|ORIGINAL ARTICLE - EVALUATIVE STUDY
|Year : 2014 | Volume
| Issue : 2 | Page : 75-79
Metabolic bone disease in low birth weight babies between 1500 and 2000 g on exclusive breast feeding
Sanjay Siddhartha1, Shobha Sharma1, Sugandha Arya1, Harish Kumar Chellani1, Neelam Roy2
1 Department of Pediatrics, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
|Date of Web Publication||31-Jul-2014|
Harish Kumar Chellani
Department of Pediatrics, Safdarjung Hospital, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Background: Metabolic bone disease of prematurity due to reduced bone mineralization is mostly described in infants of less than 1500 g. Although various guidelines recommend calcium and phosphate supplementation for low birth weight (LBW) newborns less than 1500 g and on exclusive breast feeding but there are no guidelines for those weighing above 1500 g and on exclusive breast feeding. Moreover, there is insufficient data on incidence of rickets and serum biochemical status in these babies of birth weight more than 1500g and on unsupplemented breast feeding and among term growth retarded babies. Objectives: To determine the incidence of rickets and changes in biochemical profile including serum calcium, phosphate, and alkaline phosphatase in preterm appropriate for gestational age (PTAGA) and term small for date (TSFD) babies with birth weight between 1500 and 2000 g and on unsupplemented breast feeding. Materials and Methods: It is an observational cohort study done at a tertiary care centre in northern India over a period of one year, including LBW babies between 1500 and 2000 g and on unsupplemented breast feeds. In group I, 116 PTAGA babies with birth weight 1500-2000g and on unsupplemented breast feeds were enrolled and 100 PTAGA babies completed follow up till 6 months. In group II 124 TSFD babies with birth weight 1500-2000 g and on unsupplemented breast feeds were enrolled and 100 TSFD babies completed follow up till 6 months. Biochemical parameters were done at baseline (before discharge) and were followed-up for a period of 6 months. Radiological assessment was done if clinical features of rickets appeared or serum biochemistry was suggestive of rickets. Results: Both groups, of babies, developed progressive decrease in serum calcium and phosphate levels, which was statistically significant as shown by time trend. Serum alkaline phosphatase showed significant increase from baseline in both the groups. Fourteen out of 200 (7%) babies developed radiological rickets at end of 3 months, which increased to 34/200 (17%) at end of 6 months. Serum alkaline phosphatase showed most consistent correlation with occurrence of rickets. Conclusion: LBW babies 1500-2000 g and on exclusive breast feeding are at significant risk of developing metabolic bone disease including rickets and need extra supplementation with calcium and phosphate besides Vitamin D.
Keywords: Low birth weight, metabolic bone disease, preterm appropriate for gestational age, rickets, term small for date
|How to cite this article:|
Siddhartha S, Sharma S, Arya S, Chellani HK, Roy N. Metabolic bone disease in low birth weight babies between 1500 and 2000 g on exclusive breast feeding. Astrocyte 2014;1:75-9
|How to cite this URL:|
Siddhartha S, Sharma S, Arya S, Chellani HK, Roy N. Metabolic bone disease in low birth weight babies between 1500 and 2000 g on exclusive breast feeding. Astrocyte [serial online] 2014 [cited 2022 Jul 3];1:75-9. Available from: http://www.astrocyte.in/text.asp?2014/1/2/75/137848
| Introduction|| |
Low birth weight (LBW) babies having birth weight of < 2500 g form a significant proportion of live births in India.  LBW of a newborn infant can be due to intrauterine growth restriction (IUGR) and/or prematurity. Approximately, eight million LBW infants are born each year in India and around 70-80% of them are term IUGR babies. , Among all LBW babies born (30%), 8.7% are below 2000 g and 3.4% are weighing < 1500 g at birth,  thus constituting about 5.3% of all babies weighing between 1500 and 2000 g which is a significant number annually. LBW is one of the most significant factors contributing to neonatal mortality and morbidity.
Metabolic bone disease (MBD) or osteopenia of prematurity occurring due to reduced bone mineralization is mostly described in infants of less than 1500 g, and severest form is observed in infants less than 1000 g birth weight, in which frank radiological rickets has been described in up to 57% of cases. Although exact incidence is not known, higher occurrence of postnatal rickets is also described in babies with intrauterine growth restriction  and more so in babies on exclusive breast feeding.  There is paucity of data on the effect of phosphate (Ph) and calcium (Ca) supplementation on clinical outcomes of infants with a birth weight greater than 1500 g. 
