RESEARCH PROPOSAL

1. Research title

Zinc Supplementation in Preterm Infants : Randomized Controlled Trial

2. Name of principal research coordinator

Henri Azis

3. Research co-coordinator

Risma Kerina Kaban

4. Key words
Zinc Preterm Infants

Micronutrient Growth

stunting

5. Duration of research (months)

six months

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RESEARCH DESCRIPTION

6. Background/short literature review

Prevalence of preterm newborns increases and recently more common in developing or low
socioeconomic countries. According to RISKESDAS in 2015, rate of preterm births in Indonesia is
10,2%. Nutritional problem is one of the serious problems on preterm infants. This is closely related to
conditions and complications in various organ system such as gastrointestinal tract, respiratory tract,
central nervous system and others. Unnoticed nutritional problems that often occur are micronutrient
needs. Zinc is one of micronutrient which have risk of deficiency on preterm infants. Some research
prove that zinc deficiency play a role in stunting among children.

Zinc is essential element for growth and development, but at the first of life, preterm infants are high
risk on zinc deficiency due to low in body’s zinc stores, increased endogenous zinc loss through the
intestinal lumen, and minimal zinc intake. Conditions of zinc deficiency in preterm infants can manifest
to be mild to severe, such as growth disorder, increased risk of infection, motoric function disorder,
dermatitis, diarrhea, poor bone mineralization, Retinopathy of Prematurity, Bronchopulmonary
Dysplasia, Intraventricular Hemorrhage, etc. Preterm infants with hypozyncemia could not achieve
hemostasis states because they have low zinc stores which can make them undergoing severe zinc
deficiency.

There has been many evidence from several studies that severe zinc deficiency conditions will affect
the growth and development of preterm infants as well as increase of morbidity and mortality. But until
now there is still little research and recommendations for giving zinc supplementation in preterm
infants.

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7. Problem Identification and Research Question(s)

7.1 Research Problems

• The risk of zinc deficiency in preterm infants increases due to low body stores resulting from trans
placental maternal nutrition, increased endogenous zinc loss through the intestinal lumen and
insufficient zinc intake
• Severe deficiency conditions will interfere with growth and development as well as
increase the rate of morbidity and mortality of preterm infants
• Zinc deficiency play a role in stunting among children.
• Recommendations of zinc supplementation for preterm infants is not exist

7.2 Research Questions

Are there any growths discrepancies (weight, body length and head circumference) between zinc
supplemented and non-supplemented premature infant?

7.3 Hypothesis
The growths of zinc supplemented premature infants are better than non-supplemented premature
infant.

8. General Objective, Specific Objective and Research Benefit

8.1 General Objective:

To compare the growths (weight, body length and head circumference) of zinc supplemented
premature infants and non-supplemented premature infant.

8.2 Specific Objective(s):

• To compare the prevalence of Necrotizing Enterocolitis (NEC) between zinc supplemented
premature infants and non-supplemented premature infant.
• To compare the prevalence of sepsis between zinc supplemented premature infant and non-
supplemented premature infant.
• To compare the prevalence of Bronchopulmonary Dysplasia (BPD) between zinc supplemented
premature infant and non-supplemented premature infant.
• To evaluate the side effects of zinc supplemented premature infant.

8.3 Research Benefit(s):

• As a recommendation to give zinc supplementation for premature infants.
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 • As an additional data that zinc supplementation useful for growths of premature infants.

Theoretical Framework

Interrupt cell
proliferation

Cell apoptosis

Decrease
IGF-1

Interfere intestinal Growth

Premature Infant Zinc deficiency retardation
ion transport

Decrease tymic activity

(immunity problem)
decrease function of T and NEC
B cell

Infection
BPD

feeding/diet

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9. Methods

9.1 Research Design

The study is unblinded controlled randomized clinical trial in premature infant that is admission into
perinatology ward. Consecutive sampling and block randomization are performed. There are two study
group, the treatment group (who received Zinc supplementation) and the control group (not give
supplementation).

9.2 Population and Subjects

The participants are all low birth weight (LBW) neonates (1000 – 1500 gram) with gestational age 28
to 32 weeks, consecutively observed in an neonatal intensive care unit or special care unit at Cipto
Mangunkusumo hospital Jakarta, between November 2018 until April 2019.

9.3 Inclusion, Exclusion and Drop Out Criteria

Inclusion Criteria
• All newborn infants with gestational ages 28 to 32 weeks
• All newborn infants with birth weight 1000 - 1500 grams
• Got parental consent to be included in the research with signing the agreement form

Exclusion Criteria
• Newborn infants with severe congenital disorder
• Newborn infants with gastrointestinal atresia

9.4 Sampling
Sample size is calculated to find out differences in growth indicator between treatment group and
control group. This study is analysis numeric comparative of two unpaired groups, the formula is :
0
(𝑍𝛼 + 𝑍𝛽)𝑆
𝑛 = 2$ /
𝑥1 − 𝑥2

Type I error = 5 % à Zα = 1.64 (1-tailed)

Statistical power : 80% à Zß = 0.84
Body weight
Standar deviation : 371.56*
X1 – x2 = 250*

A minimum sample size of 27 patient each group is required. To anticipate possibility drop out sample
then add 20% to become 32 samples of each group.

