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Objective: To prospectively evaluate maternal and cord blood concentrations of sclerostin - an osteocyte-secreted factor, inhibiting osteoblast differentiation and bone formation and associated with adverse metabolism - in pregnancies with normal and abnormal fetal growth., Methods: Plasma sclerostin concentrations were determined by ELISA in 80 maternal and 80 cord blood samples from asymmetric intrauterine-growth-restricted (IUGR, n = 30), large-for-gestational-age (LGA, n = 30), and appropriate-for-gestational-age (AGA, n = 20) singleton full-term pregnancies. Fourteen out of 30 mothers with LGA offspring presented with gestational diabetes mellitus (GDM)., Results: Maternal and fetal sclerostin concentrations did not differ among LGA, IUGR, and AGA groups. Fetal concentrations were higher than maternal. In LGA group, maternal concentrations were elevated in cases of GDM (b = 13.009, 95%CI 1.425-24.593, p = .029). In a combined group and the IUGR group, maternal concentrations were elevated in older mothers (b = 0.788, 95%CI 0.190-1.385, p = .010, and b = 0.740, 95%CI 0.042-1.438, p = .039, respectively)., Conclusions: Maternal and fetal sclerostin concentrations may not be differentially regulated in pregnancies complicated by abnormal fetal growth. Circulating maternal levels are higher in cases of GDM, probably implying reduced bone formation. Sclerostin up-regulation with aging may be one of the molecular pathways responsible for the observed age-related decline in bone synthesis, leading to accelerated bone loss in humans.

Objective: Gestational diabetes mellitus (GDM) may induce fetal macrosomia or growth restriction and is associated with later offspring neurodevelopmental disorders. We aimed to determine whether neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-4 (NT-4) are differentially expressed in cord blood samples at birth in large-for-gestational-age (LGA), intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) offspring of diabetic mothers, as compared to AGA controls from non-diabetic mothers., Methods: BDNF, NGF and NT-4 concentrations were prospectively determined in 80 cord blood samples from LGA (n = 15), IUGR (n = 12) and AGA (n = 33) diabetic, as well as from AGA normal (controls, n = 20) singleton full-term pregnancies., Results: Fetal BDNF concentrations considerably decreased in GDM, as compared with normal pregnancies [(b = -2.836, 95%CI -5.067 to (-0.604), p = 0.013)] and were higher in females (b = 2.298, 95%CI 0.357-4.238, p = 0.021). Cord blood NGF concentrations were lower in IUGR than AGA infants (p = 0.038)., Conclusions: BDNF is down-regulated in the fetus exposed to GDM, independently of the fetal growth pattern, probably representing a candidate mechanism underlying the association between maternal diabetes and later psychopathology. IUGR fetuses born to diabetic mothers present with NGF deficiency, which may contribute to their long-term neurodevelopmental sequelae. Gender-dependent differences in fetal BDNF may partly explain the higher prevalence of adverse neurodevelopmental outcomes following brain insults in male infants.

Objective: Intrauterine-growth-restriction-(IUGR) is associated with chronic fetal stress, as well as a phase of enhanced fetal/early postnatal insulin sensitivity, followed by a later emergence of insulin resistance. We aimed to prospectively investigate concentrations of copeptin, a sensitive marker of stress and insulin resistance, in IUGR versus appropriate-for-gestational-age-(AGA) fetuses., Methods: Cord blood copeptin concentrations were determined by ELISA in well-defined, non-distressed at birth, asymmetric IUGR (n = 30) and AGA (n = 20) full-term pregnancies. Doppler studies were indicative of placental insufficiency., Results: Cord blood copeptin concentrations were similar in IUGR cases and AGA controls, after controlling for delivery mode. Copeptin concentrations were markedly elevated in vaginally delivered fetuses (p = 0.001). No association was recorded between fetal copeptin concentrations and maternal age, parity, gestational age, or fetal gender., Conclusions: Cord blood copeptin concentrations are probably not affected by IUGR at term, in the absence of fetal distress, possibly due to a balance between copeptin up-regulation by chronic fetal stress, on one hand, and copeptin down-regulation in the presence of increased insulin sensitivity, on the other hand; thus, copeptin may not be a sensitive marker of chronic perinatal stress in healthy asymmetric IUGR infants. Cord blood copeptin seems to primarily reflect perinatal stress associated with delivery mode.

Objective: To prospectively investigate maternal concentrations of the myokine irisin in large for gestational age (LGA) and intrauterine growth restricted (IUGR) versus appropriate for gestational age (AGA) normal pregnancies and associate them with various perinatal parameters., Methods: Plasma irisin and insulin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assay (IRMA), respectively, in a cohort of 80 mothers delivering LGA (n = 30), IUGR (n = 30) and AGA (n = 20) singleton full-term infants., Results: Maternal irisin concentrations were similar among LGA, IUGR and AGA groups and did not correlate with respective insulin ones or maternal body mass index. In a combined group, maternal irisin concentrations decreased with advancing gestational age (p < 0.001) and were lower in multi-, compared to nulliparous women (p = 0.004). In the IUGR group, maternal irisin concentrations were higher in cases of smoking (p = 0.006)., Conclusions: Irisin may not be differentially regulated in insulin resistance-associated pregnancy disorders resulting in fetal macrosomia and IUGR. Maternal irisin down-regulation with advancing gestation could possibly contribute to the observed maternal fat accumulation and progressive insulin resistance towards term. Similarly, lower maternal irisin concentrations in multiparous women may reflect the documented positive association between parity and fat deposition. Irisin up-regulation in cases of smoking may indicate the need for enhanced oxygen consumption to maintain energy production under conditions of hypoxia.

