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									J N Medical College Belgaum Karnataka India
        Effect of Zinc Supplementation
During Complementary Feeding on Growth And
 Neurodevelopment –A Double Blind Placebo
                Controlled Trial

    Dr Roopa Bellad
    Dr Preeti Amarkhed
    Dr N S Mahantshetti
    Department Of Pediatrics
    J N Medical College,
    Belgaum
                      Introduction
•   Zinc -Critical for normal growth & development

•   Requirements in the first 6 months-from Breast Milk

•   Zinc status –beyond 6 months –marginal

•   Choice of complementary food -important to maintain
    adequate zn status

•   Traditional complementary foods –cereal based-low in
    bioavaiable Zn
                    Introduction
•   Developing countries -30%- 50% - low Serum &
    plasma levels of Zn.

•   Zn supplementation –Important strategy
    to meet the Zn requirements –particularly in

•      less protected environment with
•      high infectious burden
•      limited dietary options
                 Need For The Study
•    Studies on effect of zinc supplementation
                    Preterm,
                    Low birth weight /stunted infants
                    Results –inconclusive
•   Hence the present study was planned.
             Healthy ,Exclusively breast fed
             Term
             >2.5 Kg
             During complementary feeding
                     Objectives
Primary Objective
•   To determine the effect of zinc supplementation on
    linear growth and neurodevelopment.


Secondary Objectives
•   Morbidity from diarrhea and ARI

•   Estimation of serum zinc levels
               Materials & Methods
Study design
• One year double blind randomized controlled trial.
Source of data
• EBF healthy term babies, B.wt ≥ 2.5kgs visiting Well
  Baby Clinic of Pediatric OPD at KLES Hosp , Belgaum
            Materials & Methods
Sample Size
• 200 (100 each group)
  with α = 0.05
       Power - 80%
       20% drop out rate.

Randomization
• Using computer generated randomization test with
  block length of 100.
                   Selection Criteria
                          .
Inclusion criteria
Healthy term babies

Birth weight ≥ 2.5 kgs

Exclusively Breast Fed
          Exclusion Criteria
• Preterm / IUGR babies
• Top fed babies
• Metabolic or neurodegenerative
    diseases.
•   Congenital malformations (Cleft lip
    palate, CHD).
•   Severe or protracted illness in the past.
                Study plan
• Informed consent
• IRB approval
• Enrollment
      -5mths
     - Counseling -complementary feeding-as per
           National infant and young child feeding
           guidelines
     - Demographic & feeding practices data
      recorded
     - Randomization
      -Calendar to mark each day that the drug was
      administered
                    Intervention
•   Interventional group
     Zinc gluconate(syrup) 10mg /day
     2.5ml/day OD for 180 days(6-12 months)

•   Control group
     Placebo (sugar syrup )
     2.5ml/day OD for 180 days.
                     Follow ups
Three visits
•   6 /9/12/months
At each visit
 Anthropometry
 Number of episodes of diarrhea & ARI
 Review & Re enforcement of complementary feeding
 BDST                           at 12 months
 Serum Zn level estimation
 calendars were reviewed -the number of days that the
    drug doses were missed recorded.
           Outcome Measures

Anthropometric
measurements
•Weight
•Length
    knee heel length
    Crown heel

•Head circumference
               Outcome measures
•   Neurodevelopment:
     By BDST scale
     No of infants achieving each of the key milestones in
     both the groups were compared.

•   Morbidity data
     Number of episodes
          Acute respiratory infection
          Acute diarrhea
•   Serum zinc level estimation:
     By atomic absorption Spectro photometry
              Statistical analysis
•   Means in both groups were compared by paired
    students t test

•   Effect sizes-growth outcome-0.2 –large
    0.8 moderate

•   Effect of variables onstudy outcomes – Multiple
    logistic regression analysis

•   The incidence of ARI and diarrhea in the two groups
    was compared with Chi square test.
RESULTS
    Follow ups
Total -100 in each group
                          Interventional   Controls
          Parameters
                          No        %      No    %
    EDUCATION OF MOTHER
G
E   Illiterate             64      64.0%   57   57.0%

N   Primary                29      29.0%   33   33.0%

E   Secondary               5      5.0%    8    8.0%
R   Graduates               2      2.0%    2    2.0%
A   SOCIO ECONOMIC STATUS
L   Class I                 06     6.0%    05    5.0%

    Class II                33     33.0%   35   35.0%
D   Class III               53     53.0%   41   41.0%
A   Class IV                08     8.0%    19   19.0%
T   BIRTH WEIGHT
A   2.5 – 3 kgs             72     72.0%   63   63.0%
    3 - 3.5 kgs             24     24.0%   34   34.0%

