Management of bone health in preterm infants

INTRODUCTION — All neonates, and especially premature infants, are at risk for osteopenia and rickets. As a result, they must have adequate intake of calcium, phosphorus, and vitamin D to ensure adequate mineralization for bone structural integrity and growth. Premature infants require particularly high dietary concentrations of these nutrients, with additional measures guided by close monitoring.

For term neonates, either human milk or formula (when taken in adequate volume for age) provides adequate intake of calcium and phosphorus. In this group, management of neonatal bone heath is primarily focused on vitamin D supplementation, which is discussed separately. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention in the perinatal period and in infants'.)

The management of bone health in preterm infants will be reviewed here. The general approach to nutrition in premature infants is discussed in separate topic reviews. (See "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant".)

EPIDEMIOLOGY AND RISK FACTORS

Factors affecting neonatal bone health — Premature infants are at high risk for osteopenia and rickets for several reasons:

●Rapid growth – Because of their rapid growth, preterm infants have high requirements for calcium and phosphorus, which are critical components for bone structural integrity and growth.

●Shortened gestation – Preterm delivery disrupts the normal intrauterine accretion of calcium and phosphorus. The third trimester is the period of maximal placental transfer of these nutrients, reflecting the rapid skeletal growth of the fetus. Placental transfer reaches a peak accretion rate at 32 to 36 weeks gestation, with calcium transferred at 100 to 130 mg/kg of fetal weight per day and phosphorus transferred at 60 to 70 mg/kg of fetal weight per day [1-4]. As a result, the requirements of calcium and phosphorus increase with decreasing gestational age to compensate for the loss of accretion of these minerals and extremely low birth weight infants (birth weights below 1000 g) or those born before 27 weeks gestation are at particularly high risk for rickets [3].

●Intestinal absorption – In healthy preterm infants, calcium absorption is generally 50 to 60 percent from human milk and phosphorus absorption approximately 80 to 90 percent [3,5-7]. Absorption from infant formulas is slightly lower, depending on the formula composition [8]. These proportions are similar across a broad range of calcium intakes [9].

Absorption of calcium and phosphorus from the small intestine is by both active transport (transcellular) and passive diffusion (paracellular). For the first few weeks after preterm birth, most of the mineral absorption appears to be passive, based on limited data [10]. Thereafter, active transport, which requires vitamin D, becomes more important. Absorption of calcium and phosphorus is affected positively by postnatal age and vitamin D level and also varies with the dietary calcium:phosphorus ratio as well as dietary intake of lactose and fat [6]. [3,5-7]

Neonates with underlying disease may have additional impediments to absorbing these nutrients. This includes infants with short bowel syndrome (intestinal failure) [11] and those requiring certain medications that interfere with absorption, such as glucocorticoids (which inhibit intestinal transfer of calcium), phenytoin, and phenobarbital, which may indirectly inhibit calcium absorption by interfering with vitamin D metabolism.

●Renal excretion and absorption – Regulation of renal absorption and excretion is important for calcium and phosphorus balance. One important homeostatic mechanism is the secretion of parathyroid hormone in response to low calcium, resulting in reduced urinary calcium excretion. Under normal circumstances, nearly all filtered calcium is reabsorbed in the renal tubule.

In the neonate, there are two main causes of hypercalciuria, which may lead to calcium depletion:

•Loop diuretics enhance calcium excretion, which may result in nephrocalcinosis. In contrast, thiazide diuretics stimulate calcium absorption and reduce urinary calcium excretion. (See "Nephrocalcinosis in neonates", section on 'Pathogenesis'.)

•Phosphorus deficiency enhances calcium renal excretion, leading to hypercalciuria and resulting in ongoing calcium loss and potential calcium depletion [8,12]. Treatment with phosphorus will correct the phosphorus deficiency and hypercalciuria, but calcium should also be given since infants are depleted of both calcium and phosphorus.