Objective: To determine levels of adropin (implicated in insulin resistance and endothelial dysfunction) in intrauterine growth restricted (IUGR), large (LGA) and appropriate for gestational age (AGA) pregnancies., Methods: Cord-blood (UC) adropin and insulin concentrations were measured in 30 IUGR, 30 LGA and 20 AGA full-term infants and their mothers (MS)., Results: No significant differences in adropin concentrations were observed between the three groups. In the IUGR group MS adropin was significantly decreased when neonates had higher birth weights [b = -0.003, 95% CI -0.006 to 0.0, p = 0.043]. In all groups, MS adropin levels were positively correlated with UC ones (r = 0.282, p = 0.011) and were significantly increased in female neonates [b = 0.977, 95% CI 0.122-1.832, p = 0.026]. In the LGA group, MS insulin was negatively correlated with UC adropin (r =  -0.362 p = 0.049)., Conclusions: Increased maternal adropin levels in severe IUGR cases might represent a regulatory feedback mechanism against endothelial placental dysfunction. The positive correlation between maternal and umbilical cord adropin levels implies its transplacental transfer. Increased maternal adropin levels in female neonates could be attributed to interaction of adropin with fetal estrogens through vascular endothelial growth factor (VEGF). The negative correlation between maternal insulin and fetal adropin levels in the LGA group is probably attributed to their respective insulin resistance.

Objective: To determine levels of galectins (gal)-1 and -3 (implicated in angiogenesis/immunologic mechanisms) in intrauterine growth restricted (IUGR), large (LGA) and appropriate for gestational age (AGA) pregnancies, as these groups differ in fat mass, angiogenic patterns and immune responses., Methods: Cord-blood (UC) gal-1 and -3 concentrations were measured in 30 IUGR, 30 LGA and 20 AGA singleton full-term infants and their mothers (MS)., Results: IUGR, LGA and AGA groups did not differ in gal-1 and -3 concentrations. UC gal-1 levels were lower when mothers were older [b=-0.651, CI 95% -1.186 (-0.116), P=0.018] and UC gal-3 levels were increased when mothers presented gestational diabetes [b=9.836, CI 95% 3.833- (15.839), P=0.002]. In IUGRs MS gal-3 and in LGAs UC gal-1 were decreased in multiparas [b=-5.372, CI 95% -9.584- (-1.161), P=0.014], and [b=-7.540, CI 95% -14.606- (-0.473), P=0.037], respectively. No correlations were found between MS or UC gal-1 and gal-3 concentrations., Conclusions: Lower UC gal-1 levels, when mothers were older, and increased UC gal-3 levels in cases of gestational diabetes, possibly reflect angiogenic activity. In multiparas, decreased MS gal-3 and UC gal-1 levels in IUGR/LGA, respectively, might imply inflammatory response against immunosuppression expected in subsequent pregnancies, as compared to the first one.

Objective: To determine levels of the possible angioregulatory molecules netrin-1 and -4, in intrauterine-growth-restricted (IUGR), large for gestational age (LGA) (both groups characterized by altered angiogenic mechanisms) and appropriate-for-gestational-age (AGA) pregnancies., Methods: Cord blood (UC) netrin-1 and -4 concentrations were measured in 30 IUGR, 30 LGA and 20 AGA infants and their mothers (MS)., Results: Netrin-1 and -4 concentrations did not differ in all groups. UC netrin-4 increased with gestational age (b = 0.075, 95% CI 0.029-0.121, p = 0.002). In the IUGR group, MS netrin-4 decreased as birth-weight centiles increased [b = -0.058, 95% CI -0.112 to -0.004, p = 0.036]. In the LGA group, MS netrin-1 decreased with advanced gestational age [b = -0.063, 95% CI -0.105 to -0.022, p = 0.004]. In all cases, MS netrin-1 positively correlated with MS netrin-4 (r = 0.299, p = 0.007), while UC netrin-1 negatively correlated with UC netrin-4 (r = -0.239, p = 0.033)., Conclusions: Increased UC netrin-4 levels with advancing gestational age may reflect its effect on fetal development. Decreased maternal netrin-1 levels in the LGA group possibly represent a negative feedback mechanism against increased angiogenesis. Increased maternal netrin-4 levels in IUGR neonates may reflect in utero hypoxia, while the negative correlations between fetal netrin-1 and -4 levels may exert the dynamic balance between their angio- and anti-angiogenic properties.

Objective: To prospectively investigate the potential associations of the novel adipocytokines resistin, apelin and visfatin (recently implicated in bone metabolism) with bone biomarkers in fetal and neonatal blood from intra uterine growth restricted (IUGR, associated with low bone mass at birth) and appropriate for gestational age (AGA) pregnancies., Methods: Circulating concentrations of resistin, apelin and visfatin were correlated with concentrations of markers of bone formation [osteocalcin (OC), bone-specific alkaline phosphatase (BALP)] and resorption [osteoprotegerin (OPG), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and cross-linked N-telopeptide of type I collagen (NTx)] in 20 IUGR and 20 AGA full-term fetuses and neonates on postnatal day 1-(N1) and 4-(N4)., Results: In the AGA group, fetal resistin and N1 visfatin concentrations negatively correlated with respective NTx ones (r ≥ -0.472, p ≤ 0.036 in both cases). In the IUGR group, fetal and N4 resistin concentrations negatively correlated with sRANKL concentrations (r ≥ -0.583, p ≤ 0.007 in both cases). Furthermore, fetal apelin and visfatin concentrations positively correlated with fetal BALP ones (r ≥ 0.471, p ≤ 0.042, in both cases)., Conclusions: All three adipocytokines may exert a positive effect on fetal/neonatal bone metabolism, either by inhibiting bone resorption or promoting bone formation in both normal and IUGR pregnancies. Although the mechanisms behind these correlations are unclear, a modulation of perinatal bone metabolism by these adipocytokines may be suggested.

