Journal of Neonatology & Clinical Pediatrics Category: Clinical Type: Research Article

Early Versus Late Enteral Prophylactic Iron Supplementation in Preterm Infants: A Randomized Controlled Trial

Mohtarama Mostari1, Morshed Monzur Kabir2, Azmery Saima3, Afroza Islam Shuma4, Sharmin Afroze5, Mohammod Shahidullah6 and Abdul Mannan7*
1 Assistant professor, Dept. of Neonatology, Rajshahi Medical College, Rajshahi, Bangladesh
2 Junior Consultant (Orthopedics), Upazila Health Complex, Porsha, Noagaon, Bangladesh
3 Assistant surgeon, Directorate General of Health Services (DGHS), Mohakhali, Dhaka, Bangladesh
4 Assistant professor, Department of Neonatology, Dhaka Medical College, Dhaka, Bangladesh
5 Assistant professor of neonatology, Dr. M R Khan Children Hospital & Institute of Child Health, Dhaka, Bangladesh
6 Professor & Chairman, Bangladesh Shishu Hospital & Institute (BSHI), Dhaka, Bangladesh
7 Professor, Department of Neonatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

*Corresponding Author(s):
Abdul Mannan
Professor, Department Of Neonatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
Email:aminuli4343@gmail.com

Received Date: Jan 29, 2024
Accepted Date: Jan 30, 2024
Published Date: Feb 05, 2024

Abstract

Background 

Iron deficiency is commonly encountered in preterm infants and there is controversy about its timing of supplementation.  This study was aimed to evaluate the effect of early versus late iron supplementation on iron status, anthropometry and neurodevelopment of admitted preterm newborns in the neonatal intensive unit (NICU) of a tertiary care hospital. 

Methodology 

This Randomized Controlled Trial was conducted in the Department of Neonatology, BSMMU, Dhaka from August 2019 to September 2020. After taking informed written consent from the parents / guardians, 21 preterm in early group and 19 preterm in late group were included in the study. Thorough history of these newborn including demographic information were obtained at the time of enrollment and recorded in a data collection form. Iron supplementation was introduced at 2 weeks of age in early group & 6 weeks of age in late group. Sample for CBC, red cell indices, S. ferritin and C-reactive protein was sent in clinical pathology & department of Biochemistry department of BSMMU during admission, pre-intervention sample at 2 weeks in EI group and at 6 weeks in LI group & follow up sampling was done at 12 weeks in both groups. The intervention was used that ferric hydroxide polymaltose at a dose of 2 mg/kg/day of elemental iron per oral once daily mixed with expressed breast milk. Same drugs of same manufacture company with same batch number were provided to the babies. Weight, length and head circumference were measured at birth, 2 & 12 weeks of age in early group and at birth, 6& 12 weeks in late group. At 12 weeks of age, neurodevelopmental assessment was done using Bayley scales of Infant and Toddler Development, Third edition by clinical psychologists assigned from Institute for Pediatric Neurodisorder and Autism (IPNA), BSMMU. All quantitative variables were compared by unpaired t-test and categorical variables were compared by Chi-square test. Data were analyzed by statistical package for social sciences (SPSS) version 20.0. P value < 0.05 was considered as statistically significant. 

Result 

Mean gestational age and mean birth weight (gm) was 33.52±1.91 and   33.48±1.46, weeks and 1622.86±438.73 g and 1753.16±401.76 g in early and late group respectively. Female outnumber the male in early group & male outnumber the female in late group, p value was statistically significant. Comparison of red cells parameters and S. ferritin between early and late group neonates at 12 weeks showed that mean S. Ferritin (ng/ml) was significantly higher in early group (92.75±47.33 ng/mL) as compared with late group (56.95±35.06 ng/mL), (p value 0.01). At 12 weeks of age, weight, length & OFC was 4140.95±582.71 versus 4058.42±734.97 gm; 53.83±2.60 versus 54.73±2.89 cm; 37.05±1.48 versus 37.31±1.39cm (p=0.983), in Early and Late groups respectively, all p values were not statistically significant. Neurodevelopmental composite score achieved by Bayley scale III   showed mean cognitive score was 74.90±15.59 and 74.73±15.04 (p=0.973), mean motor score 71.61±13.76 versus 72.36±12.6 (p=0.859); mean language score of 83.38±12.18 and 85.94±12.27 (p=0.511) in Early and Late group respectively. 

