The goal in nourishing low birth weight (LBW) premature infants should be to minimize nutrient deficits, promptly address these deficits once identified, and avoid overnourishing or promoting postnatal growth acceleration once nutrient deficits have been corrected. The best practices for accomplishing this, particularly early after hospital discharge, have yet to be defined (1–5). Although feeding human milk (HM) to LBW infants is widely acknowledged as being superior to formula feeding (6), HM-fed infants often accrue the greatest nutritional deficits by hospital discharge (1–5,7). Recently, the ESPGHAN Committee on Nutrition recommended in this journal that HM-fed premature infants discharged home with subnormal weight for postconceptional age be provided with extra energy and nutrients (1). In this article, we investigate 1 approach of doing this, and evaluate whether providing extra energy and nutrients early after discharge results in a better bone mineralization, body composition, growth, and HM feeding during the first year of life.
With the increased survival rate of smaller premature infants, their proportionally higher nutritional requirements, and emphasis on rapid hospital discharge, there may be merit in extending in-hospital multinutrient fortification of HM to the early postdischarge period. It is known, for example, that low calcium and phosphorus intakes during initial hospitalization result in suboptimal bone mineralization in LBW infants, and if sustained, may result in metabolic bone disease (6,8). As a result, adding extra energy and nutrients, and specifically calcium and phosphorus, to HM fed to LBW infants during their inhospital course, is the current standard of care (5,6,8). More recently, Kurl et al (9) reported that breast-feeding of premature infants after hospital discharge may also be associated with low bone mineral content. This group reported that exclusive breast-feeding after hospital discharge was associated with a 7.0-fold (range 1.2–41.7) higher risk of low bone mineral content at 3-month corrected age (CA) among prematurely born infants. Wauben et al (10) have also reported a lower rate of bone mineralization between 3- and 6-month CA among Canadian LBW infants who were fed HM after hospital discharge, according to parental choice, compared with those who received standard-term formula (1.4 vs 3.9 g/week; P < 0.05).
In addressing postdischarge nutrient deficits, it is important not to inadvertently overcompensate and promote excessive weight gain, notably fat mass gain. This is a concern because both low infant birth weight and rapid postnatal weight gain are thought to be risk factors for obesity and associated complications, such as cardiovascular disease, hypertension, insulin resistance, and diabetes mellitus during adulthood (11–18).
We recently reported in a pilot study that LBW infants fed HM containing extra energy and nutrients early after hospital discharge demonstrated a more rapid rate of growth during a 12-week feeding intervention than for infants sent home on HM alone (19). Because nutrient intakes in the intervention group were more consistent with current dietary recommendations than infants fed HM alone (8), we concluded that their growth reflected earlier correction of inhospital acquired nutritional deficits. In this article, we examine the impact of this early postdischarge feeding intervention on the longer-term outcomes of these babies, including bone mineralization and body composition, as well as total and trunk fat mass, at 4- and 12-month CA. Because few data specific to the LBW infant exist exploring the impact of such a nutritional intervention on HM feeding, we also assessed the duration and exclusivity of HM use up to 1 year. We also present data on general developmental level (Bayley Scales of Infant Development II) at 18-month CA to assist in the sample size calculation for future larger studies.
PATIENTS AND METHODS
Infants were enrolled from neonatal intensive care units in the greater Toronto area. Infants born <33 weeks' gestation, weighing between 750 and 1800 g, and who received more than or equal to 80% energy from HM before hospital discharge were eligible to participate. Exclusion criteria included serious congenital anomalies that could affect growth, more than or equal to grade III periventricular or intraventricular hemorrhage, recent oral steroid treatment, severe birth asphyxia, maternal substance abuse, and inability of the mother to communicate in English. Babies were also excluded if their clinical team believed the child's medical condition dictated that postdischarge feedings needed to be nutrient enriched to > 24 kcal/fl oz or if >50% of daily feeds needed to be nutrient enriched. It would have been unethical to randomly assign these infants to the control group.