Objectives: To prospectively investigate iron homeostasis in full-term intrauterine growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) infants at birth, by evaluating cord blood concentrations of hepcidin (a bioactive molecule, principal regulator of iron metabolism, downregulated by hypoxia/iron deficiency and upregulated by inflammation), erythropoietin (EPO, a marker of prolonged fetal hypoxia), soluble transferrin receptor (sTfR, a marker of increased erythropoiesis and tissue iron deficiency), iron, ferritin, and unsaturated iron-binding capacity (UIBC)., Methods: Serum cord blood samples from 47 well-defined IUGR and 104 AGA singleton, full-term infants were analyzed for concentrations of all the aforementioned parameters by enzyme immunoassays and spectrophotometry., Results: Hepcidin concentrations were similar, while EPO concentrations were higher in IUGR cases than in AGA controls (P = 0.047). Cord blood sTfR concentrations were increased in IUGR, compared to AGA infants (P = 0.004), and negatively correlated with their customized centiles and birth weight (r = -0.238, P = 0.003 and r = -0.157, P = 0.050, respectively). Ferritin concentrations were lower in IUGR cases than in AGA controls (P = 0.039). In both groups, no correlations were observed between cord blood hepcidin concentrations and iron status indices., Conclusions: Cord blood hepcidin concentrations in term IUGRs may remain unaffected, possibly due to a balance between hepcidin downregulation by chronic fetal hypoxia (indicated by higher EPO concentrations) and impaired iron metabolism (indicated by lower ferritin and higher sTfR concentrations) on the one hand, and hepcidin upregulation by the inflammatory state characterizing IUGRs, on the other. Furthermore, our findings may possibly indicate the need for regular follow-up for detection of iron-deficient anemia, not only in preterm but also in full-term IUGR neonates., (© 2012 John Wiley & Sons A/S.)

Objective: To prospectively investigate cord blood concentrations of intestinal fatty acid-binding protein-[I-FABP, a useful marker in the early detection of necrotizing enterocolitis-(NEC)] in full-term intrauterine-growth-restricted-(IUGR, associated with NEC, regardless of gestational age) and appropriate-for-gestational-age-(AGA) pregnancies. We also aimed to determine cord blood I-FABP concentrations in IUGR cases with abnormal versus normal antenatal Doppler results and investigate a possible association with feeding intolerance or NEC., Methods: I-FABP concentrations were determined by ELISA in 154 mixed arteriovenous cord blood samples from IUGR (n = 50) and AGA (n = 104) singleton full-term infants., Results: Cord blood I-FABP concentrations did not differ between IUGR and AGA groups, as well as between IUGR infants with normal versus abnormal(however, lacking absent/ reversed end-diastolic umbilical artery flow) antenatal Doppler results. No infant presented with feeding intolerance or NEC. Customized centiles were lower in IUGR infants with abnormal versus normal antenatal Doppler results (p < 0.001)., Conclusions: Full-term IUGR infants present with normal cord blood I-FABP concentrations and do not seem to be at higher risk for developing feeding intolerance or NEC, including those with compromised fetal perfusion.

Transforming growth factor-α (TGF-α) and TGF-β1 are major anti-inflammatory cytokines and substantially contribute to normal pregnancy outcome. TGF-α stimulates placental mitosis, whereas TGF-β1 is a critical regulator of trophoblast invasion and fetal growth. We aimed to study cord blood TGF-α and TGF-β1 concentrations in intrauterine-growth-restricted (IUGR, usually associated with abnormal trophoblast invasion, uteroplacental vascular insufficiency and enhanced inflammation) and appropriate-for-gestational-age-(AGA) pregnancies, and investigate possible correlations of the above concentrations with several demographic parameters of infants at birth. Plasma TGF-α and TGF-β1 concentrations were determined by ELISA in 154 mixed arterio-venous cord blood samples from IUGR (n=50) and AGA (n=104) singleton full-term infants. After controlling for possible confounding factors (gender, birth-weight, gestational age, maternal age and parity), cord blood TGF-α and TGF-β1 concentrations were significantly higher in IUGR than AGA group (b=0.402, SE=0.179, p=0.027 and b=0.152, SE=0.061, p=0.014, respectively). Delivery mode had an effect on cord blood TGF-α and TGF-β1 concentrations, both being elevated in cases of vaginal delivery (b=-0.282, SE=0.117, p=0.018 and b=-0.123, SE=0.059, p=0.038, respectively). In conclusion, higher cord blood TGF-α and TGF-β1 concentrations may represent a compensatory response to the inflammatory process characterizing the IUGR state. Additionally, higher cord blood TGF-β1 concentrations in IUGRs could be attributed to increased shear stress, resulting from abnormal blood flow in IUGR fetal blood vessels. Finally, vaginal delivery-associated cytokine release may account for elevated TGF-α and TGF-β1 concentrations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To investigate bone and connective tissue collagen turnover in intrauterine growth restricted (IUGR) pregnancies, by determining circulating markers of type I collagen synthesis (carboxy-terminal propeptide of type I procollagen [PICP], representing bone formation) and degradation (cross-linked telopeptide of type I collagen [ICTP], representing bone resorption) as well as type III collagen synthesis (N-terminal propeptide of type-III procollagen [PIIINP], reflecting growth and tissue maturity)., Methods: Plasma PICP, ICTP and PIIINP concentrations were measured in 40 mothers and their 20 asymmetric IUGR and 20 appropriate for gestational age (AGA) full-term fetuses and neonates on postnatal day 1-(N1) and 4-(N4)., Results: Fetal PICP, fetal and N4 ICTP, as well as fetal, N1 and N4 PIIINP concentrations were higher in the IUGR group (p ≤ 0.038, in all cases). In both groups, maternal PICP, ICTP and PIIINP concentrations were lower than fetal, N1 and N4 ones (p<0.001, in each case)., Conclusions: Type I collagen turnover is enhanced in IUGR than AGA fetuses/neonates. Similarly, fetal/neonatal PIIINP concentrations are elevated in IUGR, probably due to stress, responsible for induction of tissue maturation, and/or to impaired excretory renal function, leading to reduced protein clearance. Fetal/neonatal PICP, ICTP and PIIINP concentrations are higher than maternal concentrations, possibly reflecting increased skeletal growth and collagen turnover in the former.

