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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Background

Young adults born preterm at very low birth weight (VLBW, ≤1500 g) have higher levels of cardiovascular risk factors, including impaired glucose regulation, than their term-born peers. This could be mediated through altered hypothalamic-pituitary-adrenal axis (HPAA) response to stress.

Objective

To compare HPAA, glucose and insulin responses provoked by psychosocial stress in VLBW subjects versus a comparison group of term-born controls.

Design and participants

We studied 54 unimpaired young adults, aged 19–27 years, born at VLBW and a comparison group of 40 adults born at term, group-matched for age, sex and birth hospital, from one regional centre in southern Finland. The participants underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST).

Measurements

In conjunction with TSST, we measured salivary cortisol, plasma ACTH, cortisol, glucose and insulin. Data were analysed with mixed-effects model and multiple linear regression analyses.

Results

Baseline concentrations for cortisol, ACTH, insulin and glucose were similar in VLBW and comparison groups. During TSST, analysed with mixed-effects model, overall concentrations of plasma cortisol were 17·2% lower (95% CI; 3·5 to 28·9) in the VLBW group. The VLBW group also had lower salivary (P = 0·04) and plasma cortisol (P = 0·02) responses to TSST. Insulin and glucose concentrations correlated with changes in cortisol concentrations. Accordingly, VLBW subjects had 26·5% lower increment in insulin (95% CI; 9·8–40·1). Analyses were adjusted for age, sex, body mass index, hormonal contraception, menstrual cycle phase, time of day and parental education.

Conclusions

VLBW adults have lower HPAA responses to psychosocial stress than term-born controls. This is accompanied by a lower insulin response.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Individual reactions to psychosocial stressors vary. The stress response, including that of the hypothalamic-pituitary-adrenal axis (HPAA), is an important determinant of health and disease. For example, a hyperactive HPAA has been linked with depression[1], type 2 diabetes[2] and cardiovascular disease.[2] Hyporesponsiveness of the HPAA has been linked with several conditions, including fibromyalgia, post-traumatic stress disorder, burnout and depression.[3] It has been postulated that a hyporeactive HPAA might develop after prolonged periods of stress, characterized by hyperactivity of the HPAA.[4] Neonatal intensive care after preterm birth could represent such stress. Thus, preterm birth may be a risk factor, adversely affecting the future functioning of the HPAA.

People born preterm at very low birth weight (VLBW, ≤1500 g) have, as adults, elevated risk factors for chronic noncommunicable diseases, including impaired glucose regulation,[5, 6] higher blood pressure[7-12] and lower bone mineral density.[13] Preterm birth, especially when combined with intrauterine growth restriction, also constitutes a single independent risk factor for a range of psychiatric disorders such as depression, nonaffective psychosis, bipolar affective disorder and eating disorders.[14, 15] However, preterm birth may also be associated with protective factors. Despite risk factors in young adults, studies have failed to show any association between preterm birth and coronary heart disease in older subjects.[16] Some of the outcomes may be different in subgroups of VLBW infants. For example, those born with a birth weight appropriate for gestational age (AGA, birth weight ≥ −2SD) may actually be at reduced risk of some psychiatric disorders including depression.[14]

Previous data on HPAA stress reactivity in young adults born preterm are scarce, and the results have been mixed.[17] Our primary hypothesis was that healthy young adults born at VLBW have higher HPAA response to stress compared with controls born at term. Our secondary hypothesis was that this is paralleled by a higher glucose and insulin response.

Our primary aim was to assess HPAA response to a standardized psychosocial stressor [Trier Social Stress Test, TSST[18]] in healthy young adults born preterm at VLBW compared with controls born at term. Our secondary aim was to assess insulin and glucose responsiveness to cortisol changes provoked by stress.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Study participants

Our participants come from the Helsinki Study of VLBW Adults cohort.[6] Briefly, the original cohort included 335 subjects born preterm at VLBW during 1978–1985 and discharged alive from the neonatal intensive care unit serving one regional area in southern Finland, and 314 controls born at term, group-matched for sex, age and birth hospital. In 2004–2005, those 255 VLBW and 314 control subjects who were residing in the greater Helsinki area were invited to participate in a clinical examination. Of these invited subjects, 166 VLBW and 172 controls chose to participate.[6, 13] During 2005, we invited a random sample of these participants of the previous clinical examination, excluding those who (i) were unable to stand or to manage without an assistant, (ii) used glucocorticoids or (iii) had a nightshift during the previous week. A total of 54 VLBW and 40 control participants born at term attended the TSST.

