http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–7 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.951622

ORIGINAL ARTICLE

Maternal and umbilical cord copeptin levels in pregnancies complicated by fetal growth restriction 1 ¨ _ Gu¨l Alkan Bu¨lbu¨l1, Selahattin Kumru2, Onur Erol1, Bekir Sıtkı Isenlik , Ozgu¨r O¨zdemir1, Mete C¸ag˘lar2, Musa Yılmaz3, 4 3 Mehmet Kalaycı , and Su¨leyman Aydın

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1

Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey, 2Department of Obstetrics and Gynecology, Faculty of Medicine, Du¨zce University, Du¨zce, Turkey, 3Department of Medical and Clinical Biochemistry (Fırat Hormones Research Group), Faculty of Medicine, Fırat University, Elazıg˘, Turkey, and 4Department of Medical and Clinical Biochemistry, Elazıg˘ Training and Research Hospital, Elazıg˘, Turkey Abstract

Keywords

Objective: The aim of this study was to compare maternal and fetal serum copeptin concentrations in pregnancies complicated by isolated fetal growth restriction (FGR), and uncomplicated pregnancies, and to investigate relationships between copeptin levels and clinical parameters. Methods: Maternal and fetal serum copeptin levels were measured in 21 women with pregnancies complicated by isolated FGR and 20 women with normal pregnancies (control group). Doppler assessment of the uterine and umbilical arteries was performed in each patient. Results: Maternal serum copeptin levels were significantly higher in women with isolated FGR compared to controls (p ¼ 0.042). In addition, maternal copeptin levels were inversely correlated with the uterine artery pulsatility and resistance indices and positively correlated with neonatal birth weight. Umbilical vein copeptin levels were significantly increased in neonates with adverse outcomes (p ¼ 0.001). Conclusions: Increased maternal copeptin concentration may reflect a response to stress, thus serving as a compensatory mechanism in pregnancies complicated by FGR.

Copeptin, Doppler velocimetry, fetal growth restriction, neonatal outcome, pregnancy

Introduction Fetal growth restriction (FGR) affects 7–10% of all pregnancies and is defined by underachievement of the genetic growth potential of the fetus [1]. FGR is associated with an increased risk of an adverse perinatal outcome and long-term fetal programming towards risks of developing cardiovascular disease, metabolic syndrome and neurological deficits [2]. FGR may be a consequence of several detrimental factors including aneuploidies, non-aneuploid syndromes, metabolic factors, maternal infection, poor nutrition before and during pregnancy, drug abuse, hypertension and placental disorders. Although the above risk factors have been identified, in vast majority of cases (40%), the cause still remains idiopathic [3]. Reduced placental perfusion and abnormal placentation play important roles in the onset and progression of FGR [4]. Abnormalities in uteroplacental perfusion are characterized

Address for correspondence: Onur Erol, MD, Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Muratpa¸sa, Antalya. Tel. (mobile): + 90 (532) 2524825. E-mail: dronurerol@ hotmail.com

History Received 28 March 2014 Revised 20 June 2014 Accepted 01 August 2014 Published online 18 August 2014

by selective changes in peripheral vascular resistance. Uterine artery Doppler evaluation depicts maternal vascular effects, as poor placentation results in impaired remodeling of the uterine spiral arteries resulting in an increase in peripheral resistance. Fetal well being can also be estimated by examining the fetal and fetoplacental vessels, which are known to change in a characteristic manner during pregancy [5]. A combination of fetal biometry, amniotic fluid volume assessment, fetal heart rate pattern analysis, arterial and venous Doppler velocimetry and analysis of biophysical variables allows comprehensive fetal evaluation in FGR to minimize the risk of stillbirth and perinatal morbidity [6]. It is generally accepted that FGR is associated with reductions in the supply of oxygen (O2) and nutrients across the placenta. Chronic malnutrition and hypoxia alter fetal cardiovascular dynamics and endocrine status, and, also several metabolic abnormalities have been reported in pregnancies complicated by FGR [7]. The failure of the placenta to meet fetal demands for oxygen and nutrients triggers stress-mediated fetal compensatory responses, including activation of the hypothalamic–pituitary–adrenal (HPA) axis [8]. A principal hypothalamic stress hormone is arginine vasopressin (AVP). AVP not only has hemodynamic and

