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Maternal mineral and vitamin

supplementation in pregnancy
Expert Rev. Obstet. Gynecol. 5(2), 241256 (2010)
Mohammad Yawar
Yakoob, Yasir Pervez
Khan and Zulfiqar
Ahmed Bhutta
Author for correspondence
Division of Women and Child
Health, The Aga Khan
University, Stadium Road,
POBox3500, Karachi-74800,
Pakistan
Tel.: +92 213 486 4782
Fax: +92 213 493 4294
zulfiqar.bhutta@aku.edu
Deficiency of vitamins and minerals, collectively known as micronutrients, during pregnancy can
have important adverse effects on maternal and birth outcomes. Evidence-based nutrition
interventions can make a difference and potentially avert these outcomes. Iron supplementation
has been shown to improve maternal mean hemoglobin concentration at term and reduce the risk
of anemia. Zinc supplementation has been shown to result in a small but significant reduction in
preterm births. A cluster-randomized study in Nepal showed a 40% reduction in maternal mortality
up to 12weeks postpartum with weekly vitaminA and 49% biweekly b-carotene supplementation
but subsequent large studies in Bangladesh and Ghana have failed to demonstrate any impact on
mortality. Maternal vitaminA supplementation has no role in preventing mother-to-child transmission
of HIV in HIV-infected pregnant women. Periconceptional folic acid supplementation reduces the
risk of neural tube defects, while supplementation with vitaminD reduces the incidence of
neonatal hypocalcemia with no impact on craniotabes. Iodine supplementation during pregnancy
has also been suggested to reduce the risk of perinatal and infant mortality, and the risk of
endemic cretinism at 4years of age. Calcium supplementation reduced the risk of preeclampsia
in women with low baseline calcium dietary intake, while magnesium supplementation has been
associated with a lower frequency of preterm births and adverse neurodevelopmental outcomes
in childhood. Other vitamins and minerals, such as vitaminsB, C and E, copper and selenium, have
been associated with fetal development, but their impact on pregnancy outcomes is not clear.
Given such widespread maternal vitamin and mineral deficiencies, it is logical to consider
supplementation with multiple micronutrient preparations in pregnancy. The clinical benefits of
such an approach over single-nutrient supplements are unclear, and this article explores the current
concepts, evidence and limitations of maternal multiple-micronutrient supplementation.
Keywords : folate iodine iron micronutrient supplementation pregnancy vitaminA zinc
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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures;
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Learning objectives
Upon completion of this activity, participants should be able to:
Describe the effects of iron deficiency and the effect of iron supplementation during pregnancy
Describe the effect of zinc supplementation during pregnancy
Identify the benefits of vitamin A supplementation during pregnancy
List the effect of folate supplementation during pregnancy
Describe the effects of vitamin D, calcium, and magnesium deficiency and supplementation
during pregnancy
www.expert-reviews.com
10.1586/EOG.10.8
2010 Expert Reviews Ltd
ISSN 1747-4108
241
Review
CME
Yakoob, Khan & Bhutta
Financial & competing interests disclosure
Editor
Elisa Manzotti, Editorial Director, Future Science Group, London, UK.
Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.
CME Author
Dsire Lie, MD, MSEd
Clinical Professor, Family Medicine, University of California, Irvine, Orange, California; Director of Research and Patient Development, Family Medicine,
University of California, Irvine, Medical Center, Rossmoor, CA, USA.
Disclosure: Dsire Lie, MD, MSEd, has disclosed the following relevant financial relationship: she served as a nonproduct speaker for: Topics in Health for
Merck Speaker Services.
Authors and Credentials
Mohammad Yawar Yakoob, MBBS
Research Fellow, Division of Women and Child Health, The Aga Khan University, Stadium Road, PO Box 3500, Karachi-74800, Pakistan.
Disclosure: Mohammad Yawar Yakoob has disclosed no relevant financial relationships.
Yasir Pervez Khan, MBBS
Research Fellow, Division of Women and Child Health, The Aga Khan University, Stadium Road, PO Box 3500, Karachi-74800, Pakistan.
Disclosure: Yasir Pervez Khan has disclosed no relevant financial relationships.
Zulfiqar Ahmed Bhutta, MB,BS, FRCP, FRCPCH, FCPS, FAAP, PhD
Professor and Head, Division of Women and Child Health, The Aga Khan University, Stadium Road, PO Box3500, Karachi-74800, Pakistan.
Disclosure: Zulfiqar Ahmed Bhutta has disclosed no relevant financial relationships.
Undernutrition during the reproductive age group and pregnancy

remains a major problem in countries where women usually do not
have equitable access to food, education and healthcare[101] . Many
women are undernourished at birth, stunted during childhood,
become pregnant at adolescence, and are underfed and overworked
during pregnancy and lactation, resulting in nutritional deficiencies
[102] . Most women living in developing countries experience various biological and social stresses that, combined with other factors,
increase the risk of malnutrition throughout life. These include:
poverty, lack of purchasing power, food insecurity and inadequate
diets, recurrent infections, poor healthcare, heavy work burdens,
gender inequities and limited general knowledge about appropriate nutritional practices. These factors are compounded by high
fertility rates, repeated pregnancies and short intervals between
pregnancies [1] . Undernutrition undermines the womans ability to
survive childbirth and give birth to healthy children, translating
into lost lives of mothers and their infants [102] . Nutrient deficiencies, whether clinical or subclinical, can also potentially affect
fetal growth, cognition and future reproductive performance [2] .
In the developing world, maternal and fetal undernutrition impairs
their contribution to their families and communities, as well as
their productivity and income-generating capacity [102] . It has
been shown that maternal undernutrition reduces placentalfetal
blood flow and retards fetal growth in both domestic animals
and humans [3,4] . An altered intrauterine nutritional environment
affects expression of the fetal genome, a phenomenon termed fetal
programming [5] . This impact of maternal nutritional status on
fetal programming and genetic imprinting is associated with disease in later life, such as coronary heart disease and stroke, and
the associated conditions such as hypertension and non-insulindependent diabetes. People who have low growth rates inutero
also cannot withstand the stress of becoming obese as adults [4] .
242
Burden of maternal micronutrient deficiencies

&evidence base for interventions
Nutritional deficiencies are widely prevalent globally and contribute significantly to high rates of morbidity and mortality among
mothers and their infants and children in developing countries.
The nutritional status of a woman before and during pregnancy
is important for a healthy pregnancy outcome. The prevalence of
maternal undernutrition that is, a BMI of less than 18.5kg/m2
ranges from 10 to 19% in most countries [6] . More than 20%
of women in sub-Saharan Africa, Southcentral and Southeastern
Asia, and Yemen have a BMI of less then 18.5kg/m2 [6] . In India,
Bangladesh and Eritrea, 40% of women have a low BMI, which
has adverse effects on pregnancy outcomes and increases the risk
of infant mortality [6] . Malnutrition among women manifests
itself at the macronutrient and/or the micronutrient level. More
than 40% of pregnant women around the world are anemic,
most of which is due to iron deficiency [103] . Iron, therefore, contributes to the largest prevalence of micronutrient deficiencies.
Other important deficiencies include iodine, zinc, vitaminA,
folic acid and vitaminB complex, including thiamine, riboflavin
and B12 [7] .
There is a critical window of opportunity during the early prenatal period while the fetus is still growing to prevent undernutrition during pregnancy and its effects on maternal and child
health. Evidence-based nutrition interventions can make a difference to short-term outcomes, and also offer the best opportunity for long-term growth and development. These interventions
include strategies to improve maternal nutrition before and during pregnancy, with appropriate micronutrient interventions.
Although iron-deficiency anemia is recognized as an important
risk factor for maternal and perinatal mortality globally, the contribution of other micronutrient deficiencies to adverse outcomes
Expert Rev. Obstet. Gynecol. 5(2), (2010)
CME
Maternal mineral & vitamin supplementation in pregnancy
of pregnancy is less clear. However, emerging evidence suggests

