Growth and bone mineralization of young adults weighing less than 1500 g at birth

Early Human Development 67 (2002) 101 – 112 www.elsevier.com/locate/earlhumdev

Growth and bone mineralization of young adults weighing less than 1500 g at birth $ H.A. Weiler a,b,*, C.K. Yuen c, M.M. Seshia b,c a

Department of Foods and Nutrition, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 b Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 c Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 Received 28 February 2001; received in revised form 3 January 2002; accepted 7 January 2002

Abstract Background: Preterm infants are at risk for suboptimal growth and bone mineralization compared to infants born at term but long-term outcomes into early adulthood are unclear. Aims: To determine (1) if growth and nutrition in the first year of life significantly predict the outcomes measured at adulthood and (2) whole body and regional bone mineral content (BMC) of young adults who were born preterm and weighing < 1500 g. Study design and subjects: In this descriptive follow-up study, subjects were born preterm and weighing < 1500 g (n = 25, 17.2 F 1.2 years of age) and originally participated in a 1-year follow-up study of infant growth or subjects born at term (n = 25, 17.3 F 1.4 years of age). Outcome measures: In the preterm group, relationships of growth and nutrition in the first year of life with adult anthropometry and BMC were identified using correlation and regression analysis. Birth groups were compared for measurements of anthropometry and whole body and regional BMC obtained at adulthood using t-tests. Results: After correcting for the effects of bone area using regression, rate of weight gain had a positive relationship and days to regain birth weight a negative relationship to adult BMC. Young adults, born preterm, were significantly shorter with lower whole body BMC than of those born at term, but BMC was appropriate for size. Conclusions: Growth early in life predicts subsequent attainment of growth and bone mass. Premature birth results

Abbreviations: BMC, bone mineral content; BMD, bone mineral density; CA, corrected age; GA, gestational age. $ Funded by Manitoba Medical Services Inc., 1978 – 1982 and the Children’s Hospital Foundation of Manitoba, 1997 – 1999. * Corresponding author. Department of Foods and Nutrition, University of Manitoba, H513 Duff Roblin Bldg., Winnipeg, Manitoba, Canada R3T 2N2. Tel.: +1-204-474-6798; fax: +1-204-474-7593. E-mail address: [email protected] (H.A. Weiler). 0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 2 ) 0 0 0 0 3 - 8

102

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

in lower attainment of height achieved by young adult age but bone mass is appropriate for body size. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Preterm birth; Bone mineral content; Growth; Bone

1. Introduction Preterm infants are at increased risk for suboptimal growth and bone mineralization compared to infants born at term. While some researchers speculate that nutrition early in life programs bone growth and mineralization [1,2], no study has examined, in preterm infants, the relationships between growth and nutrition in the first year of life and bone mass measured at adulthood. Recent research suggests that reduced bone mass, as indicated by bone mineral content (BMC) and density (BMD) of preterm infants compared to term infants, is related to size at birth. Bone mineral content is a reflection of bone size and BMD a reflection of how densely deposited the mineral is in bone. Hori et al. [3] reported that at 3 to 4 years of age, BMC and BMD of lumbar vertebrae 2 –4 were similar in preterm (27- to 35-weeks gestational age (GA) and < 2.5 kg) and term infants. In contrast, Armstrong et al. [4] reported lower lumbar BMD at 7 years of age in preterm infants of very low birth weight ( < 1.5 kg) compared to term infants. In addition, whole body [5,6] and radial BMC [7,8] are reported as significantly lower up to 12 and 16 years of age in children who were born preterm. When BMC is corrected to body weight, the differences between BMC of preterm and term born children become insignificant [6,7]. Only one investigation has reported radial BMC [8] after puberty, a time when peak bone mass normally is reached [9]. There appear to be two components regulating peak bone mass; the size of the skeletal envelop and the density of bone mineral [10,11]. The size of the skeletal envelop, as measured by BMC, is related to growth during the first year of life and density of bone attributed to factors such as activity [11] and sex [9]. Additionally, in infants born < 2 kg, GA (25.3 to 36.0 weeks) and weight at 1 and 7 years of age were predictive of lumbar BMC measured at 7 years of age [12]. Thus, it is conceivable that preterm birth and reduced growth during the first year of life results in long-term consequences to peak bone mass. Whether nutrition in early life has a direct or indirect effect on adult bone mass has yet to be determined. There is increasing recognition of the importance of the acquisition of optimal peak bone mass during childhood as a major preventative factor for osteoporosis [9]. Preterm infants appear to have reduced bone mass compared to term born infants [4 –8]. The longest follow-up of bone mass is 20 to 23 years where BMD, measured in lumbar vertebrae 2– 4 and femoral neck, of adults who were born preterm was similar to measurements made in young adults born at term or term and small for GA [13]. The neonatal data included only GA and weight at birth preventing identification of other determinants of bone mass measured at adulthood. Additionally, BMC beyond 16 years and in both whole body and clinically relevant regions such as the femoral neck and lumbar spine has not been examined. Thus, it is of considerable interest to assess BMC of young adults who were

