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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 1  |  Page : 8-17

Some biochemical and radiological markers of bone mineral content in premature neonates


1 Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
2 Department of Rheumatology and Immunology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt

Date of Submission24-Aug-2019
Date of Decision17-Nov-2019
Date of Acceptance12-Dec-2019
Date of Web Publication26-Mar-2020

Correspondence Address:
Wafaa A.E Abd El-Hafeez Salem
Assiut 71631
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_108_19

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  Abstract 


Background and aim Inadequate supplementation of calcium and phosphorus in preterm infants significantly increases the risk of reduction of bone mineral content. As birth weight and/or gestational age increase, metabolic bone disease prevalence decreases and vice versa. This study aims to investigate and evaluate biochemical and radiological markers as early predictors of bone mineral content in preterm infants of up to 4 months of age.
Patients and methods A case–control study included 20 preterm infants born less than 37 weeks of last menstrual period and 20 full term infants born greater than 37 weeks are involved as a full term group. Both groups are presented to the Neonatology Department, Al-Azhar University, Assuit, Egypt. Full history, full clinical examination, and investigations were done: complete blood count, serum alkaline phosphatase (ALP), serum total calcium (Ca), serum phosphorus (P), and wrist radiograph.
Results According to investigations, there was no significant difference between preterm and full term infants in serum calcium and serum ALP at birth (P>0.05 for each), while there was significant difference between preterm and full term infants according to serum phosphorus, as the mean serum phosphorus in the preterm group (1.06±0.21) was lower than the mean serum phosphorus in the full term group (2.16±0.19) (P<0.05 for each) at birth. There was significant difference between investigation results in the preterm group at 2 months and at 4 months according to serum phosphorus, serum ALP, as these investigations increase after 4 months in the preterm group. There was no significant difference according to serum calcium at 2 months and 4 months (P>0.05). Also, cases with rickets increase after 4 months in the preterm group (P<0.05 for each). There was significant difference between the age of 2 and 4 months regarding bone changes in patients with rickets, as cases with widening, cupping, and fraying increases after 4 months in the preterm group (P<0.05).
Conclusion Metabolic bone disease in preterm infants is affected by gestational age and birth weight. As birth weight and/or gestational age increase, metabolic bone disease prevalence decreases and vice versa. Assessment of serum ALP and serum phosphorus have helped to identify and expect preterm infants with high risk of metabolic bone disease.

Keywords: alkaline phosphatase, calcium, metabolic bone disease, phosphorus. bone mineral content, premature


How to cite this article:
Hamed AM, Rayan MM, Abd El-Hafeez Salem WA. Some biochemical and radiological markers of bone mineral content in premature neonates. Al-Azhar Assiut Med J 2020;18:8-17

How to cite this URL:
Hamed AM, Rayan MM, Abd El-Hafeez Salem WA. Some biochemical and radiological markers of bone mineral content in premature neonates. Al-Azhar Assiut Med J [serial online] 2020 [cited 2020 May 25];18:8-17. Available from: http://www.azmj.eg.net/text.asp?2020/18/1/8/281344




  Introduction Top


Development of the bone is one of the essential factors of fetal and postnatal growth [1]. Inadequate supply of calcium and phosphorus (Ca–P) in preterm infants significantly increases the risk of reduction of bone mineral content [2]. During the third trimester of pregnancy in mothers with good health, there is a good transfer of Ca-P through the placenta to the fetus leading to a high mineral content, while after birth the infant depends only on the nutritional supply of minerals [3]. The metabolic bone disease in preterm infants is affected by gestational age and birth weight. As birth weight and/or gestational age increase, the metabolic bone disease prevalence decreases and vice versa, about a third of infants with weight less than 1 kg at birth are osteopenic [4]. Also, inadequate vitamin D, calcium (Ca) and phosphorus (P) supplementation after birth, total parenteral nutrition for a long period, immobilization for long periods, and side effects of some drugs such as diuretics and corticosteroids prescribed to these infants may affect their bone mineralization [5]. Manifestation of osteopenia differs according to the degree of bone demineralization, as it may be clinically silent or manifested as rickets, or fractures in severe cases [6]. Assessment of serum alkaline phosphatase (ALP), serum calcium, and serum phosphorus have helped to identify preterm infants with osteopenia [7]. Backstrom et al. [8] consider that a high level of serum ALP and a low level of serum phosphorus are considered the best available screening methods for low bone mineral content.


