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Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes

Abstract

Approximately 10% of children born small for their gestational age (SGA) fail to show catch-up growth and may remain short-statured as adults. Despite treatment guidelines for children born SGA that recommend referral for growth hormone (GH) therapy evaluation and initiation by ages 2 to 4 years, the average age of GH treatment initiation is typically much later, at ages 7 to 9 years. Delayed referral for GH treatment is problematic as studies show younger age at GH treatment initiation in children born SGA is an independent predictor for responses such as optimal growth acceleration, normalization of prepubertal height, and most importantly, adult height (AH). This review discusses the importance and associated challenges of early diagnosis of children born SGA who fail to show catch-up growth, contrasts the recommended age of referral for these patients and the average age of GH treatment initiation, and discusses studies showing the significant positive effects of early referral and treatment with GH on AHs in short-statured children born SGA. To optimize the eventual height in short-statured SGA children who fail to manifest catch-up growth, a lowering of the average age of referral for GH therapy evaluation is needed to better align with consensus recommendations for SGA management. The importance of increasing parental and physician awareness that most children born SGA will do well developmentally and will optimally benefit from early initiation of GH treatment when short-statured is addressed, as is the need to shift the age of referral to better align with consensus recommendations.

Introduction

Being small for gestational age (SGA) at birth has many causes, including fetal, placental, maternal, and environmental factors [1, 2]. SGA is typically diagnosed when birth weight and/or length are at least 2 standard deviations (SDs) below the mean for gestational age, using appropriate reference data [1, 3]. Children born SGA comprise a heterogeneous group with a broad spectrum of clinical characteristics [4]. SGA may occur alongside intrauterine growth retardation (IUGR) and/or premature birth, or may be diagnosed at term in the absence of any prenatal complications. The etiology of SGA is frequently unknown, and current estimates suggest that 40% of SGA births will have no identifiable pathology. Of those 60% of SGA infants where an etiology is identified, about 50% involve maternal factors, 5% involve fetal abnormalities, and less than 5% are felt to be due to placental pathology. Maternal factors associated with SGA include inadequate nutrition; hypoxia; diabetes mellitus; drug use and abuse; vascular, hematologic, and renal disorders; infection; and sociodemographic factors. Fetal causes include congenital anomalies; chromosomal abnormalities; infection; and hormone abnormalities involving insulin, leptin, thyroid hormones, and insulin-like growth factors (IGF-1 and IGF-2). Placental factors that may result in SGA include placental insufficiency, infarction, abruption, and vascular abnormalities [1, 58].

The available SGA incidence and prevalence data are limited due to insufficient or inconsistent records for birth length and gestational age in national databases [9]. A population-based study including 3650 healthy full-term neonates born in Sweden over a 3-year period found 5.4% (N = 198) were diagnosed SGA, defined as <−2 SDs in birth length and/or weight [10]. Within the group of SGA children, 1.5% were both underweight and short, 2.4% were short only, 1.6% were underweight only. The estimated incidence of SGA births, using the definition of <−2 SDs in length or weight (equivalent to the 2.3 percentile), is 1 in 43, making SGA incidence relatively high compared with other growth disorders [11]. Most children born SGA show catch-up growth, generally defined as growth velocity (cm/year) greater than the median for chronologic age and gender, within the first 2 years of life; however, approximately 10% fail to show catch-up growth and may remain short-statured as adults [1]. Growth hormone (GH) therapy has been approved for long-term therapy of growth failure in short-statured children born SGA who show no evidence of catch-up growth by age 2 to 4 years [1, 3, 12]. The mechanisms underlying catch-up growth remain unclear [13]. Lack of catch-up growth has not been associated with any specific SGA etiology; however, preterm birth with less than 32 weeks gestation has been associated with a greater risk for no catch-up growth [3, 14].

The average age of GH treatment initiation in short-statured children born SGA is typically many years later than the recommended age of 2 to 4 years [3, 1517]. This frequent delay in GH treatment is problematic as older age at GH therapy initiation is associated with significantly reduced growth response [15, 1820]. This review discusses the importance and associated challenges of early diagnosis of SGA with failure of spontaneous catch-up growth. We contrast the recommended age of referral and GH treatment initiation, according to consensus-based guidelines, with the average age(s) reported in treatment studies; we then review the significant positive benefits of early GH treatment on optimal height outcomes in short-statured patients born SGA.

