High-risk factors for metabolic bone disease in very low birth weight infants: a multicentre retrospective study

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High-risk factors for metabolic bone disease in very low birth weight infants: a multicentre retrospective study Yuyun Chen 
Fujian Maternity and Child Health Hospital, Fujian Medical University, Fujian Children's Hospital Jian Yang 
Yongchuan Maternity and Child Health Hospital Yi Wang 
Children's Hospital of Chongqing Medical University Wei Liu 
Children's Hospital of Chongqing Medical University Zhenhua Guo  ( [email protected] )
Children's Hospital of Chongqing Medical University
Research Article
Keywords: Metabolic bone disease, Very low birth weigt infants, High-risk factors
Posted Date: August 17th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-1932908/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.   Read Full License
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Abstract Background: The occurrence of metabolic bone disease in preterm newborns is not uncommon in follow- up, although there is no consistent data on the precise incidence and potential high-risk variables contributing to its occurrence.This study aims to identify the independent risk factors of metabolic bone disease in very low birth weight (VLBW) infants. 
Methods: Between January 2017 and June 2020, clinical data from 662 newborns with VLBW were retrospectively summarized in 3 pediatric academic centers. Based on the serum alkaline phosphatase and phosphorus levels, infants were split into the MBD and control groups. General health factors, mother birth status, mechanical breathing, enteral nutrition (EN), parenteral nutrition (PN), time on EN, drug use, complications, and biochemical MBD indexes were gathered and compared between the two groups.
Results: The prevalence of MBD among the 662 cases was 17.37% in the VLBW infants. The mean birth weight (BW) and gestational age (GA) in the MBD group, were 1083.92±126.25g and 28.07±2.09wk, respectively. Between the two groups, there were signicant variations in GA and BW (P < 0.05). When compared to the control group, the MBD group's incidence of IUGR was considerably greater (P < 0.05). Starting EN, PN duration, and mechanical ventilation were signicantly different between the two groups (P < 0.05). In infants with VLBW, GA and BW each functioned as a protective factor against MBD. In VLBW newborns, MBD was attributable to three separate risk factors: PN time, commencing EN time, and IUGR.
Conclusions: There are numerous contributing variables to MBD. In infants with VLBW, GA and BW each functioned as a protective factor against MBD.
Background A systemic bone illness called metabolic bone disease (MBD) is characterized by decreased bone mineral content as a result of a problem with calcium and phosphorus metabolism. Severe cases may result in fractures, adult low stature, senile osteoporosis, and symptoms similar to rickets. Mostly in very low birth weight (VLBW) or ultra-low birth weight (ULBW) infants, MBD is more common in extremely preterm infants. VLBW is present in roughly 23% of cases, while ULBW is present in about 55% [1].With the advent of numerous new perinatal medical technologies as well as advancements in NICU diagnosis and treatment technology, more and more VLBW newborns and even ULBW infants are surviving in recent years, indicating a major increasing trend in the disease. Early prevention of high-risk variables is essential since failing to diagnose MBD can eventually result in serious sequelae, such as pathological fracture.
Infants with MBD exhibit clinical symptoms years after blood biochemical alterations and X-ray changes in the bones. There isn't yet a gold standard for MBD diagnosis[2]. It is primarily based on imaging diagnosis together with bone metabolic indices. Backstrom et al. [3] believed that the best screening tests for poor bone mineral density in preterms were serum total alkaline phosphatase (ALP) activity above
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900 IU/L and inorganic phosphate concentrations below 1.8 mmol/L, which produced a sensitivity of 100% at a specicity of 70%. Combining the criteria was in line with the Chinese expert panel's recommendations for the clinical management of MBD of prematurity in 2021 [4].Serum ALP > 500 IU/L and serum phosphorus < 1.5 mmol/L were both categorized as severe MBD in a different study, which demonstrated their great sensitivity and specicity in the diagnosis of MBD[5].
In brief, aberrant ossication, imaging, and biochemical alterations in babies brought on by a decrease in bone mineral content and metabolic disorders in premature infants are the main causes of MBD in VLBW infants. MBD cannot be diagnosed based solely on the levels of serum calcium, phosphorus, or imaging tests. This thorough investigation is required, together with clinical practice, to correctly identify MBD in VLBW newborns.
In order to identify the high risk factors for MBD, we retrospectively examined the clinical information of premature infants with birth weights below 1500g.