  Aim Top


The aim of this study was to investigate and evaluate biochemical and radiological markers as potential predictors of bone mineral content in preterm infants of up to 4 months of age.


  Patients and methods Top


Study population

This prospective, randomized, comparative study is applied on 20 preterm infants (eight males and 12 females) born less than 37 weeks of postmenstrual age. The study was approved by Al-Azhar-Assiut Faculty of Medicine ethical committee. Twenty full term infants (nine males and 11 females) born greater than 37 weeks are involved as a full term group. Both groups are presented to the Neonatology Department at Al-Azhar University at Assuit.

Inclusion criteria

This study included preterm infants with gestational age less than 37 weeks and birth weight less than 2500 g.

Exclusion criteria

We excluded infants with major congenital abnormalities, chromosomal abnormalities, suspected congenital bone or muscle disease or congenital biliary atresia as it may affect serum ALP levels. Also, we excluded infants admitted with age greater than 28 days, transferred to other neonatology centers, or died.

Study design and assessments

Complete history taking:
  1. Detailed personal history.
    1. Detailed nutritional history.
    2. Detailed history of medications.
    3. Detailed family history.
    4. Detailed past history.
  2. General and systemic examination.
  3. Investigations:
    1. Complete blood count.
    2. Serum ALP.
    3. Serum total calcium (Ca).
    4. Serum phosphorus (P).
    5. Wrist radiograph.


Signs of prematurity [9]:

  1. Gestation term of less than 37 weeks: a little mass and length of child (<2.5 kg and 47 cm).
  2. Absence or weak expression of ossification of nuclei; nose and ear cartilage mildness (auricles densely adjoined to the cranium).
  3. Nails are soft, do not reach to the tip of fingers.
  4. Superfluous fluff is saved, especially on a shoulder girdle and superior portion of the back.
  5. Boys testicles not in the scrotum omitted.
  6. In girls, major pudenda lips not covering the clitoris and small pudendal lips.


Dosage of maternal calcium supplement

In populations with low dietary calcium intake, daily calcium supplementation (1.5–2.0 g oral elemental calcium) is recommended for pregnant women [10].

Dose of calcium supplement for neonates

Usual starting oral calcium dose: 20 mg/kg/day. Can increase up to 80 mg/kg/day. Divide the daily dose into 2–4 doses mixed with feeds.

All investigations will be performed to preterm infants at birth, 2 months, and 4 months of age and performed to term infants only at birth. Results will be collected, analyzed, and discussed.

Laboratory analysis

Heparin specimens were centrifuged at 3000 rpm for 5 min and analyzed within 20–30 min after collection. Gel tube specimens were analyzed for iCa within 1 h of collection after clot formation and centrifugation at 3000 rpm for 5 min. Serum was then used for the estimation of serum calcium.

Ionized calcium was estimated using ISE on Cobas 121 analyzer (Roche Diagnostics, Indianapolis, Indiana, USA). Serum calcium was analyzed by means of a bichromatic end-point methodology using Arsenazo III reagent on Synchron CX 9 (Beckman, USA).

Alkaline phosphatase assay

Cells were washed twice by centrifugation with normal saline (0.15 mol NaCl) without phosphate buffers to remove ethanol. Cells were then preincubated in the ELF-97 developing buffer provided by the manufacturer without or with levamisole at 5 mmol/l for 15 min. Before use, the ELF-97 phosphate was filtered through a 0.2 μm centrifuge filter to remove precipitated substrate. The ELF-97 phosphate was then added to the cells in a final volume of 100 μl at the final concentration indicated by the manufacturer (1 : 20 in the provided buffer). Cells were incubated at room temperature for times ranging from 1 to 30 min, followed by the addition of levamisole at 10 mmol/l to all tubes to stop the reaction. The cells were then analyzed by flow cytometry within 1 h of reaction completion.