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

103

born preterm at a time when fortification of human milk and formula with minerals and protein to meet their requirements was not standard practice and to identify significant early life predictors of BMC. The objectives of this study were to determine if body size and whole body and regional BMC of young adults who were born preterm and weighing < 1500 g (1) are predicted by growth and nutrition in the first year of life, (2) are proportionate to body height and weight, and (3) are lower compared to young adults born at term in the same year and from the same geographical cohort.

2. Methods 2.1. Design and subjects Subjects (n = 25) were recruited from a longitudinal study designed to investigate growth of very low birth weight infants (n = 109) born, between 1978 and 1982, at either the Winnipeg Children’s Hospital or St. Boniface Hospital in Winnipeg. A total of 27 infants died during the first year of life, leaving 82 potential subjects for long-term follow-up. Inclusion criteria for long-term follow-up were birth weight less than 1500 g and less than 37-week GA. Eight subjects were excluded because of apprehension by the Winnipeg Children’s Aid Society (five) or due to cerebral palsy (three). Thirty-one out of the cohort were located, three refused participation due to the use of an X-ray source for the bone measurements and an additional three were excluded due to incomplete measurements of growth in the first year of life. Twenty-five subjects (7 males, 18 females; all Caucasian) were studied at young adult age, represented 30% of the living population of the cohort and were representative of the total cohort GA (n = 25, 30.9 F 2.1 weeks vs. n = 109, 30.2 F 2.5 weeks) and weight (n = 25, 1280 F 160 vs. n = 109, 1139 F 266 g) at birth. Three infants developed bronchopulmonary dysplasia as diagnosed by abnormal chest X-ray plus oxygen dependence at 27 days of life but were included in the data set, since they were not outliers for any measurement. No other chronic diseases affected this group of infants. Twenty-five young adults, who were born healthy at term and appropriate size and matched for age and sex (7 males, 18 females; all Caucasian), were recruited from the Manitoba Clinic, Winnipeg to serve as an age-matched comparison group. Details of nutrient intake in infancy for those born at term were not collected due to inaccurate recall of duration of breast-feeding in contrast to the hospital records available for the preterm group. All subjects were born and resided in Manitoba. This study was approved by the Faculty of Medicine Committee on the use of Human Subjects in Research, University of Manitoba. 2.2. 1-year follow-up Details of the initial follow-up are not published. After obtaining written informed parental consent, infants were followed from birth until 1 year corrected age (CA). Clinical data obtained from the medical record included GA, weight, length, head circumference, APGAR scores at 1 and 5 min, single or multiple birth and sex. Size for GA was assessed using the reference values of Usher and McLean [14]. Weight below the 3rd centile, specific to sex, was considered small for gestational age (SGA) and above the 3rd centile was

