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Advances in Clinical Medicine
Vol. 11  No. 03 ( 2021 ), Article ID: 40791 , 7 pages
10.12677/ACM.2021.113118

骨化三醇对极低出生体重儿骨代谢与合并症的影响

张俏俏*，种晓秦*，姜红

青岛大学附属医院，山东 青岛

收稿日期：2021年2月3日；录用日期：2021年2月19日；发布日期：2021年3月4日

摘要

目的：通过对极低出生体重儿(Very low birth weight infants, VLBWI)补充骨化三醇与维生素D3的临床对照研究，探讨活性维生素D制剂对VLBWI骨代谢及相关疾病的影响。方法：前瞻性对照研究，选择2019年1月~2019年10月期间入住青岛大学附属医院NICU、并取得家长知情同意的40例VLBWI为骨化三醇组，随其后入院的第1个VLBWI 40例为对照组。两组VLBWI在喂养耐受后(骨化三醇组为10.26 ± 3.76天，对照组为10.65 ± 5.20天)均给予维生素AD每日1粒(含维生素D 500 IU、维生素A 1500 IU)，骨化三醇组每日加服骨化三醇(0.125 ug)，对照组每日加服维生素D3 (400 IU)。两组VLBWI在生后24小时内及生后1月时分别测定血清25-(OH)D、碱性磷酸酶(Alkaline phosphatase, ALP)、血磷、血钙水平，矫正胎龄(Corrected gestational age, CGA) 40周时测量身长、体重、头围体格发育指标，并收集两组VLBWI住院期间临床资料。进行统计学处理。结果：1) 骨代谢指标比较：两组生后24小时及1月龄时血清25-(OH)D、血ALP、血钙、血磷水平差异均无统计学意义(P > 0.05)；两组喂养方式、TPN时间及钙磷摄入差异无统计学意义(P > 0.05)；CGA 40周时身长、体重、头围比较差异无统计学意义(P > 均0.05)。2) 围产期合并症比较：骨化三醇组机械通气时间(2.5 ± 0.5 vs 5.8 ± 0.8 d)及住院时间(49.50 ± 2.8 vs 56.00 ± 3.5 d)均低于对照组，差异有统计学意义(P < 0.05)。两组支气管肺发育不良(Bronchopulmonary dysplasia, BPD)总体发生率(23.68% vs 35.14%)，差异无统计学意义(P > 0.05)，但骨化三醇组轻度BPD发生率显著高于对照组(88.89% vs 38.46%)，中度BPD发生率明显低于对照组(0% vs 46.15%)，差异均有统计学意义(P < 0.05)；骨化三醇组败血症发生率较对照组低(10.53% vs 32.43%)，差异有统计学意义(P < 0.05)；两组VLBWI无创通气时间以及新生儿呼吸窘迫综合征(Respiratory distress syndrome, RDS)、代谢性骨病(Metabolic bone disease, MBD)发生率比较，差异无统计学意义(P > 0.05)。结论：1) VLBWI生后补充骨化三醇替代补充维生素D3对骨代谢的影响无明显差异。2) VLBWI补充骨化三醇可以缩短机械通气时间及住院时间，减轻BPD的严重程度，降低败血症的发生率。

