search text   Advanced Search

This Article Extract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wit, J.M. Articles by de Zegher, F. Search for Related Content PubMed PubMed Citation Articles by Wit, J.M. Articles by de Zegher, F. Related Collections Premature & Newborn

Preterm Growth Restraint: A Paradigm That Unifies Intrauterine Growth Retardation and Preterm Extrauterine Growth Retardation and Has Implications for the Small-for-Gestational-Age Indication in Growth Hormone Therapy

^a Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
^b Department of Pediatrics, University of Louvain, Louvain, Belgium

Abbreviations: SGA, small for gestational age • IUGR, intrauterine growth retardation • EUGR, extrauterine growth retardation • GH, growth hormone • PGR, preterm growth restraint

Small for gestational age (SGA) is defined as a birth weight and/or length >2 SDs below the gender-specific population reference mean for gestational age. However, there is confusion about various aspects of this term, as recently discussed.^1,2 The term "intrauterine growth retardation" (IUGR) is often used for the same condition but preferably should be restricted to poor growth during pregnancy according to intrauterine growth diagrams used in obstetrics.³ SGA after a normal duration of gestation (37–42 weeks) is usually followed by rapid growth after birth (catch-up growth). It has been demonstrated that almost 90% of term SGA infants catch up in height in the first 2 years of postnatal life.^4,5

On average, the human male has a birth length of 51 cm after term gestation and a final height, in the Netherlands, of 184 cm. Thus, in the 9 months before birth, he has reached almost 30% of his adult height potential. Fetal length velocity at midgestation is >10-fold higher than pubertal peak height velocity (Fig 1).

View larger version (10K): [in this window] [in a new window]   FIGURE 1 Normal length/height velocity from conception to adulthood (boys). Fetal length velocity reaches its maximum during midgestation, 10 cm/month, and declines to 35 cm/year around birth. In comparison, the median for peak height velocity during puberty is 9.42 cm/year. Postnatal height velocity (median values) is according to Dutch reference values.13

Thus, among nonsyndromatic children with growth retardation before term age, 3 major groups can be differentiated:

1. term children born SGA as a result of IUGR (Fig 2);
   
2. children born (very) preterm with appropriate size for gestational age who experienced EUGR as part of a stormy neonatal course (Fig 2); and
   
3. children born (very) preterm who experienced IUGR resulting in being SGA and experiencing EUGR.
   

View larger version (19K): [in this window] [in a new window]   FIGURE 2 IUGR and preterm EUGR: representative examples of a term SGA infant after IUGR and a preterm AGA infant with EUGR. Reference curves are for boys; the prenatal reference curve is according to Niklasson et al14; and the postnatal reference curve is according to Fredriks et al.15

Because neonatal intensive care is a relatively recent and rapidly evolving discipline, there was until now a virtual "absence of evidence" for analogies among the 3 aforementioned groups. Thanks to a set of recent data, this absence of evidence is gradually changing into "evidence of absence" of major differences between the endocrinologic-metabolic state of the second group versus that of the other 2 groups. To date, this evidence already includes key features such as body composition,^9,10 insulin sensitivity,¹¹ and blood pressure.¹² Beyond the age of 6 to 8 years, the children in these 3 groups seem to resemble each other so closely that, in the absence of a perinatal history, they are virtually indistinguishable from each other on clinical, biochemical, endocrinologic, and metabolic grounds.

Given that the short-term growth response to exogenous GH in this context may not be indicative of the long-term response,⁷ there are now 2 major ways to explore GH therapy in former premature infants with short stature:

1. The "absence of evidence for a parallelism" option implies the initiation of long-term studies up to adult height (outcome known around the year 2020).
   
2. The "evidence of absence of a difference" option would imply an extension of the SGA to a PGR indication, provided the results are monitored until such extension is conclusively validated.
   

We suggest that pediatric societies including the American Academy of Pediatrics, the American Pediatric Society/Society for Pediatric Research, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Pediatric Endocrinology issue a statement on this specific topic. Below are a few elements to consider in the anticipated debate.

• Etiology of PGR—The cause of an intrauterine growth failure that leads to the SGA condition of an infant born at or near term often remains unknown. As a rule, however, the common final pathway includes acidosis, hypoxia, and the equivalent of a fasting state, with serum levels that are low for insulin, insulin-like growth factor I, and insulin-like growth factor–binding protein-3 and high for insulin-like growth factor–binding protein-1 and GH. Extrauterine growth failure of very low birth weight premature infants is often attributed to some combination of factors, including low energy intake, infections, respiratory distress, and pharmacologic effects (eg, of glucocorticoids).
  