Diagnosis of SGA

Accurate gestational age dating and measurement of birth weight and length are critical for SGA diagnosis [3]. There are several challenges to achieving accurate gestational age dating and accurate birth weight and length measurement. The accuracy of gestational age dating depends on the method used. An estimate based on last menstrual period produces greater error compared with clinical or obstetric estimates using early ultrasound assessment [2124]. Accurate assessment of growth restriction requires careful and precise neonatal measurements, which are essential to establish size relative to gestational age [2527]. Additionally, appropriate use of population-relevant reference growth curves is also necessary for accurate diagnosis of SGA [28, 29].

Discriminating between pathologic and constitutional SGA is difficult, and guidelines for the selection of appropriate reference comparison data are evolving. The anthropometric definition of SGA does not account for background growth-modifying factors, such as maternal height, weight, ethnicity, and parity [3, 30]. These modifying factors can be used to statistically model a corrected birth weight and/or length, and may increase the likelihood of identifying abnormal fetal growth compared with constitutional smallness [30]. This approach to growth assessment adjusts for physiological variation, calculates true growth potential, and creates individually customized fetal, neonatal, and child growth curves and birth weight percentiles [3033]. Methodology for customized growth assessment is currently being developed and is not yet widely available.

To expedite appropriate early referral to GH treatment, early diagnosis of SGA and recognition of failure of spontaneous catch-up growth are critical [1, 3]. Measurements of length, weight, and head circumference should be taken every 3 months in the first year of life and every 6 months thereafter [3]. Diminished head growth, particularly when it occurs both in utero and postnatally, is especially important to follow. Little or no catch-up head growth is a significant risk factor for poor outcome as it has been associated with widespread cognitive impairments [34]. Spontaneous catch-up growth typically occurs by age 2, and is most pronounced in the first 6 to 12 months after birth [1, 3]. A child without spontaneous catch-up growth by age 3, or by age 4 in preterm infants, is unlikely to experience it later without therapeutic intervention [1, 3]. It has been shown that children born SGA have a 7-fold higher risk of being short at age 18 than do children not born SGA, and children born SGA comprise 22% of adults whose height is below −2 SD scores (SDs) [35].

Indication for GH treatment

GH treatment of short children born SGA has been approved by the US Food and Drug Administration (FDA) since 2001 and the European Medicines Agency (EMA) since 2003 [1, 3, 11]. Prior to initiating GH treatment, other causes of short stature must be excluded, including growth-inhibiting medication, chronic diseases, endocrine disorders, emotional deprivation, or syndromes associated with short stature. GH stimulation testing or the presence of GH deficiency (GHD) are not required prior to GH treatment of children born SGA as the growth benefit from GH treatment occurs whether GHD is present or not [3638]. No correlation has been found between spontaneous 24-hour GH profiles or maximal stimulated GH secretion before the start of GH treatment and adult height (AH) SDS or gain in height SDS in children born SGA [37].

Initiation of GH treatment is appropriate when the opportunity for spontaneous catch-up growth has passed [1, 3, 35, 39]. In the US, treatment is indicated in children born SGA who fail to achieve normal growth velocity by age 2. The EMA indication approves GH treatment beginning at age 4 [3]. The International Societies of Pediatric Endocrinology and the Growth Hormone Research Society consensus statement proposes that children born SGA with height below −2.5 SDs at age 2, or with height below −2 SDs at age 4, should be GH treatment eligible [3]. Thus, by age 4, initiation of GH treatment is broadly recommended in SGA children with short stature when the family feels AH is important.

Early referral for GH treatment

The average age of GH treatment initiation in children born SGA is frequently much older than the 2- to 4-year-old age range recommended by consensus guidelines [3, 15, 40]. Among 360 GH-naïve, born-SGA pediatric patients participating in the American Norditropin Studies: Web-Enabled Research (The ANSWER Program®) registry, the mean age at treatment initiation was 8.4 years [15], and among 1909 children born SGA enrolled in the Pfizer International Growth Database (KIGS; a pharmacoepidemiological survey of children treated with GH) the mean age at start of GH therapy was 9.1 years (range, 3.9-13.3) [17]. Significant variation in age of referral and GH treatment initiation for short-statured SGA patients has been shown among different countries, ranging from a mean age of 6.7 to a mean age of 9.3 [16]. The older-age treatment referral and initiation is problematic as SGA patients beginning GH therapy at ages 9–10 experience lower growth velocity and have shorter AHs compared with those treated earlier [1].

