation in pregnancy. Therefore, some
lar function and tissue physiology.45 Zinc is an essential degree of caution regarding widespread routine supple-
component for numerous antioxidant enzymes, metal- mentation practices is warranted.
loenzymes, zinc-binding factors and zinc transporters.46
Although severe zinc deficiency is relatively scarce, mild
to moderate zinc deficiency is estimated to be common CONCLUSIONS
throughout the world47 and, given the diverse range of
biological functions involving zinc, it is not surprising At present, only folic acid and iodine are recommended for
that zinc deficiency is associated with adverse pregnancy routine supplementation for all women. Intake of other
outcome and poor fetal development.48 Analysis of 21 vitamins and minerals, such as iron, calcium and vitamin
randomised control trials and 17 000 women found that D, are dependent on a woman’s abilities to meet recom-
zinc supplementation in pregnancy, compared with no mended dietary intakes based on nutritional intake alone,
treatment or placebo, reduced the risk of preterm delivery or on identified nutritional deficiencies. Although multivi-
(RR 0.86; 95% CI 0.75–0.97) but did not affect low birth tamin use is common in pregnancy, there is a lack of data
weight delivery (RR 0.93; 95% CI 0.78–1.12) or pre- supporting widespread use. Pharmacists should be aware
eclampsia (RR 0.83; 95% CI 0.64–1.08).49 of special considerations regarding vitamin and mineral
As with zinc, selenium is an antioxidant, important in supplementation in pregnancy and be prepared to provide
supporting immune function and reducing cellular balanced and up-to-date information to women.
stress. Selenium deficiency in pregnancy has been asso-
ciated with miscarriage, pre-eclampsia and fetal growth
Conflict of interests statement
restriction,50,51 and selenium supplementation has bene-
ficial effects on hypertension.52 Thus, the NHMRC rec- The authors declare that they have no conflicts of interest.
ommends an additional 10–15 micrograms/day selenium
for pregnant women,6 and most pregnancy supplements
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Journal of Pharmacy Practice and Research (2018) 48, 186–192 © 2018 The Society of Hospital Pharmacists of Australia
Micronutrient supplementation in pregnancy 191

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Journal of Pharmacy Practice and Research (2018) 48, 186–192 © 2018 The Society of Hospital Pharmacists of Australia

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