We measured weight and height and calculated body mass index (BMI; kg/m2). The participants completed a questionnaire enquiring about smoking habits, medical history, current medications (including hormonal contraception) and menstrual cycle. Highest educational attainment of either parent was used to indicate socio-economic status as the youngest participants were still living at home or just beginning their studies. The study protocol was approved by the Ethics Committee at the Helsinki and Uusimaa Hospital District. Written informed consent was obtained from each participant.

Trier Social Stress Test

The TSST is a standardized laboratory test which measures HPAA response to moderate psychosocial stress.[10, 18, 19] It includes a 5-min anticipation period and a 10-min test period, during which the participant delivers a free speech applying for a job and performs arithmetic tasks in front of a two-person committee. Stress reactivity is evaluated by repeated hormonal (ACTH, cortisol) measurements.

An intravenous line was inserted by a study nurse 45 min before baseline for collecting blood samples at baseline (15–30 min before test) and at 0, 10, 20, 30, 45, 60 and 90 min after the TSST. Salivary samples were gathered using Salivette® (Sarstedt, Nümbrecht, Germany). We measured plasma and salivary cortisol at all eight time points. Plasma ACTH, which more rapidly returns to prestress levels, was measured from the four first samples. Plasma insulin and glucose were measured at baseline, 0, 20 and 90 min; these times were chosen as we expected the concentrations to rise in response to cortisol concentrations. All samples were immediately frozen at −20 °C. The plasma samples were transferred once a week to −70 °C for storage until time of analysis. The TSST was performed between 10:45 h and 16:10 h; the test was scheduled to start at 10:50 h, 12:05 h or 13:20 h. Participants were asked to refrain from eating, drinking and smoking 2 h before the test.

Biochemical measurements

Salivary cortisol concentrations were determined using a competitive solid-phase, time-resolved fluorescence immunoassay with fluorometric end point detection (DELFIA; Wallac, Turku, Finland). Plasma cortisol concentrations were determined by ELISA (ImmunoBiological Laboratories, Hamburg, Germany) and ACTH by chemiluminescence immunofluorometric assay (Nichols Institute Diagnostics, San Clemente, USA). Cortisol and ACTH measurements were assayed in duplicate at the University of Trier, Germany. Plasma insulin concentrations were determined by Immunotech Insulin(e) IRMA kit (A Beckman coulter company, Prague, Czech Republic). Glucose concentrations were determined by enzymatic hexokinase method (Gluco-quant®; Roche Diagnostics, Tokyo, Japan).

Statistical analysis

We used IBM spss Statistics 19 (SPSS Inc., Chicago IL, USA) and R 2.8.1 (R Foundation for Statistical Computing, Vienna, Austria) for statistical analyses. Descriptive characteristics of the study participants were compared using t-test for continuous and χ2-test for categorical variables. ACTH, cortisol, insulin and glucose concentrations were log-transformed for normality. First, we analysed responses of these concentrations to TSST by mixed-effects model. Using the mixed-effects model has the advantage of taking into account within-subject correlation in studies with repeated measurements. We assessed interactions by including an interaction term with sampling time (time*VLBW/comparison group) and moderation by sex (sex*VLBW/comparison group and time*sex*VLBW/comparison group). In further analyses, we used linear regression to illustrate the magnitude of the differences between VLBW and comparison groups in commonly used indicators of HPAA, glucose and insulin responses [baseline, peak, relative increment (peak after stress/baseline value) and time-weighted areas under the curve ground (=above zero, AUCg), calculated as described[19]]. Peak after stress value was set missing if no sample was available for 0, 10 and 20 min after stress. If two or more cortisol samples or one or more ACTH, glucose or insulin concentrations were missing for a subject, a missing value was set for the AUCg. By contrast, the mixed model process includes in analysis subjects who have missing data for some of time points. We adjusted for age, sex, BMI, hormonal contraception, menstrual cycle phase, time of day (dummy-coded based on time when the TSST began: 10:50 h, 12:05 h or 13:20 h) and parental education in all analyses. A value of < 0·05 was considered statistically significant.