that micronutrients such as vitamin B12, folic acid, vitaminD
and selenium may also be important for maternal, infant and
child outcomes [810] .
Iron
Iron deficiency and iron-deficiency anemia are major public

health problems, affecting an estimated 30% of the worlds
population, mostly women of reproductive age [102] . The major
clinical manifestation of iron deficiency is anemia or a low-blood
hemoglobin concentration. Anemia affects 41.8% of pregnant
women in the world and is a risk factor for maternal morbidity
and mortality[103] . In a study conducted in India, 87% of pregnant women were found to be anemic [11] . The prevalence in other
South Asian countries varies: Bangladesh 77%, Bhutan 59%,
Nepal 65% and Sri Lanka 60% [2] . Iron deficiency, resulting in
anemia, is highly prevalent in pregnant women, and increased
requirements in pregnancy are often not met even by changes in
diet. During pregnancy, iron requirements increase substantially
due to increased requirements by the placenta and the fetus, and
is further compounded by blood loss at delivery. Studies have
shown that iron deficiency increases the rate of premature delivery and perinatal mortality [12] . Hemorrhage remains a leading
cause of maternal death in developing countries, accounting for
approximately 25% of all maternal deaths [13] , and iron deficiency
is recognized to increase the risk of mortality among anemic
women due to hemorrhage and infections.
Study or subgroup
(year)
Batu (1976)
Butler (1968)
Buytaert (1983)
Cantlie (1971)
Chanarin (1971)
Cogswell (2003)
De Benaze (1989)
Eskeland (1997)
Makrides (2003)
Milman (1991)
Puolakka (1980)
Romslo (1983)
Tura (1989)
Van Eijk (1978)
Wallenburg (1983)
Ziaei (2007)
Ziaei (2008)
Total (95% CI)
Treatment (daily)
Mean
SD Total
113.00
136.00
127.29
124.00
124.00
121.40
130.00
125.70
127.00
128.90
132.00
126.00
121.00
132.13
128.90
139.00
138.80
10.00
9.87
12.80
6.00
9.80
10.39
10.00
7.80
13.00
8.00
12.00
8.00
8.00
11.27
11.30
12.50
4.50
Control (no iron)

Mean
SD Total
30
97.00 11.00
27 135.00 7.10
24 124.07 8.05
15 11.0.00 9.00
49 114.00 9.50
90 121.70 10.48
44 122.00 10.00
24 112.80 6.50
200 120.00 12.00
99 118.90 10.00
16 111.00 9.00
22 113.00 10.00
129 119.00 10.00
15 112.79 16.11
18 125.60 11.30
370 131.80 13.60
114 127.80 4.70
22
6
21
12
46
62
25
21
193
107
15
23
112
15
20
357
120
Review
Several UN agencies recommend the universal distribution of ironfolic acid supplements to pregnant women in the
developing world. The evidence base for the effectiveness of
iron supplementation in pregnancy is strong. A review by PenaRosas and Viteri on preventive iron or iron and folic acid supplementation during pregnancy included 49 trials involving
23,200women [14] . Daily oral iron supplementation resulted
in a significantly higher maternal mean hemoglobin (Hb) concentration (mean difference [MD]: 8.83; 95%CI: 6.5511.11)
(Figure1) and a reduced risk of anemia in mothers at term (relative
risk [RR]: 0.27; 95%CI:0.170.42), compared with no intervention or placebo administration. There was also reduced risk
of iron-deficiency anemia, a significantly higher risk of hemoconcentration at term and also a higher mean Hb concentration
within 1month postpartum. The benefits to the infant included
a significant increase in birth length (MD: 0.38cm; 95%CI:
0.100.65) and higher mean ferritin concentrations at 3 and
6months of age. However, there was no significant direct evidence of benefits on maternal outcomes such as maternal mortality, severe anemia at term, preeclampsia, antepartum hemorrhage
and postpartum hemorrhage, but few studies were powered for
these effects. Similarly, infant outcomes such as perinatal death,
low birthweight, small-for-gestational age, premature delivery
and Hb concentrations at 3 and 6months were not statistically
different. Similar results were achieved for iron plus folic acid
supplementation versus no intervention or placebo. There was
a significantly higher mean Hb maternal concentration and a
Weight
Mean difference
IV, random (95% CI)
5.2%
4.7%
5.0%
5.2%
6.5%
6.8%
5.8%
6.3%
7.3%
7.3%
4.3%
5.6%
7.3%
3.2%
4.4%
7.5%
7.8%
16.00 (10.1721.83)
1.00 (-5.797.79)
3.22 (-2.959.39)
14.00 (8.0719.93)
10.00 (6.1213.88)
-0.30 (-3.683.08)
8.00 (3.0912.91)
12.90 (8.7217.08)
7.00 (4.539.47)
10.00 (7.5412.46)
21.00 (13.5628.44)
13.00 (7.7218.28)
2.00 (-0.314.31)
19.34 (9.3929.29)
3.30 (-3.9010.50)
7.20 (5.309.10)
11.00 (9.8212.18)
1286
1177 100.0%
Heterogeneity: Tau2 = 17.08; 2 = 120.52; df = 16 (p < 0.00001); I2 = 87%
Test for overall effect: Z = 7.59 (p < 0.00001)
Mean difference
IV, random (95% CI)
8.83 (6.5511.11)
-100
-50
0
50
100
Favors experimental Favors control
Figure1. Forest plot of the effect of daily iron alone versus no intervention/placebo on maternal hemoglobin concentration
at term.
SD: Standard deviation.
Data from [14] .
243
Review
reduced risk of anemia at term. Hb levels within 1month postpartum were also greater in the intervention group. There was
also a reduced risk of small-for-gestational age babies, and a
significantly greater birth length and mean birthweight in the
ironfolate group. There was no difference in maternal iron
deficiency at term or adverse maternal and infant outcomes
between the two groups. Iron and folic acid supplementation
during pregnancy also resulted in a significant 31% decreased risk
of death in children occurring from birth to 7years of age compared
with controls receiving vitaminA only (hazard ratio [HR]:0.69;
95%CI:0.490.99)[15] .
Zinc
While definite data on the prevalence of zinc deficiency are