Risk factors for rickets — Very low birth weight (VLBW) infants (birth weight <1500 g) and especially extremely low birth weight infants (birth weights <1000 g) or those born before 27 weeks gestation are at risk for developing rickets [3,13,14]. Rickets in premature infants is primarily caused by inadequate calcium and phosphorus intake and absorption rather than vitamin D deficiency. This mechanism is reflected in the risk factors for neonatal rickets, which include (table 1) [3]:

●Prematurity and VLBW (<1500 g)

●Fetal growth restriction, especially infants with birth weight <3^rd percentile for gestational age (see "Infants with fetal (intrauterine) growth restriction")

●Long-term parenteral nutrition (>4 weeks)

●Bronchopulmonary dysplasia treated with loop diuretics and/or fluid restriction

●Long-term postnatal corticosteroid use

●History of necrotizing enterocolitis or other diseases causing intestinal failure, especially in patients who undergo surgical intervention

●Feeds that do not have high mineral content (eg, due to poor tolerance of fortified feeds)

●Metabolic or endocrine disorders, including severe cholestasis or renal disease

Incidence of neonatal rickets — The incidence of neonatal rickets is declining with the use of diets with high mineral content. (See 'Fortification of feeds' below.)

The incidence of rickets increases with decreasing birth weight. In a registry study from Sweden, rickets developed in 2 percent of infants born <32 weeks gestation or <1500 g birth weight and 0.1 percent of those born between 32 and 36 weeks gestation [15]. In a separate study of infants with birth weight <1000 g, 15 percent developed rickets despite management with fortified feeds [16]. Incidence is also increased in infants with fetal growth restriction or necrotizing enterocolitis.

OVERVIEW OF MANAGEMENT — Management of bone health in preterm infants is focused on preventing rickets and encompasses:

●Providing adequate calcium and phosphorus intake to promote normal bone growth. Nutritional support during the birth hospitalization and post-discharge must account for the loss of intrauterine accretion of these nutrients, their bioavailability in enterally fed infants, and ongoing losses.

●Vitamin D supplementation (minor role).

●Laboratory monitoring to assess bone health, with the goal to detect and correct any mineral deficiency before the infant develops radiographic signs of rickets.

●For infants who develop rickets, provision of supplemental calcium and phosphorus to repair bone mineralization.

INITIAL MANAGEMENT (INPATIENT)

Parenteral nutrition — Mineral accretion is inadequate in very low birth weight (VLBW) infants who are treated with total parenteral nutrition for more than two weeks [17]. This is related, in part, to the need to limit mineral concentrations because of their solubility in parenteral nutrition solutions. However, calcium and phosphorus concentrations should be maximized to improve mineral retention. (See "Parenteral nutrition in premature infants", section on 'Calcium and phosphate'.)

Infants who receive parenteral nutrition for more than four weeks may have developed a mineral deficit that requires oral or enteral supplementation with calcium and phosphorus once feeds are established, in addition to the requirements outlined below. Therefore, these infants should have laboratory monitoring for bone health even if they are not VLBW. (See 'Laboratory monitoring' below.)

Enteral nutrition — Unfortified human milk, parenteral nutrition, and formulas designed for term infants do not contain enough calcium and phosphorus to meet the needs for bone mineralization in preterm infants. As a result, the use of these diets without fortification limits bone growth and increases the risk for osteopenia, rickets, and bone fractures.

Calcium and phosphorus requirements — The appropriate enteral intake for calcium and phosphorus is based on estimates of optimal daily bone deposition, bioavailability and absorption of these nutrients, and nutrient losses. (See 'Epidemiology and risk factors' above.)

We suggest the following intake in enteral feeds for VLBW infants (birth weight below 1500 g), consistent with guidance from the American Academy of Pediatrics [3]:

●Calcium – 150 to 220 mg/kg/day

●Phosphorus – 75 to 140 mg/kg/day

●Calcium:phosphorus ratio – Approximately 1.5 to 1.7 (mg/mg, or mass ratio), although the ideal range has not been clearly established [3,18,19]

Other organizations recommend somewhat lower targets for mineral intake:

●European guidelines recommend enteral intake of calcium 120 to 140 mg/kg/day and phosphorus 65 to 90 mg/kg/day [20]

●An international consensus group recommends calcium 120 to 200 mg/kg/day and phosphorus 60 to 140 mg/kg/day [21]

The variance among these recommendations reflects different reviews of the limited data related to providing safe intake while ensuring adequate bone mineralization. As evidenced by the ranges provided by these recommendations, no single value for calcium intake can be considered as correct. There is no convincing evidence that the differences between these guidelines lead to clinically significant benefits or risks [21].

