Cord blood copeptin concentrations in fetal macrosomia

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Metabolism www.metabolismjournal.com

Cord blood copeptin concentrations in fetal macrosomia☆ Despina D. Briana a , Stavroula Baka a , Maria Boutsikou a , Theodora Boutsikou a , Marieta Xagorari b , Dimitrios Gourgiotis b , Ariadne Malamitsi-Puchner a,⁎ a b

Department of Neonatology, Athens University Medical School, Athens, Greece Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, Athens, Greece

A R T I C LE I N FO Article history:

AB S T R A C T Background/aim. Excessive fetal growth is associated with increased adiposity and reduced

Received 14 February 2015

insulin sensitivity at birth. Copeptin, a surrogate marker of arginine vasopressin (AVP) secretion,

Accepted 19 September 2015

is upregulated in states of hyperinsulinemia and is considered one of the mediators of insulin resistance. We aimed to investigate cord blood concentrations of copeptin (C-terminal fragment

Keywords: Copeptin

of AVP pro-hormone) in healthy large-for-gestational-age (LGA) infants at term. Methods. This prospective study was conducted on 30 LGA (n = 30) and 20 appropriate-

AVP

for-gestational-age (AGA, n = 20) singleton full-term healthy infants. Cord blood copeptin

Insulin

and insulin concentrations were determined by ELISA and IRMA, respectively. Infants were

Cord blood

classified as LGA or AGA, based on customized birth-weight standards adjusted for

Fetal macrosomia

significant determinants of fetal growth. Results. Cord blood copeptin concentrations were similar in LGA cases, compared to AGA controls, after adjusting for delivery mode. However, in the LGA group, cord blood copeptin concentrations positively correlated with birth-weight (r = 0.422, p = 0.020). In the AGA group, cord blood copeptin concentrations were elevated in cases of vaginal delivery vs elective cesarean section (p = 0.003). Cord blood insulin concentrations were higher in LGA cases, compared to AGA controls (p = 0.036). No association was recorded between cord blood copeptin concentrations and maternal age, parity, gestational age or fetal gender in both groups. Conclusions. Cord blood copeptin concentrations may not be up-regulated in non-distressed LGA infants. However, the positive correlation between cord blood copeptin concentrations and birth-weight in the LGA group may point to the documented association between AVP release and increased fat deposition. Vaginal delivery vs elective cesarean section is accompanied by a marked stress-related increase of cord blood copeptin concentrations. © 2016 Elsevier Inc. All rights reserved.

1.

Introduction

An emerging body of literature indicates that fetal growth disturbances i.e. intrauterine growth restriction and fetal

macrosomia are associated with an increased risk of perinatal morbidity, mortality and adverse developmental outcomes, especially obesity-related metabolic disorders later in life [1–3]. Although a world-wide series of epidemiological and experi-

Abbreviations: LGA, large for gestational age; AGA, appropriate for gestational age; DM, diabetes mellitus; GDM, gestational diabetes mellitus; AVP, arginine vasopressin; HPA axis, hypothalamic-pituitary-adrenal axis. ☆ The authors state that they have no conflict of interest or financial support relevant to this article to disclose. ⁎ Corresponding author at: 19, Soultani Street, 10682 Athens, Greece. Tel.: +30 6944443815; fax: + 30 2107286224. E-mail addresses: [email protected], [email protected] (A. Malamitsi-Puchner). http://dx.doi.org/10.1016/j.metabol.2015.09.018 0026-0495/© 2016 Elsevier Inc. All rights reserved.