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9.5 Research Algorithm
1. Immediately after registration of the patient, detailed history is taken from mother or relatives
and physical examination is performed.
2. Gestational age is determined by maternal record and by new ballard score system.
3. Weight measure by an electronic weighing scale, which is accurate to 5 gr and calibrated
before measurement.
4. Occipito-frontal circumference is meassured with a non-elasticplastic measuring tape (1cm
wide) tot he nearest 1mm.
5. Researcher explains about this research to parents and get parental consent to be included in
the research with signing the agreement form.
6. The researcher has randomized subject usung block randomiztion and wrote the subject in an
envelope to be selected.
7. When enteral feeding is 20ml/kg/d, the neonates enrolled are randomly allocated to 2 study
groups (using block randomization). Group 1 (zinc group), who receive zinc suplement
2mg/kg/d, once daily, 2h after feeding. Group 2 (control group) who doesnt recive zinc
suplement. The supplement is given agin to subject who vomite before 15 minutes after
administration.
8. All episodes of vomiting and other adverse event are reported on the clinical chart.
9. the suplement assigned is discontinued at discharge or 38 week postconceptual age.
10. All the participant will be monitored and recorded for growth indicator, incidence of sepsis,
BPD and NEC.
11. At the last monitoring, all participant will be checked for blood zinc level.
12. Participants will be observed and researcher will analyze the datas.

Feeding protocol
1. Enteral feeding was started on the first day of life at 10ml/kg/day divide into 8 feeds by using
maternal milk/ preterm formula in all stable infants.
2. In the absence of sign of feeding intolerance in the previous 24h, enteral nutrition was
increased daily by 10 – 20 ml/kg/day.
3. Enteral nutrition is discontinued in the case of erythematic abdominal wall, absence of bowel
sound, blood in the stool and radiologic marker of NEC-Bell stage >= II.
4. Human milk fortification is added when full enteral feeding is acheived.
5. Parenteral nutrition is maintained through a central vascular acces in all infant to ensure
adequate intake of fluids, electrolyte and nutrients until full enteral feeding is reached

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9.6 Statistical Analysis
It is performed by using SPSS for window version 22. Data are expressed as mean ± standard deviation.
Differences between group in continuous variable are tested for significant with independent t-test. For
all statistical test done, p value <0.05 is considered significant.

9.7 dummy table

Mean ± SD Mean ± SD p CI 95%
Treatment group control group
Body Weight
Body length
Head
circumference

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ALUR PENELITIAN

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10. Research Budget

1. material and fotocopy : 5.000.000

2. assistant salary : 6.000.000
3. laboratory test : 20.000.000
4. transportation : 6.000.000
5. drug : 2.000.000
6. others : 1.000.000
TOTAL : 40.000.000

11. References

1. Gomella TL. Newborn Physical Examination. In : Gomella TL, editor. Neonatology :

management, procedures, on-call problems, diseases, and drugs. 5th ed. United States of
America: McGraw-Hill Companies; 2004.
2. Franko KL, Gluckman PD, Law CM, Beedle AS, Morton SMB. Low birth weight and optimal fetal
development: A global perspective. In: Kiess W, Chernausk SD, Hokken-Koelega ACS, editor.
Small for gestational age: Causes and consequences. Pediatr Adolesc Med vol 13. Switzerland:
Karger; 2009:73-85.
3. Staub E, Evers K, Askie LM. Eneteral zinc supplementation for prevention of morbidity and
mortality in preterm neonates (protocol). The Cochrane Collaboration. 2017
4. N marta, Eduardo domenech et all. The effect of zinc supplementation on linear growth, body
composition and growth factors in preterm infant. Pediatric journal vol 111 no. 5. 2003
5. Parakh manish, Gupta BD et all. Role of zinc supplementation in growth and neuro development
of premature and small for gestational age (SGA) Babies. National journal of community
medicine vol 3. 2012
6. Mohammed S el frargy. Zinc supplementation as an adjuvant treatment in neonatal sepsis. Curr
pediatr Res volume 21. 2017

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12. Time Table
Time (in months)
Activities 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th
Making proposal
Approval from ethical committee
Selecting subjects (sample)
Collection of data
Data analysis
Report submission and
presentation
Manuscript submission
• Report should be submitted before Annual meeting of Asian Society for Pediatric Research (in conjuction with
PIT 2019 in Manado)
• Research results (preliminary/final) should be presented in ASPR Manado
• Manuscript should be published in accreditated Nasional/International journal (please estimate when will the
manuscript be submitted)

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13. Principal Research Coordinator CV

Name : Henri Azis, MD, Pediatrician

Date and Place of Birth : Palembang, 1st of Desember, 1984
Current Residence : Jalan Mayor Zen Harapan Jaya II No. 16 RT. 32 RW. 08
kecamatan kalidoni Palembang 30118 Provinsi Sumatera
Selatan
Degree title : Pediatrician
Current Institution : HM Rabain Muara Enim General Hospital/Medical Faculty of
Sriwijaya University
Educational Institution :
1. General Practitioner at Medical Faculty of Sriwijaya University Palembang (2002 – 2008)
2. Pediatrician at Medical Faculty of Sriwijaya University Palembang (2011 – 2015)
3. Master of Health at Medical Faculty of Sriwijaya University Palembang (2012 – 2014)
4. Perinatology Fellowship at Cipto Mangunkusumo General Hospital Jakarta (2018)
5. Perinatology subspecialist at Medical Faculty of Indonesia University (2018 – now)

Email : dr.ajes@yahoo.co.id / ajes.dr@gmail.com

Phone : 085279000252/ 081368030455

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