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The Hospital for Children and Adolescents (E.K., L.D., M.P., S.A.) and Department of Obstetrics and Gynecology (S.A.), Helsinki University Central Hospital, 00029 HUS Helsinki, Finland; and Department of Clinical Chemistry, University of Oulu (J.R.), 90014 Oulu, Finland
Address all correspondence and requests for reprints to: Eero Kajantie, M.D., The Hospital for Children and Adolescents, Helsinki University Central Hospital, PL 280, 00029 HUS Helsinki, Finland. E-mail eero.kajantie{at}hus.fi
Abstract
Monitoring postnatal growth in very low birth weight (VLBW) infants is complicated by the difficulty of obtaining reliable measurements. A need thus exists for safe and reliable indicators of such infants’ short-term growth velocity. We set out to study whether markers of type I collagen synthesis [amino-terminal propeptide of type I procollagen (PINP)] or degradation [via the matrix metalloproteinase pathway, carboxyl-terminal telopeptide of type I collagen (ICTP)] or of type III collagen synthesis [amino-terminal propeptide of type III procollagen (PIIINP)] could serve as such indicators.
PINP, ICTP, and PIIINP were measured for 48 VLBW infants (mean birth weight, 923 g; range, 540-1485 g; mean gestational age, 27.6 wk; range, 23.7–32.7 wk) at the age of 1, 2, 4, and 8 wk. At each time point, these were compared with concurrent growth velocity rigorously assessed by frequent lower leg (knemometry) and weight measurements.
PINP showed a significant positive correlation with lower leg growth velocity at 1, 2, and 4 wk and with weight growth velocity at 2, 4, and 8 wk. PIIINP showed a significant positive correlation with lower leg growth at 1, 2, and 8 wk and with weight growth at 2 and 8 wk. The ICTP/PINP ratio, reflecting type I collagen degradation in relation to its synthesis, showed close negative correlations with lower leg growth at 1 wk (r = -0.46; P = 0.003), 2 wk (r = -0.51; P = 0.002), and 4 wk (r = -0.56; P = 0.001) and with weight growth at 2 wk (r = -0.39; P = 0.018), 4 wk (r = -0.59; P = 0.0003), and 8 wk (r = -0.53; P = 0.005). A high ICTP/PINP ratio was an accurate predictor of impaired growth; a high ICTP/PINP ratio was a more rapid and at least as sensitive and specific indicator of slow growth as weight gain.
We conclude that PINP, PIIINP, and the ICTP/PINP ratio all reflect postnatal growth velocity in VLBW infants. The most robust of these indicators is the ICTP/PINP ratio, which may thus serve as a clinical tool in assessing short-term growth of these infants.
PRETERM BIRTH INTERRUPTS a period of the highest physiological growth velocity during human life. Suboptimal postnatal growth in very low birth weight (VLBW; defined as <1500 g) infants may, apart from obviously lengthening the hospital stay, result in deviant body composition and short adult stature. Moreover, many VLBW infants have already been growth restricted in utero, and perinatal growth restriction is, in general, associated with a number of common late-onset disorders, such as cardiovascular disease (1). Optimizing postnatal growth is therefore a major concern in the care of these infants.
Maintaining optimal postnatal growth in VLBW infants is complicated by
the lack of a simple and reliable measure of growth velocity. Daily
weight measurements, affected by changes in fluid and fat deposition,
do not necessarily reflect anabolic growth, and length measurements are
inaccurate and often impossible to perform in sick ventilated infants.
Infant knemometry, the measurement of knee-heel length by means of a
purpose-built electronic caliper (2, 3), is a precise
method that can be safely performed even in infants restricted to only
minimal handling. The typical technical error of the method (
0.3 mm)
(2) is comparable to the postnatal lower leg
growth velocity of preterm infants, averaging 0.43 mm/d
(2). However, that the measurements should preferably be
performed by a single trained observer has limited the use of infant
knemometry largely to the research domain. In addition, both knemometry
and conventional weight and length measurements invariably describe
growth that has already taken place, whereas a biochemical marker would
be clinically more valuable in predicting future growth velocity.
