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of recommendationsCorticosteroids should be administered to women at a gestational age between 24 +0 and 33 +6  weeks, when preterm birth is anticipated in the next seven days, as these have been consistently shown to reduce neonatal mortality and morbidity. (Strong-quality evidence; strong recommendation). In selected cases, extension of this period up to 34 +6  weeks may be considered (Expert opinion). Optimal benefits are found in infants delivered within 7 days of corticosteroid administration. Even a single-dose administration should be given to women with imminent preterm birth, as this is likely to improve neurodevelopmental outcome (Moderate-quality evidence; conditional recommendation).Either betamethasone (12 mg administered intramuscularly twice, 24-hours apart) or dexamethasone (6 mg administered intramuscularly in four doses, 12-hours apart, or 12 mg administered intramuscularly twice, 24-hours apart), may be used (Moderate-quality evidence; Strong recommendation). Administration of two "all" doses is named a "course of corticosteroids".Administration between 22 +0 and 23 +6  weeks should be considered when preterm birth is anticipated in the next seven days and active newborn life-support is indicated, taking into account parental wishes. Clear survival benefit has been observed in these cases, but the impact on short-term neurological and respiratory function, as well as long-term neurodevelopmental outcome is still unclear (Low/moderate-quality evidence; Weak recommendation).Administration between 34 + 0 and 34 + 6 weeks should only be offered to a few selected cases (Expert opinion). Administration between 35 +0 and 36 +6  weeks should be restricted to prospective randomized trials. Current evidence suggests that although corticosteroids reduce the incidence of transient tachypnea of the newborn, they do not affect the incidence of respiratory distress syndrome, and they increase neonatal hypoglycemia. Long-term safety data are lacking (Moderate quality evidence; Conditional recommendation).Administration in pregnancies beyond 37 +0  weeks is not indicated, even for scheduled cesarean delivery, as current evidence does not suggest benefit and the long-term effects remain unknown (Low-quality evidence; Conditional recommendation).Administration should be given in twin pregnancies, with the same indication and doses as for singletons. However, existing evidence suggests that it should be reserved for pregnancies at high-risk of delivering within a 7-day interval (Low-quality evidence; Conditional recommendation). Maternal diabetes mellitus is not a contraindication to the use of antenatal corticosteroids (Moderate quality evidence; Strong recommendation).A single repeat course of corticosteroids can be considered in pregnancies at less than 34 +0  weeks gestation, if the previous course was completed more than seven days earlier, and there is a renewed risk of imminent delivery (Low-quality evidence; Conditional recommendation).

Background: Developmental adaptive processes during gestation that are known to be involved in permanent changes in physiology and metabolism or "early life programming" can adversely affect fetal brain development, impacting both brain structure and function. Data: Emerging evidence strongly supports the developmental origin of schizophrenia, which may potentially be a result of prenatal exposure to a diversity of factors, especially infections, in genetically predisposed subjects. Structural and functional brain changes during development of schizophrenia are determined by genetic components, altered expression of schizophrenia risk genes and epigenetic dysregulation. However, the precise mechanisms underlying these relationships remain unclear. Findings from human and animal studies suggest that inflammatory-immune responses and activation of oxidative stress pathways are crucial in mediating intrauterine infection-induced neurodevelopmental and neuropsychiatric diseases. Aim: Considering the high prevalence of intrauterine inflammation in the context of chorioamnionitis during human pregnancy and the paucity of knowledge on fetal programming of schizophrenia, this mini review aims to exclusively consolidate the current evidence supporting a potential association between chorioamnionitis and schizophrenia.

This study comprehensively examines clinical symptoms, laboratory findings, and placental pathology in 40 cases of singleton full-term SARS-CoV-2 negative neonates. Their mothers, previously healthy, with uncomplicated pregnancies, were infected peripartum and presented COVID-19 symptoms of various severity. Neonates had predominately diarrhea, the yet unreported absent sucking reflex, elevated COVID-19 inflammatory and ischemia/asphyxia markers as serum ferritin, interleukin-6 and cardiac troponin-T, while placentas demonstrated mild vascular and/or inflammatory lesions. We hypothesize that the above placental lesions may be associated with transient perinatal hypoxia resulting in absent sucking reflex, as well as with inflammatory cytokines transfer causing diarrhea.