    > 3.5 kgs               4      4%.0    3     3.0%

    DURATION OF BREAST FEEDING
    <12 months              85     94.4%   77   98.7%
    12 months               75     83.3%   65   83.3%
             Complementary Feeding
                                          Interventional    Controls
   Age
             Complementary Feeds
(in mths)
                                          No       %       No    %

            a) Type        Rice ganji      75    82.40%    65   80.20%


 6 to 9     b) Frequency   2 times         59    64.83%    50   61.72%


            c) Quantity    ¼ wati          54    59.30%    46   56.70%

                                           50
            a) Type        Rice and dal          55.50%    39   50.00%

                                           68
9 to 12     b) Frequency   3 times               75.5%     52   66.60%


            c) Quantity    ½ wati          48    53.3%     44   56.4%


     Time of iniation-6months
     97% -vegetarian diet
   Consumption Of The Supplement
180days
• Interventional   77.8%
• Control groups   89.7%,

< 180 days
• Interventional 22.2%
• Control groups 10.3%
 No statistically significant difference between the
                         groups.
Other Supplements
                 Anthropometry
Weight

                    Control       Interventional
      Visits                                       Total   ‘p’ value
                 Mean    S.D.     Mean    S.D.

     1st visit   7.05    ± 0.93   7.09    ± 0.78    196      0.751


     2nd visit   8.68    ± 1.32   8.76    ± 0.88    172      0.647


     3rd visit   10.13   ± 1.06   10.73   ± 0.96    168     *0.040


   The mean weight gain 3.71 ± 0.65 Vs 3.12 ± 0.57
   Effect size of 0.5906 (95% CI of 0.4028 – 0.778,
   p < 0.0001).
              Weight for age –Boys




-------Interventional
---------Control
      Weight for age –Girls




--------Interventional
------Control
                 Length


                Control        Interventional
  Visits                                        ‘p’ value
              Mean    S.D.     Mean    S.D.

  1st visit   65.48   ± 6.11   65.88   ± 3.42     0.575

  2nd visit   67.55   ± 6.39   68.00   ± 3.31     0.555

  3rd visit   68.63   ± 9.64   70.57   ± 3.36    0.046*


 Mean length gain 4.89 ± 1.68 Vs 4.05 ± 0.97
 Effect size of 0.8373
(95% CI of 0.4088 – 1.2659, p - 0.0002).
 Length for age –Boys




--------Interventional
------Control
 Length for age –Girls




--------Interventional
------Control
            Head circumference


             Interventional       Control
Visits                                          ‘p’ value
             Mean     S.D.     Mean    S.D.

1st visit     42.61   ± 4.95   42.38   ± 2.61     0.695


2nd visit     44.00   ± 5.23   43.73   ± 2.79     0.676


3rd visit     45.00   ± 4.54   45.10   ± 2.95     0.557
                          Graph No. 1: Birth weight and mean weight gain


                         4.0
Mean weight gain (Kgs)   3.5
                         3.0
                         2.5

                         2.0
                         1.5

                         1.0
                         0.5
                         0.0
                                    Cases                        Controls
                                                  Groups


                                    2.5 - 3 Kg   3 - 3.5 Kg   > 3.5 Kg



                           2.5-3.0 kg -p value < 0.000
                           3 – 3.5 p value < 0.023
                         Graph No. 2: Birth Weight versus mean length gain

                           5
                         4.5
Mean length gain (Cms)


                           4
                         3.5
                           3
                         2.5
                           2
                         1.5
                           1
                         0.5
                          0
                                  Interventional                    Control
                                                     Groups

                                     2.5 – 3 Kg    3 – 3.5 Kg   > 3.5 Kg



                          2.5 to 3 Kg p value 0.005
                          3 to 3.5kgs p value 0.049
     Duration of supplementation Vs
           weight/length gain

6

5

4
                                       mean weight
3                                      mean length
2                                      Column1

1

0
     180 days          less 180 days



    Mean length gain -P value 0.009*
             Neurodevelopment
                                   Cases (n=90) Control (n=78)    ‘p’
          Mile stones
                                   No      %       No    %       value
Stands by furniture                 90   100.00%   75   96.10%   0.060
Walks with help                     86   95.50%    73   93.50%   0.573
Stands alone                        81   90.00%    65   83.30%   0.201
Walks alone                         78   86.60%    60   76.90%   0.100
Walks up & down stairs with help    72   80.00%    54   69.20%   *0.033
Fine prehension                     85   94.40%    71   91.00%   0.391
Midline skills                      86   95.50%    70   89.70%   0.145
Spontaneous scribble                80   88.80%    64   82.00%   0.207
Inhibition command                  90   100.00%   75   96.10%   0.060
Gestures for wants                  68   75.50%    52   66.60%   0.203
Says da da                          84   93.30%    65   83.30%   *0.041
Imitates words                      76   80.00%    56   71.70%   *0.046
Two words                           61    67.70%   41   64.60%   *0.044
                Effect of variables
•   Birth weight
•   Sex
•   Education of the mother
•   Socio economic status
•   Duration of BF
•   Other supplements
•   Episodes of ARI, & Diarrhea
       Effect of variables on growth
On Multivariate analysis

•   Diarrhea -significant association with weight & length gain
    p value 0.003.