关键词

骨化三醇，维生素D3，早产儿，极低出生体重儿，骨代谢，并发症

The Effects of Calcitriol on Bone Metabolism and Diseases in VLBWI

Qiaoqiao Zhang*, Xiaoqin Chong*, Hong Jiang

The Affiliated Hospital of Qingdao University, Qingdao Shandong

Received: Feb. 3rd, 2021; accepted: Feb. 19th, 2021; published: Mar. 4th, 2021

ABSTRACT

Objective: To explore the effects of active vitamin D preparation on bone metabolism and diseases in very low birth weight infants (VLBWI), through a clinical controlled study of calcitriol and vitamin D3 supplementation. Methods: A prospective observational study was conducted in the NICU at the Affiliated Hospital of Qingdao University between January and October 2019. The VLBWI whose parents signed an informed consent form was included in the calcitriol group (n = 40); the next VLBWI admitted to the NICU following the calcitriol group was included in the control group (n = 40). Both groups of premature infants were given vitamin AD (vitamin D 500 IU, vitamin A 1500 IU) 1 capsule per day after gestational tolerance (the calcitriol group 10.26 ± 3.76 days, the control group 10.65 ± 5.20 days), the calcitriol group added calcitriol 0.125 ug per day and the control group added vitamin D3 400 IU per day. Serum 25-(OH)D, alkaline phosphatase (ALP), calcium and phosphorus levels were measured within 24 h and 1 month after birth. The length, weight and head circumference were measured at 40 weeks of corrected gestational age. The clinical data of two groups during hospitalization were recorded and statistically processed. Results: 1) Comparison of bone metabolic indexes: there was no significant difference in serum 25-(OH)D level, vitamin D status, serum ALP, serum calcium and phosphorus levels between the two groups at 1 month after birth (P > 0.05); there was no significant difference in length, weight, and head circumference between the two groups at 40 weeks of corrected gestational age (P > 0.05). 2) Comparison of perinatal comorbidities: the mechanical ventilation time (2.5 ± 0.5 vs 5.8 ± 3.2 d) and hospital stay (49.50 ± 2.8 vs 56.00 ± 3.5 d) in the calcitrol group were significantly lower than those in the control group, with statistical significance (P < 0.05). The overall incidence of bronchopulmonary dysplasia (BPD) between the two groups was 23.68% vs 35.14% (P > 0.05), but the incidence of mild BPD in the calcitriol group was significantly higher than that in the control group (88.89% vs 38.46%), and the incidence of moderate BPD in the calcitriol group was significantly lower than that in the control group (0% vs 46.15%), both of which were statistically significant (P < 0.05). The incidence of sepsis in the calcitriol group was lower than that in the control group (10.53% vs 32.43%), and the difference was statistically significant (P < 0.05). There were no significant differences in VLBWI noninvasive ventilation time, the incidence of respiratory distress syndrome (RDS) and metabolic bone disease (MBD) between the two groups (P > 0.05). Conclusions: 1) There is no significant difference in the effects of calcitriol supplementation and vitamin D3 supplementation on bone metabolism in very low birth weight infants. 2) Calcitriol supplementation in very low birth weight infants can not only shorten the duration of mechanical ventilation and hospital stay, but also reduce the severity of BPD and the incidence of sepsis.

Keywords:Calcitriol, Vitamin D3, Premature Infants, Very Low Birth Weight Infants, Metabolic Bone Disease, Complications

Copyright © 2021 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

早产儿为维生素D缺乏的高危人群，生后及时补充维生素D已成为早产儿的诊治共识。维生素D除了对极低出生体重儿(very low birth weight infants, VLBWI)骨代谢至关重要外，亦与早产儿呼吸窘迫综合征(respiratory distress syndrome, RDS)、支气管肺发育不良(bronchopulmonary dysplasia, BPD)等合并症的发生具有相关性。维生素D摄入后在小肠吸收入血，继而经过肝脏及肾脏中酶的羟化作用转变为最终活性形式，即1,25-(OH)2D (骨化三醇)。有研究表明，骨化三醇在治疗早产儿代谢性骨病(metabolic bone disease, MBD)方面，可较好地改善其骨代谢指标及骨密度 [1] [2]，因此，活性维生素D或许可以成为早产儿更好的选择。本研究旨在通过骨化三醇与维生素D3在VLBWI中的对比研究，探讨骨化三醇对VLBWI骨代谢及早产儿合并症的影响。

2. 对象与方法

2.1. 研究对象

研究对象选自2019年1月~2019年10月期间青岛大学附属医院出生体重 < 1500 g、生后2小时内入住NICU，住院时间 ≥ 30天、住院资料完整的VLBWI，随机选取1名符合标准的VLBWI纳入骨化三醇组(n = 40)，随其后入院的第1名VLBWI纳入对照组(n = 40)。

排除标准：先天性遗传代谢病、消化道畸形、肝肾功能异常；患NEC等疾病需长时间禁食；母亲患有骨代谢性疾病、甲状腺和肝肾疾病、孕期长期应用激素类药物史、住院期间死亡或自动出院的VLBWI。骨化三醇组中1例因新生儿坏死性小肠结肠炎(Neonatal necrotizing enterocolitis, NEC)、1例因先天性巨结肠被剔除，对照组中2例因NEC、1例自动出院被剔除，共获得研究对象骨化三醇组38例，对照组37例。本研究获得青岛大学附属医院伦理委员会批准，所有研究对象均获得家长知情同意并签署知情同意书。

2.2. 方法

所有研究对象均于生后24小时内及生后1月龄测定血清25-(OH)D、ALP、血磷、血钙水平。收集患儿住院期间全肠内营养(Total parenteral nutrition, TPN)持续时间、呼吸支持(机械通气、无创通气、吸氧)时间、咖啡因使用时间，MBD、RDS、BPD、败血症等发生情况，出生时及矫正胎龄(Corrected gestational age, CGA) 40周时测量身长、体重、头围体格发育指标。