American Academy of Pediatrics (AAP; 2008) recommends supplementation of 400 IU of vitamin D per day to all breastfed infants starting from few days of life after birth,  The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends Ca and phosphorous supplementation at 120-140 and 60-90 mg/kg/day, respectively, for the VLBW infants (<1500g). World Health Organization (WHO) also recommends supplementation of Ca and phosphorus in breast-fed VLBW babies, but clear recommendations regarding Ca and Ph supplementation in LBW babies ˃ 1500 g is lacking. There is also paucity of literature about Ca and Ph deficiency as well as incidence of rickets in exclusively breast-fed new borns without supplements weighing between 1500 and 2000 g, more so in term small for date (TSFD) babies. This study was undertaken to determine changes in serum calcium (SCa), serum phosphate (SPh), serum alkaline phosphatase (SALP), and incidence of rickets in exclusively breastfed babies with birth weight between 1500 and 2000 g and to compare incidence of rickets among TSFD and preterm appropriate for gestational age (PTAGA) babies at a tertiary care centre.
| Material and Methods|| |
This was a hospital-based prospective cohort study, conducted in neonatal division of pediatrics department in a tertiary care centre. In group I, 100 PTAGA babies with birth weight 1500-2000 g and on unsupplemented breast feeds were included. In group II, 100 TSFD babies with birth weight 1500-2000g and on unsupplemented breast feeds were included. Informed written consent was obtained from parents. These babies were exclusively breastfed with no Ca and Ph supplementation and were followed for a period of 6 months.
Length was measured by infantometer and head circumference was measured using nonstretchable tape to nearest of 0.1 cm. SCa was measured by colorimetric method using dye O-cresolphthale in complex on SPh was measured by colorimetric method using 10% trichloracetic acid. SALP was measured by colorimetric method. All the measurements are being done by standard laboratory procedures.
Maternal nutritional status (i.e., weight, height), SCa, phosphorus, SALP were assessed. Day one was defined as the day on which baby was on total breast feeds.
Primary outcome variables, that is, biochemical (SCa, SPh, SALP) and anthropometric parameters (weight, length, head circumference) were measured serially. Anthropometric measurements were done fortnightly for 3 months and then monthly for next 3 months. Serum measurements were done on day 1, and 1, 3, and 6 months. If SALP was raised, X-ray wrist (AP view) were done to look for features of rickets.
Hypocalcaemia was defined as SCa level below 8.5 mg/dl and hypophosphatemia was defined as SP levels below 4.8 mg/dl. SALP values above 400 IU/l were taken as high. Radiological grading of MBD was done as:
Normal: Normal density of bony cortex along shaft with normal dense white line at metaphyses and normal band of lucency in submetaphyseal region.
Grade 1: Loss of dense white line at metaphyses, increased submetaphyseal lucency, and thinning of cortex.
Grade 2: Changes of grade 1 plus irregularity and fraying of metaphyses, with splaying and cupping, that is, changes of rickets.
Grade 3: Changes of rickets with evidence of fractures.
Grade 2 and 3 were taken as rickets.
Data analysis was done using SPSS and EPI-6 Info statistical software. Comparison of development of rickets between TSFD and PTAGA was done using chi-square test. The changes in biochemical parameters were analysed using trend analysis and pairwise comparison. During follow-up, the number of babies developing rickets was observed and incidence was computed as proportion with 95% confidence interval.
| Results|| |
Study population was from closed cohort of babies born at tertiary care institute over a period of one year.
In group I, 116 PTAGA babies with birth weight 1500-2000g were enrolled. During follow up, 2 babies died, 3 babies were started on top feeds, and 11 were lost to follow up. A total of 100 PTAGA babies completed follow up till 6 months of age.
In group II, 124 TSFD babies with birth weight 1500-2000g were enrolled. During follow up, 3 babies died, 4 babies were started on top feeds, and 17 were lost to follow up. A total of 100 TSFD babies completed follow up till 6 months of age.
There was no significant difference in average weight, length, and head circumference of babies in both groups at baseline as well as on repeat measurement at 3 and 6 months (P > 0.05).
The mean age, weight, and height of the mothers of PTAGA and TSFD babies were comparable (P > 0.05).
The mothers of TSFD babies had higher mean SCa and SPh levels while lower mean SALP levels (P < 0.05).