Vitamin D requirements — Most authorities recommend vitamin D supplementation for preterm infants beginning in the neonatal period, although the benefit of supplements during the first month of life has not been established. For infants fed human milk, we begin vitamin D supplements when the infant is tolerating enteral feeds. For formula-fed infants, the formula provides sufficient vitamin D.

We suggest the following target intake, consistent with recommendations from the American Academy of Pediatrics [3]:

●For infants <1500 g body weight, initial target is 5 to 10 micrograms (200 to 400 international units) daily

●When the infant reaches ≥1500 g and is tolerating full enteral nutrition, increase vitamin D to 10 micrograms (400 international units); this is also the recommended vitamin intake for term infants

Other targets for enteral vitamin D intake are recommended by other groups:

●European guidelines suggest a higher vitamin D intake of 20 to 25 micrograms (800 to 1000 international units) daily during hospitalization or the first months of life [20]

●An international consensus group recommends intake of vitamin D between 10 and 25 micrograms (400 and 1000 international units) daily for preterm infants [21]

These guidelines were designed to achieve serum concentrations considered "sufficient" in older infants and children (usually defined as 25-hydroxyvitamin D ≥20 ng/mL), but they do not recommend routine laboratory testing of serum 25-hydroxyvitamin D in this population [9]. The variation in these recommendations reflects the uncertainty about the role of vitamin D for intestinal absorption of calcium in preterm infants. In particular, in preterm infants during the first month of life, calcium absorption appears to be primarily a passive process via a paracellular route and is not vitamin D dependent, based on limited data [10]. Although vitamin D concentrations are typically lower in preterm compared with term infants, data are limited on the relationship between vitamin D intake and serum 25-hydroxyvitamin D in preterm infants. (See 'Epidemiology and risk factors' above.)

These targets are supported by limited evidence from clinical trials in preterm infants, which suggests that vitamin D intakes between 10 and 20 micrograms (400 to 800 international units) typically achieve 25-hydroxyvitamin D concentrations >20 ng/mL [22-25]. However, the studies did not identify substantial differences in clinical outcomes across the range of vitamin D intakes, including markers of bone health (mean total-body bone mineral content and density as well as serum alkaline phosphatase activity [23]) or respiratory outcomes in extremely preterm infants [22].

Fortification of feeds — For all infants with birth weights <1500 g, we recommend fortifying feeds with calcium and phosphorus. We also routinely use multinutrient-fortified feeds for infants up to 2000 g birth weight. For infants with birth weight between 1500 and 2000 g, the primary benefits of fortified feeds are for growth since rickets is uncommon in this population.

Fortification can be accomplished by adding a human milk fortifier (HMF) to expressed human milk or by using a formula designed for preterm infants; either strategy supplies the necessary high mineral content in addition to supplemental energy (calories) and protein [3,17]. The recommendations for these products are based on weight rather than gestational age because infants with intrauterine growth restriction (also referred to as small for gestational age) also have impaired bone mineralization. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Fortification of human milk'.)

Full enteral feedings of 150 to 160 mL/kg/day of fortified human milk or preterm formula provide estimated intakes of calcium of 150 to 220 mg/kg/day, phosphorus of 90 to 140 mg/kg/day, and vitamin D of 7.5 to 10 micrograms (300 to 400 international units) daily, which meet the recommended intake for these neonates (table 2) [3]. In contrast, unfortified human milk provides insufficient intakes of these nutrients: approximately calcium 40 mg/kg/day, phosphorus 20 mg/kg/day, and negligible amounts of vitamin D. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Indications and fortifier types' and "Nutritional composition of human milk and preterm formula for the premature infant", section on 'Calcium and phosphorus'.)