A detailed description of the study design and feeding intervention is published elsewhere (19). Briefly, the day before discharge (study day 1), infants were randomized to either an intervention or control group using a randomization schedule stratified for sex and birth weight (≤1250 g, >1250 g). Those assigned to the control group were discharged home on unfortified HM (breast or expressed). In the event that an infant in the control group demonstrated poor growth, as defined by an algorithm established a priori (19), the infant's pediatrician was advised. It was at the discretion of the infants' pediatricians as to how nutrient enrichment was to be accomplished for infants in the control group; generally, a powdered postdischarge formula (unreconstituted) was added to HM.
For infants in the intervention group, nutrient enrichment of HM was achieved by providing instructions to caregivers to mix each day for 12 weeks after hospital discharge a predetermined volume (150 mL × infant weight [kg]/2) of HM with a powdered multinutrient HM fortifier (Similac HM Fortifier, Abbott Nutrition, Montreal, QC, 4 single-use packets per 100 mL HM). The volume chosen for fortification was an estimate corresponding to 50% of an infant's intake (10). The amount of fortified milk to be fed was recalculated at 4 and 8 weeks postdischarge to account for changes in infant weight and intake.
Infants in the control group were provided daily with vitamins A (1500 IU), D (400 IU), and C (30 mg). To avoid potentially high intakes of fat-soluble vitamins, infants in the intervention group were provided with drops containing only 200 IU of vitamin D (D-Vi-Sol [Mead Johnson Nutritionals, Ottawa, Canada]) and no other vitamins. Infants in both feeding groups received a daily iron supplement of 15 mg.
The study coordinator, a certified lactation consultant and former neonatal nurse, offered lactation support to mothers in both feeding groups and provided families with vitamin/iron drops, feeding devices, and use of an electric breast-pump free of charge. Families were visited in their home at hospital discharge (study day 1) and at 4, 8, and 12 weeks ±3 days postdischarge. Families attended a study clinic visit at the Hospital for Sick Children when infants were 4 (±7 days), 6 (±7 days), 12 (±10 days), and 18-month (±10 days) CA. Due to the small sample size and projected attrition with time, we did not follow infants after 18-month CA.
The study protocol was approved and annually reviewed by the human ethics committees at the Hospital for Sick Children and at each of the recruiting hospitals. Informed written consent was received from at least 1 parent. This study is registered with the US National Library of Medicine found at http://www.clinicaltrials.gov (#NCT00413985).
Growth and Body Composition
Anthropometric measurements at birth were extracted from medical records; thereafter, they were determined by a single tester according to standardized procedures (19,20). Total body bone mineral content, bone mineral density, fat mass, and lean mass were measured using dual energy x-ray absorptiometry (DXA, GE Lunar Prodigy, Buckinghamshire, UK) using enCORE software (pediatric application) in standard mode at 4- (±7 days) and 12-month CA (±10 days). All of the scans were conducted by certified technicians who were blinded to feeding assignment. Infants wore only a diaper and were wrapped in a blanket to minimize movement. Each scan lasted 60 to 90 seconds with an average radiation exposure of 0.04 mrem.
Quality control scans were performed on a daily basis using a hydroxyapatite calibration block provided by the manufacturer to simulate bone of different densities, as well as lean and fat tissue. The mean ± SD for 28 quality control scans in the lowest bone mineral density mode was 0.499 ± 0.001 g/cm2 (CV 0.2%). The manufacturer provided value was 0.495 g/cm2. There was a <2% difference between infant body weights obtained by digital scale and those calculated by the DXA scanner.
General Developmental Level
The Bayley Scales of Infant Development-Second Edition (Bayley II, Psychological Corporation, San Antonio, TX) was administered by 1 of 2 qualified psychometrists, masked to feeding assignment, at 18-month CA (±10 days) (21). This examination consists of the mental scale, which includes items that assess memory, problem solving, discrimination, classification, language, and social skills; the motor scale, which assesses control of gross and fine motor muscle groups, including walking, running, use of writing implements, and imitation of hand movements; and the behavior rating scale, which assesses qualitative aspects of the child's test-taking behavior including orientation and engagement toward tasks and emotional regulation.