干预方法：目前关于维生素D的补充形式及剂量尚未完全统一，临床上推荐早产儿应用维生素D3剂量为800~1000 IU/天 [3]。所有研究对象在其可耐受胃肠营养时每日均给予1粒维生素AD制剂(每粒含维生素A 1500 IU、维生素D 500 IU，山东达因海洋生物制药股份有限公司)；骨化三醇组每日加服骨化三醇0.125 ug (罗盖全，上海罗氏制药有限公司)，对照组每日加服维生素D3 400 IU (青岛双鲸药业股份有限公司)。

3. 相关疾病诊断标准

1) MBD：ALP > 900 IU/L且血P < 1.8 mmol/L [4]；或ALP > 500 IU/L且血P < 1.45 mmol/L [5]。2) RDS [6]：生后不久出现进行性加重的呼吸困难，同时有典型的X线胸片表现。3) BPD [7]：氧依赖(FiO2 > 21%)超过28天的新生儿。根据矫正胎龄36周/生后56天或出院时需氧情况分为：轻度：未用氧；中度：FiO2 < 30%；重度：FiO2 ≥ 30%或需机械通气。4) 败血症 [8]：确诊败血症：具有临床表现并具备下列任意一条：① 血培养或无菌体腔培养出致病菌；② 如果血培养培养出机会致病菌，则必须于另次血，或无菌体腔内，或导管头培养出同种细菌。临床诊断败血症：具有临床表现且具备下列任意一条：① 非特异性检查非特异性检查 ≥ 2条(白细胞计数减少或增多)，白细胞分类未成熟中性粒细胞/中性粒细胞比率 ≥ 0.16，C反应蛋白升高，血清降钙素原 > 2.0 ug/L，血小板计数 ≤ 100 × 109/L，微量血沉 ≥ 5 mm/h ≥ 2条；② 血标本病原菌抗原或DNA检测阳性。

4. 统计学方法

应用SPSS 22.0 软件处理数据，计量资料先进行正态性检验，符合正态分布的用均数 ± 标准差表示，两组间比较采用独立样本t检验；不符合正态分布的用中位数M (P25, P75)表示，两组间比较采用Mann-Whitney U检验。计数资料用构成比(%)描述，组间比较采用卡方检验或Fisher确切概率法。结果以P < 0.05差异有统计学意义。

5. 结果

5.1. 两组早产儿一般资料分析

骨化三醇组38例，胎龄26 + 4周~34周，其中胎龄 < 28周4例，28周~31 + 6周25例，≥32周9例；出生体重770 g~1499 g，其中<1000 g 7例，≥1000 g 31例。对照组早产儿37例，胎龄25 + 2周~33 + 3周，其中胎龄 < 28周5例，28周~31 + 6周28例，≥32周4例；出生体重580 g~1498 g，其中<1000 g 8例，≥1000 g 29例。两组早产儿胎龄、胎龄分组、出生体重、体重分组等一般资料比较差异均无统计学意义(P > 0.05)。两组早产儿出生时及CGA40周体重、身长、头围指标比较，差异均无统计学意义(P > 0.05)。两组早产儿出生时和生后1月龄骨代谢指标比较，差异均无统计学意义(P > 0.05)，见表1。

Table 1. Comparison of physical development indexes and bone metabolism indexes between two groups of premature infants

表1. 两组早产儿体格发育指标及骨代谢指标比较

注：SGA：小于胎龄儿(small for gestational age)。

5.2. 住院期间喂养及合并症比较

两组VLBWI住院期间TPN持续时间；喂养方式、钙磷摄入量；维生素 D添加时间比较差异均无统计学意义(P > 0.05)。骨化三醇组机械通气时间、住院时间较对照组VLBWI短(P < 0.05)，败血症发生率明显低于对照组VLBWI (P < 0.05)；两组BPD发生率无明显差异(P > 0.05)，但骨化三醇组VLBWI轻度BPD发生率明显高于对照组，中度BPD发生率明显低于对照组(P < 0.05)。两组VLBWI住院期间无创通气时间、MBD、RDS差异均无统计学意义(P > 0.05)。见表2。

Table 2. Comparison of feeding and complications of VLBWI during hospitalization between two groups

