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Accumulating evidence suggests that the origins of adult disease may occur during fetal life. Thus, the concept of “developmental programming” has been introduced and supported by epidemiological and experimental data. This concept supports the idea that the nutritional and hormonal status during pregnancy could interfere in metabolism control. The mechanisms responsible for this “developmental programming” remain poorly documented. Current research indicates that neurotrophins and particularly brain-derived neurotrophic factor (BDNF) may play a crucial role in this process. Although mainly expressed in the nervous system, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are immunolocalized in several regions of the human placenta and have important functions during pregnancy. BDNF serves widespread roles in regulating energy homeostasis in both fetuses and adults, by controlling patterns of fetal growth, adult feeding and physical activity, and by regulating glucose metabolism in peripheral tissues. Impaired BDNF signaling may be implicated in the etiopathogenesis of the metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes and neurological disorders. The aim of this article is to provide a brief comprehensive literary review regarding the potential implications of BDNF in “developmental programming”, through regulation of metabolism and energy balance from early life to adulthood. [ABSTRACT FROM AUTHOR]

Background/aim Excessive fetal growth is associated with increased adiposity and reduced insulin sensitivity at birth. Copeptin, a surrogate marker of arginine vasopressin (AVP) secretion, 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 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-for-gestational-age (AGA, n = 20) singleton full-term healthy infants. Cord blood copeptin and insulin concentrations were determined by ELISA and IRMA, respectively. Infants were classified as LGA or AGA, based on customized birth-weight standards adjusted for 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. [ABSTRACT FROM AUTHOR]

Background/aims Irisin, a novel myokine with antiobesity properties, drives brown-fat-like conversion of white adipose tissue, thus increasing energy expenditure and improving glucose tolerance. We aimed to investigate circulating irisin concentrations in large-for-gestational-age (LGA) and intrauterine-growth-restricted (IUGR) fetuses, both associated with metabolic dysregulation and long-term susceptibility to obesity and metabolic syndrome development. Methods Plasma irisin and insulin concentrations were determined by ELISA and IRMA, respectively, in 80 mixed arteriovenous cord blood samples from LGA ( n = 30), IUGR ( n = 30) and appropriate-for-gestational-age (AGA, n = 20) singleton full-term pregnancies. Fetuses were classified as LGA, IUGR or AGA, based on customized birth-weight standards adjusted for significant determinants of fetal growth. Results Fetal irisin concentrations were lower in IUGR cases than AGA controls (p = 0.031). Cord blood irisin concentrations were similar in LGA and AGA groups and positively correlated with birth-weight, as well as customized centiles (r = 0.245, p = 0.029 and r = 0.247, p = 0.027, respectively). Insulin concentrations were higher in LGA, compared to AGA fetuses (p = 0.036). In the LGA group, fetal irisin concentrations positively correlated with fetal insulin concentrations (r = 0.374, p = 0.042). Conclusions Impaired skeletal muscle metabolism in IUGR fetuses may account for their irisin deficiency, which may be part of the fetal programming process, leading to increased susceptibility to later metabolic syndrome development. Furthermore, irisin down-regulation may predispose IUGR infants to hypothermia at birth, by inducing less “browning” of their adipose tissue and consequently less non-shivering thermogenesis. Irisin upregulation with increasing birth-weight may contribute to a slower fat gain during early infancy (“catch-down”), by promoting higher total energy expenditure. The positive correlation between irisin and insulin in the LGA group may reflect a counterbalance of the documented hyperinsulinemia, which is partly responsible for the excessive fat deposition in the LGA fetus. [ABSTRACT FROM AUTHOR]

Summary: Accumulating data suggest that prenatal compromises leading to intrauterine growth restriction (IUGR) increase the risk for respiratory deficiencies after birth. In this respect, a growing body of epidemiological evidence in infants, children and adults indicates that small for gestational (SGA) birth weight can adversely affect lung function, thus questioning the widely accepted concept that IUGR accelerates lung maturation and improves outcome. Although the mechanisms responsible for the relationship between SGA and later lung dysfunction remain poorly documented, animal data indicate that intrauterine lung development can be adversely affected by factors associated with IUGR, namely reduced substrate supply, fetal hypoxemia and hypercortisolemia. Thus, it is suggested that fetal adaptations to intrauterine undernutrition result in permanent changes in lung structure, which in turn lead to chronic airflow obstruction. The purpose of this review is to describe and discuss the effects of IUGR on lung structure and function. [Copyright &y& Elsevier]

Abstract: 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 &y& Elsevier]

Abstract: 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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Background: Cytokines play an important role during labor and full- or preterm delivery. They influence physical immunity of the fetus–neonate and express a leading role in the perinatal period, being present in maternal and fetal tissues. Aim: To investigate whether cytokine concentrations in the mother, fetus and neonate depend on the labor and the mode of the delivery. Study design: Prospective study. Subjects: Seventy-eight healthy, non-smoking parturients (mean age 28±4, range 21–39 years, delivering vaginally: n=52 or by elective cesarean section: n=26) and their single, healthy, appropriate for gestational age, full-term neonates. Outcome measures: We correlated determined circulating levels of IL-2, sIL-2R, IL-4, sIL-4R, IL-6, sIL-6R, IL-1β, IL-8, IFN-γ, TNF-α, sTNF RI, sTNF RII and RANTES in the mothers before delivery (MS), the fetuses (UC) and the neonates in days 1 (N1) and 4 (N4) of life, with the mode of delivery. Results: sIL-2R in N1 and N4, sIL-4R in MS, IL-6 in MS and UC, IL-1β in MS, UC and N1, IFN-γ in MS and UC, TNF-α in UC, N1 and N4, sTNF RI in UC were significantly higher in cases of vaginal delivery than in cases of elective cesarean section (p ranging from 0.0005 to 0.05). Conclusions: Vaginal delivery promotes the production of various cytokines and their receptors, which are implicated in neonatal immunity. [Copyright &y& Elsevier]

