BACKGROUND: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks\' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear.
METHODS: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 g birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 h after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/day with early feeding) compared to placebo plus routine dose (400 IU/day with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at 1 month, reduce respiratory support at 36 weeks\' postmenstrual age (on an ordinal scale predictive of later adverse outcomes), and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months\' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability.
CONCLUSIONS: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterm infants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results.
BACKGROUND: ClinicalTrials.gov NCT05459298. Registered on July 14, 2022.

Caffeine is a routinely prescribed pharmacological active compound in neonatal intensive care units (NICU) for treating apnea of prematurity (AOP), which also decreases the risk of bronchopulmonary dysplasia and cerebral palsy in neonates. Caffeine-induced excessive calcium loss can promote the development of metabolic bone disease (MBD) in preterm neonates. This study aimed to evaluate the effect of the caffeine regimen on the development of osteopenia of prematurity (OOP), using serum alkaline phosphatase (serum-ALP) concentrations as a surrogate marker at the 4th week of life.
This retrospective cohort study was conducted including neonates of < 32 weeks gestational age (GA) and birth weight < 1500 g, admitted to NICU from April-2017 to December-2018 and received caffeine therapy till 28 days of life for AOP. Based on serum-ALP levels, formed the high and low-ALP groups. Neonatal characteristics, caffeine regimen, risk factors for OOP, including duration of parenteral nutrition (PN), exposure to medicines associated with MBD, and intake of essential vitamins and minerals, were compared in both groups. Predictors of OOP were analyzed through logistic regression.
From the total of 268 participants, 52 (19%) developed OOP, mostly female (61.5%). In the high ALP group, the serum-ALP levels were significantly higher than in the low-ALP group (725.0 ± 143.8 vs 273.6 ± 55.0 units/L, p < 0.001). The high-ALP group received significantly (p < 0.001) higher daily and cumulative caffeine doses and were associated with a higher likelihood of developing OOP in this study cohort [cumulative dose (mg) (AOR = 1.082 95% CI 1.011 to 1.157) and daily dose (mg/kg/day) (AOR = 2.892 95% CI 1.392 to 6.007)]. Smaller GA was found directly related to OOP. Among the other medical risk factors, phosphorus intake was significantly low in the high-ALP group. No, significant relationship between duration of PN and use of steroids and diuretics, and intake of vitamins and minerals were identified.
The daily and cumulative doses of caffeine and smaller GA are associated with the development of OOP in this study cohort. Clinical randomized control studies are needed to validate the outcomes and determine the range of safest and most effective caffeine doses for treating AOP in preterm neonates.

Measuring bone mineral density (BMD) is important for surveying osteopenia in premature infants. However, the clinical availability of dual-energy X-ray absorptiometry (DEXA) for standard BMD measurement is very limited, and it is not a practical technique for critically premature infants. Developing alternative approaches for DEXA might improve clinical care for bone health. This study aimed to measure the BMD of premature infants via routine chest X-rays in the intensive care unit. A convolutional neural network (CNN) for humeral segmentation and quantification of BMD with calibration phantoms (QRM-DEXA) and soft tissue correction were developed. There were 210 X-rays of premature infants evaluated by this system, with an average Dice similarity coefficient value of 97.81% for humeral segmentation. The estimated humerus BMDs (g/cm3; mean ± standard) were 0.32 ± 0.06, 0.37 ± 0.06, and 0.32 ± 0.09, respectively, for the upper, middle, and bottom parts of the left humerus for the enrolled infants. To our knowledge, this is the first pilot study to apply a CNN model to humerus segmentation and to measure BMD in preterm infants. These preliminary results may accelerate the progress of BMD research in critical medicine and assist with nutritional care in premature infants.

Metabolic bone disease (MBD) of prematurity remains a significant comorbid condition in preterm, low birth weight infants. As the majority of in utero calcium (Ca) and phosphorus (Phos) accretion occurs during the third trimester, many of these children have inadequate mineral stores and are at risk for deficiencies of Ca and Phos. While fortification of formula has allowed for increased mineral delivery to premature infants, intestinal immaturity prevents optimal absorption. This is compounded by immobilization, delayed establishment of enteral feeds, long term parenteral nutrition and medications that may alter mineral levels. Over time, biochemical changes occur and accompany MBD, with poor bone mineralization during this period increasing the risk for complications such as osteopenia, rickets and fractures. Screening is largely based on risk factors, but despite the 2013 AAP Consensus Statement, there remains significant variation in screening practices across institutions. A combination of laboratory and radiologic testing is often used to diagnose and manage MBD of prematurity, but there exists a lack of consensus on which screening tests and thresholds to use. This is in part related to a lack of normative data and clinical trials for preterm infants, and a result, a lack of evidence-based guidelines on the diagnosis and timing of potential treatment. Biochemical markers, such as serum Phos, alkaline phosphatase (ALP) and parathyroid hormone (PTH), have shown some benefit in the diagnosis of MBD in some studies, but have not always been reproducible. Radiographs may identify different degrees of skeletal changes, but these changes may not be detected until later in MBD development. Other modalities, such as DXA and ultrasound, have also been used, but these may be limited by lack of standards in preterm infants or lack of availability in some centers. Further research, more specifically clinical trials, are needed to determine which combination of tests can detect MBD at its earliest, in order to promote early treatment and prevent short- and long-term complications of MBD.

