See “Have We Reached the Limits With Regard to Amino Acid/Protein Intakes in Preterm Infants?” by van Goudoever and Moltu on page 797.
What Is Known
- Extremely preterm infants have high nutrient requirements because of limited nutrient stores and rapid postnatal growth.
- Preterm infants commonly experience postnatal growth failure.
- Energy and protein intakes are associated with postnatal growth.
What Is New
- Comprehensive data are shown on estimated enteral and parenteral intakes of 25 micronutrients during the first 70 postnatal days in a population-based cohort of extremely preterm infants.
- Infants received less amount of folate and many minerals, whereas supply of many water-soluble vitamins and iron were higher compared with estimated requirements.
- Low intakes of folate and excessive iron supply were independent risk factors of poor growth.
Recent advances in neonatal intensive care have greatly improved survival rates for extremely premature infants (<27 weeks of gestation), but there are still concerns about the risk for morbidity and later disability (1,2). Because of rapid growth, and limited stores of macronutrients and micronutrients at birth, extremely preterm infants have extraordinarily high nutrient requirements (3,4).
Growth of preterm infants is often used to monitor nutritional intakes and the goal is to achieve growth similar to that in utero (5,6). Still, many extremely preterm infants develop extrauterine growth restriction (7,8). Recently, we reported insufficient intakes of energy and macronutrients to be associated with severe growth failure in extremely preterm infants, even when taking severity of illness into account (9).
Micronutrients are essential for growth and development, but there are risk for both deficiency and toxicity (10). Even though fluid and macronutrient intakes usually are calculated on a daily basis for extremely preterm infants, the intake of micronutrients is generally not known by clinicians, but depends on the composition of enteral and parenteral nutrition products used and the nutrition regimens.
Many micronutrients (eg, folic acid, iodine, zinc, sodium, chloride, calcium, magnesium, vitamin A, phosphorous, manganese, and pyridoxine) are important for weight and length growth in infants (11–13). Several micronutrients, including iron, zinc, copper, iodine, selenium, chloride, folate, and vitamin A, are important for brain development and brain growth, which, in turn, are related to head growth (13–15), whereas calcium, phosphorus, and vitamin D are essential for bone mineralization (16). Nevertheless, it is still unclear to what extent micronutrient intakes affect early growth in extremely preterm infants. To our knowledge, no populations-based study has reported comprehensive data on mineral and vitamin supply in extremely preterm infants during hospital stay.
The aim of the present study was to describe the intakes of micronutrients in extremely preterm infants during the first 70 days of life and to explore the possible correlations between such intakes and postnatal weight, length, and head circumference (HC) growth. We hypothesized that one or several micronutrients would be significantly associated with growth during hospital stay, even when considering macronutrient intakes and severity of illness.
For the present study, we included infants who survived >24 hours after birth from the Extremely Preterm Infants in Sweden Study (EXPRESS) (1). The infants were born during a 3-year period (2004–2007) and had a gestational age of <27 weeks. Comprehensive prospective data on cohort characteristics, neonatal morbidity, and infant mortality have previously been reported (1,2). Total energy and macronutrient intakes and growth outcome during the first 70 days have recently been published (9). Briefly, that study showed that total energy intake, enteral fluid, and macronutrient intakes were significantly associated with postnatal growth. Infants with necrotizing enterocolitis who underwent surgery and infants with major congenital or chromosomal anomalies as well as infants with severe cholestasis were excluded, as previously described.
All available data on nutritional intakes and growth (weight, length, and HC), from birth until discharge, were retrospectively derived from hospital records. During the first 70 days, detailed daily data on all actual intakes of enteral and parenteral fluids were retrieved from birth (day 0) through day 28 and thereafter for 1 day/ wk (day 35, 42, etc) until death (n = 72), discharge (n = 10), or when nutritional data no longer were accessible (n = 55). Because the care of extremely preterm infants is centralized in Sweden, most of the data for the first 28 days were collected from the 7 university hospitals. For those infants who were transferred to a county hospital (45%), data collection was continued using records from each hospital.