hard to come by, several studies in the literature highlight the
likelihood of widespread mild-to-moderate zinc deficiency in
pregnant women[2] . The prevalence of zinc deficiency in developing countries is probably similar to that of nutritional iron
deficiency, as the same dietary pattern induces both, with a
high prevalence in South Asia, most of sub-Saharan Africa and
parts of Central and South America [6] . Caulfield etal. have
stated that 82% of pregnant women worldwide are likely to
have inadequate usual intakes of zinc [16] . Zinc plays a role in a
large number of metabolic synthetic reactions. During periods
of rapid growth and higher micronutrient requirements, such
as infancy, adolescence and late pregnancy, girls and women
are most susceptible to zinc deficiency. Severe zinc deficiency,
although uncommon, has been related to spontaneous abortion
and congenital malformations (i.e., anencephaly), while milder
forms have been linked with low birthweight, intrauterine growth
retardation and preterm delivery[17] . Besides, mild zinc deficiency
may also be related to complications of labor and delivery such
as prolonged or inefficient first-stage and protracted secondstage labor, premature rupture of membranes, and the need for
assisted or operative delivery [17] . The mechanisms underlying
these associations are not clear, making it difficult to explain why
such relationships have not been replicated in most randomized
controlled trials(RCTs).
The Cochrane review on zinc supplementation in pregnancy by
Mahomed etal. included 17 trials involving over 9000 women
and their babies [18] . There was a significant, although small,
reduction in preterm births based on 13RCTs and 6854 women
(RR: 0.86; 95%CI: 0.760.98) (Figure 2) . The effect on low
birthweight was nonsignificant (RR: 1.05; 95%CI: 0.941.17)
based on 11studies. Other primary maternal or neonatal outcomes such as pregnancy-induced hypertension or preeclampsia, prelabor rupture of membranes, antepartum hemorrhage,
instrumental vaginal birth, maternal infection, postpartum
hemorrhage, mean birthweight, small-for-gestational age, and
infant morbidities such as neonatal sepsis, respiratory distress
syndrome and neonatal intraventricular hemorrhage were no
different between zinc and control groups. There was a small
effect in favor of the zinc group for cesarean section (four trials
with high heterogeneity) and for the induction of labor in a
single trial.
244
CME
VitaminA
VitaminA is an important micronutrient affecting the health

of pregnant women and the fetus. Studies have shown that vitaminA deficiency is widespread throughout the developing world.
VitaminA deficiency has long been recognized in much of South
and Southeast Asia (India, Bangladesh, Indonesia, Vietnam,
Thailand and the Philippines) by the common presentation of
clinical cases of xerophthalmia or night blindness, mostly in the
latter half of the pregnancies [19,20] . Poor maternal vitaminA status
affects its concentration in breast milk as well [21,22] . VitaminA
deficiency during pregnancy can result in fetal wastage, although
high doses in early pregnancy can be teratogenic as well [23] . A
cluster-randomized trial by West etal. from Nepal showed that
all-cause maternal mortality up to 12weeks postpartum was
reduced by weekly vitaminA (RR: 0.60; 95%CI: 0.370.97)
and b-carotene supplementation (RR: 0.51; 95%CI: 0.300.86)
compared with the placebo group [24] . Fetal or early infant survival was not found to be improved with supplementation in this
trial [25] . However, published data are awaited from other recent
follow-up studies in Bangladesh (West KP etal. [2007], Unpublished
Data) and Ghana (Kirkwood BR etal. [2009], Unpublished Data) that did
not support such an effect of vitaminA on maternal mortality.
The potential role of vitaminA for the prevention of motherto-child transmission (MTCT) of HIV has also been recently
reviewed [26] . The review considered trials with HIV-infected
pregnant women. There was no evidence of an impact of antenatal
vitaminA supplementation on the risk of MTCT of HIV (three
trials; 2022women; RR: 1.05; 95%CI: 0.781.41) (Figure3) . It
improved birthweight (MD: 89.78; 95%CI: 84.7394.83), but
with no impact on preterm birth, stillbirths or infant death. There
was also no impact on maternal mortality based on one trial
(RR:0.49; 95%CI: 0.045.37).
Folic acid
Pregnant and lactating women are at increased risk of folic acid

deficiency because their dietary folic acid intake is insufficient to
meet their physiological requirements and the metabolic demands
of the growing fetus. The WHO compiled available information
on the prevalence of anemia, which included the prevalence of folic
acid deficiency. The percentage of pregnant women with a serum
folic acid level of less than 3ng/ml according to a WHO report
in 1992 was highest among women in Sri Lanka (57%), followed
by India (41.6%), Myanmar (13%) and Thailand (15%) [27,28] .
Maternal folic acid deficiency is associated with megaloblastic
anemia owing to folic acids role in DNA synthesis. Folic acid
deficiency interferes with DNA synthesis, causing abnormal cell
replication [29] . Low folic acid levels around the time of conception
may cause neural tube defects (NTDs) in infants. Folic acid supplementation of women during the periconceptional period reduces
the incidence of NTDs such as anencephaly and spina bifida [30,31] .
The Cochrane review by Lumley etal. shows that periconceptional
folic acid significantly reduces incidence of NTDs (RR: 0.28;
95%CI: 0.130.58) (Figure4) , including NTDs among women
with (RR: 0.31; 95%CI: 0.140.66) and without (RR:0.07;
95%CI: 0.001.33) prior NTDs [32] . Folate supplementation did
CME
Review
Low zinc or nutrition

Study or subgroup
(year)
Bangladesh (2000)
Chile (2001)
Denmark (1996)
Indonesia (2001)
Nepal (2003)
Pakistan (2005)
Peru (1999)
Peru (2004)
USA (1983)
USA (1989)
USA (1995)
Subtotal (95% CI)
Zinc
Events Total
34
14
33
5
127
22
29
7
5
50
30
194
249
585
92
628
121
521
109
87
268
294
3148
Control
Events Total
34
30
49
6
137
10
30
5
4
68
38
216
258
621
87
593
121
495
113
90
288
286
3168
Weight
Risk ratio
M-H, Fixed (95% CI)
7.5%
6.9%
11.1%
1.4%
32.9%
2.3%
7.2%
1.1%
0.9%
15.3%
9.0%
95.8%
1.11 (0.721.72)
0.48 (0.260.89)
0.71 (0.471.10)
0.79 (0.252.49)
0.88 (0.711.08)
2.22 (1.094.45)
0.92 (0.561.51)
1.45 (0.474.44)
1.29 (0.364.66)
0.79 (0.571.09)
0.77 (0.491.20)
0.87 (0.760.99)
Total events
356
411
Heterogeneity: = 14.17; df = 10 (p = 0.17); I2 = 29%
Test for overall effect: Z = 2.11 (p = 0.03)
Risk ratio
M-H, Fixed (95% CI)
0.01
0.1
1
Favors experimental
10
100
Favors control
Normal zinc or nutrition

Study or subgroup
(year)
UK (1989)
UK (1991a)
Zinc
Events Total
10
2
243
30
Control
Events Total
Weight
Risk ratio
M-H, Fixed (95% CI)
17
1
243
22
4.0%
0.3%
0.59 (0.271.26)
1.47 (0.1415.17)
Subtotal (95% CI)