Objective: To prospectively investigate the potential role of the lectin pathway of complement in intrauterine-growth-restriction (IUGR, associated with impaired immunocompetence and increased risk for neonatal infections), by determining cord blood concentrations of mannose-binding lectin (MBL), H-ficolin and L-ficolin (important mediators of neonatal innate immunity) in IUGR and appropriate for gestational age (AGA) pregnancies. Furthermore, we aimed to describe correlations among cord blood MBL, H- and L-ficolin concentrations and with several demographic parameters of the infants at birth., Methods: Serum MBL, H- and L-ficolin concentrations were determined by ELISA in 154 mixed arteriovenous cord blood samples from IUGR (n = 50) and AGA (n = 104) singleton full-term infants., Results: Cord blood MBL concentrations were significantly lower in IUGR cases than AGA controls (p = 0.029). No differences in cord blood H- and L-ficolin concentrations were observed between groups. In the IUGR group, cord blood MBL concentrations negatively correlated with respective L-ficolin ones (r = -0.442, p = 0.001)., Conclusions: The relatively decreased MBL expression in IUGR fetuses at term could possibly contribute to IUGR-associated neonatal immunodeficiency, predisposing to increased susceptibility to infections. The negative correlation between MBL and L-ficolin concentrations in the IUGR group might suggest an underlying immune variation and needs to be further investigated.

The objective was to investigate circulating concentrations of bone formation markers (undercarboxylated osteocalcin [Glu-OC], an established marker of bone formation during fetal and early postnatal life], and Dickkopf-1 [DKK-1], a natural inhibitor of osteoblastogenesis during fetal development]) in intrauterine-growth-restricted (IUGR; associated with impaired fetal skeletal development) and appropriate-for-gestational-age (AGA) pregnancies. Circulating concentrations of Glu-OC and DKK-1 were determined by enzyme immunoassay in 40 mothers and their 20 asymmetric IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Parametric tests were applied in the statistical analysis. No significant differences in Glu-OC concentrations were observed between IUGR and AGA groups, whereas fetal DKK-1 concentrations were lower in the IUGR group (P = .028). In both groups, maternal Glu-OC and DKK-1 concentrations were lower than fetal, N1, and N4 concentrations (P ≤ .012 in all cases), whereas fetal Glu-OC concentrations were higher than N1 and N4 ones (P ≤ .037 in all cases). In addition, N1 Glu-OC concentrations were higher than N4 concentrations (P = .047). Finally, maternal Glu-OC and DKK-1 concentrations positively correlated with fetal, N1, and N4 ones (r ≥ 0.404, P ≤ .01 in all cases). Fetal/neonatal bone formation may not be impaired in full-term asymmetric IUGR infants, as indicated by the similar Glu-OC concentrations in both groups. Fetal DDK-1 concentrations are lower in the IUGR group, representing probably a compensatory mechanism, favoring the formation of mineralized bone. Fetal/neonatal bone turnover is markedly enhanced compared with maternal one and seems to be associated with the latter in both late pregnancy and early postpartum., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate circulating concentrations of omentin-1 and vaspin (adipocytokines predominantly secreted by visceral adipose tissue and not yet investigated in perinatal life) in maternal, fetal, and neonatal samples from intrauterine growth-restricted (IUGR; associated with altered development of adipose tissue) and appropriate-for-gestational-age (AGA) pregnancies and to correlate them with the respective insulin concentrations. Serum omentin-1 and vaspin concentrations were determined by enzyme immunoassay in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and day 4 (N4). Both hormones were detectable in fetal and neonatal blood (omentin-1 [mean ± SD, in nanograms per milliliter]: AGA vs IUGR group--fetal: 11.32 ± 1.88 vs 10.47 ± 1.30, N1: 10.74 ± 1.42 vs 10.46 ± 1.54, and N4: 10.90 ± 2.72 vs 11.35 ± 3.92; vaspin [median, minimum-maximum; in nanograms per milliliter]: AGA vs IUGR group--fetal: 0.39 [0.04-19.06] vs 0.40 [0.05-1.34], N1: 0.40 [0.04-16.70] vs 0.44 [0.23-3.34], and N4: 0.49 [0.02-8.89] vs 0.55 [0.06-3.92]). No significant differences in omentin-1 or vaspin concentrations were observed between IUGR and AGA groups, whereas fetal and N1 insulin concentrations were lower in the former (P = .025 and P = .027, respectively). In both groups, fetal omentin-1 concentrations were higher (P ≤ .018), whereas vaspin concentrations were lower (P ≤ .001), than maternal ones. Furthermore, maternal vaspin concentrations were higher in cases of cesarean delivery (P = .024). Omentin-1 and vaspin concentrations did not correlate with the respective insulin ones. In conclusion, omentin-1 and vaspin are present in the fetus and neonate. Perinatal concentrations of omentin-1 and vaspin are similar in IUGR cases and AGA controls--despite lower insulin concentrations in the former--and do not correlate with the respective insulin concentrations. Higher omentin-1 concentrations in the fetus may be crucial to enhance a growth-promoting effect, whereas lower maternal vaspin concentrations in cases of vaginal delivery may be attributed to spontaneous term delivery inflammation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Clara cell protein (CC16) is an immunomodulatory/anti-inflammatory broncho-alveolar-derived molecule and a biomarker of pulmonary epithelial cells maturity and alveolo-capillary membrane injury. Intrauterine growth-restricted (IUGR) neonates may present with structural lung immaturity, impaired immunocompetence and increased risk for respiratory infections and chronic obstructive lung disease in later life., Objectives: To investigate circulating CC16 concentrations in maternal, fetal, and neonatal samples from IUGR and appropriate for gestational age (AGA) pregnancies., Methods: Serum CC16 concentrations were determined by EIA in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses-neonates on postnatal days 1 (N1) and 4 (N4)., Results: No significant differences in CC16 concentrations were observed between IUGR and AGA groups. In both groups, maternal CC16 concentrations were lower compared to N1 and N4 ones (P < 0.001 in each case). Fetal CC16 concentrations were significantly lower compared to N1 and N4 ones (P < 0.001 in each case). In the AGA group, N1 CC16 concentrations were significantly higher than N4 ones (P < 0.001). Combining groups, N1 CC16 concentrations positively correlated with gestational age (r = 0.364, P = 0.021). Finally, the effect of gender, parity, and maternal age on CC16 concentrations was not significant., Conclusions: The lack of differences in CC16 concentrations between IUGR and AGA groups possibly suggests that the lung immaturity and later respiratory diseases, associated with the former, may not be related to early CC16 deficiency. CC16 concentrations increase with advancing gestational age and peak on the first day of life, possibly indicating a vital role of the protein in fetal lung maturation and extrauterine pulmonary adaptation., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To determine cord blood levels of calprotectin, a protein that is increased in inflammatory states and released by activated neutrophils has apoptosis-inducing activity., Materials and Methods: Cord-blood calprotectin concentrations were determined in intrauterine-growth-restricted (IUGR, usually associated with increased neutrophil activation and apoptosis, n=50) and appropriate-for-gestational-age (AGA, n=110) single full-term pregnancies, and were correlated with perinatal demographic parameters., Results: No significant differences exists between the IUGR and AGA groups, implying that calprotectin at birth does not reflect increased neutrophil activation and apoptosis expected in IUGR. However, in IUGRs, calprotectin concentrations increased with every gestational week [b=45.3, 95% confidence interval (CI): 13.5-77.1, P=0.006], suggesting concomitant up-regulation of neutrophil activation and apoptosis. A combined group showed significantly decreased calprotectin concentrations in cesarean sections [b=-74.5, 95% CI: -115.2-(-33.9), P<0.001], pointing to excessive inflammatory response in vaginal deliveries. Finally, birth weight, customized centile, gender, maternal age and parity do not impact on cord blood calprotectin concentrations., Conclusions: Cord blood calprotectin concentrations at term are independent of intrauterine growth, gender, parity and maternal age and probably do not reflect the increased neutrophil activation and excessive apoptosis expected in IUGR.