In total, 25 micronutrients were studied and nutritional data for 15,878 individual days were retrieved from hospital records. Nutrition was assessed as intakes of micronutrients (per kg per day) from all parenteral and enteral products. Nutrient intakes from non-human sources were calculated using data from the manufacturers. The content of each micronutrient in human milk was estimated using published values (sodium, potassium, calcium, phosphorus, magnesium, copper, zinc, vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, niacin, biotin, pantothenic acid (17), chloride, selenium, iodine, iron, vitamin C, vitamin B12 (18), folate (19) manganese (13)). Because the content of some micronutrients (eg, vitamin A (20), zinc, copper, calcium, vitamin K, magnesium (17)) changes during the first weeks postpartum, different micronutrient contents were used for early (≤28 days) and mature (>28 days) human milk. Transfused blood products were included in total fluid and nutrient intake. The nutritional contents of blood products were calculated from published values (21,22). Fluids from drug infusions, for example, flush solutions, were also included, and the contents of electrolytes such as chloride and sodium in these fluids were obtained from the manufacturer's product information. When the type of flush solution was not known, it was assumed to be sodium chloride.
Intakes from enteral and parenteral sources were added in the final analyses and, as the infants received much more enteral nutrition than parenteral nutrition during the whole investigated period, parenteral intakes were converted to enteral by adjusting for the enteral absorption rate of each micronutrient (enteral intakes + [parenteral intakes/intestinal absorption rate]). This sum is henceforth referred to as adjusted enteral intakes (AEI).
AEIs were calculated using the following intestinal absorption rates: sodium 0.9, chloride 0.9 (23), potassium 0.85 (13), calcium 0.54 (24), phosphorus 0.9, magnesium 0.78, selenium 0.8, manganese 0.08, vitamin K 0.29, pantothenic acid 0.5 (25), copper 0.6 (26), iron 0.25 (27), zinc 0.5 (26,28), iodine 0.9 (29), vitamin A 0.8 (30), vitamin D 0.5, vitamin E 0.45 (31), vitamin C 0.8 (32), thiamine 0.95 (33), riboflavin 0.55 (34), pyridoxine 0.75 (35), vitamin B12 0.5 (36), folate 0.5 (37), niacin 1.0 (38), and biotin 0.5 (39).
For comparison to parenteral requirements (12,25), intakes were also calculated as adjusted parenteral intakes (parenteral intakes/[enteral intakes × intestinal absorption rate]).
We used a Swedish longitudinal sex-specific growth curve to calculate standard deviation score (SDS) of weight, length, and HC (40). Morbidity data were prospectively collected as previously described (1,2). Precise durations were available for each episode of mechanical ventilation and postnatal steroids. Because only start date and number of episodes were available for antibiotic treatment we assumed that each episode was 7 days.
Data were analyzed by using SPSS Statistical software (Version 21.0 for Windows, SPSS Inc. Chicago, IL). Continuous variables are presented as mean ± SD, and variables not normally distributed are presented as median and 10th to 90th percentile. The level of significance was set at P < 0.05.
We included data during the first 70 postnatal days and data were analyzed in three postnatal age intervals: 0–28, 29–70 and 0–70 days.
Univariate linear regression analyses of energy intake, macronutrient intakes, and possible confounders were performed within each time interval and each growth outcome (9). Included possible confounders were gestational age, birth SDS and baseline SDS (SDS values at day 28) of all growth outcomes, treatment with postnatal steroids or antibiotics, duration of mechanical ventilation, blood and plasma transfusions, clinical risk index for babies (CRIB), and proportion of enteral fluid intake.
In addition, linear regression analyses adjusted for intakes of energy, protein, and enteral fluids were performed for all micronutrients in each time interval and for each growth outcome (weight, length, and HC). Micronutrients that were significant in at least 2 of 3 time intervals were included in the final multiple linear regression. To further analyze the effects of chloride intake, data on serum chloride were included in the analyses. This was possible because laboratory data of serum concentrations of some nutrition-related biomarkers, such as serum chloride, also were obtained from the infants’ hospital records.
Finally, multiple linear regression analyses were performed for each growth outcome and each time interval using a stepwise procedure, including all significant micronutrients and significant variables from our recent publication of macronutrient intakes and growth outcomes in this cohort (9).