Dietary intake diaries were mailed to parents 3 days before each home and clinic visit. Parents were instructed to determine their baby's breast milk, expressed milk, and other fluid intake using a validated test-weighing procedure (22). To capture changes in HM feeding that may have occurred between clinic visits, at each visit the study coordinator asked mothers about the frequency of HM feeding since the last visit. Energy and select nutrient intakes (protein, calcium, phosphorus, zinc, iron, vitamin A, and vitamin D) at 6- and 12-month CA were estimated using HM composition values from the literature, manufacturer label claims for infant formulas and the powdered HM fortifier, and the Canadian Nutrient File (Health Canada, version 2001b).
On the basis of the work of Wauben et al (10), we estimated a sample size of 34 infants would allow for the detection of a 1-SD difference in bone mineral content (28 g) between feeding groups at 12-month CA, with 80% power and an α level of 0.05. We did not anticipate that this sample size would be sufficient to detect hypothesized differences in scores (∼0.25 SD) on the mental or motor scales of the Bayley II (23). The Bayley II was included in this pilot study as an exploratory outcome variable to determine the appropriate sample size for inclusion of the Bayley in larger future studies.
Statistical analyses for this intent-to-treat study included all enrolled infants as randomized. No infant was withdrawn from the study by the investigators due to compliance with the feeding protocol. Data for all of the infants until they either completed or exited the study early were analyzed using SAS for Windows version 9.1 (SAS Institute, Cary, NC). Continuous variables measured at >1 time point were analyzed using a mixed repeated-measures ANOVA (PROC MIXED) controlling for sex and birth weight strata (≤1250 or ≥1251 g). Duration of HM feeding was not prognostic of anthropometric measurements and, therefore, was not included in the statistical models assessing growth outcomes. Because data for the amount of milk consumed (mL · kg−1 · day−1 and % of all milk feeds) at 6- and 12-month CA were not normally distributed and could not be transformed to produce a normal distribution, these outcomes were assessed at each time point by the Wilcoxon rank-sum test. Differences between feeding groups in scores of general development were assessed by analysis of covariance (parametric data) controlling for sex and birth weight stratum (≤1250 g, >1250 g) or Wilcoxon rank-sum test (nonparametric data). All statistical tests of hypotheses were 2-tailed with an α level of 0.05 for main effects and an α level of 0.10 for interactions.
Infants who were born small-for-gestational age (SGA, <10th percentile) were included in the study because they represent a sizeable proportion of the preterm population. All of the statistical analyses of growth and body composition were rerun without these infants to ensure that their inclusion did not influence study findings. One infant later diagnosed with a structural anomaly of the brain was removed from these additional analyses and from both primary and secondary statistical analysis of neurodevelopmental testing results.
Thirty-nine infants were randomized to either the control group (n = 20) or the intervention group (n = 19) (Fig. 1). Of these infants, 34 completed the 12-week postdischarge intervention period (17 per group). On average, infants were 2.5-month CA at the end of the feeding intervention. Two infants in the control group were fed HM containing a powdered postdischarge formula during the feeding intervention phase of the study to address poor growth. These infants were included in all of the statistical analyses as randomized. Thirty-four infants attended their 4-month CA clinic visit, and 30 infants remained in the study until the 12-month CA visit. At 12-month CA, 3 babies were too fussy to have their body composition measured (2 control, 1 intervention). Twenty-nine infants attended the 18-month CA clinic visit, and results on the Bayley II were obtained from 27 infants. Infants lost to follow-up after the feeding intervention period either moved or were traveling at the time of the study visit.
Although baseline family and infant demographics did not differ significantly between groups, the control group showed a trend toward older gestational age (P = 0.06) and fewer male infants (P = 0.07) (Table 1). The potential impact of these trends on outcomes was addressed by including the randomization strata (birth weight and sex), as planned, in all statistical analyses. As described in detail elsewhere, there were no differences between the groups with regard to their in-hospital course or feeding history (eg, cases of confirmed systemic infection and necrotizing enterocolitis, days on parenteral nutrition, days to full enteral feeding) (19). Likewise, there were no differences in the mean weight, length, or head circumference between feeding groups at birth or study day 1; hence, the trajectory of growth was assumed to be equal before study initiation (study day 1).