Unfortified human milk and formula designed for term infants have insufficient calcium and phosphorus concentrations to achieve optimal intake for bone mineralization in early preterm infants [26,27]. Use of fortified human milk or preterm formula improves mineral retention and bone mineral content compared with unfortified feeds (table 3) and reduces the risk of rickets [28]. While clinical trial data on calcium and phosphorus supplementation in preterm infants are extremely limited [29,30], the available observational data suggest that use of fortified human milk or preterm formula substantially reduces the risk of rickets in VLBW infants. In older studies carried out prior to the routine practice of fortifying feeds in preterm infants, reported rates of rickets in VLBW infants ranged from 30 to 50 percent [31-33]. By contrast, reported rates of rickets among VLBW infants managed with fortified feeds in the modern era are substantially lower, ranging from 10 to 15 percent [16,34-36]. Although other improvements in neonatal care and nutrition may have contributed to reduced rates of rickets between the two eras, it is unlikely to fully explain the difference. Further support comes from several small trials and observational studies in which mineral supplementation was associated with improved radiographic and laboratory indices of bone mineralization and had no significant adverse effects [37-41]. (See "Nutritional composition of human milk and preterm formula for the premature infant", section on 'Calcium and phosphorus'.)

Physical stimulation — It has been proposed that lack of physical activity contributes to poor bone health in preterm infants. Data from several small trials suggest possible short-term benefits of a neonatal physical therapy program on weight gain and bone mineralization in preterm infants, but the evidence is insufficient to understand the potential benefits or risks [42]. The therapy typically consists of passive range of motion and joint compression exercises performed for 5 to 15 minutes daily [43]. Many programs, including ours, now have physical therapists working with preterm infants on a regular basis, although these efforts are not specifically directed towards bone health.

Laboratory monitoring — Because preterm infants are at risk for rickets, all VLBW infants (birth weight <1500 g) should have laboratory monitoring throughout the birth hospitalization to detect any evidence of bone-related abnormalities [3].

Our suggested approach depends on risk factors (algorithm 1):

●Infants with VLBW or other risk factors – Measure serum phosphorus and alkaline phosphatase activity beginning four weeks after birth and repeated every two weeks thereafter until discharge. Other risk factors include prolonged parenteral nutrition or prolonged postnatal corticosteroids, regardless of birth weight (table 1).

●Infants with short bowel syndrome or other malabsorptive syndromes – In addition to the above for alkaline phosphatase and phosphorus, measure serum vitamin D concentrations, inorganic phosphorus, and magnesium as parenteral nutrition is weaned and periodically thereafter. (See "Chronic complications of short bowel syndrome in children", section on 'Metabolic bone disease and rickets'.)

We do not use parathyroid hormone levels to detect patients at risk for bone disease. A small study suggested that serum parathyroid hormone can be used as a marker of severe metabolic bone disease [44]. However, this is insufficient evidence to establish a benefit of this testing and such testing would add considerable cost to routine evaluations.

Interpretation and next steps — Next steps depend on the laboratory results and trend (algorithm 1):

●Normal pattern of alkaline phosphatase activity – VLBW infants without metabolic bone disease typically have alkaline phosphatase activity values that rise at four to six weeks after birth and peak at 400 to 800 international units/L and then decrease by 8 to 10 weeks as the infant completes the transition to enteral feeds. Monitoring can be discontinued once stable values are demonstrated on full enteral feeds (eg, once the serum alkaline phosphatase activity has peaked and is declining to <500 to 600 international units/L, with serum phosphorus ≥4 mg/dL). (See 'Infants with no evidence of bone disease' below.)

●Elevated alkaline phosphatase activity – Alkaline phosphatase activity ≥1000 international units/L suggests the possibility of rickets [16]. In these patients, we obtain radiographs of the wrist and/or knees to confirm the diagnosis of rickets. (See 'Infants with rickets' below and "Overview of rickets in children", section on 'Laboratory findings'.)

Infants with intermediate elevations of alkaline phosphatase activity (eg, >800 international units/L) are at risk for rickets and should be monitored. If the alkaline phosphatase activity is rising or exceeds 1000 international units/L, we perform radiographic evaluation for rickets. If the alkaline phosphatase activity is stable, we repeat this test every two weeks until it is clearly declining.

