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Linus Pauling Institute

Micronutrient Research for Optimum Health

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Micronutrient Needs During Pregnancy and Lactation

Nutrient needs during the life stages of pregnancy and lactation are increased relative to women who are not pregnant or lactating. In fact, energy requirements increase by an estimated 300 kcal/day during pregnancy and 500 kcal/day during lactation (1). Likewise, the requirements for most micronutrients (vitamins and nutritionally essential minerals) are higher during pregnancy and lactation; this article discusses micronutrient needs during these life stages. Micronutrient Requirements During Pregnancy Pregnancy is associated with increased nutritional needs due to the physiologic changes of the woman and the metabolic demands of the embryo/fetus. Proper maternal nutrition during pregnancy is thus imperative for the health of both the woman and the offspring. Maternal malnutrition during pregnancy has been associated with adverse outcomes, including increased risk of maternal and infant mortality as well as low birth weight newborns (<2,500 grams)a measure that accounts for preterm birth and intrauterine growth restriction of the fetus (2, 3). Select nutrient deficiencies have also been linked to congenital anomalies and birth defects. In addition, gestational undernutrition has been implicated in increasing the offsprings susceptibility to chronic disease (i.e., type 2 diabetes, hypertension, coronary artery disease, and stroke) in adulthood, a phenomenon sometimes called Barkers hypothesis, the thrifty phenotype hypothesis, or the fetal origin of adult disease hypothesis (4, 5) Maternal undernutrition often refers to malnutrition caused by insufficient caloric (energy) intake from macronutrients (carbohydrates, protein, and lipids) during pregnancy, but micronutrient deficiencies are also a form of undernutrition. Multiple micronutrient deficiencies commonly co-exist in pregnant women, especially in less developed nations (6). Daily requirements for many micronutrients during pregnancy are higher to meet the physiologic changes and increased nutritional needs of pregnancy. Good nutritional status prior to conception is also important for a healthy pregnancy. For instance, folic acid supplementation during the periconceptional period (about one month before and one month after conception) dramatically reduces the incidence of devastating birth defects called neural tube defects (see Folic Acid below). Thus, folic acid supplementation (at least 400 mcg/day) is recommended for all women capable of becoming pregnant (7-9). A well-balanced diet throughout pregnancy is necessary to supply the developing embryo/fetus with micronutrients. In addition to folic acid supplementation, iron supplementation is generally needed to meet the increased demands for this mineral during pregnancy (see the section on Iron below). Folic acid-iron supplementation is universally recommended during pregnancy (6). However, many health care providers recommend that pregnant women take a daily multivitamin/mineral or a daily prenatal supplement that includes folic acid, iron, and several other micronutrients to ensure that all micronutrient needs are met. Presently, there is little scientific evidence that supplementation with multiple micronutrients has

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advantages over iron-folic acid supplementation with respect to various pregnancy and birth outcomes, but studies are somewhat conflicting (10-13). The Food and Nutrition Board (FNB) of the Institute of Medicine establishes life-stage specific dietary reference intakes (DRIs) for each micronutrient; these reference values should be used to plan and assess dietary intakes in healthy people (14, 15). The DRIs include the estimated average requirement (EAR), the recommended dietary allowance (RDA), the adequate intake (AI), and the tolerable upper intake level (UL). The RDA, which is the average daily dietary intake level of a nutrient sufficient to meet the requirements of almost all (97.5%) healthy individuals in a specific life stage and gender group, should be used in the planning of diets for individuals (16). The FNB establishes an AI when an RDA cannot be determined. The below recommendations are specific to the life stages of pregnancy and lactation. For most micronutrients, the RDA or AI for pregnant women is increased compared to nonpregnant women of the same age (see the table, RDA for Micronutrients During Pregnancy). The discussion below largely focuses on these recommendations for select micronutrients during pregnancy but also notes major concerns for micronutrient toxicity or teratogenicity. The UL is the highest level of daily intake that is likely to pose no risk of adverse health effects in almost all individuals of a specified life stage. For the UL for each micronutrient during pregnancy, see the table, UL for Micronutrients During Pregnancy. Dietary Reference Intakes Set by the FNB: RDA for Micronutrients During Pregnancy Micronutrient Biotin Folic Acid Niacin Pantothenic Acid Riboflavin Thiamin Vitamin A Age 14-50 years 14-50 years 14-50 years 14-50 years 14-50 years 14-50 years 14-18 years 19-50 years Vitamin B6 Vitamin B12 Vitamin C 14-50 years 14-50 years 14-18 years 19-50 years Vitamin D Vitamin E Vitamin K 14-50 years 14-50 years 14-18 years 19-50 years Calcium 14-18 years 19-50 years Chromium 14-18 years 19-50 years Copper 14-50 years RDA 30 mcg/day (AI) 600 mcg/daya 18 mg/day
b

6 mg/day (AI) 1.4 mg/day 1.4 mg/day 750 mcg (2,500 IU)/day 770 mcg (2,567 IU)/day 1.9 mg/day 2.6 mcg/day 80 mg/day 85 mg/day 15 mcg (600 IU)/day 15 mg (22.5 IU)/day 75 mcg/day (AI) 90 mcg/day (AI) 1,300 mg/day 1,000 mg/day 29 mcg/day (AI) 30 mcg/day (AI) 1 mg/day
d c c

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Fluoride Iodine Iron Magnesium

14-50 years 14-50 years 14-50 years 14-18 years 19-30 years 31-50 years

3 mg/day (AI) 220 mcg/day 27 mg/day 400 mg/day 350 mg/day 360 mg/day 2 mg/day (AI) 50 mcg/day 1,250 mg/day 700 mg/day 4,700 mg/day (AI) 60 mcg/day 1,500 mg/day (AI) 12 mg/day 11 mg/day 450 mg/day (AI)