Motivated by the up to now disastrous outcomes of the COVID-19 pandemic, we attempted a flashback to the so-called "Plague of Athens," which indicated a serious contagious disease, having taken place between 430 and 426 BC. The ancient pandemic was meticulously described by the Athenian historian and general Thucydides. We compared, as much as possible, the following parameters: background conditions, spreading of the pandemics, preceded and concurrent adverse events, duration and waves of the pandemics, symptoms, implicated infectious agents/diseases and mental/psychosocial consequences. The current pandemic was preceded by a global economic crisis, which particularly affected deprived population groups, while the ancient one started on the second year of a catastrophic civil war. Rivalry and different political systems between now (US/China) and then (Athens/Sparta) superpowers were the basis for conspiracy scenarios, concerning origins of the pandemics, which resulted to huge numbers of deaths, particularly in overcrowded and poor areas/cities. Both pandemics not sparing any age, sex, nationality, social group, may have had a zoonotic component, besides being air-born. However, their spreading is/was remarkably rapid, presenting 3-4 waves and lasting for several years. Some somatic signs and symptoms of the diseases coincide. Although for COVID-19, SARS-CoV-2 has been identified as causing agent, the antique pandemic has most probably been attributed to typhoid fever, although this is still a matter of debate. Additionally, both pandemics affected mental health and psychosocial behavior in close similarity. It is noteworthy, that in both eras physicians and healthcare workers, despite physical and psychological exhaustion, in the majority, presented admirable resilience and willingness to help suffering fellow people, often at the expense of their own lives. The considerable number of comparable features between COVID-19 and the "Plague of Athens" confirms that pandemics may present over time important similarities in their origin, evolution and outcomes.

Latest knowledge assigns the origins of autism spectrum disorder (ASD)-currently affecting 1% of children- to intrauterine life, when fetal brain develops. Besides genetics, environmental factors, responsible for epigenetic changes contributed to its rising incidence. In vitro fertilization (IVF) and the most widely used intracytoplasmic sperm injection (ICSI) are implicated in epigenetic changes. A series of studies examined the impact of ICSI on ASD in the offspring. Results are usually conflicting, due to inherent problems of study design and power, mixed IVF/ICSI cases and not exclusively ASD diagnoses included. Furthermore, preterm birth, low birthweight infants, advanced parental age, hormonal disturbances, all associated with ICSI, are known factors affecting ASD. While solid data supporting ICSI contribution to currently alarming ASD increase are lacking, exploration of underlying molecular mechanisms would strengthen possible associations. In the meanwhile, ICSI use should be restricted to male-factor infertility cases.

"Prenatal/fetal programming," implying structural/functional disorders of developing tissues/organs, consequent to an adverse intrauterine environment leading to asymmetric intrauterine growth restriction (IUGR), predisposes to metabolic syndrome and noncommunicable diseases in adulthood, in the framework of the "Developmental Origins of Health and Disease" (DOHaD) concept. DOHaD consequences are associated with adipose tissue, particularly the visceral one, occurring in relative abundance in IUGR infants. Adipose tissue secretes numerous hormones, collectively called adipocytokines, as leptin, adiponectin, ghrelin, resistin, apelin, visfatin, omentin, vaspin, preadipocyte factor-1 (Pref-1), fatty acid-binding protein-4, lipocalin-2, and others, implicated in fetal growth, body metabolism, energy homeostasis, and insulin resistance. Early identification of adipocytokines as biomarkers predicting later metabolic disorders/diseases in IUGR individuals, enabling relevant protective interventions, would be of utmost importance. Current data do not support this perspective, due to controversial results in the literature, with the eventual exception of visfatin and possibly Pref-1.