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mental studies have linked poor prenatal growth to insulin resistance-associated diseases [1,4], the mechanisms involved in being born large for gestational age (LGA) and its short- and long-term consequences are less understood [2,5]. Gestational diabetes mellitus (GDM), maternal obesity, excessive weight gain during pregnancy and variations in genes related to the secretion and action of insulin and insulin growth factors have been implicated in the pathophysiology of the LGA phenotype [6,7]. Insulin is an essential endocrine regulator of intrauterine growth [8]. However, excess insulin production in utero induces fetal macrosomia and chronic tissue hypoxia [9], alterations in fetal adipose tissue development and permanent changes in the regulation of metabolic and hormonal functions, leading to impaired glucose homeostasis and cardiovascular disease later in life [2,5]. Previous data also showed increased fat accumulation and reduced insulin sensitivity in LGA newborns at birth [9,10]. High birth weight does not necessarily equate to increased fetal growth, since infants can be LGA, as a result of individual normal genetic variation. Thus, the use of customized birth weight standards that are adjusted for significant determinants of birth weight are considered more appropriate for identifying subjects with true excessive fetal growth, which are at risk for experiencing long-term adverse outcomes [11]. Arginine vasopressin (AVP), also known as antidiuretic hormone, is secreted by the pituitary gland and acts as a main regulator in the homeostasis of the cardiovascular and renal systems [12]. AVP plays a crucial role in the endocrine stress response to a variety of diseases [13]. Hypoxia has been described to augment a strong AVP release in various animal models [14,15], and similarly fetal distress in humans has been found to trigger a decisive AVP response [16]. Measurements of circulating AVP levels are cumbersome, because of its instability and short half-life [17]. Copeptin (C-terminal fragment of AVP pro-hormone), which is a stable by-product of AVP synthesis and can quantitatively be determined in plasma, is secreted in equimolar amounts to AVP, thus reliably reflecting AVP release [17]. The AVP system has recently been implicated in various obesity-related metabolic disorders, including the metabolic syndrome [18–20]. Numerous studies have consistently shown that higher plasma copeptin concentrations are independently associated with higher glucose and insulin concentrations, higher degree of insulin resistance, obesity and diabetes mellitus (DM) [18–21]. Evidence suggests that AVP is an amplifier of the hypothalamic-pituitary-adrenal (HPA) axis along with corticotropin releasing hormone (CRH) and that the AVP system exerts a disturbing effect on normal glucose and insulin metabolism through stress-mediated HPA axis activation [18,22]. More interestingly, plasma copeptin independently predicts DM and obesity development during long-term followup [20] and is currently considered a promising novel marker of insulin resistance [18]. Given the significance of glucose and insulin in fetal growth [8], and the fundamental role of copeptin in insulin metabolism [18–21], it is reasonable to assume that copeptin may play a regulatory role in excessive fetal growth. The present prospective study was conducted to test the

hypothesis that cord blood concentrations of copeptin are up-regulated in LGA infants, as compared to appropriate for gestational age (AGA) controls, since the former present with increased fat deposition and reduced insulin sensitivity at birth [9,10]. Thus, we sought to determine, for the first time to our knowledge, cord blood copeptin and insulin concentrations in healthy full-term, non-distressed, well-characterized LGA and AGA infants. We also aimed to investigate the impact of various perinatal factors on cord blood copeptin concentrations at birth.

2.

Material and Methods

The study protocol was approved by the ethics committee of our university hospital. Signed informed consent was obtained from the participating mothers before enrollment. The study population was identified among a larger study cohort previously described (data under publication). Briefly, fifty parturients giving consecutively birth either to 20 AGA or 30 LGA (birth-weight above the 90th customized centile) fullterm singleton infants were included. The Gestation Related Optimal Weight (GROW) computergenerated program was used to calculate the customized centile for each pregnancy [11]. Significant determinants of birth weight (maternal height and booking weight, ethnicity, parity, gestational age and gender) were entered to adjust the normal birth weight centile limits. Infants were considered eligible for enrollment if born at term. Gestational age was determined by the best estimate from a combination of the first day of the mother's last menstrual period and an early ultrasound scan in the first trimester. Additional inclusion criteria were singleton pregnancies, absence of fetal distress at birth and elective cesarean section without preceding contractions or rupture of membranes. Indications for elective cesarean section were previous section, fetal macrosomia, breech presentation and section on demand. LGA status was attributed to GDM [23] in five cases, all treated with diet. In 13 LGA cases mothers were overweight (25 < body mass index < 30 kg/m2) or obese (body mass index > 30 kg/m2) [24]. In the AGA group, mothers were healthy non-smokers. Pregnancies with chromosomal aberrations, fetal malformations, genetic syndromes, congenital or intrauterine infections were excluded. One- and five-minute Apgar scores were ≥ 8 in all neonates. All infants were healthy at birth and presented with normal cord blood arterial pH, base excess, as well as lactate values [25]. Clinical characteristics of participating mothers and infants of both groups are shown in Table 1. Mixed arteriovenous blood samples were collected immediately after birth by puncture of the doubly-clamped umbilical cords, reflecting the fetal state, in pyrogen-free tubes and were immediately centrifuged. The supernatant plasma was kept frozen at − 80 °C until assay. The measurement of plasma copeptin concentrations was performed by ELISA (Phoenix Pharmaceuticals Inc, D-76133, Karlsruhe, Germany). The minimum detectable concentration, intra- and interassay coefficients of variation were 0.08 ng/ml, < 10% and < 15%, respectively.

