1. Micronutrients 2007

2. Micronutrient Status Important throughout the reproductive years: –Periconceptual period –Pregnancy –Lactation –Inter-pregnancy interval

3. Multiple Micronutrient Deficiencies Occur with Poor Diets Most historic research on iron, folate, iodine Increasing understandings about less recognized deficiencies. Nutrients deficiencies interact: example vitamin A supplements can decrease rates of iron deficiency anemia in some populations.

4. Vitamins and Minerals Increased needs in pregnancy associated with: –DNA/RNA synthesis –Increased blood volume –bone mineralization & structure –Increased energy metabolism

5. Vitamins and Minerals Some nutrients of special concern due to low dietary levels in the population & extra demands of pregnancy IOM report, 1990: Vitamins B 6, D, E iron calcium zinc magnesium

6. Proposed Criteria for Selecting the WIC Food Package – IOM, 2004 Highest Priority Nutrients* Calcium Iron Magnesium Vitamin E Fiber Potassium Also Consider Vitamin A Vitamin C Vitamin D Vitamin B 6 Folate * for adolescent and adult women of reproductive age

7. Proposed Criteria for Selecting the WIC Food Package – IOM, 2004 Nutrients of concern with regard to excessive intake Sodium Food energy Total fat Nutrients to limit in the diet Saturated fat Cholesterol Trans fatty acids

8. Vitamins and Minerals Risks for low vitamin and mineral status include: –low income –restricted energy intake –adolescence –vegan (Calcium, B 12, D, zinc) –Non white status (Calcium)

9. Vitamins and Minerals Vitamin and mineral needs are increased by: –alcohol consumption –tobacco use –multiple fetuses

10. The issue of Vitamin-Mineral Supplements The consumption of more food to meet energy needs and the increased absorption and efficiency of nutrient utilization that occurs in pregnancy are generally adequate to meet the needs for most nutrients. However, vitamin and mineral supplementation is appropriate for some nutrients and situations. Nutrition and lifestyle for a healthy pregnancy outcome.J AM Diet Assoc 2002

11. Fat Soluble Vitamins Placental transport is by simple diffusion, so fetus is not protected against high maternal intakes Excess Vitamin A is associated with multiple congenital anomalies –concerns appear to start at 8,000 IU –ACOG and AAP define excessive as > 1,600 RE (twice the RDA) –1 IU = 0.3 RE all trans retinol

12. High levels of retinol intake during the first trimester of pregnancy result from use of over- the-counter vitamin/mineral supplements (Voyles et al. JADA, Sept., 2000) N=64 women recruited at initial prenatal visit to obstetrics office in university town. Household income and educational levels were higher than national averages. Women completed questionnaires and three day food records. 2 physicians in office prescribed routine prenatal vitamins, the third did not.

13. Voyles, cont. - Adherence 23% who were prescribed vitamins did not take them. 26 % who were prescribed vitamins took OTC supplements instead. 58% of those who were not prescribed took over the counter supplements. 9 of 10 women who had excessive intakes took OTC supplements

14. Voyles, Retinol Intakes (n=64) 20 had intakes < 800 RE 34 had intakes between 800 and 1,600 RE 10 had intakes > 1,600 RE Mean intake of vitamin A from food sources alone was 159% of the RDA

15. Voyles, Applications Most women can meet vitamin A needs with food alone. Supplements need to be carefully considered: many women taking OTC supps before pregnancy IOM recommendation is to avoid supps with vitamin A in first trimester

16. Vitamin A RDA - 2001 Non Pregnant = 700 mg RAE (retinol activity equivalents) Pregnant –Age 14-18:  g 750 –Age 19-30:  g 770 –Age 31-50:  g 770 Increase based on accumulation of vitamin A in the newborn’s liver (usually about half of total body vitamin A) UL for pregnancy –Age 14-18: 2,800  g/day preformed vitamin A –Age 19-50: 3,000  g/day preformed vitamin A

17. Vitamin D DRI - 1997 “Women, whether pregnant or not, who receive regular exposure to sunlight do not need vitamin D supplementation.” AI for pregnancy and non-pregnancy –14-50: 5.0  g  IU)/day UL for pregnancy and non-pregnant –50  g (2000 IU)/day –Excess associated with fetal hypercalcemia, aortic stenosis, abnormal skull development/premature closure of fontanel