The aim of this study was to investigate possible alterations in circulating concentrations of surfactant protein D (SP-D)-an important component of the innate immune system that is upregulated in pulmonary diseases-in appropriate for gestational age (AGA) and intrauterine growth-restricted (IUGR) pregnancies, because the latter are characterized by structural lung immaturity, impaired immunocompetence, and increased risk of respiratory infections and chronic obstructive lung disease in later life. Serum SP-D concentrations were determined in 40 mothers and their 20 IUGR and 20 AGA full-term fetuses-neonates on postnatal day 1 (N1) and 4 (N4). Fetal SP-D concentrations were higher in the IUGR group (b = 18.16, 95% CI: 6.86-29.47, P = .002) and negatively correlated with infants' customized centiles and gestational age (r = -.326, P = .04, and r = -.446, P = .004, respectively). In both groups, fetal SP-D concentrations were lower than N1 and N4 ones (P

Background: The Fas-Fas ligand (FasL) pathway of apoptosis contributes to immune tolerance at the fetomaternal interface and has been ascribed a role in implantation and placental development. Intrauterine growth restriction (IUGR) may be associated with impaired maternal-fetal tolerance, resulting in increased trophoblast apoptosis and uteroplacental vascular insufficiency., Objectives: To investigate soluble Fas (sFas) and FasL (sFasL) concentrations in maternal, fetal and neonatal serum of IUGR and appropriate-for-gestational-age (AGA) pregnancies., Methods: Circulating sFas and sFasL concentrations were determined in 40 mothers and their 20 IUGR (due to several etiologies) and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and 4 (N4)., Results: No significant differences in sFas and sFasL concentrations were observed between groups. In both groups, maternal sFas concentrations were increased compared to fetal, N1 and N4 ones (p< or =0.005 in AGA and p < 0.001 in IUGR, in all cases). On the other hand, maternal sFasL concentrations were lower compared to fetal, N1 and N4 ones (p < 0.001 in all cases). Fetal sFasL concentrations were increased compared to maternal, but lower compared to N4 sFasL ones (p < 0.001 in AGA and p < or = 0.020 in IUGR, in all cases). N4 sFasL concentrations were elevated compared to N1 ones (p < 0.001)., Conclusions: Circulating maternal, as well as fetal sFas and sFasL concentrations do not differ between AGA controls and IUGR cases, irrespectively of the etiology of the latter. Furthermore, the results of this study imply an acceleration of Fas-FasL-mediated apoptosis during delivery and a respective decrease postpartum in both normal and IUGR pregnancies., (Copyright 2009 S. Karger AG, Basel.)

Background: Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are main determinants of bone resorption., Objectives: To investigate OPG and soluble RANKL (sRANKL) concentrations in maternal, fetal and neonatal serum of IUGR patients and appropriate for gestational age (AGA) pregnancies. Additionally, plasma intact parathormone (PTH) concentrations were evaluated., Methods: Circulating OPG, sRANKL and PTH concentrations were measured in 40 mothers and their singleton full-term fetuses-neonates (AGA: n = 20, and IUGR: n =20) on postnatal days 1 (N1) and 4 (N4)., Results: No significant differences in OPG, sRANKL or PTH concentrations were observed between AGA and IUGR groups. In both groups, maternal OPG concentrations were elevated compared with fetal, and N1 and N4 concentrations (p < or = 0.045 in all cases). N4 sRANKL concentrations were elevated compared with maternal, fetal and N1 ones (p < or = 0.01 in all cases). Fetal and N1 sRANKL concentrations correlated positively with PTH levels (r = 0.642, p = 0.024 and r = 0.584, p = 0.046, respectively)., Conclusions: The lack of a difference in circulating OPG, sRANKL or PTH concentrations between IUGR cases and AGA controls suggests that the low bone mass of IUGR infants may not be related to higher bone resorption rates. The increased maternal, compared with fetal/neonatal, OPG concentrations may suggest their placental origin. The lower OPG and higher sRANKL concentrations in fetuses and neonates could represent high bone resorption rates., (Copyright 2009 S. Karger AG, Basel.)

