Micronutrients

2011

Micronutrient Status

• Important throughout the reproductive years:– Periconceptual period– Pregnancy– Lactation– Inter-pregnancy interval

Multiple Micronutrient Deficiencies Occur with Poor Diets

• Usually not isolated deficiencies

• Nutrients deficiencies interact: example vitamin A supplements can decrease rates of iron deficiency anemia in some populations.

Vitamins and Minerals

• Risks for low vitamin and mineral status include:– low income– restricted energy intake– adolescence– vegan (Calcium, B12, D, zinc)– Non white status (Calcium)

Vitamins and Minerals

• Vitamin and mineral needs are increased by:– alcohol consumption– tobacco use– multiple fetuses

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 B6

• Folate

*for adolescent and adult women of reproductive age

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

Vitamins and Minerals

• Increased needs in pregnancy associated with:– DNA/RNA synthesis– Increased blood volume– bone mineralization & structure– Increased energy metabolism

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 2008

Cochrane: Multiple-micronutrient supplementation for women during pregnancy, 2006

• Nine trials (15,378 women): Bangladesh, Nepal, Zimbabwe, Chicago, Guinea-Bissau, Pakistan, Tanzania, Mexico.

• When compared with supplementation of two or less micronutrients or no supplementation or a placebo, multiple-micronutrient supplementation resulted in a statistically significant decrease in the number of low birthweight babies (relative risk (RR) 0.83; 95% confidence interval (CI) 0.76 to 0.91), small-for-gestational-age babies (RR 0.92; 95% CI 0.86 to 0.99) and in maternal anaemia (RR 0.61; CI 0.52 to 0.71).

Just Iron and Folic Acid?

• “these differences lost statistical significance when multiple-micronutrient supplementation was compared with iron folic acid supplementation alone.”

• Further research: 1) beneficial maternal or fetal effects and 2)assess the risk of excess supplementation and potential adverse interactions between the micronutrients.

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

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.

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

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

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

Vitamin A RDA - 2001

• Non Pregnant = 700 g 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

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 gIU)/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

Vitamin D DRI: 2010

• RDA for pregnant and non- pregnant women ages 19-30 = 600 IU/day

• Population goal: mean 25 OHD levels above 50 nmol/L (20 ng/mL)

• “This thorough review found that information about the health benefits beyond bone health- benefits often reported in the media – were from studies that provided often mixed and inconclusive results, and could not be considered reliable.”

Tolerable Upper Limit

• Upper level intake = 4,000 IU/day• “starting point of 10,000 IU/day reflects first

data concerning adverse effects related to all-cause mortality, falls and fractures, and CVD risk.”

• “Intake values in the range of 4,000 IU/day would not appear to cause serum 25OHD levels to exceed 125 to 150 nmol/L, a concentration which is at the high end of the range of serum levels associated with nadir risk of outcomes such as all-cause mortality.”

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

Vitamin D inadequacy in pregnancy: biology, Outcomes,

and interventions. Dror and Allen, Nutr Rev. 2010

• Some evidence for role of vitamin D in: fetal brain development, fetal bone mineralization, immune function.

• Potential long term impact of fetal vitamin D exposure from epi studies of birth season: diabetes, MS, some cancers, schizophrenia.

• Previous findings of supravalvular arotic stenosis with high vitamin D related to exaggerated response of those with Williams Syndrome to oral vitamin D supplements.

Vitamin D: Emerging Understandings

• Widespread deficiencies

• Disparities

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.

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 conc1

25(OH)D deficiency2,3

25(OH)D under the detection

limit3,4

n (%) n (%)

Western (reference) (n = 105)

52.7 ± 21.65 8 (8) 1 (1)

Turkish (n = 79) 15.2 ± 12.16 66 (84)6 17 (22)6

Moroccan (n = 69) 20.1 ± 13.56 56 (81)6 3 (4)

Other non-Western (n = 105)

26.3 ± 25.96 62 (59)6 9 (9)7

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

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

Prevalence of Vitamin D Deficiency% Insufficient % Deficient

White Infants 42 10

White Mothers 56 5

Black Infants 47 29

Black Mothers 51 46

Prevalence of Vitamin D Insufficiency & Clinical Associations among Veiled E African Women in

WA Reed. J women’s health, 2007

• N=75, All had low 25(OH)D, study done in Seattle in March and April

Reed, et al.