104

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

considered appropriate (AGA). Anthropometric measurements after birth included weight and length weekly until discharge and at 6 and 12-month CA. Average daily weight gain (g/ kg/day) was calculated between birth and discharge using weekly weight measurements. Weight was measured to the nearest gram using an electronic balance and length measured to the nearest millimeter using an infant length board. During hospitalization, intake of human milk or formula was recorded. Human milk was not fortified with minerals or human milk fortifiers as is currently recommended. Infants fed formula received either standard preterm (81 kcal/100 ml) or term formula (68 kcal/100 ml) depending on GA at birth, growth and time to discharge. During follow-up visits, mothers were asked about type of milk fed to their infants providing an estimate of duration of breast-feeding. 2.3. 16 – 19-year follow-up All subjects and parents (for those under 18 years of age) completed written informed consent forms prior to any measurement. All measurements were completed at the Manitoba Clinic, Winnipeg. Subjects wore a T-shirt, shorts without any metal, and socks; subjects were asked to remove any other items such as jewelry, glasses and shoes. Weight was measured to the nearest 0.1 kg using a standard upright balance and height measured to the nearest millimeter using a wall-mounted stadiometer. Standard deviation scores (Zscores) were calculated for weight and height for age using reference data from the National Center for Health Statistics [15]. Whole body, total hip, femoral neck and lumbar vertebrae 1 – 4 were measured for BMC using a Hologic 4500 W (Hologic, Waltham, MA, USA) in array mode. All measurements were conducted and analyzed/interpreted by one investigator (HW). Whole body scans were analyzed using software version 8.16a:5, total hip, femoral neck and lumbar vertebrae 1 – 4 using version 8.20a:5 and according to manufactures specifications. Whole body BMC was corrected to height (cm), weight (kg) and lean mass (kg) to establish if BMC was proportionate to body size and muscle mass. Coefficients of variation (%) were calculated based on triplicate scans of 14 subjects and yielded a result of 1.2% for fat, 0.2% for lean, 0.5% for BMC and 0.64% for bone area. Pubertal status was not assessed using Tanner staging or biochemical assessment of sex steroid hormones. For girls, however, self-reported age at first menstruation was similar between birth groups (preterm 12.6 F 1.1 and term 12.9 F 0.8 years of age). 2.4. Statistical analysis Means and standard deviations were calculated for each outcome measurement. In the preterm group, correlations were used to detect variables measured during the first year with significant relationships to those obtained at adulthood. Early life variables that were significantly correlated to outcomes measured at adolescence were then included in multiple linear regression models to indicate significant predictors of weight, height and BMC measurements. Regression analysis of bone also included the independent variables age and as suggested by Prentice et al. [16], bone area, weight and height to account for the influence of body size. A maximum of four factors was permitted in the final model. Correlation and regression analyses were not applied to the term birth group as data prior to 16 years were not available. To compare birth groups for measurements at 16– 19 years

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

105

of age, differences between groups were identified using two-tailed t-tests. A P-value less than 0.05 was considered significant for all tests.

3. Results 3.1. 1-year follow-up Infants had an average GA of 30.9 F 2.1 weeks, birth weight of 1280.8 F 160.0 g and length of 39.6 F 2.0 cm. Six infants were SGA. Five infants were twins. Infants required 16.0 F 5.2 days to regain birth weight and gained weight at a rate of 10.2 F 3.0 g/kg/day and length 0.8 F 0.4 cm/week between birth and discharge. During hospitalization, 22 infants were fed human milk for 6.4 F 3.3 weeks (range 1– 12 weeks). After discharge, six mothers continued to breast-feed (3 –24 weeks). Average duration of feeding human milk in the first year of life was 10.1 F 9.5 weeks (range 1– 33 weeks). Weight at discharge from hospital (38.6 F 1.9-week GA) was 2303.8 F 327.0 g and length 45.6 F 1.6 cm. Weight at 6-month CA was 4634.8 F 962.2 g and length 64.8 F 2.9 cm and at 12-month CA weight was 9114.8 F 1342.9 g and length 73.3 F 3.1 cm. Weight at 6-month CA was positively related to weight at 12-month CA (r = 0.66, P < 0.01) and length at 6-month CA was positively related to length at 12-month CA (r = 0.75, P < 0.01). Significant relationships with measurements made earlier were not observed. 3.2. 16– 19-year follow-up At 16 – 19 years, weight was associated with weight at 6- (r = 0.47, P < 0.05) and 12month CA (r = 0.59, P < 0.05) and height associated with length at 12-month CA (r = 0.50, Table 1 Characteristics of young adults born, preterm with birth weight < 1500 g, or at term Variable

Preterm

Term

Age (year) Weight (kg) Z-score Height (cm) Z-score BMI (kg/m2) Fat mass (%) Lean mass (kg) Whole body BMC (g) Whole body BMC (g/kg weight) Whole body BMC (g/cm height) Whole body BMC (g/kg lean mass) Lumbar 1 – 4 BMC (g) Total hip BMC (g) Femoral neck BMC (g)

17.2 F 1.2 60.8 F 13.4 0.6 F 1.5 164.8 F 6.4 0.3 F 1.0 22.3 F 3.9 24.3 F 3.9 41.71 F 8.73 2087 F 386 34.8 F 4.3 12.6 F 2.0 49.8 F 5.9 54.45 F 11.15 33.26 F 7.66 4.31 F 0.83

17.3 F 1.4 66.5 F 14.8 1.1 F 1.5 172.1 F 9.7 * 1.2 F 1.5 * 22.3 F 3.3 21.8 F 7.0 43.59 F 9.23 2326 F 547 * 35.1 F 4.4 13.4 F 2.5 48.9 F 5.6 61.02 F 12.72 * 37.87 F 13.11 * 4.68 F 1.22

Data are mean F SD, n = 25. * P < 0.05 by t-test.