Phosphorus assay

Phosphorus (Pi) Colorimetric Assay Kit (Phosphomolybdate method).

Radiological assessment

Enrolled premature infants underwent radiological examination of the forearm with a portable radiographic machine at corrected term age. Radiological examination of the forearm with the portable radiographic machine was performed by a single radiographer. Infants were exposed to radiation dose at 50–55 kVp (kilovolt peak) and 0.5 mAs. Diagnostic reference level was 68 kVp/0.5 mAs. Comments on radiographic findings were made by a radiologist who was blinded to laboratory findings.

Statistics

Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM-SPSS Inc., Chicago, Illinois, USA) program was used for data analysis. Data were described and expressed in tables as mean±SD. Frequency and percentages were expressed in qualitative data. χ2-tests were used for comparison of qualitative data. Quantitative variables were compared using independent sample t-test. Spearman correlation coefficient (r) was performed for correlation between continuous variables. P values of less than 0.05 were considered significant.


  Results Top


This study is applied on 20 preterm infants born less than 37 weeks of postmenstrual age, and 20 full term infants greater than 37 weeks as a full term group ([Table 1]).
Table 1 Comparison between preterm group and full term group according to demographic characteristics

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There was statistically significant difference between preterm and full term infants according to their gestational age, as the mean gestational age in the preterm group (32.45±1.73) was lower than the mean gestational age in the full term group (38.8±1.54) (P<0.05). However, there was no statistically significant difference between two groups according to age, sex, and type of delivery (P>0.05 for each). The Appearance, Pulse, Grimace, Activity, Respiration (APGAR) score show a significant decrease in the preterm group (P<0.05) ([Table 2]).
Table 2 Comparison between preterm and full term groups according to investigations at birth

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According to investigations, there was no statistically significant difference between preterm and full term infants in serum calcium, ionized calcium, and serum ALP (P>0.05 for each), while there was significant difference between preterm and full term infants according to serum phosphorus, as the mean serum phosphorus in preterm group (1.06±0.21) was lower than the mean serum phosphorus in the full term group (2.16±0.19) (P<0.05 for each) ([Table 3]).
Table 3 Comparison between investigation results in the preterm group at birth, at 2 months, and at 4 months

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There was statistically significant difference between investigation results in the preterm group at birth, at 2 months, and 4 months according to serum phosphorus, serum ALP, as these investigations increase after 4 months in the preterm group. Also, cases with rickets increase after 4 months in the preterm group (P<0.05 for each), while there was no statistically significant difference according to serum calcium and ionized calcium (P>0.05) ([Table 4]).
Table 4 Comparison between wrist radiograph bone changes in the preterm group at 2months and 4 months

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There was significant difference between the age of 2 months and 4 months regarding bone changes in patients with rickets, as cases with widening, cupping, and fraying increase after 4 months in the preterm group (P<0.05) ([Table 5]).
Table 5 Comparison between preterm infants supplemented by Ca and vitamin D. at 2 months and 4 months

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There was no significant difference between the age of 2 months and 4 months regarding oral vitamin D supplementation (P>0.05), while there was significant difference between the age of 2 months and 4 months regarding calcium supplementation, as the number of infants taking calcium supplement increases markedly at 4 months (P<0.05) ([Table 6]).
Table 6 Correlation between serum calcium, serum phosphorus, serum alkaline phosphatase, and preterm infants’ birth weight

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There was significant positive correlation between serum calcium and ionized calcium, serum phosphorus, and preterm infants’ weight at birth (P<0.05), while there was significant negative correlation between serum ALP and preterm infants’ weight at birth (P>0.05) ([Table 7]).
Table 7 Relation between serum calcium, serum phosphorus, serum alkaline phosphatase at birth and maternal complications during labor