273
Total events
12
18
Heterogeneity: 2 = 1.53; df = 1 (p = 0.47); I2 = 0%
265
4.2%
0.64 (0.311.32)
3433
100.0%
0.86 (0.760.98)
Total (95% CI)
3421
Total events
368
429
Heterogeneity: 2 = 15.36; df = 12 (p = 0.22); I2 = 22%
Test for subgroup differences: not applicable
Risk ratio
M-H, Fixed (95% CI)
0.01
0.1
1
Favors experimental
10
100
Favors control
Figure2. Forest plot of the effect of zinc versus no zinc on preterm birth.
Data from [18] .
not significantly increase rates of miscarriage, ectopic pregnancy

or stillbirth, although there was a possible increase in multiple
gestation. Increased risk of low-birthweight babies is also one of
the major associations of low folic acid levels during pregnancy[2] .
From a nutritional perspective, much of the interest in folic acid
deficiency has centered around low birthweight and NTDs.
However, with recent observations of elevated homocysteine levels
in folic acid deficiency and the implications for increased risk of
subsequent cardiovascular diseases, studies on folic acid deficiency
should assume a higher priority [33] . For years folic acid has been
supplemented with iron during pregnancy, mostly owing to its
effects on the hematological system [34] . Its effects on other birth
outcomes such as low birthweight, preterm delivery and perinatal
mortality are still unclear [35] .
VitaminD
Maternal vitamin D deficiency is a widespread public health

problem, especially in the developing world. VitaminD deficiency during pregnancy has been linked with a number of serious short- and long-term health problems in offspring, including
impaired growth, skeletal problems, Type1 diabetes, asthma and
schizophrenia [36] . Milk is only vitaminD-supplemented in a
few countries, such as the USA. The major source of vitaminD
is skin synthesis. With a high prevalence of vitaminD deficiency
and poor dietary calcium intake, the problem is likely to worsen
during pregnancy owing to the active transplacental transport
of calcium to the developing fetus. VitaminD deficiency early
in pregnancy has been associated with a fivefold increased risk
of preeclampsia [37] . Besides this, vitaminD deficiency during
245
Review
CME
Vitamin A
Events Total
Study or subgroup
(year)
Coutsoudis (1999)
Fawzi (2002)
Semba (2002)
70
155
67
319
453
242
Placebo
Events Total
70
113
82
313
445
250
Weight
Risk ratio
M-H, random (95% CI)
30.9%
36.7%
32.4%
0.98 (0.731.31)
1.35 (1.101.65)
0.84 (0.641.11)
Total (95% CI)

1014
1008 100.0%
292
265
Total events
Heterogeneity: Tau2 = 0.05; 2 = 8.08; df = 2 (p = 0.02); I2 = 75%
1.05 (0.781.41)
Risk ratio
0.01
0.1
Favors experimental
10
100
Favors control
Figure3. Forest plot of the impact of antenatal vitaminA supplementation in HIV-infected pregnant women on
mother-to-child transmission of HIV.
Data from [26] .
pregnancy has important consequences for the newborn, including fetal hypovitaminosis D, neonatal rickets and tetany, and
infantile rickets [3840] .
VitaminD status at birth is closely related to that of the mother.
The fetus at birth (cord blood) will contain approximately
5060% of the maternal circulating concentrations of 25(OH)D
[41] . VitaminD supplementation during pregnancy may therefore help to improve the fetal and newborn vitaminD status
and reduce the risk of vitaminD deficiency in the early months
of life. The review by Mahomed et al. on vitamin D supple
mentation during pregnancy [42] reports data from two trials
that had clinical outcomes [4346] . In the London (UK) trial, the
mothers had higher mean daily weight gain and a lower number
of low-birthweight infants [4446] . In the French trial, however,
the supplemented group had lower birthweights [43] . There was an
87% reduction in the incidence of neonatal hypocalcemia (odds
ratio [OR]: 0.13; 95%CI: 0.020.65), while no impact on cranio
tabes (softening of the skull) with supplementation (OR:0.40;
95%CI: 0.091.65) was seen.
Folate
supplements
Study or subgroup
(year)
Events
Total
In the USA, the current dietary reference intake for vitaminD

during pregnancy is 200400IU per day. However, there is data
that supplementation of mothers with 400IU per day during the
last trimester of pregnancy did not significantly increase circulating 25(OH)D concentrations in the mothers or their infants at
term [47] . Other studies have also shown that mothers who were
deficient in vitaminD at the beginning of their pregnancy were
still deficient at the end of their pregnancy, despite being supplemented with 8001600IU vitaminD per day throughout their
pregnancy [48] . There are data to support the notion that doses
exceeding 1000IU vitaminD per day (200010,000IU/day) are
required to achieve a robust normal concentration of circulating
25(OH)D [4951] , but this is an area that needs further research.
Similarly, it is said that 400IU of vitaminD per day during lactation is also inadequate, and insufficient to increase or even sustain
the vitaminD status of mothers or their breastfeeding infants [52] ,
and that higher doses are recommended. More detailed studies are
required to determine the appropriate vitaminD requirements of
lactating mothers to achieve sufficient concentrations in breast milk.
Control
Events Total
Weight
2391
88
51
602
6.7%
5.4%
20.1%
67.9%
0.07 (0.001.32)
0.17 (0.014.24)
0.42 (0.082.23)
0.29 (0.120.71)
Total (95% CI)

3293
3132 100.0%
Total events
8
32
0.28 (0.130.58)
Czeizel (1994)
Kirke (1992)
Laurence (1981)
MRC (1991)
0
0
2
6
2471
169
60
593
6
1
4
21
Risk ratio
Risk ratio
0.01
0.1
1
10
100
Favors experimental Favors control
Figure4. Forest plot of the impact of the use of periconceptional folate and/or multivitamins on neural tube defects.
Data from [32] .
246
CME
Iodine
Iodine is required for the synthesis of thyroid hormones, which

are required for the regulation of cell metabolism throughout
the lifecycle [102] . Iodine deficiency is most serious in pregnant
women and young children. During pregnancy, iodine deficiency
adversely affects fetal development. Extreme iodine deficiency
may cause fetal death (stillbirths or abortions), or severe physical
and mental growth retardation, a condition known as cretinism
[104] . Endemic cretinism is prevented by the correction of iodine
deficiency, especially in women before and during pregnancy. The
potential adverse effects of mild-to-moderate iodine deficiency
during pregnancy are unclear. It can cause a range of problems
in the fetus, referred to as iodine deficiency disorders: fetal loss,
stillbirth, goiter, congenital anomalies and hearing impairment.
The mental retardation resulting from iodine deficiency during
pregnancy is irreversible [105] .
A review by Haider and Bhutta on iodine supplementation in
pregnancy showed a 29% significant reduction in deaths during
infancy and early childhood with maternal iodine supplementation (two studies; RR: 0.71; 95%CI: 0.560.90) (Figure5) [53] .
Similarly, there was a 73% reduced risk of endemic cretinism at
4years of age with iodine supplementation in pregnancy (one
study; RR: 0.27; 95%CI: 0.120.60). This shows the public
health importance of iodine supplementation in pregnancy to
avoid adverse outcomes in the fetus or child, especially in areas
where iodine deficiency is endemic.
Calcium
Calcium is required for the skeletal development of the fetus [7] .