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Plasma insulin concentrations were measured by IRMA (Immunotech a.s, 10227, Prague 10 – Czech Republic). The minimum detectable concentration, intra- and interassay coefficients of variation were 0.5 μIU/ml, 4.3% and 3.4%, respectively.

3.

Statistical Analysis

Data regarding copeptin and insulin were not normally distributed (Kolmogorov–Smirnov test); thus they underwent logarithmic transformation. Cord blood copeptin and insulin concentrations were not normally distributed even after logarithmic transformation, thus nonparametric procedures were applied to examine any differences between groups. Student's t-test or Mann–Whitney U test, where applicable, was used to examine any differences between continuous variables. Pearson's chi square test estimated differences between categorical variables. Pearson's or Spearman correlation coefficient was used, where appropriate, to examine any positive or negative correlations. IBM SPSS version 22.0 (IBM SPSS, Armonk, NY) was used for all calculations. A p < 0.05 was considered statistically significant.

4.

Results

Determined median (ranges) values of cord blood copeptin concentrations in the LGA and AGA groups were 0.13 ng/ml

Table 1 – Demographic data of participating mothers and their infants. Variables

AGA [mean ± SD/ LGA [mean ± SD/ p median (range)] median (range)] value

Birthweight (grams) Gestational age (weeks) Customized centile Maternal age (years) Gender, N (%) Male Female Mode of delivery, N (%) Vaginal Cesarean section Parity, N (%) First Other Diabetes mellitus, N (%) No Yes Smoking, N (%) No Yes

3375.0 ± 266.85

4179.3 ± 239.3

39.1 ± 0.9

38.99 ± 0.9

56.0 (78.0–35.0)

95.5 (100.0–90.0)

34.0 ± 4.8

32.9 ± 4.4

10 (50.0) 10 (50.0)

21 (70.0) 9 (30.0)

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(1.37–0.08) and 0.19 ng/ml (2.1–0.08), respectively, and are presented in Fig. 1. Cord blood copeptin concentrations were similar in LGA cases, compared to AGA controls, after controlling for delivery mode. Cord blood copeptin concentrations did not differ between LGA and AGA groups, either delivered vaginally or by cesarean section. In the LGA group, cord blood copeptin concentrations positively correlated with birth-weight (r = 0.422, p = 0.020) (Fig. 2). In the AGA group, cord blood copeptin concentrations were elevated in cases of vaginal delivery vs elective cesarean section (p = 0.003) (Fig. 3). Cord blood insulin concentrations were higher in LGA cases, compared to AGA controls (p = 0.036) (Fig. 4). However, no differences in cord blood insulin or copeptin concentrations were recorded between LGA infants born to mothers without GDM (n = 25) and AGA (n = 20) controls in a subgroup analysis. Cord blood copeptin concentrations did not correlate with respective insulin ones in the study group. No association was recorded between cord blood copeptin concentrations and maternal age, parity, gestational age or fetal gender in both groups.

5.