18. Vitamin D: Emerging Understandings Maternal vitamin D status associated with bone mineralization in 9 year olds Some preliminary observational reports find that vitamin D status is association with risk of: –Autoimmune diseases such as multiple sclerosis & rheumatoid arthritis –Malignancies

19. Copyright ©2006 CMA Media Inc. or its licensors Hollis, B. W. et al. CMAJ 2006;174:1287-1290 Fig. 2: The endocrine, paracrine and intracrine functions of vitamin D

20. Vitamin D: Emerging Understandings Widespread deficiencies Disparities

21. Vitamin D Deficiency in Selected Populations Van der Meer et al. Am J Clin Nutr. 2006 Chart review of serum 25-hydroxyvitamin D status of 358 pregnant women in the Netherlands Used conservative estimates (<25 nmol/l for vitamin D deficiency –Deficiency cutoff based on array of biomarkers adversely affected by vit D is <80 nmol/l.

22. TABLE 2 Mean serum 25-hydroxyvitamin D [25(OH)D] concentrations in subjects and proportions of subjects with deficiency or with concentrations under the detection limit 1 Means compared by using ANOVA and Dunnett’s test; vitamin D data were log transformed and weighted by inverse cell variances. 2 Deficiency = < 25 nmol 25(OH)D/L. 3 Means compared by using logistic regression. 4 Under the detection limit = <7 nmol 25(OH)D/L. 5 ± SD (all such values). 6 P 0.001. 7 P 0.05. 25(OH)D conc 1 25(OH)D deficiency 2, 3 25(OH)D under the detection limit 3, 4 n (%) Western (reference) (n = 105) 52.7 ± 21.6 5 8 (8)1 (1) Turkish (n = 79)15.2 ± 12.1 6 66 (84) 6 17 (22) 6 Moroccan (n = 69)20.1 ± 13.5 6 56 (81) 6 3 (4) Other non-Western (n = 105) 26.3 ± 25.9 6 62 (59) 6 9 (9) 7

23. High Prevalence of Vitamin D Deficiency in Black and White Women Living in the Northern US (Simhan, J Nutr, 2007) 200 Black, 200 white women in Pittsburg >90% taking prenatal vitamins Increase in status from winter to summer: –White: 0.23 nmol/l –Black: 0.16 nmol/l

24. Vitamin D status Classification (Simhan, cont.) Serum 25(0H)D (25 hydroxy vitamin D) –Deficiency = <37.5 nmol/ L –Insufficiency = between 37/5 and 80 nmol/L –Sufficiency = > 80nmol/L

25. Prevalence of Vitamin D Deficiency InsufficiencyDeficiency White Infants4210 White Mothers565 Black Infants4729 Black Mothers5146

26. Vitamin E Supplementation in Pregnancy: Cochrane, 2005 “Women supplemented with vitamin E in combination with other supplements compared with placebo were at decreased risk of developing clinical pre- eclampsia (RR 0.44, 95% CI 0.27 to 0.71, three trials, 510 women) using fixed-effect models; however, this difference could not be demonstrated when using random- effects models (RR 0.44, 95% CI 0.16 to 1.22, three trials, 510 women).”

27. Vitamin E Supplementation in Pregnancy: Cochrane, 2005 “There were no differences between women supplemented with vitamin E compared with placebo for any of the secondary outcomes.” Author’s conclusions: “The data are too few to say if vitamin E supplementation either alone or in combination with other supplements is beneficial during pregnancy.”

