Persistent Short Stature, Other Potential Outcomes, and the Effect of Growth Hormone Treatment in Children Who Are Born Small for Gestational Age

Normal embryonic and fetal growth proceeds at a predictable rate throughout pregnancy. The predictability of normal intrauterine growth across similar populations at comparable altitudes has permitted the development of standardized reference curves that can be used to compare certain physical characteristics of the newborn according to estimated gestational age. These curves are then used to determine whether the newborn is small for gestational age (SGA), appropriate for gestational age (AGA), or large for gestational age.Reduced ambient oxygen at high altitude slows gestational growth, so standards are different from those at sea level. In 1966, Lubchenco et al1 published intrauterine growth curves of white infants, predominantly from the middle and upper socioeconomic classes, who were born in Denver at 5000 feet above sea level. Data included birth weight, head circumference, and crown-heel length of newborns from 26 to 42 weeks’ gestational age, as estimated by the day of onset of the last menstrual period (LMP). From this information, fetal growth curves were drawn for the 10th, 25th, 50th, 75th, and 90th percentiles.In 1969, Usher and McLean2 published intrauterine growth curves for a sample of white infants who were from widely varying socioeconomic backgrounds and born in Montreal at an altitude of 100 feet above sea level. Birth weight, birth crown-heel length, head circumference, and 5 additional variables of newborns from 25 to 44 weeks’ gestational age were collected. From the data, these researchers drew fetal growth curves that presented mean values ± 2 standard deviations (SD), which correspond approximately to the 97th and the 3rd percentiles for birth weight, length, and other measures against gestational age. Because of the difference in birth size for those born at higher altitudes, the Usher and McLean data are applicable to a greater portion of the population in North America than are the Lubchenco data.Careful measurement of birth length and weight is necessary for establishing whether a newborn is SGA, AGA, or large for gestational age, but accurate gestational dating is the main prerequisite.3 The most precise dating method is serial ultrasonographic measurements, including estimates of fetal weight, head circumference, and abdominal circumference, beginning at 8 to 13 weeks’ gestation. LMP, fundal height measurements, and detection of the fetal heartbeat are less accurate ways to assess gestational age.Accurate diagnosis of SGA is particularly important not only because SGA newborns are at increased risk for perinatal morbidity and mortality4–9 but also because these infants are at increased risk for long-term sequelae. The potential long-term adverse outcomes of SGA birth include persistent short stature and the psychosocial disadvantages associated with short stature in general10–21 and specifically with short stature in children who are born SGA and fail to catch up.22–31 These psychosocial disadvantages, which include peer-group alienation, low self-esteem, impaired social dynamics, behavioral problems, and lower educational achievement and professional success, together with failure to achieve catch-up growth provide a rationale for treating short children who are born SGA with growth hormone (GH). Two publications suggest that GH therapy may ameliorate these psychosocial effects.32,33Other potential consequences of SGA birth include adverse neurodevelopmental outcomes23,24,26,34–36; increased insulin resistance37; dyslipidemia38; and a metabolic syndrome (syndrome X) that consists of type 2 diabetes, hypertension, and obesity.39 No data are available to indicate whether GH treatment affects these consequences. This article reviews SGA birth and addresses the rationale for GH therapy in children who are born SGA.SGA has been defined in various publications in different ways, including birth weight or length below the 10th percentile, 5th percentile, or 3rd percentile for gestational age, making it difficult to standardize incidence and prevalence data. For example, the Third National Health and Nutrition Examination Survey, which defined SGA as birth weight below the 10th percentile for gestational age, found the prevalence of SGA in a sample population of infants and children between 2 and 47 months to be 8.6%.40 Lower prevalence data would have been reported if SGA had been defined more strictly.A recommended definition is that used by Usher and McLean2: birth length and/or weight below an SD score (SDS) of −2 (ie, less than third percentile). Using this definition, Albertsson-Wikland and Karlberg41 reported that 3.1% of infants who were born at term in Sweden between 1973 and 1975 were of low birth weight, 3.5% were of low birth length, and 1.5% were of both low birth weight and low birth length.SGA is a statistically descriptive term that correlates birth length and/or weight with gestational age and is, therefore, a postpartum diagnosis. It does not refer to fetal growth, although it may be a consequence of diminished fetal growth. In contrast to SGA, the terms intrauterine growth restriction and or intrauterine growth retardation (IUGR), which are often used interchangeably with SGA, suggest that intrauterine growth has been documented to be insufficient. To document adequately impaired fetal growth and a diminished growth velocity in utero, at least 2 intrauterine size assessments must be performed.42 Thus, IUGR should be considered a prenatal diagnosis, currently based primarily on serial measurements of fetal ultrasound parameters.43Selection of the most useful single biometric parameter depends on the timing and purpose of measurement; crown-rump length is the best parameter for early dating of pregnancy, whereas biparietal diameter maintains the closest correlation with gestational age in the second trimester. When ultrasound rather than LMP is used to determine gestational age, birth weight percentiles are lower early in gestation and greater late in gestation. Accordingly, as