Manganese Molybdenum Phosphorus

14-50 years 14-50 years 14-18 years 19-50 years

Potassium Selenium Sodium Zinc

14-50 years 14-50 years 14-50 years 14-18 years 19-50 years

Choline
a

14-50 years

AI, adequate intake Dietary Folate Equivalents b NE, niacin equivalent: 1 mg NE = 60 mg tryptophan = 1 mg niacin c Retinol Activity Equivalents d Alpha-tocopherol e Considered an essential nutrient, although not strictly a micronutrient Vitamins Biotin: Biotin is needed as a cofactor for carboxylase enzymes and for the attachment of biotin to molecules, such as proteins, in a process known as biotinylation (17). Rapidly dividing cells of the developing fetus require the vitamin for synthesis of essential carboxylase enzymes and for histone biotinylation. Biotin appears to be broken down more rapidly during pregnancy, and biotin nutritional status declines during the course of pregnancy (18). Thus, the biotin requirement is likely increased during pregnancy, although the AI of 30 mcg/day does not change for pregnancy (19). Research suggests that a substantial number of women develop marginal or subclinical biotin deficiency during normal pregnancy, which often is not clinically identified (18, 20-24). Currently, it is estimated that at least one-third of women develop marginal biotin deficiency during pregnancy (25). In one study, over half of pregnant women had abnormally high excretion of a metabolite (3hydroxyisovaleric acid) thought to reflect decreased activity of a biotin-dependent enzyme. In a study of 26 pregnant women, biotin supplementation decreased the excretion of this metabolite compared to placebo, suggesting that marginal biotin deficiency may be relatively common in pregnancy (22). In a more recent study, the incidence of decreased lymphocyte propionyl-CoA carboxylase activity (a marker of biotin deficiency) in pregnancy was greater than 75% (18 out of 22 women) (21). Although the level of biotin depletion is not severe enough to cause diagnostic

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signs or symptoms, such observations are sources of concern because subclinical biotin deficiency has been shown to cause birth defects in several animal species (18). The potential risk for teratogenesis (abnormal development of the embryo or fetus) from biotin deficiency makes it prudent to ensure adequate biotin intake preconceptionally and throughout pregnancy. Since pregnant women are advised to consume supplemental folic acid prior to and during pregnancy (see Folic Acid below) to prevent neural tube defects, it would be easy to consume supplemental biotin (at least 30 mcg/day) in the form of a multivitamin that also contains at least 400 mcg of folic acid. Toxicity at this level of biotin intake has never been reported. It is important to note that several prenatal supplements on the market in the U.S. do not contain biotin. Folic Acid: The terms folic acid and folate are often used interchangeably, but folic acid is the synthetic form of the vitamin that is only found in fortified foods and supplements. Folic acid is more bioavailable than folate from foods (see the separate article on Folic Acid); folic acid is converted to biologically active forms of folate in the body. Recently, a nature-identical folate in the form of a calcium salt, Metafolin , has become commercially available. Although more research is needed, Metafolin appears to be comparable to folic acid in bioavailability and physiological activity and may also be less likely to mask an undiagnosed vitamin B12 deficiency or interfere with antifolate drugs (26). Folate is needed for amino acid and nucleic acid (DNA and RNA) metabolism. Adequate folate status is critical to embryonic and fetal growth developmental stages characterized by accelerated cell division. In particular, folate is needed for closure of the neural tube early in pregnancy, and periconceptional supplementation with folic acid has been shown to dramatically reduce the incidence of neural tube defects (NTDs) (27-29). NTDs are devastating congenital malformations that are can occur as either anencephaly or spina bifida. Because these birth defects occur between 21 to 27 days after conception (30), often before many women recognize their pregnancy, it is recommended that all women capable of becoming pregnant take supplemental folic acid. A recent systematic review of five trials, including 6,105 women, found that periconceptional folic acid supplementation, alone or with other micronutrients, was associated with a 72% lower risk of NTDs (29). While the optimal dose of folic acid for NTD prevention is not yet known, doses of less than 1 mg/day of folic acidthe level set as the tolerable upper intake level (UL) for adultsare used to prevent NTDs in healthy women (31). The RDA for pregnant women is 600 mcg/day of dietary folate equivalents (DFE), which is equivalent to 300 mcg/day of synthetic folic acid on an empty stomach or 353 mcg/day of synthetic folic acid with a meal (see the separate article on Folic Acid). The U.S. Preventive Services Task Force recommends a daily supplement of 400-800 mcg of folic acid for all women planning or capable of pregnancy (9). Supplemental folic acid use at the higher end of this suggested range has been recommended by some (31, 32), and 800 mcg/day from supplements plus dietary intake is safe for women of childbearing age. A Hungarian randomized controlled trial conducted in 5,453 well-nourished women found that periconceptional consumption of a multivitamin/mineral supplement that contained 800 mcg of folic acid reduced the incidence of first occurrence NTDs by about 90% compared to a supplement containing only copper, manganese, zinc, and vitamin C (28, 31, 33). Multivitamin/mineral supplements marketed in the U.S. commonly contain 400 mcg of folic acid, and many prenatal supplements marketed in the U.S. contain 800 mcg of folic acid. Folic acid may also be present in the food supply: several countries have programs of mandatory folic acid fortification to help reduce the incidence of NTDs; for example, the U.S. FDA implemented legislation in 1998 requiring the fortification of all enriched grain products with folic acid (34). Moreover, folic acid supplementation in the form of a daily multivitamin may be more effective in reducing NTDs than when used alone (reviewed in 31). Doses of greater than 1 mg/day of folic acid are used pharmacologically to treat hyperhomocysteinemia and to prevent reoccurrence of NTDs

