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					Food Fortification with Micronutrients
     Needs of Food Monitoring

           Jacob Selhub PhD
        Tufts University, Boston
      Micronutrients Fortification of Staple Foods

•   Gather data
•   Identify target population
•   Identify nutrients for fortification
•   Determine potential means for distribution
•   Determine levels of enrichment
•   Establish means for monitoring
    Micronutrients Fortification of Staple Foods
        Establishing means for monitoring
Monitoring of enriched foods

•    Vitamin Mix. Easy to determine content. Micronutrients are highly
     concentrated and can easily be determined by HPLC and other
     simple methods

•    Raw food material (e.g. flour). Requires more sophisticated
     detection methodology. Need to determine endogenously containing
     micronutrients in addition to what has been added

•    Final food products (Bread, Pasta, etc). Crucial. Needs for specific
     methods is even more demanding. Must distinguish between
     incomplete extraction and destruction or loss of micronutrient during
     food processing. In pasta for example, because it is prepared by
     boiling the water and then throwing the water away, we run into
     problem of a consumption of enriched pasta which has been deleted
     of its micronutrients.
          Analysis of fortified and nonfortified breads (E. Haleva)

product              riboflavin   thiamin      Folic acid     Iron
Nonenriched Bagel    0.4          1.1          0.1            8


Nonenriched          0.34         0.8          0.1            17
Soybread


Nutrient Added       2.82         3.94         1.1            26
Baget-1              3.22         6.03         1.4            42.8
Baget 2              3.04         5.72         1.2            41.3
Rye bread-1          3.06         3.68         0.9            45.3
Rye bread -2         2.86         3.24         1.05           44.4
Pompornikel bread-   3.1          4.04         0.96           38.5
1
Pompornikel bread-   3.02         3.76         0.99           39.4
1
Russian bread-1      2.98         3.36         0.91           33.7
Russian bread-2      2.96         3.68         0.96           43.2
Light soy bread-1    3.44         4.6          1.13           53.5
Light soy bread-2    3.38         4.14         1.27           54.8
Farmer,s bread1      3.42         4.56         0.88           46.1

Farmer’s bread -2    3.52         4.3          1.1            47.7
   Analysis of fortified bread for micronutrients
     (Dr E Haleva, Israel Health Ministry)

                      Composition
Nutrient    Mix      100gFlour 100gBread 100gBread
                      (15.6mg    (Endogenous (measured)
                        mix)      +Fortified)
  Niacin    29.96%     4.67mg      2.80mg        ND
 Thiamin     3.74%    0.583mg     0.505mg      0.441
Riboflavin 2.54%      0.396mg     0.324mg      0.313
Folic Acid 0.99%      0.154mg     0.120mg     0.110mg
   B12     0.0067%       1ug       0.65ug       0.12-
                                              0.470ug
  Iron     25.70%     4.009mg      4.1mg       4.1mg
       Impact of Folic Acid Fortification on Plasma Folate Distribution in the
           Framingham Offspring Cohort (Jacques et al, NEJM 1999)

              0.5                               0.5

                                                                                Pre
                                                0.4
                                                                                Post
              0.4
                                                0.3


              0.3                               0.2


                                                0.1
              0.2
                                                0.0
                                                   0   10   20   30   40   50    60    70

              0.1


              0.0
                 0        10        20     30          40 50                    60          70
                                       Plasma Folate (ng/mL)
From Jacques et al NEJM 1999;340:1449-54
                                Folic Acid Fortification
                         in the Framingham Offspring Cohort
                                 From Jacques et al NEJM 1999;340:1449-54




                                     No Supplement Use                      Supplement Users

                                        Pre               Post                Pre         Post

                                                      Plasma folate, ng/mL

    Exam 5                              4.6                4.6              11.4          11.7
                                     (4.4-4.8)          (4.3-4.9)        (10.5-12.4)   (10.4-13.1)

    Exam 6                              4.8              10.0*†             14.1†         18.9*†
                                     (4.6-5.1)         (9.3-10.7)        (13.1-15.2)   (17.0-20.9)


   * pre - and post- fortif ication groups significa ntl y differe nt ( p<0.01).
   † ba seline a nd follow-up v alue s si gnificantly differe nt (p<0. 01).