Background: Survivin (a member of the inhibitors of apoptosis family) is important for fetal development, placental survival and differentiation. Intrauterine growth restriction (IUGR) and fetal macrosomia, due to maternal diabetes mellitus (DM) are associated with excessive and decreased feto-placental apoptosis, respectively. The aim was to study survivin concentrations in cord blood at term in IUGR, large-for-gestational-age (LGA, due to gestational DM) and appropriate-for-gestational-age (AGA) pregnancies., Patients and Methods: Survivin concentrations were determined in 160 mixed arterio-venous cord blood samples from IUGR (n=48), LGA (n=11) and AGA (n=101) singleton full-term infants., Results: No significant differences in survivin concentrations in cord blood were observed between groups. The effect of birthweight, customized centile, gestational age, gender, delivery mode and parity on survivin concentrations was not significant., Conclusion: Survivin concentrations in cord blood at term are independent of intrauterine growth, gender, parity and delivery mode. Thus, they probably do not reflect the disturbances of feto-placental apoptosis expected in IUGR and fetal macrosomia due to gestational DM.

Objective: To investigate circulating concentrations of human fetuin-A (important fetal glycoprotein, involved in vascular pathology and bone metabolism) in mothers, fetuses and neonates from intrauterine-growth-restricted (IUGR, associated with low bone mass at birth and metabolic syndrome in adult life) and appropriate-for-gestational-age (AGA) pregnancies., Methods: Serum fetuin-A concentrations were prospectively measured in 40 mothers, the doubly-clamped umbilical cords (representing fetal state) and their 20 IUGR and 20 AGA full-term neonates on postnatal day 1 (N1) and 4 (N4)., Results: No significant differences in fetuin-A concentrations were observed between groups, or between maternal, fetal and neonatal samples in both groups. In the AGA group, maternal fetuin-A concentrations positively correlated with fetal and N1 ones (r = 0.599, p = 0.005 and r = 0.469, p = 0.037, respectively). In the IUGR group, maternal fetuin-A concentrations positively correlated with N4 ones (r = 0.541, p = 0.014)., Conclusion: Serum fetuin-A concentrations do not differ between IUGR cases and AGA controls. Maternal and fetal fetuin-A concentrations are similar and positively correlated, indicating the likelihood of passive transplacental transfer of this substance.

Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. We aimed to investigate the effect of IUGR on bone metabolism in mother/infant pairs, by determining circulating biochemical markers of bone turnover in IUGR and appropriate for gestational age (AGA) pregnancies. Circulating markers of bone formation [bone specific alkaline phosphatase (BALP), total alkaline phosphatase (ALP), osteocalcin (OC)] and bone resorption [cross-linked N-telopeptide of type I collagen (NTx)], as well as intact parathormone (PTH), calcium and phosphorus levels were measured in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal days 1 (N1) and 4 (N4). No significant differences in BALP, ALP, OC, NTx, PTH, calcium or phosphorus levels were observed between the AGA and the IUGR groups. In both groups, maternal BALP levels were lower compared to fetal, N1 and N4 levels (p< or =0.005 in all cases). In the AGA group, maternal NTx and OC levels were lower compared to fetal, N1 and N4 levels (p<0.001 in all cases), and fetal NTx levels were lower compared to N1 and N4 ones (p<0.001 and p=0.002, respectively). In the IUGR group, maternal OC levels were lower compared to fetal, N1 and N4 ones (p<0.001 in each case) and fetal OC levels were elevated compared to N1 and N4 ones (p<0.001 and p=0.003, respectively). N4 NTx levels were elevated compared to maternal, fetal and N1 levels (p=0.009, p<0.001 and p=0.002, respectively) and fetal NTx levels were lower compared to N1 and N4 ones (p=0.001 and p<0.001, respectively). Finally, positive correlations were found between maternal NTx and BALP (r=0.332, p=0.037), as well as ALP (r=0.329, p=0.038) levels, and between maternal, fetal, N1, N4 BALP and respective ALP levels (r=0.432, p=0.005, r=0.534, p=0.001, r=0.778, p<0.001, r=0.694, p<0.001, respectively). In conclusion, maternal, fetal and neonatal bone turnover in IUGR cases may not differ from respective bone metabolism in AGA controls. In addition, fetal and neonatal bone remodeling is markedly enhanced and independent of maternal bone turnover in late pregnancy.

Ischemia-modified albumin (IMA) is a sensitive biomarker of cardiac ischemia. Intrauterine growth restriction (IUGR) may imply fetal hypoxia, resulting in blood flow centralization in favour of vital organs (brain, heart, adrenals--"brain sparing effect"). Based on the latter, we hypothesized that cord blood IMA levels should not differ between IUGR and appropriate-for-gestational-age (AGA) full-term pregnancies. IMA was measured in blood samples from doubly-clamped umbilical cords of 110 AGA and 57 asymmetric IUGR pregnancies. No significant differences in IMA levels were documented between AGA and IUGR groups. IMA levels were elevated in cases of elective cesarean section (P = .035), and offspring of multigravidas (P = .021). In conclusion, "brain sparing effect" is possibly responsible for the lack of differences in cord blood IMA levels at term, between IUGR and AGA groups. Furthermore, higher oxidative stress could account for the elevated IMA levels in cases of elective cesarean section, and offspring of multigravidas.