Conclusion 

Early iron supplementation at 2 weeks of age in preterm newborn result in significantly higher serum ferritin level than late iron supplementation group but hemoglobin, red cell indices, anthropometry & neurodevelopmental outcome did not differ significantly in between early & late iron supplementation groups.

Keywords

Early Versus Late Enteral; Prophylactic; Iron Supplementation; Preterm Infants.

Introduction

Prematurity is one of the important causes of neonatal morbidity and mortality globally as well as in Bangladesh. It is also associated with the long-term sequelae. In south central Asia, the highest incidence for low birth weight is in Bangladesh 22.6 percent (National Low Birth-weight Survey, Bangladesh, 2015) [1]. The commonest micronutrient deficiency in the world is iron deficiency (ID) which fallouts in approximately one billion cases of anemia worldwide [2]. Preterm infants are more susceptible to develop iron deficiency during their first six postnatal months. Iron deficiency is more prevalent in preterm infants and those exclusively breast-fed infants who are not getting iron supplementation. Around 25% to 85% of preterm infants develop evidence of iron deficiency during infancy [2]. During the third trimester of pregnancy, significant fetal iron accretion occurs [2]. The infant’s gestational age and birth weight are strongly influenced by the size of the infant’s iron (Fe) store at birth. Even though, the concentration of iron in the liver, spleen and kidney remains relatively constant during gestation, there is an increase in total iron content because of growth of the iron storage organs. Possible factors for developing iron deficiency in premature infants include small iron stores at birth, rapidly increasing red cell mass, maternal conditions like diabetes mellitus, hypertension etc., increased hemolysis, and decrease red blood cell life span, low level of circulating erythropoietin levels, frequent blood sampling and loss of blood due to surgery [2]. Deficiency of iron in infancy is associated with neurodevelopmental deficits, poor physical growth, gastrointestinal disturbances, thyroid dysfunction, altered immunity and temperature instability, delayed maturation of the auditory brainstem response and abnormalities of memory and behavior [3]. Mild neurologic abnormalities, such as broad gait, dysdiadochokinesis or dysmetria is found at 5 years of age in preterm infants who received iron supplementation from 2 months of age than who received iron supplementation from 2 weeks after birth. Late supplemented group had poorer cognitive performance. Thus, early iron deficiency seems to affect neurodevelopment outcome adversely in preterm infants [4]. Early iron (EI) supplementation could potentially improve iron stores and prevent their depletion also [2].  

The timing of prophylactic enteral iron supplementation in preterm babies has been a matter of great controversy. But it is unclear that what time to administer prophylactic iron supplementation in preterm infants. In fact, the different international associations recommend different timings for initiation of iron supplementation for these babies. American Academy of Pediatrics (AAP) and the Nutrition Committee of Canadian Pediatric Society have recommended delayed iron supplementation in preterm very low birth weight infants at 4 weeks and 6–8 weeks postnatal age, respectively. The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommend initiation over a wide range of 2–6 weeks of age [2].   A wide spectrum of measures has been used to diagnose iron deficiency such as hemoglobin (Hb), mean  corpuscular  volume  (MCV)  and red  cell  distribution  width  (RDW), serum ferritin concentration.  Despite being a major neonatal problem, limited data is available for Bangladeshi infants. Therefore, a randomized controlled study was conducted to compare the iron status and its effect on anthropometry & neurodevelopment in between early and late iron supplementation group.