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There was significant relation between serum calcium and ionized calcium, serum phosphorus, serum ALP at birth and maternal complications during labor (P>0.05) ([Table 8]).
Table 8 Relation between serum calcium, serum phosphorus, serum alkaline phosphatase at birth and feeding history

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There was significant relation between serum calcium, serum phosphorus, and serum ALP at birth and during Breastfeeding (P<0.05), while there was no significant relation between serum calcium, ionized calcium, serum phosphorus, serum ALP at birth and during bottle or complementary feeding (P>0.05) ([Table 9]).
Table 9 Relation between serum calcium, serum phosphorus, serum alkaline phosphatase at birth and maternal calcium intake

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There was no significant relation between serum phosphorus, serum ALP at birth and maternal calcium intake (P>0.05), while there was significant relation between serum calcium and ionized calcium at birth and maternal calcium intake (P<0.05) ([Table 10]).
Table 10 Relation between serum calcium, serum phosphorus, serum alkaline phosphatase and calcium supplementation at 2 months

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There was no significant relation between, serum phosphorus, serum ALP, and calcium supplementation at 2 months (P>0.05), while there was significant relation between serum calcium and ionized calcium and calcium supplement (P<0.05) ([Table 11]).
Table 11 Relation between serum calcium, serum phosphorus, serum alkaline phosphatase, and calcium supplementation at 4 months

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There was no significant relation between serum phosphorus, serum ALP, and calcium supplementation at 4 months (P>0.05), while there was significant relation between serum calcium and ionized calcium and calcium supplementation (P<0.05) ([Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7]).
Figure 1 Correlation between serum calcium, phosphorus, and preterm infants’ weight at birth.

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Figure 2 Wrist radiograph demonstrating metaphyseal widening and fraying at 2 months.

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Figure 3 Wrist radiograph demonstrating metaphyseal and fraying at 2 months.

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Figure 4 Wrist radiograph demonstrating metaphyseal widening and fraying at 2 months.

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Figure 5 Wrist radiograph demonstrating metaphyseal widening and fraying at 2 months.

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Figure 6 Wrist radiograph demonstrating metaphyseal widening and fraying at 4 months.

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Figure 7 Wrist radiograph demonstrating metaphyseal cupping at 4 months.

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  Discussion Top


Our study is a prospective case full term study aimed at assessing serum Ca, ionized calcium and P levels, serum ALP level and radiograph of the wrist as potential predictors of bone mineral content in preterm infants. We studied 40 infants: 20 preterm infants less than 37weeks of gestational age and less than 2500 g birth weight. Twenty full-term infants born at >37 weeks are involved as a full term group.

We demonstrated significant difference between preterm and full term infants according to gestational age, as the mean gestational age in preterm group (32.45±1.73 weeks) is lower than the mean gestational age in the full term group (38.8±1.54 weeks) (P=0.044). Gestational age is considered to be an important factor for phosphorus metabolism and bone mineral content. As the preterm infants most probably have immature kidneys and as tubular reabsorption of phosphorus is deficient, renal excretion of phosphorus is increased [11].

We observed no significant difference between preterm and full term infants according to sex (P=0.535). Our findings disagreed with Peacock et al. [12] who studied 120 preterm infants and observed that male gender was at high risk for decreased bone mineral content (BMC), decreased serum level of phosphorus concentrations with increased renal phosphorus excretion. They explained a delayed maturation of the kidneys function in male gender compared with females due to the role of sex hormones in the regulation of the immune system as is known for the development and maturation of pulmonary function.

Our study has shown a significant difference between preterm and full term infants according to maternal history of anemia; hypertension (HTN) and urinary tract infection (UTI) were found in large numbers in the preterm group (P=0.001). We also found a significant difference between preterm and full term infants according to complications during labor such as pre-eclampsia, abruptio placentae, and multiple pregnancy (P=0.001). The high incidence of osteopenia and rickets in neonates with intrauterine growth restriction is explained by chronic placenta insufficiencies such as preeclampsia, chorioamnionitis, and placental infection, resulting in impaired phosphorus transport and decreased bone mineralization [13].