Collagens are the major connective tissue proteins, with type I collagen being the only collagen found in mineralized bone and, together with type III, the most abundant collagen in soft tissues (4). The turnover of collagen, both synthesis and degradation, is more abundant during growth and involves the production of specific by-products useful as markers of the turnover rate. For type I collagen, markers of synthesis include the carboxyl-terminal and amino-terminal propeptides of type I procollagen (PICP and PINP), and markers of degradation include the carboxyl-terminal telopeptide of type I collagen (ICTP). The synthesis of type III collagen is reflected by the amino-terminal propeptide of type III procollagen (PIIINP) (4). PICP, ICTP, and PIIINP indeed reflect growth velocity in childhood (5, 6, 7), and findings regarding the use of PICP in monitoring the postnatal growth of premature infants are promising (8).
With this background, we hypothesized that PINP, ICTP, and PIIINP reflect the postnatal growth velocity of VLBW infants and conducted this study to elucidate their potential utility as surrogate growth markers in clinical practice.
Subjects and Methods
Study population
To concentrate the study effort on infants at a high risk for
impaired postnatal growth, we chose a study population of 48 VLBW
infants comprised of two arms. All infants weighing less than 1000
g (n = 32) were recruited. Of those with a birth weight between
1000–1500 g (n = 16), only those with a respiratory distress
syndrome requiring surfactant treatment were recruited, because these
infants are more susceptible to growth impairment (9).
Surfactant treatment was considered to be indicated if the infant was
less than 24 h of age and was treated in a respirator with an
inspired air oxygen fraction over 40%, a mean airway pressure over 7
cm H2O, or an arterial/alveolar oxygen ratio less
than 0.24. The clinical characteristics of the infants are shown in
Table 1
.
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Informed consent was obtained from the parents. The study protocol was approved by the institutional review boards of Helsinki University Central Hospital, Helsinki City Maternity Hospital, and Jorvi Hospital.
Study protocol
Blood samples. Blood samples were obtained at the age of 1 wk (7–9 d), 2 wk (12–16 d), 4 wk (26–30 d), and 8 wk (53–59 d) through an indwelling arterial catheter, by venipuncture or by heelstick. The lithium heparin or EDTA tubes were spun immediately at 1000 x g for 10 min, and the plasma was separated and frozen at -70 C until analysis.
Clinical follow-up. The study period continued from birth to
9 wk of age. The study setting was the Neonatal Intensive Care Unit of
the Hospital for Children and Adolescents at Helsinki University
Central Hospital and, when intensive care was no longer required, two
local step-down neonatal units. Similar treatment and nutrition
guidelines were followed by the clinicians in these units. Three
infants died during the study period. Due to blood sample volume
constraints and the transfer of some infants to other hospitals, not
all assays and measurements could be performed for all infants (Fig. 1). Individual nutritional intake was
calculated daily for energy and protein, and the mean intake of each
nutrient during the 3 d before each blood sample was used in the
data analysis. Possible postnatal glucocorticoid dose (hydrocortisone
or dexamethasone) was recorded for 24 h before each blood sample,
and if dexamethasone was used, the dose was transferred into
hydrocortisone equivalents by multiplying it by 25. Obstetric data,
including the use of maternal antenatal betamethasone (12 mg, im, twice
at 12-h intervals, treatment repeated in 7–10 d, recorded as yes/no),
were collected from hospital records.
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Infant weight was recorded daily as a routine procedure of the neonatal ward, which includes the use of the same scales for each infant. Weight growth velocity (grams per d) for each blood sample time point was calculated with linear regression as lower leg growth velocity.
PINP, ICTP, and PIIINP assays
The intact PINP, ICTP, and intact PIIINP concentrations were determined by specific immunoassays for human antigens (Orion Diagnostica Ltd., Espoo, Finland). The intra- and interassay coefficients of variation are 4.6–10.3% and 3.1–10.8% for PINP, 2.8–6.2% and 4.1–7.9% for ICTP, and 4.4–6.1% and 4.1–18% for PIIINP in a wide range of concentrations, respectively. The sensitivities are 2 µg/liter for PINP, 0.5 µg/liter for ICTP, and 0.2 µg/liter for PIIINP, respectively.
Data analysis
PINP, ICTP, and PIIINP as well as all growth and nutrition data gave a good fit to the normal distribution at all time points. The ICTP/PINP ratio did not follow the normal distribution at any time point, and logarithmic transformation was used. The distribution of the glucocorticoid dose was extremely skewed, with many infants receiving no glucocorticoid, and the rest receiving a highly variable dose (mean dose, 1.1 mg; SD, 2.3 mg; range, 0–13.4 mg). Therefore, at each blood sampling point the infants were categorized according to glucocorticoid dose: 0, no glucocorticoid; 1, glucocorticoid dose below 1.5 mg hydrocortisone equivalents/kg·d; and 2, glucocorticoid dose over 1.5 mg hydrocortisone equivalents/kg·d.