Growth, Bone Mineralization, and Body Composition
Infants in the intervention group were approximately 1.2 kg heavier at the end of their first year of life compared with those in the control group (P = 0.0035) (Fig. 2). Previously reported differences between groups in the length of infants during the feeding intervention (19) were sustained to 12-month CA (P = 0.001). In contrast, the difference in mean head circumference was no longer statistically significant at 12-month CA. A statistically significant interaction was found between feeding group and birth weight for head circumference (P = 0.005). Infants born ≤1250 g in the intervention group had a significantly larger mean head circumference than those in the control group during the first year of life (P < 0.0001). No significant difference in mean head circumference (P = 0.95) was observed between feeding groups among the infants born >1250 g. Reanalysis of the same growth data, with the omission of SGA infants and an infant queried for hydrocephalus postrandomization did not change these findings.
Total body bone mineral content was significantly greater in the intervention compared with the control group at 4- and 12-month CA (P = 0.02) (Table 2). This effect disappeared when the results were adjusted for infant length (P = 0.25). These results persisted when SGA infants and the infant queried for hydrocephalus were excluded from the analyses. There were no significant differences between the control and intervention groups in lean, fat, or trunk fat mass or bone mineral density at 4- and 12-month CA.
General Developmental Level
No statistically significant differences were found between feeding groups in the mental, motor, or behavior rating scale scores assessed at 18-month CA (Table 3). Two infants in each feeding group had a mental scale score indicative of significantly delayed performance (<70), and 3 infants in the control group and 1 in the intervention group had a mental scale score consistent with mildly delayed performance (70–84). One infant in the control group had a motor scale score indicative of significant delay; whereas 2 infants in the control group and 1 in the intervention group had a motor scale score consistent with mildly delayed performance. As shown in Table 3, there were no differences in the mean developmental ages predicted from the facet scores of the mental/motor scales between feeding groups. However, there was a trend toward infants in the intervention group having a greater number of successfully completed tasks on the language (10.5, 9–12 [median 25th–75th percentiles] vs 7, 2–12) (P = 0.053) and motor (12, 11.5–12.50 vs 11, 8–13, P = 0.067) facets than in the control group.
Human Milk Feeding and Introduction of Solids
The duration of HM feeding did not differ significantly between feeding groups; however, there was a trend for the infants in the control group to be fed HM for a longer period of time (P = 0.13) (Table 4). The volume of HM consumed (mL · kg−1 · day−1) among infants in the control group was greater than that of the intervention group at 6-month CA (P = 0.035), but not 12-month CA. By the 6-month CA visit, 2 infants in the control group and 5 infants in the intervention group were no longer being fed HM. Of the 5 infants weaned in the intervention group, 2 were twins. The length of time from birth to the introduction of solids did not differ.
Except for zinc and phosphorus, the energy and nutrient intakes of infants did not differ between feeding groups at 6- and 12-month CA (Table 5). Mean zinc and phosphorus intakes in both groups significantly exceeded current dietary recommendations for healthy term infants (24).
Growth, Bone Mineralization, and Body Composition
Data from this pilot study suggest that the early differences in anthropometric measures previously reported for LBW infants fed HM containing extra energy and nutrients for 12 weeks after hospital discharge versus HM alone are maintained for at least the first year of life. Specifically, infants fed extra energy and nutrients after discharge tended to be heavier (P = 0.07) and were longer (P = 0.02) at the end of the 12-week feeding intervention and their weights (P = 0.0035) and lengths (P = 0.001) remained different at least until 12-month CA, compared with infants sent home on HM alone. As was the case at the end of the 12-week feeding intervention, among infants born less than or equal to 1250 g, those in the intervention group had a larger head circumference to 12-month CA (P = 0.0009, P < 0.0001, respectively). We previously reported that nutrient intakes of infants fed fortified milk during the feeding intervention were greater and more consistent with current dietary recommendations than infants fed HM alone (8,19). Hence, we conclude that the sustained differences in growth reflect earlier correction of inhospital-acquired nutritional deficits among infants in the intervention group.
We are unaware of any other study in which HM-fed LBW infants have been randomized to receive multinutrient fortification of their milk after hospital discharge; however, the growth differences reported herein are similar to, albeit more sustained, than those we previously reported for a large sample of LBW infants (n = 463) sent home predominantly on HM versus some or all of their feedings from nutrient-enriched preterm formula according to parental choice (7). Furthermore, the growth results reported herein are consistent with observations of faster growth rates among LBW infants fed nutrient-enriched as opposed to a standard term formula early after hospital discharge in many (23,25–31) but not all studies (32,33).