The reasons for the current practice of delayed referral are unclear. One possibility is that parent attitudes and preferences regarding treatment influence physician decision making. For example, physicians were 40% more likely to recommend GH therapy for a child with short stature, not specific to SGA, if the family strongly desired GH treatment compared with a family neutral about treatment [41]. Parental realization of the importance of optimal growth may be delayed due to the presence of other comorbid conditions during the early developmental period of their child born SGA. Parents of children born with extreme SGA, comorbid systemic diseases, and high risk of mortality may feel fortunate for the survival of their child and, comparatively, may not believe short stature is as important an outcome. In particular, among children born SGA with a poor cognitive developmental prognosis, height may be considered unimportant. Parents may simply be pleased to have a reasonably healthy child after a difficult beginning and they may not seek treatment for short stature until the child is older than the optimal referral age. Parents need to be educated that most children born SGA will do well developmentally, that children without spontaneous catch-up growth are highly likely to remain short as adults, and that GH treatment, when initiated at an early age, will improve childhood growth rate and AH.

Alternatively, delayed referral could be due to beliefs of the treating pediatrician or primary care physician. Children born SGA typically leave the care of neonatologists before they are 2 years old and receive care from a pediatrician or primary care physician. Pediatricians and primary care physicians may not consider height to be a concern among patients who are short but healthy until the optimal referral age has passed. It is important to educate families and physicians about the significance of the age of referral because studies show younger age at GH treatment initiation is an important predictor of response to GH therapy [15, 18, 19].

Younger age and growth response to GH treatment

Effectiveness of GH treatment in short-statured children born SGA has been well demonstrated [12, 13, 42, 43]. A 4-year study of GH treatment in SGA and GHD children enrolled in the NordiNet® international outcome study (IOS) demonstrated similar height improvement in SGA and GHD children, supporting the idea that GH treatment in non-GHD patients is as effective as it is in GHD children [44]. The cumulative mean height standard deviation score (∆HSDS) was 1.60 in SGA and 1.55 (P = 0.412) in GHD children, and height was within the normal range after 4 years of GH treatment in 68% of SGA children and 79% of GHD children.

A 2-year study of GH treatment in children enrolled in the ANSWER Program registry found the largest ∆HSDS at 1 and 2 years occurred in patients with multiple pituitary hormone deficiency (MPHD) (0.85, 1.20; year 1, year 2) and SGA (0.80, 1.18), compared with GHD (0.61, 1.06), idiopathic short stature (ISS) (0.54, 0.90), and Turner Syndrome (TS) (0.50, 0.82) patients [40]. After 2 years of GH treatment among children enrolled in the IOS and ANSWER Program, greater ∆HSDS was found for patients with SGA compared with GHD (1.03 versus 0.97; P = 0.047).

However, therapeutic response is variable and age at GH treatment initiation is a critical factor in predicting growth outcome. Mathematical models developed to predict optimal growth following GH therapy in children born SGA show younger age at treatment initiation is a key predictor of growth response [19, 45]. The most important determinants of greater first-year growth during GH therapy in short children born SGA were younger age and higher dose of GH [19, 45]. The models show growth velocity during the first year of treatment, which is significantly influenced by age at treatment initiation, is the most important predictor of subsequent growth, suggesting AH outcome is indicated by the initial response to GH [19]. Greater long-term growth response observed in AH SDs in children born SGA was shown to depend on the duration of GH treatment, with younger age at treatment initiation and longer phase of treatment producing greater height increases [45].

Younger age at GH treatment initiation is associated with greater short-term height response (see Table 1[15, 16, 19, 46, 47]). A comparison among children born SGA and enrolled in NordiNet IOS from 5 European countries (N = 433) found the greatest changes in height standard deviation score (∆HSDS) occurring during the first year of GH treatment in countries where children were younger (mean age 6.7) at treatment initiation (P < 0.0001) [16]. Among males, the change from baseline ∆HSDS in the first year of GH treatment was significantly greater for patients who started GH treatment at a younger age (ie, younger than age 11 [∆HSDS = 0.82, N = 101], than it was for patients who were older than age 11 [∆HSDS = 0.27, N = 30], P < 0.0001) [15]. ∆HSDS in years 1–2 of GH treatment was greater in SGA patients enrolled in the NordiNet IOS (N = 423) who were younger at GH treatment initiation [18]. ∆HSDS following 1 year of GH treatment was significantly greater in prepubertal (∆HSDS = 0.75, N = 24) compared with pubertal (∆HSDS = 0.40, N = 15, P = 0.016) short-statured SGA children [47]. Among very young (ages 2–5) SGA children, the greatest gain in growth velocity during the first 2 years of GH treatment occurred in those younger than age 4 (1.7 SDS, N = 16) compared with children older than 4 (1.2 SDS, N = 23, P < 0.05) [46].