•   Other variables- not statistically significant
             Effect of variables on
              Neurodevelopment
Significant effect
                Duration of BF
                Birth. Weight
• Duration of BF influenced –
                   walking alone,
                   walking up & down stairs with help,
                   pincer grasp
         p value 0.001, 0.016, 0.045
• Birth weight - Two words with meaning
                 p value 0.040.
• Others -–no statistically significant independent influence
  on neurodevelopment of the baby
                      Serum Zinc Levels


         Groups                              Sr zinc levels
                                No
                                           Mean              SD
      Interventional            20       198.90           47.19

      Controls                  10       133.90           68.65


ighly significant statistically with an effect size was 65.025 (CI 95%, 21.38 to
108.66, p
= 0.005).
                                   Morbidity

ARI
                          6 to 9 months                9 to 12 months
        No. of                      Control                       Control
                        Cases                         Cases
        episodes
                   No      %       No     %      No      %       No     %
                                                 66
  Nil              84     92.30%   60   74.00%          73.30%   43   55.10%

                                                 22
  Once             07     7.60%    20   24.60%          24.40%   24   30.70%

                                                 02
  ≥2               00     0.00%    01   1.20%           2.20%    11   14.10%

                                                 90
  Total            91     100%     81     100%          100%     78   100%

Overall incidence –Interventional-32.2%
                     Control      58.9%
6-9 months p = 0.001          9 to 12months p = 0.014.
                              Diarrhea

                    6 to 9 months                 9 to 12 months
  No. of                      Control                       Control
                  Cases                         Cases
  episodes
             No      %       No     %      No      %       No       %
Nil          60     68.90%   37   45.60%   81     90.00%   65      83.30%

Once         31     34.00%   34   41.90%   09     10.00%   13      16.60%

≥2           00     00.00%   10   12.30%   00     00.00%   00      00.00%

Total        91     100%     81     100%   90      100%    78      100%



         Overall incidence -42.2% Vs 62.8%
         six to nine months only p = 0.007
Discussion



ZINC SUPPLEMENTATION & GROWTH
Study         Age       Country    Preterm Dosage      Effect      Len
                                   /LBW    Duration of on          gth
              Breast                       supplementa             gain
              fed/top                      tion        Weight
              fed                                      gain

Walravens     BF        Developin ++          5mg/day * 3   +++    +++
et al         4-9       g –africa             months
              months    Low
                        income

Krebs et al   2-6                  ++         5 mg/day      +++    +
              months
              BF
 Hamadani     1-6       Bangalad   ++                       +++    +++
JD et al      months    esh        Zn
                                   deficien
                                   cy
Heinig J et   4-6       USA        Healthy                  --     ---
              months               term
Present       6-12      India      Term       10 mg/day     ++++   +++
study         months               Normal     6 mts                +
                                   weight
Zinc & Neurodevelopment
Study, no, & age                  Dose & duration of zinc Outcome in the zinc group
Friel et al. 1993                11 mg zinc/l of formula v. 6.7     Higher loco-motor development score
50 neonates, ,1500 g . .29 ±3wk. mg zinc/l of zinc; 6 mo            (Griffiths Sub Scales)

Ashworth et al. 1998
1500±2499 g,                      1 mg zinc/d v. placebo            No difference in mental, psychomotor
term,134 neonates                 5 mg of zinc/day with no          development or behavior.
     71 neonates                  concurrent controls               Highest ratings on all Behavior Scales
                                  8 weeks                           (Bayley et al and Wolke et al) at 12 months


Sazawal et al. 1996               10 mg zinc/day; 1 month           Spent 72 % more time performing higher
       93 subjects,                                                 movement activities. Greater effect in boys
      12±23 months
.
Bentley et al. 1997               10 mg zinc/day; 7 months          More time in sitting, playing than lying; less
          85 subjects,                                              time in crying.
         6±9 months
Cavan et al. 1993 162 subjects,   10 mg zinc/day; 25                No difference on mental concentration or
7±8 years                         weeks                             short term memory
Gibson et al. 1989                10 mg zinc/day; 12 mo             No difference in average attention span
60 subjects, 5±7 years                                              scores
Hamadani JD et al                 five mg of zinc daily from four   No differences in motor development
4-6 months                        week to six months of life        lower cognitive scores

Present study,2007-2008           10 mg zinc/day.6 months           More number of babies achieved the motor
                200                                                 milestones and language milestones
              6-12 months
    Zinc supplementation & growth

•   These studies there was scanty information on the
    type and quantity of the complementary foods offered
    to the infants.



•   Many studies have shown a positive effect of zinc
    supplementation in stunted, LBW and small for
    gestational age infants.
                      Strengths
•   Study design (randomized double-blind placebo
    controlled trial)

•   Similar and well matched groups

•   Adequately supervised administration of the
    supplements.
                     Limitations
•   Lack of baseline data -serum zinc



•   A more sensitive developmental assessment tools
    like Baileys
                       Conclusions
    •   Zinc supplementation did have significant effect on
                         Linear growth
                         Neurodevelopment

•   Reduced morbidity from diarrhea & respiratory illness
    in second 6 mths of life



•   Significant increase in Serum zinc levels
                   Conclusion
To evaluate
• Multi-centric
• Larger sample size
• Longer follow up,
• Use of a more sensitive tool neuro developmental
  assessment
• Baseline serum zinc concentration,

								
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