Materials And Methods

This Randomized Controlled Trial was performed in the Department of Neonatology, BSMMU, and Dhaka city over a twelve- month period from August 2019 to September 2020 after approval by IRB. A written informed consent was taken from parents. Admitted inborn neonate preterm < 37 weeks of gestation & who reached enteral feeds of >120 mL/kg/day by 2 weeks postnatal age were included in this study. Babies with multiple gestation, major congenital anomaly, ABO or Rh hemolytic disease were excluded. Newborns were randomized at 2 weeks of age when reach feeds >120 mL/kg/day or on exclusive breast feeding. The enrolled neonates were randomly assigned with computer-generated random number tables via software named 'Random Allocation Software, to receive either of the intervention. Any babies who reach feeds >120 mL/kg/day or on exclusive breast feeding got discharge before 2 weeks of age then randomization was done at 2 weeks of age & contact with parents over phone about pre-intervention blood samplings. Babies were brought by parents for pre-intervention blood sampling. After blood sampling, parents were advised to give oral iron supplementation. In babies, whose iron supplementation was started at 2 weeks of postnatal age considered as early initiation (EI) group. In those iron supplementation was started at 6 weeks of postnatal age considered as late initiation (LI) group.

Details of maternal and perinatal medical history and anthropometry were recorded for each neonate. Gestational age was calculated from the first day of last menstrual period (LMP) for mothers with regular menstrual cycle. Where LMP was not known, early ultrasonography was used for gestational age. But, when both were missing, New Ballard Score was used for gestational age assessment [5]. 

During admission, venous blood sampling was done and it was taken as baseline investigation. 2 ml blood sample was taken into 2 tubes:  EDTA (ethylene diamine tetra acetic acid) tube for complete blood  count  (CBC)  [Hb as g/dl, packed  cell  volume (PCV) as %,  mean  corpuscular  volume  (MCV) as fl, mean  corpuscular  hemoglobin concentration  (MCHC) as g/dl and  red cell  distribution  width  (RDW) as %],  and  plain  tube for  S. ferritin & CRP. Red cell parameters were  assessed using fully automated blood cell counter (Sysmex, XT-4000i model, Japan)  and different parameters including Hb, RBCs count, hematocrit (Hct), means  corpuscular hemoglobin (MCH), Mean corpuscular volume (MCV),mean corpuscular  hemoglobin  concentration (MCHC)  were  assessed in clinical pathology department of BSMMU. Serum ferritin was measured as ng/ml by fully automated bidirectional interfaced chemi-luminescent immune assay and CRP was measured automatically as mg/L (Siemens Dimension R×L Max’ machine (USA) in Biochemistry department of BSMMU. 

The intervention was used that ferric hydroxide polymaltose at a dose of 2 mg/kg/day of elemental iron per oral once daily mixed with expressed breast milk when they met eligibility criteria. When babies were eligible for early group in hospital stay, iron supplementation was given. But when babies were at home & eligible for early & late group supplementation then parents or guardian were communicated over phone and they brought their babies for blood sampling. Drop ferric hydroxide polymaltose (Drop Compiron) was manufactured by Incepta Pharmaceutical Company, Bangladesh. Same batch number (19011) of drug was supplied by me to all the babies. They were advised how to give oral iron, dosage of iron & observe any complications after supplementation of iron. Parents were also advised to maintain a chart about daily iron supplementation which was supplied.

Venous blood sampling was done at 2 weeks of postnatal age in case of early initiation group and at 6 weeks of age in case of late initiation group before starting of iron supplementation. Like baseline investigation, 2 ml venous blood sample was measured for S. ferritin, Hemoglobin, red cell indices & CRP. At 12 weeks of age, venous blood sampling was done in both groups & blood sample was measured for S. ferritin, hemoglobin, red cell indices & CRP. 

Anthropometry like weight, length and head circumference were measured on at birth, 2, 6 & 12 weeks of age. In Early group it was taken at birth, 2 weeks & 12 weeks of age. In late group it was taken at birth, 6weeks & 12 weeks of age. The newborns weights were taken without clothing soon after birth on an electronic scale with a precision of 10 g [Model 914, SALTER]. Those babies whose birth could not be attended weight were taken within 12 hours of birth. The length was measured by infantometer in cm. The baby was laid on his/her back with the head against the fixed head board. My helper colleagues held the baby’s head so that the eye angle- external ear canal line was vertical and also kept the body straight. With my one hand, baby’s knees were pressed down to straight the baby’s legs fully and with the other hand, the sliding footboard was placed to touch the baby’s heels firmly. When the foot board in place, the baby’s length was read on the meter scale in cm. Head circumference or OFC (occipital frontal circumference) was measured over the most prominent part on the back of the head (occiput) and just above the eyebrows (supraorbital ridges) by using a measuring tape. 