Background: Lipocalin-2 (LCN-2) has been identified as an osteoblast-secreted hormone regulating immunity, inflammation and metabolic homeostasis and has emerged as a diagnostic and prognostic biomarker for acute kidney injury in neonates. We investigated the impact of fetal growth on antepartum maternal serum, cord serum and breast milk LCN-2 concentrations and the associations of the latter with perinatal parameters., Methods: Maternal serum, cord serum and breast milk LCN-2 concentrations were measured by ELISA in samples from 80 mothers who delivered 40 appropriate (AGA), 20 large for gestational age (LGA) and 20 intrauterine growth restricted (IUGR) neonates, classified by customized weight centiles. LCN-2 concentrations were associated with birth weight, customized centile, gender, maternal age and delivery mode., Results: Antepartum maternal serum LCN-2 concentrations were significantly higher in women delivering AGA infants compared to the other two groups. Cord blood LCN-2 concentrations were significantly higher compared to maternal ones; furthermore, they were significantly elevated in the IUGR group compared to the LGA one ( p = .019). Lowest concentrations were detected in breast milk, which did not differ between the three growth groups. A negative correlation was documented between cord blood LCN-2 concentrations and customized centiles ( r : -0.304, p = .007)., Conclusions: The higher cord serum LCN-2 concentrations, compared to maternal ones, may point to its fetal origin and potential role in intrauterine growth. The negative correlation of cord LCN-2 concentrations with customized centiles, possibly implies reduced nephron endowment/subclinical kidney damage in IUGR neonates. The extremely low LCN-2 breast milk concentrations could imply that the secretion of LCN-2 from maternal circulation to breast milk is not influenced by factors leading to intrauterine growth pathology.

Intraventricular hemorrhage (IVH) is a main complication of prematurity, inversely associated with gestational age and birth weight. Low-grade IVH (I and II), diagnosed by cranial ultrasound, had long been considered rather not to affect neurodevelopmental and motor outcome, a view challenged by several literature reports. However, diversity in studies design, periods of subjects' collection, cohort characteristics, demographic data, maternal or neonatal comorbidities, neuroimaging methods, evaluation tools, short-or-long-term follow-up by the same or different examiners, as well as other parameters and confounders make comparisons among reports very difficult, not allowing solid conclusions. Older, but also newer investigations claim both possible outcomes: impairment or not of cognitive and motor abilities in very preterm infants with low-grade IVH. Thus, the current suggestion in the relevant literature is not to rely only on the results of cranial ultrasounds, but to also implement classic, or even more advanced MRI techniques at term equivalent age to preterm infants with grade I or II IVH. In addition, the continuation of close follow-up during school age is warranted.

Objective: Lactation is associated with a dramatic increase of maternal bone turnover, leading to a reversible bone loss. Early life nutrition may influence later osteoporosis risk. Proteins synthesized by the group of wingless (Wnt) genes are key mediators of osteoblastogenesis and bone formation. We aimed to investigate maternal milk and serum concentrations of the inhibitors of the Wnt signaling pathway, Dickkopf-1 (DKK-1) and sclerostin. Material and methods: In 80 women, maternal milk and serum concentrations of DKK-1 and sclerostin were determined by ELISA on the 3rd-4th day postpartum. Concentrations were associated with various maternal, gestational and neonatal characteristics. Results: DKK-1 and sclerostin were detectable in early milk [mean ± SD: 817.17 ± 259.61 pg/mL, median (range) 258.04 (2452.40-53.17) pg/mL, respectively] at significantly lower concentrations than in maternal serum [mean ± SD: 3375.36 ± 416.75 pg/mL, median (range) 16 200.54 (58 832.00-3012.60) pg/mL, respectively], ( p  < .000). Maternal milk sclerostin concentrations positively correlated with respective serum ones ( r  = 0.599, p  = .000). Maternal serum and milk sclerostin concentrations positively correlated with maternal body mass index ( r  = 0.37, p  = .001 and r   =0.38, p  = .000, respectively), while maternal serum sclerostin concentrations were higher in primiparas ( p  = .002). Conclusion: DKK-1 and sclerostin are present in early human milk at significantly lower concentrations, compared with maternal serum, probably contributing to the short- and long-term benefits of mother's milk for bone health. Moreover, the large amounts of both substances in maternal serum may represent disruption of the Wnt cascade, contributing to the well-known lactation-associated bone loss, which seems to be greater in primiparas and obese mothers.