We compared perinatal and current descriptive characteristics for the participants of this study (54 VLBW and 40 control participants) with the remaining cohort subjects who previously participated in a clinical examination (112 VLBW and 132 controls)[6]; the participants in the current study were recruited from this group. All descriptive characteristics were separately compared for VLBW and control groups. There were no differences in gestational age, birth weight, sex or incidence of preeclampsia, multiple pregnancy or small for gestational age (SGA, birth weight <−2SD)[20] between the participants of the current study and the group they were recruited from (all P-values ≥ 0·1). Also, age, daily smoking, use of hormonal contraception, parental education, adult height and BMI were similar in participants and the remaining cohort group (all P-values ≥ 0·1).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Characteristics of our study participants are shown in Table 1. The VLBW participants' gestational ages ranged between 24 and 36 weeks and birth weights between 600 and 1500 g. In the comparison group, gestational ages ranged between 38 and 42 weeks and birth weights between 2889 and 4900 g. No gender differences were found between the effects of preterm birth at VLBW on the study outcomes (mixed model P-values for interaction sex*VLBW status >0·3; time*sex*VLBW >0·4). Therefore, we report combined results.

Table 1. Descriptive characteristics of the study participants
CharacteristicVLBW (= 54)Term (= 40) P a Missing values, VLBW/Term
  1. Bold values denote statistically significant P-values (P < 0.05).

  2. VLBW, very low birth weight (≤1500 g).

  3. a

    The t-test for continuous and the chi-square test for categorical variables.

  4. b

    SGA, small for gestational age, birth weight <−2SD.

Birth
Gestational age, mean (SD), week29·4 (2·3)40·2 (1·1) <0·0001 0/0
Birth weight, mean (SD), g1103 (212·4)3639 (455·6) <0·0001 0/0
Birth weight SDS, mean (SD)−1·5 (1·5)0·1 (1·0) <0·0001 0/0
Women, n (%)28 (51·9)23 (57·5)0·80/0
Men, n (%)26 (48·1)17 (42·5)0·70/0
SGAb, n (%)23 (42·6)0 0/0
Preeclampsia, n (%)12 (22·2)4 (10·0)0·26/1
Twin, n (%)7 (13·0)0 0/0
Triplet, n (%)1 (1·9)0 0/0
Current
Age, mean (SD), y23·1 (2·2)23·5 (2·0)0·50/0
Height, mean (SD), cm
Women161·5 (6·9)165·7 (6·7) 0·03 0/0
Men174·3 (8·2)180·2 (4·9) 0·006 0/0
BMI, mean (SD), kg/m2
Women21·7 (3·3)23·7 (4·6)0·10/0
Men22·3 (4·2)23·9 (3·1)0·20/0
Daily smoking, n (%)19 (35·8)10 (25·8)0·30/2
Menstrual cycle phase if no hormonal contraception, n (%)
Day 1–85 (35·7)5 (33·3)0·73/2
Day 9-6 (42·9)8 (53·3)
Use of hormonal contraceptives, n (%)14 (50·0)9 (39·1)0·40/0
Parental education, n (%)
Elementary5 (9·3)3 (7·5) 0·04 0/0
High school14 (25·9)4 (10·0)
Intermediate19 (35·2)15 (37·5)
University16 (29·6)18 (45·0)

Cortisol and ACTH concentrations

Baseline concentrations, peak after stress, increments and AUCg are shown in Table 2. In the mixed model analysis, overall concentrations of HPAA reactivity measures were lower in VLBW participants, although this was statistically significant for plasma cortisol only (= 0·02) (Fig. 1). Moreover, VLBW participants had on average lower increase in plasma and salivary cortisol (P-values for time*VLBW status=0·02 and 0·04, respectively). These differences are further illustrated by a lower peak value of plasma cortisol after stress in VLBW participants [−17·0% (95% CI; −29·3, −2·7%) = 0·02].

Table 2. ACTH, cortisol, glucose and insulin concentrations of the study participants
Meana (SDb)VLBW (= 54)Term (= 40) P c Missing values, VLBW/Term
  1. Bold values denote statistically significant P-values (P < 0.05).

  2. VLBW, very low birth weight (≤1500 g).

  3. a

    Geometric mean denotes the nth root of the product of n individual values.

  4. b

    Geometric standard deviation denotes the relative increase in a variable corresponding to one standard deviation unit change in the logarithm of the variable.

  5. c

    All analyses are adjusted for age, sex, BMI, hormonal contraception, menstrual cycle phase, time of day and highest parental education.

  6. d

    Log (peak after stress/baseline value).

  7. e

    Area under the curve with respect to ground (above zero).