The current study has found significant difference between preterm and full term infants according to weight. The mean weight in the preterm group (1.90±0.28) was lower than the mean weight in the full term group (2.99±0.42). Figueras-Aloy et al. [14] observed low bone mineral density in about 17% of their studied preterm neonates (<31 weeks gestation and birth weight <1.500 g).

We also found no significant difference between preterm and full term infants of serum calcium at birth (P=0.203). And no significant difference in the preterm group at birth, at 2 months and at 4 months (P=0.657). This was in agreement with the results reported by Visser et al. [15]. In a study of 40 preterm infants, within normal serum calcium level was observed in their studied osteopenic infants, and they explained a normal calcium level due to the effect of parathormone which stimulates calcium reabsorption and maintains its normal level in the blood. In a national screening of some neonatal units in the UK designed to assess babies at risk of osteopenia of prematurity, they demonstrated that serum calcium is not a potential marker for metabolic bone disease as normal infants can normalize serum calcium level in spite of loss of bone calcium. The level can also increase with increased phosphorus excretion and hypophosphatemia [16]. Hung et al. [17] reported normal levels of serum calcium in premature infants with low bone density (<34 weeks’ gestation) as well as in non-osteopenic infants.

Our study has shown that there was no significant difference between preterm and full term infants in serum ALP at birth (P=0.604). We also found significant difference between preterm and full term infants according to serum phosphorus, as the mean serum phosphorus in the preterm group (1.06±0.21) is lower than the mean serum phosphorus in the full term group (2.16±0.19). According to the serum phosphorus level, Hitrova et al. [18] reported that the low serum phosphorus level during the first 2 weeks of life (P<1.6 mmol/l) followed by a gradual increase up to normal phosphorus levels at 8 weeks after birth can be considered a good marker to detect osteopenia of prematurity.

There was significant difference between investigation results in preterm infants at 2 and 4 months according to serum phosphorus and serum ALP, as these investigations increase after 4 months in preterm infants (P=0.001). Newly, some authors have observed that preterm infants with low serum phosphorus levels (<2 mmol/l) are at high risk of metabolic bone disease (MBD), and levels less than 1.8 mmol/l more suspicious to have signs of rickets in radiographic findings. They say that a combination of serum phosphorus levels with serum ALP levels give high specificity and sensitivity for identification of infants with high risk of low bone mineral content and osteopenia [16]. This agreed with other authors who showed that serum ALP levels greater than four times normal adult levels is considered a good marker of metabolic bone disease. Serum ALP levels greater than 600 IU/l has 100% diagnostic sensitivity and 70% specificity in the absence of hepatic disease [19] According to radiographic evaluation, we observed that only four (20%) infants had evidence of rickets at 2 months (10%) such as widening and (10%) fraying. Eleven infants (55%) had evidence of rickets at 4 months (25%) such as widening (b%), fraying, and (5%) cupping (P=0.001). Mitchell and colleagues selectively investigate 32 low birth weight infants who have serum ALP level greater than 800 IU/l for manifestation of rickets in the radiograph. All had evidence of decreased bone density and 18/32 (56%) had radiological rickets [20]. A retrospective review by Faienza and colleagues between 2009 and 2011 showed 43% (112 of 258 preterm infants) with radiological evidence of osteopenia [21]. Also Hung et al. [17] studied 18 premature infants (<34 weeks’ gestation); about 39.1% of the study infants have MBD of prematurity on radiographic examination. Viswanathan et al. [22] showed that 30.9% of preterm infants they studied have radiological manifestation of rickets, with spontaneous fractures in 33.8%.