表2. 两组VLBWI住院期间喂养及合并症比较

注：*为Fisher精确检验所得P值；钙磷摄入量是指达到完全肠内喂养时的量；RDS为呼吸窘迫综合征；BPD为支气管肺发育不良；MBD为代谢性骨病。

6. 讨论

随着围产医学的进步和VLBWI救治水平的提高，极低及超低出生体重儿存活率逐年增高，随之而来的MBD、BPD等并发症发生率也日益增多。既往研究表明，维生素D作为钙磷代谢的调节因子，在VLBWI骨骼健康中发挥重要作用。随着对维生素D与VLBWI健康的研究逐渐深入，人们发现1,25-(OH)2D尚有促进胎肺及新生肺发育和成熟，调节免疫细胞生长、分化及抑制炎症因子活化等多种作用，与VLBWI常见疾病如 RDS、BPD、败血症等密切相关。研究发现骨化三醇应用于VLBWI MBD治疗在改善骨代谢指标及骨密度方面有较好的疗效，且未增加高血钙、高血磷、高尿钙等副作用 [2]，因此骨化三醇作为维生素D的活性制剂，进入体内后无需代谢可直接发挥作用，对于脏器功能不成熟、酶活性低下的VLBWI不失为一种更好的选择。

本研究中两组早产儿临床资料匹配，结果提示提示骨化三醇联合维生素D对于早产儿血清骨代谢指标以及体格发育的影响与900 IU维生素D的作用相当，MBD发生率差异亦无统计学意义。表明VLBWI生后补充骨化三醇替代补充维生素 D3对骨代谢的影响无明显差异，维生素D对钙磷代谢的调节以及成骨作用的发挥均是通过其最终活性形式1,25-(OH)2D完成的。

1,25(OH)2D 可以与形成 PS 的Ⅱ型肺泡上皮细胞中的VDR结合，从而促进PS相关磷脂的合成以及 PS 的分泌 [9]。研究发现，孕期补充维生素D改善新生儿维生素D营养状况可降低RDS发生率 [10]。邱杰等人 [11] 的研究发现，1,25-(OH)2D还可通过促进肺发育、降低气道敏感性及抑制炎症因子活化等多个途径降低BPD发生。1,25-(OH)2D可通过炎症细胞因子间接调节BPD的发病，如Chen等 [12] 用1,25-(OH)2D处理高氧暴露的动物发现，该动物炎症细胞因子和肿瘤坏死因子-α的表达显著下调，高氧诱导后的肺损伤明显减轻。本研究中骨化三醇组BPD严重程度明显降低，既往研究一致 [13]。研究还发现维生素D能减少与氧气有关的肺部炎症以及缩短早产儿呼吸机使用时间等 [14]，缩短有创通气时间、降低呼吸机相关感染风险，缩短住院时间、降低医院内感染风险。本研究表明，极低出生体重儿生后补充骨化三醇较维生素D3可明显减轻BPD严重程度、缩短机械通气时间及住院时间，此与已有研究相一致。

既往研究发现，出生时维生素D缺乏的新生儿，其发生败血症发生率增加，母亲妊娠期和新生儿期补充维生素D可降低败血症发生率 [15] [16]。印度Dhandai R [17] 等人一项前瞻性观察性研究发现缺乏维生素D的新生儿比维生素D水平充足的新生儿有更大的风险发生败血症。本研究中骨化三醇组败血症的发生率低于对照组。其可能机制是维生素D诱导释放抗菌肽，诱导调节性T细胞的分化改善免疫力，减少与氧气有关的肺部炎症有关 [14]。而这种诱导是通过其最终活性形式1,25-(OH)2D (骨化三醇)与不同组织及器官中相应的VDR结合来发挥的。

7. 结论

本研究结果表明，VLBWI生后补充骨化三醇替代补充维生素D3对骨代谢的影响无明显差异，补充骨化三醇可以缩短机械通气时间及住院时间，减轻BPD的严重程度，降低败血症的发生率。但本研究样本量较少，观察时间相对短，对于骨化三醇发挥作用的具体生物学机制尚未明确，未来需要进行更大样本、远期临床对照研究，以进一步评价骨化三醇在VLBWI中的应用疗效。

文章引用

张俏俏,种晓秦,姜 红. 骨化三醇对极低出生体重儿骨代谢与合并症的影响
The Effects of Calcitriol on Bone Metabolism and Diseases in VLBWI[J]. 临床医学进展, 2021, 11(03): 831-837. https://doi.org/10.12677/ACM.2021.113118

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  15. 15. Cizmeci, M.N., Kanburoglu, M.K., Akelma, A.Z., et al. (2015) Cord-Blood 25-Hydroxyvitamin D Levels and Risk of Early-Onset Neonatal Sepsis: A Case-Control Study from a Tertiary Care Center in Turkey. European Journal of Pediatrics, 174, 809-815. https://doi.org/10.1007/s00431-014-2469-1

  16. 16. Xiao, D., Zhang, X., Ying, J., et al. (2019) Association between Vitamin D Status and Sepsis in Children: A Meta-Analysis of Observational Studies. Clinical Nutrition, 39, 1735-1741.

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    18. NOTES

    *共同第一作者。

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