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Expert Rev. Obstet. Gynecol. 5(2), 241–256 (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, PO Box 3500, Karachi-74800, Pakistan Tel.: +92 213 486 4782 Fax: +92 213 493 4294 [email protected] †

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 12 weeks postpartum with weekly vitamin A and 49% biweekly b-carotene supplementation but subsequent large studies in Bangladesh and Ghana have failed to demonstrate any impact on mortality. Maternal vitamin A 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 vitamin D 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 4 years 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 vitamins B, 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 • vitamin A • zinc

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10.1586/EOG.10.8

© 2010 Expert Reviews Ltd

ISSN 1747-4108

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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 Désirée 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: Désirée 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 Box 3500, 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 woman’s 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 placental–fetal 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 in utero 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 18.5 kg/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 18.5 kg/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, vitamin A, folic acid and vitamin B 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)

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Maternal mineral & vitamin supplementation in pregnancy

of pregnancy is less clear. However, emerging evidence suggests that micro­nutrients such as vitamin B12, folic acid, vitamin D and selenium may also be important for maternal, infant and child outcomes [8–10] .

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Iron

Iron deficiency and iron-deficiency anemia are major public health problems, affecting an estimated 30% of the world’s 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

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Several UN agencies recommend the universal distribution of iron–folic 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 23,200 women  [14] . Daily oral iron supplementation resulted in a significantly higher maternal mean hemoglobin (Hb) concentration (mean difference [MD]: 8.83; 95% CI: 6.55–11.11) (Figure 1) and a reduced risk of anemia in mothers at term (relative risk [RR]: 0.27; 95% CI: 0.17–0.42), 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 1 month postpartum. The benefits to the infant included a significant increase in birth length (MD: 0.38 cm; 95% CI: 0.10–0.65) and higher mean ferritin concentrations at 3 and 6 months 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 6 months 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 (10.17–21.83) 1.00 (-5.79–7.79) 3.22 (-2.95–9.39) 14.00 (8.07–19.93) 10.00 (6.12–13.88) -0.30 (-3.68–3.08) 8.00 (3.09–12.91) 12.90 (8.72–17.08) 7.00 (4.53–9.47) 10.00 (7.54–12.46) 21.00 (13.56–28.44) 13.00 (7.72–18.28) 2.00 (-0.31–4.31) 19.34 (9.39–29.29) 3.30 (-3.90–10.50) 7.20 (5.30–9.10) 11.00 (9.82–12.18)

1286 1177 100.0% Heterogeneity: Tau2 = 17.08; χ2 = 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 (6.55–11.11) -100 -50 0 50 100 Favors experimental Favors control

Figure 1. 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] .

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Review

reduced risk of anemia at term. Hb levels within 1 month 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 iron–folate 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 7 years of age compared with controls receiving vitamin A only (hazard ratio [HR]: 0.69; 95% CI: 0.49–0.99) [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 et al. 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 et al. included 17 trials involving over 9000 women and their babies [18] . There was a significant, although small, reduction in preterm births based on 13 RCTs and 6854 women (RR: 0.86; 95% CI: 0.76–0.98) (Figure  2) . The effect on low birthweight was nonsignificant (RR: 1.05; 95% CI: 0.94–1.17) based on 11 studies. 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

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Vitamin A

Vitamin A is an important micronutrient affecting the health of pregnant women and the fetus. Studies have shown that vitamin A deficiency is widespread throughout the developing world. Vitamin A 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 vitamin A status affects its concentration in breast milk as well [21,22] . Vitamin A 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 et al. from Nepal showed that all-cause maternal mortality up to 12 weeks postpartum was reduced by weekly vitamin A (RR: 0.60; 95% CI: 0.37–0.97) and b-carotene supplementation (RR: 0.51; 95% CI: 0.30–0.86) 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 et al. [2007], Unpublished Data) and Ghana (Kirkwood BR et al. [2009], Unpublished Data) that did not support such an effect of vitamin A on maternal mortality. The potential role of vitamin A 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 vitamin A supplementation on the risk of MTCT of HIV (three trials; 2022 women; RR: 1.05; 95% CI: 0.78–1.41) (Figure 3) . It improved birthweight (MD: 89.78; 95% CI: 84.73–94.83), 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: 0.04–5.37). 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 3 ng/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 acid’s 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 et al. shows that periconceptional folic acid significantly reduces incidence of NTDs (RR: 0.28; 95% CI: 0.13–0.58) (Figure 4) , including NTDs among women with (RR: 0.31; 95% CI: 0.14–0.66) and without (RR: 0.07; 95% CI: 0.00–1.33) prior NTDs [32] . Folate supplementation did Expert Rev. Obstet. Gynecol. 5(2), (2010)