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G. A. Bu¨lbu¨l et al.

osmoregulatory effects but also plays a crucial role in the endocrine stress response to a variety of conditions, including hemorrhagic and septic shock with reflecting individual stress level [9]. Plasma AVP is unstable due to its short biological half-life (24 min) and rapidly cleared from the plasma, rendering reliable measurements difficult. Copeptin, the stable C-terminal region of the AVP precursor molecule, is cleaved from pro-AVP during processing and is secreted in an equimolar concentration with AVP, but its main role in the circulation is still unknown. Copeptin is relatively stable in serum and thereby serves as a reliable surrogate of the vasopressin level; therefore, it is a surrogate marker for vasopressin release and might act as a marker for stress response [10]. To date, no study has investigated maternal and fetal copeptin levels in pregnancies complicated by FGR [11]. Therefore, we aimed to investigate copeptin concentrations in the maternal, placental and fetal compartments and compared those levels in normal pregnancies and those complicated by isolated FGR. In addition, correlations between copeptin levels and demographic characteristics, Doppler parameters and neonatal outcomes were assessed. We speculate that activation of the HPA axis by AVP (copeptin) as a consequence of placental ischemia/hypoxia-induced stressful condition in FGR may be one of the mediators of its association with FGR.

Methods This case–control study was conducted at the Antalya Training and Research Hospital, Antalya, Turkey, between January 2012 and December 2012. Eligible participants were recruited from delivery service of our institution. The Ethics Committee of the institution approved the study (approval no: 2012-038), and all patients who agreed to participate signed informed consent forms. In the study period, 30 pregnant women with isolated FGR were admitted to our department. We finally included 21 women with pregnancies complicated by isolated FGR beyond 34 weeks of gestation; these pregnant women had no sign of pre-existing or pregnancy-induced hypertension or pre-eclampsia. No other risk factor associated with FGR was obvious. The control group consisted of 20 healthy normotensive pregnant women with fetuses appropriate-forgestational-age (AGA). We included only AGA infants delivered after 34 weeks to ensure matching with the FGR group. All participants were admitted to the hospital for delivery. Exclusion criteria were a pregnancy exhibiting fetal chromosomal aberration or malformation; a multiple pregnancy; the taking of medication or smoking during pregnancy; and the presence of any concurrent medical disease (such as essential hypertension, diabetes mellitus, a vascular or inflammatory disease or renal failure) known to affect the parameters under investigation. In addition, to avoid a possible hypoxic effect of labour on copeptin levels, we selected only women who were delivered by elective cesarean section, thus in the absence of labour or premature rupture of membranes. The indication for elective cesarean section in all patients of the control group was a previous cesarean section; in the FGR group, the indications were non-reassuring fetal

