First- and Second-Trimester Reference Intervals for Thyroid Hormones during Pregnancy in “Rhea” Mother-Child Cohort, Crete, Greece

Estimation and interpretation of thyroid function tests in pregnant women is of utmost importance for maternal, fetal and neonatal health. Our objective was to calculate laboratory- and geography-specific reference intervals for thyroid hormones during pregnancy in an iodine-sufficient area of the Mediterranean, Crete, Greece. This project was performed in the context of “Rhea” mother-child cohort. Fulfillment of extensive questionnaires and estimation of free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and antithyroid antibodies were performed. The reference population was defined using inclusion criteria regarding thyroidal, obstetric, and general medical status of women. Reference interval for TSH was 0.05–2.53 μIU/mL for the first and 0.18–2.73 μIU/mL for the second trimester. 6,8% and 5,9% of women in the first and second trimester, respectively, had TSH higher than the upper reference limit. These trimester-specific population-based reference ranges are essential in everyday clinical practice for the correct interpretation of thyroid hormone values and accurate classification of thyroid disorders

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Estimation and interpretation of thyroid function tests in pregnant women is of utmost importance for maternal, fetal and neonatal health. Our objective was to calculate laboratory-and geography-specific reference intervals for thyroid hormones during pregnancy in an iodine-sufficient area of the Mediterranean, Crete, Greece. This project was performed in the context of "Rhea" mother-child cohort. Fulfillment of extensive questionnaires and estimation of free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and antithyroid antibodies were performed. The reference population was defined using inclusion criteria regarding thyroidal, obstetric, and general medical status of women. Reference interval for TSH was 0.05-2.53 μIU/mL for the first and 0.18-2.73 μIU/mL for the second trimester. 6,8% and 5,9% of women in the first and second trimester, respectively, had TSH higher than the upper reference limit. These trimester-specific population-based reference ranges are essential in everyday clinical practice for the correct interpretation of thyroid hormone values and accurate classification of thyroid disorders