Methods
Patients A total of 662 with very low birth weight were collected in the three academic pediatric centers between January 2017 and June 2020, and there were 320 males and 342 females. Inclusion criteria: 1) less than 1500g; 2) hospital admission within 24 hours of birth, and healthy survival; 3) complete archival data. Exclusion criteria:1) patients with congenital genetic and metabolic diseases, severe congenital gastrointestinal malformations, and congenital heart disease, 76 patients were excluded; 2) the patients' guardians did not sign the informed consent form. 47 patients were excluded.
Diagnostic criteria of MBD ALP > 900 IU/L, phosphorus < 1.8mmoL/L
Data collection
1. General conditions of infants: gender, gestational age, birth weight, small for gestational age. 2. Conditions of maternal: multiple pregnancies, premature rupture of membranes, gestational
hypertension, gestational diabetes mellitus, gynecological inammation. 3. Birth status: mode of delivery, asphyxia, intrauterine growth retardation (IUGR). 4. During the hospital stay: start EN time, time of parenteral nutrition (PN), time of mechanical
ventilation. 5. Use of drugs during hospitalization:furosemide, phenobarbital sodium, Steroids, caffeine,
aminophylline. . Complication: sepsis, neonatal necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) in
VLBW infants .
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Statistical analysis Statistical analysis was carried out by using SPSS 25.0 software. The chi-square test was used to compare rates for the counting data, which were expressed as the number of instances and percentage [n (percent)], while the t-test was used to compare the two groups for the measuring data with a normal distribution. The results of the univariate analysis indicated that the logistic regression analysis used the variables with statistical signicance to identify the independent risk factors of MBD.
Results
General situation There are 115 infants with serum ALP > 900IU/L and phosphorus < 1.8mmol/L. The incidence of MBD is 17.37% (115/662) in VLBW infants. In the MBD group, the mean gestational age (GA) was 28.07 ± 2.09 weeks, and the mean birth weight (BW) was 1083.92 ± 126.25 g. There were signicant differences in GA and BW between the two groups (P < 0.05) (Table 1).
Table 1 Comparison of GA and BW between the two groups
(mean ± sd) Group n GA (wk) BW (g)
MBD 115 28.07 ± 2.09 1083.92 ± 126.25
Control 547 30.79 ± 1.88 1298.81 ± 135.87
t   3.27 4.37
P   ≤ 0.01 ≤ 0.01
IUGR in the MBD group was considerably greater than in the control group (P < 0.01) Other than that, the MBD group had greater levels of gynecological inammation and gestational diabetes mellitus than the control group (P < 0.05). Gender, mode of conception, maternal illnesses during pregnancy, history of asphyxia, number of pregnancies, and placental function did not signicantly differ between the two groups (P > 0.05). (Table 2). The MBD group used more furosemide, phenobarbital sodium, steroids, caffeine, and aminophylline than the control group did (Table 2). The timing of the commencement of EN, the start of PN, and the start of mechanical ventilation varied signicantly between the two groups (P < 0.05). (Table 2).
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Table 2 Comparison of general information between the two groups [n (%)]
  MBD Control t/χ2 P value
Multiple pregnancy 43(37.39) 158(28.88) 3.25 0.0713
Premature rupture of membranes 27(23.48) 180(32.91) 1.12 0.2884
Gestational hypertension 61(51.69) 237(43.33) 3.62 0.0569
Gestational diabetes mellitus 24(20.87) 71(12.98) 4.81 0.0283
Gynecological inammation 10(8.69) 16(2.93) 8.39 ≤ 0.01
Cesarean delivery 104(90.43) 464(84.83) 2.45 0.1173
Asphyxia 5(4.35) 43(7.86) 1.74 0.1866
IUGR 28(24.35) 21(3.84) 58.31 ≤ 0.01
Male 63(54.78) 257(46.98) 2.31 0.1282
Furosemide 52(45.22) 103(18.83) 36.89 ≤ 0.01
Phenobarbital sodium 80(69.56) 202(36.93) 41.39 ≤ 0.01
Steroids 21(18.26) 12(2.19) 51.79 ≤ 0.01
Caffeine 89(77.39) 344(62.89) 8.83 ≤ 0.01
Aminophylline 86(74.78) 196(35.83) 58.95 ≤ 0.01
Start EN time (d) 1.83 ± 0.24 1.34 ± 0.18 4.35 ≤ 0.01
PN(d) 31.89 ± 5.88 19.37 ± 2.92 5.43 ≤ 0.01
Mechanical ventilation(d) 25.09 ± 4.67 11.90 ± 2.02 8.23 ≤ 0.01
Complications Sepsis, NEC, and BPD prevalence rates in the MBD group were substantially greater than those in the control group (P < 0.05). (Table 3).