Data from the present study also suggest that LBW infants who receive HM with added energy and nutrients early after discharge will have greater whole-body bone mineral content during their first year of life compared to those sent home on HM alone (P = 0.02). The fact that the higher whole-body bone mineral content (∼28%) was observed at 4 months of age indicates that the skeleton was responsive to the intervention early in life. The fact that whole-body bone mineral density did not differ among groups suggests that the infants in the intervention group had more bone because they were bigger babies with longer skeletons. These observations are consistent with the conclusion derived by Koo et al (34) that one of the strongest determinants of bone mineral status in healthy term infants is body size. Our observations suggest that the strategy used for nutrient enrichment of HM in this study supported an increase in bone mineral content that was proportional to that of overall growth.
Although comparison of whole-body mineral content across studies must be approached with extreme caution given the vast assortment of DXA instrumentation and software used, it is interesting to note that the bone mineral content of infants in our study fell well below those reported for preterm infants fed infant formula (10,33,35,36) and below that of HM-fed term or preterm born infants (10,37,38). Their bone mineral content was, however, similar to that of economically disadvantaged term-born breast-fed infants from the Gambia who are thought to have significantly lower total body calcium content than babies in the western world (39). We suspect that the lower whole body bone mineral content of infants in our study versus the few available other reports of western LBW infants, reflects the exclusivity of HM feeding in our sample. In healthy term-born infants, breast-feeding is associated with lower whole-body bone mineral content than formula feeding for at least the first 6 months of life (38).
Measures of total lean and fat mass and trunk fat mass did not differ between feeding groups, suggesting that that the strategy used for nutrient enrichment of HM in this study supported a proportional increase in both lean and fat mass. It has been reported that preterm infants and term-born male infants fed HM have a higher percentage of body fat after hospital discharge compared with those fed formula (10,40). It is speculated that this difference is due to the lower protein energy ratio of HM compared with infant formula, which leads to less lean mass production and hence greater fat deposition (10). We previously reported a statistically significant difference in the protein intake of infants randomized to the intervention versus the control group during the 12-week feeding phase of the study (P = 0.03), with mean protein intakes of infants fed fortified milk closer to dietary recommendations (8,19). However, herein we did not find a statistically significant association between protein intake during the feeding intervention and lean or fat mass at 4- or 12-month CA. We acknowledge that we did not analyze the protein or other nutrient content of mothers' milk in this study but rather relied on literature values for this information, which could have influenced these findings. Average percent fat mass at 12-month CA in the present study (15%–16%) was lower than that reported by others (10,35,36). Although it remains to be seen what percent fat mass is optimal for the best possible health outcomes, our data suggest that nutritional intervention in HM-fed infants early after discharge does not result in a higher percentage of body fat at the end of their first year of life.
General Developmental Level
We understood before commencing the study that our sample size would likely be insufficient to detect hypothesized differences (∼0.25 SD) in the Bayley II scales of mental and motor development but included this assessment tool to help ascertain an appropriate sample size for future studies (23). Interestingly, there was a trend toward infants in the intervention group to have a greater number of successfully completed tasks in the language (P = 0.053) and motor (P = 0.067) facets of the mental and motor scales than those in the control group. Given our sample size and number of other developmental comparisons that did not show statistically significant differences, it would be inappropriate to make too many inferences about these findings. Observational studies support the general principle that premature infants who grow well during infancy (and by inference are adequately nourished) generally have better developmental outcomes (5,41,42). The few available studies of premature infants fed nutrient-enriched versus standard term formulas after hospital discharge generally do not support a developmental advantage (23,43); although the applicability of these results to HM-fed infants is uncertain because the latter group of infants are generally at greater risk of suboptimal nutrition early after discharge (1,2,4–7,44,45).
