Published online August 1, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. 640-643 (doi:10.1542/peds.2006-0103)
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ARTICLE

Long-term Height Gain of Prematurely Born Children With Neonatal Growth Restraint: Parallellism With the Growth Pattern of Short Children Born Small for Gestational Age

Martijn J.J. Finken, MDa,b, Friedo W. Dekker, PhDb, Francis de Zegher, MD, PhDc, Jan M. Wit, MD, PhDa for the Dutch Project on Preterm and Small-for-Gestational-Age-19 Collaborative Study Group

a Departments of Pediatrics
b Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
c Department of Woman and Child, University of Leuven, Leuven, Belgium


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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BACKGROUND. It is unknown whether children born very preterm (<32 weeks' gestation) with appropriate size for gestational age, who grow poorly in the first postnatal months (ie, preterm growth restraint), show a similar growth pattern as children born small for gestational age.

OBJECTIVE. Childhood growth and adult height of children with preterm growth restraint were compared to those of very preterm small-for-gestational-age and non–preterm-growth-restraint children.

METHODS. Data were drawn from the Project on Preterm and Small-for-Gestational-Age Infants cohort. Preterm growth restraint was considered to have occurred after appropriate-size-for-gestational-age birth and if length and/or weight was below –2 SD score at 3 months postterm.

RESULTS. Among 380 very preterm children, 274 experienced no preterm growth restraint and showed near-normal growth, whereas 79 (21%) experienced preterm growth restraint and subsequently displayed a growth pattern similar to that of very preterm small-for-gestational-age children (n = 27). Adult height of these children was –1.1 to –1.2 SD score. Very preterm small-for-gestational-age and preterm-growth-restraint children with a height below –2 SD score at 5 years had an adult height of approximately –2.5 SD score.

CONCLUSIONS. Childhood growth and adult height were similar in very preterm small-for-gestational-age and preterm-growth-restraint children. These long-term findings further strengthen the plausibility of extending the small-for-gestational-age indication for growth hormone therapy in such a way that preterm-growth-restraint children are no longer excluded if they have a short stature persisting beyond the age of ~5 years.

Key Words: follow-up studies • prospective study • neonatal morbidity • premature infants • growth patterns

Abbreviations: PGR—preterm growth restraint • AGA—appropriate size for gestational age • SGA— small for gestational age • SDS—SD score • GH—growth hormone

There is increasing evidence that children who experienced a transient phase of preterm growth restraint (PGR) display a persistent ensemble of sequelae that are independent of whether the PGR occurred in utero (resulting in a small-for-gestational-age [SGA] infant), ex utero (preterm birth followed by poor neonatal growth), or in both perinatal phases. To date, this evidence already encompasses features like body composition, insulin sensitivity, and blood pressure (reviewed in Wit et al1). From the age of ~6 to 8 years onward, the PGR subgroups converge their pathophysiological patterns so that, in the absence of a perinatal history, they become nearly indistinguishable on clinical, biochemical, endocrine, or metabolic grounds. Here, we extend this concept further: up to adult height (age ~19 years), the growth pattern of very preterm appropriate-size-for-gestational-age (AGA) PGR children was compared with that of very preterm appropriate-size-for-gestational-age non-PGR and SGA children.


   METHODS
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 METHODS
RESULTS
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Growth data were extracted from the prospective Project on Preterm and Small-for-Gestational-Age (POPS) study, which follows a nationwide cohort of very preterm (<32 weeks' gestation) and/or very-low-birth weight (<1500 g) infants born in the Netherlands in 1983.2 For this specific study, only the very preterm nonsyndromic white subjects were included, provided that their growth data (length and weight) at birth and at 3 months postterm were complete (n = 380). Size at 3 months postterm was used as proxy for size at term.

Length until the age of 2 years postterm was measured to the nearest 1 cm in the supine position, fully extended with the heels in contact with a baseboard. At ages 5 and 19 years, standing height was measured to 1-mm accuracy. Sizes at birth and beyond birth were converted to SD score (SDS) using Swedish and Dutch references, respectively.3,4

By definition,5 very preterm subjects (<32 gestational weeks) with birth length and/or weight below –2 SD were classified as SGA, whereas those with birth length and weight above or equal to –2 SD and length and/or weight at 3 months below –2 SD were labeled as AGA PGR, and those with birth length and weight above or equal to –2 SD and length and weight at 3 months also above or equal to –2 SD were labeled AGA non-PGR. Target height was calculated as midparental height + 6.5 (–6.5 for females) + 4.5 cm (correction for Dutch secular trend). Ethical approval and written informed consent was obtained from all of the participants.