• Timing of PGR—In SGA infants born at or near term, it is often unknown whether the PGR started in the last trimester or earlier. In preterm neonates, direct documentation of the extrauterine growth failure is possible (weight, length, and head circumference). In other words, in term SGA infants, the PGR may or may not have started before the third trimester, whereas in preterm AGA newborns, the PGR is usually known to have occurred during the third trimester.
  
• Etiology and timing of PGR: relevance for the SGA indication—In the current SGA indication for GH therapy, little attention is given to the etiology of the SGA condition (syndromatic conditions, however, are excluded) or to the timing (early versus late gestation) of the PGR. Given that the net impact of an early growth-restraining insult on subsequent stature may depend more on its timing than on the nature of the insult, the only change that we propose in the current SGA indication for GH therapy is that the timing of the growth restraint be judged at term age rather than at birth.
  
• Terminology and implementation—We propose to maintain the well-established indicators of size at birth, such as SGA, appropriate for gestational age (AGA), and large for gestational age (LGA), and to complement them (for preterm infants) with their equivalents at term (40 weeks): small at term (SAT), appropriate at term (AAT), and large at term (LAT). According to this terminology, the proposed change in the SGA indication for GH would result in an SAT indication for GH therapy. Implementation of this approach would require that neonatologists include "size at term" as an obligatory part of their follow-up (weight, length, and head circumference) and always include information on this size at term in their reports of (very) preterm infants. Such data then could be used as indices of growth in the first 40 weeks if ever the option of GH therapy has to be contemplated because of persistent short stature in childhood.
  
• Impact of switching from an SGA to a PGR or SAT indication for GH therapy—On the basis of our clinical experience, we estimate that the quantitative impact of an extension from an SGA to a PGR indication will be in the range of 10%. In fact, thus far, the limited number of preterm AGA children with persistent short stature⁸ has restrained academic centers, including ours, and the pharmaceutical industry from engaging in long-term GH studies within this patient population.
  

	FOOTNOTES

 
Accepted Sep 9, 2005.

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

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

	REFERENCES

TOP REFERENCES

 

1. Laron Z, Mimouni F. Confusion around the definition of small for gestational age (SGA). Pediatr Endocrinol Rev. 2005;2 :364 –365[Medline]
2. Wit JM, Finken MJ, Rijken M, Walenkamp MJ, Oostdijk W, Veen S. Confusion around the definition of small for gestational age [letter]. Pediatr Endocrinol Rev. 2005;3 :52 –53[Medline]
3. Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet. 1992;339 :283 –287[CrossRef][ISI][Medline]
4. Albertsson-Wikland K, Karlberg J. Natural growth in children born small for gestational age with and without catch-up growth. Acta Paediatr Suppl. 1994;399 :64 –70[Medline]
5. Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, De Muinck Keizer-Schrama SM, Drop SL. Children born small for gestational age: do they catch up? Pediatr Res. 1995;38 :267 –271[ISI][Medline]
6. Niklasson A, Engstrom E, Hard AL, Albertsson-Wikland K, Hellstrom A. Growth in very preterm children: a longitudinal study. Pediatr Res. 2003;54 :899 –905[CrossRef][ISI][Medline]
7. De Zegher F, Hokken-Koelega A. Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term. Pediatrics. 2005;115 (4). Available at: www.pediatrics.org/cgi/content/full/115/4/e458
8. Knops NB, Sneeuw KC, Brand R, et al. Catch-up growth up to ten years of age in children born very preterm or with very low birth weight. BMC Pediatr. 2005;5 :26[CrossRef][Medline]
9. Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health. 1992;46 :184 –186[Abstract]
10. Euser AM, Finken MJ, Keijzer-Veen MG, et al. Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm. Am J Clin Nutr. 2005;81 :480 –487[Abstract/Free Full Text]
11. Hofman PL, Regan F, Jackson WE, et al. Premature birth and later insulin resistance. N Engl J Med. 2004;351 :2179 –2186[Abstract/Free Full Text]
12. Keijzer-Veen MG, Finken MJ, Nauta J, et al. Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in the Netherlands. Pediatrics. 2005;116 :725 –731[Abstract/Free Full Text]
13. Gerver WJ, de Bruin R. Paediatric Morphomimetics: A Reference Manual. 2nd ed. Maastricht, Netherlands: Universitaire Pers Maastricht; 2001
14. 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]
15. 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]

This article has been cited by other articles:

				J Rotteveel, M M van Weissenbruch, and H A Delemarre-Van de Waal Decreased insulin sensitivity in small for gestational age males treated with GH and preterm untreated males: a study in young adults. Eur. J. Endocrinol., June 1, 2008; 158(6): 899 - 904. [Abstract] [Full Text] [PDF]

This Article Extract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wit, J.M. Articles by de Zegher, F. Search for Related Content PubMed PubMed Citation Articles by Wit, J.M. Articles by de Zegher, F. Related Collections Premature & Newborn

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved.