|
Indian Pediatr 2015;52:
951-955 |
|
Zinc Supplementation in Preterm Neonates and
Neurological Development: A Randomized Controlled Trial
|
NB Mathur and Devendra K Agarwal
From Department of Neonatology, Maulana Azad Medical
College, New Delhi, India.
Correspondence to: Dr NB Mathur, Director Professor
and Head, Department of Neonatology, Maulana Azad Medical College, New
Delhi 110 002, India.
Email: [email protected]
Received: October 22, 2014;
Initial review: December 04, 2014;
Accepted: August 14, 2015.
|
Objective: To assess the effect
of zinc supplementation on neuro-development and growth of preterm
neonates.
Setting: Referral neonatal unit of a teaching
hospital.
Design: Open-labeled Randomized controlled trial.
Participants: 100 preterm neonates.
Intervention: Participants randomized to receive
oral zinc (study group) or not (controls).
Main Outcome Measures: Primary: Neuro-development
status at 40 weeks post conceptional age and at 3 month corrected age
using Amiel-Tison neurologic assessment. Secondary: anthropometry
and serum alkaline phosphatase at 3 months corrected age.
Results: At 40 weeks post-conceptional age,
greater number of zinc supplemented infants demonstrated alertness and
attention pattern normal for their age (P=0.02). Higher number of
controls showed signs of hyper-excitability at 40 week post-conceptional
age (P=0.001) and 3 months corrected age (P=0.003). At 3
month corrected age, mean serum alkaline phosphatase level was
significantly higher in the study group compared to controls.
Conclusion: Zinc supplementation till 3 month
corrected age in preterm breastfed infants improves alertness and
attention pattern; and decreases signs of hyperexcitability, and
proportion with abnormal reflexes.
Keywords: Micronutrient, Neurodevelopment, Outcome,
Prematurity.
|
Z inc may be essential for brain function as well
as for growth in the fetus and child [1]. Zinc deficiency may be
particularly relevant to early development, growth and function of many
organ systems, including the neurologic system [2,3]. Studies have shown
reduced levels of zinc in low birth weight infants [4,5], that may
account for increased morbidity and growth failure in such neonates.
With a small liver, very limited hepatic stores of zinc [6] and
increased requirements for catch-up growth, they are at risk for zinc
deficiency. There is a paucity of studies evaluating effect of zinc on
neuro-development in preterm neonates. The present study evaluated the
effect of zinc supplementation on neurological development,
anthropometry and serum alkaline phosphatase at 3 month corrected age in
preterm infants.
Methods
This randomized controlled trial was conducted in the
referral neonatal unit of a teaching hospital providing care to neonates
born in community hospitals or at home. The participants were 100
consecutively admitted preterm neonates <7 days old at admission. The
predefined sample size was based on convenience. Neonates with major
congenital malformations and those not receiving anything orally for 7
days were excluded. Eligible neonates admitted during the study period
(March 2011 through December 2011) were randomized either to receive
zinc gluconate (2 mg/kg/day of elemental zinc) [7] or no zinc using
website generated random allocation sequence. Randomization sequence was
concealed using sealed opaque envelopes. Written informed consent was
obtained from the parents. The study was approved by the institutional
ethical committee.
Zinc was given once daily till 3 months of corrected
age in the study group. Syrup zinc was procured from hospital supply and
administered by nursing staff till discharge. After discharge from
hospital, the mother administered the supplements. Before discharge, the
mother was trained to administer the supplements and advised to give a
repeat dose if the baby vomited the supplement within 30 minutes of
administration. Infants in both groups were given 4 mL/kg/day of an oral
calcium and vitamin D preparation (elemental Calcium 125 mg, Phosphorus
55 mg, Vitamin D3 125 IU per 5 mL), 1 mL/day of multivitamin drops
(containing: Vitamin B1 2 mg, Niacinamide 10 mg, D-panthenol 3 mg,
Tocopherol acetate 1.5 mg, Vitamin B6 1 mg, Biotin 20 mcg, Vitamin C 40
mg, Vit A 1000 IU, Vit D2 400 IU), and vitamin E drops containing
Tocopherol acetate 5 mg/kg body weight daily. Iron drops 2 mg/kg body
weight daily was started at 4 weeks of postnatal age [7]. Weight, length
and head circumference were measured daily till discharge, after which
infants were followed up weekly till 40 weeks post-conceptional age, and
then monthly till 3 months of corrected age. Nude weight was recorded
using an electronic weighing scale with an accuracy of 5 g. Length was
measured from crown to heel in supine position, using an infantometer,
to the nearest of 1 mm. The occipito-frontal circumference was recorded
using non- stretchable measuring tape with an accuracy of 1 mm using
cross-tape technique.