Correlations between growth and nutrition variables and the markers of collagen turnover were assessed by linear regression separately at each blood sampling point. The relationships between markers of collagen turnover and other clinical data were examined by forward stepwise multiple regression analysis after the data for all blood sampling points were pooled. In the pooled dataset, the repeated measurements structure of the design was adjusted for by creation of a dummy variable for each infant as described by Glantz et al. (11). The multiple regression analyses were calculated for each marker of collagen turnover as a dependent variable and for one clinical variable at a time together with the set of dummy variables as dependent variables. Significance was assigned as P < 0.05.
To assess the value of the ICTP/PINP ratio in detecting slow concurrent growth, the diagnostic test characteristics (sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio) were calculated for different cut-off points of the ICTP/PINP ratio. Slow growth was defined as a lower leg growth velocity below 0.2 mm/d, which is about half the average growth velocity of healthy preterm infants (2). Test sensitivity was defined as the proportion of infants with slow growth who were correctly identified by the ICTP/PINP ratio, and test specificity was the proportion of infants not having slow growth who were correctly identified by the ICTP/PINP ratio. Correspondingly, positive predictive value was calculated as the proportion of infants with a positive test result (ICTP/PINP ratio indicating slow growth) who were correctly diagnosed, and negative predictive value was the proportion of infants with negative test results (ICTP/PINP ratio not indicating slow growth) who were correctly diagnosed. Odds ratio was defined as the ratio between the odds of slow growth in infants with a positive test result and the odds of slow growth in infants with a negative test result. These diagnostic test characteristics do not by themselves take into account the repeated measurements design of the study; however, the odds ratio can be calculated both by deriving it from a logistic regression equation, which allows adjustment for repeated measurements, and in the traditional way described above, unadjusted. Therefore, the validity of the diagnostic test characteristics in this repeated measurements setting was evaluated by calculating both repeated measurements adjusted and unadjusted odds ratios. The adjusted odds ratio was obtained by backward stepwise logistic regression with lower leg growth velocity (1 if <0.2 mm/d, 0 otherwise) as the dependent variable. The ICTP/PINP ratio (1 if higher than the specified limit, 0 if lower), the individual patient factor, and the interaction between the ICTP/PINP ratio and the individual patient factor served as covariates in the analysis. Correspondingly, to compare the ICTP/PINP ratio and weight gain as indicators of VLBW infants’ growth velocity, similar calculations were performed for different weight growth velocity cut-off points. The individual patient factor and weight growth velocity were defined as categorical covariates, which is analogous to the aforementioned method of the creation of dummy variables for each subject (11).
The data were analyzed by SPSS version 8.0.1 for Windows (SPSS, Inc., Chicago, IL).
Results
Growth velocity
The mean lower leg and weight growth velocities increased with
postnatal age (Fig. 1
) with no difference between male and female
infants. Infants born at a higher gestational age grew faster than more
premature infants especially at 2 and 4 wk (Table 2). No correlation was evident between
relative birth weight and either lower leg or weight growth velocity.
The dose of glucocorticoids showed a negative correlation with both
lower leg and weight growth velocities at most time points (Table 2).
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The energy intake (mean ± SD) was 88 ± 16 kcal/kg·d (wk 1), 100 ± 20 kcal/kg·d (wk 2), 112 ± 24 kcal/kg·d (wk 4), and 131 ± 13 kcal/kg·d (wk 8). Correspondingly, the protein intake was 3.1 ± 0.6 g/kg·d (wk 1), 3.0 ± 0.7 g/kg·d (wk 2), 2.9 ± 0.7 g/kg·d (wk 4), and 3.3 ± 0.3 g/kg·d (wk 8). Neither energy nor protein supply showed any significant correlation with lower leg growth velocity. The only significant correlations between weight growth velocity and nutrient intake were a positive correlation with energy supply at 2 wk (r = 0.40; P = 0.002) and 4 wk (r = 0.44; P = 0.003) and a positive correlation with protein supply at 4 wk (r = 0.31; P = 0.04).