Calcium also plays a role in neuromuscular function and blood
coagulation. Besides the effect of calcium on bone and mineral
development of the fetus, its deficiency alters membrane permeability and smooth muscle contractility, which in turn could affect
blood pressure, as well as lead to premature uterine contractions
and subsequent delivery [7] .
Calcium supplementation during pregnancy reduces the risk of
high blood pressure (with or without proteinuria) by 30% (RR:
0.70; 95%CI: 0.570.86) [54] . It also significantly reduced the
risk of preeclampsia by 52% (RR: 0.48; 95%CI: 0.330.69),
but significance was achieved only in women on a low-calcium
Study or subgroup
(year)
Iodine
Events Total
Control
Events Total
Weight
Review
diet for this outcome. Maternal death/serious morbidity was

also reduced (RR: 0.80; 95%CI: 0.650.97) [54] . There was
no overall effect on preterm birth (ten trials; 14,751women;
RR:0.81; 95%CI: 0.641.03). According to a recent article,
calcium intake was not a significant predictor of skeletal response
to pregnancy in well-nourished women [55] . At present, there is
also no strong evidence demonstrating that improving maternal
calcium status has a long-term positive effect on childhood bone
mass [56] .
Magnesium
Dietary intake studies during pregnancy have consistently shown

below-recommended intakes of magnesium, especially in those
from disadvantaged backgrounds [57] . Preeclampsia was not
shown to be affected by magnesium supplementation. Many studies from developed countries, however, have found fewer preterm
births and less intrauterine growth retardation with magnesium
supplementation during pregnancy [5860] . Unfortunately, data are
not available from developing countries. One of the recent reviews
of micronutrient efficacy concluded that the only supplements
that affected birthweight were magnesium (which reduced smallfor-gestational age births by 30%) and calcium (which reduced
the risk of low birthweight) [61] . The review by Makrides etal.
on magnesium supplementation included seven trials, recruiting
2689women [62] . Magnesium treatment was associated with a
lower frequency of preterm births (RR: 0.73; 95%CI: 0.570.94)
compared with placebo. However, there was no impact on the
risk of preeclampsia, miscarriage, stillbirth or neonatal mortality.
Maternal hospitalization was significantly reduced with magnesium treatment, and a reduction was also seen in antepartum
hemorrhage. The risk of low birthweight and small-for-gestational
age babies was also significantly reduced.
Other vitamins & minerals
There have been associations of thiamine, vitamin B6 and B12

deficiencies with fetal development [7] , but they remain largely
of unknown importance for pregnancy outcomes. In a controlled trial in HIV-infected women, Fawzi etal. found significant
reductions in intrauterine growth retardation and preterm births,
as well as lower perinatal mortality with high-dose B vitamins,
Risk ratio
Pharoah (1987)
66
498
97
534
69.3%
0.73 (0.550.97)
Thilly (1978)
27
197
42
202
30.7%
0.66 (0.421.03)
Total (95% CI)

695
736 100.0%
Total events
93
139
0.71 (0.560.90)
Risk ratio
0.01
0.1
1
Favors experimental
10
100
Favors control
Figure5. Forest plot of the impact of iodine supplementation versus no iodine in pregnancy on infant and early
childhoodmortality.
Data from [53] .
247
Review
as well as vitamins C and E [63] . Interest has also been increasing

with the observation that homocysteinemia is associated with
adverse pregnancy outcomes. Deficiencies in vitaminB (riboflavin, B6 and B12) are known to increase the level of homocysteine
in plasma, which in turn has been shown to be associated with
placental abruption, stillbirth, very low birthweight and preterm
deliveries, as well as higher rates of preeclampsia and NTDs in
the offspring [64] . Apart from studies on folate, there are few
data on the relationship between the B-vitamin status of pregnant women and risk of adverse pregnancy outcomes. The early
prevention of B-vitamindeficiencies is also important to prevent
the iron depletion throughout pregnancy, and to prevent preterm
delivery [65] .
The review by Rumbold etal. on vitaminC supplementation in pregnancy included five trials involving 766 women[66] .
The risk of stillbirth (three trials; 539 women; RR: 0.87;
95%CI: 0.411.87), perinatal death (two trials; 238women;
RR: 1.16; 95% CI: 0.612.18), birthweight (one trial;
100women; weighted MD: -139.00g; 95%CI: -517.68239.68)
or intrauterine growth restriction (two trials; 383 women;
RR: 0.72; 95% CI: 0.491.04) was not different between
women supplemented with vitaminC alone or in combination
with other supplements and placebo. Women supplemented
with vitaminC compared with placebo were at increased risk
of giving birth preterm (three trials; 583women; RR: 1.38;
95%CI:1.041.82). The risk of preeclampsia was significantly
decreased in the fixed-effect model (four trials; 710women; RR:
0.47; 95%CI: 0.300.75); however, this difference could not
be demonstrated when using a random-effects model (four trials; 710women; RR: 0.52; 95%CI: 0.231.20). The vitamin
E review had four trials on 566 women at high risk or with
preeclampsia, and showed results similar to those of vitaminC
supplementation [67] . There was no difference in the risk of
stillbirth, neonatal death, perinatal death, preterm birth, intra
uterine growth restriction or birthweight. The risk of clinical
preeclampsia was decreased in the fixed-effect models (three
trials; 510women; RR: 0.44; 95%CI: 0.270.71).
Regarding selenium supplementation, a randomized trial
from Tanzania on HIV-infected pregnant women showed
no significant effect on maternal CD4 cell counts or viral
load [10] . There was a marginal impact on low birthweight
(RR: 0.71; 95% CI: 0.491.05) and fetal death (RR: 1.58;
95%CI: 0.952.63). It also had no effect on maternal, neonatal or overall child mortality, but reduced the risk of child
mortality after 6weeks (RR:0.43; 95%CI: 0.190.99). Studies
have shown that selenium and copper deficiencies/excesses may
also be associated with adverse outcomes of pregnancy. In a
cross-sectional study of 166Zairian pregnant women, low birthweight infants had a mean umbilical serum selenium concentration lower than normal birthweight infants (p<0.02) [68] .
In another observational study, serum selenium concentrations
were significantly lower in preterm infants than full-term infants
(0.54 vs 0.60mumol/l; p=0.01), whereas infants that were
small-for-gestational age did not differ in serum selenium concentrations from infants that were adequate-for-gestational age.
248
CME
Serum selenium concentrations in malformed infants tended

to be lower than in normal infants (0.55 vs 0.60 mumol/l;
p=0.09), but the difference was not statistically significant,
probably owing to the small number [69] . Among HIV-infected
women, low selenium status may increase the risk of MTCT of
HIV and poor pregnancy outcomes such as low birthweight,
small-for-gestational age, preterm birth and fetal death [70] . High
zinc and copper levels have been associated with preterm birth
and low birthweight. Excess zinc can cause a suppressed immune
response, decreased high-density lipoprotein cholesterol and a
reduced copper status [71] . In an observational study in Poland,
Wasowicz etal. found that both zinc and copper concentrations
were significantly higher in plasma of preterm infants compared
with full-term infants [72] . The mothers of preterm infants and
low birthweight babies also had significantly higher plasma
copper concentrations. Similarly, serum copper measured at
delivery was negatively associated with birthweight in another
cross-sectional study [73] . These findings warrant better-designed
prospective studies.
Multiple micronutrient supplements
Although micronutrient deficiencies exist in pregnant women,