Cord blood adipokines and their effect on fetal and early postnatal growth

Background: A substantial body of epidemiological evidence suggests that an adverse intrauterine environment, elicited by maternal dietary or placental insufficiency, may “program” susceptibility in the fetus for a low birth weight and a later development of cardiovascular or metabolic diseases such as obesity, insulin resistance and type 2 diabetes. On the other hand, increased birth weight has also been implicated in the development of metabolic disturbances. Maternal metabolic status with its various components, along with the thyroid status during pregnancy could influence the intrauterine environment substantially and represent a potential causative mechanism, however this hypothesis has not been adequately explored. In this regard, the quest for the study of in utero environment has generated an effort to identify biomarkers that could predict the risk of early development of obesity. Adipokines and particularly leptin are among the most promising markers examined. Recent work has highlighted the importance of this hormone during critical windows of development in the pathogenesis of programming related disorders with evidence that both central and peripheral mechanisms are involved. Aim: The overall aim of the project was to examine the effect of maternal metabolic and thyroid status during pregnancy on the regulation of pre- and postnatal growth (infancy and early childhood), via its possible effects of cord blood leptin (“intrauterine programming”)Specific aims included:1.creation of reference ranges for the levels of TSH, free T3 and T4 in pregnant women in Crete, 2.assessment of the relationship between thyroid disorders/serologic thyroid autoimmunity and pregnancy complications/birth outcomes, 3.evaluation of the relationship between early pregnancy metabolic syndrome and risk for gestational diabetes and preterm term,4.creation of reference ranges for the normal values of cord blood leptin, 5.evaluation of the effects of maternal weight before and during pregnancy on the levels of cord blood leptin, 6.study of the relationship between cord blood leptin and neonatal anthropometric measurements in the literature and performance of a meta analysis, and7.assessment of the relationship between cord leptin and fetal/infant and childhood growthMethods: The present analysis uses data from the “Rhea” birth cohort. The “Rhea” project is a mother-child study which examines prospectively a population-based cohort of pregnant women and their children at the prefecture of Heraklion, Crete, Greece. Pregnant women (Greek and immigrant) who became pregnant within a 12-month period, starting in February 2007, were contacted and asked to participate in the study. The first contact was made before 15 weeks’ gestation, at the time of the first major ultrasound examination, and participants were invited to provide blood and urine samples and to participate in a face-to-face interview. Women were contacted again at various times during pregnancy, at birth, at 8-10 weeks after delivery and for child follow-up at the 6th and 18th month, and at 4 years of age. Face-to face completed questionnaires together with self-administered questionnaires and medical records were used to obtain information on dietary, environmental and psychosocial exposures during pregnancy and early childhood. The study was approved by the ethical committee of the University hospital of Heraklion, Crete, Greece and all mothers provided written informed consent after complete description of the study.Analyses of all biological samples (maternal, umbilical cord blood and child serum) were performed in the Laboratory of Experimental Endocrinology, Biochemistry and Immunology of the University Hospital of Heraklion, Crete (Greece). The conduction of the meta analysis as well as the determination of reference ranges for the levels of maternal thyroid hormones and cord blood leptin for was performed using standard guidelines. Potential confounders included characteristics that have an established or potential association with the exposure (metabolic status, thyroid status and cord blood leptin) and/or the outcomes of interest (pregnancy complications, birth and growth outcomes).Univariate associations between dependent and independent variables were studied using Pearson’s Chi-square test for categorical variables and ANOVA tests for continuous ones. In cases of non-normally distributed variables, non-parametric Mann-Whitney or Kruskal-Walis tests were used instead.Associations of exposure with the outcomes of interest were estimated with multivariable log-binomial or log-Poisson regression models, for binary outcomes or, multivariable linear regression models for continuous outcomes after adjusting for confounders. We reported b coefficients and 95% CIs for all continuous outcomes, and relative risks (RRs) with 95% CIs for categorical outcomes. Effect modification was assessed through inclusion of the interaction term in the models and stratified analyses accordingly. All association testing was conducted assuming a 0.05 significance level and a two-sided alternative hypothesis.Statistical analysis was performed using the statistical package STATA, version 13 (StataCorp, College Station, TX, USA) and SPSS, version 18 (SPSS INC, Chicago, IL). ResultsLaboratory- and geography- specific reference intervals were calculated for thyroid hormones during