Baseline concentrations
ACTH, pmol/l3·5 (1·8)3·6 (2·5)0·64/1
Plasma cortisol, nmol/l325·3 (1·4)302·3 (1·8)0·54/1
Salivary cortisol, nmol/l7·0 (1·7)6·1 (2·0)1·03/3
Insulin, mU/l6·8 (2·1)7·3 (2·1)0·74/1
Glucose, mmol/l4·6 (1·1)4·7 (1·1)0·34/1
Peak after stress
ACTH, pmol/l8·5 (2·7)11·3 (2·7)0·36/2
Plasma cortisol, nmol/l471·3 (1·5)509·4 (1·5) 0·03 6/2
Salivary cortisol, nmol/l12·7 (1·9)13·7 (2·0)0·34/2
Insulin, mU/l9·7 (1·9)11·5 (1·9)0·64/1
Glucose, mmol/l5·0 (1·1)5·1 (1·1)0·24/1
Increments d
ACTH2·5 (1·9)3·1 (2·6)0·56/2
Plasma cortisol1·4 (1·4)1·7 (1·5)0·16/2
Salivary cortisol1·7 (1·9)2·3 (2·2)0·25/4
Insulin1·3 (1·7)1·5 (1·5)0·086/2
Glucose1·1 (1·1)1·1 (1·1)0·36/2
Time-weighted area under curve e
ACTH5·9 (1·9)7·8 (2·2)0·27/6
Plasma cortisol349·4 (1·4)352·8 (1·6)0·28/9
Salivary cortisol7·5 (1·6)8·4 (1·9)0·15/8
Insulin9·7 (2·0)12·0 (2·3)0·68/9
Glucose6·3 (1·1)6·6 (1·1)0·38/9
image

Figure 1. Mean plasma ACTH, plasma cortisol, salivary cortisol, plasma glucose and insulin concentrations among adults born at very low birth weight (VLBW; ≤1500 g) (continuous lines) and the comparison group born at term (dashed lines) during the Trier Social Stress Test. Mixed model results are also presented as mean differences (95% CI). All analyses are adjusted for age, sex, body mass index, hormonal contraception use, menstrual cycle phase, time of day and highest parental education.

Download figure to PowerPoint

Glucose and insulin concentrations

Glucose and insulin concentrations correlated with plasma cortisol during the TSST (mixed model standardized regression correlation coefficients 0·22 and 0·20, respectively, < 0·001; adjusted 0·17, < 0·001 and 0·10, = 0·06). In the mixed model analysis, the difference in the overall levels or increases in plasma glucose or insulin were not statistically significant between the VLBW and comparison groups (Fig. 1). Insulin concentrations increased 1·3-fold in the VLBW group and 1·5-fold in the comparison group (Table 2); accordingly, the increment of insulin was 26·5% lower in VLBW participants (95% CI; 9·8–40·1, adjusted for covariates in Fig. 1).

Comparison of VLBW adults born small and AGA

We compared those 23 VLBW participants born SGA[20] with the 31 VLBW participants born AGA. All overall concentrations were similar, but glucose and insulin responsiveness were higher in the VLBW-SGA group (P-values time*SGA status <0·001 and 0·01, respectively).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

To our knowledge, this is the first study reporting HPAA response to psychosocial stress in preterm-born VLBW subjects as young adults. Contrary to our hypothesis, we found that VLBW subjects have significantly lower HPAA response after psychosocial stress compared with the comparison group born at term. Lower cortisol concentrations correlated with lower insulin and glucose levels. Our results were not explained by age, sex, BMI, hormonal contraception, menstrual cycle phase, time of performing TSST or parental education.

It has been suggested that prolonged exposure to stress leads to a hypoactive HPAA.[17] Our study indicates that premature birth, which is associated with several pre- and postnatal adversities, such as undernutrition, infections and repeated painful treatments as a part of routine neonatal intensive care, may be such a stress experience. Although HPAA stress response using TSST in adult VLBW people has not been studied previously, a study of 8–12 year olds, born at any degree of prematurity, showed attenuated salivary cortisol responses to TSST for Children.[21] That result did not reach statistical significance, perhaps because of small sample size, as the study comprised 18 preterm children and 18 same-sex friends as controls. Furthermore, a lower cortisol response to immunization has been reported in 4 month olds born at extremely low gestational age compared with full-term infants.[22] The same group reported lower salivary cortisol levels in preterm infants at 3 months of corrected age compared with term infants, shifting to significantly higher cortisol levels in extremely preterm infants at 8 and 18 months of corrected age, perhaps indicative of long-term effects of prematurity on the HPAA.[23] Interestingly, higher cortisol in these extremely preterm infants at 8 months predicted more internalizing symptoms at 18 months.[24] Although our study in young adults again showed a lower HPAA response in the preterm VLBW group, neither of these studies found any difference between VLBW or extremely preterm groups born SGA and AGA.