When babies were brought for follow up at 12 weeks weight was taken without any cloth before feeding and after voiding by the same weighing machine with a precision of 10 gm [Model 914, SALTER]. Length and OFC were taken in the same procedure when babies were brought for follow up at 12 weeks. 

Infants were followed up at 12 weeks of age by detail neurological examination and developmental assessment. To evaluate development, Bayley scales of Infant and Toddler Development, Third edition was used. This assessment was done by clinical psychologists assigned from Institute for Pediatric Neurodisorder and Autism (IPNA), BSMMU, on the schedule date, who were blinded about patient’s diagnosis. In the Bayley III, cognitive development, expressive and receptive language, and fine and gross motor development all were evaluated. Developmental delay was classified as “delayed” if a Bayley III score below 70 on any of the subscales. Reference values were taken from textbook of neonatology, Roberton, 5th edition [6].  All data were analyzed using the Statistical Package for Social Science (SPSS) version 20. P

Results

Among 145 admitted preterm neonates, 72 babies were eligible for the study. Till completion of the study, 40 babies completed follow up at 12 weeks, among them 21 babies were in early initiation (EI) group & 19 babies were in late initiation (LI) group as shown in Figure 1.

 Figure 1: Flow chart of patient enrollment

In table 1, baseline characteristics of mothers and neonates were observed. Mean gestational age, mean birth weight and most of the characters were similar in both groups. In Early group, slight female predominance (61.9%) and in late group, slight male (78.9%) predominance was observed. Baseline Mean Serum ferritin, hemoglobin, Hematocrit, RBC count, mean corpuscular volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, CRP were also similar in both groups.  p- value was not significant as observed in table 2. When red cell parameters and iron status was compared at 12 weeks between both groups, in table 3, mean S. Ferritin (ng/ml) was significantly high in Early group (92.75±47.33 ng/mL) as compared with   Late group (56.95±35.06 ng/mL), p value was statistically significant (p value 0.01) Other parameters were not changed significantly.

Parameter

Early group(n=21)

Late group(n=19)

p-value

Birth weight (gm)

1622.86±438.73

1753.16±401.76

0.335ns

Gestational age (weeks) n (%)

33.52±1.91

33.48±1.46

0.935ns

Sex of the baby, n (%)                   

 

 

0.009s

Male

8 (38.1)

15 (78.9)

 

Female

13 (61.9)

4 (21.1)

 

Small for gestational age

9 (42.86)

5 (26.32)

0.273ns

Antenatal complications

 

Gestational Diabetes Mellitus

4 (19.04)

6 (31.57)

0.361ns

Pregnancy-induced

hypertension

15 (71.4)

11 (57.89)

0.370ns

Maternal UTI

3 (14.29)

2 (10.53)

0.720ns

Premature rupture of

membranes

3 (14.29)

5 (26.32)

0.342ns

APH

Mode of delivery

3(14.29)

2(10.53)

0.72ns

0.835ns

Vaginal delivery

5  (23.81)

4 (21.05)

 

Caesarean section

16 (76.19)

15 (78.95)

 

Transfusion before 12 weeks

8 (38.1)

7 (36.84)

0.935ns

Bloodletting >8% before 12 weeks

8 (38.1)

7 (36.84)

0.935ns

Length at birth

41.17±2.93

40.882.61

0.477ns

OFC at birth

29.712.43

29.70±1.55

0.147ns

Table 1: Baseline characteristics of mothers and neonates in between two groups at birth 

Continuous data are presented as mean±SD and categorical data as number and percentage Statistical test: Chi square test, Independent Sample t test. S, significant; ns, not significant.