106

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

Fig. 1. Whole body bone mineral content (BMC) against height (a), weight (b) and lean mass (c) in 16 – 19-yearold adults who were born preterm (solid diamonds) or at term (open diamonds). n = 25 per birth group.

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

107

P < 0.05). On average as young adults, those born preterm were of similar weight and body composition, but lower height compared to those born at term regardless of correction using Z-scores (Table 1). Whole body, lumbar and total hip BMC were also reduced in the preterm group (Table 1). Correction of whole body BMC to weight, lean mass and height removed differences between birth groups suggesting that BMC was proportionate to body size. Since recruitment of a term group of equal height was not possible in this research, the data for whole body BMC against height, weight and lean mass in both groups are shown in Fig. 1. Those in the term born group who were shorter, weighed less or had lower lean mass than the average for the group, had similar amounts of whole body BMC as did those in the preterm group who were of similar size. The strongest relationship of variables measured in infancy to height at 16 –19 years was with weight at 12-month CA (r = 0.75, P < 0.001) compared to length at 12 months (r = 0.50, P < 0.05), whereas weight at 16 – 19 years was most strongly related to weight at 12 months (r = 0.59, P < 0.01) but also with length at 12 months (r = 0.48, P < 0.05), weeks of human milk both in hospital (r = 0.39, P < 0.05) and total duration (r = 0.51, P < 0.01). Weight at birth and gestational age at birth were not related with any other outcome measurement with exception of days to recover birth weight (r = 0.40, P < 0.05). Adult weight related to adult height (r = 0.68, P < 0.001). While body composition or quality of growth is important, lack of differences in fat and lean masses was not observed between the term and preterm birth groups (Table 1) and thus, regression analysis not conducted for these outcomes. Adult weight consistently had the strongest relationships to BMC of whole body, lumbar, total hip and femoral neck (Table 2). To demonstrate the variability of the measurements, whole body BMC is presented in graphical form in association with early life variables that were significantly related; birth weight regained, weight at 12-month CA, human milk in hospital and in total (Fig. 2). It is notable that feeding unfortified human milk appears to have a negative impact on weight and BMC using correlation analysis, but this does not hold true when the influence of body size is accounted for using regression analysis.

Table 2 Correlation coefficients between outcome measurements taken during the first year of life and young adulthood with measurements of bone mineral content in young adults who were born preterm and weighing < 1500 g Variable Birth weight regained (day) Weight gain (g/kg/day) Weight, 12-month CA (g) Length, 12-month CA (cm) Human milk in hospital (week) Human milk in total (week) Weight at 16 – 19 years (kg) Height at 16 – 19 years (cm)

Whole body

Lumbar 1 – 4

0.47** 0.28 0.49* 0.21 0.45* 0.50* 0.79*** 0.66***

0.39* 0.19 0.17 0.11 0.11 0.23 0.54** 0.45*

Total hip 0.40* 0.45* 0.49* 0.18 0.55** 0.48** 0.74*** 0.56**

Femoral neck 0.636 0.37* 0.45* 0.18 0.53** 0.53** 0.83*** 0.63***

Given the 32 correlations made and a P-value < 0.05 as criteria for significance, 1 – 2 significant relationships would be expected due to chance alone vs. the 22 significant relationships reported above. * P < 0.05. **P < 0.01. *** P < 0.001.

108

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

Fig. 2. Relationships between whole body bone mineral content (BMC) measured at 16 – 19 years with days required to regain birth weight (a), weight at 12-month corrected age (CA) (b), weeks of human milk in hospital (c) and in total (d). n = 25.