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(31). Women who have had a previous NTD-affected pregnancy may be advised to consume up to 4 mg/day (4,000 mcg/day) of folic acid if they are planning a pregnancy, but the level of supplementation should be prescribed by their medical provider (see the CDC recommendations). Inadequate folate status may also be linked to other birth defects, such as cleft lip, cleft palate, and limb malformations, but the support for these findings is not as clear or consistent as the support for NTDs (29). However, results of some case-control studies (35-39) and controlled trials (27, 40) have suggested that periconceptional supplementation with a multivitamin containing folic acid may protect against congenital cardiovascular malformations, especially conotruncal (outflow tract) and ventricular septal defects. A 2006 systematic review and meta-analysis concluded that such supplementation was associated with a 22% lower risk of cardiovascular defects in casecontrol studies and a 39% lower risk in cohort studies and randomized controlled trials (41). Impaired folate status during pregnancy may also be associated with other adverse pregnancy outcomes. Elevated blood homocysteine levels, considered an indicator of functional folate deficiency, have been associated with increased risk of preeclampsia, premature delivery, low birth weight, very low birth weight (<1,500 grams), NTDs, and stillbirth (42). Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube, in order to decrease the risk of other potential problems during pregnancy. Riboflavin: Riboflavin is a component of flavocoenzymes involved in energy metabolism as well as antioxidant functions. The Food and Nutrition Board of the Institute of Medicine recommends that all pregnant women consume 1.4 mg of riboflavin daily. Riboflavin deficiency has been implicated in preeclampsiaa pregnancy-associated complication characterized by elevated blood pressure, protein in the urine, and edema (significant swelling). Preeclampsia is estimated to affect 2-8% of all pregnancies (43), and about 5% of women with preeclampsia progress to eclampsia, a significant cause of maternal death (44). Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (44). Although the specific causes of preeclampsia are not known, decreased intracellular levels of flavocoenzymes could cause mitochondrial dysfunction, increase oxidative stress, and interfere with nitric oxide release and thus blood vessel dilation. All of these changes have been associated with preeclampsia, but there have been few studies on the association of riboflavin nutritional status and the condition. A study in 154 pregnant women at high risk for preeclampsia found that those who were riboflavin deficient were 4.7 times more likely to develop preeclampsia than those who had adequate riboflavin nutritional status (45). However, a small randomized, placebo-controlled, double-blind trial in 450 pregnant women at high risk for preeclampsia found that supplementation with 15 mg of riboflavin daily did not prevent the condition (46). Vitamin A: Adequate maternal status of vitamin A is critical for a healthy pregnancy. Forms of the vitamin, known as retinoids, are involved in the regulation of gene expression, cellular proliferation and differentiation, growth and development, vision, and immunity (see the separate article on Vitamin A). The retinoids, retinol and retinoic acid, are essential for embryonic and fetal development (47); for example, retinoic acid functions in forming the heart, eyes, ears, and limbs (48). Forms of vitamin A are also necessary for maternal health. Vitamin A deficiency during pregnancy has been linked to impaired immunity, increased susceptibility to infection, and increased risk of maternal morbidity and mortality (49-52). Vitamin A deficiency may exacerbate iron-deficiency anemia, which is relatively common during pregnancy (see section on Iron below), because cosupplementation with vitamin A and iron seems to ameliorate anemia more effectively than either micronutrient supplement alone (53). Vitamin A deficiency is a major public health problem worldwide, especially in developing nations, where availability of foods containing preformed vitamin A (retinol) is limited (for information on food sources of vitamin A, see the separate article

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on Vitamin A). The RDA during pregnancy is 750-770 mcg/day (2,500-2,567 IU/day) of preformed vitamin A (see the Table above). Although normal embryonic and fetal development require sufficient maternal vitamin A intake, consumption of excess preformed vitamin A during pregnancy has been demonstrated to cause birth defects. An increased risk of vitamin A-associated birth defects has not been observed at supplemental doses below 3,000 mcg (10,000 IU)/day of preformed vitamin (54). However, because a number of foods in the U.S. are fortified with preformed vitamin A, the Linus Pauling Institute recommends that pregnant women avoid multivitamin or prenatal supplements that contain more than 1,500 mcg (5,000 IU) of vitamin A. Vitamin A from beta-carotene is not known to increase the risk of birth defects, although the safety of high-dose beta-carotene supplements in pregnancy has not been well studied. Moreover, pharmacological use of retinoids by pregnant women causes serious birth defects; thus, tretinate, isotretinoin (Accutane), and other retinoids should not be used during pregnancy or if there is a possibility of becoming pregnant (55). Use of tretinoin (Retin-A), a topically applied retinoid, is not recommended due to potential for systemic absorption. It is important to note that retinoids tend to be very long acting; birth defects have been reported to occur months after discontinuing retinoid therapy (56). Retinoids are used therapeutically to treat retinitis pigmentosa, acute promyelocytic leukemia, various skin diseases, and other conditions. Vitamin B6: Vitamin B6 has diverse roles in the body, including nervous system function, red blood cell formation and function, steroid hormone function, nucleic acid synthesis, and niacin formation. Pyridoxal, pyridoxine, and pyridoxamine are three forms of the vitamin. The RDA for vitamin B6 during pregnancy is 1.9 mg/day. Supplementation with high-dose vitamin B6 may help mitigate nausea and vomiting in pregnancy (commonly called morning sickness). Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. The vitamin was included in the medication Bendectin, which was prescribed for the treatment of morning sickness and later withdrawn from the market due to unproven concerns that it increased the risk of birth defects. The results of two double-blind, placebo-controlled trials that used 25 mg of pyridoxine every eight hours for three days (57) or 10 mg of pyridoxine every eight hours for five days (58) suggest that vitamin B6 may be beneficial in alleviating morning sickness. Each study found a slight but significant reduction in nausea or vomiting in pregnant women. A systematic review of placebocontrolled trials on nausea during early pregnancy found vitamin B6 to be somewhat effective (59), but evidence of its effectiveness is extremely limited (60). However, it should be noted that nausea and vomiting in early pregnancy usually resolves without any treatment, making it difficult to perform well-controlled trials. Vitamin B6 at the above-mentioned dosages is considered safe during pregnancy, and the vitamin has been used in pregnant women without any evidence of fetal harm (58, 61). The tolerable upper intake level (UL) during pregnancy is 80-100 mg/day; see the table, UL for Micronutrients During Pregnancy. Vitamin B12: In humans, vitamin B12 is needed as a cofactor for two enzymes. One converts homocysteine to the amino acid, methionine. Methionine is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions (62). DNA methylation that occurs during embryonic and fetal development modulates gene expression, cell differentiation, and the formation of organs (63). Thus, adequate vitamin B12 status during pregnancy is critical. Inadequate dietary intake of vitamin B12 causes elevated homocysteine levels, which have been associated with adverse pregnancy outcomes, including preeclampsia, premature delivery, low birth weight (<2,500 grams), very low birth weight (<1,500 grams), neural tube defects (NTDs), and stillbirth (42). Moreover, low serum levels of vitamin B12 during pregnancy have been directly linked to an increased risk for NTDs (64, 65), and there is some concern that folic acid supplementation during pregnancy may mask the clinical diagnosis of vitamin B12 deficiency. For these reasons, adequate vitamin B12 intake during pregnancy (RDA=2.6 mcg/day) is important.