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).”

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.”

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

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

• (Note: High maternal vitamin C levels associated with false positive tests for urinary glucose as well as cramps, nausea, and diarrhea).

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

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

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).”

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).”

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.”

Combined vitamin C & E supplementation during pregnancy for preeclampsia prevention:

Cochran, 2007

• 4 RCTs, n=4680• All trials: vitamin C dose = 1,000 mg, vitamin

E dose 400 mg• “Combined vitamin C and E supplementation

during pregnancy does not reduce the risk of preeclampsia, foetal or neonatal loss, SGA, or pre-term birth.”

• Combined vitamin C and E supplementation should be discouraged

Cochrane, Vitamin C & E Supplementation

Intervention Control

Fetal/neonatal loss

2.6% 2.3%

SGA 20.6% 20%

Pre-term 19.5% 18%

Water Soluble Vitamins - B6

• 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

B6 – adverse effects

• Inconclusive studies of toxicity have linked to:– Congenital defects

– B6 dependency

– Antilactogenic effects

UL for B6

• UL for non-pregnant adults = 100 mg/day

• UL for pregnancy– 14-18: 80 mg/day– 19 and older: 100 mg/day

Pyridoxine (vitamin B6) supplementation in pregnancy

(Cochran, 2006)

• Five trials (1646 women)

• “There is not enough evidence to detect clinical benefits of vitamin B6 supplementation in pregnancy and/or labour other than one trial suggesting protection against dental decay.”

Folic Acid - NTD• NTD - 2,500 births per year in US; 1/1000 births

• 50-70% may be preventable with adequate maternal folic acid status.

• NTD etiologies and folic acid pathways may be multiple mechanisms:– Main function of folate is participation in one-carbon

transfers, important in methylation rx and purine/pyrimidine synthesis, regulation DNA synthesis & function; affects important events in embryogenesis

Risk of NTD is Higher With

• Maternal obesity /diabetes

• Hx of previous child or relative with NTD

• In Hispanic & non-Hispanic whites compared to black and asian

• Use of some antiseizure meds (valproic acid, carbamazepine)

Folic Acid - Recommendations

• 1992 - USPHS: 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.

• May, 2009 – USPSTF “recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 of folic acid.”

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.

Neural tube defect rates per 10,000 population, by race/ethnicity and fortification period status --- National Birth Defects Prevention Network, 1995--2007

MMWR. August 13, 2010 / 59(31);980-984

After mandatory fortification began in 1998, NTD prevalence declined 30%–40% among the three largest racial and ethnic groups.

Folate Status in Women of Childbearing Age, by Race/Ethnicity:

MMWR, January 2007

                                                                                

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

• Recently, 5-methyl-tetrahydrofolate (5-MTHF) has been proposed as an alternative to folic acid supplementation .

Cochrane, 2010: Effects and safety of periconceptional folate supplementation

for preventing birth defects –

• 5 trials, 6105 women (1949 hx of NTD)• protective effect of daily folic acid

supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52.

MMWR - Knowledge and use of folic acid, Annual Reports from March of Dimes Gallup

Survey1995 1997 2003 2004 2005 2007

Taking FA 25% 30% 32% 40% 33% 40%

Aware of FA 52% 66% 79% 77% 84% 81%

Know that FA prevents birth defects

5% 11% 21% 24% 25%

Know that FA should be taken before pregnancy

2% 6% 10% 12% 7% 12%

http://www.cdc.gov/datastatistics/2008/folicacid/

Racial/Ethnic Differences in the Birth Prevalence of Spina Bifida --- United States,

1995—2005 (MMWR, 2009)

• “Additional public health efforts targeting women with known risk factors (e.g., obesity and certain genetic factors) likely are needed to further reduce the prevalence of spina bifida in the United States.”

• Hispanic and non-Hispanic black women are less likely to consume supplements with folic acid than non-Hispanic white women.