Objective: Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, which play a crucial role in genomic stability. Telomere shortening has been proposed as a biomarker for the onset of age-related diseases. This study aimed to determine whether restricted or increased intrauterine growth affects leukocyte telomere length (LTL) at birth. Materials and methods: One hundred sixty-five ( n  = 165) full-term neonates participated in the study. Fetuses were classified as intrauterine growth restriction (IUGR, n  = 21), large-for-gestational-age (LGA, n  = 15), or appropriate-for-gestational-age (AGA, n  = 129), based on customized birth-weight standards. Mixed arteriovenous cord blood samples were collected for isolation of leukocyte DNA. The LTL was measured using multiplex monochrome quantitative real-time PCR and telomeric restriction fragments through Southern blot analysis (terminal restriction fragment [TRF]). Results: Despite differences among groups in birth weight, length and head circumference, LTL did not differ among AGA (6.78 ± 0.58), IUGR (10.54 ± 1.80), and LGA (11.95 ± 2.42) neonates ( p  = .098). Cord blood IGF-1 and IGFBP-3 concentrations were higher in the LGA group. LTL positively correlated with birth length ( r  = 0.176, p  = .032). Conclusions: Intrauterine growth does not seem to affect LTL at birth. Further studies, comprising a larger sample size of IUGR, LGA, and AGA neonates, are required to determine whether growth at birth influences LTL.

This invited review aimed at presenting the evidence concerning neurodevelopmental outcomes, particularly cerebral palsy (CP), motor disability, cognitive impairment, mental retardation, any major disability, blindness and deafness in cases of twins, conceived after in vitro fertilization, presenting fetal/intrauterine growth restriction (FGR/IUGR) or being prematurely born. FGR/IUGR, prematurity and zygosity affect neurodevelopmental outcome; CP is higher in term infants, those presenting with FGR/IUGR, as well as in survivors of intrauterine co-twin death; cognitive ability of twins versus singletons mainly relates to confounding factors, as FGR/IUGR and prematurity, while evidence for differences in behavioral and psychiatric disorders between twins and singletons is limited. The impact of IVF per se has not been documented. Nevertheless, available literature, usually of heterogeneous and retrospective nature, diverges in the criteria for neurodevelopmental delay. Furthermore, differences in selection/exclusion criteria and small mixed cohorts, including the full range of complications, make comparison of the existing studies difficult. Future studies should focus in confirming the lack of IVF impact on twins' neurodevelopment and general health, in comparing long-term outcome of naturally conceived twins with those conceived following assisted reproduction techniques and in including evaluation of individual, longitudinal trajectories of growth, and development. In this respect, worldwide population-based registries will enable more precise description of neurodevelopmental outcomes among twins.

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.

Aim and Methods: Dried blood spots from 2149 newborns were examined to diagnose congenital cytomegalovirus (cCMV)., Results: Prenatal CMV-IgG antibodies had been measured during prenatal care in 1287 (60.3%) of mothers and 980 (76.1%) of them were found seropositive. cCMV incidence was 0.47%. All newborns were asymptomatic; 9/10 were born post nonprimary maternal infection; two developed sensorineural hearing loss., Conclusions: In a country where prenatal CMV testing is common and therefore a false sense of control might prevail, nonprimary maternal infection should not be overlooked. Indeed, women of childbearing age should be educated on CMV prevention measures irrespectively to their serostatus.

Background: Socioeconomic factors associated with twins/multiples have been sparsely studied., Methods: Data, regarding twin out of total births from 1996 to 2015, were extracted from databases of the Hellenic Statistical Authority and analyzed., Results: Twinning rate in Greece has increased from 1996 and onwards, in parallel with advanced maternal age and decline in total births. Higher twin rates are associated with higher maternal education, better paid parental occupations, and thus wealthier families, married maternal status, while immigrants present a lower twinning rate than Greeks. Lastly, the years of the economic crisis, starting in the year 2008 and still continuing, are characterized by a higher percentage of twins., Conclusions: Our findings should be mainly attributed to the postponement of fertility, as well as the treatment of infertility with transfer of multiple embryos, when assisted reproductive technologies are applied.