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Because the vitamin is found only in foods of animal origin, the American Dietetic Association recommends that vegans and lacto-ovo vegetarians take supplemental vitamin B12 (66). To ensure a daily intake of 6-30 mcg of vitamin B12 in a form that is easily absorbed, the Linus Pauling Institute recommends that women who are planning a pregnancy take a daily multivitamin supplement or eat a breakfast cereal fortified with vitamin B12 (for more information, see the separate article on Vitamin B12). Vitamin C and Vitamin E: Because oxidative stress has been implicated in the pathogenesis of preeclampsia (67), nutritional status of the two antioxidant vitamins, vitamin C and vitamin E, may be important in preventing the condition. These vitamins have other biological functions; for more information, see the separate articles on Vitamin C and Vitamin E. Several trials have investigated whether supplementation with vitamins C and E improves pregnancy-associated hypertension or preeclampsia, but evidence supporting such an effect is largely lacking. An early placebo-controlled trial found that supplementation with 1,000 mg/day of vitamin C and 400 mg of vitamin E (RRRalpha-tocopherol) was associated with a 61% reduction in incidence of preeclampsia in women at increased risk for the condition (68). However, more recent randomized controlled trials have not found supplementation at these dosages to be effective in preventing preeclampsia in high- or lowrisk women (69-74). Nevertheless, adequate intake of antioxidant vitamins is important throughout pregnancy. According to data from the U.S. National Health and Nutrition Examination Survey (NHANES), 31% and 93% of U.S. adults do not meet the estimated average requirement (EAR) for vitamin C and vitamin E, respectively (75). For the Linus Pauling Institutes recommendations concerning these antioxidants, see the Supplements section in the LPI Rx for Health. Vitamin D: In 2010, the Food and Nutrition Board (FNB) of the Institute of Medicine set the RDA for vitamin D at 15 mcg (600 IU)/day for all pregnant women (76). The FNB based this recommendation on a limited number of studies using bone health as the only indicator, assuming minimal sun exposure. Vitamin D, however, has a number of other roles in disease prevention and health (see the separate article on Vitamin D), and several vitamin D researchers believe that vitamin D requirements for adults, including pregnant women, are higher than the current RDA (77-81). A number of studies indicate that vitamin D deficiency and insufficiency are quite common among pregnant women (82-90). Vitamin D is found in very few foods and prenatal supplements often contain only 10 mcg (400 IU) of vitamin D. Sunlight exposure is the main source of the vitamin: vitamin D3 (cholecalciferol) is synthesized in skin cells following exposure to ultraviolet-B radiation. However, the contribution of sun exposure to vitamin D status depends on many factors, including latitude, skin color, amount of skin exposed, duration of exposure, and the use of sunscreens, which effectively block skin production of vitamin D. Thus, vitamin D supplementation throughout pregnancy is likely needed to achieve body levels thought to benefit fetal and maternal health. The Linus Pauling Institute recommends that generally healthy adults, including pregnant women, take 2,000 IU (50 mcg) of supplemental vitamin D daily. Because sun exposure, diet, skin color, and obesity have variable, substantial impact on body vitamin D levels, measuring serum levels of 25hydroxyvitamin Dthe clinical indicator of vitamin D statusis important. The Linus Pauling Institute recommends aiming for a serum 25-hydroxyvitamin D level of at least 80 nmol/L (32 ng/mL). Vitamin K: The adequate intake (AI) for vitamin K (90 mcg/day for women aged 19-50 years and 75 mcg/day for those aged 14-18 years) is not increased during pregnancy, and a tolerable upper intake level (UL) has not been set for vitamin K. However, if taken during pregnancy, a number of drugs, including warfarin, rifampin, isoniazid, and anticonvulsants, may increase the risk of neonatal vitamin K deficiency and hemorrhagic disease of the newborn (91).

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Minerals Calcium: Although 200-250 mg/day of calcium is transferred to the fetus, primarily in the last trimester, dietary intake requirements of calcium are not increased due to maternal physiological adaptations. The RDA is 1,300 mg/day for women aged 14-18 years and 1,000 mg/day for women aged 19-50 years. In particular, the efficiency of intestinal calcium absorption doubles during pregnancy, and the mineral can also be transiently mobilized from maternal stores to support fetal needs for calcium. Permanent demineralization of bone during pregnancy has not been observed (76, 92). Moreover, there is no evidence from randomized controlled trials that calcium supplementation during pregnancy confers any benefit to maternal or fetal bone health (93, 94). Calcium intake during pregnancy, however, may influence the risk for pregnancy-induced hypertension (PIH). PIH, which occurs in 10% of pregnancies and is a major health risk for pregnant women and the fetus, is a term that includes gestational hypertension, preeclampsia, and eclampsia. Gestational hypertension is defined as an abnormally high blood pressure that usually th develops after the 20 week of pregnancy. In addition to gestational hypertension, preeclampsia includes the development of edema (severe swelling) and proteinuria (protein in the urine). Preeclampsia may progress to eclampsia (also called toxemia) in which life-threatening convulsions and coma may occur (95). Although the cause of PIH is not entirely understood, calcium metabolism appears to play a role. Risk factors for PIH include first pregnancies, multiple gestations (e.g., twins or triplets), chronic high blood pressure, diabetes, and some autoimmune diseases. Data from observational studies suggest an inverse relationship between dietary calcium intake and the incidence of PIH. Additionally, a recent systematic review of randomized, placebocontrolled trials reported that calcium supplementation during pregnancy ( 1,000 mg/day) was associated with a 35% lower risk of high blood pressure and a 55% lower risk of preeclampsia; the risk reduction for preeclampsia was even stronger for women considered to be at high risk for the condition (78% lower risk compared to placebo) and women with low dietary intake of calcium (64% lower risk compared to placebo) (96). This analysis also found that calcium supplementation lowered the risk of preterm birth by 24%, but no significant effect of calcium supplementation was found regarding the risk of stillbirth, neonatal mortality before hospital discharge, or maternal mortality (96). Chromium: Chromium is known to enhance the action of insulin; therefore, several studies have investigated the utility of chromium supplementation for the control of blood glucose levels in type 2 diabetes (see the separate article on Chromium). However, its use in gestational diabetesa condition that affects 3-5% of all pregnancies in the U.S.has not been well studied. Gestational diabetes is a glucose intolerance that usually appears in the second or third trimester of pregnancy; blood glucose levels must be tightly controlled to prevent adverse effects on the developing fetus and other pregnancy complications. After delivery, glucose tolerance generally reverts to normal, but women are at a heightened risk of developing type 2 diabetes (97). In fact, a recent systematic review and meta-analysis found that the risk of developing type 2 diabetes in women diagnosed with gestational diabetes is more than 7-fold higher than women not diagnosed with gestational diabetes (98). Gestational diabetes is also considered a risk factor for cardiovascular diseases (97). Two observational studies found that serum levels of chromium in pregnant women were not associated with glucose intolerance or gestational diabetes (99, 100), although serum chromium levels may not necessarily reflect tissue chromium levels. An 8-week placebo-controlled trial in 24 women with gestational diabetes found that supplementation in the form of chromium picolinate (4 mcg/day of chromium per kilogram of body weight) was associated with lower fasting blood glucose and insulin levels (101). However, it is important to note that insulin therapy was still required to normalize the severely elevated levels of blood glucose concentrations. Thus, more research, especially from randomized controlled trials, is needed to determine whether chromium supplementation has any utility in the treatment of gestational diabetes.