Human Milk Feeding
As expected, the duration of HM feeding in this study was longer than most others have reported in the literature for premature infants, likely reflecting the fact that babies in our study were predominantly HM fed at discharge and that their mothers received a significant amount of lactation support (46). We previously reported that exclusivity of HM feeding of premature infants until term CA is a strong predictor of duration of HM feeding (7). There was a trend toward longer breastfeeding in the control group, which did not reach statistical significance. Furthermore, at the 6-month CA visit, we found a difference in the volume (mL · kg−1 · day−1) of human consumed. In contrast, at the end of the 12-week postdischarge feeding intervention, we saw no difference in the volume of HM consumed between the intervention and control groups (99 ± 24 and 102 ± 24 mL · kg−1 · day−1, respectively) (19). Why we saw differences in HM feeding after but not during the 12-week feeding intervention cannot be definitively elucidated using the present study design. However, there are several possible explanations. We know from studies with term infants that introduction of supplemental feedings does affect HM feeding (47). Because LBW infants are fed for several weeks during their inhospital course by routes other than directly at the breast, it is not clear whether data from studies with term-born infants can be immediately extrapolated to this population (48). Nonetheless, it is reasonable to hypothesize that mothers and babies accustomed to supplemental feeding after hospital discharge may feel more comfortable to wean earlier. Another hypothesis is that the mothers of larger babies may perceive that their babies are ready to be weaned earlier (49). Finally, although mothers had access to ad libitum lactation support for the entire duration of the study, prescheduled visits were considerably more frequent during the 12-week intervention phase compared to afterwards. This facilitated greater opportunity during the early discharge phase of the study to encourage mothers to continue HM feeding and promptly address challenges with breast-feeding.
Strengths and Limitations of Study
The strengths of this pilot study include that infants were randomized to their postdischarge feeding assignment, thereby eliminating the possible bias associated with observational studies. Furthermore, all of the outcomes were tested within a tight age range. Important limitations with this pilot study include its small sample size and the fact that mothers had access to a level of lactation support not typically available in the community. Lastly, we did not include a formula-feeding reference group in our study. Inclusion would have helped assess whether infants in the intervention group, in fact, grow like their formula-fed counterparts after discharge. Due to the absence of published data on HM-fed infants after discharge, inclusion of a formula-fed reference group would have also facilitated comparison of our study findings with the larger literature on formula-fed infants after hospital discharge.
The addition of a multinutrient fortifier to approximately half of the milk fed to predominantly HM-fed infants for 12 weeks after hospital discharge results in sustained differences in weight, length, and bone mineral content for the first year of life compared with infants sent home on HM alone. Moreover, this nutritional intervention supported a proportional increase in whole body bone mineral content, as determined by the similar bone mineral density, and did not promote an increase in percent body fat mass or trunk fat mass. Although the duration of HM feeding was considerably longer than most reports for LBW infants, our data do suggest that the intervention did affect exclusivity of HM feeding at 6-month CA. Confirmation of the findings reported herein in larger studies with lactation support levels more typically available are warranted. Such studies are necessary before postdischarge supplementation of HM can be recommended on a broad scale.
As reviewed in detail by others elsewhere, there is considerable evidence in the literature that both feeding type (eg, breast vs formula feeding) as well as early nutritional status (eg, undernourished, adequately nourished, vs overnourished) of LBW infants can independently influence longer-term health outcomes including neurodevelopment, immunity, bone mineralization, adult stature, bone mineralization, adiposity, and early biomarkers of cardiovascular disease (14,50,51). Given the consistently documented advantage of HM over formula feeding on many of the aforementioned health outcomes, our goal was to examine 1 possible strategy to support HM feeding after hospital discharge by expeditiously correcting nutrient deficits. The latter is a frequently cited concern (1). Whether we struck the right balance of promoting HM feeding with that of meeting nutrient needs to maximize longer-term health outcomes is worthy of additional investigation.
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The Post-Discharge Feeding Study Group also included Sobia Khan, Karen Weishuhn, Mary Webster and Dineke Klaassen (Hospital for Sick Children); Kirsten Kotsopoulos (Mount Sinai Hospital); Kirsten McFadyen and Pauline Darling (St. Michael's Hospital); Andrea Nash (Sunnybrook Hospital); Debby Arts-Rodas (St. Joseph's Health Care); Sandra Gabriele (Credit Valley Hospital); Jaimie MacKinnon (Credit Valley Hospital); Peter Azzopardi (Scarborough Hospitals); and Jelena Popovic (Toronto East General).