The SCa level during the follow up period was higher among the TSFD babies as compared with PTAGA babies but the difference was found to be statistically significant only at baseline and 3 months of follow up (P < 0.05, t-test). The SPh levels were comparable in both the groups. The SALP was found to be higher in PTAGA babies during the follow up period of 6 months, though the difference was not statistically significant (P > 0.05) [Table 1].
|Table 1: Biochemical Parameters of PTAGA and TSFD Babies During Follow Up Period|
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On repeated measure analysis or trend analysis, SCa levels were found to be progressively falling over the follow up period of 6 months both in PTAGA and TSFD babies. This trend was statistically significant (P < 0.05). In both PTAGA and TSFD babies, on pairwise comparison it was observed that there was significant fall in SCa levels from baseline to 1 month, between 1 and 3 months, and also from 3 to 6 months of follow up (P<0.05) [Figure 1].
|Figure 1: Trend of Serum Calcium levels among the PTAGA and TSFD babies during the follow up period.|
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On repeated measure analysis or trend analysis, SPh levels progressively decreased over the follow up period of 6 months both in PTAGA and TSFD babies. This trend was statistically significant (P < 0.05). In both PTAGA and TSFD babies, on pairwise comparison it was observed that there was significant fall in SPh levels from baseline to 1 month, between 1 and 3 months, and also from 3 to 6 months of follow up (P < 0.05) [Figure 2]
|Figure 2: Trend of Serum Phosphate levels among the PTAGA and TSFD babies during the follow up period.|
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On repeated measure analysis or trend analysis, there was progressive rise in SALP levels over follow up period of 6 months both in PTAGA and TSFD babies. This trend was statistically significant (P < 0.05). In both PTAGA and TSFD babies, on pairwise comparison it was observed that there was significant rise in SALP levels from baseline to 1 month, between 1 and 3 months, and also from 3 to 6 months of follow up (P < 0.05) [Figure 3].
|Figure 3: Trend of Serum Alkaline Phosphatase levels among the PTAGA and TSFD babies during the follow-up period.|
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At 3 months of age, about one-third (28.6%) of the radiological rickets cases had SPh levels less than 4.8 mg/dl, while only 6.5% of the normal cases had levels below 4.8 mg/dl. This difference was found to be statistically significant (P < 0.05). A larger proportion (78.6%) of babies with radiological rickets had SALP level of more than 400 IU/L as compared with normal babies (8.6%) and it was statistically significant (P < 0.05) [Table 2]. None of the cases in both the groups had SALP level above 800 IU/L.
|Table 2: Biochemical Parameters According to Presence of Radiological Rickets Among PTAGA and TSFD Babies at 3 Months of Age|
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At 6 months of age, significantly larger proportion of babies with radiological rickets had SCa levels (64.7%) below 8.5 mg/dl, SPh levels (85.3%) below 4.8 mg/dl (P < 0.05). None of the normal babies had SALP above 800 IU/L while 58.8% of the babies having radiological rickets had values above 800 IU/L (P < 0.05). Also, all the babies with radiological rickets had SALP above 400 IU/L while only 10.2% of the normal babies had levels above 400 IU/L and this difference was also highly significant (P < 0.05) [Table 3].
|Table 3: Biochemical Parameters According to Presence of Radiological Rickets Among PTAGA and TSFD Babies at 6 Months of Age|
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| Discussion|| |
MBD in newborns includes disorders resulting in inadequate mineralization or demineralization of bones due to substrate (Ca and Ph) or vitamin D deficiency. Osteopenia of prematurity is MBD of predominantly premature LBW babies and its incidence is reported to be 20-30% in very low birth weight (VLBW) babies and 60-75% in extremely low birth weight (ELBW) babies.  Cause is primarily considered to be Ph deficiency due to low reserves, further aggravated by exclusive breast feeding, which is poor in Ph (14 mg/dl).  Frank radiological rickets has been reported in up to 57% of infants weighing ˂ 1000 g.  Many studies have reported osteopenia and rickets in VLBW and ELBW babies on unsupplemented breast milk. ,, Unsupplemented breast milk in VLBW infants (birth weight <1500 g) has shown to result in slower weight and length gains. , Since there is strong and consistent evidence that feeding mother's own milk to preterm infants of any gestation is associated with a lower incidence of infections and necrotising enterocolitis, ,, breast feeding is uniformly recommended to all babies irrespective of birth weight. International and national organizations describe the importance of providing phosphorus and Ca supplementation to infants who weigh <1500 g at birth. , There is lack of data regarding incidence of rickets and status of biochemical profile (SCa, Ph, ALP) in LBW newborns between 1500 and 2000 g on exclusive breast feeding without supplements, less so in SFD babies, which form majority of LBW population (approximately 80%) in our country. This prospective study was done in low birth babies born at tertiary care centre weighing between 1500 and 2000 g on unsupplemented breast feeding, and their biochemical, anthropometric profiles were followed till 6 months of age to look into any significant difference in biochemical trends and incidence of radiological rickets in the two groups. All the mothers were booked cases with routine and regular supplements provided from the hospital during pregnancy. A total of 240 LBW babies were enrolled in the study, out of which 200 completed the study with 100 babies in each group. One group had PTAGA babies below 37 weeks of gestation with average gestational age of 32 weeks and other group had TSFD babies with average gestational age of 41 weeks. There was no significant difference in average weight, length, and head circumference of babies in both groups at baseline as well as on repeat measurement at 3 and 6 months (P>0.05). Similarly maternal profiles with respect to mean weight, age, and height were comparable in two groups (P > 0.05), but mean SCa and SPh levels were higher and SALP levels were lower in mothers of TSFD group suggesting better biochemical status in them. Baseline mean SCa in PTAGA was lower than TSFD group but at 6 months there was no significant difference in mean values of Ca in the two groups [Table 1]. Trend analysis showed consistent and significant decrease in SCa with time in both the groups [Figure 1], same trend of decreasing serum levels of Ph with time was observed, although there was no significant difference in mean levels of Ph in the two groups at any point of time [Table 1], [Figure 2]. Decreasing serum levels of Ca and Ph correlated with significant increase in SALP levels in both groups at 0, 3, and 6 months [Table 1]. However, change in SPh and SALP between 3 and 6 months was more apparent in PTAGA group [Figure 3].