Table 1 Age at treatment initiation and short-term GH treatment outcomes in children born SGA

Younger age at initiation of GH treatment is also associated with greater long-term height response (see Table 2[20, 3638, 45, 48]). In a long-term prediction model of height SDS at the onset of puberty, younger age at GH therapy initiation was associated with greater height outcome at puberty in short-statured SGA children (N = 150) [20]. Younger age at GH treatment initiation was also associated with better AH following long-term GH treatment in short SGA children (N = 38) [49]. Among 77 short-statured, prepubertal children born SGA, better catch-up growth to AH in response to GH treatment was noted in children who were younger at the start of GH treatment (r = −0.56, P < 0.0001) [36]. Among children treated for >2 years before puberty, the mean gain in height was 1.7 SDS, compared with 0.9 SDS (P <0.001) when treatment was initiated <2 years before the onset of puberty [36]. Long-term, continuous GH treatment (mean duration, 7.8 years), in children born SGA (N = 54) resulted in normalization of AH in most, with 98% reaching an AH within their target height range; younger age at the start of GH treatment was significantly associated with greater gain in height SDS from the start of GH treatment until AH (r = −0.36, P <0.01) [37]. Alternatively, GH treatment initiation in short adolescents born SGA (mean age, 12.7 years) has produced a more limited growth response with a mean height gain of 1.1 SDS and 47% of treated patients reaching AH in the normal range for the general population [50].

Table 2 Age at treatment initiation and long-term GH treatment outcomes in children born SGA

In addition to better growth outcomes, the greater growth response to GH treatment among younger patients born SGA may result in cost savings. A lower GH dose of approximately 33 mcg/kg/day from treatment initiation to AH is effective in children born SGA not extremely short-statured (eg, height above −3 SD), especially if treatment begins at ages 4–6 [51]. Children beginning GH therapy in late prepuberty or extremely short-statured at treatment initiation often receive a higher dose (≥50 mcg/kg/day) for optimal short-term catch-up growth, and then can be tapered back to 33 mcg/kg/day. Thus, a better cost of GH treatment-to-height benefit outcome ratio may be achieved when GH treatment begins at an early age because a greater growth response occurs at a lower GH dose.

Safety of GH treatment in children born SGA

The long-term safety of GH treatment in childhood has been under intense recent discussion due to the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) mortality data from France suggesting increased all-cause, bone tumor-related, and circulatory system disease-related mortality over the mean 17.3-year follow-up period among adults who had received GH treatment as children (N = 6928) for the diagnoses of idiopathic isolated GHD, neurosecretory dysfunction, idiopathic short stature or born SGA [52]. However, the preliminary data from Belgium, The Netherlands, and Sweden (N = 2543) contrasted with the report from France in that the majority of the 21 deaths that occurred over the follow-up period were due to accidents or suicide and not a single case of death was related to cancer or cardiovascular disease [53]. Questions have been raised about the SAGhE data from France due to methodological limitations of the study, including the lack of an ideal control group of untreated patients, and in August 2011, the FDA stated the evidence of increased risk of death is inconclusive [54, 55].

Additionally, multiple reports have demonstrated GH is safe for use at currently recommended doses in short-statured children born SGA [17, 37]. GH treatment has been shown safe across heterogeneous groups of children born SGA, including very young (ages 2–5) children born SGA, preterm (gestation ≤36 weeks) children born SGA, and in children born SGA who were both preterm and very young [46, 56, 57]. Continuous GH treatment over 6 years was well tolerated in 54 children with short stature born SGA [37]. Relative insulin resistance occurred but there was no adverse effect on glucose levels or development of diabetes and no GH related adverse events were detected [37]. Similarly, among 84 SGA children participating in the US SGA trial from the KIGS Database, a reduction in insulin sensitivity occurred during GH treatment, but no patients developed impaired glucose tolerance or overt diabetes mellitus [17].

The International SGA Advisory Board states that because insulin resistance may increase during GH therapy, reviewing for a family history of type 2 diabetes mellitus (T2DM) is important [1]. Annual screening of carbohydrate status, such as hemoglobin A1c, a fasting or postprandial glucose, and insulin levels, is suitable in lean children without a family history of diabetes. If pubertal children are obese, have a family history of T2DM, or have acanthosis nigricans, glucose homeostasis should be monitored more frequently and intensely (using A1c in addition to oral glucose tolerance test with insulin measurements when indicated). Additionally, fasting serum lipids and blood pressure should be periodically monitored during long-term GH therapy.