early pregnancy in Crete (first trimester: TSH: 0.05-2.53 μIU/mL, free T3:2.36-8.01 pmol/L and free T4: 12.22-19.69 pmol/L and second trimester: TSH: 0.18-2.73 μIU/mL, free T3:2.73-8.12 pmol/L and free T4: 11.19-18.66 pmol/L.The combination of high TSH and thyroid autoimmunity was associated with a 4 fold increased risk for gestational diabetes (RR: 4.3, 95% CI = 2.1, 8.9). High TSH values without the presence of thyroid autoimmunity were associated with 10% increased risk of overall caesarean sections (RR: 1.1, 95% CI = 1.0, 1.2). Thyroid antibodies per se increased the risk of spontaneous preterm birth by 70% (RR: 1.7, 95%CI = 1.1, 2.8). The combination of high TSH and thyroid autoimmunity was associated with a 3-fold increased risk for low birth weight neonates (RR: 3.1, 95% CI = 1.2 – 8.0), while high TSH values without thyroid autoimmunity were also associated with increased risk for low birth weight neonates (RR: 2.6, 95% CI = 1.1, 5.9). Women with metabolic syndrome were in high risk for gestational diabetes (GDM, RR=3.17, 95 %CI: 1.06, 9.50).and preterm birth (relative risk (RR) = 2.93, 95% CI: 1.53, 5.58), whereas among the components of metabolic syndrome, the most significant risk factor for prematurity was hypertension (RR = 2.32, 95% CI: 1.28, 4.20). The risk for medically indicated preterm deliveries was increased in women with metabolic syndrome (RR = 5.13, 95% CI: 1.97, 13.38). Fetal weight growth restriction was associated with elevated levels of insulin in early pregnancy (RR = 1.14, 95% CI: 1.08, 1.20) and elevated levels of diastolic blood pressure (RR = 1.27, 95% CI: 1.00, 1.61).Regarding the meta analysis, a PubMed search was performed between 1994 and 2009 and manual search of reference lists of retrieved articles. Forty-four studies met the inclusion criteria. All studies reported a positive correlation between leptin levels and birth weight. The combined correlation coefficient (r) was 0.46 [95%CI 0.43, 0.5]. Statistically significant positive correlations were also found for birth length (r=0.29, 0.23-0.34) and ponderal index (r=0.36, 0.31-0.41). There was no indication of publication bias.The derived reference intervals of cord blood leptin levels for male neonates were 1.4 – 18.2 ng/mL and for females 2.0 – 25.8 ng/mL.Each 1 kg/m2 increase in pre-pregnancy BMI was associated with a 10% increased risk for delivering a neonate with high cord blood leptin levels, while maternal pre-pregnancy overweight/obesity increased two fold the risk of giving birth to a neonate with hyperleptinemia (adjusted RR: 2.1 [95% CI: 1.4, 3.2] after adjustment for confounders. Excessive weight gain during pregnancy, i.e. more than recommended, was associated with a 3-fold increased risk for cord blood hyperleptinemia (RR: 3.0, [95% CI: 1.5, 6.3]).High levels of log leptin were positively associated with birth weight (β-coef: 176.5 [95% CI: 133.0, 220.0]), head circumference (β-coef: 2.5 [95% CI: 0.7, 4.2]) and ponderal index (β-coef: 1.0 [95% CI: 0.6, 1.4]) after adjustment for confounders. In overweight-obese mothers, increased log leptin was associated with increased birth weight β-coef: 219.1g [95% CI: 152.3, 285.9]), while the effect was much lower for mothers with normal weight (β-coef: 150.5 g [95% CI: 93.1, 207.9]).In a multivariable analysis, higher cord blood leptin was strongly associated with slow weight gain during the first 3 and 6 months of age (RR: 1.23 [95%CI: 1.05, 1.45] and RR: 1.52 [95%CI: 1.09, 2.13] for slow weight gain, respectively). Conversely, low leptin levels at birth conferred an 80% higher risk of a rapid weight gain during the first 3 months of life (RR: 1.83 [95%CI: 1.17, 2.85]). Each SD increase in cord leptin was associated with decreased weight and height in all ages 2 to 4 years. Neonates born with low leptin levels had more than 1 cm increased height in early childhood, while those with higher cord leptin developed lower weight and BMI during this period. Cord blood leptin was not associated with any of the cardiometabolic risk factors measured in early childhood [skinfold thicknesses, blood pressure, lipid levels, CRP and adipose tissue hormones].ConclusionsThe aim of this thesis was the study of the intrauterine programming of neonatal and infant growth and the way this is affected by the maternal metabolic status. Maternal status was evaluated both with pre-pregnancy and gestational metabolic syndrome and obesity, as well as with thyroidal status in the first trimester of pregnancy. Both of these constituents of maternal metabolism proved able to affect the intrauterine milieu, lead to adaptive changes in organs and tissues and ultimately modify the pattern of neonatal growth. Both neonatal and infant growth predispose to the future development of metabolic syndrome and obesity in childhood and adult life. For the study of the in utero environment we used cord blood leptin which proved to be a valid biomarker capable to predict neonatal, infant and childhood growth.According to our results, metabolic syndrome during the first trimester of pregnancy (3.6% of Rhea population) was associated with preterm birth, while some of its components (insulin and diastolic pressure) correlated with intrauterine growth restriction. Additionally, increased maternal body weight, either pre-pregnancy (33.3% of mothers had an increased BMI) or during gestation (23.4% of mothers gained more than the recommended weight), had an impact on the intrauterine