Table 3 Comparison of complications between the two groups
[mean ± sd, n (%)]
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Multivariate logistic analysis GA, BW, IUGR, PN time, and commencing EN time were identied as independent risk variables for MBD in VLBW babies by multivariate logistic regression analysis. In newborns with VLBW, GA and BW were protective factors against MBD (Table 4).
Table 4 Multivariate logistic analysis of MBD risk factors
  b SE. P OR 95%CI
GA -0.786 0.134 ≤ 0.01 0.457 0.356–0.665
BW -0.501 0.276 ≤ 0.01 0.634 0.341–0.899
IUGR 1.735 0.675 ≤ 0.01 5.863 1.756–18.879
Start EN time(d) 0.987 0.229 ≤ 0.01 2.542 1.690–4.047
PN(d) 1.528 0.269 ≤ 0.01 5.976 3.217–10.549
Discussion The survival rate of VLBW or ULBW infants considerably increased as the degree of therapy for premature infants continued to advance. MBD has thus become more common in premature infants[6, 7]. Previous research has shown that a number of risk factors, such as premature delivery, low birth weight, medications that inuence the metabolism of calcium and phosphorus, long-term parenteral nutrition, and a delayed start to total enteral feeding, are associated with the development of MBD[6]. Additionally, the placenta provides the majority of the needed nutrients for the developing fetus, and the mother's nutritional health throughout pregnancy has a direct impact on the growth of the fetus[8]. Celestial bodies of the MBD group have insucient calcium and phosphorus reserves.When combined with prolonged fasting following delivery, intravenous nourishment alone is unable to provide nutritional needs, resulting in insucient calcium and phosphorus intake.
The bone mineral content of premature infants with gestational age < 32 weeks is 25–70% lower than that of term infants due to complications that affect the metabolism of calcium, phosphorus, and vitamin D. These complications include premature birth, sudden interruption of mineral transport, sudden changes in hormone levels, insucient supplementation of calcium, phosphorus, and vitamin D in early enteral and parenteral nutrition after birth, or an improper proportion of calcium and phosphorus[9].Our research demonstrates that the GA and BW were signicantly lower in the MBD group as compared to the control group. GA (OR = 0.457) and BW (OR = 0.634) were independently protective factors for MBD in VLBW babies, according to multivariate analyses. MBD has been linked to fast bone growth in the weeks following birth, insucient prenatal calcium and phosphorus storage, and insucient postnatal intake [10]. Because approximately 80% of the calcium and phosphorus reserves form between 24 and 40 weeks of gestation [11], the smaller the GA, the less calcium and phosphorus the fetus receives from the
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mother, causing a lack of signicant inorganic substances in synthetic bones and increasing the likelihood of MBD.
Chin et al[12] found that IUGR is an independent risk factor for MBD.The prevalence of MBD in VLBW babies with IUGR was found to be considerably higher in this study. IUGR was identied as an independent risk factor for MBD in VLBW babies by multivariate analysis. And the majority of IUGR cases were linked to maternal illnesses that occurred during pregnancy. According to our study, the MBD group had higher levels of gynecological inammation and gestational diabetes mellitus than the control group. Numerous factors have an impact on how bones develop and mineralize. Protein and energy are necessary for the creation of the collagen matrix, whereas calcium and phosphorus are necessary for the mineralization of bones[13].Reduced intrauterine transport of calcium, phosphorus, and other minerals is caused by maternal pregnancy problems like gestational diabetes mellitus and complex infections, which also raises the risk of MBD.
Caffeine, diuretics, and steroid use can result in calcium and phosphorus metabolism problems as well as bone mineral loss[11]. According to earlier research[1, 14], these medicines may inuence bone production and resorption, increasing the risk of MBD. In this study, univariate analysis revealed that the MBD group had greater consumption rates for caffeine, diuretics, steroids, phenobarbital sodium, and aminophylline. Inhibiting osteoblast growth, reducing calcium absorption in the gastrointestinal tract, and promoting calcium excretion in the renal tubules are all effects of glucocorticoids and loop diuretics, respectively.
The risk of MBD can increase as a result of phenobarbital's ability to accelerate the breakdown of 25 (OH) D[15]. According to previous research [16], there is a direct link between long-term caffeine usage and the development of MBD. While the use of diuretics had no statistically signicant relationship with osteopenia of preterm, steroids did. Further large sample studies are required. These variances may be attributed to the inclusion criteria for patients and various drug dosing times. In the MBD group, BPD was more common and MV lasted an average of longer than it did in the control group. In addition to taking into account the link between gestational age and organ immaturity, infants with BPD frequently require hormones, diuretics, and caffeine, which causes a lack of bone mineralization. Besides, mechanical factors are crucial in fetal mineral growth[17]. Because of respiratory conditions, low resistance, and infections, premature infants frequently require invasive ventilator-assisted ventilation after birth. These conditions make it dicult to distinguish between non-invasive and invasive ventilation for an extended period of time. Reducing the stimulation of mechanical forces to reduce the load on the bones and promote the production of new bone[18].