Conclusions

SGA diagnosis is challenging, and guidelines for the selection of appropriate reference comparison data continue to evolve. Early diagnosis of SGA with failure to show catch-up growth and early referral to GH therapy are needed. In short-statured children born SGA without catch-up growth, early referral for GH evaluation and therapy is critical for optimal growth acceleration, normalization of prepubertal height, and improvements in AH. The average age of treatment referral varies, and often exceeds the International Societies of Pediatric Endocrinology and Growth Hormone Research Society consensus guidelines (that recommend referral at ages 2–4) by many years. The reasons for this referral delay are not known but likely involve parental and physician attitudes about the importance of early growth in children born SGA. Most children born SGA will do well developmentally, and it is essential that parents understand the benefits of GH treatment for short stature that accrue at a younger age of treatment initiation. Optimizing eventual height in short-statured patients born SGA without catch-up growth is most efficiently done by lowering the age of referral for GH evaluation and treatment to a time in childhood where initiation of treatment provides optimal benefit and aligns with consensus recommendations for SGA management.

Abbreviations

AH:

adult height

ANSWER:

American Norditropin Studies: Web-Enabled Research

EMA:

European Medicines Agency

GH:

growth hormone

GHD:

GH deficiency

HSDS:

height standard deviation score

ΔHSDS:

change in height standard deviation score

IGF-1:

IGF-2, insulin-like growth factors

IOS:

international outcome study

ISS:

idiopathic short stature

IUGR:

intrauterine growth retardation

KIGS:

Pfizer International Growth Database

MPHD:

multiple pituitary hormone deficiency

SD:

standard deviation

SDS:

SD score

SGA:

small for gestational age

TS:

Turner Syndrome

T2DM:

type 2 diabetes mellitus.

References

  1. 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 (6 Pt 1): 1253-1261.

    PubMed  Google Scholar 

  2. McCowan L, Horgan RP: Risk factors for small for gestational age infants. Best Pract Res Clin Obstet Gynaecol. 2009, 23 (6): 779-793. 10.1016/j.bpobgyn.2009.06.003.

    PubMed  Google Scholar 

  3. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A: Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007, 92 (3): 804-810.

    CAS  PubMed  Google Scholar 

  4. Ester W, Bannink E, van Dijk M, Willemsen R, van der Kaay D, de Ridder M, Hokken-Koelega A: Subclassification of small for gestational age children with persistent short stature: growth patterns and response to GH treatment. Horm Res. 2008, 69 (2): 89-98. 10.1159/000111812.

    CAS  PubMed  Google Scholar 

  5. Neerhof MG: Causes of intrauterine growth restriction. Clin Perinatol. 1995, 22 (2): 375-385.

    CAS  PubMed  Google Scholar 

  6. Wollmann HA: Intrauterine growth restriction: definition and etiology. Horm Res. 1998, 49 (Suppl 2): 1-6.

    CAS  Google Scholar 

  7. Heinrich UE: Intrauterine growth retardation and familial short stature. Baillieres Clin Endocrinol Metab. 1992, 6 (3): 589-601. 10.1016/S0950-351X(05)80114-4.

    CAS  PubMed  Google Scholar 

  8. Pollack RN, Divon MY: Intrauterine growth retardation: definition, classification, and etiology. Clin Obstet Gynecol. 1992, 35 (1): 99-107. 10.1097/00003081-199203000-00015.

    CAS  PubMed  Google Scholar 

  9. Loftus J, Heatley R, Walsh C, Dimitri P: Systematic review of the clinical effectiveness of Genotropin (somatropin) in children with short stature. J Pediatr Endocrinol Metab. 2010, 23 (6): 535-551.

    CAS  PubMed  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. Saenger P, Czernichow P, Hughes I, Reiter EO: Small for gestational age: short stature and beyond. Endocr Rev. 2007, 28 (2): 219-251.

    CAS  PubMed  Google Scholar 

  12. Chatelain P, Carrascosa A, Bona G, Ferrandez-Longas A, Sippell W: Growth hormone therapy for short children born small for gestational age. Horm Res. 2007, 68 (6): 300-309. 10.1159/000107935.

    CAS  PubMed  Google Scholar 

  13. Jung H, Rosilio M, Blum WF, Drop SL: Growth hormone treatment for short stature in children born small for gestational age. Adv Ther. 2008, 25 (10): 951-978. 10.1007/s12325-008-0101-3.