the institutional use of ultrasonography rather than LMP for gestational dating has increased, there has been a decrease in the mean gestational age by approximately 1 week, accompanied by a recorded increase in the preterm delivery rate.44 Ideally, intrauterine growth curves that are based on ultrasonographic dating rather than LMP should be developed and used when gestational age is assessed by ultrasonography.There are no good data for the estimation of the prevalence of SGA. Data provided by the Centers for Disease Control and Prevention’s National Center for Health Statistics indicate that there were 4 058 814 live births in the United States in 2000, 7.6% of which were low birth weight (<2500 g) and 1.42% were very low birth weight (VLBW; <1500 g).45 The percentage with low birth weight is substantially higher for black infants: 13.1%. The National Center for Health Statistics, however, does not provide data on birth length or gestational age, making it impossible to determine what percentage of low-birth weight infants were premature, SGA, or AGA.Furthermore, the intrauterine growth curves used to classify neonates as SGA or AGA were developed during the 1960s using ethnically homogeneous populations.2,46 Because the data on which these curves were based have been extrapolated to the the curves are less than accurate when across population and may in and of SGA For example, et reported in that infants who were born in United were and and had than white et found that the prevalence of SGA birth infants who were born between and at a higher using standards for gestational age or than the prevalence using standards developed in the 1960s the Centers for Disease Control and published growth curves for the United States that more the and there has been no to intrauterine growth et found in the standards for diagnosis of SGA in the United Because there is no population from which to the percentiles used to SGA, the birth that as the in various published may by to at term and by more than that at and weeks’ gestation. The for intrauterine growth curves based on standard reference populations is In and to of birth weight for gestational age on by and in the These researchers reported that birth weight percentiles were in preterm births and in births when LMP used to gestational age. ultrasound is to the birth weight percentiles early in gestation and the percentiles late in as ultrasonographic indicate an increase in growth rate beginning between and which is with a to growth from the of the crown-rump length from measurement at and the growth rate to although the crown-rump length by during this of fetal growth data that the decrease in growth rate a of to a This of fetal growth may the of the in the weight to of are by of whereas at 26 the is to fetal growth can be by or or together include which more than other has been with fetal growth et found that the of and psychosocial risk as and during pregnancy, associated with an increased of an SGA The most risk with a risk of reported that during associated with a risk of for an SGA risk may approximately of of IUGR to be a consequence of is in the fetal as early as weeks’ and fetal GH increase 25 to weeks’ which these GH can be in fetal by the of the GH is with of approximately in which the the of GH in fetal development in is because newborns have normal birth of GH and growth to the can and fetal et found that fetal growth not in who were not GH growth by to GH which the of are that are to are by the but also in other and in an and to in and suggest that a in fetal growth particularly in In the of fetal in is primarily by which fetal insulin and the is the fetal in prenatal The of in fetal growth by et who a with GH normal and of as a of a 4 and which a and the by in fetal growth. have that of the in a of fetal growth, with growth failure In of the in a similar failure of fetal growth but normal growth. of both in comparable growth that has an on fetal growth, with a on growth. are no comparable data for of are associated with fetal growth of but there is no et and in by between and weeks’ gestation from normal and with weight at birth or estimated from ultrasonographic as the of fetal were higher in with above the mean for gestational age than in with below the mean whereas were comparable in the 2 In not in with IUGR were lower than those in normal of the gestational age et of and by during the second of from with normal growth and from to have IUGR on the of prenatal and but not or were lower in the IUGR The of fetal in had no on these hormone et from normal newborns and IUGR newborns and found that IUGR had and GH at In of and GH may be similar in as by et who the of GH and in term of normal and IUGR These found that IUGR increased of both GH and with normal at term and that this increased in to the in fetal has been that IUGR is a syndrome by to a of including and the of persistent short stature in children with IUGR may be similar to that in children who have short stature and to if a may be the for an of in SGA associated with not only growth failure but also an increased risk of a metabolic syndrome type 2 diabetes, hypertension, and in This is with the which that in may in to to only of the SGA then persistent short stature in children who are born SGA may be a of GH or mean of GH decrease from 25 to in the period to 5 to and early and then increase during the of short children who were born SGA have of normal GH the of GH and/or have of GH most have reported that GH is et found that children who were born SGA and are short at or 2 of age less GH than children of short stature who were born Because low have been GH in short children who were born of the with to has been recommended in these may persistent short stature in children who were born SGA and have normal GH to GH has been in children with short stature and normal GH and a similar may be for persistent short stature in SGA children with normal GH of children with IUGR has to the of a of children with low low and increased This from a second by normal and normal In it has been found that short children who were born SGA and have