Discussion

In contrast to our hypothesis, the data presented in this study suggest that cord blood concentrations of copeptin, a surrogate marker of AVP, are similar in LGA non-distressed infants and AGA controls, after controlling for delivery mode. However, cord blood copeptin concentrations positively correlated with birth weight in the LGA group. Recently, there is a growing interest in the study of the LGA phenotype, due to its strong association with obesity, cardiometabolic disease and insulin resistance-related diseases during the lifespan in several human studies [2,5–7,26,27]. The exact mechanisms underlying this association are not clearly defined.

<0.001 0.773 <0.001 0.643 0.235

0.035 11 (55.0) 9 (45.0)

7 (23.3) 23 (76.7)

12 (60.0) 8 (40.0)

15 (50.0) 15 (50.0)

0.569

0.381 20 (100.0) 0 (0.0)

25 (83.3) 5 (16.7)

20 (100.0) 0 (0.0)

26 (86.7) 4 (13.3)

0.544

Fig. 1 – Box and whisker plots of cord blood (UC) copeptin concentrations in the appropriate for gestational age (AGA) and large for gestational age (LGA) groups. Horizontal line represents the median and each box the interquartile range (IQL). Symbols represent outliers (cycles) and extreme values (asterisk).

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Fig. 2 – Positive correlation between cord blood (UC) copeptin concentrations and birth-weight in the large for gestational age (LGA) group.

A decrease in insulin sensitivity seems to be already present in the LGA human fetus at birth, suggesting that metabolic dysregulation starts in utero [9,10]. In accordance, Catalano et al [28] demonstrated a positive close association between fetal adiposity and fetal insulin resistance in a human study. However, the authors could not rule out whether reduced insulin sensitivity is the result of increased fat deposition [28]. In this respect, intrauterine hyperinsulinemia increases oxygen consumption and induces chronic tissue hypoxia-related stress in the LGA fetus in both human and animal studies [29,30]. Relatively, experimental and human data suggest that GDM may induce placental genes, which program chronic stress

Fig. 3 – Box and whisker plots of cord blood (UC) copeptin concentrations in cases of elective cesarean section versus vaginal delivery in the appropriate for gestational age (AGA) group. Horizontal line represents the median and each box the interquartile range (IQL). Symbols represent extreme values (asterisk).

Fig. 4 – Box and whisker plots of cord blood (UC) insulin concentrations in the appropriate for gestational age (AGA) and large for gestational age (LGA) groups. Horizontal line represents the median and each box the interquartile range (IQL). Symbols represent outliers (cycles) and extreme values (asterisk).

[31,32]. Based on the above and taking into consideration that stress-mediated activation of the HPA axis is implicated in the pathogenesis of insulin resistance [22,33], it is tempting to speculate that chronic stress in the LGA fetus may also contribute to the documented impaired insulin sensitivity at birth [9,10,28]. An adverse fetal/neonatal metabolic profile [34] and longterm LGA outcome are not exclusively related to GDM or obesity [35,36]. Being born LGA to nondiabetic, nonobese mothers is also associated with diverse effects on cardiometabolic risk factors at prepuberty and adulthood [35,36]. In fact, it is noteworthy that history of GDM has been observed in 20– 27% of LGA newborns [34,37], implying that most of the LGA offspring are born to nondiabetic mothers. In accordance, only five out of 30 fetuses in our cohort were born to mothers diagnosed with GDM [23]. Additionally, only 13 out of 30 mothers with LGA offspring presented with overweight/ obesity [24]. Data from numerous recent human studies suggest that AVP, one of the stress hormones, plays an important role in impaired glucose homeostasis and insulin resistance associated disorders [18–20,38–40], although the exact mechanisms have not yet been elucidated. The activation of the HPA axis by AVP in chronic stress has been suggested to be the main mediator of copeptin association with insulin resistance and the metabolic syndrome [18]. However, published data suggest that the contribution of AVP to glucose and lipid metabolism seems to be rather complex [41–44], probably justifying the lack of upregulation of cord blood copeptin concentrations in our cohort comprising LGA infants, expected to be exposed to chronic fetal stress. A positive correlation between cord blood copeptin concentrations and birth-weight was demonstrated in our LGA cohort. Given the lack of association between cord blood copeptin and insulin concentrations in the LGA group, the above correlation seems to be independent of the