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Iodine: Iodine requirements are increased by more than 45% during pregnancy: the RDA for pregnant women is 220 mcg/day compared to 150 mcg/day for women who are not pregnant. Adequate intake of this mineral is needed for maternal thyroid hormone production, and thyroid hormone is needed for myelination of the central nervous system and is thus essential for normal fetal brain development (102). Maternal iodine deficiency has been associated with increased incidence of miscarriage, stillbirth, and birth defects. Severe iodine deficiency during pregnancy can result in congenital hypothyroidism and neurocognitive deficits in the offspring (102, 103). One of the most devastating effects of maternal iodine deficiency is congenital hypothyroidism. A severe form of congenital hypothyroidism may lead to a condition that is sometimes referred to as cretinism and result in irreversible mental retardation. Cretinism occurs in two forms, although there is considerable overlap between them. The neurologic form is characterized by mental and physical retardation and deafness; the neurologic form of cretinism results from maternal iodine deficiency that affects the fetus before its own thyroid is functional. The myxedematous or hypothyroid form is characterized by short stature and mental retardation (103). Moreover, even mild forms of maternal iodine deficiency may have adverse effects on cognitive development in the offspring (104), and iodine deficiency is now accepted as the most common cause of preventable brain damage in the world (105). Thus, adequate intake of the mineral throughout pregnancy is critical. A daily supplement providing 150 mcg of iodine, as recommended by the American Thyroid Association (106), will help to ensure that U.S. pregnant women consume sufficient iodine. However, it is important to note that several prenatal supplements and some multivitamin/mineral supplements on the market in the U.S. do not contain iodine, presumably because manufacturers assume that women receive sufficient iodine through iodized salt and other food sources. For more information on iodine and iodine deficiency disorders, see the separate article on Iodine. Iron: Iron requirements are significantly increased during pregnancy: the RDA is 27 mg/day for pregnant women of all ages compared to 15-18 mg for nonpregnant women. Many women have dietary iron intakes below current recommendations. National surveys in the U.S. indicate that the average dietary iron intake is about 12 mg/day in nonpregnant women and 15 mg/day in pregnant women (107). Iron is needed for a number of biological functions (see the separate article on Iron), but during pregnancy, the mineral is generally needed to support growth and development of the fetus and placenta and to meet the increased demand for red blood cells to transport oxygen. Intestinal absorption of dietary iron increases during the second and third trimesters to accommodate for expansion of red cell mass (107). Maternal blood volume expands by almost 50% during pregnancy, which results in a hemodilution of red blood cells (108). Despite maternal physiologic changes that enhance iron absorption, many women develop irondeficiency anemia during pregnancy. The World Health Organization estimates that the worldwide prevalence of anemia among pregnant women is 42%; the prevalence of anemia is much higher in less developed nations compared with industrialized nations (109). Anemias can be caused by deficiencies in other micronutrients, such as folate or vitamin B12, but iron deficiency is the primary cause of anemia during pregnancy (1). Iron-deficiency anemia causes an estimated 115,000 maternal deaths each year (110), and severe iron deficiency during pregnancy has been associated with increased risk of low birth weight infants (<2,500 grams), premature delivery, and perinatal mortality (111). However, evidence that iron-deficiency anemia is a causal factor in poor pregnancy outcomes is still lacking (112, 113). Iron status of the woman at the time of conception is important for a healthy pregnancy, to avoid postpartum anemia, and to provide the breast-feeding infant with sufficient iron stores until six months of age, when complementary feeding is recommended. Because of the increased demands for the mineral during the second and third trimesters of pregnancy, iron supplementation (30 mg/day) is usually recommended beginning at 12 weeks gestation (114). Absorption of nonheme iron, which is the form of iron found in supplements, is affected by a number of enhancers (e.g.,