PINP
The mean PINP concentration increased with postnatal age (Fig. 1),
with no significant difference between male and female infants or
between infants exposed or not exposed to antenatal betamethasone
treatment. A positive correlation between PINP and ICTP was observed at
1 and 2 wk (r = 0.55 and r = 0.65, respectively; both
P 
0.0001), but not at 4 or 8 wk. In addition, a
positive correlation between PINP and PIIINP was observed at all time
points (range for r = 0.57–0.69; all P
0.0004). Infants with higher PINP concentrations also had higher lower
leg growth velocity (1, 2, and 4 wk; Table 3) and higher weight growth velocity (2,
4, and 8 wk; Table 3). There was, as well, a clear positive correlation
between PINP concentration and gestational age at birth (Table 4) and a negative correlation between
PINP and relative birth weight (Table 4). The only statistically
significant correlations between PINP concentration and intake of
nutrients were with energy at 2 wk (r = 0.53; P =
0.001) and with protein at 1 wk (r = -0.31; P =
0.041). The dose of glucocorticoids showed a negative correlation with
PINP (Table 4).
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The mean ICTP concentration showed an inverse U-shaped curve in
relation to postnatal age, with the highest median ICTP at 2 wk (Fig. 1). There was neither a difference between sexes nor between infants
exposed or not exposed to antenatal betamethasone treatment.
Correlation with growth velocity was not obvious: statistically
significant were only a positive correlation with lower leg growth
velocity at 2 wk (r = 0.40; P = 0.018) and a
negative correlation with weight growth velocity at 1 wk (r =
-0.39; P = 0.010). No correlation was observed with
gestational age at birth, relative birth weight, or nutrient intake. A
significant positive correlation existed with the dose of
glucocorticoids (Table 4).
ICTP/PINP ratio
An ICTP/PINP concentration ratio was calculated to assess the
ratio of the degradation of type I collagen to its synthesis. This
ratio decreased with increasing postnatal age, showing a high
interindividual variation, with some infants having very high ratios,
especially at 1 and 2 wk (Fig. 1). At all time points, the average
ICTP/PINP ratio was similar in male and female infants as well as in
infants exposed or not exposed to antenatal betamethasone
treatment.
The ICTP/PINP ratio appeared to reflect growth velocity, with slowly
growing infants showing high ratios. This was indicated by a negative
correlation with lower leg growth velocity at 1, 2, and 4 wk and with
weight growth velocity at 2, 4, and 8 wk (Table 3 and Fig. 2). In addition, the ICTP/PINP ratio
showed a negative correlation with gestational age at birth and a
positive correlation with birth weight SD score (Table 4).
Moreover, a positive correlation was observed between the ICTP/PINP
ratio and the dose of glucocorticoid (Table 4). The only statistically
significant correlations between ICTP/PINP ratio and intake of
nutrients were with energy at 2 wk (r = -0.55; P
= 0.0005) and protein at 1 wk (r = 0.39; P =
0.009).
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. The validity of these figures in the
repeated measurements setting of this study is indicated by the
similarity of the odds ratios unadjusted and adjusted, by logistic
regression, for repeated measurements (Table 5).
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The mean PIIINP concentration increased with postnatal age (Fig. 1). There was no difference between male and female infants or between
infants exposed or not exposed to antenatal betamethasone treatment.
The PIIINP concentration showed a positive correlation with lower leg
growth velocity at 1, 2, and 8 wk and with weight growth velocity at 2
and 8 wk (Table 3). At 4 wk, there were two outliers, twins with a low
growth velocity (-0.05 and -0.10 mm/d; -0.65 and -3.0 g/d) and high
PIIINP (279 and 270 µg/liter, respectively). If these were excluded,
the correlation with weight growth velocity at 4 wk became
statistically significant (r = 0.43; P = 0.016).
The PIIINP concentration showed a positive correlation with gestational
age and a negative correlation with relative birth weight (Table 4). In
addition, a negative correlation existed with glucocorticoid dose. With
nutrient intake, the only statistically significant correlation was
with energy at 2 wk (r = 0.35; P = 0.032).
Discussion
In studying whether the markers of type I and III collagen turnover, by reflecting the growth process itself, would have any potential as clinically useful indicators of growth velocity, we found that the most informative growth indicator was the ICTP/PINP ratio, mirroring the rate of type I collagen degradation, compared with its synthesis. A high ICTP/PINP ratio indicated decreased growth velocity with a surprisingly high sensitivity and specificity, given the morbidity and clinical heterogeneity of this study population.
