OBJECTIVE. Preterm infants are at increased risk to develop insulin resistance and high blood pressure. The influence of growth during childhood is not well established.
METHODS. We investigated childhood growth patterns in relation to blood pressure and insulin sensitivity, measured by the hyperinsulinemic euglycemic clamp, in young adults. We compared 29 subjects born preterm appropriate for gestational age, 28 subjects born preterm small for gestational age, and 30 subjects born at term with a normal birth weight.
RESULTS. Insulin sensitivity expressed as Mi value (glucose disposal mg/kg/min (insulin levels pmol/l) × 100) was lower in infants in the POPS-AGA (18.2) and POPS-SGA (15.2) groups than in the CON group (24.7). Systolic and diastolic blood pressure (mmHg) were higher in infants in the POPS-AGA (132/72) and POPS-SGA (127/71) groups than in the CON group (118/65). The preterm-born subjects, in lowest insulin sensitivity quartile had a higher height standard deviation score at ages 1, 2, and 5 years and a higher weight SD score at ages 2, 5, 10, 19, and 21 years than did those in the lowest insulin sensitivity quartile. The infants in the highest systolic blood pressure quartile had a higher height SD score at 3 months of age and at ages 2, 5, 10, 19, and 21 years and a higher weight SD score at ages 1, 2, 5, 10, 19, and 21 years than those in the lowest systolic blood pressure quartile.
CONCLUSIONS. Young adults born preterm have lower insulin sensitivity and higher blood pressure than controls. Increments in height and weight during childhood are associated with lower insulin sensitivity and higher blood pressure in adulthood.
Since the report by Barker and Osmond in 19861 that a low birth weight is associated with an increased risk of cardiovascular disease, evidence has accumulated that size at birth is associated with many risk factors for cardiovascular disease, such as hypertension and insulin resistance.2–4 In small-for-gestational-age (SGA) infants born at term, impaired growth during the last trimester of pregnancy is usually the result of impaired placental function. In contrast, preterm infants are at risk of severely impaired growth related to the lack of an optimal environment normally provided by the uterus.
Irving et al4 described adults born moderately premature who had an increased basal blood pressure and increased fasting plasma glucose level in adulthood. In addition, Hofman et al2 observed a reduction in insulin sensitivity in children who were born preterm. Hovi et al3 recently found increased indexes of insulin resistance and glucose intolerance in young adults with a very low birth weight. Whether the metabolic abnormalities in preterm-born subjects are related to childhood growth patterns is not known. In earlier studies, catch-up growth was recognized as a risk factor.5–10
In the present study, insulin sensitivity was investigated in young adults born prematurely. We used the hyperinsulinemic euglycemic clamp technique, which is the gold standard for estimating insulin sensitivity.11,12 Furthermore, blood pressure was investigated. Subjects born preterm who were appropriate for gestational age (AGA) and SGA were compared with subjects born at term as controls. It was hypothesized that prematurity, especially when accompanied with a low birth weight for gestational age, predisposes for (1) reduced insulin sensitivity in adulthood, whereby catch-up growth during childhood is detrimental for insulin sensitivity, and (2) high blood pressure in adulthood.
SUBJECTS AND METHODS
Participants were recruited from the Project on Premature and Small for Gestational Age Infants (POPS) cohort.13 The POPS cohort comprises 94% of Dutch neonates (n = 1338) who were born alive in 1983 with a gestational age of <32 weeks and/or with a birth weight <1500 g. Addresses for the subjects and families were available from the POPS database. Information on disabilities was also available from the database. Participants with disabilities were excluded and not approached for this study. Participants were approached by telephone. Subsequently, an information letter was sent. After 3 weeks, participants were approached again by telephone.
From the POPS cohort we selected 47 subjects born prematurely with an appropriate birth weight for gestational age (birth weight standard deviation score [SDS] between 0 and 2: POPS-AGA) who had been treated in our NICU during the neonatal period. Six (13%) subjects could not be traced, 5 (11%) were not eligible because of pregnancy and serious disease, and 4 (9%) refused to participate. Thirty (64%) POPS-AGA subjects, 15 men and 15 women, agreed to participate. Characteristics at birth are shown in Table 1. Of the participants in the POPS-AGA group (birth weight SDS ± SD: 1.1 ± 0.26; range: 0.67–1.81) 1 woman was excluded from the analysis because of morbid obesity.