Parameter

Early group(n=21)

Late group(n=19)

p- value

Serum ferritin (ng/mL)

204.03± 102.09  

225.79± 131.32  

0.560ns

Hemoglobin (g/dL)

17.80±2.40

17.90± 2.23

0.893ns

Hematocrit (40-54 %)

50.66±6.82          

51.87±6.95          

0.582ns

RBC count (4.5-5.5*10^12/L).

4.85±0.56834      

4.81±0.67529      

0.838ns

Mean corpuscular volume (80-96 fL).

103.66±6.09        

107.65±8.67                        

0.098ns

Mean corpuscular hemoglobin (27-32 pg).

25.96±2.34                          

25.50±2.21196   

0.531ns

Mean corpuscular hemoglobin concentration (31-35 g/dl)               

34.88±1.14          

35.63±5.05          

0.508ns

RDW(%)

19.12±   2.15       

19.12±1.80          

0.977ns

s-CRP (mg/L)

1.32±1.57

1.55±2.55

0.730ns

Table 2: Baseline Serum Ferritin, Red cell indices & CRP of 2 groups at admission 

Data are presented as mean ± SD and number (percentage) unless otherwise indicated.

Parameters

Early group(n=21)

Late group(n=19)

p-value

S.Ferritin(ng/ml)

92.75±47.33

56.95±35.06

0.01s

Hb(g/dl) 

10.10±1.29

9.92±1.76

0.715ns

Hct(%)

29.58±3.27          

28.88±5.15

0.609ns

RBC count                                                   

(*106/L)

3.96±0.645

3.90±      0.89

0.837ns

MCV(fl)

75.85±6.98          

74.80±6.17

0.098ns

MCH(pg)                   

25.96±2.34          

25.50±2.21

0.531ns

MCHC(g/dl)              

34.20±1.10          

34±1.44

0.608ns

RDW(%)

15.09±1.81                          

15.70±3.79

0.511ns

s-CRP (mg/L)

2.16±2.68             

1.35±1.58

0.262ns

Table 3: Comparison of Ferritin & hematological parameters in early & late group neonates at 12 weeks 

All values were given as mean±SD. Statistical test: Independent Sample t test. S, significant; ns, not significant. 

Follow up of anthropometry at 12 weeks revealed, no significant change in both groups Table 4. The comparison of follow up score by Bayley scale III at 12 weeks of age also showed no significant difference as shown in table 5.

Parameters

Early group(n=21)

(mean± SD)

Late group(n=19)

(mean± SD)

p-value

Weight(gm)

4140.95±582.71

4058.42±734.97

0.695 ns

Length(cm)

53.83±2.60

54.73±2.89

0.291 ns

OFC (cm)

37.05±1.48

37.31±1.39

0.983 ns

Table 4: Comparison of anthropometry at 12 weeks of age

Statistical test: Independent t-test

BSID III scales

Early group(n=21)

Late group(n=19)

p-value

Cognition

74.90±15.59

74.73±15.04

0.973ns

Motor

71.61±13.76

72.36±12.63

0.859ns

Language

83.38±12.18

85.94±12.27

0.511ns

Table 5: Comparison of composite scores of BSID III at 12 weeks follows up period