After accounting for independent variables obtained at adulthood (such as age, weight, height or bone area), four of the six independent variables obtained by 1 year of age significantly contributed to prediction of adult size and BMC using multiple linear regression (Tables 3 and 4). The rate of weight gain between birth and discharge from hospital did not significantly contribute in any regression model. Weight, but not length, at 12Table 3 Regression coefficients for variables related to anthropometric measurements in young adults who were born preterm and weighing < 1500 g Anthropometric variable

Independent variables

Coefficient

P-value

Height (cm), R = 0.80, Radjusted = 0.75

Constant Age at measurement (year) Weight at measurement (kg) Weight at 12-month CA (g) Human milk total weeks (week) Constant Height at measurement (cm) Length at 12-month CA (cm) Human milk total weeks (week) Days to regain birth weight (day)

80.267 2.173 0.217 0.004 0.257 185.642 1.079 0.845 0.614 1.239

0.001 0.018 0.010 0.001 0.021 0.004 0.004 0.176 0.015 0.107

Weight (kg), R = 0.71, Radjusted = 0.64

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

109

Table 4 Regression coefficients for variables related to bone mineral content of young adults who were born preterm and weighing < 1500 g Bone mineral content (g)

Independent variables

Coefficient

P-value

Whole body, R = 0.93, Radjusted = 0.91

Constant Bone area (cm2) Height at measurement (cm) Age (year) Length at 12-month CA (cm) Constant Bone area (cm2) Height at measurement (cm) Age (year) Weight gain birth to term (g/kg/day) Constant Bone area (cm2) Weight at measurement (kg) Length at 12-month CA (cm) Days to regain birth weight (day) Constant Bone area (cm2) Weight at measurement (kg) Length at 12-month CA (cm) Days to regain birth weight (day)

1957.85 1.89 20.17 65.51 16.86 33.78 1.91 0.86 6.44 1.36 21.11 0.94 0.14 0.36 0.27 3.35 0.73 0.04 0.06 0.04

0.049 0.001 0.006 0.019 0.033 0.379 0.001 0.003 0.001 0.014 0.182 0.001 0.038 0.047 0.040 0.127 0.004 0.001 0.015 0.029

Lumbar 1 – 4, R = 0.85, Radjusted = 0.81

Total hip, R = 0.91, Radjusted = 0.88

Femoral neck, R = 0.88, Radjusted = 0.85

month CA contributed to adult height; but did not contribute significantly to adult weight. Total duration of feeding human milk positively contributed to adult height, but negatively so to adult weight. When total duration of human milk was accounted for, feeding in hospital did not add to any regression equation. The number of days to regain birth weight negatively contributed to BMC of total hip and femoral neck. Length at 12-month CA negatively contributed to whole body, total hip and femoral neck BMC.

4. Discussion During infancy and childhood, BMC corrected for size is similar between those born preterm or at term [3– 8]. The present study extends these observations to include whole body and regional BMC at early adulthood. Those born preterm are shorter giving rise to lower values for BMC, but equal amounts of mineral when corrected to weight, height or lean mass. Correlation analysis indicated that time required to regain birth weight negatively relates to BMC regardless of whole body or regional assessment suggesting that delay in recovery of birth weight has lifelong effects on skeletal size. Additionally, weight at 1 year is significantly and positively related to BMC of whole body and hip measured almost two decades later suggesting that attempts to enhance growth may also enhance adult BMC. This speculation is supported by Kurl et al. [12] and their report of a positive relationship between weight at 1 year of age and lumbar BMC at 7 years of age in children born preterm. Likewise, in women who were born at term, weight at 1 year relates to BMC of the lumbar spine and femoral neck [11]. Bone mass of term born infants is also