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testing in 14 patients and previous caesarean sections in 7 patients. Caesarean section was performed in a standardized way for all participants under general anesthesia. Prior to anesthesia, subjects were oxygenated for 3–5 min with 100% O2. Induction of anesthesia was performed using 5–7 mg/kg thiopental intravenous (i.v.) and 0.6 mg/kg rocuronium i.v. as a muscle relaxant. Oral intubation was achieved using a no. 7.5 endotracheal tube. Anesthesia was administered with 1 minimum alveolar concentration sevoflurane in 50% O2/air. After delivery, 2 lg/kg fentanyl was administered intravenously, and sevoflurane was continued in O2–N2O mixture (1:1). Anesthesia was discontinued at the end of surgery, and extubation was performed with the patient awake and cooperative. Surgery duration was defined as the time elapsed between the skin incision and skin closure. Birth weight was measured immediately after delivery and neonatal assesstment was performed by an experienced neonatologist in order to rule out any fetal malformation or aneuploidy that may accompany FGR. Gestational age was determined by the date of the last menstrual period and confirmed by ultrasonographic examination performed during the first trimester. Body mass index (BMI) values were calculated using the following formula: weight (kg)/height (m2). FGR was defined as an estimated fetal weight below the 10th percentile, using the formula of Hadlock et al., and was confirmed postnatally [12]. AGA was defined as an estimated fetal weight within the 10–90th percentiles of a standard growth cure. Birth-weight centiles were defined using gender-specific national standard growth curves [13]. Adverse neonatal outcome was defined as admission to the neonatal intensive care unit (NICU) for indications such as hypoglycaemia, hypocalcaemia, respiratory distress syndrome (RDS), intraventricular hemorrhage, a need for total parenteral nutrition, necrotizing enterocolitis, sepsis, disseminated intravascular coagulation or generalized hypotonia. All patients underwent Doppler examination at admission for delivery. Doppler examinations were performed using a 2–7-MHz transabdominal transducer (Logic5 Pro; GE Medical Systems, Milwaukee, WI) in the lateral decubitus position to avoid supine hypotension. Doppler measurements were performed in the absence of fetal movements and during voluntarily suspension of maternal breathing. Spectral Doppler parameters were determined automatically from three or more consecutive waveforms, holding the angle of insonation as close to 0  as possible. Umbilical artery Doppler velocimetry was performed on a free loop of the umbilical cord located distant from the points of fetal and placental insertions. Both uterine arteries were assessed at the level at which they crossed the external iliac arteries. The mean values of parameters derived from both uterine arteries were calculated and used in statistical analyses. The presence of bilateral notching in the Doppler waveform of the uterine artery and an absent or reversed diastolic flow evident in the umbilical artery waveform were also recorded. Maternal venous blood samples were collected from a forearm vein prior to cesarean section. Fetal blood samples were taken separately from the umbilical artery and vein immediately after delivery of the placenta. Blood samples were placed into sterile EDTA-containing test tubes and

Maternal and fetal copeptin level

DOI: 10.3109/14767058.2014.951622

centrifuged at 3000 rpm for 15 min. Serum was aliquoted and stored at 80  C prior to analysis. Copeptin levels were measured in all three compartments [maternal, placental (umbilical vein) and fetal (umbilical artery)] using a competitive enzyme immunoassay kit (Phoenix Pharmaceuticals, Belmont, CA; Catalog # EK-065-32; the Copeptin-Human EIA Kit), according to the manufacturer’s instructions. The assay sensitivity was 0.12 ng/mL. The intra- and inter-assay coefficients of variation were 510% and 515%, respectively. All absorbances were measured using an ELX 800 ELISA reader (BioTek Instruments Inc., Winooski, VT) located at the Department of Medical Biochemistry, Firat University. All measurements are expressed as ng/mL.

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Statistical analysis All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL) software, version 18.0. Data distribution was assessed by the Kolmogorov–Smirnov test. Categorical variables are presented as percentages, and continuous variables as mean ± standard deviations if normally distributed, or as median (minimum-maximum) if not. The statistical significance of any intergroup difference was assessed using Fisher’s exact test for categorical variables, and Student’s t-test or the Mann–Whitney U-test for continuous variables. Correlations between copeptin levels and other variables were evaluated by using Spearman’s rank test. A receiver operating characteristic (ROC) curve was constructed to define the copeptin threshold level predicting adverse neonatal outcomes. All of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and odds ratio (OR) were calculated based on cut-off points obtained by the ROC curve. A two-sided p50.05 was considered statistically significant.