Statistical test: Independent t-test

Discussion

In this study, there was used oral iron polymaltose complex at a dose of 2 mg/kg/day according to the American Academy of Pediatrics (AAP) and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommendations [7]. The two time periods were chosen for the two groups (2 weeks and 6 weeks, respectively). It was based on the ESPGHAN recommendations and on the evidence that supplemental iron gets well incorporated into red blood cells when the onset of erythropoiesis is starts at 6-8weeks [7].  We used colloidal ferric hydroxide because of the presence of high elemental iron (52.26%) and its easy availability in the form of appropriate drop formulation. In this study ferric hydroxide (iron polymaltose complex) was used & had better absorption with minimal gastric irritation. It could be easily converted to soluble form by the action of gastric acid and reduced to ferrous form by the mucoproteins present in the secretions of the stomach and the small intestine. In this study serum ferritin was used as an indicator of iron stores and each ferritin value was correlated with the hs-CRP value to detect the effect of inflammation. Baseline characteristics of the studied neonates were presented in mean birth weight (gm) was 1622.86±438.73 in early group & 1753.16±401.76 in late group, which was almost similar in both the groups. Mean gestational age was 33.52±1.91 and   33.48±1.46weeks of early group and late group neonates respectively. In Early group babies, there was slight female predominance (61.9%) and in late group, there was slight male (78.9%) predominance (Table 4.1). Serum ferritin (ng/mL) was 204.03± 102.09 in EI group &225.79± 131.32 in LI group, p- value 0.56. Hemoglobin (g/dL) was 17.80±2.40 in EI group & 17.90± 2.23 in LI group. There was no statistically significant difference in the gestational age, anthropometric parameters, baseline ferritin & hemoglobin values between the two groups, these results were similar to the previous observations by Joy R et al [8]. 

 In this study serum, ferritin level on follow-up at 12 weeks in the Early Iron supplementation (EI) group was significantly higher than the Late iron supplementation group (LI). In Early supplementation, (EI) group serum ferritin was 92.75±47.33 and the late iron supplementation group (LI) was 56.95±35.06, p-value 0.01, p value was significant. Similar findings were observed by others [8,9].  In this study we found that a delay in initiation of iron supplementation led to a decrease in serum ferritin. Similarly, early initiation of iron   supplementation led to an increase in iron stores within the margin of safety (25–200 ng/mL). Similar, findings were found in Joy R et al., so thereby justifying early initiation of iron supplementation in preterm VLBW babies. In contrast to this study results Franz A, et al. did not detect any significant differences in serum ferritin levels, presumably due to the greater blood transfusion requirements in the LI group. Sankar M, et al. found no difference in serum ferritin in EI & LI group because of small sample size [10,11]. This difference might be due to heterogeneity of study populations, with different gestational ages, birth weights and timing of iron initiation. At 12 weeks weight was 4140.95±582.71 versus 4058.42±734.97 (gm) (p value 0.6985); length was 53.83±2.60 versus 54.73±2.89 (p value.0291), head circumference was 37.05±1.48 versus 37.31±1.39cm (p value 0.983) in Early & late group respectively. We did not find any difference in weight, length and head circumference between the EI and LI groups at 12 weeks. These results were similar to the previous observations by Joy et al., Franz et al. and Friel et al [8,10,12]. Comparison of   follow up score by Bayley   scale III at 12 weeks of age. Mean cognitive score was 74.90±15.59 and 74.73±15.04; mean motor score 71.61±13.76 and 72.36±12.63; mean language score was in 83.38 ±12.18 and 85.94±12.27 in Early and Late group respectively. In all three parameters p value were not statistically significant. Joy et al., found clinically significant short-term neurological improvement at 12 weeks of life in the EI group but was not statistically significant. Their study lacks long-term follow up [8]. On the other hand, Steinmacher et al. demonstrated more mild neurological abnormalities and poorer cognitive performance at 5 years of age in the LI group (iron supplementation at 2 months) than in the EI group (iron supplementation at 2 weeks) [4]. This study was a single centered study with small sample size. BSID III was not done by single clinical psychologist. Moreover, long-term follow up was not also performed which could add valuable information on outcome of those babies after 12 weeks.

Conclusion

Early iron supplementation at 2 weeks of age in preterm newborn result in significantly higher serum ferritin level than late iron supplementation group but hemoglobin, red cell indices, anthropometry & neurodevelopment outcome did not differ significantly in between early & late iron supplementation groups.

References

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Citation: Mostari M, Kabir MM, Saima A, Shuma  AI, Afroze S, et al.  (2024) Early Versus Late Enteral Prophylactic Iron Supplementation in Preterm Infants: A Randomized Controlled Trial. J Neonatol Clin Pediatr 11: 120.

Copyright: © 2024  Mohtarama Mostari, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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