    CAS  PubMed  Google Scholar 

  14. Itabashi K, Mishina J, Tada H, Sakurai M, Nanri Y, Hirohata Y: Longitudinal follow-up of height up to five years of age in infants born preterm small for gestational age; comparison to full-term small for gestational age infants. Early Hum Dev. 2007, 83 (5): 327-333. 10.1016/j.earlhumdev.2006.07.002.

    PubMed  Google Scholar 

  15. Ross J, Lee PA, Gut R, Germak J: Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study. Int J Pediatr Endocrinol. 2010, 2010: 494656-10.1186/1687-9856-2010-494656.

    PubMed Central  PubMed  Google Scholar 

  16. Lee PA, Gruters A, Tauber M, Pienkowski C, Pedersen BT, Rakov V: One year growth hormone (GH) treatment response in short children born small for gestational age (SGA) dependent on baseline characteristics: data from the NordiNet international outcome study (IOS). Poster presented at the 90th Annual Meeting of the Endocrine Society, San Francisco, CA. 2008

    Google Scholar 

  17. Cutfield WS, Lindberg A, Rapaport R, Wajnrajch MP, Saenger P: Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res. 2006, 65 (Suppl 3): 153-159.

    CAS  PubMed  Google Scholar 

  18. Lee PA, Gruters A, Tauber M, Oliver I, Pienkowski C, Snajderova M, Tonnes Peterson B, Rakov R: Similar change in height standard deviation scores during the first 2 years of growth hormone therapy for children with growth hormone deficiency, multiple pituitary hormone deficiencies and short children born small for gestational age: data from the NordiNet® international outcome study (IOS) [abstract]. Horm Res. 2009, 72 (Suppl 3): 443-

    Google Scholar 

  19. Ranke MB, Lindberg A, Cowell CT, Wikland KA, Reiter EO, Wilton P, Price DA: 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 (1): 125-131. 10.1210/jc.2002-020867.

    CAS  PubMed  Google Scholar 

  20. de Ridder MA, Stijnen T, Hokken-Koelega AC: Prediction model for adult height of small for gestational age children at the start of growth hormone treatment. J Clin Endocrinol Metab. 2008, 93 (2): 477-483. 10.1210/jc.2007-1381.

    CAS  PubMed  Google Scholar 

  21. Ananth CV: Menstrual versus clinical estimate of gestational age dating in the United States: temporal trends and variability in indices of perinatal outcomes. Paediatr Perinat Epidemiol. 2007, 21 (Suppl 2): 22-30.

    PubMed  Google Scholar 

  22. Dietz PM, England LJ, Callaghan WM, Pearl M, Wier ML, Kharrazi M: A comparison of LMP-based and ultrasound-based estimates of gestational age using linked California livebirth and prenatal screening records. Paediatr Perinat Epidemiol. 2007, 21 (Suppl 2): 62-71.

    PubMed  Google Scholar 

  23. Lynch CD, Zhang J: The research implications of the selection of a gestational age estimation method. Paediatr Perinat Epidemiol. 2007, 21 (Suppl 2): 86-96.

    PubMed  Google Scholar 

  24. Callaghan WM, Dietz PM: Differences in birth weight for gestational age distributions according to the measures used to assign gestational age. Am J Epidemiol. 2010, 171 (7): 826-836. 10.1093/aje/kwp468.

    PubMed  Google Scholar 

  25. Lawrence EJ: Part 1: a matter of size: evaluating the growth-restricted neonate. Adv Neonatal Care. 2006, 6 (6): 313-322. 10.1016/j.adnc.2006.08.006.

    PubMed  Google Scholar 

  26. Sifianou P: Small and growth-restricted babies: drawing the distinction. Acta Paediatr. 2006, 95 (12): 1620-1624. 10.1080/08035250600714326.

    PubMed  Google Scholar 

  27. Zhang J, Merialdi M, Platt LD, Kramer MS: Defining normal and abnormal fetal growth: promises and challenges. Am J Obstet Gynecol. 2010, 202 (6): 522-528. 10.1016/j.ajog.2009.10.889.

    PubMed Central  PubMed  Google Scholar 

  28. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS: New intrauterine growth curves based on United States data. Pediatrics. 2010, 125 (2): e214-e224. 10.1542/peds.2009-0913.

    PubMed  Google Scholar 

  29. Marconi AM, Ronzoni S, Bozzetti P, Vailati S, Morabito A, Battaglia FC: Comparison of fetal and neonatal growth curves in detecting growth restriction. Obstet Gynecol. 2008, 112 (6): 1227-1234. 10.1097/AOG.0b013e31818bdc7e.