environment, as the latter was reflected on the levels of cord blood leptin. The correlation between maternal undernutrition and restricted fetal growth, low birth weight and ultimately increased risk for metabolic syndrome in adulthood were already known from the late ‘80s. With current data, one can hypothesize a transgenerational obesity cycle, whereby women with high pre-pregnancy BMI give birth to overweight children with a high risk to become obese later in life.Maternal thyroidal status during the first trimester of pregnancy was associated with an increased risk for the delivery of a low birth weight neonate, as well as with prematurity. The present study is the first study performed in pregnant women in the geographical area of Crete. Although the prevalence of thyroid autoimmunity was comparable to other countries, we observed a two-fold increased frequency of high TSH levels. Moreover, women with high TSH had a twofold higher risk for low birth weight, while the combined presence of high TSH and thyroid autoantibodies tripled this risk. The fundamental role of thyroid hormones in fetal growth and tissue maturation, through the anabolic roles of growth hormone and IGF-1, is well established.In our study, we assessed the value of cord blood leptin as a biomarker of neonatal and infant growth and its capability to predict childhood obesity. Specifically, leptin showed a potential to modulate intrauterine programming of childhood obesity, through its direct influence of neonatal growth (as the latter is reflected in the anthropometric measurements at birth), but also through its effect on the pattern of growth during early infancy and on early childhood BMI.In conclusion, both the pre- and the postnatal environment constitute critical periods for the determination of long-term metabolic risk. Leptin, with its pleiotropic actions, participates in the mechanisms of appetite, growth and metabolic rate early in life. Intrauterine exposure to an obesity-prone environment, along with a genetic predisposition, is capable of “programming: the metabolic profile of these children. Additional data on the short- and long-term consequences of the intrauterine exposure to leptin are necessary, in order to delineate the early determinants of obesity and develop preventive strategies to effectively prevent obesity and its metabolic consequences in childhood.Εισαγωγή: Ολοένα και αυξανόμενος όγκος ιατρικών μελετών προτείνει ότι αρκετές ασθένειες της ενήλικης ζωής προγραμματίζονται ενδομήτρια από το περιγεννητικό περιβάλλον. Η υπόθεση του εμβρυικού προγραμματισμού προτάθηκε από τον Barker τη δεκαετία του ’80, μετά από σειρά επιδημιολογικών παρατηρήσεων που συνέδεαν το χαμηλό βάρος γέννησης με αυξημένο κίνδυνο για αντίσταση στην ινσουλίνη, σακχαρώδη διαβήτη τύπου 2 και μεταβολικό σύνδρομο ενήλικης ζωής. Εναλλακτικά, το υψηλό βάρος γέννησης έχει ενοχοποιηθεί για την ανάπτυξη αντίστοιχων μεταβολικών διαταραχών. Το μητρικό μεταβολικό σύνδρομο με τις συνιστώσες του μαζί με το θυρεοειδικό προφίλ θα μπορούσαν να αποτελούν έναν υπεύθυνο αιτιολογικό μηχανισμό, ωστόσο η υπόθεση αυτή δεν έχει ερευνηθεί επαρκώς. Για τη μελέτη και εκτίμηση της ποιότητας της ενδομήτριας ζωής, γίνεται τα τελευταία χρόνια προσπάθεια ανεύρεσης αξιόπιστων βιολογικών δεικτών. Πολλά υποσχόμενη κατηγορία είναι οι ορμόνες που παράγονται από το λιπώδη ιστό και ονομάζονται αδιποκίνες. Κυριότερος εκπρόσωπος των αδιποκινών είναι η λεπτίνη, της οποίας η συνεισφορά στην εμβρυική και βρεφική ανάπτυξη αποτελεί αντικείμενο μεγάλου ερευνητικού ενδιαφέροντος. Σκοπός: Ο συνολικός στόχος αυτής της μελέτης είναι η εκτίμηση της επίδρασης του μητρικού μεταβολικού και θυρεοειδικού προφίλ στην ανάπτυξη τόσο προ- όσο και μετα-γεννητικά (βρεφική ηλικία και πρώιμη παιδική ηλικία), μέσω επίδρασης στη λεπτίνη ομφαλίου λώρου.Ειδικοί σκοποί:•η δημιουργία εύρους φυσιολογικών τιμών για τα επίπεδα της TSH, της ελεύθερης Τ3 και Τ4, σε εγκύους στην Κρήτη•η διερεύνηση της σχέσης μεταξύ νόσων του θυρεοειδούς / ορολογικής θυρεοειδικής αυτοανοσίας και επιπλοκών κύησης / περιγεννητικών αποτελεσμάτων•η διερεύνηση της σχέσης μεταξύ μεταβολικού συνδρόμου στην αρχή της κύησης και κίνδυνου για ανάπτυξη διαβήτη κύησης και για γέννηση πρόωρου ή υπολειπόμενης ενδομήτριας ανάπτυξης νεογνού•η δημιουργία εύρους φυσιολογικών τιμών λεπτίνης ομφαλίου λώρου•η αξιολόγηση της επίδρασης του μητρικού σωματικού βάρους πριν και κατά τη διάρκεια της εγκυμοσύνης στα επίπεδα λεπτίνης ομφάλιου λώρου•η μελέτη της σχέσης μεταξύ λεπτίνης ομφαλίου λώρου και νεογνικών ανθρωπομετρικών μετρήσεων στη βιβλιογραφία και η εκτίμηση του συνόλου των αποτελεσμάτων αυτών μέσω μιας μεταανάλυσης•η διερεύνηση της σχέσης μεταξύ λεπτίνης ομφαλίου λώρου και εμβρυικής/ βρεφικής και παιδικής ανάπτυξηςΜεθοδολογία: Η παρούσα μελέτη χρησιμοποιεί τον πληθυσμό μελέτης της προοπτικής μελέτης μητέρας-παιδιού «Ρέα». Η πρώτη συνάντηση με τις γυναίκες πραγματοποιήθηκε πριν από τη συμπλήρωση της 15ης εβδομάδας κύησης. Οι συμμετέχουσες κλήθηκαν να δώσουν δείγματα αίματος και ούρων και να συμμετέχουν στη συμπλήρωση ερωτηματολογίων με συνέντευξη. Στη συνέχεια, νέες συναντήσεις πραγματοποιήθηκαν τον 6ο μήνα της εγκυμοσύνης και κατά τον τοκετό. Σχετικά με την παρακολούθηση των παιδιών, ακολούθησε συνάντηση στους έξι και δεκαοκτώ μήνες, καθώς και τέσσερα έτη μετά τη γέννηση. Η συλλογή δεδομένων έγινε από ερωτηματολόγια, από τον ιατρικό φάκελο και την κλινική εξέταση μητέρων και παιδιών. Οι πληροφορίες που συλλέχτηκαν αφορούσαν πλήθος παραγόντων, όπως κοινωνικό-δημογραφικά στοιχεία, διατροφή, εκθέσεις σε περιβαλλοντικούς παράγοντες, τρόπο ζωής, ιατρικό ιστορικό, πορεία κύησης, νοσηρότητες, ανθρωπομετρικές μετρήσεις και άλλα. Η μελέτη εγκρίθηκε από την Επιτροπή Βιοηθικής και Δεοντολογίας του Πανεπιστημιακού Νοσοκομείου Ηρακλείου (AM: 96/6-2-2007) και όλοι οι συμμετέχοντες έδωσαν έγγραφη συγκατάθεση μετά από πλήρη περιγραφή της μελέτης. Οι αναλύσεις των βιολογικών δειγμάτων της μελέτης έγινε στο Βιοχημικό, Ενδοκρινολογικό και Ανοσολογικό Εργαστήριο του Πανεπιστημιακού Νοσοκομείου Ηρακλείου.