●Low phosphorus – Many infants with metabolic bone disease have a low serum phosphorus in addition to elevated alkaline phosphatase activity. Both laboratory abnormalities are markers for mineral insufficiency and should improve with standard mineral supplementation.

Other infants have a persistent low phosphorus (<4 mg/dL) but normal patterns of alkaline phosphatase activity. This combination of findings is usually associated with normal bone health, in which the low phosphorus is likely primarily caused by rapid growth and indicates a need for additional phosphorus for nonbone tissue growth. In this case, oral phosphorus should be given in addition to the usual fortification strategy until the serum phosphorus increases to >5 mg/dL.

SUBSEQUENT MANAGEMENT

Infants with no evidence of bone disease — For infants who reach a body weight of 2000 g and have no laboratory evidence of metabolic bone disease (serum alkaline phosphatase <800 international units/L and falling, with serum phosphorus ≥4 mg/dL) or ongoing risk factors for rickets (table 1), the mineral content of the feeds can be decreased (algorithm 1). The transition to feeds with lower mineral content is typically done quickly (eg, over three days) and during the final week before hospital discharge.

The strategy for changing to a transitional diet with lower mineral content depends on the infant's mode of feeding:

●If the infant transitions to direct breastfeeding, his or her mineral intake naturally decreases as the proportion of direct breastfeeding increases. Some of these infants may require supplemental feeds to maintain adequate intakes of energy and other nutrients. (See "Breastfeeding the preterm infant", section on 'Transition to full breastfeeding'.)

●If the infant is fed expressed breast milk by bottle, the amount of human milk fortifier (HMF) can be reduced. Alternatively, the HMF can be stopped and a preterm formula used for a few feedings each day.

●If the infant is formula fed, he or she can change from preterm formula to a "transitional" formula.

After the dietary transition and hospital discharge, we continue the transitional diet, as outlined above, for at least a few weeks. The decision to transition to an unfortified diet is driven primarily by growth considerations and is discussed separately (see "Growth management in preterm infants"). We repeat laboratory monitoring only if there are residual risk factors or other concerns for rickets, such as relatively high alkaline phosphatase activity at discharge. Vitamin D supplements should be continued for breastfed infants (10 micrograms [400 international units] daily). (See 'Vitamin D requirements' above.)

Infants with ongoing risk for rickets — Ongoing risk for infants is indicated by either (algorithm 1):

●Laboratory evidence of metabolic bone disease – Serum alkaline phosphatase activity persistently ≥800 international units/L with or without serum phosphorus <4 mg/dL

●Ongoing risk factors – Such as prolonged parenteral nutrition, fluid restriction, or malabsorptive disease (table 1)

For these infants, we optimize the high-mineral diet (fortified human milk or preterm infant formula) and repeat the laboratory tests approximately every two weeks.

The target for calcium and phosphorus intake depends on the level of concern and the infant's mode of feeding. As an example, an infant with mildly abnormal serum alkaline phosphatase activity who is directly breastfeeding may be supplemented by giving two to four bottle feeds daily of fortified human milk or preterm formula.

The next steps for this group of infants depend upon the trend in alkaline phosphatase activity:

●Rising trend – Perform radiographic evaluation for rickets

●Stable – Continue high-mineral diet, with monthly laboratory monitoring

●Declining trend – Transition to lower-mineral diet, as described above; recheck alkaline phosphatase activity several weeks after transition if there are ongoing concerns or risk factors

Infants with rickets

Clinical features and diagnosis — Rickets in premature infants typically develops between 3 and 12 weeks of age. The condition is not usually clinically apparent and is identified on routine laboratory screening by elevated alkaline phosphatase activity (>1000 international units/L), with or without low serum phosphorus (<4 mg/dL).

The diagnosis is confirmed based on radiographs of the knee or wrist. Diagnostic findings are widening of the epiphyseal plate and loss of definition of the zone of provisional calcification at the epiphyseal/metaphyseal interface, similar to those for older infants with nutritional rickets (image 1).