28. Water Soluble Vitamins - C Potential for dependency in the newborn (reported with vitamin C and B 6 ) Vitamin C is actively transported across placenta as well as simple diffusion so potential for high fetal levels exists High maternal vitamin C levels associated with false positive tests for urinary glucose as well as cramps, nausea, and diarrhea

29. Vitamin C RDA - 2000 Maternal plasma vitamin C concentration falls in pregnancy, so additional vitamin C is needed to assure transfer to the fetus. 7 mg vitamin C prevents scurvey in infants so RDA for pregnancy was increased by 10 mg over non-pregnant. RDA 14-18: 80 mg vitamin C 19-30: 85 mg vitamin C 31-50: 85 mg vitamin C

30. UL for Vitamin C in Pregnancy Vitamin C is actively transported from maternal to fetal blood, but toxic effects are not well documented and UL is the same for pregnant and non-pregnant. TUL –14-18: 1,800 mg vitamin C –19 and older: 2,000 mg vitamin C

31. Cochrane: Vitamin C Supplementation in Pregnancy (2005) 5 trials involving 766 women Three trials supplemented women with 1000 mg vitamin C per day and two trials supplemented women with 500 mg vitamin C per day

32. Cochrane: Vitamin C Supplementation in Pregnancy (2005) No difference was seen between women supplemented with vitamin C alone or in combination with other supplements compared with placebo for: –Stillbirth –Perinatal death –Birthweight

33. Cochrane: Vitamin C Supplementation in Pregnancy (2005) Results re preeclampsia were unclear due to heterogeneity of studies. “Women supplemented with vitamin C were at decreased risk of preeclampsia when using a fixed-effect model (RR 0.47, 95% CI 0.30 to 0.75, four trials, 710 women), however this difference could not be demonstrated when using a random-effects model (RR 0.52, 95%CI 0.23 to 1.20, four trials, 710 women).”

34. Cochrane: Vitamin C Supplementation in Pregnancy (2005) “Women supplemented with vitamin C compared with placebo were at increased risk of giving birth preterm (RR 1.38, 95% CI 1.04 to 1.82, three trials, 583 women).”

35. Cochrane: Vitamin C Supplementation in Pregnancy Conclusions: –“The data are too few to say if vitamin C supplementation either alone or in combination with other supplements is beneficial during pregnancy. –“Preterm birth may have been increased with vitamin C supplementation.”

36. Emerging Findings: B Vitamin Deficiencies and Homocysteinemia in Pregnancy ( Allen, AJCN, 2005) Low intakes of folate, riboflavin, B 6, B 12 are associated with elevated Hcy Elevated plasma homocysteine (Hcy) is associated with increased risk of: –Placental abruption –Still-births –VLBW –Preterm delivery –Preeclampsia –Neural tube defect

38. Potential Mechanisms for Adverse Impact of Hcy in Pregnancy Hcy increases oxygen free radical concentrations, increases oxidative stress and placental ischemia Hcy causes inflammatory response Hypermethylation of DNA/altered gene expression Hcy is thronbogenic

39. Water Soluble Vitamins - B 6 Inconclusive studies have linked to: –depression in pregnancy –decreased apgars with low maternal status –one study found good results for women with severe nausea who were treated with 25 mg each 8 hours RDA for pregnancy (1998) –1.9 mg/day for all ages

40. B 6 – adverse effects Inconclusive studies of toxicity have linked to: –Congenital defects –B 6 dependency –Antilactogenic effects

41. UL for B 6 UL for non-pregnant adults = 100 mg/day UL for pregnancy –14-18: 80 mg/day –19 and older: 100 mg/day

42. Folic Acid - NTD NTD - 2,500 births per year in US. 50-70% may be preventable with adequate maternal folic acid status. Etiologies and pathways remain unknown. Some population groups - Mexican Americans, Native Americans - at higher risk.

43. Folic Acid - Recommendations 1992 - USPHSD: women of childbearing age consume 400 mcg folic acid per day. 1998 - IOM: women consume 400 mcg synthetic folic acid per day from supplements or fortified foods. January 1998 - USFDA: fortification of the food supply at 140 mcg/100 grams of flour.

44. Folic Acid: Fortification 0.14 mg per 100g cereal grain products 0.035 mg per slice of bread 0.10 mg per serving breakfast cereal Low level consumers can have intakes of 0.23-0.25 mg. Women with low intake range of recommended food group servings will consume 0.5 mg per day total folate.

45. Folic Acid Supplements Dietary folate is about half as absorbable as synthetic folic acid. Public health recommendations have focused on message to all women of childbearing age to take a supplement of synthetic folic acid.