Background: Although socioeconomic disparities adversely affect health, studies referring to the "healthy immigrant effect" imply more favorable health outcomes in immigrants than natives. We aimed to investigate the impact of immigration on several perinatal parameters., Methods: Birth records (01/01/2010 - 31/12/2014) from a public maternity hospital in Athens, Greece were reviewed for maternal (ethnicity, age, delivery mode) and neonatal (gender, birthweight, gestational age) variables. Immigrants were classified by country of origin, according to Human Development Index. Comparison of results between Greeks and immigrants were made. Stratification by maternal age (< and ≥35 years) was conducted to test for confounding and interaction., Results: Almost one-third of 7506 deliveries applied to immigrants; 36.3% of Greeks and 19.2% of immigrants [risk ratio (RR) = 0.53, 95% confidence interval (CI) = 0.52-0.54] delivered at ≥35 years; 10.5% of Greek and 7.0% of immigrant neonates weighted <2500 g (RR = 0.67, 95% CI = 0.61-0.74); 10.9% of Greeks and 8.1% of immigrants were born <37 wks (RR = 0.74, 95% CI = 0.67-0.82); 55.7% of Greeks and 48.2% of immigrants delivered by caesarean section (RR = 0.87, 95% CI = 0.85-0.88)., Conclusion: We found that immigrant women deliver at a younger age, vaginally, more mature, and heavier neonates. Furthermore, we confirmed that the protective effect of immigrant status could not be explained by maternal age only.

Since 2008, Greece suffers a severe economic crisis. Adverse health outcomes have been reported, but studies on perinatal health are sparse. We aimed to examine the impact of economic crisis on perinatal parameters during early and established crisis periods. Birth records of 14 923 neonates, born in a public maternity hospital from 2005-2014, were reviewed for maternal (age, delivery mode) and neonatal (gender, birthweight, gestational age) variables. Univariable analysis tested the association of study variables with time-periods 2005-2007, 2009-2011 and 2012-2014. Multivariable logistic regression analysis identified factors independently associated with low birthweight (LBW) (<2500 g), prematurity (<37 weeks) and caesarean section (CS). During 2012-2014, compared to 2005-2007, LBW rate increased from 8.4 to 10.5% (RR 1.16; 95%CI 1.01-1.33); prematurity from 9.7 to 11.2% (RR 1.09; 95%CI 0.96-1.24), comprising mainly late-preterm neonates; CS from 43.2 to 54.8% (RR 1.21; 95%CI 1.16-1.26). Maternal age ≥30 years was risk factor for LBW, prematurity and CS; LBW was additional risk factor for CS. However, LBW and CSs increased during the study period, independently of maternal age. In conclusion, impaired perinatal parameters, manifested by increasing maternal age, LBW, prematurity and CS rate, were observed during the years of economic decline, with possible adverse consequences for later health.

Objective: Fetal macrosomia is associated with cardiac hypertrophy and increased cardiovascular risk. Cardiac biomarkers may play diagnostic/prognostic role in cardiovascular disease. We tested whether cardiac biomarkers are differentially expressed in cord blood samples of full-term singleton large-for-gestational-age (LGA), as compared to appropriate-for-gestational-age (AGA) pregnancies., Methods: Cardiotrophin-1 (CT-1), Titin, pentraxin (PTX-3) and soluble CD36 (sCD36) concentrations were determined in 80 cord blood samples from a) LGA pregnancies due to maternal diabetes (n = 8), overweight/obese (n = 11), excessive weight gain (n = 7), without specific pathology (n = 14), b) AGA normal pregnancies (controls, n = 40). Neonates were classified as LGA or AGA based on customized birth weight (BW) standards., Results: CT-1 and Titin concentrations were higher in LGA than AGA pregnancies (p < .001 and p = .023, respectively). A subgroup analysis (in the LGA group) showed increased CT-1 concentrations only in diabetic pregnancies. PTX-3 and sCD36 concentrations were similar in LGA and AGA fetuses. In the LGA group, PTX-3 concentrations positively correlated with birth-weight (r = .416, p = .008) and respective sCD36 concentrations (r = .443, p = .004)., Conclusion: Higher Titin concentrations in LGAs possibly represent a candidate molecular mechanism underlying the association between fetal macrosomia and cardiomyocyte/diastolic dysfunction. CT-1 is up-regulated only in LGAs exposed to maternal diabetes. PTX-3 and sCD36 are probably not affected by excessive fetal growth.