normal GH higher to achieve a growth velocity similar to that of These children to be The may be an or a children who were born SGA and with GH were found to have a in height that and to (ie, GH and and insulin with low or of may GH higher than the GH for treatment of short Because short SGA children are for GH GH is not GH is the measurement of is appropriate in short SGA children because these may suggest and as a reference for the between the and insulin in short children with IUGR has been with short normal and short children with IUGR had higher of insulin and of and insulin during an This to the that to insulin may have to these to the in the IUGR to determine whether and increased insulin be to of the in children who were born SGA, researchers assessed GH and and and in short SGA children and short weight with short SGA children had insulin and insulin which were to of GH The that to the of GH and in short SGA children may to insulin Thus, although there is of and insulin SGA the incidence of and the precise or is as growth has been defined as a height velocity greater than normal a period of growth the of which is to the height what or would have if growth had not been to a short who born SGA, catch-up growth is considered to have been when the height SD below the mean for age. This definition does not the growth which may be greater than −2 Accordingly, of catch-up growth in a short who born SGA may be defined as a height that below −2 SD for catch-up growth as a height velocity above the of normal for and age and/or during a defined period of a period of growth and assessed the incidence and risk of persistent short stature SGA infants by a birth length in a of In this most of these infants catch-up growth during the months and by 1 only below −2 in of those short catch-up growth, so that at although the of SGA infants catch during approximately catch and short as In approximately of infants with birth length below −2 achieve catch-up growth in length, during the of this that children who are born SGA and not catch-up growth and short at 2 are at high risk for short stature in The risk of short stature at is if SGA is based on length and if SGA is based on When the of children who have not it is important to height because a portion of these children may have short stature based on SGA or failure to catch defined different were not et SGA as birth weight below the 10th percentile for gestational age, reported that of SGA infants short at et also SGA as birth weight below the 10th percentile for gestational age, that an period of catch-up growth, the mean height of infants born SGA can be to at approximately the percentile early with a mean of at 4 children who are born SGA and catch-up growth, height and only during for age were at to 4 at to and approximately SD at with short it is to because short stature is not and treatment is not the and GH for the long-term treatment of growth failure in children who were born SGA and fail to catch-up growth by age The for treatment 2 of age is the that height is not to this age. Thus, children who are than 2 should be considered for therapy if not have of catch-up growth and if greater height for age would be on the of is to The rationale for GH therapy is primarily to increase growth rate in short children who were born SGA and have persistent short stature so that may a height the normal for and age and the height percentile may associated with short data be necessary to determine whether GH treatment metabolic and neurodevelopmental as as to document use of GH to increase the height of short children GH therapy has been used in a large of short data are and treatment has not been to treatment often depends on the type of that the In and may the of of these is the of this It is that greater and greater of short children who not have a diagnosis of GH are This children with short short and growth failure as a consequence of those for which GH is as and SGA. of GH therapy not more these children than has been for that height of the of short in and height are with the between height and For example, published that short children are more to be in than those and who may GH therapy for SGA children with persistent short the the and of GH for of height during of short children who were born most may been by of age, because the growth to GH is at treatment should not be catch-up growth, if is the of growth age is considered to with the of catch-up growth. children who were born SGA and have not been with of age has not been with more growth or It that in age with the to at the onset of increase in Thus, although a in age can be considered to be with the of catch-up growth for the age should not be a when whether to a of GH age have in growth rate on GH with with to height in short children who were born SGA and were with GH are It is whether there is a to height long-term although data suggest that there may be a and short children who were born SGA to above height with GH at a of used a low mean GH of to children with with this low of GH associated with a of a height of only are of and The of GH 2 in children who were born SGA have been assessed by and the children had a mean age of mean age of and mean height of The children were to no treatment or of GH at a of or height velocity the of treatment ± in the ± in the and ± in the values during the second were ± ± and ± difference between the and the treatment for and between the 2 treatment during the growth as height velocity 1 SD above the in of the and of the during the of it in and during the second with no in including those similar used to the of GH in short children who were born SGA and who at had a mean age of and a mean height of ± but the the period to a third children no were with GH at and were with GH at 42 children 2 of and children therapy for a third In the the mean in height ± during the and ± during the second with no growth during the In the that with the mean in height ± during the of ± during the second and ± during the third a in the in height for the that with ± during the of ± during the second and ± during the third the third of the