The present study has been approved (Dnr 138–2008) by the ethics committee, Lund, Sweden.
In total, 531 extremely preterm infants were included in the analyses. Infant characteristics, energy, macronutrient intakes, and growth during the first 70 days have previously been published (9). Mean gestational age was 25 weeks and 2 days. Weight, length, and HC (mean ± SD) at birth was 765 ± 1.1 g, 32.7 ± 2.5 cm, and 23.2 ± 1.6 cm, respectively. Infants showed severe growth failure and SDS for weight, length, and HC decreased by 2.1, 2.3, and 1.5 SD, respectively, between birth and day 28.
During this time period (2004–2007) all newborn infants, including extremely preterm infants, in Sweden received a dose of 1 mg of vitamin K1 (phytonadione [Konakion Novum], F.Hoffmann-La Roche Ltd, Basel, Switzerland) directly after birth, either intramuscularly or intravenously.
Standard practice at all participating hospitals was to feed infants maternal milk or, if not available, banked donor human milk. Human milk fortifiers (HMFs) were gradually added to human milk as soon as infants reached and/or tolerated full enteral volume. The most frequently used HMF was Enfamil powder (Mead Johnson, Mediq Sweden AB, Kungsbacka, Sweden), which during the study period contained all of the studied vitamins and most minerals with a notable exception of iodine. At a minority of hospitals, Nutriprem (Cow & Gate, Nutricia, Mediq Sweden AB) HMF was used; this product contains all studied vitamins and most of minerals with a notable exception of iron.
Oral vitamin supplements were started approximately at 2 to 4 weeks postnatal age or when infants received full enteral nutrition depending on local practice. The most frequently used multivitamin supplement was Protovit (F.Hoffmann-La Roche Ltd) containing vitamin A, vitamin E, vitamin D, and all studied water-soluble vitamins except folate and B12. Oral supplements of iron were started approximately after 4 weeks postnatal age at all hospitals and infants also often received oral capsules or mixture of calcium lactate and sodium phosphate from approximately 2 to 3 weeks postnatal age.
Intakes of 25 micronutrients, stratified into different time intervals during the first 70 days are shown in Tables 1 and 2. During the first 28 days, intakes (AEI) of calcium, phosphorus, magnesium, zinc, copper, selenium, iodine, vitamin D, and folate were lower than estimated enteral requirements, whereas intakes of iron, vitamin K, and several water-soluble vitamins were higher than estimated enteral requirements (Table 1). Using adjusted parenteral intakes gave similar results except that manganese, vitamin E, and B12 intakes (but not vitamin D) were lower than the estimated parenteral requirements (Table 2).
High intakes of iron were explained by blood transfusions, during the first 28 days of life infants received a median (25th–75th percentile) of 6 (3–9) blood transfusions, resulting in 75 (44–120) mL/kg of blood. The high vitamin K intake was mainly a result from the single dose of vitamin K given at birth.
During the time interval 29 to 70 days, intakes of most micronutrients increased compared with the first 28 days of life but low intakes of calcium, phosphorous, zinc, copper, and folate remained. Intakes of folate were actually lower during the second time interval, and the supply of iron decreased during the time interval 29 to 70 days.
Associations Between Micronutrient Intakes and Postnatal Growth
First, linear regression analyses were performed, adjusting for intakes of energy, protein, and enteral fluids. The following micronutrients were significantly (negatively or positively) associated with weight gain in at least 2 of the 3 investigated time intervals: chloride (−), iron (−), copper (+), iodine (+), and folate (+). The following micronutrients were significantly associated with length gain in at least 2 of the 3 time intervals: sodium (−), chloride (−), iron (−), vitamin D (+), riboflavin (+), folate (+), and B12 (+). The following micronutrients were significantly associated with HC growth in at least 2 of the 3 time intervals: sodium (−), chloride (−), iron (−), iodine (+), vitamin C (−), and B12 (+), data not shown.