At each visit, history related to pattern of feeding,
diarrhea, respiratory illness, fever, lethargy, vomiting or any other
illness in the intervening period was recorded. Adverse effects of oral
zinc supplement (vomiting following administration) were enquired at
each visit. All mothers were counseled at each visit about care of
infants particularly maintaining temperature, breastfeeding, nutritional
supplements, prevention of infections, immunization and date of next
follow up. All infants were exclusively breastfed during the entire
study period. Compliance to zinc administration was monitored using a
compliance sheet given to mother at discharge. Compliance was checked at
each visit by entries in the sheet, and also by measuring residual
volume of drug in the bottle.
Neuro-development status was evaluated at 40 weeks
post conceptional age and at 3 months corrected age using Amiel-Tison
method [8,9] by a single observer. The examiner circled a score of 0,1
or 2, according to the information given in the technical description of
this method for each maneuver. The examiner was not blinded. A score of
0 indicates a typical result for that age, within the normal range. A
score of 1 indicated a moderately abnormal result for that age. A score
of 2 indicated a definitely abnormal result. Serum alkaline phosphatase
was estimated by Olympus auto analyzer using spectrophotometric method
at enrolment and at 3 months corrected age.
Cranial ultrasound was done in all neonates <35 weeks
at enrolment and on follow-up. Brainstem evoked auditory response (BERA)
was performed in all infants at 40 weeks post-conceptional age and at 3
months corrected age.
The data were analyzed using SPSS version 12.
Continuous variables were tested using student t-test and for
categorical variables, Pearson Chi-square test was applied. For
variables with non- Gaussian distribution, Mann-Whitney test was
applied. Wilcoxan signed rank test was used to compare pre- and post-
intervention variables within the same group. A per protocol
analysis was done.
Results
During the study period, 50 neonates were randomized
in each of zinc and control arm. The study was completed by 37 neonates
in zinc group and 35 neonates in control group. Overall loss to follow
up at 3 month corrected age was comparable in both zinc (13%) and
control group (15%) (Fig. 1). Baseline demographic
characteristics were comparable in both groups (Table I).
|
Fig. 1 Flow of the Participants in the
Study.
|
TABLE I Baseline Characteristics at Admission in the Study Population
Variable |
Zinc Group |
Control Group |
|
N=50 |
N=50 |
Gestational age (wks)# |
33.4 (2.2) |
33.4 (2.3) |
Maternal age (y)# |
24 (3) |
24 (8) |
Age at enrollment (d)# |
2.6 (1.5) |
2.9 (1.7) |
Admission weight (g)# |
1603.7 (452) |
1630.8 (479) |
Male gender |
33 (66) |
32 (64) |
Small for gestation (SGA) |
33 (66) |
35 (70) |
Intra ventricular hemorrhage |
3 |
6 |
Hypoglycemia |
2 (4) |
1(2) |
Apnea |
12 (24) |
14 (28) |
Shock |
6 (12) |
5 (10) |
Pneumonia |
14 (28) |
17 (34) |
Hyperbilirubinemia$ |
12 (24) |
15 (30) |
#Values in mean (SD); all other in no.(%); $requiring
phototherapy. |
Table II shows findings of Amiel-Tison
neurologic assessment in study population. The scores for all parameters
were similar in both the groups at enrolment. At 40 weeks post
conceptional age, none of the infants in Zinc group and 13% in control
group showed moderate deficit in attention span (P = 0.02). At 3
month corrected age, most infants had normal alertness and attention in
both groups, with moderate deficit in 3% in zinc group and 6% in
controls.