110

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

influenced by modifiable maternal factors including diet, activity and smoking as well as parental birth weight and paternal height [17]; if this applies to infants, born preterm and their subsequent growth and bone mineralization are unknown. Whether regaining birth weight and infant growth are markers for the effect of clinical course or nutrition on bone development is unclear. Children at 12 years of age who had bronchopulmonary dysplasia as a result of preterm birth have significantly lower BMC of whole body compared to children who were born at term [5]. Infants receiving exogenous glucocorticoid in the first 3 weeks of life have reduced radial BMC at estimated term date and significantly lower whole body length at 6-month CA [18], an outcome of linear bone growth. Each of these examples of reduced BMC due to severe clinical course could be confounded by delayed age at full feeding volume, fluid restrictions and delay in whole body growth. The subjects in the present investigation were relatively healthy preterm infants, with only one receiving steroids and three developing chronic lung disease. It is possible that the number of days to regain birth weight is a marker for degree of immaturity and physiological response to preterm birth, since regaining weight negatively relates to GA at birth (r = 0.40, P < 0.05). Feeding human milk to preterm infants is well documented as adequate nutrition to support growth and bone mineralization when human milk fortifiers are added [2,19]. The negative influence of feeding human milk to preterm infants on BMC observed herein implies that unfortified human milk is not adequate to support bone growth and has longterm consequences to skeletal size. The duration of feeding unfortified human milk negatively related to BMC of all sites measured except for the lumbar spine using correlation analysis. After accounting for body size using more powerful regression analysis, there is no evidence of such a relationship. Current reports of feeding fortified human milk to preterm infants in hospital suggest that mineralization is similar to that of formula-fed infants after correction to body size [2]. Fewtrell et al. [6] also observed no relationship between nutrition in early life, (mother’s own milk, banked breast milk or preterm formula), and whole body BMC measured at 12 years of age. Subsequently, Fewtrell et al. [20] reported that growth, throughout infancy and childhood, predicts BMC at 8 to 12 years of age. In particular, length standard deviation score at birth negatively related to BMC later in childhood. The authors hypothesize that a greater rate of catch-up growth in infancy (0– 18-month CA) is linked to higher BMC in childhood. In the present study, standard deviation scores were not calculated at birth because expression of deviations from a reference point (50th percentile) is affected by the source of data; i.e., percentile references for size at birth do not overlap with percentiles for reference data after term birth. Absolute height was not predicted by length at 12-month CA suggesting that catchup growth occurred thereafter in those infants who were shorter at 1 year. Our observation of an inverse relationship between length at 12-month CA with BMC of whole body, hip and femoral neck, after accounting for body size using regression analysis, supports the hypothesis of Fewtrell et al. [20]. The cause of a relationship between greater rate of catchup growth and greater BMC is unknown, but nutrient intake might be linked through effects on whole body growth. While this study is limited by the small sample size and the type and amount of data on nutrition collected in the original study of growth in the first year of life, the interpretation of long-term BMC and growth is consistent with other larger investigations. Powls et al.

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112

111

[21] observed no relation between GA and birth weight and estimated final adult height regardless of gender. Those born preterm were shorter and lighter than those born at term, but had equal skin-fold thickness and weight. On average, Z-scores for height were 0.48 standard deviations lower than the comparison group. This parallels the observations in our study of young adults, where percent body fat and body mass index are similar in preterm and term born subjects, but height Z-scores were lower by 0.9 standard deviations in the preterm group. The duration of feeding human milk in the first year of life had a negative influence on body weight and positive influence on height at 16 to 19 years of age using regression analysis. Fewtrell et al. [6] reported lower body mass index and skinfold thickness in 8- to 12-year-old children born preterm. The three studies suggest that the growth spurt of puberty increases body weight and fat, but that height continues thereafter to be limited in association with preterm birth. The cause of reduced height is not clear, although it could be linked to physiological events early in life. Lucas et al. [22] speculated that higher alkaline phosphatase in the newborn period is linked with shorter length at 18 months [22] that continues out to 12 years of age [23]. In the present study, a similar relationship between alkaline phosphatase at 1 week of life and length at 12 months was observed (r = 0.48, P = 0.046 n = 18, data not shown due to incomplete data set). However, alkaline phosphatase was not associated with height at 16 – 19 years or BMC. While puberty was not assessed, the similar age of first menstruation in the females suggests that reductions in height and BMC in the preterm group were not due to delays in maturation. It is interesting that while whole body, lumbar and total hip BMC were reduced as was height in the preterm birth group, femoral neck BMC was not. The variability among the preterm and term groups for measurements for BMC was comparable for each site implying that measurement error did not influence the results for femoral neck. While speculative, it is possible that reductions in height do not manifest in altered geometry of the femoral neck. Warner et al. [24] reported regression equations for BMC of the same sites. Their larger data set, in 6 – 18-year-old children, suggests that height contributes to femoral neck BMC to a lesser degree than to the whole body, spine or hip. In summary, growth and nutrition during the first year of life of preterm infants are related to body size and growth to BMC at the onset of adulthood. While height was reduced, bone mass was appropriate to body size. It is possible, given the significant advances in neonatal nutrition since 1978 – 1982, that this study cannot be reproduced through longitudinal prospective studies. Neonates born in the 21st century have the advantage of new feeding regimens including earlier feeding, human milk fortifiers and specially designed formulae. Nonetheless, growth failure continues as a long-term sequelae of preterm birth despite nutritional management. Prospective longitudinal studies are required to confirm the influence of growth and nutrition after preterm birth on attainment of adult BMC and to determine if risk for developing osteoporosis later in life can be reduced by achieving optimal nutrition in infancy. References [1] Bishop NJ, King FJ, Lucas A. Increased bone mineral content of preterm infants fed with a nutrient enriched formula after discharge from hospital. Arch Dis Child 1993;68:573 – 8. [2] Wauben IPM, Atkinson SA, Shah JK, Paes B. Growth and body composition of preterm infants: influence of