Για τη θέσπιση εύρους φυσιολογικών τιμών θυρεοειδικών ορμονών και λεπτίνης ομφαλίου λώρου καθώς και για τη συγγραφή της μεταανάλυσης ακολουθήσαμε πρότυπες κατευθυντήριες οδηγίες.Οι συγχυτικοί παράγοντες που συμπεριλήφθηκαν στα τελικά πολυπαραγοντικά μοντέλα αποτελούνταν από μεταβλητές, με δυνητική ή τεκμηριωμένη σχέση με τις μεταβλητές «έκθεσης» ή/και «αποτελέσματος».Για τις μονοπαραγοντικές συσχετίσεις των κατηγορικών μεταβλητών, χρησιμοποιήθηκε ο έλεγχος Pearson chi-square ή το Fisher’s exact test, ενώ για τη σύγκριση συνεχών μεταβλητών οι δοκιμασίες T-test και οne way ANOVA για τους παραμετρικούς ελέγχους και οι δοκιμασίες Kruskal-Wallis και Mann-Whitney για τους μη παραμετρικούς.Για να μελετηθεί η επίδραση των επιμέρους «εκθέσεων» στα αντίστοιχα αποτελέσματα, εφαρμόστηκαν μοντέλα λογαριθμικής διωνυμικής παλινδρόμησης ή λογαριθμικής παλινδρόμησης κατά Poisson, μοντέλα λογιστικής παλινδρόμησης ή γραμμικής παλινδρόμησης, λαμβάνοντας υπόψη την ύπαρξη συγχυτικών παραγόντων. Η τροποποίηση αποτελέσματος εκτιμήθηκε με τη δοκιμασία του λόγου πιθανοφάνειας. Σε όλες τις αναλύσεις, ως επίπεδο στατιστικής σημαντικότητας ορίστηκε το p<0.05, ενώ υπολογίστηκαν τα διαστήματα εμπιστοσύνης στο 95%.Η στατιστική ανάλυση των δεδομένων έγινε με τη χρήση των στατιστικών πακέτων STATA, έκδοση 10.0 (StataCorp LP, College Station, Texas) και SPSS, έκδοση 18 (SPSS INC, Chicago, IL). Αποτελέσματα: Το εύρος φυσιολογικών τιμών για το 1ο τρίμηνο της κύησης ήταν: TSH 0.05 έως 2.53 μIU/mL, ελεύθερη Τ3 2.37 - 8.02 pmol/L και ελεύθερη Τ4 12.23 – 19.69 pmol/L. Για το δεύτερο τρίμηνο, τα αντίστοιχα διαστήματα αναφοράς ήταν: 0.18 – 2.73 μIU/mL για την TSH, 2.73 – 8.13 pmol / L για την ελεύθερη Τ3, και 11.20 - 18.66 pmol / L για την ελεύθερη T4.Ο συνδυασμός υψηλής TSH και ορολογικής αντιθυρεοειδικής αυτοανοσίας συσχετίστηκε με αυξημένο κατά τέσσερις φορές κίνδυνο για διαβήτη κύησης (RR: 4.3, 95 % CI = 2.1 - 8.9) και η ύπαρξη υψηλών τίτλων αντιθυρεοειδικών αντισωμάτων αύξησε τον κίνδυνο για αυτόματο πρόωρο τοκετό κατά 70% (RR: 1.7, 95 % CI = 1.1 με 2.8). Η υψηλή TSH σχετίστηκε με τριπλάσιο κίνδυνο για γέννηση χαμηλού βάρους νεογνού είτε στον ορό υπήρχαν αντιθυρεοειδικά αντισώματα (RR: 3.1 , 95 % CI = 1.2 – 8.0), είτε όχι (RR: 2.6, 95 % CI = 1.1 - 5.9).Οι γυναίκες με μεταβολικό σύνδρομο είχαν υψηλότερο κίνδυνο για την ανάπτυξη διαβήτη κύησης (RR = 3.17, 95%CI: 1.06 - 9.50) και γέννηση πρόωρου νεογνού (relative risk (RR) = 2.93, 95% CI: 1.53, 5.58), ενώ μεταξύ των συνιστωσών του μεταβολικού συνδρόμου, ο πιο σημαντικός παράγοντας κινδύνου για προωρότητα ήταν η υπέρταση (RR: 2.92, 95%CI : 1.57 – 9.77). Η γέννηση νεογνού με υπολειπόμενη ενδομήτρια ανάπτυξη συσχετίστηκε με αυξημένα επίπεδα ινσουλίνης στην αρχή της κύησης (RR: 1.14, 95%CI: 1.08 - 1.20) και αυξημένα επίπεδα διαστολικής αρτηριακής πίεσης (RR: 1.27, 95%CI: 1.00 – 1.61).44 μελέτες πληρούσαν τα κριτήρια για εισαγωγή στη μεταανάλυση διερεύνησης της σχέσης μεταξύ λεπτίνης ομφαλίου λώρου και νεογνικών ανθρωπομετρικών μετρήσεων. Όλες οι μελέτες ανέδειξαν μια μέτρια αλλά σαφή θετική συσχέτιση μεταξύ επιπέδων λεπτίνης ομφαλίου λώρου και βάρους γέννησης, με συνολικό συντελεστή συσχέτισης (r) 0.46 [95%CI 0.43, 0.50]. Στατιστικά σημαντική θετική συσχέτιση βρέθηκε και μεταξύ λεπτίνης και μήκους γέννησης (r = 0.29 [95%CI 0.23, 0.34]), όπως επίσης και με το δείκτη παχυσαρκίας ponderal index (r = 0.36 [95%CI 0.31,0.41]). Δεν υπήρχαν ενδείξεις για ύπαρξη σφάλματος δημοσίευσης. Τα διαστήματα αναφοράς για τα φυσιολογικά επίπεδα λεπτίνης ομφαλίου λώρου ήταν 1.4 – 18.2 ng / mL για τα άρρενα και 2.0 – 25.8 ng / mL για τα θήλεα νεογνά.Οι μητέρες που ήταν υπέρβαρες/παχύσαρκες πριν από την εγκυμοσύνη είχαν διπλάσιο κίνδυνο για υπερλεπτιναιμία ομφάλιου λώρου (RR: 2.1 [95% CI: 1.4, 3.2]), ενώ η αύξηση του σωματικού βάρους κατά τη διάρκεια της εγκυμοσύνης, πάνω από τις ευρωπαϊκές συστάσεις, συνδέθηκε με τρεις φορές αυξημένη λεπτίνη ομφάλιου λώρου (RR: 3.0 [95% CI: 1.5, 6.3]).Τα υψηλά επίπεδα λεπτίνης συσχετίστηκαν θετικά με το βάρος γέννησης (β- coef : 176.5 [ 95 % CI: 133.0, 220.0]), την περίμετρο κεφαλής (β-coef: 2.5 [95 %CI: 0.7, 4.2]) και το δείκτη παχυσαρκίας ponderal index, (β - coef: 1.0 [95 %CI : 0.6 , 1.4]), ενώ η υπολεπτιναιμία με τον πρόωρο τοκετό (OR : 6,9 [95 % CI: 3.6– 13.2]).Τα νεογνά που γεννήθηκαν με χαμηλά επίπεδα λεπτίνης ομφάλιου λώρου είχαν σχεδόν 80% αυξημένο κίνδυνο για ταχεία αύξηση του σωματικού βάρους κατά τους πρώτους 3 μήνες της ζωής (RR : 1.83 [95 % CI: 1.17, 2.85]). Αντίθετα, η αύξηση της λεπτίνης κατά μια σταθερά απόκλιση, σχετίστηκε με αυξημένο κίνδυνο για αργή αύξηση σωματικού βάρους τόσο κατά τους 3 όσο και κατά τους 6 πρώτους μήνες ζωής (RR : 1.23 [95 % CI : 1.05 , 1.45] και RR: 1.52 [95 % CI : 1.09 , 2.13]). Τα αυξημένα επίπεδα λεπτίνης ομφαλίου λώρου σχετίστηκαν με ελαττωμένο βάρος και ύψος σε όλες τις ηλικίες από τα 2 έως τα 4 έτη. Η λεπτίνη ομφαλίου λώρου δεν σχετίστηκε με κανένα κ