    PubMed Central  PubMed  Google Scholar 

  30. Gardosi J: New definition of small for gestational age based on fetal growth potential. Horm Res. 2006, 65 (Suppl 3): 15-18.

    CAS  PubMed  Google Scholar 

  31. Figueras F, Gardosi J: Should we customize fetal growth standards?. Fetal Diagn Ther. 2009, 25 (3): 297-303. 10.1159/000235875.

    CAS  PubMed  Google Scholar 

  32. Mamelle N, Boniol M, Riviere O, Joly MO, Mellier G, Maria B, Rousset B, Claris O: Identification of newborns with Fetal Growth Restriction (FGR) in weight and/or length based on constitutional growth potential. Eur J Pediatr. 2006, 165 (10): 717-725. 10.1007/s00431-005-0045-4.

    PubMed  Google Scholar 

  33. Narchi H, Skinner A: Infants of diabetic mothers with abnormal fetal growth missed by standard growth charts. J Obstet Gynaecol. 2009, 29 (7): 609-613. 10.1080/01443610903100625.

    CAS  PubMed  Google Scholar 

  34. Frisk V, Amsel R, Whyte HE: The importance of head growth patterns in predicting the cognitive abilities and literacy skills of small-for-gestational-age children. Dev Neuropsychol. 2002, 22 (3): 565-593. 10.1207/S15326942DN2203_2.

    PubMed  Google Scholar 

  35. Karlberg J, Albertsson-Wikland K: Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res. 1995, 38 (5): 733-739. 10.1203/00006450-199511000-00017.

    CAS  PubMed  Google Scholar 

  36. Dahlgren J, Wikland KA: Final height in short children born small for gestational age treated with growth hormone. Pediatr Res. 2005, 57 (2): 216-222. 10.1203/01.PDR.0000148716.71231.81.

    CAS  PubMed  Google Scholar 

  37. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A: Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose–response GH trial. J Clin Endocrinol Metab. 2003, 88 (8): 3584-3590. 10.1210/jc.2002-021172.

    CAS  PubMed  Google Scholar 

  38. Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A: Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose–response trial. J Clin Endocrinol Metab. 1999, 84 (9): 3064-3070. 10.1210/jc.84.9.3064.

    CAS  PubMed  Google Scholar 

  39. 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 (2): 267-271. 10.1203/00006450-199508000-00022.

    CAS  PubMed  Google Scholar 

  40. Lee PA, Germak J, Gut R, Khutoryansky N, Ross J: Identification of factors associated with good response to growth hormone therapy in children with short stature: results from the ANSWER Program®. Int J Pediatr Endocrinol. 2011, 2011: 6-10.1186/1687-9856-2011-6.

    PubMed Central  PubMed  Google Scholar 

  41. Finkelstein BS, Singh J, Silvers JB, Marrero U, Neuhauser D, Cuttler L: Patient attitudes and preferences regarding treatment: GH therapy for childhood short stature. Horm Res. 1999, 51 (Suppl 1): 67-72.

    CAS  PubMed  Google Scholar 

  42. Maiorana A, Cianfarani S: Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics. 2009, 124 (3): e519-e531. 10.1542/peds.2009-0293.

    PubMed  Google Scholar 

  43. Labarta JI, Ruiz JA, Molina I, De Arriba A, Mayayo E, Longas AF: Growth and growth hormone treatment in short stature children born small for gestational age. Pediatr Endocrinol Rev. 2009, 6 (Suppl 3): 350-357.

    PubMed  Google Scholar 

  44. Blankenstein O, Oliver I, Snajderova M, Christesen HT, Lee PA, Rakov V, Pederson BT, Saevendahl L: Long-term GH treatment response in short children born SGA is comparable to that in GHD children: data from the NordiNet® IOS. Endocr Rev. 2011, 32 (Suppl 3): P1-P750.

    Google Scholar 

  45. Ranke MB, Lindberg A: Height at start, first-year growth response and cause of shortness at birth are major determinants of adult height outcomes of short children born small for gestational age and Silver-Russell syndrome treated with growth hormone: analysis of data from KIGS. Horm Res Paediatr. 2010, 74 (4): 259-266. 10.1159/000289570.