TABLE II Amiel-Tison Neurologic Assessment in Zinc-supplemented and Control Infants
Timing |
Score |
P value |
|
Zinc group
|
Control group |
|
Score |
0 |
1 |
2 |
0 |
1 |
2 |
|
Alertness and attention |
|
|
|
|
|
|
|
At enrolment (n=100) |
37 |
12 |
1 |
31 |
17 |
2 |
0.38 |
At 40 weeks (n=77) |
38 |
0 |
0 |
34 |
5 |
0 |
0.02 |
At 3 months (n=72) |
36 |
1 |
0 |
33 |
2 |
0 |
0.54 |
Hyper-excitability |
|
|
|
|
|
|
|
At enrolment (n=100) |
46 |
4 |
0 |
47 |
3 |
0 |
0.33 |
At 40 weeks (n=77) |
37 |
1 |
0 |
30 |
9 |
0 |
0.001 |
At 3 months (n=72) |
36 |
1 |
0 |
25 |
10 |
0 |
0.003 |
Bicipital reflex |
|
|
|
|
|
|
|
At enrolment (n=100) |
4 |
11 |
35 |
12 |
9 |
29 |
0.08 |
At 40 weeks (n=77) |
27 |
10 |
1 |
14 |
21 |
4 |
0.01 |
At 3 months (n=72) |
34 |
3 |
0 |
22 |
10 |
3 |
0.01 |
Patellar reflex (knee jerk) |
|
|
|
|
|
|
|
At enrolment (n=100) |
4 |
12 |
34 |
9 |
11 |
30 |
0.31 |
At 40 weeks (n=77) |
27 |
11 |
0 |
14 |
21 |
4 |
0.002 |
At 3 months (n=72) |
33 |
4 |
0 |
20 |
12 |
3 |
0.006 |
Alertness and attention: Moderate deficit (1), Severe
deficit (2); Hyper-excitability: No signs (0), Signs compatible
with normal life (1), Uncontrollable(2); Bicipital reflex:
Normal (0), Very brisk (1), Clonus (2), Absent (2); Patellar
reflex (knee jerk): Normal (0), Very brisk (1), Clonus (2),
Absent (2). |
Higher number of neonates in control group had signs
of hyperexcitability compatible with normal life and brisk bicipital
reflex response at 40 weeks post conceptional age and at 3 month
corrected age. Brisk patellar reflex at 40 weeks and 3 months was also
more frequently seen in control group.
There was no difference in both groups at 40 weeks
post conceptional age and 3 month corrected age with respect to visual
and ocular signs, hearing abnormality, muscle tone, motor activity,
involuntary movements, dystonia, cutaneous reflex, primitive reflex and
asymmetric tonic neck reflex.
Body weight, length and head circumference were
comparable in both the groups 3 month corrected age. (Web
Table I). The mean (SD) serum alkaline phosphatase levels were
significantly elevated at 3 month corrected age in zinc group [298 (54)
vs. 272 (55) IU/L, P=0.046] (Fig. 2).
|
Fig. 2 Change in serum Alkaline
phosphatase through study period.
|
During the post-discharge follow up till 3 month
corrected age, infants in zinc group had fewer re hospitalization
episodes (8 vs. 19); episodes of respiratory infections were 2
vs. 6, diarrhea 3 vs 8 and sepsis 3 vs. 5 (OR 0.23; CI
0.08-0.64; P=0.05). Post-discharge mortality was 4 in control
group (9.3%) compared to 1 in zinc group (2.4%) (OR 0.21). The four
deaths in control group were due to respiratory infection, diarrhea,
septicemia and unidentified cause in one neonate each. The death in zinc
group was due to sudden infant death syndrome.
No adverse event of zinc supplementation was
observed.
Discussion
In the present study, higher number of zinc
supplemented infants demonstrated alertness and attention pattern normal
for age compared to non-supplemented infants at 40 weeks post
conceptional age, but not at 3 month corrected age. Infants in
non-supplemented group were more likely to show signs of
hyper-excitability, including insufficient sleep, excessive crying and
frequent startling when assessed at 40 weeks and 3 month corrected age.
We found no significant difference in gain in weight, length and head
circumference between groups. Serum alkaline phosphatase in the zinc
group was significantly higher.
The strength of our study was a robust tool for early
evaluation of neurodevelopment status. For assessing the efficacy of
neuroprotection, it is important to evaluate occurrence of early
transient signs before they disappear due to neuroplasticity.
Limitations of the study are the small sample size without a priori
calculation. We did not use any placebo in control group. The study was
not blinded and serum zinc and copper levels were not estimated. The
long-term consequences of these findings are also largely unknown.
Friel, et al. [18] assessed 52 preterm infants
for neurological development using Griffith’s Mental Development Scale,
and showed that maximum motor developmental score at 12 months were
higher in the zinc-supplemented than the placebo group. However, a trial
in low birth weight term infants using Bayley Scale of Infant
Development found that zinc supplementation for eight weeks from birth
did not improve the mental and psychomotor scores at 6 and 12-months
[11]. Preterm infants are likely to have higher zinc deficit and dietary
requirements as nearly 60% fetal zinc is acquired during third trimester
of pregnancy [12]. Therefore, the response to zinc supplementation may
be variable amongst preterm and term SGA low birth weight neonates.
However, most of the zinc supplementation trials have been done in
heterogeneous population of low birth weight neonates including term
AGA, and have not segregated the data for preterm babies [13-18].
