Ariadne Malamitsi-Puchner

Intrauterine growth restriction and adult disease: the role of adipocytokines.

Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve his/her intrinsic growth potential, due to anatomical and/or functional disorders and diseases in the feto-placental-maternal unit. IUGR results in significant perinatal and long-term complications, including the development of insulin resistance/metabolic syndrome in adulthood. The thrifty phenotype hypothesis holds that intrauterine malnutrition leads to an adaptive response that alters the fetal metabolic and hormonal milieu designed for intrauterine survival. This fetal programming predisposes to an increased susceptibility for chronic diseases. Although the mechanisms controlling intrauterine growth are poorly understood, adipose tissue may play an important role in linking poor fetal growth to the subsequent development of adult diseases. Adipose tissue secretes a number of hormones, called adipocytokines, important in modulating metabolism and recently involved in intrauterine growth. This review aims to summarize reported findings concerning the role of adipocytokines (leptin, adiponectin, ghrelin, tumor necrosis factor (TNF), interleukin-6 (IL6), visfatin, resistin, apelin) in early life, while attempting to speculate mechanisms through which differential regulation of adipocytokines in IUGR may influence the risk for development of chronic diseases in later life.

The role of adipocytokines in fetal growth

Cumulative evidence suggests that the origins of obesity may occur during fetal development. In this respect, the concept of “developmental programming” was introduced and supported by experimental and epidemiological data. This concept supports the idea that the nutritional and hormonal status during pregnancy could irreversibly interfere in metabolism control. The mechanisms responsible for this developmental programming remain poorly documented. However, recent research indicates that adipocytokines may play a critical role in this process. Thus, leptin, adiponectin, and the recently identified resistin, visfatin, and apelin, all exert effects on fat, muscle, and liver cells early in life. The aforementioned adipocytokines are secreted by adipocytes and human placenta during fetal life and may play a major role in the etiopathogenesis of the metabolic syndrome. This review will focus on the intrauterine expression of adipocytokines, their contribution to the hormonal control of fetal growth, and their role in restricted and exaggerated intrauterine growth.

Euthyroid Hyperthyrotropinemia in Children Born after in Vitro Fertilization

CONTEXT Assisted reproduction techniques are now commonly used. Although classic in vitro fertilization (IVF) started almost 30 yr ago, few long-term systematic prospective studies of children conceived with assisted reproduction have been performed. OBJECTIVE Our objective was to investigate thyroid function in children conceived after IVF vs. naturally conceived controls. POPULATIONS AND METHODS A total of 106 children conceived after classic IVF and 68 naturally conceived controls, aged 4-14 yr, were studied. All children were thoroughly examined, and serum T(3), T(4), TSH, anti-thyroid peroxidase, and anti-thyroglobulin antibodies were measured. A second TSH determination and a thyroid ultrasound were performed for TSH higher than 5 microIU/ml, and children were considered to have persistent hyperthyrotropinemia, if the TSH elevation was confirmed. RESULTS Seven IVF children but none of the controls had persistent elevations of circulating TSH, suggesting euthyroid hyperthyrotropinemia or subclinical primary hypothyroidism (P = 0.044). TSH was significantly higher in the IVF group than in controls (P = 0.046), whereas no significant differences in the concentrations of T(3) or T(4) were observed. None of the children had detectable circulating antithyroid antibodies in either group. CONCLUSIONS A significant elevation of serum TSH compatible with a mild TSH resistance of the thyroid were found in IVF children compared with controls. This was not due to the presence of antithyroid autoantibodies. We suggest that this might represent a slight epigenetic developmental abnormality related to the preimplantation manipulation of the embryo. Further studies are needed to confirm these findings and to better determine their etiopathogenesis and clinical significance.

Small for gestational age birth weight: impact on lung structure and function

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.

Blood visfatin concentrations in normal full-term pregnancies

Aim: To prospectively investigate blood visfatin concentrations during the perinatal period in normal pregnancies.

Omentin-1 and vaspin are present in the fetus and neonate, and perinatal concentrations are similar in normal and growth-restricted pregnancies

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.

Circulating apelin concentrations in mother/infant pairs at term

Aim: To prospectively investigate circulating concentrations of the adipokine and angiogenic factor apelin in mother/infant pairs and correlate them with respective insulin concentrations.

Fetal concentrations of the growth factors TGF-α and TGF-β1 in relation to normal and restricted fetal growth at term

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.

Perinatal role of hepcidin and iron homeostasis in full-term intrauterine growth–restricted infants

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).

Cord blood chemerin and obestatin levels in large for gestational age infants

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.