Objective: It was the aim of this study to investigate circulating levels of beta(2)-microglobulin (a marker of renal function) in mothers and fetuses/neonates from intrauterine growth-restricted (IUGR, characterized by impaired nephrogenesis) and appropriate for gestational age (AGA) pregnancies., Methods: Serum beta(2)-microglobulin levels were determined in 40 parturients and their 20 IUGR and 20 AGA fetuses/neonates on postnatal days 1 (N1) and 4 (N4). Comparatively, creatinine concentrations were measured., Results: No significant differences in beta(2)-microglobulin levels were observed between the 2 groups. In both groups, maternal serum beta(2)-microglobulin levels were significantly lower than fetal, N1 and N4 levels (in all cases p < 0.001 in the AGA group and p or= 0.342 and p

Background: The adipocytokine resistin inhibits adipogenesis and induces insulin resistance. Intrauterine growth-restricted (IUGR) neonates have reduced fat mass and changes of endocrine/metabolic mechanisms, predisposing to insulin resistance and metabolic syndrome in adult life., Objectives: To investigate plasma resistin concentrations in maternal, fetal and neonatal samples from IUGR and appropriate-for-gestational-age (AGA) pregnancies and correlate them with respective insulin concentrations., Methods: Plasma resistin and insulin concentrations were determined in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and day 4 (N4)., Results: No significant differences in resistin concentrations were observed between AGA and IUGR groups. In the AGA group, maternal resistin concentrations were significantly lower compared to fetal, N1 and N4 ones (p = 0.003, p = 0.017 and p = 0.039, respectively). Maternal resistin concentrations positively correlated with fetal ones (r = 0.527, p = 0.02). In the IUGR group, maternal resistin concentrations were significantly lower compared to N1 (p < 0.001) and positively correlated with N4 concentrations (r = 0.626, p = 0.007). In both groups, the effect of gender, mode of delivery, parity and adjusted birth weight (customized centiles) on resistin concentrations was not significant. No correlation between resistin and insulin concentrations was documented., Conclusions: Lack of difference in resistin concentrations between IUGR and AGA groups, and lack of correlation between resistin and insulin concentrations as well as customized centiles, possibly suggests that resistin may not be directly involved in the regulation of insulin sensitivity and adipogenesis in the perinatal period. Mode of delivery and parity are not associated with circulating resistin concentrations., (Copyright (c) 2007 S. Karger AG, Basel.)

Background: Intrauterine growth restricted (IUGR) fetuses are those with estimated weight <10th customized centile, displaying signs of chronic malnutrition and hypoxia leading to brain sparing effect. Neurotrophins, [Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)] are important for pre- and post-natal brain development., Aims: To investigate circulating NGF, BDNF, NT-3 and NT-4 levels in IUGR and appropriate for gestational age (AGA) fullterm fetuses and neonates (day-1 [N1] and day-4 [N4]) and in their mothers., Study Design: Prospective case control study., Subjects: 60 mothers and their single 30 IUGR and 30 AGA fullterm fetuses and neonates., Outcome Measures: Determination, by enzyme immunoassays, of NGF, BDNF, NT-3 and NT-4 plasma levels., Results: No statistically significant differences existed between IUGR and AGA maternal, fetal and neonatal levels of BDNF, NT-3 and NT-4. NGF was significantly higher in AGA than IUGR maternal (p=0.007), fetal (p=0.01), neonatal day 1 (p=0.043) and 4 (p=0.003) plasma, and positively correlated with the infants' centiles and birthweights. IUGR and AGA maternal neurotrophins were higher than the respective fetal and neonatal ones and no correlation with gender or delivery mode in both groups was observed., Conclusions: In the perinatal period, circulating levels of BDNF, NT-3 and NT-4 do not differ in IUGR and AGA pregnancies, in contrast to NGF levels, which are higher in the AGA group. NGF is the only neurotrophin correlating with customized centiles and birthweights of the infants. Neurotrophin concentrations are higher in maternal plasma and do not depend on gender.

Objective: The objective of this study was to investigate possible alterations in circulating levels of the adipocytokine visfatin in intrauterine growth-restricted and normal pregnancies, given that these groups differ considerably in fetal nutrition, body fat mass, and metabolic/endocrine mechanisms., Methods: Serum visfatin levels were prospectively measured by enzyme immunoassay in 40 mothers and their 40 singleton term fetuses and neonates on postnatal days 1 and 4. Twenty neonates had intrauterine growth restriction (birth weight < or = 3rd customized centile, adjusted for parameters that influence growth potential), and 20 were appropriate for gestational age., Results: Circulating maternal visfatin levels were significantly elevated in pregnancies with intrauterine growth restriction compared with control pregnancies with appropriate-for-gestational-age infants and negatively correlated with customized centiles in the group with intrauterine growth restriction. Postnatal day-1 and -4 visfatin levels were significantly higher in neonates with intrauterine growth restriction compared with neonates who were appropriate for gestational age. Postnatal-day-1 prefeeding insulin levels were significantly lower in neonates with intrauterine growth restriction., Conclusions: Pathologic conditions in pregnancy that lead to intrauterine growth restriction could be responsible for elevated maternal visfatin levels. Higher visfatin levels in neonates with intrauterine growth restriction may serve as an early marker with prognostic value for later development of insulin resistance or type 2 diabetes, whereas lower insulin levels may indicate reduced beta-cell mass and/or impaired beta-cell function.

Intrauterine growth restriction (IUGR) implies fetal hypoxia, resulting in blood flow redistribution and sparing of vital organs (brain, heart). Serum cardiac Troponin-I (cTnI), a well-established marker of myocardial ischaemia, was measured in 40 mothers prior to delivery, the doubly clamped umbilical cords (representing fetal state), and their 20 IUGR and 20 appropriate-for-gestational-age (AGA) neonates on day 1 and 4 postpartum. At all time points, no differences in cTnI levels were observed between the AGA and IUGR groups. Strong positive correlations were documented between maternal and fetal/neonatal values (r > or = .498, P < or = .025 in all cases in the AGA and r > or = .615, P < or = .009 in all cases in the IUGR group). These results may indicate (a) normal heart function, due to heart sparing, in the IUGR group (b) potential crossing of the placental barrier by cTnI in both groups.