Gestational age and birth weight were independent protective variables for MBD, according to a multivariate analysis. The peak of osteogenesis occurs at 35 weeks of gestation, and premature infants, especially very premature infants, miss the best stage of mineral deposition such as calcium and phosphorus[19]. Three months after conception, when 80 percent of the fetal mineral reserve is present, the absorption rate is the fastest. Metabolic bone disease is also independently at risk due to low birth
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weight. Low birth weight babies must complete the catch-up growing of their bones after delivery. Babies with birth weights under 1000g have undeveloped digestive systems. It is challenging to provide adequate mineral intake since they are readily confounded by digestive tract illnesses such necrotizing colitis (NEC) and small bowel syndrome, which cause decreased intestinal intake, delayed PN, and impaired mineral absorption. According to earlier research[20], the EN start time and PN time are the two most important risk factors in this study. The 2015 Canadian feeding recommendations[21] advise beginning enteral feeding within 24 hours of birth, nishing it within one week for newborns with very low birth weights, and nishing it within two weeks for newborns with ultra-low birth weights. Both the entire enteral feeding and the average milk opening time in this study fell short of the recommendations.In addition to the early gestational age and low birth weight, the critical group also has many early problems, compromised gastrointestinal function, and other concerns.
Due to the shorter gestational age and more immature intestinal development in the study group, the incidence of NEC in the MBD group was greater than that in the control group. This group began enteral feeding later and maintained entire enteral feeding for a considerable amount of time, which raised the risk of NEC. Infants with NEC also experience prolonged fasting, intestinal obstructions that prevent calcium and phosphorus absorption, and a need for parenteral feeding for all nutritional supplements. Parenteral nutrition's lack of sucient calcium and phosphorus for VLBW infants' growth and development increases their chance of developing MBD[22].
Conclusions In conclusion, MBD in VLBW newborns has become a more serious issue, and its associated risk factors cover a broad range of problems. Based on this study, there are several independent risk factors for MBD, including low gestational age, low birth weight, IUGR complications, delayed enteral feeding, and parenteral nutrition. Strengthening prenatal care, lowering pregnancy complications, actively implementing enteral nutrition, cutting down on parenteral nutrition, and sensibly using caffeine, diuretics, and steroids are necessary as independent risk factors for metabolic osteopathy in VLBW infants. These actions are effective preventative measures for MBD.
Abbreviations ALP: Alkaline Phosphatase
NEC: Necrotizing Enterocolitis
PN: Parenteral Nutrition
Declarations Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Acknowledgements
The Children's Hospital of Chongqing Medical University, the Yongchuan Maternity and Child Health Hospital, and the Fujian Maternity and Child Health Hospital of Fujian Medical University  provided assistance with the data collection responsibilities. Each author contributed to a different aspect of the project, took part in its design, assisted in data analysis, and gave me feedback on how to change the essay's nal draft. 
Funding
This work was supported by the Natural Science Foundation of Chongqing (CSTC2020jcyj-msxmX0249). The study's design, data collection, analysis, or interpretation did not involve the funding source. The sponsor had no inuence on the report's creation or the choice to submit it for publication. 
Contributions
Each author contributed signicantly and gave their approval to the nal draft. ZG contributed to literature searches, study design, data analysis, writing, and critical revision. YC and ZG contributed to data analysis and critical revision. YW contributed to methodology and data analysis. JY and WL contributed to data acquisition. All authors read and approved the nal manuscript 
Corresponding author
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The Fujian Maternity and Child Health Hospital of Fujian Medical University, the Children's Hospital of Chongqing Medical University, and the Yongchuan Maternity and Child Health Hospital all participated in this multi-center study. The ethical assessment of the information acquired in the institutions had the approval of the Fujian Maternity and Child Health Hospital of Fujian Medical University (2020KY057), the Children's Hospital of Chongqing Medical University (2020-118), and the Yongchuan Maternity and Child Health Hospital (2020-LY-019). Before the study began, each participant's guardian completed an informed consent form, and they all received a debrieng after the evaluation. The study's participation was entirely voluntary, and every participant's guardians were made aware of their freedom to revoke consent or stop taking part at any moment. All procedures in the study were carried out in accordance with national ethical guidelines for medical and health research involving human subjects, as well as the 1964 Helsinki Declaration and its subsequent amendments. 
Consent for publication
The authors declare no conicts of interest.
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