Detection of KPC, NDM and VIM-Producing Organisms Directly from Rectal Swabs by a Multiplex Lateral Flow Immunoassay

We report a preliminary evaluation of the NG-Test CARBA 5 immunochromatographic assay for detecting carbapenemases directly from rectal swabs on the same day of sampling. Thirty fecal swabs were examined for carbapenemase-producing organisms (CPOs) by conventional culture, PCR, and NG-Test CARBA 5. Each sample was tested by the immunochromatographic assay five times, including direct testing and incubation in trypticase soy broth for 1, 2, 3, and 4 h. Twenty patients yielded CPOs by culture. Immunochromatographic and PCR results were concordant and detected the same 25 carbapenemases (11 KPC, 8 VIM, and 6 NDM). In five cases, we detected co-carriage of KPC and VIM. Compared with PCR, the sensitivity of NG-Test CARBA 5 for the detection of KPC, VIM, and NDM was 80% without incubation, 88% with one hour, 92% with two, and 100% with three hours incubation, while specificity was 100% for all time points. All samples containing adequate fecal content were detected by NG-Test CARBA 5 concordantly with PCR, without incubation. NG-Test CARBA 5 is a reliable test that rapidly detects the presence of carbapenemases at the same day of sampling, directly from rectal swabs. It thus provides early information to guide antimicrobial treatment and infection control interventions