From Jacques et al NEJM 1999;340:1449-54
                            Folic Acid Fortification
                     in the Framingham Offspring Cohort



                                           No Supplement Use                   Supplement Users

                                              Pre            Post               Pre        Post

                                                    Plasma folate <3 ng/mL (%)

      Exam 6                                20.7             1.7*†               0.9         0.0
                                         (18.2-23.2)       (0.0-5.4)          (0.0-5.0)   (0.0-5.9)


     * pre- and post-fortification groups significantly different (p<0.01).
     † baseline and follow-up values significantly different (p<0.01).




From Jacques et al NEJM 1999;340:1449-54
      Impact of Folic Acid Fortification on Plasma Homocysteine Distribution in the
                             Framingham Offspring Cohort

                            0.4                  0.4



                                                 0.3
                                                                           Pre
       Relative Frequency




                                                                           Post
                            0.3
                                                 0.2



                            0.2                  0.1



                                                 0.0
                                                    0   5   10   15   20   25   30   35
                            0.1


                            0.0
                               0   5   10    15     20     25                   30        35
                                         Homocysteine (umol/L)
From Jacques et al NEJM 1999;340:1449-54
Folic Acid Fortification in the Framingham Offspring Cohort.
          Effect on the Prevalence of Elevated tHcy
                 (From Jacques et al NEJM 1999;340:1449-54)



         No Supplement Use             Supplement Users

                     Elevated tHcy (>13umol/L)

          Pre            Post           Pre             Post

          21.0            9.8*†         4.2              7.8
       (18.2-23.8)     (5.6-14.0)    (0.0-8.9)       (1.2-14.3)
    Placebo-Controlled Intervention with B Vitamins and Iron-fortified Bread
                     in Helathy Israeli Women Volunteers
                Gabriel Levy S, Kaluski- Nitzan D, ,Selhub J Mekori Y.
     Tel Aviv university- Tel Aviv, Ministry of Health-Jerusalem , Tufts university-
                       Boston, Meir general hospital- Kefar Sava


• Objective: To investigate the effects of fortified bread consumption on B-
  complex and iron status.

• Design: Single-blinded, randomized placebo- controlled intervention trial.

• Subjects: 246 women employee at "Meir" hospital.

• Duration: 6 weeks.

• Intervention: Daily consumption based on the usual consumption, of
  unfortified bread (placebo) or fortified (per 100g flour) with 140 ug folic acid,
  1 mcg vitamin B12 and 4.4 mg iron plus other vitamins (niacin, riboflavin and
  thiamine). Food Frequency Questionnaires were usded to assess the dietary
  intake. The consumption of other commercially fortified grain products were
  avoided.
Vitamins, homocysteine and ferritin levels before and after six
     Weeks intake of enriched bread vs placebo control
plasma concentration      group       baseline         after        mean         p
                                                   intervention   difference


                         Placebo      8.9 ±0.4      9.7 ± 0.6        0.5
   Folate (ng/ml)                                                              *0.036
                       Experimental   8.6 ± 0.4      9.9 ±0.5        1.2

                         Placebo      419 ±11.7     455 ±14.2       33.6

 Vitamin B12)pg/ml(                                                            *0.023
                       Experimental   415 ±13.8     478 ±15.8       60.7

                         Placebo      7.7 ±0.2      8.0 ±0.24       0.37
  tHcy ( nmol/ml)                                                              0.183
                       Experimental   7.6 ±0.22     7.8 ± 0.23      0.13

                         Placebo      35.7 ± 2.8    31.5 ±2.6       - 3.1      0.191
  Ferritin (ng/ml)
                       Experimental   29.3 ±1.7     26.2 ±1.6        -2.2
Effect of 6 weeks intake of enriched bread on plasma
Homocysteine (tHcy) levels in women with an initial
                      tHcy >11


    plasma           group        baseline        after       p
 concentration                                intervention


                    Placebo
                                 12.4 ±0.41   11.8 ±0.79
                     N=11
 tHcy (nmol/ml)                                              0.003
                  Experimental
                                 13.9 ±0.81    10.5 ±0.90
                     N=15
      Results of the 6 weeks intervention of plasma ferritin
      among women volunteers with ferritin concentration<11 ng/ml



   plasma         group       baseline       after      mean        p
concentration                            intervention Difference

                  Pacebo     9.5 ±0.57    8.8 ±0.90     -0.26
  Ferritin         N=43
                                                                   0.037
  (ng/ml)       Experimental 9.7 ±0.63    12.8 ±1.5     +3.34
                   N=40
     Proposal for Estimation of Dietary and Nutrient Adequacy
 of Palestinian Communities residing in the West Bank and Gaza in
      Support of the Introduction of Wheat Flour Fortification