supplementation is provided for only one or two micro
nutrients, with observed benefits on child growth, health, neuro
development and pregnancy outcomes. As indicated previously,
many population groups in the developing world suffer from
multiple nutrient deficiencies. Concurrent deficiencies of vitaminA, zinc, iron and iodine have been recognized in women of
reproductive age and during pregnancy. Given that mere changes
in dietary habits are considered insufficient to meet micronutrient requirements in pregnancy and alleviate pre-existing deficits,
in 1999 the UNICEF/WHO/UN University proposed a prenatal supplement known as the United Nations International
Multiple Micronutrient Preparation (UNIMMAP) containing
15micronutrients, including iron and folic acid, which could
provide one recommended daily allowance of each [74] . It consists
of iron 30mg, folic acid 400g, zinc 15mg, copper 2.0mg,
selenium 65g, vitaminA 800g retinol equivalent, vitamin B1
1.4mg, vitamin B2 1.4mg, niacin 18mg, vitamin B6 1.9mg,
vitamin B12 2.6g, vitaminC 70mg, vitaminD 5g, vitamin
E 10mg and iodine 150g. It is hoped that these multiplemicronutrient supplements (MMSs) could potentially replace
standard ironfolate supplements for pregnant women in lowand middle-income countries. The micronutrients given in such
a combination can possibly have additive or even synergistic
effects on the health of the mother and her baby, and be a costeffective strategy to address multiple-micronutrient deficiencies
in developing countries. It should, however, be noted that in
RCTs on UNIMMAP, the control group was given 60mg iron,
while the UNIMMAP contained only 30mg iron. Thus, some of
the benefit of UNIMMAP may have been reduced if iron dosages
higher than 30mg are considered to be necessary.
The latest review on MMSs in pregnancy is the series of
three papers in the Food and Nutrition Bulletin [7577] . Multiple
micronutrients compared with controls (receiving ironfolate)
CME
increased the mean birthweight (pooled estimate: +22.4 g;

95%CI: 8.336.4g) and significantly reduced the incidence of
low birthweight (pooled OR: 0.89; 95%CI: 0.810.97) and smallfor-gestational age (pooled OR: 0.90; 95%CI:0.820.99). In
mothers with a BMI of 20kg/m2 or higher, the intervention effect
on birthweight remained significant: +39.0g (95%CI:+22.0 to
+56.1g), compared with -6.0g (95%CI: -28.8 to +16.8g) in
mothers with a BMI of less than 20kg/m2. The difference was
highly significant (p<0.001) and did not change after adjustment for maternal age and education. Multiple micronutrients
were not associated with an increase in gestation or reduction
in preterm births. Furthermore, MMS was not associated with
the incidence of stillbirth (OR: 1.01; 95%CI: 0.881.16), but
there was a nonsignificant 23% increase in early neonatal mortality (OR: 1.23; 95%CI: 0.961.59) and a nonsignificant 11%
increase in perinatal mortality (OR: 1.11; 95%CI: 0.931.33).
The pooled data also showed a nonsignificant 6% reduction in
late neonatal mortality (OR: 0.94; 95%CI: 0.731.23). The
aforementioned series did not cover any maternal outcomes. In
the review by Haider and Bhutta, supplementation with multiple
micronutrients versus ironfolate was associated with comparable
effects on maternal anemia based on one trial (RR: 1.23; 95%CI:
0.821.83) [78] . A randomized trial on multivitamin supplements
(vitamin B complex, vitaminC and vitamin E) found that a single
dose of the recommended dietary allowance (RDA) may be as
efficacious as multiple doses of the RDA in decreasing the risk of
adverse pregnancy outcomes among HIV-infected women [79] ,
and the effects of multiple and single doses were similar on low
birthweight, preterm birth, small-for-gestational age, and fetal
or early infant death.
There is considerable debate on the efficacy of providing
multiple micronutrient supplements during pregnancy and concerns have been expressed on potential adverse effects with an
increase in neonatal mortality in less developed healthcare systems
with suboptimal maternal care [1,80] . This may not be relevant in
circumstances where skilled care and facility births are available.
Further studies are needed to determine the effectiveness and
safety of MMS in health system settings.
Suggested interventional strategies
Maternal nutrition interventions to improve maternal and neonatal health include supplementation with micronutrients such
as iron, folate and calcium, and also macronutrients such as
balanced energy and protein diets. The review by Bhutta etal.
on interventions to address maternal and child undernutrition
derived the data of over 388studies from 139countries to find
preventive and therapeutic strategies to address undernutrition
deficiencies [53] . These interventions include disease-control
measures, as well as dietary diversification, supplementation
and food-fortification strategies. Maternal nutrition interventions are not only entirely feasible, but also affordable and cost
effective. Nutrition interventions are among the best investments in development that countries can undertake, provided
that these can be implemented at scale with community participation. Large-scale programs, including the provision of
Review
vitamins and minerals through fortified foods and supplements

during pregnancy, have been successful in many countries. At the
Copenhagen Consensus in 2008, micronutrient supplementation
and fortification were identified as among the most cost-effective
interventions to address infant and child undernutrition globally,
with a costbenefit ratio of 9.517.3 (estimated annual gains
of US$3.7billion for net investments of US$346.4million).
However, other than iron fortification, the group identified no
strategies for addressing the size of the problem among women
of reproductive age [81] .
Supplementation strategies
The usual approach to improving micronutrient status during

pregnancy that is, for iron and folic acid is supplementation.
This approach has been beset with many problems, including
limited supplies, lack of trained healthcare workers, and poor
compliance to the supplementation schedule either owing to side
effects or other reasons, with suboptimal effects on anemia [82] .
More research is needed on the routine use of MMS during pregnancy in developing country settings before it can replace the
decades-old ironfolic acid, especially in settings where facilitybased deliveries are not available and overall maternal care is
suboptimal. In addition, attention should be focused on other
complementary strategies, such as the fortification of foods with
micronutrients, which may prove to be more sustainable and do
away with the problem of compliance.
Fortification
This may be an alternative strategy to provide essential micro