Comparative Evaluation of Vitek 2 and Etest versus Broth Microdilution for Ceftazidime/Avibactam and Ceftolozane/Tazobactam Susceptibility Testing of <i>Enterobacterales</i> and <i>Pseudomonas aeruginosa</i>

Ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) are novel antibiotics with activity against multidrug-resistant Gram-negative pathogens. Nevertheless, resistance to both agents has been reported emphasizing the need for accurate and widely accessible susceptibility testing. In the present study, Vitek 2 and Etest CAZ and C/T MIC results for 100 non-repetitive clinical isolates (83 Enterobacterales and 17 P. aeruginosa, whereof 69 challenge isolates) were compared to the standard broth microdilution (BMD) method. EUCAST breakpoints were used for assessing the categorical (CA) and essential (EA) agreement between the methods along with the corresponding error rates. The Vitek 2 performance was comparable to that of BMD for testing both antimicrobial agents exceeding the ISO requirements (CA 98–99%, EA 96–100%, major errors (MEs) 0–1%, very major error (VMEs) 1%). Likewise, the Etest provided accurate results for CZA and C/T testing against Enterobacterales and P. aeruginosa, respectively (CA 100%, EA 97–100%, MEs 0%, VMEs 0%). On the contrary, EA of 85% and 6% VME rate were found for CZA Etest and P. aeruginosa. Overall, Vitek 2 measurements of CZA and C/T susceptibility correlated closely with the reference BMD, indicating that it can represent a suitable alternative to BMD for susceptibility testing of Enterobacterales and P. aeruginosa. The Etest did not fulfill the ISO performance criteria of EA and VME for CZA and P. aeruginosa. Further studies are needed to assess whether the Etest allows a reliable assessment of CZA and C/T EUCAST MICs

Leptin levels in cord blood and anthropometric measures at birth: a systematic review and meta-analysis

P&gt;Karakosta P, Chatzi L, Plana E, Margioris A, Castanas E, Kogevinas M. Leptin levels in cord blood and anthropometric measures at birth: a systematic review and meta-analysis. Paediatric and Perinatal Epidemiology 2010. The role of intrauterine environment in the development of obesity is increasingly recognised. Adipokines and specifically leptin have been examined as potential biomarkers predicting early development of obesity. We conducted a systematic review and meta-analysis of the epidemiological evidence for the association between leptin levels in cord blood and anthropometric measurements at birth in healthy mother-newborn pairs. A PubMed search was performed between 1994 and 2009 and manual search of reference lists of retrieved articles. Forty-four studies met the inclusion criteria set. All studies reported a positive correlation between leptin levels and birthweight. The combined correlation coefficient (r) was 0.46 [95%CI 0.43, 0.50]. Leptin levels explained 21% of variation in birthweight. Results were similar in males (r = 0.55; 0.40, 0.68) and females (r = 0.60; 0.50, 0.69), and between Caucasians (r = 0.45; 0.39, 0.51) and eastern Asian populations (r = 0.47; 0.37, 0.55). Statistically significant positive correlations were also found for birth length (r = 0.29; 0.23, 0.34) and ponderal index (r = 0.36; 0.31, 0.41). There was no indication of publication bias (Egger’s test P-value = 0.23). This meta-analysis shows a clear but moderate correlation between leptin levels in cord blood and birthweight that is observed in different population groups