Preterm infants are at risk of growth failure and metabolic bone disease due to insufficient nutrient supply in postnatal life. An ample provision of protein, energy, calcium and phosphates through parenteral or/and enteral nutrition is crucial for bone growth and mineralization. Additional vitamin D supplementation improves bone mineralization and enhance intestinal absorption of minerals.

Background It is known that thyroid hormones have effects on bone development. In particular, the effect of thyroid hormones on osteopenia of prematurity (OOP) has not been examined in preterm infants. Our study aimed to examine the relationship between OOP and congenital hypothyroidism (CH) in preterm infants. Methods Very low birth weight infants (VLBW, <1500 g) were included in the study. Thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels were measured on postnatal day 5. Serum calcium, phosphorus and alkaline phosphatase (ALP) levels were studied as standard screening parameters for OOP at postnatal week 4. Patients with serum ALP level >700 IU/L were included in the OOP group. We intended to figure out the relationship between OOP and CH in infants. Results In our study, OOP frequency was 14.9% among 543 VLBW infants. There was no statistically significant difference between groups with and without CH (21.7% and 14.8%, respectively) in terms of OOP (p=0.632). Gestational age (GA) was significantly lower in infants with diagnosed OOP (p<0.001, p<0.001, respectively). In addition, the prevalence rates of mothers with preeclampsia, small for gestational age (SGA), respiratory support requirement, late-onset neonatal sepsis (LOS), bronchopulmonary dysplasia (BPD) and full enteral feeding time were found to be higher in the OOP group (p<0.05). Conclusions We found that thyroid hormones had no effect on OOP in preterm infants. Therefore, future randomized controlled studies as well as long-term outcome studies are warranted on this topic.

Caffeine, the most commonly used medication in Neonatal Intensive Care Units, has calciuric and osteoclastogenic effects.
To examine the association between the cumulative dose and duration of therapy of caffeine and osteopenia of prematurity, a retrospective cohort study was conducted including premature infants less than 31 weeks and birth weight less than 1500 g. Osteopenia of prematurity was evaluated using chest X-rays on a biweekly basis over 12 weeks of hospitalization.
The cohort included 109 infants. 51% had osteopenia of prematurity and 8% had spontaneous rib fractures. Using the generalized linear mixed model, caffeine dose and duration of caffeine therapy showed a strong association with osteopenia of prematurity. Steroids and vitamin D were also significantly correlated with osteopenia of prematurity while diuretic use did not show a statistically significant effect.
The cumulative dose and duration of therapy of caffeine, as well as steroid are associated with osteopenia of prematurity in this cohort. Future studies are needed to confirm these findings and determine the lowest dose of caffeine needed to treat effectively apnea of prematurity.

OBJECTIVE: In this study, we aimed to investigate the utility of tubular reabsorption of phosphorus in the diagnosis of osteopenia of prematurity in addition to biochemical markers.
METHODS: Premature babies with a gestational age of ≤32 weeks and/or a birth weight of ≤1 500 g who were hospitalized in the neonatal intensive care unit between June 2009 and March 2011 were included in the study. These babies were evaluated at the 40th gestational week and serum calcium, phosphorus, alkaline phosphatase, urea, creatinine, urinary calcium and phosphorus levels were measured and tubular reabsorption of phosphorus was determined. The subjects who had bone graphy findings and/or an alkaline phosphatase level of >400IU/L and a phosphorus value of <3.5 mg/dL were considered osteopenic. The levels of tubular reabsorption of phosphorus of the osteopenic patients were compared with the ones of the non-osteopenic patients. The study was initiated after obtaining ethics committee approval (date: 04.29.2009/213).
RESULTS: During the study period, a total of 698 premature babies were hospitalized in our neonatology unit. A diagnosis of osteopenia of prematurity was made in 24 of 190 subjects who met the study criteria. The level of tubular reabsorption of phosphorus was compared with the serum calcium, phosphorus and alkaline phosphatase levels measured at the 40th gestational week and alkaline phosphatase was found to be significantly increased in the group with a high tubular reabsorption of phosphorus (≥%95). When the subjects with a phosphorus level of <3.5 mg/dL and an alkaline phosphatase level of >499 IU were compared with the newborns who were found to have a tubular reabsorption of phosphorus of ≥%95 for the objective of evaluating the specificity and sensitivity of tubular reabsorption of phosphorus, the sensitivity, specificity, positive predictive value and negative predictive value of tubular reabsorption of phosphorus in the diagnosis of osteopenia were found to be 27%, 82%, 17% and 89%, respectively. When the osteopenic and non-osteopenic patients were compared in terms of the levels of tubular reabsorption of phosphorus, no statistically significant difference was found.
CONCLUSIONS: It was thought that it was not appropriate to use tubular reabsorption of phosphorus alone in the diagnosis of osteopenia of prematurity.