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: To determine maternal colostrum/serum concentrations of the bioactive substances irisin, adropin and copeptin and investigate their association with several perinatal parameters and pathologic conditions during pregnancy., Methods: In a cohort of 81 mothers with full-term deliveries, colostrum/serum concentrations of irisin, adropin and copeptin were prospectively evaluated by ELISA on Day 3-4 postpartum., Results: Copeptin and adropin were detectable in human colostrum at higher, while irisin at lower concentrations than in maternal serum (p < 0.001 in all cases). Colostrum adropin and copeptin concentrations positively correlated with maternal serum ones (r = 0.421, p < 0.001 and r = 0.304, p = 0.006, respectively)., Conclusions: Irisin, adropin and copeptin are present in colostrum and we speculate that they may be implicated in postnatal adaptation with respect to thermoregulation, vascular adaptation, glucose metabolism, lung function and fluid homeostasis. These findings may possibly enhance the necessity for early breastfeeding, particularly of infants born by cesarean section, who are prone to hypothermia, breathing disorders and dehydration.

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.

This report refers to preterm birth in Ancient Greece based on mythological, historical and archeological data. The two antique goddesses, patronesses of labor and birth, Artemis and Eileithyia, cared for full-term, as well as preterm infants, among them for the mythological preterms Dionysos and Eurystheus. The former was rapidly transported by Hermes and received special care by the nymphs Hyades in a mountain cave with "incubator" properties. Historical data are related to the nine months duration of a normal pregnancy, to the definition of "Elitomina" (preterms), the lower limit of viability, the causes for preterm birth, the existence of small for gestational age infants and relevant causes, the physical examination of neonates and postpartum care. Lastly, excavations in Athens and Astypalaia discovered burials - in wells or pots - of preterm infants with gestational age 24-37 weeks.

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 investigate a necrotizing enterocolitis (NEC) cluster of late preterm and term neonates (gestational age ≥34 weeks)., Methods: We conducted a descriptive and a case-control study. Medical records of neonates with modified Bell stage ≥ IB NEC and matched controls were reviewed, in addition to microbiological and environmental investigation. Study variables included maternal/delivery and neonatal factors, medications, procedures and feeding practices. Univariable/multivariable logistic regression analyses were performed for all and for stage ≥ II cases., Results: Out of 1841 late preterm and term neonates, 10 stage IB and 10 stage ≥ II [mean(SD) birthweight 2529.3 (493.04) g, gestational age 36.96 (1.48) weeks] presented with NEC symptomatology at mean 4.6 (range 2-8) days. Nearly all (19/20) resulted from high-risk pregnancies and received postpartum intermediate care. All were exclusively or partly formula fed. Most (14/20) were born by cesarean delivery. Eight underwent surgery, with no fatality. Intermediate care (p = 0.006), transient tachypnea (p = 0.049), not receiving breast milk (p = 0.019) and in addition intrauterine growth restriction (IUGR) (p = 0.017) for stage ≥ II cases were independently associated with NEC., Conclusions: Late preterm and term neonates in need of intermediate care, with IUGR and transient tachypnea were susceptible to NEC; feeding with breast milk was an important protective factor.

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.

This brief outline associates twins with several aspects of life in Ancient Greece. In Greek mythology twins caused ambivalent reactions and were believed to have ambivalent feelings for each other. Very often, they were viewed as the representatives of the dualistic nature of the universe. Heteropaternal superfecundation, which dominates in ancient myths, explains on one hand, the god-like qualities and, on the other hand, the mortal nature of many twins. An assumption is presented that legends referring to twins might reflect the territorial expansions of Ancient Greeks in Northern Mediterranean, around the Black Sea, in Asia Minor, as well as North East Africa. In conclusion, in Greek antiquity, twins have been used as transitional figures between myth and reality.

Objective: Intrauterine growth restriction (IUGR) has been associated with decreased supply of crucial substrates to the fetus and affects its growth and development by temporarily or permanently modifying gene expression and function. However, not all neonates born by calorie restricted mothers are IUGR and there are no reports regarding their brain protein expression vis-à-vis that of their IUGR siblings. Here, we investigated the expression of key proteins that regulate growth and development of the brain in non-IUGR newborn pups versus IUGR siblings and control pups., Methods: Rat brain proteins were isolated from each group upon delivery and separated by two-dimensional gel electrophoresis (2-DE)., Results: 14-3-3 Protein, calreticulin, elongation factor, alpha-enolase, fascin, heat-shock protein HSP90 and pyruvate kinase isozymes were significantly increased (p < 0.05) in samples obtained from IUGR newborn pups compared to non-IUGR. Conversely, collapsin response mediator proteins, heat-shock70 and peroxiredoxin2 were decreased in IUGR group compared to non-IUGR., Conclusions: In our experimental study, IUGR pups showed an altered proteomic profile compared to their non-IUGR siblings and non-IUGR controls. Thus, not all offspring of calorie-restricted mothers become IUGR with the accompanying alterations in the expression of proteins. The differentially expressed proteins could modulate alterations in the energy balance, plasticity and maturation of the brain.

