Zinc is an essential element that pervades all aspects of biology and the populations in India are thought to be deficient in zinc. A preliminary study in India suggested that zinc supplementation of low birth weight (LBW: less than 2.5kg at birth) infants may reduce death. In a controlled trial the impact of daily zinc supplementation (1 RDA dose) in LBW infants on death and severe disease requiring hospitalization will be evaluated. LBW infants born in a large Government hospital in Kolkata, will be assigned to receive either a zinc syrup (5mgm elemental daily) or a placebo from 4 weeks to 6 months and the rate ratios for death and severe disease will be compared. If found beneficial, this targeted intervention will be an important public health tool for reducing infant mortality rate in India.

Objectives:

i.To determine the impact of daily administration of 1 RDA (5 mg) of elemental zinc to LBW infants from 4 weeks to 6 months of life on all-cause mortality. ii.To determine the impact of zinc supplementation on severe morbidity requiring hospitalization.

Rationale:

i.The prevalence of LBW is high in Asia, particularly in South Asian countries like India, Pakistan and Bangladesh. LBW infants have a high neonatal and infant mortality and morbidity rates.

ii.A recent preliminary study showed that zinc supplementation of LBW infants reduced mortality (Sazawal et al., 2001).

iii.A targeted intervention in LBW infants starting at about 4 weeks of age is programmatically highly attractive. It can be combined with immunization program and with recent recommendation to give iron and folate to infants.

iv.The fact that mortality rate is very high in LBW infants means a relatively smaller study will give us results suitable for a policy decision.

Study population and location:

The infants will be recruited at birth at the maternity ward of M.R. Bangur General Hospital where more than 6000 deliveries take place in a year.

Preliminary data collected by us from four hospitals in West Bengal showed that little over 37% of the babies born there have a birth weight of less than 2500 g. LBW infants born at these hospitals will be recruited in this study and followed up at home. Mainly the urban and peri-urban poor use these Government hospital.

Sample size:

Taking a figure of infant mortality rate of 40/100 in LBW infants and assuming that at least 50% of these deaths occur between 4 weeks and 6 months of age, we expect 20 deaths per 100 infants during the observation period for this study. Assuming a mortality rate reduction of 30% with similar assumption the total (plus 10% for deviated courses) sample size should be 1360 in LBW infants. If we expect a reduction in mortality rate by 25%, the total sample size would be 1900 infants which include 10% for deviated course. We propose to recruit 2000 LBW infants to the study.

Inclusion criteria:

All births at M.R. Bangur General Hospital will be screened for the following enrolment criteria:

1. Weight at birth less than 2500 g
2. The infant is likely to stay in the city for the next 6 months
3. Absence of gross congenital malformation

Randomization and blinding:

A master randomization code will be prepared by using permuted blocks of random numbers using block lengths of 4, 6 and 8. This code will be sent to the Pharmaceutical Company who will number the bottles containing the formulation or placebo for each child according to the randomization chart and the bottles will be labeled only with the serial numbers of the child in the study. The final code will be kept with the company and a copy with another individual designated by the institutional ethical committee. The zinc syrup and the placebo will be similar in appearance, consistency and taste.

In case of any reported or detected illness by the field workers, free drugs will be provided and hospitalization facilitated when required.

Intervention:

Each infant in the study will receive placebo or 5 mg of elemental zinc (1 RDA) as zinc gluconate syrup daily from 4 weeks of age.

Measurement of study outcome:

Deaths if any will be recorded at each contact (i.e., 8 weeks from the start of supplementation), again 20 weeks from birth (i.e., 16 weeks of supplementation) and at 24 weeks. The cause of death will be ascertained by a verbal autopsy using an instrument developed and validated by WHO.

Available hospital records will be examined and a team of pediatricians will independently review verbal autopsy questionnaires. The diagnosis will be made by consensus or through discussion.

• Similarly, illness events requiring hospitalization will be documented at 12 weeks, 20 weeks and 24 weeks. A questionnaire will be used and hospital records examined.
• At 20 weeks weight and length will be measured and recorded. Weight will be measured by a precision balance within 10 g and length by a measuring board within 0.1 cm.
• At 24 weeks a sub-sample of 300 infants will be tested for serum zinc concentration.

Data management and statistical analysis:

The data will be entered into a desktop computer and edited using a software EPI Info (CDC, Atlanta, USA and WHO, Geneva) and analyzed by EPI Info and another software named Stata (Stata Corporation, Texas, USA). The main comparison will be between those who received zinc and those who received placebo.

Ethical considerations:

An independent ethical committee (which regularly reviews research projects of this institution) reviewed the project proposal and approved it. The purpose and the procedures will be explained to the mother of the eligible infant and a written consent will be obtained from each of them before they are included.

The dose of zinc to be administered will be 1 RDA for the age. Zinc deficiency is commonly known to occur in LBW infants and administering physiological doses of zinc should be desirable and safe. In clinical trials, administration of 1 or 2 RDA zinc to LBW infants, to normal weight infants and to many thousands of children has not demonstrated any adverse effects. Given that zinc is safe and that substantial evidence of major benefit of giving zinc on morbidity has been demonstrated, the proposed intervention is ethically justified.

• Pneumonia
• Diarrhea
• Any Severe Illness
• All Cause Mortality

Inclusion Criteria:

• Weight at birth less than 2500gm
• The infant is likely to stay in the city for the next 6 months
• Absence of gross congenital malformation