In severe cases, rickets may present with fractures (image 2). This was illustrated in a multicenter retrospective study of chest radiographs of infants born at <37 weeks gestation, in which rib fractures were identified in 26 of 1446 infants (1.8 percent) [45]. The median age at the time of detection was 14 weeks, and the median-corrected gestational age was 39 weeks. Most infants had multiple fractures, and 40 percent of the fractures were located posteriorly. Rib fractures were attributed to osteopenia of prematurity in two-thirds of the patients (n = 17 patients).

Initial management — Management of neonatal rickets involves (algorithm 1):

●Calcium and phosphorus replacement – For enterally fed infants, rickets is treated by providing supplemental calcium and phosphorus, typically delivered by feeding fortified human milk or premature formula (table 2) [28,46]. If the infant develops rickets despite fortified feeds, we review the intake and feeding strategy to ensure calcium and phosphorus intake at the high end of the recommended ranges. (See 'Calcium and phosphorus requirements' above and 'Fortification of feeds' above.)

In some infants, fluid limitations or feeding intolerance may limit the use of recommended amounts of HMF or preterm formulas. These infants may require additional calcium and phosphorus supplements, which we implement as follows [3]:

•Elemental calcium is initiated at 20 mg/kg/day and increased as tolerated to a maximum dose of 70 to 80 mg/kg/day. These doses refer to supplemental dosing and do not include the calcium content from breast milk or formula. In our practice, we typically use calcium glubionate solution; however, if this is not available, calcium carbonate or other formulations may be used.

•Elemental phosphorus is initiated at a dose of 10 to 20 mg/kg/day and increased as tolerated to a maximum dose of 40 to 50 mg/kg/day. In our practice, we typically give oral doses of the intravenous formulation of either sodium or potassium phosphate. If these are not available, we use an oral solution of sodium and potassium phosphate (Neutra-Phos).

For infants on parenteral nutrition, provide the maximum allowable parenteral mineral concentrations in their parenteral nutrition formulation. Calcium and phosphate content in parenteral nutrition is limited by concerns about precipitation, as described separately (see "Parenteral nutrition in premature infants", section on 'Calcium and phosphate'). These infants typically require subsequent oral supplementation once enteral feeds are established.

●Vitamin D – Rickets in preterm infants is primarily a disorder of calcium and phosphorus deficiency and generally is not mediated by vitamin D deficiency. In our institution, we typically increase vitamin D to 20 micrograms (800 international units) daily for infants with confirmed rickets to ensure vitamin D sufficiency while proceeding with other interventions. (See 'Vitamin D requirements' above.)

●Fracture prevention and management – Premature infants with rickets are at high risk for fractures, which may occur accidentally during routine care by the medical team or family. Caregivers should be advised to handle the infant gently.

If fractures occur, they are managed conservatively with supplemental minerals and vitamin D rather than surgical intervention. Because fractures are common in infants with neonatal rickets, further evaluation for genetic causes of bone fractures such as osteogenesis imperfecta is generally unnecessary.

●Infants with cholestasis or renal disease – Infants with severe cholestasis or other chronic illnesses may need prolonged supplementation with high doses of calcium, phosphorus, and vitamin D. If cholestasis or renal disease is severe, oral vitamin D may not be adequate to form active 1,25-dihydroxyvitamin D and vitamin D may need to be administered directly as the active form calcitriol (1,25-dihydroxyvitamin D), with appropriate monitoring of serum calcium to avoid hypercalcemia.

Monitoring and subsequent management

After initiating calcium and phosphorus supplementation, as outlined above, the next steps are:

●Measure phosphorus and alkaline phosphatase activity every two weeks

●Obtain follow-up radiographs after approximately six weeks

Most infants treated with increased calcium and phosphorus have improved radiographic findings after several weeks, and serum phosphorus concentration and alkaline phosphatase activity normalize.

Once biochemical values have improved and radiographs show signs of healing, supplemental calcium and phosphorus may be weaned over two to four weeks and ultimately stopped. No specific laboratory criteria have been defined, but we typically stop the mineral supplements when the serum alkaline phosphatase value is <500 to 600 international units/L and trending downward, unless the infant has malabsorptive disease or other reasons for a high mineral requirement.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breastfeeding and infant nutrition" and "Society guideline links: Pediatric bone health" and "Society guideline links: Nutrition support (parenteral and enteral nutrition) for neonates including preterm infants".)