112

[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

[15] [16] [17]

[18]

[19] [20] [21]

[22] [23] [24]

H.A. Weiler et al. / Early Human Development 67 (2002) 101–112 nutrient fortification of mother’s milk in hospital and breast-feeding post-hospital discharge. Acta Paediatr 1998;87:780 – 5. Hori C, Tsukahara H, Fujii Y, Kawamitsu T, Konishi Y, Yamamoto K, et al. Bone mineral status in pretermborn children: assessment by dual-energy X-ray absorptiometry. Biol Neonate 1995;68:254 – 8. Armstrong C, Chan GM, Moyer-Mileur L, Archuleta M. Seven year follow-up of preterm infants’ bone mineralization (abstract). Pediatr Res 1997;41:190A. Giacoia GP, Venkataraman PS, West-Wilson KI, Faulkner MJ. Follow-up of school-age children with bronchopulmonary dysplasia. J Pediatr 1996;130:400 – 8. Fewtrell MS, Prentice A, Jones SC, Bishop NJ, Stirling D, et al. Bone mineralization and turnover in preterm infants at 8 – 12 years of age: the effect of early diet. J Bone Miner Res 1999;14:810 – 20. Rubinacci A, Sirtori P, Moro G, Galli L, Minoli I, Tessari L. Is there an impact of birth weight and early life nutrition on bone mineral content in preterm born infants and children? Acta Paediatr 1993;82:711 – 3. Helin I, Landin LA, Nilsson BE. Bone mineral content in preterm infants at age 4 to 16. Acta Paediatr Scand 1985;74:264 – 7. Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8 – 17 years of age. Calcif Tissue Int 1996;59:344 – 51. Frost HM. Bone ‘‘mass’’ and the ‘‘mechanostat’’: a proposal. Anat Rec 1987;219:1 – 9. Cooper C, Cawley M, Bhalla A, Egger P, Ring F, Morton L, et al. Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res 1995;10:940 – 7. Kurl S, Heinonen K, Lansimies E, Launiala K. Determinants of bone mineral density in prematurely born children aged 6 – 7 years. Acta Paediatr 1998;87:650 – 3. Hamed HM, Purdie DW, Ramsden CS, Carmichael B, Steel SA, Howey S. Influence of birth weight on adult bone mineral density. Osteoporosis Int 1993;3:1 – 2. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74: 901 – 10. Hamill PVV, Drizd TA, Johnson Cl, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607 – 29. Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to sizerelated artifacts in the identification of bone mineral determinants. Am J Clin Nutr 1994;60:837 – 42. Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, et al. Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition and activity during pregnancy. J Bone Miner Res 2001;16:1694 – 703. Weiler HA, Paes B, Shah J, Atkinson SA. Longitudinal assessment of growth and bone mineral accretion in prematurely born infants treated for chronic lung disease with dexamethasone. J Early Hum Dev 1997;47: 271 – 86. Lucas A, Fewtrell MS, Morley R, Lucas PJ, Baker BA, Lister G, et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr 1996;64:142 – 51. Fewtrell M, Prentice A, Cole T, Lucas A. Effects of growth during infancy and childhood on bone mineralization and turnover in preterm children aged 8 – 12 years. Acta Paediatr 2000;89:148 – 53. Powls A, Botting N, Cooke RWI, Pilling D, Marlow N. Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables. Arch Dis Child Fetal Neonat Ed 1996;75: F152 – 7. Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High alkaline phosphatase activity and growth in preterm neonates. Arch Dis Child 1989;64:902 – 9. Fewtrell M, Cole T, Bishop N, Lucas A. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr 2000;137:668 – 73. Warner JT, Cowan FJ, Dunstan FDJ, Evans WD, Webb DKH, Gregory JW. Measured and predicted bone mineral content in healthy boys and girls aged 6 – 18 years: adjustment for body size and puberty. Acta Paediatr 1998;87:244 – 9.