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Low zinc or nutrition

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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 (0.72–1.72) 0.48 (0.26–0.89) 0.71 (0.47–1.10) 0.79 (0.25–2.49) 0.88 (0.71–1.08) 2.22 (1.09–4.45) 0.92 (0.56–1.51) 1.45 (0.47–4.44) 1.29 (0.36–4.66) 0.79 (0.57–1.09) 0.77 (0.49–1.20) 0.87 (0.76–0.99)

Total events 356 411 Heterogeneity: χ² = 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 (0.27–1.26) 1.47 (0.14–15.17)

Subtotal (95% CI) 273 Total events 12 18 Heterogeneity: χ2 = 1.53; df = 1 (p = 0.47); I2 = 0% Test for overall effect: Z = 1.20 (p = 0.23)

265

4.2%

0.64 (0.31–1.32)

3433

100.0%

0.86 (0.76–0.98)

Total (95% CI)

3421

Total events 368 429 Heterogeneity: χ2 = 15.36; df = 12 (p = 0.22); I2 = 22% Test for overall effect: Z = 2.32 (p = 0.02) Test for subgroup differences: not applicable

Risk ratio M-H, Fixed (95% CI)

0.01 0.1 1 Favors experimental

10 100 Favors control

Figure 2. 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] . www.expert-reviews.com

Vitamin D

Maternal vitamin  D deficiency is a widespread public health problem, especially in the developing world. Vitamin D deficiency during pregnancy has been linked with a number of serious short- and long-term health problems in offspring, including impaired growth, skeletal problems, Type 1 diabetes, asthma and schizophrenia [36] . Milk is only vitamin D-supplemented in a few countries, such as the USA. The major source of vitamin D is skin synthesis. With a high prevalence of vitamin D 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. Vitamin D deficiency early in pregnancy has been associated with a fivefold increased risk of preeclampsia [37] . Besides this, vitamin D deficiency during 245

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Vitamin A Events Total

Study or subgroup (year) Coutsoudis (1999) Fawzi (2002) Semba (2002)

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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 (0.73–1.31) 1.35 (1.10–1.65) 0.84 (0.64–1.11)

Total (95% CI) 1014 1008 100.0% 292 265 Total events Heterogeneity: Tau2 = 0.05; χ2 = 8.08; df = 2 (p = 0.02); I2 = 75% Test for overall effect: Z = 0.32 (p = 0.75)

1.05 (0.78–1.41)

Risk ratio M-H, random (95% CI)

0.01

0.1

1

Favors experimental

10

100

Favors control

Figure 3. Forest plot of the impact of antenatal vitamin A 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 [38–40] . Vitamin D status at birth is closely related to that of the mother. The fetus at birth (cord blood) will contain approximately 50–60% of the maternal circulating concentrations of 25(OH)D [41] . Vitamin D supplementation during pregnancy may therefore help to improve the fetal and newborn vitamin D status and reduce the risk of vitamin D 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 [43–46] . In the London (UK) trial, the mothers had higher mean daily weight gain and a lower number of low-birthweight infants [44–46] . 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: 0.02–0.65), while no impact on cranio­ tabes (softening of the skull) with ­supplementation (OR: 0.40; 95% CI: 0.09–1.65) was seen.

Folate supplements Study or subgroup (year) Events Total

In the USA, the current dietary reference intake for vitamin D during pregnancy is 200–400 IU per day. However, there is data that supplementation of mothers with 400 IU 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 vitamin D at the beginning of their pregnancy were still deficient at the end of their pregnancy, despite being supplemented with 800–1600 IU vitamin D per day throughout their pregnancy  [48] . There are data to support the notion that doses exceeding 1000 IU vitamin D per day (2000–10,000 IU/day) are required to achieve a robust normal concentration of circulating 25(OH)D [49–51] , but this is an area that needs further research. Similarly, it is said that 400 IU of vitamin D per day during lactation is also inadequate, and insufficient to increase or even sustain the vitamin D status of mothers or their breastfeeding infants [52] , and that higher doses are recommended. More detailed studies are required to determine the appropriate vitamin D 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 (0.00–1.32) 0.17 (0.01–4.24) 0.42 (0.08–2.23) 0.29 (0.12–0.71)