From the POPS cohort we selected 42 subjects born prematurely SGA (birth weight SDS less than −2 SDs: POPS-SGA). These subjects were treated in the neonatal period in different centers. One year before the start of our study, 22 subjects participated in a study on renal function. Three (7%) subjects could not be traced, and 10 (24%) refused to participate. Twenty-eight (67%) subjects (13 men, 15 women) agreed to participate. Originally, the definition of SGA in the POPS-SGA group was birth weight SDS less than −2 SDs. Because the high refusal rate led to small group size, we changed the definition to the group of children within the cohort with the lowest birth weight SD, which seemed to be between −2.64 and −1.37 SDs (birth weight SDS ± SD: −2.0 ± 0.34). Fourteen SGA subjects had a birth weight SDS lower than minus]2 SDS. The remaining 14 subjects had birth weight SDS ranging from −1.37 SDs and −1.99 SDs. The range of birth weight SDSs between the SGA and AGA groups did not overlap. Characteristics at birth are shown in Table 1.
The control group (CON) was recruited by advertisement in the hall of the VU University medical faculty. The group comprised of 30 subjects, 15 men and 15 women, born in 1983. From the history we gathered that they were born at term (37–42 weeks), with an AGA birth weight.
Overall, most (75%) women used oral contraceptives. Tests were performed throughout the menstrual cycle, because it was not possible to schedule appointments in the early follicular phase because of logistic reasons.
Perinatal parameters (birth weight, birth length, gestational age, Apgar score, congenital anomalies) and obstetric parameters were known since birth. Birth weight and birth length were converted to SDSs by using Swedish reference standards14 because Dutch SDS reference values for birth weight and length are unavailable. Birth weight SDS was considered as a measure of intrauterine growth. Follow-up data for growth (height, weight, BMI) at the ages of 3 months, 6 months, 12 months, 24 months, 5 years, 10 years, 14 years, and 19 years were available for most POPS subjects, but not for the controls. Observations at age 14 were left out of the analysis because of paucity of measurements. Follow-up growth data were converted to SDSs according to Dutch reference standards.15 For the analysis of changes in the infant or childhood growth pattern, height and weight SDSs were analyzed longitudinally.
Subjects arrived at the examination room after an overnight fast.
Measurement of the subjects' weight and height was performed by using an electronic scale and stadiometer (SECA, Hanover, MD). Weight was measured to the nearest 0.1 kg, and height was measured to the nearest 0.1 cm. BMI was calculated as weight/height squared and expressed as BMI SDS. Waist circumference was measured at the level of the umbilicus after full expiration and hip circumference at the level of the greater trochanter, both with the use of a flexible tape measuring to 0.1-cm accuracy. Four skinfold-thickness measures were taken in duplicate by a single observer on the nondominant side of the body by using a calibrated Harpenden (Baty International, West Sussex, United Kingdom) skinfold caliper at the triceps, biceps, and subscapular and suprailiacal regions. The sum of the 4 skinfold thicknesses was used as a measure of overall subcutaneous fatness. Fat mass and the corresponding fat-free mass were computed by using the equations of Durnin and colleagues16,17 and compared with biometrical impedance analysis (BIA 101/S Akern RJL systems, Detroit, MI) measurements. BIA measurements were used for analyses.
Blood pressure was obtained with an automatic blood pressure device (Dinamap, Critikon, Germany). Three measurements were taken at the nondominant arm in supine position after 15 minutes of rest with an appropriately sized cuff for arm diameter. Mean values were used in statistical analysis.
Before the clamp study, a blood sample was obtained for measurement of creatinin levels.
Hyperinsulinemic Euglycemic Clamp
Subsequently, the hyperinsulinemic euglycemic clamp was performed to determine insulin sensitivity by peripheral glucose uptake as described by De Fronzo et al.18 Insulin (Velosulin [Novo Nordisk, Bagsvaerd, Denmark]) was infused at a rate of 60 mU/kg per hour after a priming dose of 6 mU/kg. Hepatic glucose production is known to be suppressed in nondiabetic subjects by this infusion rate. The blood glucose level was measured every 5 minutes (2300 STATplus C [Yellow Springs Incorporated, Yellow Springs, OH]). Blood glucose levels were clamped to a level of 5 mmol/L. During the last hour, every 15 minutes blood was drawn to determine plasma insulin concentrations. Euglycemia (5 mmol/L) was maintained with 20% D-glucose infusion. Under steady-state conditions of euglycemia, the rate of exogenous glucose infusion is equal to the rate of insulin-stimulated glucose disposal. Insulin sensitivity was calculated from the glucose infusion rate (milligrams per minute) between 60 and 120 minutes of the euglycemic clamp, divided by body weight and expressed as M value (glucose disposal mg/kg per min) and Mi value (glucose disposal mg/kg per min/ [insulin levels pmol/L] × 100). The Mi value better reflects glucose disposal than the M value because of correction for individual differences of insulin clearance.