Results The baseline characteristics of all study patients are listed in Table 1. Mean maternal age and BMI were similar in both groups. Gravida and parity were significantly higher in the control group (p ¼ 0.038 and p ¼ 0.041, respectively). The Doppler parameters of pulsatility indices (PIs) and resistance indices (RIs) of the umbilical and uterine arteries were significantly higher in the FGR group than in healthy controls (p ¼ 0.007 and p50.001 for PIs, p ¼ 0.001 and p ¼ 0.002 for RIs, respectively). In FGR group, bilateral uterine notch was found in four women, whereas in the control group, notch was detected in any of the women.Gestational age at delivery, birth weight, birth weight percentile and the 5-min APGAR score were significantly lower in the FGR group (p50.001, p50.001, p50.001 and p ¼ 0.01, respectively). The mean duration of the surgery was 37.7 ± 3.2 min in the control group and 38.4 ± 3.4 min in the FGR group (p ¼ 0.47). In the control group, no neonate required NICU admission, whereas in the FGR group, adverse neonatal outcomes were noted in six neonates. Of these, RDS was established in five infants because of a requirement for respiratory support for more than 24 h, and one infant required total parenteral nutrition. The mean duration of NICU stay was 2.6 ± 4.7 d. No neonatal death occurred.

Table 1. Demographic, Doppler velocimetry characteristics of the study population.

Variables Maternal Age (years) Gravida Parity BMI (kg/m2) Doppler parameters Umbilical artery PI Umbilical artery RI Uterine artery PI Uterine artery RI Neonatal Gestational age at delivery (weeks) Birth weight (g) Birth weight percentile 5 min APGAR score Adverse neonatal outcome

3

and

neonatal

Control group (n ¼ 20)

FGR group (n ¼ 21)

p value

28.7 ± 5.6 2 (1–5) 1 (0–4) 29.9 ± 3.5

27.1 ± 5.1 1(1–5) 0 (0–4) 28.2 ± 3.9

0.381 0.038 0.041 0.14

0.68 ± 0.16 0.51 ± 0.14 0.62 ± 0.21 0.41 ± 0.1

1 ± 0.49 0.007 0.68 ± 0.23 0.001 1 ± 0.37 50.001 0.55 ± 0.13 0.002

39.2 ± 0.8

37.5 ± 1.5

50.001

3515 ± 363 69 ± 23 9 (9–9) –

2192 ± 297 2±3 9 (7–9) 6 (28.6)

50.001 50.001 0.01 0.02

Values are given as mean ± SD, median (range) or number (percentage) as indicated. FGR, fetal growth restriction; BMI, body mass index; PI, pulsatility index; and RI, resistance index.

Table 2. Comparison of maternal and umbilical cord copeptin levels in control subjects and FGR group. Copeptin (ng/ml)

Control group (n ¼ 20)

FGR group (n ¼ 21)

p value

Maternal UA UV

0.26 ± 0.17 0.27 ± 0.12 0.32 ± 0.14

0.36 ± 0.18 0.33 ± 0.27 0.33 ± 0.19

0.042 0.999 0.979

Values are given as mean ± SD. FGR, fetal growth restriction; UA, umbilical artery; and UV, umbilical vein.

Table 2 shows the comparison of copeptin levels between the compartments of each group. Maternal serum copeptin levels were significantly higher in the FGR group than in controls (p ¼ 0.042). Although the copeptin levels of the umbilical artery and vein were somewhat higher in the FGR than the control group, the differences were not significant (p ¼ 0.999 and p ¼ 0.979, respectively). As shown in Table 3, neonates with adverse outcomes had significantly higher umbilical vein copeptin levels compared to those with no adverse outcomes (p ¼ 0.001), whereas the maternal and umbilical artery copeptin levels did not differ significantly between the two groups (p ¼ 0.697 and p ¼ 0.062, respectively). Using the ROC curve, a threshold value (umbilical vein copeptin level) for adverse neonatal outcome was calculated. A value of 0.322 ng/mL was associated with a sensitivity of 100%, a specificity of 86.7%, a PPV of 75% and an NPV of 100% (Figure 1). Neonates with umbilical vein copeptin levels 40.322 ng/mL were more likely to have an adverse outcome (OR ¼ 4; 95% CI ¼ 1.205–13.283). Neonates with non-reassuring fetal heart rate pattern had significantly higher umbilical artery copeptin level than those born by elective repeat cesarean delivery in the FGR group (1.74 ± 0.23 ng/mL versus 0.31 ± 018 ng/mL, p ¼ 0.038).