All of the auxological data were normally distributed. Length/height measurements were compared between AGA PGR and AGA non-PGR groups, as well as between AGA PGR and SGA groups, using the independent samples t test. These comparisons were repeated after adjustment for perinatal morbidity, using linear regression analysis. Statistical significance was defined as a P < .05. To adjust for possible bias caused by the relatively greater availability of growth data of taller persons at the age of 19 years, missing data for adult height SDS was predicted from the available height SDS data at 5 years through imputation for each group separately by linear regression analysis.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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There were 1338 children in the original cohort, of whom 1012 were born before 32 weeks of gestation. Of those, 683 were still alive at the age of 1 year. After exclusion of 7 syndromic children and persons from nonwhite ancestry, 571 subjects were left. Complete data for size (length and weight) at birth and at 3 months postterm was available for 380 children. The AGA PGR condition (n = 79 [21%]) was threefold more prevalent than SGA (n = 27 [7%]). Among AGA PGR children, 22 were PGR for weight, 21 for length, and 36 for both.

Table 1 lists a selection of conditions that may have contributed to prenatal and/or postnatal growth restraint. Comparing AGA PGR with AGA non-PGR and SGA children, the AGA PGR group was characterized by a low gestational age and, accordingly, by a high prevalence of respiratory distress syndrome and prolonged ventilation. There was also a greater proportion with intracranial hemorrhage and on glucocorticoid therapy among AGA PGR children than among those born AGA without PGR.


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  		TABLE 1 Prevalence of Prenatal and Postnatal Characteristics of Very Preterm Children

 
Table 2 summarizes the growth patterns of the groups up to adult height. The growth patterns of AGA PGR and SGA groups were similar from the age of 3 months postterm onward. At birth, AGA PGR children were somewhat shorter and lighter than AGA non-PGR children. Throughout childhood, stature of AGA PGR children was shorter than that of AGA non-PGR children. These differences persisted after correction for the variables listed in Table 1 (data not shown).


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  		TABLE 2 Spontaneous Growth of Very Preterm Children

 
Table 3 shows that, among AGA PGR children, the prevalence of short stature is close to 20%, as it is among very preterm SGA children. A short stature at the age of 5 years in these 2 groups points to a high risk (~90%) of short stature in adulthood, whereas a stature equal to or above –2 SD at 5 years old was associated with a low prevalence (~10%) of short stature in adulthood. AGA PGR and SGA children with a height below –2 SDS at the age of 5 years had a median adult height of approximately –2.5 SDS.


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  		TABLE 3 Short Stature at the Age of 5 Years Points in AGA PGR and in SGA Children to a High Risk (~90%) of Short Stature in Adulthood; Conversely, a Stature Equal to or Above –2 SD at 5 Years Old Implies a Low Risk (~10%) of Short Stature in Adulthood

 

   DISCUSSION
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 METHODS
 RESULTS
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CONCLUSIONS
 REFERENCES
 
In this population-based study of very preterm children, the AGA non-PGR children displayed a virtually normal growth pattern, whereas the AGA PGR and SGA children grew in a way that has been described previously for SGA children born at term.6,7 The present data are the first to document the spontaneous growth pattern of AGA PGR children up to adult stature. Hence, they are also the first to evidence that AGA PGR children, if still short (height below –2 SD) at 5 years old, have a similar risk (~90%) to become short adults as do SGA children (whether born preterm or not) who are still short at that age. The striking long-term parallelism between AGA PGR children and SGA children is herewith extended to linear growth up into adulthood.

The present findings corroborate the rationale to extend the current growth hormone (GH) indication for short SGA children in such a way that it harbors also those very preterm born AGA PGR children who still have a height below –2 SD at the age of 5 years. Departing from the numbers in this article, it can be estimated that a PGR extension of the current SGA indication for GH would increase the number of eligible children by ~10%. Because average adult height SDS is very close to mean height SDS in childhood and as younger children respond more to exogenous GH,8 such therapy should preferably start at an early age.

In our study, no bias could have been introduced by the high neonatal mortality rate,2 because the indication for GH therapy is determined beyond the toddler age range. However, because mortality of very preterm infants has dramatically declined between 1983 and the mid-1990s, especially because of a reduction in mortality from respiratory distress syndrome,9 the sicker children (presumably with PGR) survive nowadays. This increasing survival rate has also resulted in a rising incidence of bronchopulmonary dysplasia,9 which implies that the prevalence of short stature may be higher in the next generation of very prematurely born children.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Prematurely born children who experienced PGR were found to have a growth pattern similar to that of SGA children. These data corroborate a concept in which short AGA PGR children are considered to be pathophysiological equivalents of short SGA children. The present evidence undermines the current policy to exclude PGR survivors from GH therapy if their small size evolves toward a short stature in childhood.