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vitamin C) as well as inhibitors (e.g., polyphenols found in tea and coffee). In general, iron supplements are better absorbed on an empty stomach. High doses of iron supplements taken together with zinc supplements on an empty stomach can inhibit the absorption of zinc (107, 115); supplemental iron at 38-65 mg/day of elemental iron may decrease zinc absorption (116). For more information about dietary and supplemental sources of iron, as well as the side effects and safety of iron, see the separate article on Iron. Magnesium: The mineral magnesium plays a number of important roles in the structure and the function of the human body (see the separate article on Magnesium), and adequate intake of the mineral is needed for normal embryonic and fetal development. Maternal magnesium deficiency has been associated with premature labor and has also been implicated in the pathogenesis of Sudden Infant Death Syndrome (SIDS) (117). National dietary surveys indicate that magnesium insufficiency is relatively common in the U.S., with 56% of American adults not meeting the EARthe nutrient intake value that is estimated to meet the requirement of half of the healthy individuals in a particular life stage and gender group (75). Good sources of magnesium include green leafy vegetables, whole grains, and nuts (see Sources in the separate article on magnesium). Several multivitamin/mineral and prenatal supplements do not contain magnesium or contain no more than 100 mg of magnesium. Preeclampsia-eclampsia (toxemia of pregnancy) is a disease that is unique to pregnancy and may occur anytime after 20 weeks gestation through six weeks following birth. Preeclampsia is defined as the presence of elevated blood pressure, protein in the urine, and severe swelling (edema) during pregnancy. Eclampsia occurs with the addition of seizures to the triad of symptoms. Approximately 5% of women with preeclampsia go on to develop eclampsia, which is a significant cause of maternal death (44). Intravenous administration of high-dose magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with preeclampsia-eclampsia in late pregnancy or during labor (118-120). Magnesium is believed to relieve cerebral blood vessel spasm, increasing blood flow to the brain (121, 122). Zinc: The RDA for zinc is increased during pregnancy (11-12 mg/day; see the table, RDA for Micronutrients During Pregnancy), and pregnant women, especially teenagers, are at increased risk of zinc deficiency. It has been estimated that 82% of pregnant women in the world may have inadequate intake of dietary zinc (123), leading to poor nutritional status of the mineral. Poor nutritional status of zinc during pregnancy has been associated with a number of adverse outcomes, including low birth weight (<2,500 grams), premature delivery, labor and delivery complications, and congenital anomalies (124). However, the results of maternal zinc supplementation trials in the U.S. and developing countries have been mixed (125). Trials designed to examine the effect of zinc supplementation on labor and delivery complications have also generated mixed results, although few have been conducted in zinc-deficient populations (123). A recent systematic review of 17 randomized controlled trials found that zinc supplementation during pregnancy was associated with a 14% reduction in premature deliveries; the lower incidence of preterm births was observed mainly in low-income women (126). This analysis, however, did not find zinc supplementation to benefit other indicators of maternal or infant health (126). It is important to note that supplemental levels of iron (38-65 mg/day of elemental iron), but not dietary levels of iron, may decrease zinc absorption (116). Because iron supplementation is recommended during pregnancy (see Iron above), pregnant women who take more than 60 mg/day of elemental iron may want to take a prenatal or multivitamin-mineral supplement that also includes zinc (127). Other Nutrients

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Choline: Choline can be synthesized by the body in small amounts, but dietary intake is needed to maintain health (128). Choline is present in a wide variety of foods, with good sources including wheat germ, eggs, pork, and liver (129); however, pregnant women should minimize their consumption of liver due to its high content of preformed vitamin A (see Vitamin A above). The adequate intake (AI) for pregnant women is 450 mg/day of choline. Choline is essential for embryonic and fetal brain development. The choline metabolite betaine is a source of methyl (CH3) groups required for methylation reactions. DNA methylation that occurs during embryonic and fetal development modulates gene expression, cell differentiation, and the formation of organs (63). Women with low dietary intake of choline have been observed to have a higher risk of neural tube defects (NTDs), but it is not known if supplementation with choline or betaine, like supplementation with folic acid (see Folic Acid above), will lower the incidence of NTDs. A case-control study (424 NTD cases and 440 controls) found that women in the highest quartiles of choline and betaine intake, in combination, had a 72% lower risk of an NTD-affected pregnancy compared with the lowest quartiles in combination (130). A more recent case-control study (80 NTD-affected pregnancy and 409 controls) found that the lowest levels of serum choline during mid-pregnancy were associated with a 2.4-fold higher risk of NTDs (131), but serum levels of choline during mid-pregnancy may not necessarily correlate with serum levels during early pregnancy. More research is needed to determine whether choline is involved in the etiology of NTDs. Maternal intake of choline during pregnancy could possibly also affect cognitive abilities of the offspring. Choline supplementation in pregnant rats, as well as rat pups during the first month of life, leads to improved performance in spatial memory tests months after choline supplementation has been discontinued (132). A review by McCann et al. discusses the experimental evidence from rodent studies regarding the availability of choline during prenatal development and cognitive function in the offspring (133). It is not clear whether findings in rodent studies are applicable to humans. More research is needed to determine the role of choline in the developing brain and whether choline intake during pregnancy is useful in the prevention of memory loss or dementia in humans. Further, choline is important for homocysteine metabolism during pregnancy. Methyl groups derived from choline may be used to convert homocysteine to methionine. Elevated blood homocysteine levels have been associated with increased incidence of miscarriage as well as pregnancy complications, such as preeclampsia, premature delivery, low birth weight (<2,500 grams), very low birth weight (<1,500 grams), NTDs, and stillbirth (42). Essential Fatty Acids: Although not micronutrients, certain fatty acids are required in the maternal diet during pregnancy and lactation; the U.S. Institute of Medicines adequate intake (AI) recommendations for omega-3 and omega-6 fatty acids during pregnancy and lactation are listed in the separate article on Essential Fatty Acids. For more information on the importance of omega-3 fatty acids during these life stages, see two sections in the separate article on essential fatty acids: Visual and Neurological Development and Pregnancy and Lactation. Information about environmental contaminants in fish and supplements is included in the sections, Contaminants in Fish and Contaminants in Supplements. Safety Dietary Reference Intakes Set by the FNB: UL for Micronutrients During Pregnancy Micronutrient Biotin Age 14-50 years UL ND
a

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Folic Acid

14-18 years 19-50 years

800 mcg/day

b b

1,000 mcg/day 30 mg/day

b b

Niacin

14-18 years 19-50 years

35 mg/day ND ND ND

Pantothenic Acid Riboflavin Thiamin Vitamin A

14-50 years 14-50 years 14-50 years 14-18 years 19-50 years

2,800 mcg (9,333 IU)/dayc 3,000 mcg (10,000 IU)/day 80 mg/day 100 mg/day ND 1,800 mg/day 2,000 mg/day 100 mcg (4,000 IU)/day 800 mg (1,200 IU)/day
d d c

Vitamin B6 Vitamin B6 Vitamin B12 Vitamin C

14-18 years 19-50 years 14-50 years 14-18 years 19-50 years

Vitamin D Vitamin E

14-50 years 14-18 years 19-50 years

1,000 mg (1,500 IU)/day ND 3,000 mg/day 2,500 mg/day ND 8 mg/day 10 mg/day 10 mg/day 900 mcg/day 1,100 mcg/day 45 mg/day 350 mg/day 9 mg/day 11 mg/day 1,700 mcg/day 2,000 mcg/day 3,500 mg/day ND 400 mcg/day 2,300 mg/day (AI)
e