Total (95% CI) 3293 3132 100.0% Total events 8 32 Heterogeneity: Tau2 = 0.00; χ2 = 1.19; df = 3 (p = 0.76); I2 = 0% Test for overall effect: Z = 3.38 (p = 0.0007)

0.28 (0.13–0.58)

Czeizel (1994) Kirke (1992) Laurence (1981) MRC (1991)

0 0 2 6

2471 169 60 593

6 1 4 21

Risk ratio M-H, random (95% CI)

Risk ratio M-H, random (95% CI)

0.01 0.1 1 10 100 Favors experimental Favors control

Figure 4. Forest plot of the impact of the use of periconceptional folate and/or multivitamins on neural tube defects. Data from [32] .

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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: 0.56–0.90) (Figure 5) [53] . Similarly, there was a 73% reduced risk of endemic cretinism at 4 years of age with iodine supplementation in pregnancy (one study; RR: 0.27; 95% CI: 0.12–0.60). 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: 0.57–0.86) [54] . It also significantly reduced the risk of preeclampsia by 52% (RR: 0.48; 95% CI: 0.33–0.69), but significance was achieved only in women on a low-calcium Study or subgroup (year)

Iodine Events Total

Control Events Total

Weight

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diet for this outcome. Maternal death/serious morbidity was also reduced (RR: 0.80; 95% CI: 0.65–0.97)  [54] . There was no overall effect on preterm birth (ten trials; 14,751 women; RR: 0.81; 95% CI: 0.64–1.03). 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 [58–60] . 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 et al. on magnesium supplementation included seven trials, recruiting 2689 women [62] . Magnesium treatment was associated with a lower frequency of preterm births (RR: 0.73; 95% CI: 0.57–0.94) 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 et al. found significant reductions in intrauterine growth retardation and preterm births, as well as lower perinatal mortality with high-dose B vitamins, Risk ratio M-H, random (95% CI)

Pharoah (1987)

66

498

97

534

69.3%

0.73 (0.55–0.97)

Thilly (1978)

27

197

42

202

30.7%

0.66 (0.42–1.03)

Total (95% CI) 695 736 100.0% Total events 93 139 Heterogeneity: Tau2 = 0.05; χ2 = 8.08; df = 2 (p = 0.02); I2 = 75% Test for overall effect: Z = 0.32 (p = 0.75)

0.71 (0.56–0.90)

Risk ratio M-H, random (95% CI)

0.01 0.1 1 Favors experimental

10 100 Favors control

Figure 5. Forest plot of the impact of iodine supplementation versus no iodine in pregnancy on infant and early childhood mortality. Data from [53] .

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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 vitamin B (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-vitamin deficiencies is also important to prevent the iron ­depletion throughout pregnancy, and to prevent preterm delivery [65] . The review by Rumbold et al. on vitamin C supplementation in pregnancy included five trials involving 766 women [66] . The risk of stillbirth (three trials; 539  women; RR: 0.87; 95% CI: 0.41–1.87), perinatal death (two trials; 238 women; RR: 1.16; 95%  CI: 0.61–2.18), birthweight (one trial; 100 women; weighted MD: -139.00 g; 95% CI: -517.68–239.68) or intrauterine growth restriction (two trials; 383 women; RR:  0.72; 95%  CI: 0.49–1.04) was not different between women supplemented with vitamin C alone or in combination with other supplements and placebo. Women supplemented with vitamin C compared with placebo were at increased risk of giving birth preterm (three trials; 583 women; RR: 1.38; 95% CI: 1.04–1.82). The risk of preeclampsia was significantly decreased in the fixed-effect model (four trials; 710 women; RR: 0.47; 95% CI: 0.30–0.75); however, this difference could not be demonstrated when using a random-effects model (four trials; 710 women; RR: 0.52; 95% CI: 0.23–1.20). The vitamin E review had four trials on 566 women at high risk or with preeclampsia, and showed results similar to those of vitamin C 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; 510 women; RR: 0.44; 95% CI: 0.27–0.71). 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:  0.49–1.05) and fetal death (RR: 1.58; 95% CI: 0.95–2.63). It also had no effect on maternal, neonatal or overall child mortality, but reduced the risk of child mortality after 6 weeks (RR: 0.43; 95% CI: 0.19–0.99). Studies have shown that selenium and copper deficiencies/excesses may also be associated with adverse outcomes of pregnancy. In a cross-sectional study of 166 Zairian pregnant women, low birthweight infants had a mean umbilical serum selenium concentration lower than normal birthweight infants (p