that had age similar in the and The of the growth were the GH the age at the of treatment the the greater the growth and the height greater the the greater the growth a increase in and and a in insulin 2 of GH treatment with there no on or the between GH and from a large of in the National were to the to GH treatment in children with short stature associated with IUGR or with syndrome or short stature the mean age ± the mean age and the mean height ± for with For with the mean age ± the mean age ± and the mean height ± at were with of GH at a of approximately for to 4 with of growth increased by to in both during the of treatment who had IUGR and 4 of treatment a height of ± whereas the height of those with to only ± In no in there no the that there to that height would the term in GH but only of treatment 4 have found no between psychosocial and short stature in normal children or other a The that an those to infants are in of the between height and psychosocial or were in children with short stature as a of a of and only SGA children The were in who were born SGA, but the adverse outcomes were not to persistent short between and has been in SGA infants and AGA who were born SGA had lower on the of at months and on the at 13 months The that SGA infants may be more to adverse social than infants who are born AGA and that the may be an of both social and to were used at and in SGA infants and AGA infants using age, were lower the children who were born SGA at 1 at 2 at and at 5 and/or and were of at of age. The indicate that infants who are born SGA are at greater risk for adverse outcomes than infants who are born from the National have been to compare the and development of children with IUGR with these in normal at of age were lower and development 5 lower children with IUGR when children with birth were from the between SGA birth and and has been at and by outcomes for SGA infants with those for AGA the were for other the found that late and failure to or the were more those who were born Birth data were used to assess and achievement at and and other measures at 26 of age 13 with normal birth weight and who were born SGA in who were born SGA had small but in achievement at and were less to or professional and reported lower of than those with normal birth of to determine whether catch-up growth and in early In this were born short for gestational age and were born for gestational age. low birth weight and short birth length increased the risk for and on standard The most important of failure to achieve catch-up growth in This is the only to suggest of measures in with catch-up and assessed who were born SGA or AGA at term by data to the of when the the height in these 2 not who were born SGA had lower and educational than the AGA a between g) in SGA infants and on at and with infants who were born The infants who were born SGA were at than those who were born AGA found that children who were born SGA and had g) had lower on measures of and at to than children who were born The infants had the incidence of behavioral and educational These are with the that IUGR in infants has a long-term and that may in the early of with a of were reported to have been less to from high less to be in and more to have lower achievement than those who were born only of the and of the reported a height below the third percentile, so the to short stature is of short children who are for GH therapy may a of which is often a consequence of of social or These may to low achievement and The of GH treatment on psychosocial in children with short stature to be when accompanied by an increase in height and in has also been reported 2 of however, of during the achievement of although this be at least in an of GH of of to be and the prevalence of behavioral and children with short stature by GH or short stature and a The mean height of children with GH increased SD to and the mean height of the children with increased SD to The of GH treatment on also for behavioral were higher in the children with short stature than in the at more in the of GH these in children with GH and with also in the of children in the GH social problems, and of GH on height and of with syndrome has been by a GH treatment and a at from to who were with GH for 2 a increase in growth although the rate with the growth rate in the a correlation between growth and the of as more more more more and less in the but not in the no correlation between growth rate and in of of 2 of children with short stature has been by et that with GH for at least 2 included children with GH children with and children with no the beginning of were at least of age. The second included children who had short stature with no and were not with no difference between the 2 in of as assessed by with to and physical self-esteem, or with and used to for a between GH treatment at of age in a of short but normal were and 5 with those in short and the a height increase to 5 No were found at or 5 in and or self-esteem, although both of short children less with height than the should be defined as a birth weight and/or length at least 2 below the mean for gestational age. diagnosis is important because SGA newborns are at risk for increased morbidity and and SGA children are at increased risk for persistent short stature and associated long-term adverse psychosocial is in the standards for diagnosis in the United and intrauterine growth curves based on ultrasonographic gestational dating and standard reference populations are of catch-up growth in a short who born SGA may be defined as height at least 2 SD below the mean for age. of SGA infants not catch-up growth by 2 of age, but the prevalence of persistent short stature with who not catch by 2 are at high risk for short stature in with of short not SGA children who not catch to at least the −2 SD are short in to from short may not be for GH therapy is and when in of to to increase the height of short children who were born SGA. children who were born SGA may be to which the greater of the higher stature during is associated with adverse which may be when growth is with GH data in terms of can be