    CAS  PubMed  Google Scholar 

  46. Argente J, Gracia R, Ibanez L, Oliver A, Borrajo E, Vela A, Lopez-Siguero JP, Moreno ML, Rodriguez-Hierro F: Improvement in growth after two years of growth hormone therapy in very young children born small for gestational age and without spontaneous catch-up growth: results of a multicenter, controlled, randomized, open clinical trial. J Clin Endocrinol Metab. 2007, 92 (8): 3095-3101. 10.1210/jc.2007-0078.

    CAS  PubMed  Google Scholar 

  47. Carvalho-Furtado AC, Naves LA: Clinical predictors of response in the first year of recombinant growth hormone treatment in short children born small for gestational age [abstract]. Horm Res. 2009, 72 (Suppl 3): 341-

    Google Scholar 

  48. Arends NJ, Boonstra VH, Mulder PG, Odink RJ, Stokvis-Brantsma WH, Rongen-Westerlaken C, Mulder JC, Delemarre-Van de Waal H, Reeser HM, Jansen M, Waelkens JJ, Hokken-Koelega AC: GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol (Oxf). 2003, 59 (6): 779-787. 10.1046/j.1365-2265.2003.01905.x.

    CAS  Google Scholar 

  49. Xatzipsalti M, Maggina P, Panagiotou E, Polychroni I, Delis D, Stamogiannou LN: Final height and body composition in growth hormone-treated short Greek children born small for gestational age [abstract]. Horm Res. 2009, 72 (Suppl 3): 378-

    Google Scholar 

  50. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL: Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. J Clin Endocrinol Metab. 2003, 88 (4): 1587-1593. 10.1210/jc.2002-021123.

    CAS  PubMed  Google Scholar 

  51. 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): e458-e462. 10.1542/peds.2004-1934.

    PubMed  Google Scholar 

  52. Carel JC, Ecosse E, Landier F, Meguellati-Hakkas D, Kaguelidou F, Rey G, Coste J: Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short htature: preliminary report of the French SAGhE Study. J Clin Endocrinol Metab. 2012, 97 (2): 416-425. 10.1210/jc.2011-1995.

    CAS  PubMed  Google Scholar 

  53. Savendahl L, Maes M, Albertsson-Wikland K, Borgstrom B, Carel JC, Henrard S, Speybroeck N, Thomas M, Zandwijken G, Hokken-Koelega A: Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, the Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE Study. J Clin Endocrinol Metab. 2012, 97 (2): E213-E217. 10.1210/jc.2011-2882.

    PubMed  Google Scholar 

  54. Rosenfeld RG, Cohen P, Robison LL, Bercu BB, Clayton P, Hoffman AR, Radovick S, Saenger P, Savage MO, Wit JM: Long-term surveillance of growth hormone therapy. J Clin Endocrinol Metab. 2012, 97 (1): 68-72. 10.1210/jc.2011-2294.

    CAS  PubMed  Google Scholar 

  55. Malozowski S: Reports of increased mortality and GH: will this affect current clinical practice?. J Clin Endocrinol Metab. 2012, 97 (2): 380-383. 10.1210/jc.2011-3363.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. de Kort SW, Willemsen RH, van der Kaay DC, Duivenvoorden HJ, Hokken-Koelega AC: Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children?. Clin Endocrinol (Oxf). 2009, 70 (4): 582-587. 10.1111/j.1365-2265.2008.03484.x.

    CAS  Google Scholar 

  57. Garcia RA, Longui CA, Kochi C, Arruda M, Faria CD, Calliari LE, Monte O, Pachi PR, Saenger P: First two years' response to growth hormone treatment in very young preterm small for gestational age children. Horm Res. 2009, 72 (5): 275-280. 10.1159/000245929.

    CAS  PubMed  Google Scholar 

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Acknowledgement

Funding to support the preparation of this manuscript was provided by Novo Nordisk Inc. We wish to thank Lynanne McGuire, PhD, of MedVal Scientific Information Services, LLC for providing medical writing and editorial assistance, including composing the first draft of the manuscript. MedVal received payment for these services. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP2 Guidelines.”

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Dr. Houk has no competing interests to declare. Dr. Lee has served as an advisory board member for Novo Nordisk Inc., and his institution has received grant funding from Novo Nordisk Inc. as part of the American Norditropin® Studies Web-Enabled Research (ANSWER) Program. Dr. Lee is also a member of the Editorial Board for the International Journal of Pediatric Endocrinology.

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CH & PL were the primary investigators, interpreted the data, critically reviewed and provided final approval of this manuscript.

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Houk, C.P., Lee, P.A. Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes. Int J Pediatr Endocrinol 2012, 11 (2012). https://doi.org/10.1186/1687-9856-2012-11

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