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Table 4 summarizes correlations of copeptin levels in maternal or fetal serum with Doppler index values. Few correlations were evident. Significant inverse correlations between maternal copeptin level, on the one hand, and uterine artery PI (Figure 2A) and uterine artery RI (Figure 2B), on the other, were apparent. No significant correlation was found between maternal copeptin level and any of maternal age (r ¼ 0.103, p ¼ 0.521), BMI (r ¼ 0.182, p ¼ 0.254), gestational age at delivery (r ¼ 0.288, p ¼ 0.068), umbilical artery copeptin level (r ¼ 0.016, p ¼ 0.921) or umbilical vein copeptin level (r ¼ 0.050, p ¼ 0.756). However, the maternal copeptin level showed a significant positive correlation with neonatal birth weight (Figure 2C).

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Discussion We found that maternal copeptin levels were significantly higher in pregnancies complicated by FGR than in healthy controls. Our results indicate the significance of copeptin as a Table 3. Maternal and umbilical cord serum copeptin levels in neonates with adverse outcomes in FGR group. Copeptin (ng/ml)

Adverse neonatal outcome (n ¼ 6)

No adverse neonatal outcome (n ¼ 15)

p value

Maternal UA UV

0.25 ± 0.1 0.49 ± 0.39 0.55 ± 0.15

0.27 ± 0.2 0.26 ± 0.19 0.25 ± 0.13

0.697 0.062 0.001

Values are given as mean ± SD. UA, umbilical artery and UV, umbilical vein.

marker of the stress response. To our knowledge, this is the first study to investigate maternal and fetal levels of copeptin in pregnancies complicated by FGR. Placental ischemia/hypoxia-induced oxidative stress in FGR is thought to cause release of factors into the maternal and fetal circulations that, in turn, trigger pathophysiological changes and an endocrine response [14,15]. AVP-mediated activation of the HPA axis plays a role in maternal and fetal adaptations to such stressful conditions. Increased maternal copeptin concentration as a consequence of FGR may reflect a response to stress, thus the mother may be aware that she is carrying a small-for-gestational-age fetus. In such stressful situations, expression of AVP and corticotropin-releasing hormone triggers production of adrenocorticotropic hormone and cortisol, both well-known markers of the humoral stress response. AVP activates chromaffin cells in the adrenal medulla to increase epinephrine synthesis, subsequently contributing to hyperglycemia by stimulating glycogenolysis in the liver [16]. Cortisol impedes the action of insulin in promoting glucose uptake by cells, stimulating glucagon secretion and glycogenolysis, ultimately elevating plasma glucose levels. The combined effect of such perturbations may be a need to maintain a higher maternal–fetal glucose gradient to ensure adequate fetal glucose metabolism under chronically stressed conditions; the process may be adaptive in nature [17]. Likewise, an increase in the level of cortisol transfer to the fetus has long been suggested to be a potential pathogenic pathway triggering FGR [18]. Serum cortisol is proportional to stress levels, and by reflecting stress levels, cortisol predicts prognostic outcome

Figure 1. Receiver-operating characteristics (ROC) curve for umbilical vein copeptin level in predicting adverse neonatal outcome (area under the curve ¼ 0.956, p ¼ 0.001).