   ACKNOWLEDGMENTS
 
This specific part of the POPS-19 study was supported by a grant from the Netherlands Organization for Scientific Research. The POPS-19 study was supported by grants from the Netherlands Organization for Health Research and Development, Edgar Doncker Foundation, Foundation for Public Health Fundraising Campaigns, Phelps Foundation, Swart-van Essen Foundation, Foundation for Children's Welfare Stamps, TNO Quality of Life, Netherlands Organization for Scientific Research, Dutch Kidney Foundation, Sophia Foundation for Medical Research, Stichting Astmabestrijding, and Royal Effatha Guyot group. Prof de Zegher is a Senior Clinical Investigator of the Fund for Scientific Research, Flanders, Belgium.

Participants of the Dutch POPS-19 Collaborative Study Group include: TNO Quality of Life, Leiden (E.T.M. Hille, C.H. de Groot, H. Kloosterboer-Boerrigter, A.L. den Ouden, A. Rijpstra, S.P. Verloove-Vanhorick, J.A. Vogelaar); Emma Children's Hospital AMC, Amsterdam (J.H. Kok, A. Ilsen, M. van der Lans, W.J.C. Boelen-van der Loo, T. Lundqvist, H.S.A. Heymans); University Hospital Groningen, Beatrix Children's Hospital, Groningen (E.J. Duiverman, W.B. Geven, M.L. Duiverman, L.I. Geven, E.J.L.E. Vrijlandt); University Hospital Maastricht, Maastricht (A.L.M. Mulder, A. Gerver); University Medical Center St Radboud, Nijmegen (L.A.A. Kollée, L. Reijmers, R. Sonnemans); Leiden University Medical Center, Leiden (J.M. Wit, F.W. Dekker, M.J.J. Finken); Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam (N. Weisglas-Kuperus, M.G. Keijzer-Veen, A.J. van der Heijden, J.B. van Goudoever); VU University Medical Center, Amsterdam (M.M. van Weissenbruch, A. Cranendonk, H.A. Delemarre-van de Waal, L. de Groot, J.F. Samsom); Wilhelmina Children's Hospital, UMC, Utrecht (L.S. de Vries, K.J. Rademaker, E. Moerman, M. Voogsgeerd); Máxima Medical Center, Veldhoven (M.J.K. de Kleine, P. Andriessen, C.C.M. Dielissen-van Helvoirt, I. Mohamed); Isala Clinics, Zwolle (H.L.M. van Straaten, W. Baerts, G.W. Veneklaas Slots-Kloosterboer, E.M.J. Tuller-Pikkemaat); Royal Effatha Guyot Group, Zoetermeer (M.H. Ens-Dokkum); and Association for Parents of Premature Infants (G.J. van Steenbrugge).


   FOOTNOTES
 
Accepted Mar 23, 2006.

Address correspondence to Martijn J. J. Finken, MD, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail: m.j.j.finken{at}lumc.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Wit JM, Finken MJ, Rijken M, de Zegher F. Preterm growth restraint: a paradigm that unifies intrauterine growth retardation and preterm extrauterine growth retardation, and that has implications for the small-for-gestational-age indication in growth hormone therapy. Pediatrics. 2006;117 (4). Available at: www.pediatrics.org/cgi/content/full/117/4/e793
  2. Verloove-Vanhorick SP, Verwey RA, Brand R, Gravenhorst JB, Keirse MJ, Ruys JH. Neonatal mortality risk in relation to gestational age and birthweight. Results of a national survey of preterm and very-low-birthweight infants in the Netherlands. Lancet. 1986;1 :55 –57[CrossRef][Medline]
  3. Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P. An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977–1981). Acta Paediatr Scand. 1991;80 :756 –762[ISI][Medline]
  4. Fredriks AM, Van Buuren S, Burgmeijer RJ, et al. Continuing positive secular growth change in the Netherlands 1955–1997. Pediatr Res. 2000;47 :316 –323[ISI][Medline]
  5. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003;111 :1253 –1261[Abstract/Free Full Text]
  6. Hokken-Koelega AC, De Ridder MA, Lemmen RJ, et al. Children born small for gestational age: do they catch up? Pediatr Res. 1995;38 :267 –271[ISI][Medline]
  7. Albertsson-Wikland K, Karlberg J. Natural growth in children born small for gestational age with and without catch-up growth. Acta Paediatr. 1994;399 (suppl):64 –70
  8. Ranke MB, Lindberg A, Cowell CT, et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab. 2003;88 :125 –131[Abstract/Free Full Text]
  9. Stoelhorst GM, Rijken M, Martens SE, et al. Changes in neonatology: comparison of two cohorts of very preterm infants (gestational age <32 weeks): the Project on Preterm and Small for Gestational Age Infants 1983 and the Leiden Follow-up Project on Prematurity 1996–1997. Pediatrics. 2005;115 :396 –405[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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