46. MMWR, September 2005

47. MMWR - Knowledge and use of folic acid, Annual Reports from March of Dimes Gallup Survey 19951997200320042005 Taking FA25%30%32%40%33% Aware of FA52%66%79%77%84% Know that FA prevents birth defects 5%11%21%24%25% Know that FA should be taken before pregnancy 2%6%10%12%7%

48. Folate Status in Women of Childbearing Age, by Race/Ethnicity: MMWR, January 2007

49. "Why do you not take any vitamin or mineral supplements on a daily basis?" (2005 survey) forgetting to take supplements (28%) perceiving they do not need them (16%) believing they get needed nutrients and vitamins from food (9%).

50. "For what specific need would you start taking a vitamin or mineral supplement?" (2005 survey) being sick or in poor health (20%) a doctor's recommendation (20%) the need for energy (9%) being pregnant (8%) being deficient in any vitamins or minerals (7%) balancing the diet (6%) keeping bones strong (6%) 11% cited no specific need that would motivate them to begin taking a vitamin or supplement. Among women who reported not consuming a vitamin or mineral supplement daily, 31% indicated they had received a doctor's recommendation.

51. MMWR, September 2005

52. MMWR, May 2004

53. Emerging Issues: It’s more than folate…. NTD and B12 (Ray, Epidemiology, 2007) –In the presence of folate fortification, women with the lowest B 12 status have 190% increased risk of NTD compared to those with the highest B 12 status

54. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1999)

56. Iron General statements RDA Routine Supplementation Screening Treatment for Iron Deficiency Anemia

57. Iron Iron stores at conception predict risk of iron deficiency anemia in later pregnancy. Studies of the impact of iron deficiency are inconsistent due to study design and populations –In developing countries maternal iron status is often found to predict infant iron status. –Some studies find that maternal iron deficiency is associated with preterm delivery In US postpartum iron deficiency anemia is common in WIC mothers (27% overall, 48% non-Hispanic blacks) –Postpartum anemia is associated with postpartum depression

58. RDA for Iron, 2001 Non Pregnant –19-50: 18 mg/day Pregnant –14-50: 27 mg/day UL (based primarily on GI effects) –14-50: 45 mg/day

59. Estimated Deposition of Iron: IOM 2001 StageFetusUmbilicus and Placenta Total (mg) T125530 T27525100 T314545190 Total24575320

60. Absorbed Iron Requirements StageBasal Losses Erythrocyte Mass (mg/day) Fetus and placenta (mg/day_ Total absorbed requirement T10.8960.271.2 T20.8962.71.204.7 T30.8962.72.005.6

61. Dietary Iron Requirements During Pregnancy StageAbsorbed Iron Requirement Absorpbtion (%) Requirement (mg/day) T11.2186.4 T24.72518.8 T35.62522.4

62. US Preventative Services Task Force Prevalence: Hgb < 10 g/dl is present in 20- 40% of pregnant women, due largely to expansion of blood volume. Burden: observational data confirm modest associations between severe anemia and adverse maternal and infant outcomes. Efficacy: Trials find improved hematological indices not improved clinical outcomes

63. US Preventative Services Task Force: Iron Supplementation in Pregnancy Safety: Unintentional overdosing, hemochromatosis, GI symptoms Compliance: Prescribed Fe supps taken correctly by 70%, not at all by 10% Recommendation: Evidence is insufficient to recommend for or against routine iron supplementation during pregnancy.

64. IOM Pregnancy requires an additional 6 mg Fe/day in T2 and T3 Fe deficiency is common in pregnancy Fe supps maintain Hgb levels during pregnancy. Percentage of iron absorbed declines as the amount given increases. High does increase side effects and decrease compliance. Recommendation: Small dose (30mg) after 12 weeks for all pregnant women.

65. Cochrane Review of 20 Trials- 1999 “Iron supplementation appears to prevent low haemoglobin at birth or at six weeks post-partum.” “Iron supplementation had no detectable effect on any substantial measures of either maternal or fetal outcome.”