Objective: To measure serial serum concentrations of the angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG) in the periovulatory and secretory phase of normal menstrual cycles in healthy women and to determine their peaks, which might reflect the stage of their critical angiogenic action.Design: Prospective study.Setting: University departments of obstetrics and gynecology.Participant(s): Thirty-three healthy Swedish women with regular menstrual cycles.Intervention(s): Serial blood samples were collected from each woman. Luteinizing hormone surge was identified by testing morning urine.Main outcome measure(s): Circulating levels of VEGF, bFGF, and ANG.Result(s): Circulating peak concentrations were determined for VEGF on day 0 and 9 after ovulation, for bFGF on day 1 before ovulation and day 9 after ovulation, and for ANG on day 3 after ovulation.Conclusion(s): Circulating VEGF increased in a stage-dependent cyclic fashion. Basic FGF peaked during the late proliferative and mid secretory phase. Circulating ANG showed increased expression around the early secretory phase of the cycle. [Copyright &y& Elsevier]

Background: Brain-derived neurotrophic factor (BDNF) is abundant in brain and peripheral nerves, affects normal development, growth and survival and is implicated in immune response. Aim: To determine in single preterm (P) and fullterm (F) neonates, circulating intra- and extrauterine levels of BDNF, supposingly reflecting their neuronal and immune maturity. Study design: Prospective study. Subjects: Thirty healthy, appropriate for gestational age (AGA) F (mean gestational age 39.2±1.4 weeks), 15 healthy AGA P (29.4±1.3 weeks), and their mothers. Outcome measures: BDNF was measured by enzyme immunoassay methods in the serum of: mothers at the first stage of labor (MS), the umbilical cord (UC) and the neonates on days 1 (N1) and 4 (N4) postpartum. Results: Levels of BDNF in (a) FMS did not differ from PMS, but both were significantly higher than respective (F or P) UC, N1 and N4 (p ranging from <0.01 to <0.001), (b) FUC, FN1 and FN4 were significantly higher than PUC (p<0.001), PN1 (p<0.03) and PN4 (p<0.02), respectively, (c) PN1 increased significantly as compared to PUC (p<0.05). Conclusions: Higher BDNF MS levels may reflect the mature nervous and immune systems of mothers. Higher BDNF levels in F than P may also be due to advanced maturity in the former. Increased BDNF levels in PN1 as compared to PUC may indicate stimulation of immune response with exposure to antigenic stimuli from the extrauterine environment. Nevertheless, this stimulation is insufficient in P, who by decreasing N4 levels are by far less protected than F. [Copyright &y& Elsevier]

Objective: To detect the levels of visfatin and leptin in the serum as well as in the follicular fluid (FF) of polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian stimulation and to compare them with the levels found in age- and weight-matched normally ovulating women under IVF treatment.Design: Prospective study.Setting: Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece.Patient(s): Forty patients with diagnosed PCOS and 40 age- and weight-matched non-PCOS control women enrolled in the IVF program.Intervention(s): Blood and FF samples were collected from all subjects at oocyte retrieval.Main Outcome Measure(s): Visfatin and leptin levels were measured in serum and FF using ELISA.Result(s): Serum visfatin levels were significantly increased in women with PCOS, whereas FF visfatin levels, which were lower than serum levels, did not differ between groups. Serum leptin levels did not differ between groups and were lower than FF levels.Conclusion(s): Women with polycystic ovaries exhibit significantly increased serum visfatin and decreased FF leptin levels compared with control subjects of similar age and body mass index, indicating a probable role for visfatin in the general state of insulin resistance and a local contribution in the follicle for leptin in patients undergoing IVF treatment. [ABSTRACT FROM AUTHOR]

Abstract: 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 ≤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. [Copyright &y& Elsevier]

Background: After birth, apoptosis rates might slow down, compared to those in utero. Thus, factors, attenuating the apoptotic process, like the soluble forms of Fas/FasL system, may increase. Aim—study design: Soluble Fas (sFas) and soluble Fas ligand (sFasL) concentrations were measured in maternal serum (MS), umbilical cord (UC) and neonatal serum in the first (1N) and fifth (5N) days after birth in order to evaluate the alterations of these molecules during the early neonatal period. Subjects and methods: Soluble molecules were estimated in 35 healthy, appropriate for gestational age, full-term neonates, their mothers and in 25 healthy, nonpregnant women, age-matched to the mothers (controls), using enzyme immunoassays. Results: sFas concentrations in MS (p<0.01), UC (p<0.0001), 1N (p<0.0003) and 5N (p<0.02) were lower than those in controls. Neonatal sFas concentrations showed a significant increase from UC to 5N (p<0.001). In contrast, sFasL concentrations were significantly elevated in all neonatal samples (UC, 1N and 5N) compared to those in MS and controls (p<0.0001), showing also a significant elevation from UC to 5N (p<0.0001). Conclusion: Our results demonstrate increasing serum concentrations of the soluble molecules sFas and sFasL during the first days after birth, indicating possibly a gradual decrease of apoptosis in early neonatal life. [Copyright &y& Elsevier]