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.

Objective: To investigate possible associations of the novel adipocytokines resistin, apelin and visfatin (implicated in the complex control of bone biology) with several biochemical determinants of bone turnover in maternal blood from normal pregnancies and pregnancies complicated by gestational hypertensive disorders (preeclampsia or pregnancy-induced hypertension)., Methods: Circulating maternal concentrations of resistin, apelin and visfatin were correlated with circulating 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 full-term pregnancies (20 normal and 20 complicated by gestational hypertensive disorders)., Results: In normal pregnancies, no correlation was recorded between maternal concentrations of adipocytokines and the above bone biomarkers. In pregnancies with gestational hypertensive disorders, maternal apelin concentrations negatively correlated with NTx ones (r = -0.489, p = 0.034), while maternal visfatin concentrations positively correlated with OPG ones (r = 0.464, p = 0.039)., Conclusions: No associations were found between maternal concentrations of all three studied adipocytokines and respective concentrations of bone biomarkers in normal pregnancies. By contrast, in pregnancies with gestational hypertensive disorders, maternal concentrations of apelin and visfatin correlated with respective concentrations of indices of bone turnover. Further prospective studies are needed to clarify these relationships.

Objective: To describe associations among maternal/gestational/neonatal characteristics and midpregnancy amniotic fluid concentrations of the main angiogenic markers vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)., Methods: In a cohort of 206 normal full-term pregnancies, midpregnancy amniotic fluid VEGF and PlGF reference values were recorded. Possible associations among the above concentrations and various parameters, such as maternal age and body mass index, race, parity, smoking, gestational age, delivery mode, birth-weight and fetal gender were investigated., Results: Midpregnancy amniotic fluid concentrations of both VEGF and PlGF increased with increasing gestational age (r = 0.173, p = 0.013 and r = 0.255, p < 0.001, respectively), whereas PlGF concentrations positively correlated with birth-weight (r = 0.154, p = 0.027). The effect of the other above-mentioned parameters on VEGF and PlGF concentrations was not significant., Conclusions: In normal pregnancies, midgestation amniotic fluid VEGF and PlGF concentrations positively correlate with gestational age. Furthermore, midgestation amniotic fluid PlGF concentrations may be a predictor of neonatal birth weight.

Objective: To investigate possible alterations in cord blood levels of adipokines, chemerin and obestatin (secreted by adipose tissue and associated with later development of insulin resistance/metabolic syndrome), as well as insulin, in large for gestational age (LGA) and appropriate for gestational age (AGA) pregnancies, granted that these groups differ in body fat mass and metabolic/endocrine mechanisms., Methods: Cord blood chemerin, obestatin, and insulin concentrations were prospectively measured in 40 LGA (9 born from diabetic and 31 from nondiabetic mothers) and 40 AGA singleton full-term infants., Results: Cord blood chemerin concentrations were significantly higher in LGA compared with AGA neonates (b = 38.91, SE 9.29, p < 0.001). In contrast, no significant differences in obestatin concentrations were observed between groups. Insulin levels were significantly elevated as customized centiles increased (b = 0.003, SE = 0.001, p = 0.032)., Conclusions: Higher chemerin concentrations in LGA neonates possibly reflect the increased adipose tissue in this group. Lack of difference between the two groups in circulating levels of obestatin-possibly a sensitive marker of insulin resistance-might be due to development of metabolic disorders later in life.

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.

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.