Furthermore, associations between micronutrient intakes and postnatal growth were investigated in stepwise multivariate regression analyses (Tables 3 and 4). These analyses included all significant micronutrients listed above, and those macronutrients and disease-related variables, which were significant predictors of growth in our previous publication of this cohort (9). In the multivariate model for day 0 to 28, folate remained positively correlated with both weight and length gain. In contrast, negative correlations were observed between the intakes of two micronutrients (iron and chloride) and growth of length and HC (Table 3). Between days 29 and 70, iodine was positively correlated with weight gain, B12 was positively correlated with both length gain and HC growth, and chloride was negatively correlated with weight and length gain (Table 3). When investigating associations between micronutrient intakes and growth outcomes during the entire time interval of 70 days, a significant positive association was observed between intakes of folate and weight, as well as length gain (Table 4). Iron and chloride intakes were negatively associated with length gain and HC growth, respectively. Parenteral and enteral distribution of included micronutrients (0–70 days) is presented in Table 5.
We present comprehensive data on intakes of 25 micronutrients during the first 70 postnatal days in a population-based cohort of extremely preterm infants with a gestational age <27 weeks (Tables 1 and 2). Intakes of several micronutrients such as calcium, phosphorus, magnesium, selenium, zinc, copper, folate, and vitamin D were lower than estimated requirements, whereas intakes of other micronutrients, for example, iron, vitamin K, and water-soluble vitamins (eg, thiamine, riboflavin, and pyridoxine) were higher than estimated requirements (12,25). When adjusting for macronutrient intake and disease severity, we found that intakes of folate were significantly positively associated with growth outcomes, whereas intakes of iron and chloride were negatively associated with growth in extremely preterm infants during the first 70 days of life.
Intakes of folate were lower than estimated requirements and folate intakes also decreased after 28 days of life; the slightly higher intakes of folate during the first 28 days were mainly explained by folate content in parenteral solutions. Enteral sources of folate were mainly human milk and HMF. Infants in this cohort usually did not receive full dose HMF, which would explain the lower folate intakes. At a minority of hospitals, additional folate capsules were given as oral supplements. We observed a positive correlation between folate intake and both weight and length gain. It has been shown that supplementation of folic acid increases weight and height in stunted and underweight term born infants and toddlers (41). Our finding suggests that folate may play an important role in the growth of extremely preterm infants as well.
Iodine intake was low during the first 28 days of life. Iodine mainly originates from enteral sources and there was a positive association between iodine intake and weight gain, even though this result was not consistent during the whole time period. Iodine repletion increases the concentrations of insulin-like growth factor 1 and insulin-growth factor binding protein 3, which was associated with improved somatic growth in moderately iodine-deficient school-age children (42). We can only speculate that there may be a similar effect in extremely preterm infants. It has been shown that iodine intakes are insufficient in hospitalized preterm infants and infants with prolonged parenteral nutrition are particularly at risk for iodine deficiency (43). The HMF that was most frequently used during the study period did not contain iodine. This illustrates the importance of the micronutrient contents of HMFs, which probably can be further optimized in the future.
Vitamin B12 was positively associated with length gain and HC growth during days 29 to 70. A recent randomized controlled trial showed that poor vitamin B12 status in stunted and underweight 6- to 30-month-old infants contributes to faltering growth (41). Because vitamin B12 intakes in our cohort were not lower than the estimated requirements, the association with growth (which was only observed in the 29–70-day interval) may be a chance finding.
Our results showed an overall low intake of calcium, phosphorus, magnesium, and vitamin D. It is well known that these micronutrients are essential for bone mineralization and bone growth and has been associated with weight gain (13,16). Surprisingly, neither of those micronutrients remained significant in relation to growth outcomes in our final analyses. Because many of these micronutrients interact with each other, it is difficult in the present study to establish the clear relation between insufficient intake and growth outcome. Nevertheless, insufficient intakes of these micronutrients may contribute to poor bone mineralization, which was not investigated in the present study.
Zinc plays an essential role as a cofactor of many enzymes, and it is well recognized that zinc deficiency leads to impairment of physical growth (44). In our study, infants had a zinc intake much lower than estimated enteral requirements, yet we did not find any significant association between zinc intake and growth outcome. This may be due to high iron intakes, low intakes of other micronutrients, and the deficits of energy and protein intakes in this particular group of infants.