Vitamin K Calcium

14-50 years 14-18 years 19-50 years

Chromium Copper

14-50 years 14-18 years 19-50 years

Fluoride Iodine

14-50 years 14-18 years 19-50 years

Iron Magnesium Manganese

14-50 years 14-50 years 14-18 years 19-50 years

Molybdenum

14-18 years 19-50 years

Phosphorus Potassium Selenium Sodium

14-50 years 14-50 years 14-50 years 14-50 years

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Zinc

14-18 years 19-50 years

34 mg/day 40 mg/day 3,000 mg/day 3,500 mg/day

Choline

14-18 years 19-50 years

ND, not determinable because data are lacking Applies to the synthetic form in fortified foods and supplements c Applies to only preformed vitamin A (retinol) d Applies to any form of supplemental alpha-tocopherol e Applies only to the supplemental form f Considered an essential nutrient, although not strictly a micronutrient
b

Maternal Micronutrient Requirements During Lactation Breast-feeding confers health benefits to the child as well as the mother (134). Breast milk is the ideal source of nutrition for the infant and also contains a number of bioactive compounds important in immunity, such as antibodies, cytokines, antimicrobial agents, and oligosaccharides (135). The American Academy of Pediatrics recommends exclusive breast-feeding for the first six months of infancy and continued breast-feeding, with introduction of complementary foods, at least 12 months postpartum and then as long as mutually desired by the mother and child (136). The World Health Organization recommends exclusive breast-feeding for the first six months of life and continued breastfeeding, with complementary feeding, up to two years or more postpartum (137). There are, however, a few exceptions when breast-feeding is contraindicated, including those listed on the CDC Web site. Lactation is extremely energy expensive, and macronutrient requirements for breast-feeding women are even higher than during pregnancy. Likewise, the intake recommendations (RDA or AI) for most micronutrients, which are based on amounts secreted in breast milk, are higher for lactating women compared to pregnant women (see the table, RDA for Maternal Micronutrients During Lactation). One notable exception is the RDA for iron, which is significantly lower during lactation (9-10 mg/day) compared to pregnancy (27 mg/day) (107). Breast milk is considered to be low in iron; however, the iron content of breast milk is not influenced by changes in maternal iron status, such as through maternal supplementation (50). The RDA for folate is also lower during lactation compared with pregnancy. Dietary intake recommendations for calcium remain unchanged for lactating women compared to recommendations for nonlactating women, and calcium content in breast milk does not reflect maternal intake of the mineral. Adequate calcium is maintained in breast milk because of maternal physiological changes that involve transient bone resorption; increased maternal intake of calcium through diet and supplementation does not prevent maternal bone demineralization, and studies have shown that maternal bone mineral content is restored upon weaning (138). In general, the amounts of water-soluble vitamins (B vitamins and vitamin C) in breast milk reflect maternal intake from diet and/or supplements. Thus, meeting daily intake recommendations for these micronutrients is important for the health of the child. Maternal vitamin deficiencies can negatively affect infant growth and development; for instance, vitamin B12 deficiency during infancy can impair brain development and cause neurological problems (139). Vitamin B12 deficiency has been documented in nursing infants of mothers who have untreated pernicious anemia and also in women who are strict vegetarians (vegans) (140). Vitamin B12 is found only in foods of animal origin, and lactating women who follow such strict vegetarian diets should take supplemental vitamin B12. Vitamin B12 deficiency that results from pernicious anemia can easily be corrected with high-dose daily supplementation or with monthly intramuscular injections of the vitamin (see the separate article on Vitamin B12). Moreover, the concentrations of other water-soluble vitamins in breast milk, including thiamin, riboflavin, and vitamin B6, are strongly dependent on maternal

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intake of these vitamins (50). Further, levels of vitamin C in human milk vary with the vitamin C status of the mother. Vitamin C supplementation can moderately increase levels of the vitamin in breast milk, especially in lactating women with poor vitamin C status 141, and maternal intakes of 100 mg/day maximize the amount of vitamin C in breast milk (142). Compared to water-soluble vitamins, the concentrations of fat-soluble vitamins (vitamins A, D, E, and K) in breast milk are less correlated with maternal dietary intake. The RDA for vitamin A during lactation is 1,200-1,300 mcg/day (4,000-4,333 IU/day). At such levels of maternal intake, breast milk is a good source of vitamin A and provides the infant with a sufficient amount of the vitamin (143). In contrast, breast milk is considered to be low in vitamins D and K. Vitamin D levels in human milk are dependent on maternal vitamin D status, which is determined by the womans sun exposure and dietary and supplemental intake. Vitamin D levels are low in breast milk, presumably because many women have insufficient vitamin D status. Vitamin D supplementation during lactation has been shown to improve vitamin D status in the woman and the infant (144). The RDA for lactating women is 600 IU/day of vitamin D, but intake at this level in the absence of sun exposure likely results in insufficient amounts for the infant. To prevent vitamin D deficiency and rickets in infants, the American Academy of Pediatrics recommends that all breast-fed and partially breast-fed infants be given a vitamin D supplement of 400 IU/day (145). Liquid vitamin D supplements are commercially available for infant supplementation. The Linus Pauling Institute recommends that all adults take 2,000 IU/day of supplemental vitamin D and aim for a serum 25hydroxyvitamin D level of at least 80 nmol/L (32 ng/mL). Human milk is also relatively low in vitamin K. Thus, exclusively breast-fed newborns are at increased risk for vitamin K deficiency. In general, newborns have low vitamin K status for the following reasons: 1) vitamin K is not easily transported across the placental barrier; 2) the newborn's intestines are not yet colonized with bacteria that synthesize vitamin K; and 3) the vitamin K cycle may not be fully functional in newborns, especially premature infants (146). Vitamin K deficiency in newborns may result in a bleeding disorder called vitamin K deficiency bleeding (VKDB). Because VKDB is life-threatening and easily prevented, the American Academy of Pediatrics and a number of similar international organizations recommend that an injection of phylloquinone (vitamin K1) be administered to all newborns (91). Additionally, the vitamin E content in breast milk varies with maternal diet and vitamin E supplement use (141, 143). The RDA for vitamin E during lactation is 19 mg/day (28.5 IU/day) of alpha-tocopherol. National surveys indicate that more than 90% of U.S. adults have daily vitamin E intakes below 12 mg (18 IU) (75). Maternal dietary intake recommendations for the 14 essential minerals during lactation are shown in the table below, RDA for Maternal Micronutrients During Lactation. The content of minerals in breast milk does not correlate well with maternal intake or status, except for iodine and selenium (1, 135). Iodine requirements are increased during lactation: breast-feeding women require 290 mcg/day of iodine (102). Iodine-deficient women who are breast-feeding may not be able to provide sufficient iodine to their infants who are particularly vulnerable to the effects of iodine deficiency (see Newborns and infants in separate article on iodine). A daily supplement providing 150 mcg of iodine, as recommended by the American Thyroid Association (106), will help to ensure that U.S. breast-feeding women consume sufficient iodine during these critical periods. Additionally, the RDA for selenium is slightly higher for lactating women, and selenium content in breast milk reflects maternal intake (147). Dietary Reference Intakes Set by the FNB: RDA for Maternal Micronutrients During Lactation Micronutrient Biotin Folic Acid Niacin Pantothenic Acid Age 14-50 years 14-50 years 14-50 years 14-50 years RDA 35 mcg/day (AI) 500 mcg/day 17 mg/day
b a