SUMMARY AND RECOMMENDATIONS

●Premature infants are at risk for osteopenia and rickets. Infants with very low birth weight (VLBW; <1500 g) have particularly high requirements for calcium and phosphorus because of their rapid growth and to compensate for the loss of accretion of these nutrients during the third trimester of pregnancy. (See 'Factors affecting neonatal bone health' above.)

●The main risk factor for rickets in VLBW infants is insufficient intake of calcium and phosphorus. Other risk factors include long-term parenteral nutrition, use of loop diuretics, and fluid restriction (table 1). (See 'Risk factors for rickets' above.)

●Prevention of rickets in premature infants focuses on providing adequate calcium and phosphorus intake. Unfortified human milk, parenteral nutrition, and formulas designed for term infants do not contain enough calcium and phosphorus to fully meet the needs for normal bone mineralization in these infants. In general, rickets in preterm infants is not mediated by vitamin D deficiency. (See 'Enteral nutrition' above.)

•For all VLBW infants, we recommend fortifying feeds with calcium and phosphorus (Grade 1B). Mineral fortification substantially reduces the risk of rickets and fractures and has no adverse effects within the recommended range for intake. This can be accomplished by adding a commercial multinutrient human milk fortifier (HMF) to human milk or by feeding a preterm infant formula (table 2). Either of these strategies also provides supplemental energy and protein, which have other benefits. Most institutions provide fortified feeds for infants 1500 to 2000 g primarily to provide additional protein and energy for growth rather than specifically for rickets prevention. (See 'Fortification of feeds' above.)

•For preterm infants, we suggest vitamin D supplementation beginning during the birth hospitalization rather than deferring supplementation until after hospital discharge (Grade 2C). The approach is generally similar to guidelines for term infants. Vitamin D supplements in recommended ranges are safe and may have benefits on bone health in some preterm infants or after the neonatal period, based on very limited data. For VLBW infants, we target vitamin D intake between 5 and 10 micrograms (200 and 400 international units) daily and increase to 10 micrograms (400 international units) daily when the infant reaches 1500 g of body weight and is tolerating full enteral nutrition. (See 'Vitamin D requirements' above.)

●For all VLBW infants, we suggest routine laboratory testing with alkaline phosphatase activity and phosphorus. We initiate testing at four weeks of age and repeat the tests every two weeks until the infant is on full enteral feeds and the alkaline phosphatase activity is decreasing (algorithm 1). (See 'Laboratory monitoring' above.)

•This testing can be discontinued once the serum alkaline phosphatase activity has peaked and then declined to less than approximately 500 international units/L and the infant is on appropriate enteral nutrition. These infants can also transition to feeds with lower mineral content (eg, unfortified human milk or transitional formula). For healthy infants, this transition is typically done during the final week before hospital discharge. Vitamin D supplementation should be continued. (See 'Infants with no evidence of bone disease' above.)

•If serum alkaline phosphatase activity rises to ≥1000 international units/L at any point (or ≥800 international units/L with an increasing trend), the infant should be evaluated for rickets by performing a radiograph of the wrist and/or knee. (See 'Infants with rickets' above.)

•Infants with intermediate results on laboratory testing (eg, alkaline phosphatase activity 800 to 1000 international units/L and stable or serum phosphorus <4 mg/dL) or those with additional risk factors for rickets may require prolonged dietary fortification and laboratory monitoring, including after hospital discharge. (See 'Infants with ongoing risk for rickets' above.)

●Rickets is suggested by serum alkaline phosphatase activity ≥1000 international units/L, and the diagnosis is confirmed by wrist and/or knee radiographs (algorithm 1). For preterm infants with rickets, we suggest increasing the calcium and phosphorus intake (Grade 2C). We target calcium and phosphorus at the upper end of the recommended range, which can generally be provided by feeds of fortified human milk or formula designed for premature infants. In addition, we suggest adequate vitamin D supplementation (10 to 20 micrograms [400 to 800 international units] daily) (Grade 2C). However, most neonatal rickets is not mediated by vitamin D and the requirement in preterm infants is not well established. (See 'Infants with rickets' above.)