nutrients through the fortification of staple foods or other products. Iron fortification increases the hemoglobin level in women of
child-bearing age and during pregnancy [83] . Studies have shown
larger effects on hemoglobin by fortified food in comparison to
other interventions. Along with the iodization of salt, adding
such vitamins and minerals such as iron, zinc, vitaminA and
folic acid to staple foods and condiments is a cost-effective way
to improve the vitamin and mineral intake of the overall population, including women of reproductive age. As of March 2009,
approximately 30% of the worlds wheat flour produced in large
roller mills was fortified, while 57countries had legislation mandating the fortification of one or more types of flour with either
iron or folic acid [106] . Although many foods such as fats, oils
and margarine have been fortified for years in some countries,
this approach has not yet been scaled up in many lower income
countries [84] . Through increased efforts by various partnerships
and alliances, it is expected that food fortification will continue
to gain momentum.
There are, however, many challenges to the food fortification
programs and several factors must be taken into consideration.
The carrier needs to be a staple food of the target population.
In addition, centralized processing is necessary, and frequent as
well as reasonably constant consumption is desirable. The fortifying agent must have adequate physicochemical, organoleptic and
bioavailability characteristics. This means that the color, taste,
odor and appearance of the carrier food must not be affected.
249
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CME
The total cost of the final product must not significantly increase
with fortification. Besides, it is necessary to have a monitoring
and control system that guarantees both adequate nutrient concentration and program compliance. In case of potentially toxic
nutrients, excessive concentrations should not be added that could
put a population at risk. Legal issues include the facts of whether
the program should be compulsory or voluntary, and whether it
should be financed by the government or the private sector, or
both. Even if food fortification programs are mandatory, they
may fail to secure compliance; therefore, different approaches
for adequate implementation may be adopted, possibly including
fiscal and tariff incentives [107] . It is also important to demonstrate and document the costbenefit ratio of the intervention in
order to gain objective evidence to support the continuance of
these programs [85] . Besides, in areas where subsistence farming
is practiced, fortification is not likely to be a practicable solution
to nutrient deficiencies.
Technologically, it would be necessary to maintain the overall
quality of the product in terms of the bioavailability of the fortifying agent. Despite an increase in bioavailability, the products
quality may be at risk, especially its stability. Iron, for example,
may react with fatty acids in the fortified food, forming free radicals that induce oxidation. Any alterations that affect consumer
acceptability of the product should be avoided. Some options
for the future include microencapsulation of nutrients, the use
of nutrient-bioavailability stimulants (the addition of ascorbic
or other organic acids to promote iron absorption) and the
elimination of inhibitors of mineral absorption in the intestine
(e.g.,phytates) [107] . Fortification is certainly an effective micronutrient deficiency control strategy whose coverage needs to be
expanded. It should, however, be viewed as a complementary
strategy, and it will not be able to replace interventions such
as iron supplementation during pregnancy (and other micro
nutrient control strategies among other population groups), at
least in the short term.
Dosage & potential interactions
shows the recommended daily micronutrient intake during pregnancy and lactation based on recommendations provided by the American Academy of Pediatrics and American
College of Obstetricians and Gynecologists [57] . The current
recommendation for pregnant women is to provide a standard
daily dose of 60mg iron and 400g folic acid for 6months, or
if this duration of treatment cannot be achieved during pregnancy, then either to continue supplementation during the postpartum period or to increase the dose of iron to 120mg daily
during pregnancy [86] . In those areas where iron is fortified in
foods, the recommended daily dose of iron during pregnancy
is 30mg. Given that multiple deficiencies can coexist, we need
to determine the efficacy of multiple micronutrients to replace
ironfolate for pregnant women in developing countries, even
though their use has become common practice in developed
countries [87] .
Table1
Interactions & potential adverseeffects
Constipation is a common side effect of high-dose iron supplements, with other gastrointestinal effects
being nausea, vomiting and diarrhea [14] .
Table1. Recommended daily micronutrient intake during pregnancy
The frequency and severity of these side
and lactation.
effects varies according to the amount of
Micronutrient
Nonpregnant
Pregnancy
Lactation
elemental iron released in the stomach, and
women
is one of the main reasons for poor compliIron
15mg
30mg
15mg
ance with iron preparations in pregnancy.
Besides this, there is growing evidence of
Zinc
8mg
11mg
12mg
the existence of metabolic interactions
Calcium
1000mg
1000mg
1000mg
between micronutrients such as copper,
Iodine
150 g
220 g
290 g
zinc and iron. Excess iron can lower zinc
Selenium
55 g
60 g
70 g
nutritional status and vice versa [88,89] ; similarly, copper and zinc compete with each
VitaminA
700 g
770 g
1300 g
other[90,91] . VitaminA deficiency contribVitamin B:
utes to anemia by interfering with iron utili Thiamin (B1)
1.1mg
1.4mg
1.4mg
zation [87] . Besides vitaminA, other micro Riboflavin (B2)
1.1mg
1.4mg
1.6mg
nutrients can also enhance the absorption
of other micronutrients, such as vitaminC,
Niacin
14mg
18mg
17mg
increasing iron bioavailability [92] . As can
Vitamin B6
1.21.5mg
1.9mg
2.0mg
be seen, these interactions may be positive
Vitamin B12
2.4 g
2.6 g
2.8 g
or negative, and we do not have significant
Folate
0.4mg
0.6mg
0.5mg
scientific data on this aspect. The issues
related to the interactions between microVitaminC
75mg
85mg
120mg
nutrients and the coexistence of micro- and
VitaminD
5 g
5 g
5 g
macro-nutrient deficiencies require serious
Vitamin E
15mg
15mg
19mg
considerations before MMSs are given to
Data from [57].
pregnant women.
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CME
Conclusion
Micronutrient deficiencies during pregnancy, either singly or

in combination, can have important effects on pregnancy outcomes. Interventions; for example, folic acid supplementation,
should start well before conception (in the reproductive age) to
prevent adverse effects such as NTDs, as embryogenesis occurs
early in pregnancy and the woman must have adequate micronutrient levels to offset any deficiency before and early in pregnancy. For other outcomes, interventions after the pregnancy is
detected may be effective. Iron and folic acid supplementation is
currently recommended for all pregnant women in developing
countries. In population groups where the prevalence of anemia
is above 20% among women of reproductive age and mass fortification programs of staple foods with iron and folic acid are
unlikely to be implemented within 12years, weekly ironfolic
acid supplementation should be considered as a strategy for the
prevention of iron deficiency. The weekly supplement should
contain 60mg iron in the form of ferrous sulfate (FeSO4.7H2O)
and 2800g folic acid [108] .
Multiple micronutrient supplements are routinely used by pregnant women in developed nations and by the rich in developing countries, but these are not currently routinely prescribed
to pregnant women in low- or middle-income countries in lieu
of ironfolate. The increase in birthweight and reduction in
small-for-gestational age births by MMS means that such interventions need to be complemented with facility-based care for
delivery (intrapartum care) to preempt and prevent potentially
adverse neonatal outcomes due to obstructed labor and possible
birth asphyxia. MMSs are also known to be more effective in
women with a higher BMI [75] ; therefore, food supplements may
also be considered in addition to MMSs to overcome wasting,
which may also worsen pregnancy outcomes. Apart from supple
mentation, other complementary dietary approaches should also
be considered, such as fortification. Fortification can effectively
address prepregnancy folate deficiency and help improve iron
status among women of reproductive age. It can provide improved
micrountrient intake and help improve maternal nutrition, as well
as pregnancy outcomes. However, fortification cannot obviate the
need for iron (and folate) supplementation during pregnancy in
most settings.
Expert commentary
Existing and emerging research linking micronutrient deficiencies during pregnancy with adverse birth outcomes is an exciting
development. Supplementation of micronutrients; for example,
ironfolate, has been the decades-old way of preventing and treating iron-deficiency anemia during pregnancy. In those areas where
the prevalence of anemia is high and mass fortification of iron
is unlikely to meet the needs of the population, weekly rather
than daily iron supplementation is recommended for women
of the reproductive age group. Folic acid supplementation has a
definite role to play in reducing both occurrent (first time) and
recurrent NTDs. Micronutrient supplementation can also have
a positive impact on other birth outcomes: zinc and magnesium
supplementation reduces preterm births, the effects being small
Review
but significant. Their recommendation for pregnancy, however,

is still weak. For many micronutrient deficiencies such as zinc,
the mechanism by which they are associated with adverse pregnancy outcomes is unclear, and such associations have not been
replicated in most RCTs. For some micronutrients; for example, copper, RCTs of its supplementation during pregnancy are
lacking. This is an area of future research.
Deficiencies of multiple micronutrients may coexist, suggesting supplementation in one tablet with more than one micronutrient, including ironfolate. The efficacy of the UNIMMAP
supplement is still being determined, and multiple micronutrients, although widely used in developed countries and among
the wealthy in developing countries, are still not routinely used
for pregnant women in developing countries. The composition
of iron in UNIMMAP is 30mg, which may be less than the
recommended dose of 60mg daily iron by the WHO. Further
research in terms of more RCTs needs to be carried out to establish their efficacy for women in the developing world. There is
some concern about a possible increase in early neonatal mortality
with the MMS supplements, and so more research needs to be
conducted in this regard.
Five-year view
Micronutrient supplementation during pregnancy is an emerging