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hyperinsulinemia recorded in the study group and probably reflects the documented association between AVP release and increased fat deposition [18–20,45]. Nevertheless, when excluding the effect of GDM, by conducting a subgroup analysis comprising LGA infants born to mothers without GDM and AGA controls, no differences were observed in cord blood insulin or copeptin concentrations. Thus, it may be speculated, that hyperinsulinemia in the macrosomic group is mainly related to GDM. In a previous study comprising preterm infants born after cesarean section without prior labor, estimated fetal weight less than the fifth percentile was associated with significantly elevated cord blood copeptin levels [46]. However, these infants were small for gestational age preterms, who had to be delivered by cesarean section without prior labor. The authors conclude that cord blood copeptin is a highly sensitive marker of fetal distress [46]. In another study comprising healthy infants born at a gestational age 35 weeks or older, plasma copeptin levels at birth were not associated with birth-weight [47]. Nevertheless, this later study does not investigate plasma copeptin concentrations according to fetal growth patterns. The results of this study also indicate a marked increase of cord blood copeptin concentrations in cases of vaginal delivery versus elective cesarean section in full-term nondistressed infants, in accordance with previous reports [16,46,48,49]. The physiological stress of vaginal birth induces a unique surge in cord blood copeptin concentrations [48]. On the other hand, abdominal delivery without preceding contractions has no effect on cord blood copeptin concentrations at birth, unless other stressors are present, such as birth acidosis or asphyxia [16,46]. Thus, it has been postulated that the physiological stress of spontaneous labor induces important changes in the fetal homeostatic system, which serves to prime the fetus for postnatal adaptation, and AVP is implicated in this process, exerting beneficial effects [48]. In addition, no gender-related differences were recorded regarding cord blood copeptin concentrations in our population, in line with experimental data [50]. By contrast, sexual disparity of copeptin at birth has been found in a very recent study, indicating increased activation of the AVP system in newborn boys, as compared with girls [47]. Similarly, adult men consistently show higher copeptin values, as compared with women [20,45,51]. A limitation of this study is the relatively small sample size and, therefore, confirmation by future prospective cohorts is needed. Furthermore, the assumptions for conducting a multivariate regression analysis were not met, and thus, non parametric tests for the analysis of data were used. Nevertheless, a major strength of the study is the strict inclusion criteria applying to a clearly defined population of healthy, non-distressed at birth, macrosomic infants, which allowed to reliably investigate the influence of the LGA status on cord blood copeptin concentrations at birth. In conclusion, cord blood copeptin concentrations may not be up-regulated in non-distressed well-characterized LGA infants, but positively correlate with birth-weight, probably pointing to the documented association between AVP release and increased fat deposition. Vaginal delivery versus elective cesarean section is accompanied by a marked stress-related

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increase of cord blood copeptin concentrations. However, a pathophysiological role of AVP in excessive fetal growth cannot be excluded, and future studies are needed to further elucidate copeptin secretion, metabolism and action during the perinatal period.

Author Contributions Despina D. Briana: Had responsibility for data analysis and principally writing the manuscript. Stavroula Baka: Participated in the development of the protocol, execution of the study and writing the manuscript. Maria Boutsikou: Performed the statistical analysis of the data. Theodora Boutsikou: Had responsibility for patient enrollment. Marieta Xagorari: Contributed to the conduction of the laboratory measurements. Dimitrios Gourgiotis: Participated in the analytical framework of the study and performed laboratory determinations. Ariadne Malamitsi-Puchner: Had primary responsibility for protocol development, patient screening enrollment, outcome assessment and critically reviewing the manuscript.

Funding Financial support: none.

Disclosure Statement Conflicts of interest: none.

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