Table 4. Correlation of Doppler parameters with copeptin levels (Spearman’s rank test). Copeptin levels

Umbilical artery PI

Umbilical artery RI

Uterine artery PI

Uterine artery RI

Maternal Umbilical artery Umbilical ven

r ¼ 0.131, p ¼ 0.413 r ¼ 0.009, p ¼ 0.956 r ¼ 0.230, p ¼ 0.148

r ¼ 0.219, p ¼ 0.169 r ¼ 0.107, p ¼ 0.504 r ¼ 0.107, p ¼ 0.505

r ¼ 0.372, p ¼ 0.017* r ¼ 0.099, p ¼ 0.537 r ¼ 0.132, p ¼ 0.411

r ¼ 0.335, p ¼ 0.032* r ¼ 0.092, p ¼ 0.568 r ¼ 0.127, p ¼ 0.428

PI, pulsatility index and RI, resistance index. *Statistically significant.

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DOI: 10.3109/14767058.2014.951622

(A) 2.5

(B) 1.4

p=0.017 r=−0.372

Uterine artery RI

Uterine artery PI

p=0.032 r=−0.335

1.2

2 1.5 1 0.5

1 0.8 0.6 0.4 0.2 0

0 0

0.2

0.4

0.6

0.8

1

0

0.2

(C) 1

0.6

0.8

1

p=0.026 r=0.349

0.9 Maternal copeptin level

0.4

Maternal copepn levels

Maternal copepn levels

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5

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

1000

2000

3000

4000

5000

Neonatal birth weight (gr)

Figure 2. Correlation of maternal copeptin levels with uterine artery pulsatility index (PI), uterine artery resistance index (RI) and neonatal birth weight: (A) negative correlation of uterine artery PI (r ¼ 0.372, p ¼ 0.017); (B) negative correlation of uterine artery RI (r ¼ 0.335, p ¼ 0.032); and (C) positive correlation of neonatal birth weight (r ¼ 0.349, p ¼ 0.026).

in different diseases. However, cortisol is influenced by strong circadian rhythm and its measurement as a free hormone is demanding. These characteristics of cortisol place copeptin as a more reliable hormone for determination of stress levels [19]. In recent years, copeptin has been proposed to serve as a diagnostic and prognostic marker in those with various illnesses and disorders. Copeptin has been evaluated as a diagnostic marker in patients with diabetes insipidus [20]. The prognostic accuracy of copeptin levels has been analysed in patients with sepsis, pneumonia, lower respiratory tract infections, hemorrhagic or ischemic stroke and myocardial infarction [21–24]. Copeptin levels were found to accurately reflect disease severity and to discriminate patients with unfavorable outcomes from those with favorable outcomes [25]. Furthermore, increased copeptin levels have been associated with insulin resistance and metabolic syndrome [26]. So far, few studies have investigated the relationship between pregnancy and copeptin. In the literature, no information is available on serum copeptin concentration changes throughout pregnancy. In addition, exact mechanisms regulating copeptin secretion during pregnancy have not been fully elucidated. A recent study found that serum copeptin levels did not differ in women with gestational diabetes mellitus compared to healthy controls [27]. Another study described markedly increased serum copeptin levels in patients diagnosed with pre-eclampsia compared to women with normal ongoing pregnancies of similar gestational ages. In addition, the serum copeptin level was correlated with the severity of disease [28]. Burkhardt et al. found that umbilical