Consortium lead investigators: Jacob Selhub, PhD – Tufts University;Ziad
   Abdeen PhD, – AlQuds University;
 Drora Fraser, PhD – Ben Gurion University
Co-investigators:
Irwin H Rosenberg, MD,Aron Troen DPhil, Paul F Jacques, ScD – Tufts
   University
Radwan Qasrawi, PhD – AlQuds University
Natalya Bilenko, M.D. – Ben Gurion University

Initial Funding: MOST/USAID
MOST/USAID representative: Dr Omar Dary
        Proposal for Estimation of Dietary and Nutrient Adequacy
    of Palestinian Communities residing in the West Bank and Gaza in
         Support of the Introduction of Wheat Flour Fortification

•      To establish a representative baseline of the micronutrients status
       of those segments of population who are at risk of micronutrient
       insufficiency. These include: a) children aged 4-7 years, b) non-
       pregnant women of child bearing age, (age 15-49), and c) older
       adults over the age of 60 years; in regionally representative
       populations drawn from the Nablus region, the Hebron region and
       the Gaza region.

•      This baseline will provide the basis for the future assessment of the
       impact of this fortification on the said population

•      The design of this study should provide a model for other countries
       who are planning fortification of their staple foods with
       micronutrients.
    Proposal for Estimation of Dietary and Nutrient Adequacy
of Palestinian Communities residing in the West Bank and Gaza in
     Support of the Introduction of Wheat Flour Fortification
Sample Estimate
For folate, 300 subjects per group will be needed to detect a 15% increase,
   180 subject for a 20% increase, 120 subjects for a 25% increase, 55
   subjects for a 40% increase and 38 subjects for a 50% increase.
For vitamin B12, 170 subjects per group will be needed to detect a 15%
   increase, 95 subject for a 20% increase, 60 subjects for a 25% increase, 25
   subjects for a 40% increase and 20 subjects for a 50% increase.
For ferritin, 35 subjects per group will be needed to detect a 15% increase, 20
   subject for a 20% increase, and only 15 subjects for a 25% increase.


In order to be conservative in our estimates, we propose a study size of
    approximately 210 subjects per group (70 per region per age
    group), for a total of 630 subjects in the three regions. This will also
    allow for stable estimates of all but the more extreme percentile
    estimates for the distribution of these biomarkers.
                              Specific Aims:
Phase 1 – baseline sampling to be completed prior to the implementation
                   of fortification in September 2005


1. To collect baseline blood samples and data on pre-fortification
    micronutrient intake including:
    – Demographic information on participating households
    – Food intake data as assessed by a 24 hr recall questionnaire which
        was adapted for the Palestinian population and used in previous
        surveys in the West Bank and Gaza
    – A blood sample of 5-8mL (5 mL for children, 8 mL for adults)
        collected in metal-free test tubes, and separated into plasma and
        RBC fractions.

2. To calculate bread and flour consumption and micronutrient intake
    from 24 hour recall dietary intake questionnaires using the SurveyNet
    and the SR-17 database in the format of previous dietary surveys
    conducted in recent years by Al Quds University (see appendix).
                            Specific Aims:
                    Phase 2 – baseline blood analysis


3. To analyze the collected samples for hematocrit and the determination
   of the following analytes, by the following methods that are routinely
   used in our laboratories:
    – Plasma ferritin by ELISA
    – Plasma iron and zinc by atomic absorption
    – Folate and B12 using Immulite 1000
    – Homocysteine by HPLC
    – Plasma vitamin A by HPLC
    – Plasma 25-hydroxy D by HPLC
    – Plasma PLP (B6) by radioenzymatic assay
    – B1 and B2 by determining respective activity coefficients for
       erythrocyte transketolase and glutathione reductase
                          Specific Aims:
               Phase 3 – Post fortification follow up

4. To utilize the same organization one year after the implementation of
    fortification, for the collection of post-fortification data from the same
    three regions and to the extent possible from the same individuals (not
    receiving food aid from WFP or UNRWA), which include:
• Demographic information on participating household.
• Food intake using 24 hour recall questionnaires
• Blood samples

• 5. To assess effects of fortification on micronutrients status by
  comparing blood micronutrients levels before and after fortification
  after adjusting for possible changes in demographic status and food
  intakes.