field. In the next 5years, more work is expected, especially on formulations such as UNIMMAP. The coming years will establish
whether MMSs are feasible for prescription to pregnant women
in lieu of ironfolate. More RCTs will come into play that will
establish if they have an adverse impact on neonatal mortality,
especially in areas where intrapartum maternal care is suboptimal. The importance of food supplements to prevent or overcome
wasting with MMS will also come into light, as MMSs are found
to be more effective in women with a higher BMI.
Relating to single micronutrients, research with regards to the
mechanism behind how zinc deficiency causes congenital anomalies and if zinc is also important periconceptionally such as folic
acid to prevent congenital malformations will arise. Future work
will also focus on discovering the molecular mechanisms by which
deficiencies of different micronutrients impact on pregnancy outcomes; for example, the association of zinc with the premature
rupture of membranes and prolonged labor. More research is also
expected with regards to how folic acid deficiency causes NTDs
and on the relationship of folic acid deficiency with low birthweight. Other interesting areas awaiting further research include
the impact of vitaminA supplementation on maternal mortality,
as recent trials from Ghana and Bangladesh have shown no effect
of vitaminA supplementation on this outcome. The future may
also see more RCTs on the supplementation of micronutrients
such as copper and selenium, considered less important at the
moment, and whether this helps to reduce adverse pregnancy
outcomes or not. Copper supplementation during pregnancy
is one field that is a major research gap at present, as little is
known whether it is of benefit or detriment in terms of adverse
pregnancy outcomes, as current data are only available based on
observational studies.
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Review
CME
Key issues
Nutritional deficiencies are widely prevalent globally and contribute significantly to maternal and child morbidity and mortality.
Micronutrient deficiencies are associated with adverse pregnancy outcomes such as low birthweight and preterm birth.
Iron supplementation reduces the risk of anemia in mothers at term.
Folic acid supplementation reduces the incidence of neural tube defects.
Zinc supplementation has a small but significant impact on preterm births; however, its recommendation is weak.
VitaminA may reduce maternal mortality, but results of ongoing studies are awaited.
Other minerals and vitamins, such as iodine, calcium, magnesium, vitaminD, selenium, and vitaminsB6, B12, C and E, may also be
important for maternal, infant and child outcomes.
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Review
CME
Maternal mineral and vitamin supplementation in pregnancy

To obtain credit, you should first read the journal article. After
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1.
A 28-year-old pregnant woman receives iron

supplementation for iron deficiency anemia from the
second trimester. Which of the following is least
likely to be a benefit of this supplementation?
Activity Evaluation
Where 1 is strongly disagree and 5 is strongly agree
1 2 3 4 5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning
to occur.
3. The content learned from this activity will
impact my practice.
4. The activity was presented objectively and
free of commercial bias.
4. In addition to reducing the risk for neural tube

defects, what other benefits may be expected from
folate supplementation during pregnancy?
A Reduced risk for miscarriage
A Increased birth length
Reduced risk for stillbirth
Reduced risk for postpartum hemorrhage
Reduced risk for low birth weight
Reduced risk for anemia at term
D Higher infant ferritin concentration at 6 months

2. Which of the following is most likely to be a benefit
of zinc supplementation in pregnant women?
A Lower rate of low-birth-weight infants

B
Lower risk for preeclampsia
Lower risk for premature rupture of membranes
D Lower rate of preterm delivery

3. A 30-year-old pregnant woman from Nepal receives
weekly vitamin A supplementation throughout
pregnancy. Which of the following is most likely to
be a benefit of this intervention?
A Reduced maternal mortality

B
Improved infant survival
Reduced risk for mother-to-child transmission of HIV
D Reduced risk for preterm birth
256
in this CME activity are eligible for AMA PRA Category 1

Credits. Through agreements that the AMA has made with
agencies in some countries, AMA PRA credit is acceptable as
evidence of participation in CME activities. If you are not licensed
in the US and want to obtain an AMA PRA CME credit, please
complete the questions online, print the certificate and present it
to your national medical association.
D All of the above

5. Which of the following daily minimum doses of
vitamin D during pregnancy and lactation has been
shown to reduce the risk for neonatal rickets and
maternal preeclampsia in women who are
vitaminDdeficient?
A The current data suggest that 200400 IU have been

maternal preeclampsia
The current data suggest that 600800 IU have been

maternal preeclampsia
The current data suggest that 10001200 IU have

been shown to reduce the risk for neonatal rickets
and maternal preeclampsia
D The current data suggest that more studies are
needed to establish the recommended dose of

vitamin D needed to reduce the risk for neonatal
rickets and maternal preeclampsia
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Review

Maternal mineral and vitamin

Medscape: Continuing Medical Education Online

2010 Expert Reviews Ltd

Yakoob, Khan & Bhutta

Financial & competing interests disclosure

Undernutrition during the reproductive age group and pregnancy

Burden of maternal micronutrient deficiencies

Maternal mineral & vitamin supplementation in pregnancy

of pregnancy is less clear. However, emerging evidence suggests

Iron deficiency and iron-deficiency anemia are major public

Control (no iron)

While definite data on the prevalence of zinc deficiency are

Yakoob, Khan & Bhutta

VitaminA is an important micronutrient affecting the health

Pregnant and lactating women are at increased risk of folic acid

Maternal mineral & vitamin supplementation in pregnancy

Low zinc or nutrition

Normal zinc or nutrition

Subtotal (95% CI)

Total (95% CI)

not significantly increase rates of miscarriage, ectopic pregnancy

Maternal vitamin D deficiency is a widespread public health

Yakoob, Khan & Bhutta

Total (95% CI)

In the USA, the current dietary reference intake for vitaminD

Total (95% CI)

Expert Rev. Obstet. Gynecol. 5(2), (2010)

Maternal mineral & vitamin supplementation in pregnancy

Iodine is required for the synthesis of thyroid hormones, which

Calcium is required for the skeletal development of the fetus [7] .

diet for this outcome. Maternal death/serious morbidity was

Dietary intake studies during pregnancy have consistently shown

There have been associations of thiamine, vitamin B6 and B12

Total (95% CI)

as well as vitamins C and E [63] . Interest has also been increasing

Yakoob, Khan & Bhutta

Serum selenium concentrations in malformed infants tended

Although micronutrient deficiencies exist in pregnant women,

Maternal mineral & vitamin supplementation in pregnancy

increased the mean birthweight (pooled estimate: +22.4 g;

vitamins and minerals through fortified foods and supplements

The usual approach to improving micronutrient status during

This may be an alternative strategy to provide essential micro

Yakoob, Khan & Bhutta

Interactions & potential adverseeffects

Expert Rev. Obstet. Gynecol. 5(2), (2010)

Maternal mineral & vitamin supplementation in pregnancy

Micronutrient deficiencies during pregnancy, either singly or

but significant. Their recommendation for pregnancy, however,

Micronutrient supplementation during pregnancy is an emerging

Yakoob, Khan & Bhutta

among HIV-infected pregnant women in

Papers of special note have been highlighted as:

Bhutta ZA, Haider BA. Prenatal

Barker DJ, Clark PM. Fetal undernutrition

Wu G, Bazer FW, Cudd TA, Meininger

Black RE, Allen LH, Bhutta ZA etal.

Ramakrishnan U, Manjrekar R, Rivera J,

de Benoist B. Conclusions of a WHO

Indian Council of Medical Research. Task

Comprehensive review of iron