cord plasma copeptin levels were markedly increased in pregnancies complicated by FGR, compared to healthy controls [29]. Our results did not corroborate this finding. The discrepancy may be explained by differences in the gestational ages of the two FGR populations and the criteria used to define FGR. In the cited work, the mean gestational age was 34.3 weeks, thus less than in our study, and FGR was defined by an estimated fetal weight below the fifth percentile, in combination with increased umbilical artery RI. The vasopressin-copeptin system of the neonate is strongly activated upon induction of perinatal stress in all of very preterm, late preterm and term infants, suggesting that the vasopressin-copeptin system is already functional at an early gestational age [30]. Foda et al. showed that neonates born by vaginal delivery had elevated copeptin cord serum levels, compared to those born by elective repeat cesarean delivery, associated with the stress of vaginal delivery [31]. Schlapbach et al. reported that copeptin cord blood concentrations were strongly associated with factors linked to perinatal stress, such as birth acidosis and asphyxia [32]. These findings are in line with those of our study; we found that umbilical vein copeptin levels were higher in neonates with adverse outcomes. Currently, Doppler velocimetry is used in the obstetric field as a non-invasive method for evaluating uterofetoplacental circulation. However, Doppler velocimetry of the fetal vessels, which has been used successfully to reduce the risk of perinatal morbidity in FGR, loses its predictive ability when approaching term. In this study, a significant inverse correlation between maternal copeptin levels and uterine artery indices indicate that copeptin may influence the

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function of endothelial cells. Indeed, AVP leads to vasodilatation under hypoxic conditions through AVP receptormediated endothelial release of nitric oxide [33]. Since copeptin reflects AVP concentration, the association of maternal copeptin level with neonatal birth weight may be secondary to increased hepatic gluconeogenesis and glycogenolysis due to glucocorticoids, glucagon and epinephrine released under stress (all of which are regulated by AVP). Elevation of AVP leads to increase in abdominal fat deposition [34]. Increased maternal copeptin serum concentrations favor a state of insulin resistance, which enhances the availabilty of glucose to the fetus. Another interesting finding was no correlation between maternal and umbilical cord (both artery and vein) copeptin levels. This may explain by the fact that both mother and fetus respond stress condition independently in FGR. Chronic endogenous stress induces important changes in the fetal homeostatic system, which serve to prime the fetus for postnatal adaptation. Although higher umbilical artery copeptin level was observed in the FGR than the control group, the difference was not statistically significant. This finding suggests that, in these cases, higher copeptin concentration in umbilical artery reflects a stress response to prevent neonatal hypoglycemia at birth by facilitating hepatic glucose production. It is interesting to note that increased umbilical vein copeptin levels were associated with adverse neonatal outcomes in the FGR group. A possible explanation for this might relate to lower gestational age at delivery or FGR. The influence of placenta on maternal and fetal copeptin concentrations remains unknown. As the maternal and umbilical vein copeptin levels vary in FGR and control groups, this observation leads to our hypotesis that measured copeptin levels in umbilical vein are of placental orgin. Of note, in the FGR group, umbilical vein copeptin level was lower than the maternal compartment. Diminished placental mass and reduction of placental function in FGR might contribute to this finding. As we did not investigate the placental copeptin expression, these apparently unknown features will require further investigation to clarify. Several limitations of our study should be noted. Our study results must be interpreted with caution as this is an exploratory study with inherent limitations owing to the small sample size. Another limitation is the difference in gestational age at delivery between the two groups. Our study design did not allow us to include, in the control group, women who had been delivered (by elective cesearean section) of neonates similar in gestational age to those of women whose pregnancies were complicated by FGR. In our opinion, the difference in gestational age between the two groups was negligible, as we did not find any significant correlation between maternal copeptin levels and gestational age. In conclusion, our results add to the body of literature on the possible association of copeptin levels with FGR. It is difficult to infer whether high copeptin level, as a consequence of activation of the HPV axis, is a cause or effect of FGR. Further research is needed in order to confirm the role of copeptin as a novel marker in the pathophysiology of FGR.

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Declaration of interest The authors have no conflicts of interest.

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DOI: 10.3109/14767058.2014.951622

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Maternal and umbilical cord copeptin levels in pregnancies complicated by fetal growth restriction.

Abstract Objective: The aim of this study was to compare maternal and fetal serum copeptin concentrations in pregnancies complicated by isolated fetal...
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