For statistical analysis, we used SPSS 15 for Windows (SPSS Inc, Chicago, IL). Results in Tables 1 and 2 are expressed as mean ± SD. Differences between the groups and relation with other factors were tested by linear regression analysis. In preterm infants, quartiles of height and weight SDS were analyzed longitudinally by using linear mixed models. A P value of <.05 was considered to be statistically significant on the basis of 2-sided testing.
The study was approved by the local ethical committee. All subjects gave written informed consent to participate.
Clinical Characteristics of the Groups
Table 2 shows the characteristics of the groups at the time of the study.
All subjects were born in 1983. SGA subjects were shorter in comparison with subjects in the POPS-AGA (P = .04) and CON (P = .003) groups. No differences in renal function were observed.
Fat mass derived from skinfold measurements was well correlated with fat mass derived from BIA analysis (R = 0.87; P < .0001). BIA measurements were used for additional analyses
Results on insulin sensitivity are shown in Table 3. Insulin sensitivity expressed as a Mi value was lower in subjects in the POPS-AGA (P = .004) and POPS-SGA (P < .0001) groups than in the CON group (Table 3). The difference in insulin sensitivity between subjects in the POPS-AGA and CON groups decreased after adjustment for subscapular, suprailiacal, and sum of skinfold measurements. The difference in insulin sensitivity between subjects in the POPS-SGA and CON groups decreased after adjustment for fat percentage and subscapular, suprailiacal, and sum of skinfold measurements and increased after adjustment for weight and fat mass. The difference in insulin sensitivity between subjects in the POPS-SGA and POPS-AGA groups only became significant after adjustment for fat mass.
In women, adjustment for oral anticonceptives (OAC) use did not influence the differences in insulin sensitivity between those in the POPS-AGA and CON groups (crude B = −5.3, P = .1 vs adjusted B = −5.6, P = .1), those in the POPS-SGA and CON groups (crude B = −8.5, P = .01 vs adjusted B = −8.7, P = .01), or those in the POPS-AGA and POPS-SGA groups (crude B = −3.2, P = .33 vs adjusted B = −3.0, P = .35).
Systolic Blood Pressure
Results on systolic blood pressure are shown in Table 4. Systolic blood pressure was higher in subjects in the POPS-AGA (P < .0001) and POPS-SGA (P = .01) groups than in the CON group. The difference in systolic blood pressure between subjects in the POPS-AGA and CON groups decreased after adjustment for insulin sensitivity and subscapular and suprailiacal skinfold measurements. The difference in systolic blood pressure between subjects in the POPS-SGA and CON groups decreased after adjustment for insulin sensitivity and subscapular and suprailiacal skinfold measurements and increased after correction for current height.
Diastolic Blood Pressure
Results on systolic blood pressure are shown in Table 5. Diastolic blood pressure was higher in subjects in the POPS-AGA (P = .001) and POPS-SGA (P = .007) groups than in the CON group. The difference in diastolic blood pressure between subjects in the POPS-AGA and CON groups decreased after correction for insulin sensitivity. The difference in diastolic blood pressure between subjects in the POPS-AGA and CON groups decreased after correction for insulin sensitivity, subscapular skinfolds, and sum of skinfold measurements.
Infant and Childhood Growth Patterns
For subjects in the POPS-AGA and POPS-SGA groups, height and weight SDS were analyzed longitudinally. Quartiles were used for reasons of contrast. The lowest quartile for insulin sensitivity was characterized by higher height SDS at ages 1, 2, and 5 years, as well as higher weight SDS at ages 2, 5, 10, 19, and 21 years compared with the group with the highest quartile for insulin sensitivity (Table 6; Fig 1 A and B).
When height SDS was adjusted for weight SDS, the differences between the insulin sensitivity quartiles were no longer significant except for height at 21 years, whereas a trend was observed for 1 year of age (Table 6).
The growth pattern of the group with the highest quartile for systolic blood pressure was characterized by higher height SDSs at the ages of 3 months and at 2, 5, 10, 19, and 21 years and by a higher weight SDS at ages 1, 2, 5, 10, 19, and 21 years compared with those in the group with the lowest quartile for systolic blood pressure (Table 7; Fig 1 C and D).
When height SDS was adjusted for weight SDS, the differences between the systolic blood pressure quartiles were no longer significant except for height at 3 months and 10 years of age, whereas a trend was observed for height at 2 and 5 years of age (Table 7).