To maximize the validity of growth assessment, we chose to use repeated measurements of both lower leg length and total body weight. Lower leg length measured always by the same observer using an infant knemometer gives an accurate and specific estimate of skeletal growth velocity during periods as short as 1–2 wk (3). Being virtually unaffected by changes in hydration (2, 3), it is, in our opinion, closest to the gold standard of measurements of skeletal growth in preterm infants. Even the negative lower leg growth velocities occasionally observed in this and previous studies have been shown to be reproducible (12, 13). In addition, we measured the growth velocity of total body weight, which also reflects soft tissue growth and is the most commonly used growth velocity indicator in VLBW infants. However, weight is also affected by changes in hydration, changes most pronounced during the switch from the fetal to the postnatal hydration pattern. This fact would favor lower leg growth velocity over weight growth velocity as a measurement of anabolic growth, especially during wk 1 and 2 of our study. The reverse seemed to apply in this population at 8 wk, when the distribution of lower leg growth velocity was narrow, with most infants growing more than 0.4 mm/d, whereas during the same period a relatively wide variation occurred in weight growth velocity.
Over 90% of the organic matrix of bone is type I collagen, which is the only collagen found in mineralized bone and is abundant even in various soft tissues (4). Skeletal growth comprises two continuous parallel processes: bone formation by osteoblasts and bone resorption by osteoclasts, jointly called bone modeling (14). Bone formation involves the synthesis, and bone resorption involves the degradation of type I collagen, the combination of which is defined as collagen turnover (4).
The concentrations of markers of type I and III collagen turnover decrease from the fetal period to adulthood, reflecting changes in growth velocity. Their concentrations in cord serum are about 50-fold higher than those in adults (4, 15). Our findings, supported by those from two recent studies (8, 16), show that in VLBW infants the rate of collagen I synthesis is dramatically reduced after birth and then restored within a few weeks. The alterations in type III collagen synthesis are similar, but less dramatic, and both are accompanied by changes in growth velocity.
In childhood, markers of type I and III collagen turnover reflect growth velocity (5, 6, 7). It has been questioned whether this applies to VLBW infants, who have a high rate of collagen turnover and often severe morbidity. We found that in these infants, both PINP and PIIINP indeed reflect individual variation in growth velocity. With regard to type I collagen synthesis, a similar relationship has not been observable in all studies (16), but we studied a relatively large population and assessed growth velocity by frequent and precise measurements. The PINP concentration is likely to reflect type I collagen synthesis in both the skeleton and soft tissues, which is supported by its positive relationship with both lower leg and weight growth velocities.
The rate of type I collagen degradation in VLBW infants, as assessed by the ICTP assay, did not follow the same postnatal pattern as PINP and PIIINP. We found that it increased by 2 wk of age and thereafter decreased. The degradation of type I collagen is an essential part of normal skeletal growth, but may be increased in various pathological conditions (4). Osteoclasts are able to degrade type I collagen by at least two different pathways. In normal bone resorption, the predominant enzyme involved is cathepsin K. The matrix metalloproteinase (MMP) pathway is likely to be operative in conditions associated with local destruction of bone tissue, such as rheumatoid arthritis or multiple myeloma (17), in rachitis (18), and also when cathepsin K is defective, as in pycnodysostosis (19). ICTP, the epitope of which is destroyed by cathepsin K, is likely to reflect the MMP pathway and has been suggested to indicate pathological bone resorption and deviant growth (17). However, the high ICTP concentration in the normal fetus (4) suggests that the MMP pathway, indicated by ICTP, is important in normal fetal and postnatal growth as well as in pathological conditions associated with increased type I collagen degradation. In normal bone turnover, type I collagen synthesis (reflected by PINP) and degradation are tightly coupled. In VLBW infants, the pathological degradative processes of type I collagen may be aggravated by the catabolic state of a sick infant, inadequate nutrition, or glucocorticoid treatment. Therefore, to create an index of abnormal type I collagen degradation, we adjusted the ICTP concentrations for type I collagen synthesis by calculating the ICTP/PINP ratio.
A main finding of this study was the close relationship between the ICTP/PINP ratio and growth velocity. In detecting concurrent slow growth, a high ICTP/PINP ratio showed a sensitivity and specificity as well as positive and negative predictive values comparable to those of many other tests in routine clinical use. For instance, similar test performance figures have been obtained for one or two CRP measurements in detecting neonatal sepsis (20). Although the sensitivity and specificity calculations do not include adjustment for repeated measurements of same subjects, the similarity and overlapping confidence intervals of the repeated measures adjusted and unadjusted odds ratios indicate the appropriateness of these calculations in our study population. In particular, in detecting slow skeletal growth, we found the ICTP/PINP ratio to be at least as sensitive and specific as weight growth velocity, which is the commonly used growth indicator in neonatal units. Moreover, weight growth velocity can only be assessed post-hoc, whereas the ICTP/PINP ratio indicates the prevailing growth velocity and thus has the potential of offering the clinician a simple way to detect impaired growth promptly enough to allow possible modifications in treatment.