66. Centers for Disease Control. Recommendations to prevent and control iron deficiency in the United States. MMWR.1998;47:1-36. No conclusive evidence for benefit of universal iron supplementation Recommend 30 mg/d starting at first prenatal visit because many women have reduced Fe stores with pregnancy For Tx of low hct or hbg: 60-120 mg/d –If no response evaluate mean cell volume and serum ferritin

67. Emerging Iron Issues (Scholl, AJCN, 2005 & Rao, Semi fetal neonatal med) Oxidant Mediated Tissue Injury –Iron overload can lead to oxidative stress –Iron overload can increase risk of type 2 diabetes –Increased maternal iron stores are associated with excretion of 8-OH-dG, a marker of oxidative damage to DNA in the maternal-fetal unit.

68. Emerging Iron Issues (Zimmerman, Lancet, 2007) Selective plan breeding & genetic engineering are promising new approaches to improve dietary iron quality in populations consuming “monotonous” plant based diet.

69. Recommendations for Routine Iron Supplementation in Pregnancy

70. Zinc - Adapted from Janet King 1999 Severe maternal zinc deficiency is teratogenic in rats Zinc is available to the fetus from maternal tissues Both survey and experimental research on zinc in human pregnancy have inconclusive results due to issues of study design

71. Zinc - cont. Kirksey et al. AJCN, 1994: –Low income Egyptian women –Only 2 mg zinc available when look at phytate-zinc molar ratio –20% of variance of birthweight attributed to plasma Zn in second trimester –39% of variance of birthweight attributed to maternal weight at 3 mos. gest.... and plasma Zn in second trimester

72. Zinc Poor maternal zinc status: –limits fetal growth –influences length of gestation –increases risk of maternal complications

73. Zinc Absorption in Pregnancy (Fung et al, AJCN, 1997) Note: In 2001 IOM stated that evidence for compensatory increases in zinc absorbtion was not strong

74. Zinc Absorption Reduced by: –phytate –supplemental iron GI diseases –Crohn’s –diarrhea disease –intestinal by-pass

75. Zinc metabolism Needs increased by hepatic sequestering and increased urinary losses: –trauma –infection –smoking –alcoholism –chronic strenuous exercise

76. Cochrane Collection: Zinc& Pregnancy April, 2007 Background : low serum zinc levels may be associated with –prolonged labor –Atonic postpartum hemorrhage –PIH –Preterm labor –Post-term pregnancy

77. Cochrane Collection: Zinc 17 RCTS; >9,000 women Outcomes –Lower risk of preterm birth (RR, 0.86, 0.76- 0.98) –No consistent impact on other outcomes –The highest impact was found in studies among low-income women

78. Cochrane Collection: Zinc Conclusions: “The 14% relative reduction in preterm birth for zinc compared with placebo was primarily in the group of studies involving women of low income and this has some relevance in areas of high perinatal mortality. There was no convincing evidence that zinc supplementation during pregnancy results in other useful and important benefits. Since the preterm association could well reflect poor nutrition, studies to address ways of improving the overall nutritional status of populations in impoverished areas, rather than focusing on micronutrient and or zinc supplementation in isolation, should be an urgent priority.”

79. Zinc RDA, 2001 Increased RDA based on average daily rates of zinc accumulation in pregnancy Non-pregnant woman –19-50: 8 mg Pregnant woman –14-18: 12 mg –19-50: 11 mg

80. Calcium Fetus requires 25 to 30 g calcium Most fetal calcium accretion in third trimester Maternal absorption, increases early in pregnancy and maternal Ca stores increases in preparation for third trimester demands 1,25(OH) 2 D concentrations increase in pregnancy

81. Calcium Absorption

82. A longitudinal study of calcium homeostasis during human pregnancy and lactation (Ritchie et al, AJCN, 1998) N=14, white, middle-upper income well nourished women who consumed ~1200 g Ca daily Exams: prepregnancy T1 (8-10 weeks of pregnancy T2 (23-26 weeks) T3 (34-36 weeks) EL (6-10 weeks postpartum) 5-2 months post menses

84. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1999) Institute of Medicine (IOM Institute of Medicine (IOM Dietary calcium intake does not appear to influence changes in maternal bone mass during pregnancy There is a lack of a relationship between the number of previous pregnancies and BMD. Some studies find a positive relationship between number of children born and radial BMD, total body calcium, and risk of hip fracture.

85. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1999) Institute of Medicine (IOM Institute of Medicine (IOM “Adaptive maternal responses to fetal calcium needs include an enhanced efficiency of absorption, which is modulated through changes in calciotropic hormones. Thus, provided that dietary calcium intake is sufficient for maximizing bone accretion rates in the nonpregnant state, the AI does not have to be increased during pregnancy.”

86. Dietary calcium and pregnancy-induced hypertension: is there a relation? Ritchie LD, King, JC. Am J Clin Nutr. 2000:71(suppl):1371S-4S

87. Effect of routine calcium supplementation during pregnancy on relative risk (RR) of preeclampsia SubgroupTypical RR (95% CI) Low-risk (n = 6 trials)0.79 (0.65, 0.94) High-risk 2 (n = 4 trials)0.22 (0.11, 0.43) Adequate-calcium diet 0.86 (0.71, 1.05) (900 mg/d)(n = 4 trials) Low-calcium diet (<900 mg/d) (n = 6 trials)0.32 (0.21, 0.49) Those at high risk: teenagers, had had preeclampsia previously, had increased sensitivity to angiotension II, or had preexisting hypertension.

88. Effect of routine calcium supplementation during pregnancy on relative risk (RR) of high blood pressure SubgroupTypical RR (95% CI) Low-risk (n = 6 trials) 0.84 (0.76, 0.92) High-risk 2 (n = 3 trials)0.35 (0.21, 0.57) Adequate-calcium diet (900 mg/d) (n = 4 trials) 0.90 (0.81, 0.99) Low-calcium diet 0.49 (0.38, 0.62) (<900 mg/d) (n = 5 trials).

89. Review Conclusions “Ca supplementation during pregnancy for women with deficient calcium intake is a promising preventive strategy for preeclampsia.”

90. Emerging Issues: Calcium “There is evidence to support associations between maternal calcium intake in pregnancy and offspring blood pressure at ages 1-9.” (Bergel, BMC Pediatri, 2007)

91. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1999) Institute of Medicine (IOM) Institute of Medicine (IOM)

92. Calcium: IOM Recommendations If intake is < 600 mg: –Encourage increased dietary sources –Consider supplemental calcium

93. Cochrane Collection: Magnesium Background and objectives: Many women, especially those from disadvantaged backgrounds, have intakes of magnesium below recommended levels. Magnesium supplementation during pregnancy may be able to reduce fetal growth retardation and pre-eclampsia, and increase birthweight. The objective of this review was to assess the effects of magnesium supplementation during pregnancy on maternal, neonatal and pediatric outcomes.

94. Cochrane Collection: Magnesium Main results: Six trials involving 2637 women were included. Only one of these trials was judged to be of high quality. Compared with placebo, oral magnesium treatment from before the 25th week of gestation was associated with a lower incidence of preterm birth (odds ratio 0.71, 95% confidence interval 0.52 to 0.95). There was also less maternal hospitalization during pregnancy, fewer cases of antepartum hemorrhage, a lower incidence of low birthweight and small for gestational age infants. Poor quality trials are likely to have resulted in a bias favoring magnesium supplementation.

95. Cochrane Collection: Magnesium Reviewers' conclusions: There is not enough high quality evidence to show that dietary magnesium supplementation during pregnancy is beneficial.

96. 2004 DRI for Sodium AI for pregnancy is the same as that for non- pregnant adolescent girls and women: –Age 14-18: 1.5 g/day –Age 19-30: 1.5 g/day –Age 31-50: 1.5 g/day UL is also the same (“inadequate data to support a different intake level for Na intake in pregnant women) –Age 19-50: 2.3 g/day –> 95% of men and 75% of women exceed this level

97. 2004 DRI for Water AI based on total water (drinking water, beverages and food). Pregnant women ages 14-50: 3.0 L/day (includes ~10 cups as total beverages) Non-pregnant women aged 19-50: 2.7 L/day

98. 2004 DRI for Potassium Pregnant women have increased ability to conserve K in the face of high Na diet. Overall accretion during pregnancy is small. AI is the same as for non-pregnant: 4.7 g/day. –Current median intake in US women is 2.1-2.3 g/day. No UL is set because danger is low for healthy women during normal pregnancy.