• Hispanic women have a 15%-25% higher rate of pregnancies affected by neural tube defects than women of other races and ethnicities.

http://www.cdc.gov/features/folicacid/

Additional Opportunities to Prevent NTD with Folic Acid Fortification – MMWR –

August 2010

• Most concerns re excess intake of folic acid associated with excessive supplement use rather than fortification.

• Hispanic women may need additional folic acid:– Consider fortification of corn masa flour

"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%). • Among women who reported not consuming a

vitamin or mineral supplement daily, 31% indicated they had received a doctor's recommendation.

Remember to take folic acid every day:

Do it with another daily activity such as: •Brushing your teeth •Having breakfast •Getting ready to go to bed

Place your vitamins where you can see them: •In your purse •On your desk •On the kitchen counter

http://www.cdc.gov/features/folicacid/

Emerging Issues: Is it more than folate?

• NTD and B12 (Ray, Epidemiology, 2007)

– In the presence of folate fortification, women with the lowest B12 status have 190% increased risk of NTD compared to those with the highest B12 status

Copyright ©2009 The American Society for Nutrition

Zeisel, S. H Am J Clin Nutr 2009;89:673S-677S

FIGURE 1 Choline and folate metabolic pathways intersect

Choline too…

• Major source of methyl groups in the diet• Critical during fetal development

– Stem cell proliferation & apoptosis– Alters brain and spinal cord function/influences

risk of NTD & lifelong memory– Low choline diet increases risk of NTD– Helps maintain normal homocysteine

concentrations (high hcy associated with NTD)

Zeisel. Ann Rev Nutr. 2006

Pre- and Postnatal Health: Evidence of Increased Choline Needs (Caudill, JADA 2010)

• Human fetus receives large amount of choline during gestation

• In animal models pregnancy depletes hepatic choline

• Neonates have blood choline levels three times higher than maternal levels

• Majority of pregnant/lactating women not consuming recommended levels.

• Prenatal vitamins have no choline

Funded by Egg Nutrition Center & National Cattlemen’s Beef Association

Single Carbon Metabolism: Zeisel AJCN Supplement, 2009

• Significant proportion of population consuming low levels of folate and choline

• Could result in altered methelation & related epigenetic effects on gene expression

• Infant not protected from inadequate intake of mother

• Research needs before routine supplementation: – Impact of common genetic variants on nutrient

requirements– Risk of excessive intake/supplementation

Iron

• General statements

• RDA

• Routine Supplementation

• Treatment for Iron Deficiency Anemia

• Emerging Issues

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

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

Estimated Deposition of Iron: IOM 2001

Stage Fetus Umbilicus and Placenta

Total (mg)

T1 25 5 30

T2 75 25 100

T3 145 45 190

Total 245 75 320

Absorbed Iron Requirements

Stage Basal Losses

Erythrocyte Mass (mg/day)

Fetus and placenta (mg/day_

Total absorbed requirement

T1 0.896 0.27 1.2

T2 0.896 2.7 1.20 4.7

T3 0.896 2.7 2.00 5.6

Dietary Iron Requirements During Pregnancy

Stage Absorbed Iron Requirement

Absorpbtion (%)

Requirement (mg/day)

T1 1.2 18 6.4

T2 4.7 25 18.8

T3 5.6 25 22.4

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

US Preventative Services Task Force: Iron Supplementation in

PregnancySafety: 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.

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.

Cochrane 2010: Effects and safety of preventive oral iron or iron+folic acid supplementation for

women during pregnancy

• 49 trials; 23,200 pregnant women• daily iron supplementation associated with increased

haemoglobin levels in maternal blood both before and after birth & reduced risk of anaemia at term– no difference between women receiving intermittent or daily

supplementation

• Side effects and haemoconcentration (a haemoglobin level greater than 130 g/L) were more common among women who received daily iron or iron+folic acid supplementation than among those who received no treatment or placebo.