Monocyte-chemotactic-protein-1 (MCP-1) plays vital roles in immune response, angiogenesis, and pregnancy outcome. We investigated plasma MCP-1 concentrations in 40 mothers and their 20 intrauterine-growth-restricted (IUGR) and 20 appropriate-for-gestational-age (AGA) fetuses and neonates on postnatal days 1 (N1) and 4 (N4). Maternal and fetal MCP-1 concentrations were decreased (P<001 and P = .018, resp.), whereas N1 MCP-1 concentrations were elevated in IUGR group (P = .012). In both groups, fetal MCP-1 concentrations were lower compared to N1 and N4 ones (P = .045, P = .012, resp., for AGA, P< .001 in each case for IUGR). Reduced maternal and fetal MCP-1 concentrations in IUGR may reflect failure of trophoblast invasion, suggesting that down-regulation of MCP-1 may be involved in the pathogenesis of IUGR. Increased MCP-1 concentrations in IUGR neonates and higher postnatal ones in all infants may be attributed to gradual initiation of ex utero angiogenesis, which is possibly enhanced in IUGR.

Insulin-like growth factor (IGF)-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA) and 20 intrauterine-growth-restricted (IUGR) fetuses and neonates on day 1 (N1) and day 4 (N4) postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P < .001 and P = .037, resp.). N1 insulin levels were lower in IUGR (P = .048). Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r = .374, P = .035, r = .608, P < .001, r = .485, P = .006, and r = .654, P = .021, resp.). Female infants presented elevated fetal and N4 IGF-I levels (P = .023 and P = .016, resp.). Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

Objective: To investigate changes in NT-proBNP in intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) pregnancies., Methods: NT-proBNP levels were measured in 40 mothers (MS), umbilical cords (UC), and their 20 IUGR/ 20 AGA neonates on day 1 (N1) and day 4 (N4)., Results: UC, N1, and N4 NT-proBNP was lower in IUGR pregnancies (p

The objective of this study was to investigate circulating levels of cystatin C (an important endogenous marker of renal function) in mothers, fetuses, and neonates from intrauterine growth-restricted (IUGR; characterized by impaired nephrogenesis) and appropriate-for-gestational-age (AGA) pregnancies. Serum cystatin C levels were measured by enzyme immunoassay in 40 parturients and their 20 IUGR (or= 0.376 and P

Background: N-terminal parathyroid hormone-related protein has a vital role in regulating cell growth and differentiation, uteroplacental vasodilatation, uterine muscle relaxation, and placental transport. These functions are compromised in intrauterine growth restriction. We aimed to investigate N-terminal parathyroid hormone-related protein concentrations in maternal, fetal, and neonatal plasma of intrauterine-growth-restricted and appropriate for gestational age pregnancies., Methods: Plasma N-terminal parathyroid hormone-related protein levels were determined in 40 mothers and their 20 intrauterine-growth-restricted and 20 appropriate for gestational age singleton full-term fetuses and neonates on postnatal days 1 and 4., Results: Fetal N-terminal parathyroid hormone-related protein levels were significantly lower in the intrauterine growth restriction group (b=1.166, 95%CI: 0.430-1.902, p=0.003) and correlated with the customized centiles of the infants (r=0.407, p=0.009). In the appropriate for gestational age group, neonatal day 1 N-terminal parathyroid hormone-related protein levels were significantly lower compared to maternal (p<0.001) and fetal (p=0.022) ones. Fetal and neonatal day 1 levels were significantly lower in males (b=-1.303, 95%CI: -2.508 to -0.097, p=0.036, and b=-0.802, 95%CI: -1.5 to -0.105, p=0.027, respectively). In the intrauterine growth restriction group, maternal N-terminal parathyroid hormone-related protein levels were significantly increased compared to fetal (p<0.001) and neonatal day 1 (p=0.001) levels., Conclusions: The reduced fetal N-terminal parathyroid hormone-related protein concentrations in intrauterine growth restriction may reflect compromised placental function and impaired fetal growth, suggesting that N-terminal parathyroid hormone-related protein may be involved in the pathogenesis of intrauterine growth restriction.

Background: Angiogenesis, a critical process for growth and development is altered in intrauterine growth restriction (IUGR). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, soluble (s) VEGFR-1 and VEGFR-2 represent a regulatory system, essential for both physiological and pathological angiogenesis., Aim: To study the implication of sVEGFR-1-a VEGF antagonist-in IUGR., Study Design: Prospective study., Methods: Twenty-five IUGR and 15 appropriate for gestational age (AGA) full-term fetuses and neonates with their mothers were included in the study., Outcome Measures: sVEGFR-1 levels were determined by enzyme immunoassay in the serum of: mothers (MS), umbilical cords (UC)-representing fetal state - and neonates on day 1 (N1) and 4 (N4) of life., Results: MS, UC, N1 and N4 sVEGFR-1 levels in IUGR were significantly higher compared to respective AGA cases (p = 0.005, p = 0.026, p = 0.005 and p = 0.017, respectively). In IUGR and AGA groups, maternal sVEGFR-1 levels were significantly higher than fetal and neonatal levels (p in all cases < 0.001). The latter presented in both IUGR and AGA groups a significant decrease from UC to N4 (p in all cases < 0.01). MS, N1 and N4 sVEGFR-1 levels negatively correlated with the infants' customized centiles [(r = -0.489, p = 0.001), (r = -0.440, p = 0.004), (r = -0.431, p = 0.006), respectively]., Conclusions: Higher sVEGFR-1 levels in the IUGR as compared to the AGA group possibly reflect the predominance of antiangiogenic mechanisms present in IUGR. The decrease of sVEGFR-1 levels from UC to N4 may represent ex utero initiation of growth and development and therefore, prevalence of angiogenic mechanisms.