The association between birth weight and HPAA response to TSST has been studied previously.[17] A lower birth weight was associated with greater salivary cortisol response in 7–9-year-old boys[25] and young healthy male twins.[26] The twin study also suggested higher responses among those born at an earlier gestational age. In another study, TSST at 60–70 years of age provoked lower cortisol and ACTH concentrations in those born with lower birth weight, mostly after term pregnancy.[19] These discrepancies are perhaps explained by a variety of mechanisms underlying low birth weight, which may all have different effects on long-term HPAA function. Furthermore, both hyper- and hypoactive HPAA have been associated with later health.[3] As we found no differences in HPAA response between VLBW-SGA and VLBW-AGA subgroups, we assume the blunted HPAA response provoked by TSST to be caused by immaturity at birth rather than intrauterine growth retardation.

Associations of early life markers with autonomic nervous system and blood pressure responses to stress have been extensively studied.[17] In the present cohort, VLBW adults showed higher diastolic blood pressure responses than controls.[10] In relation to these studies, responses in metabolic markers such as insulin and glucose have been largely neglected. We found that insulin concentrations, starting from a similar baseline value, increased 1·3-fold in the VLBW group and 1·5-fold in the term group. As expected, a lower increase in insulin was predicted by lower cortisol response. This is in contrast with the insulin increase after a 75 g oral glucose load, which was higher in VLBW adults (6·1-fold) than in controls (5·1-fold).[6] Although the increase produced by stress is low as compared by that produced by oral glucose load the finding is nevertheless of note as a potential protective factor.

Major strengths of this study are the standardized stressor test,[18] the use of a wide range of measurements rather than salivary cortisol only[21, 25, 26] and adjustment for most important confounders.

Limitations of our study include a relatively small sample size which is due to the labour-intensive test but is, however, larger than or similar to most previous studies in the field.[21, 25, 26] While our sample size is reasonable to assess differences between VLBW and comparison groups, our finding of no sex interactions should be treated with caution as sex differences are a common characteristic of HPAA stress response studies.[27] The time of performing the TSST was between 10:45 and 16:10, and the actual tests were scheduled to start at 10:50 h, 12:05 h or 13:20 h, which was adjusted for in all analyses. At this time interval, the responses to TSST are comparable.[28] A possible limitation of our study is that all samples were initially stored at −20 °C and transferred once a week for storage at −70 °C. It is unlikely that this procedure would have had any substantial effect on the results. Furthermore, as a result of major improvements in modern neonatal intensive care, today's extremely preterm-born survivors should not be directly compared with the group of VLBW adults we now investigated. However, both our study participants and the preterm babies born today are subjected to repeated stressful situations, for example, infections and repeated painful treatments during intensive neonatal care, which may impact on future HPAA function. It is also of note that preterm birth is caused by a variety of reasons, which may have different impacts on future HPAA function. This may limit the extent to which the data can be generalized in the preterm-born population. One additional limitation of this study is that we were unable to control for lifetime stressful experiences or current perceived stress in the study participants.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

In summary, our study suggests that young adults born preterm at VLBW have a diminished HPAA response to psychosocial stress, reflected also by a lower insulin response. Our results reinforce previous suggestions that both hyper- and hypocortisolism may be programmed early in life.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The authors do not have any financial or other conflict of interests related to the manuscript to disclose.

This study was supported by grants from the Academy of Finland, the Finnish Foundation for Pediatric Research, the Finnish Special Governmental Subsidy for Health Sciences, the Jalmari and Rauha Ahokas Foundation, the Juho Vainio Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, the University of Helsinki, the Perklén Foundation, the Research Foundation for the Orion Corporation, the Signe and Ane Gyllenberg Foundation, the Sigrid Jusélius Foundation, the Waldemar von Frenckell Foundation, the Yrjö Jahnsson Foundation, the Finnish Medical Foundation, the Otto A. Malm Donation Fund, the Emil Aaltonen Foundation, Medical Society of Finland (Finska Läkaresällskapet) and Victoriastiftelsen.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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