Author’s Conclusions:

• Prenatal supplementation with iron or iron+folic acid provided either daily or weekly is effective to prevent anaemia and iron deficiency at term

• No evidence of reduction in substantive maternal and neonatal adverse clinical outcomes (low birthweight, delayed development, preterm birth, infection, postpartum haemorrhage)

• Side effects & may suggest the need for revising iron doses and schemes of supplementation during pregnancy

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

Yes No Maybe Not enough evidence

IOM - NAS (1990)

Nat'l Perinatal Epi Proj. - Oxford

US Surgeon General (1988)

US preventive Services Task Force (1993)

FASEB (1991)

USPHS Ex. Panel on Prenatal care (1989)

Cochran Review (1999)

CDC (1998)

Recommendations for Routine Iron Supplementation in Pregnancy

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.

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

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

Zinc

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

Zinc Absorption in Pregnancy(Fung et al, AJCN, 1997)

Dietary Znmg/day

%absorbed

Amountabsorbedmg/d

Pre-pregnancy

9.7 14.6 1.4

24-36weeks

11.8 18.9 2.2

34-36weeks

12.4 19.4 2.4

Note: In 2001 IOM stated that evidence for compensatory increases in zinc absorbtion was not strong

Zinc Absorption

• Reduced by:– phytate– supplemental iron

• GI diseases– Crohn’s– diarrhea disease– intestinal by-pass

Zinc metabolism

• Needs increased by hepatic sequestering and increased urinary losses:– trauma– infection– smoking– alcoholism– chronic strenuous exercise

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

Cochrane Collection: Zinc Supplementation

• 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

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.”

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

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 increase in preparation for third trimester demands

• 1,25(OH)2D concentrations increase in pregnancy

Calcium Absorption

Stage Absorption

Non- pregnant 27%

5-6 months ofpregnancy

54%

Term 42%

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

Total BodyBMD (g/cm2)

TrabecularBMD (mg/ cm3)

Prepregnancy 1.156 162.9

Postdelivery 1.162 163.7

EL 1.153 147.7

Postmenses 1.143 164.3

Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and

Fluoride (1999)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.

Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and

Fluoride (1999)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.”

Cochrane, 2006: Ca supplementation during pregnancy for preventing hypertensive disorders

and related problems

• 12 studies• “Ca supplementation appears to almost halve

the risk of pre-eclampsia and to reduce the rare occurrence of the composite outcome “death or serious morbidity. There were not other clear benefits or harms.”

• Effect greatest for high risk women and those with low Ca intake.

Effect of routine calcium supplementation during pregnancy on relative risk (RR) of preeclampsia

Subgroup Typical RR (95% CI)

Low-risk (n = 6 trials) 0.79 (0.65, 0.94)

High-risk2 (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.

Ritchie LD, King, JC. Am J Clin Nutr. 2000:71(suppl):1371S-4S

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)

Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and

Fluoride (1999)Institute of Medicine (IOM) 2010 non-

pregnant 2010 Pregnant

1999 non-pregnant

1999 pregnant

1989 RDA

Calcium (mg)

1000 (RDA) 1000 (RDA) 1000 (AI) 1000 (AI) 1200

Phosphorus (mg)

700 (RDA) 700 (RDA)

1200

Magnesium (mg)

310 (RDA) 350 (RDA)

320

Vitamin D

600 (RDA IU) 600 (RDA, IU)

5 (mcg, AI) 5 (AI) 10

Fluoride (mg)

3 (AI) 3 (AI) none

Recommended Intakes

2010 non-pregnant

2010 Pregnant

1999 non-pregnant

1999 preg. 1989RDA

Calcium(mg)

1000 (RDA) 1000 (RDA) 1000 (AI) 1000 (AI) 1200

Phosphorus(mg)

700 (RDA) 700 (RDA) 1200

Magnesium(mg)

310 (RDA) 350 (RDA) 320

Vitamin D 600 (RDA, IU) 600 (RDA, IU) 5 (mcg, AI) 5 (AI) 10

Fluoride(mg)

3 (AI) 3 (AI) none

1 mcg vitamin D = 40 IU

Calcium: IOM Recommendations

• If intake is < 600 mg:– Encourage increased dietary sources– Consider supplemental calcium

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.

Cochrane : Magnesium

• 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.

Cochrane Collection: Magnesium

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

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

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

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.