At the end of 3 months, radiological rickets was observed in 7% (14) babies, with increased SALP (˃400 IU/L) in 79% of these babies, whereas only 8% babies in radiologically normal group had SALP ˃400 IU/L [Table 2], hence SALP shows best correlation with rickets. SALP ˃800 IU/L was not seen in any baby at 3 months despite presence of rickets. SPh was low (˂4.8 mg/dl) in approximately one-third, that is, 28.6% of the babies with radiological rickets and in only 6% of normal babies. SCa was least sensitive marker for rickets.
Incidence of rickets increased to 17% (34) at 6 months and all babies (34), that is, 100% of them had SALP˃400 IU/L, whereas levels ˃800 IU/L was seen in 59% of these babies. Only 10% of radiologically normal babies had SALP˃400 IU/L and none of them had levels ˃800 IU/L. Significant number of babies 65% and 85% had low SCa (˂8.5 mg/dl) and low SPh (˂4.8 mg/dl), respectively, in babies with radiological rickets [Table 3].
To minimize confounding factor of maternal biochemical status, babies with and without rickets at 3 months were correlated with maternal mean SCa, SPh, and SALP and correlation was found to be insignificant.
Assessment of MBD or rickets of prematurity can be done on clinical, biochemical, and radiological basis. Rickets implies radiological disease at the growing ends of the long bones and is apparent with at least 40% loss of bone mineralization, manifesting usually after 6 weeks of age.  Earliest biochemical indicators of osteopenia are decreased serum phosphorus concentration and increased SALP activity.
The majority of bone mineralization, along with Ca and Ph accretion occurs during the third trimester of pregnancy. From 24 weeks onwards, accretion rate of approximately 120 mg of Ca and 60 mg phosphorus/kg/day occurs to meet demand of rapid growth.  Infants born preterm therefore have depleted stores of these minerals especially Ph and this compounded with poor postnatal intake, increases the risk of osteopenia in preterm LBW babies.
There is evidence that the placenta has a role in bone mineral concentration (BMC). Vitamin D is converted to 1, 25-dihydrocholecalciferol in the placenta, which is important in the transfer of Ph across the placenta to the fetus.  Higher incidence of postnatal rickets is reported in babies with intrauterine growth restriction,  suggesting that chronic damage to the placenta may alter substrate transport. Severe demineralization has also been described in infants born to mothers with chorioamnionitis and placental infection.  It has been found that umbilical cord blood nutrients were lower in preterm LBW infants compared with term babies. 
Breast milk, either direct or expressed depending on gestational age and weight, is considered ideal feed for all newborns. Although the breast milk of mothers with pretermbabies has higher concentration of several nutrients such as energy, protein, Ca, and folate, but there is no increase in the concentration of many micronutrients including Ph and vitamin D, hence exclusive breast feeding without supplementation of micronutrients has been shown to be deficient for preterm babies and one of the causes of osteopenia or decreased mineralization in LBW babies. 
Takada et al. found evidence of rickets in 40% of premature infants fed with human breast milk compared with 16% of those fed with formula supplemented with Ca and phosphorus.
A total of 90% of ALP in infants is of bone origin and is thought to reflect bone turnover. Kovar et al. suggested that an ALP greater than five times the upper adult limit of normal is an indicator of the risk of rickets.  The present study highlights the increased vulnerability of LBW babies >1500 g both preterm as well as TSFD on exclusive breast feeding, to the development of MBD including rickets. However, this study has limitations that vitamin D levels and bone densitometry were not correlated with the findings of the study.
| Conclusion|| |
LBW babies ˃1500 g, both preterm as well as small for date, on exclusive breast feeding are at high risk of osteopenia and MBD including rickets and there is need to formulate clear recommendations regarding Ca and Ph supplementation along with vitamin D for this group of babies.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]