Objective: To examine the impact of oral glutamine (Gln) supplementation on gut integrity and on the incidence of necrotizing enterocolitis (NEC)/septicemia of premature neonates., Methods: Preterm neonates (n = 101, gestational age <34 weeks, birth weight <2000 g) were randomly allocated to receive from day 3 to day 30 postpartum, either oral Gln (0.3 g/kg/day, n = 51-Gln group) or placebo (caloreen-isocaloric, n = 50-control group). Intestinal permeability was determined from the urinary lactulose/mannitol recovery (L/M ratio) following their oral administration and assessed at three time points: day 2 (before first administration), day 7 and day 30 of life. The incidence of NEC and septicemia over the study period was also recorded., Results: A decrease of lactulose recovery at days 7 (p = 0.001) and 30 (p < 0.001) and a decrease of L/M ratio at day 7 (p = 0.002) were observed only in the Gln group. Lactulose recovery and L/M ratio at day 7 (p = 0.022 and p = 0.004, respectively), as well as lactulose recovery (p = 0.001), mannitol recovery (p = 0.042), and L/M ratio (p = 0.001) at day 30, were decreased in the Gln group as compared to controls. NEC and septicemia were lower in the Gln group at the end of the first week (p = 0.009 and p = 0.041, respectively) and up to the end of the study (p < 0.001 and p = 0.048, respectively)., Conclusion: Oral Gln administration may have beneficial effects on intestinal integrity and the overall incidence of NEC/septicemia in preterm infants.

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.

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

Objective: To determine postnatal changes in neonatal serum concentrations of interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and its soluble receptor (sIL-4R)., Methods: Forty-five healthy term neonates, 25 of the neonates' mothers and 27 healthy adults (controls) participated in the study. Cytokine concentrations were measured in blood samples from the umbilical cord, from the neonates on the 1st and 5th day after birth, from mothers and from controls., Results: IFN-gamma concentrations were significantly lower in the umbilical cord, compared to concentrations in the controls (p < 0.04), and increased significantly from the umbilical cord to levels in neonates on day 5 (p < 0.03). In mothers and the umbilical cord, IFN-gamma concentrations were dependent on the mode of delivery, being higher after vaginal delivery than after elective Cesarean section (p < 0.005; p < 0.006, respectively). IL-4 concentrations in the umbilical cord for 1-day and 5-day neonates were significantly elevated compared to those in mothers (p < 0.001; p < 0.0007; p < 0.0001, respectively) and controls (p < 0.05; p < 0.01; p < 0.006, respectively). sIL-4R concentrations in all neonatal samples were significantly elevated compared to those in controls (p < 0.0001), the highest being found in 1-day-old neonates. A strong negative correlation was found between IL-4 and sIL-4R concentrations in 1- and 5-day-old neonates (r = -0.48, p < 0.002; r = -0.45, p < 0.0065, respectively). Moreover, IFN-gamma/IL-4 ratio increased significantly from the umbilical cord to 5 days of life (p < 0.03)., Conclusions: Our findings indicate an earlier development of IL-4 than IFN-gamma, which could be viewed as a developmental characteristic in the ontogeny of the immune system.

This study investigated serum levels of basic fibroblast growth factor (b FGF), a potent angiogenic factor, during distinct periods of the female life and compared them with corresponding levels in age-matched males. Healthy females (n = 59) and males (n = 53) were included in the study, divided into six groups: fetuses (cord blood), neonates, children, adults (females in proliferative and secretory phase), pregnant and "elderly" men and women. Serum b FGF levels were measured by an enzyme immunoassay. No statistically significant difference was found between both genders. Blood levels in fetuses and neonates were significantly increased as compared to adults (p = 0.01, p = 0.02, respectively). Restricting the analysis to females, all age groups, but fetuses (p = 0.05), demonstrated no difference when compared to proliferative phase adults. In conclusion, b FGF serum levels do not differ between males and females and are elevated in fetal and neonatal life, when growth and development are enhanced.

This study investigated serum angiogenin levels of the potent angiogenic factor angiogenin, during fetal and neonatal life, childhood, adulthood, pregnancy and postmenopause and compared them with respective levels in age-matched males. Serum angiogenin levels were measured by an enzyme immunoassay in 139 healthy male and female subjects, allocated in the above six groups. Multiple linear regression applied (a) for both genders and (b) only for females showed serum angiogenin levels in adults to differ statistically highly significantly from levels in cord blood (P = 0.0001), neonates (P = 0.0001), children (P = 0.0001), and pregnant women (P = 0.01), but not from "elderly" subjects (P = 0.80). A significant difference existed between levels in the proliferative and secretory phase of the menstrual cycle (P = 0.006). Furthermore, a significant trend for serum angiogenin levels with advancing age groups was noted (P = 0.0001). In conclusion, serum angiogenin levels increase significantly from fetal life to adulthood, possibly implying additional biological functions to that of angiogenesis.