We demonstrated there was difference of no statistical significance regarding oral vitamin D supplementation of preterm infants at 2 and at 4 months of age, while there was significant difference between them regarding calcium supplement, as the number of infants taking calcium supplement increase markedly at 4 months (P=0.022). The Expert Panel of the Life Sciences Research Office of Pediatrics recommended that an adequate nutritional intake of calcium, phosphorus, and vitamin D adequately at early life and passive phybsical exercises may decrease risk of osteopenia and may stimulate proper growth and development of premature infants [3]. The current study found significant positive correlation between serum calcium, ionized calcium, serum phosphorus and preterm infants’ weight at birth (r=0.018; P=0.012) (r=0.534; P=0.015). Serum calcium, ionized calcium, and serum phosphorus levels increased with increased birth weight. This was in agreement with Yeste et al. [23] who studied 80 preterm infants who showed positive correlations between BMD at 0–1.5 months and birth weight (r=0.31; P=0.002).

There was significant relation between serum calcium, ionized calcium ionized, serum phosphorus, and serum ALP at birth and breastfeeding (P=0.002), while there was no significant relation between serum calcium, ionized calcium, serum phosphorus, serum ALP at birth, and bottle-feeding (P=0.337). This agreed with Pereira-Da-Silva et al. [24] who reported that infants receiving fortified breast milk or use of a specific formula for premature infants had higher BMD values. As absorption of calcium present in breast milk is more than absorption of calcium present in formula, it reach to a rate of 70%, compared with 25–30% for formula calcium. This disagreed with Fewtrell et al. [25] who showed that nutrition of premature infants with breast milk is not always accompanied with high bone mineral content.We demonstrated that there was significant relation between serum calcium and calcium ionized at birth and maternal calcium intake (P=0.001), while there was no significant relation between serum phosphorus and serum ALP at birth and maternal calcium intake (P=0.255). This was in agreement with Christmann et al. [26] who study the history and compliance of mothers of premature infants with osteopenia to calcium intake during pregnancy. They found three-fourths of mothers of osteopenic infants have no history of calcium intake during their pregnancy. Koo et al. [27] found that low calcium intake in diet by mothers during pregnancy resulted in high risk of low bone mineral content of premature infants, and calcium supplement to mothers with deficient nutritional calcium intake is associated with increased bone mineral content of the whole body in full term infants.

In contrast, Zhao et al. [28] concluded that calcium intake of women during gestation had no link with bone mineral content in the first postnatal year. The difference was present as the studies were not limited to mothers of preterm infants.

We also found significant relation between serum calcium and calcium ionized in relation to calcium supplementation at 2 and 4 months (P=0.001). of the Ybarra [29] study reported that premature infants on breast milk and who received calcium and vitamin D 800 IU supplement daily have bone mineral content better than infants who received vitamin D only, and more of infants with no history of calcium or vitamin D supplementation have manifestation of rickets.


  Conclusion Top


  1. The rate of neonatal metabolic bone disease is increasing with decreased gestational age and/or birth weight and vice versa.
  2. High alkaline phosphatase and low serum phosphorus levels can be considered as reliable markers to expect the status of mineralization of bone and the need to evaluate preterm infants radiologically.
  3. Radiologic evidence of metabolic bone disease was 20% among premature infants of gestational age less than 37 weeks at 2 months and 55% at 4 months.


Recommendations

After we have done our study we recommend:
  1. All infants should be monitored for MBD if they are born before 37 weeks of gestation, or if their birth weight is less than 1500 g, or if they have received total parenteral nutrition for a long period. Monitoring includes serum ‘bone profile’ (calcium, phosphorus, and alkaline phosphatase).
  2. A measure of 800 IU/day vitamin D as a supplement has been suggested if MBD biomarkers are abnormal.
  3. In addition, breastfeeding should be encouraged.
  4. Also, we should encourage daily calcium intake for mothers during pregnancy.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]



 

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  In this article
   Abstract
  Introduction
  Aim
  Patients and methods
  Results
  Discussion
  Conclusion
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