To conclude, zinc supplementation till 3 month
corrected age in preterm breastfed infants improves alertness and
attention pattern, and decreases signs of hyper-excitability and
abnormal patellar and bicipital reflex.
Contributors: NB: conceived and designed the
study, interpreted the results, finalized the manuscript and shall be
guarantor for the paper; DK: collected the data and drafted the
manuscript. Both authors approved the final version of manuscript.
Funding: None; Competing interests: None
stated.
What is Already Known?
•
Zinc has a role in cellular
growth and production of enzymes necessary for the synthesis of
RNA and DNA.
What This Study Adds?
•
Zinc supplementation till 3 month corrected age in preterm
breastfed infants improves alertness and attention pattern and
decreases signs of hyperexcitability and abnormal reflex.
|
References
1. Black M. Zinc deficiency and child developmental.
Am J Clin Nutr. 1998;68(suppl):464-9.
2. Pfeiffer CC, Braverman ER. Zinc, the brain and
behavior. Biol Psychiatry. 1982; 17:513-32.
3. Halas ES, Eberhardt MJ, Diers MA, Sandstead SS.
Learning and memory impairment in adult rats due to severe zinc
deficiency during lactation. Physiol Behav. 1983;30:371-81.
4. Friel JK, Andrews WL. Zinc requirement of
premature infants. Nutrition. 1994;10:63-5.
5. Bahl L, Chaudhuri LS, Pathak RM. Study of serum
zinc in neonates and their mothers in Shimla Hills (Himachal Pradesh).
Indian J Pediatr. 1994;61:571-5.
6. Zlotkin SH, Cherian MG. Hepatic metallothionein as
a source of zinc and cysteine during the first year of life. Pediatr
Res. 1988;24:326-9.
7. Agostoni, C, Buonocore G, Carnielli VP, de Curtis
M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm
infants: commentary from the European Society of Pediatric
Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J
Pediatr Gastroenterol Nutr. 2010;50:85-91.
8. Amiel-Tison C, Gosselin J. Neurological
development from birth to six years. The John Hopkins University Press.
Baltimore.2001. p. 101-9.
9. Amiel-Tison C. Update of the Amiel-Tison
neurologic assessment for the term neonate or at 40 weeks corrected age.
Pediatr Neurol. 2002;27:196-212.
10. Friel JK, Andrews WL, Matthew JD, Long
DR, Cornel AM, Cox M, et al. Zinc supplementation in
very-low-birth-weight infants. J Pediatr Gastroenterol Nutr.
1993;17:97-104.
11. Ashworth A, Morris SS, Lira PI, Grantham-McGregor
SM. Zinc supplementation, mental development and behaviour in low birth
weight infants in northeast Brazil. Eur J Clin Nutr. 1998;52:223-7.
12. Gulani A, Bhatnagar S, Sachdev HP. Neonatal zinc
supplementation for prevention of mortality and morbidity in breastfed
low birth weight infants: Systematic review of randomized controlled
trials: Indian Pediatr. 2011;48: 111-7.
13. Sazawal S, Black RE, Menon VP, Dinghra
P, Caulfield LE, Dhingra U, et al. Zinc supplementation in
infants born small for gestational age reduces mortality: A prospective,
randomized, controlled trial. Pediatrics. 2001;108:1280-6.
14. Lira PI, Ashworth A, Morris SS. Effect of zinc
supplementation on the morbidity, immune function, and growth of
low-birth-weight, full term infants in northeast Brazil. Am J Clin Nutr.
1998;68:418-24.
15. Taneja S, Bhandari N, Rongsen-Chandola T,
Mahalanabis D, Fontaine O, Bhan MK. Effect of zinc supplementation on
morbidity and growth in hospital-born, low-birthweight infants. Am J
Clin Nutr. 2009;90:385-91.
16. Osendrap SJ, Santosham M, Black RE, Wahed MA, Van
Raaij JM, Fuchs GJ. Effect of zinc supplementation between 1 and 6 mo of
life on growth and morbidity of Bangladeshi infants in urban slums. Am J
Clin Nutr. 2002;76:1401-8.
17. Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A,
Bhandari N. Efficacy of zinc supplementation in reducing the incidence
and prevalence of acute diarrhea: A community-based, double blind,
controlled trial. Am J Clin Nutr. 1997;66:413-8.
18. Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha
A, Bhan MK. Zinc supplementation reduces the incidence of acute lower
respiratory infections in infants and preschool children: a double
blind, controlled trial. Pediatrics. 1998;102:1-5.
|
|
|
|