Growth in VLBW infants may be affected by several factors, among them disease severity, nutrition, glucocorticoid treatment, and catch-up growth potential after intrauterine growth retardation. Although our study population was greatly heterogeneous with regard to these factors, the ICTP/PINP ratio remained an accurate indicator of growth velocity per se. Such a robust indicator is potentially useful in clinical decision-making when assessing the short-term effects of different treatments on growth. In addition, ICTP and PINP can be analyzed by commercially available kits from a small volume of sample. Therefore, the ICTP/PINP ratio is probably the most promising single surrogate measure to assess the growth of sick VLBW infants, and it certainly merits evaluation as a growth indicator in older children as well. However, before the ICTP/PINP ratio can be readily recommended for routine clinical use in all premature infants, our findings should be confirmed in a less morbid population.
The decrease in type I and III collagen turnover by age is manifest already in the fetus; markers of collagen turnover in cord blood decrease with increasing gestational age (8, 15, 21). However, we found that in postnatal VLBW infants the case is the opposite: gestational age is one of the most important determinants of PINP and PIIINP concentrations, and the correlation is positive. In a study with birth weight as an inclusion criterion, infants with a higher gestational age are likely to be growth retarded in utero and experience catch-up growth after birth. However, no relationship between postnatal growth velocity and growth retardation in utero could be demonstrated in this population. Therefore, the most likely explanation is that this finding reflects merely the faster clinical improvement of infants with a higher gestational age, resulting in faster recovery of growth and of collagen turnover after preterm birth.
The effect of postnatal glucocorticoid therapy is well documented in preventing chronic lung disease in VLBW infants, but due to concerns about short- and long-term side-effects, controversy exists regarding the optimal glucocorticoid indications and dose (reviewed in Refs. 22, 23, 24). Among the numerous harmful effects is an often dramatic decrease in growth velocity (5, 7, 12), which in childhood has been shown to be accompanied by a decrease in type I and III collagen turnover (5, 7). Our finding that both PINP and PIIINP showed a negative and ICTP a positive correlation with glucocorticoid dose implies that changes in collagen turnover also occur in VLBW infants treated with glucocorticoids. This highlights the concern about possible long-term effects of deviant bone modeling and body composition (25, 26).
Inadequate nutrition is a common problem in sick VLBW infants and may lead to suboptimal growth (27) and decreased collagen turnover (8). Unexpectedly, we were able to show a positive correlation between the rates of type I and III collagen synthesis and energy intake only at 2 wk, and the only relationship between collagen turnover and protein intake was a negative one (1 wk). However, most infants achieved the recommended energy intake by 4 wk of age, and the recommended protein intake even as early as 1 wk of age. This may mask existing nutritional influences in this population.
We conclude that in sick VLBW infants, PINP, the ICTP/PINP ratio, and PIIINP all reflect postnatal growth velocity. In diagnosing impaired short-term growth, the most robust of these indicators is the ICTP/PINP ratio, which shows a significant diagnostic value.
Acknowledgments
The personnel of the Neonatal Intensive Care Unit of the Hospital for Children and Adolescents and the neonatal wards of Helsinki City Maternity Hospital and Jorvi Hospital as well as the laboratory personnel of these hospitals are gratefully acknowledged for invaluable help in recruiting patients and collecting blood samples.
Footnotes
This work was supported by grants from Finska Läkaresällskapet, the Foundation for Pediatric Research, the Helsinki University Central Hospital Research Fund, Wiipurilaisen Osakunnan Stipendirahastot, and The Yrjö Jahnsson Foundation.
Abbreviations: ICTP, Carboxyl-terminal telopeptide of type I collagen; MMP, matrix metalloproteinase; PICP, carboxyl-terminal propeptide of type I procollagen; PIIINP, amino-terminal propeptide of type III procollagen; PINP, amino-terminal propeptide of type I procollagen; VLBW, very low birth weight.
Received January 26, 2001.
Accepted May 21, 2001.
References
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