AEI of iron was 3 to 4 times higher than the enteral estimated requirements during the first 28 days and during all 70 days, respectively. Even though infants received iron as oral drops and HMF containing iron, the high iron supply was explained by blood transfusions, and most blood transfusions occurred during the first 28 days of life. We observed a negative effect of excessive iron intake on length gain and HC growth during the first 28 postnatal days and during the whole investigated time interval of 70 days. The strongest association was between iron intake and length gain during the early postnatal phase (0–28 days). Our results are supported by studies in term infants which suggest that high iron intakes may negatively affect growth (45,46). An alternative explanation for the negative association between iron intakes and longitudinal growth may be that blood transfusions are a marker of morbidity, which in turn is related to poor growth. The association, however, remained when adjusting for other morbidity-related variables.
The median intakes of chloride were slightly higher than estimated recommended values, there are, however, scarce data on chloride requirements in extremely preterm infants. During the whole study period (0–70 days), chloride mainly originated from enteral sources such as human milk and many infants also received oral sodium chloride supplements. Even though it is well known that sodium chloride deprivation impairs growth in infants (47), we observed a negative association between chloride intakes during the first 70 days of life and weight and HC growth. In additional analyses (not shown), we did not find any negative correlation between serum chloride concentrations and growth in univariate regression analyses. This suggests that the observed correlation between chloride and growth is not causal. We instead speculate that extra sodium chloride is given to infants with more immature renal function, which in turn may be correlated to poor growth.
Infants received an excessive intake of vitamin K and high intakes of many water-soluble vitamins, such as thiamine, riboflavin, pyridoxine, pantothenic acid, and biotin. The extremely high intake of vitamin K was due to the routine administration of 1 mg vitamin K at birth in Sweden, during the years 2004 to 2007, a recommendation, which has since been revised. High intakes of water-soluble vitamins were explained by a combination of the use of HMF and oral multivitamin drops. We did not find that these high intakes of some vitamins had any adverse effect on growth, but it cannot be excluded that excessive vitamin intakes may have other negative effects. It is therefore crucial to optimize the composition of supplements and HMF and routines for their use.
The strength of the present study is that it is a population-based study with meticulous nutritional data collection (a total of 15,878 days for the included infants). Limitations of the study include the retrospective study design and the lack of standardized measurements of weight, length, and HC during hospitalization. Furthermore, micronutrient content in human milk were not analyzed and the nutritional content of flush solutions were not always systematically noted in hospital records. Also, micronutrient losses were not measured in the present study. There is a lack of high-quality studies of intestinal absorption rates of different micronutrients in preterm infants and some of the absorption values used in our calculations were derived from studies in older children or adults, which is a limitation. Lastly, despite adjusting for macronutrient intakes and other possible confounders in this observational study, residual confounding cannot be excluded and causal effects can thus not be proven.
In summary, this is the first study to show comprehensive data on micronutrient intakes in extremely preterm infants during hospital stay. Intakes of calcium, phosphorus, magnesium, zinc, copper, selenium, vitamin D, and folate were lower than estimated requirements, whereas intakes of iron, vitamin K, thiamine, riboflavin, pyridoxine, pantothenic acid, and biotin were higher than estimated requirements. Even when considering macronutrient intakes and severity of illness, several micronutrients were independent predictors of postnatal growth. Low intakes of folate were associated with poor weight and length growth. High iron intakes were associated with poor length and HC growth. Optimized early micronutrient intakes may improve early growth in extremely preterm infants. Specifically, it may be beneficial to provide adequate folate intakes and limit iron intakes from blood transfusions in this population of infants. The results of the present study highlight the need for more studies regarding micronutrients in preterm infants, for example, absorption studies and intervention studies using single or multiple micronutrients.
The authors acknowledge Ann-Cathrine Berg, Cecilia Ewald, Anne Rosenkvist, Caroline Törnqvist, and Vera Westin for entering and checking nutritional and growth data, and Andreas Tornevi for statistical support.
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Keywords:© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
extremely preterm infants; folate; growth; iron; micronutrients