7 mg/day (AI)

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Riboflavin Thiamin Vitamin A

14-50 years 14-50 years 14-18 years 19-50 years

1.6 mg/day 1.4 mg/day 1,200 mcg (4,000 IU)/day 1,300 mcg (4,333 IU)/day 2.0 mg/day 2.8 mcg/day 115 mg/day 120 mg/day 15 mcg (600 IU)/day 19 mg (28.5 IU)/dayd 75 mcg/day (AI) 90 mcg/day (AI) 1,300 mg/day 1,000 mg/day 44 mcg/day (AI) 45 mcg/day (AI) 1.3 mg/day 3 mg/day (AI) 290 mcg/day 10 mg/day 9 mg/day 360 mg/day 310 mg/day 320 mg/day 2.6 mg/day (AI) 50 mcg/day 1,250 mg/day 700 mg/day 5,100 mg/day (AI) 70 mcg/day 1,500 mg/day (AI) 13 mg/day 12 mg/day 550 mg/day (AI)
c c

Vitamin B6 Vitamin B12 Vitamin C

14-50 years 14-50 years 14-18 years 19-50 years

Vitamin D Vitamin E Vitamin K

14-50 years 14-50 years 14-18 years 19-50 years

Calcium

14-18 years 19-50 years

Chromium

14-18 years 19-50 years

Copper Fluoride Iodine Iron

14-50 years 14-50 years 14-50 years 14-18 years 19-50 years

Magnesium

14-18 years 19-30 years 31-50 years

Manganese Molybdenum Phosphorus

14-50 years 14-50 years 14-18 years 19-50 years

Potassium Selenium Sodium Zinc

14-50 years 14-50 years 14-50 years 14-18 years 19-50 years

Choline
a

14-50 years

AI, adequate intake Dietary Folate Equivalents b NE, niacin equivalent: 1 mg NE = 60 mg tryptophan = 1 mg niacin c Retinol Activity Equivalents

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d e

Alpha-tocopherol Considered an essential nutrient, although not strictly a micronutrient

Safety The tolerable upper intake level (UL) for each micronutrient is shown in the table below, UL for Maternal Micronutrients During Lactation. The UL, established by the Food and Nutrition Board of the Institute of Medicine, is the highest level of daily intake that is likely to pose no risk of adverse health effects in almost all individuals. Dietary Reference Intakes Set by the FNB: UL for Maternal Micronutrients During Lactation Micronutrient Biotin Folic Acid Age 14-50 years 14-18 years 19-50 years Niacin 14-18 years 19-50 years Pantothenic Acid Riboflavin Thiamin Vitamin A 14-50 years 14-50 years 14-50 years 14-18 years 19-50 years Vitamin B6 Vitamin B6 Vitamin B12 Vitamin C 14-18 years 19-50 years 14-50 years 14-18 years 19-50 years Vitamin D Vitamin E 14-50 years 14-18 years 19-50 years Vitamin K Calcium 14-50 years 14-18 years 19-50 years Chromium Copper 14-50 years 14-18 years 19-50 years Fluoride Iodine 14-50 years 14-18 years UL ND
a b b

800 mcg/day

1,000 mcg/day 30 mg/day

b b

35 mg/day ND ND ND

2,800 mcg (9,333 IU)/day

c c

3,000 mcg (10,000 IU)/day 80 mg/day 100 mg/day ND 1,800 mg/day 2,000 mg/day 100 mcg (4,000 IU)/day 800 mg (1,200 IU)/day
d d

1,000 mg (1,500 IU)/day ND 3,000 mg/day 2,500 mg/day ND 8 mg/day 10 mg/day 10 mg/day 900 mcg/day

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19-50 years Iron Magnesium Manganese 14-50 years 14-50 years 14-18 years 19-50 years Molybdenum 14-18 years 19-50 years Phosphorus Potassium Selenium Sodium Zinc 14-50 years 14-50 years 14-50 years 14-50 years 14-18 years 19-50 years Choline
f

1,100 mcg/day 45 mg/day 350 mg/day 9 mg/day 11 mg/day 1,700 mcg/day 2,000 mcg/day 4,000 mg/day ND 400 mcg/day 2,300 mg/day (AI) 34 mg/day 40 mg/day 3,000 mg/day 3,500 mg/day
e

14-18 years 19-50 years

ND, not determinable because data are lacking Applies to the synthetic form in fortified foods and supplements c Applies to only preformed vitamin A (retinol) d Applies to any form of supplemental alpha-tocopherol e Applies only to the supplemental form f Considered an essential nutrient, although not strictly a micronutrient
b

References Written in July 2011 by: Victoria J. Drake, Ph.D. Linus Pauling Institute Oregon State University Reviewed in July 2011 by: Andrew E. Czeizel, M.D., Ph.D., Sc.D. Professor, Emeritus Scientific Director Foundation for the Community Control of Hereditary Diseases Budapest, Hungary This article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland. Copyright 2011-2012 Linus Pauling Institute Disclaimer The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is

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made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional. The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.

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