In subjects born SGA at term, low birth weight is associated with an increased risk to develop insulin resistance, hypertension, and cardiovascular disease.10,19–30 Both prenatal and postnatal growth were suggested to explain part of the relation between low birth weight and adult disease. Prenatally, subjects who are exposed to an adverse environment may develop permanent compensatory responses to survive that become mismatched when the postnatal circumstances are not unfavorable any more.31 Postnatally, catch-up growth of weight and height in subjects born SGA at term has been recognized as a risk factor for the development of hypertension,32,33 ischemic heart disease,34 and insulin resistance.35 Preterm born infants are at risk of severely impaired growth during the early postnatal period, which might be comparable to the third trimester in term-born SGA infants. Despite being fed hypercalorically, preterm infants are not able to gain weight appropriately.36 In addition, during the neonatal period, preterm infants can be exposed to a cascade of acute problems including lung disease, infections, anemia, and intraventricular hemorrhage.
In the present study, we demonstrate that insulin sensitivity is decreased in preterm-born subjects. The differences between the individuals in the POPS groups and the CON group were partly explained by differences in central body fat, represented by suprailiacal and subscapular skinfolds. In the POPS-SGA group, adjustment for weight and total body fat increased the difference with subjects in the CON group, which may indicate that smaller body size protects against the development of insulin resistance.
The difference in insulin sensitivity between subjects in the POPS-AGA and POPS-SGA groups only became significant after correction for fat mass irrespective of body size.
Our study is the first, to our knowledge, that presents measurements of insulin sensitivity in preterm-born young adults by using the clamp design, which is considered the gold standard for measuring insulin sensitivity.11,12 Irving et al4 were the first to report that preterm infants are exposed to similar cardiovascular risks as adults born SGA. They found increased fasting glucose and higher blood pressure in adults born moderately prematurely. With respect to insulin resistance, Hofman et al2 published intravenous glucose tolerance test data on preterm-born children. By using the minimal model assessment,37 they found that preterm infants displayed a 40% reduction of insulin sensitivity compared with controls. As in our study, they found that insulin sensitivity was not significantly different between the preterm SGA and AGA groups.2 Recently, Hovi et al3 performed standard 75-g oral glucose tolerance tests in 169 individuals with very low birth weight and 169 controls. They found that young adults with a very low birth weight had significantly higher blood pressure, higher fasting insulin, 2-hour insulin, and 2-hour glucose concentrations, and a higher homeostasis model assessment (HOMA) index after a standard 75-g oral glucose tolerance test.3
Similar to Irving et al and Hovi et al, we found that blood pressure is higher in preterm individuals. We also found that this difference is partly explained by differences in insulin sensitivity. A new finding is that difference between POPS-SGA and CON subjects was strongly influenced by current height, which may suggest that stunting of growth protects against the development of high blood pressure.
Our study also indicates that not only birth weight and gestational age but also growth patterns during infancy and childhood are of great importance for insulin sensitivity and blood pressure in later life. Increased growth during infancy is usually expected, especially in those with low birth weight who demonstrate catch-up growth during this period.
Increased height gain between 1 and 5 years of age and increased weight gain between 2 and 21 years of age were strongly associated with lower insulin sensitivity, whereas increased height gain between 1 and 21 years of age and weight gain between 2 and 21 years of age were strongly associated with higher systolic blood pressure. The observed parallelism between height and weight SDSs can be interpreted to mean that height gain is a marker for gain in adiposity. Alternatively, it is possible that mechanisms involved in height gain lead to insulin resistance. However, independent of the interpretation, it is clear that spontaneous catch-up growth in height in subjects born prematurely is unfavorable.
Several studies have shown that the trajectory of growth of subjects that later develop glucose intolerance, hypertension, and coronary heart disease is often characterized by the crossing of SDS lines, normally still within the reference range.8,38,39 Thus, the changes in height or weight SDS are more important than the cross-sectional means of SDS values throughout childhood.
Young adults born prematurely have a reduced insulin sensitivity and increased blood pressure compared with controls. Increments in height and weight during childhood contribute to the development of insulin resistance and high blood pressure in young adulthood.
We thank Prof Dr S.P. Verloove-Vanhorick and the Dutch POPS collaborative study group for their willingness to perform and collaboration with the present study.
- Accepted December 12, 2007.
- Address correspondence to Joost Rotteveel, MD, VU Medical Center, Department of Pediatrics, PO Box 7057, 1007 MB Amsterdam, Netherlands. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Insulin sensitivity is decreased in preterm born subjects.
What This Study Adds
The development of insulin sensitivity is associated with childhood growth patterns of both height and weight.
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