Metabolic syndrome in early pregnancy and risk of preterm birth

The authors determined the association between metabolic syndrome in early pregnancy (mean, 11.96 weeks) and the risk of preterm birth in the mother-child cohort study (>Rhea> Study) in Crete, Greece, 2007-2009. Maternal fasting serum samples were collected, and blood pressure was measured at the time of the first major ultrasound examination (n=625). Multivariable log-binomial regression models were used. Women with metabolic syndrome were at high risk for preterm birth (relative risk (RR)=2.93, 95% confidence interval (CI): 1.53, 5.58), with the highest risk observed for medically indicated preterm births (RR=5.13, 95% CI: 1.97, 13.38). Among the components of metabolic syndrome, the most significant risk factor was hypertension (RR=2.32, 95% CI: 1.28, 4.20). An elevation of 10 mm Hg in diastolic blood pressure increased the relative risk for preterm birth by 29% (RR= 1.29, 95% CI: 1.08, 1.53), while a per unit increase in the low density lipoprotein/high density lipoprotein cholesterol ratio increased this risk by 19% (RR=1.19, 95% CI: 1.02, 1.39). Fetal weight growth restriction was associated with elevated levels of insulin (RR=1.14, 95% CI: 1.08, 1.20) and diastolic blood pressure (RR=1.27, 95% CI: 1.00, 1.61) in early pregnancy. These findings suggest that women with metabolic syndrome in early pregnancy had higher risk for preterm birth.This work was partly supported by the European Union Integrated Project NewGeneris, 6th Framework Program (contract FOOD-CT-2005-016320), and by the European Union-funded project HiWATE, 6th Framework Program (contract Food-CT-2006-036224).Peer Reviewe

Gender-specific reference intervals for cord blood leptin in Crete, Greece

Cord leptin is a biomarker of fetal growth and adiposity with a role in predicting weight gain during the first months of life and childhood obesity. Our objective was to calculate gender-specific reference intervals for cord blood leptin in healthy neonates in Crete, Greece. We used data from the prospective mother-child cohort (”Rhea” study) in Crete, Greece. The analysis included 398 neonates chosen with strict inclusion criteria based on maternal and fetal characteristics. Cord leptin reference intervals for male neonates were 1.4-18.2 ng/mL and for females 2.0-25.8 ng/mL. Females had higher leptin levels (median 7.4; IQR 4.7-10.9) compared to males (median 4.9; IQR 3.2-7.6) (p &lt; 0.001). Conclusion Gender-specific reference ranges are essential in clinical practice for correct interpretation of leptin values in cord blood and early detection of childhood obesity

Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes

Context: Maternal thyroid dysfunction, especially in early pregnancy, may lead to pregnancy complications and adverse birth outcomes. Few population-based prospective studies have evaluated these effects and results are discrepant. Objective: We examined the association of thyroid function and autoimmunity in early pregnancy with adverse pregnancy and birth outcomes. Setting and Participants: The study used data from the prospective mother-child cohort >Rhea> study in Crete, Greece. A total of 1170 women with singleton pregnancies participated in this analysis. Maternal serum samples in the first trimester of pregnancy were tested for thyroidhormones (TSH, free T4, and free T3) and thyroid antibodies (thyroid peroxidase antibody and thyroglobulin antibody). Multivariable log-Poisson regression models were used adjusting for confounders. Main Outcome Measures: Outcomes included gestational diabetes, gestational hypertension/preeclampsia, cesarean section, preterm delivery, low birth weight, and small-for-gestational-age neonates. Results: The combination of high TSH and thyroid autoimmunity in early pregnancy was associated with a 4-fold increased risk for gestational diabetes [relative risk (RR) 4.3, 95% confidence interval (CI) 2.1- 8.9)] and a 3-fold increased risk for low birth weight neonates (RR 3.1,95%CI 1.2- 8.0) after adjustment for several confounders. Women positive for thyroid antibodies without elevated TSH levels in early pregnancy were at high risk for spontaneous preterm delivery (RR 1.7, 95% CI 1.1-2.8), whereas the combined effect of high TSH and positive thyroid antibodies did not show an association with preterm birth. Conclusions: High TSH levels and thyroid autoimmunity in early pregnancy may detrimentally affect pregnancy and birth outcomes. Copyright © 2012 by The Endocrine Society.This work was supported by the European Uniuon Integrated Projects NewGeneris, Sixth Framework Programme (Contract FOOD-CT-2005-016320), and Chicos, Seventh Framework Programme (Contract Health-F2-2009-241604).Peer Reviewe