• 6. To construct a generalized working model for assessing impact of
  fortification in other regions of the world.
    Micronutrients fortification. Monitoring
                    efficacy
Monitoring Risks and Benefits.
Establishing baseline to determine clinical efficacy is much
  more difficult.
Must rely on comparison with historical data; e.g. Since
  folate fortification, NTD affected births in the US dropped
  20% and there are some suggestions that stroke incidence
  declined during the same period.
However monitoring must also cover new trends and risks in
  the population
Dietary Folate and Vitamin B12 Intake and Cognitive
Decline Among Community-Dwelling Older Persons
      Morris et al. Arch Neurol. 2005;62:641-645

   Objective: To examine the association between
   rates of age-related cognitive change and dietary
              intakes of folate and vitamin
    Differences in the Rate of Cognitive Change (b) in elderly over 65 years old,
    During 6 Years by Dose Level of Folate Vitamin Supplementation, Chicago
                Health and Aging Project, 1993-2002 (Morris, 2005)




 Folate Supplement   No. of Patients    Age-Adjusted Model*      Multiple-Adjusted Model*
     Dose, µg/d                        b (SE)         P Value      b (SE)       P Value


       1-200              224          -.01 (.01)      .39      -.01 (.01)        .25

      201-399             303          -.01 (.01)      .39      -.01 (.01)        .18

        400               380          -.004 (.01)     .61      -.01 (.01)        .22

     401-1200             270          -.02 (.01)      .01      -.03 (.01) .      .001


*Age-adjusted model includes age, quintiles of folate intake, time, and time interactions
with age and quintiles of folate intake.
*Multiple-adjusted model includes terms from the age-adjusted model plus sex, education,
race, vitamin E intake from food, total vitamin C intake, and time interactions with
all covariates. The model for folate intake from food sources also includes terms for
multivitamin use (yes or no).
  NK cytotoxicity across tertiles of folate or folic acid, stratified
                   by age (Troen et al, submitted)

                          All women                  Age 50-59                   Age 60-75
                       Differenc             N    Difference      P-           Difference
pmol/mL           N                P-value                                N                  P-value
                         e (β)                        (β)        value             (β)
Folic Acid
       0 – 1.7    34     Ref.         Ref.   17      Ref.        Ref.     17      Ref.        Ref.
     1.8 – 3.0    38     -2.30        0.43   23     -3.10        0.40     15     -9.13        0.07
          3.0 +   33     -5.12        0.09   20     -2.96        0.36     13     -12.83       0.001
     (p-trend)                     (0.09)                        (0.38)                      (0.002)
5-Methyl-
THF
      0 – 31.9    35     Ref.         Ref.   19      Ref.        Ref.     16      Ref.        Ref.
   32.0 – 51.9    37     -2.90        0.30   25     -6.00        0.04     12     -3.63        0.57
       52.0 +     33     4.48         0.17   16      2.55        0.48     17     -0.19        0.98
     (p-trend)                     (0.25)                        (0.50)                      (0.79)
NK cytotoxicity across tertiles of folate or folic acid, stratified
                 by age (Troen et al, submitted)

                        All women                  Age 50-59                 Age 60-75

                     Differenc             N    Difference      P-          Difference    P-
pmol/mL         N                P-value                               N
                       e (β)                        (β)        value            (β)      value

Total Folate

     0 – 34.9   31     Ref.       Ref.     16     Ref.         Ref.    15     Ref.       Ref.
  35.0 – 53.9   40     -4.86      0.09     27     -8.09        0.02    13     -5.05      0.43
      54.0 +    34     2.90       0.39     17     0.63         0.86    17     -0.52      0.93
                                                               (0.6)                     (0.66)
    (p-trend)                    (0.47)
  . Natural killer cell cytotoxicity among women age 60-75, stratified by the
presence of unmetabolized plasma folic acid (adjusted means + SE at effector-
                         to-target ratios 25:1 and 12.5:1)
                            35
                                                                           NK 25:1
  % Cytotoxicity (+/- SE)


                            30
                                                                           NK 12.5:1
                            25
                            20
                            15
                            10
                             5                                        P trend =0.004
                             0
                                   0-1.7      1.8-3.0       >3.1
                                 Unmetabolized Folic Acid (pmol/mL)
          Micronutrients Fortification

• In the design of a fortification program it is
  important to include means of monitoring and
  evaluation to insure effectiveness and efficacy and
  for the assessment of potential benefits and risks

				
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