Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.

• Klíčová slova
• inflammation, metabolism, metabolomics, placenta, preterm birth,
• Publikační typ
• časopisecké články MeSH

Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.

• MeSH
• biologické markery MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• náchylnost k nemoci MeSH
• placenta metabolismus   MeSH
• předčasný porod diagnóza   etiologie   metabolismus   MeSH
• regulace genové exprese MeSH
• rizikové faktory MeSH
• stanovení celkové genové exprese MeSH
• těhotenství MeSH
• transkriptom * MeSH
• tryptofan metabolismus   MeSH
• výpočetní biologie metody   MeSH
• výsledek těhotenství MeSH
• zánět komplikace   etiologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• tryptofan MeSH

The aim of the study was to demonstrate that preterm birth (PTB) is associated with altered C19MC microRNA expression profile in placental tissues. Gene expression of 15 placental specific microRNAs (miR‑512‑5p, miR‑515‑5p, miR‑516‑5p, miR‑517‑5p, miR‑518b, miR‑518f‑5p, miR‑519a, miR‑519d, miR‑519e‑5p, miR‑520a‑5p, miR‑520h, miR‑524‑5p, miR‑525‑5p, miR‑526a and miR‑526b‑5p) was compared between groups: 34 spontaneous PTB, 108 preterm prelabor rupture of membranes (PPROM) and 20 term in labor pregnancies. Correlation between variables including relative microRNA quantification in placental tissues and the gestational age at delivery, white blood cell (WBC) count at admission and serum levels of C‑reactive protein at admission in patients with PPROM and PTB was determined. Expression profile of microRNAs was different between PPROM and term in labor pregnancies, PTB and term in labor pregnancies, and between gestational age‑matched PPROM and PTB groups. When compared with term in labor pregnancies, while C19MC microRNAs showed a downregulation in PPROM pregnancies (miR‑525‑5p), in PTB pregnancies C19MC microRNAs were upregulated (miR‑515‑5p, miR‑516‑5p, miR‑518b, miR‑518f‑5p, miR‑519a, miR‑519e‑5p, miR‑520a‑5p, miR‑520h, and miR‑526b‑5p) or showed a trend to upregulation (miR‑519d and miR‑526a). In comparison to PTB pregnancies, the PPROM group demonstrated a significant portion of downregulated C19MC microRNAs (miR‑516‑5p, miR‑517‑5p, miR‑518b, miR‑518f‑5p, miR‑519a, miR‑519d, miR‑519e‑5p, miR‑520a‑5p, miR‑520h, miR‑525‑5p, miR‑526a and miR‑526b‑5p). In the group of PPROM pregnancies, a weak negative correlation between the gestational age at delivery and microRNA gene expression in placental tissue for all examined C19MC microRNAs was observed. PTB pregnancies showed a positive correlation (miR‑512‑5p, miR‑515‑5p, miR‑519e‑5p) or a trend to positive correlation (miR‑516‑5p, miR‑518b, miR‑520h) between particular C19MC microRNAs and maternal WBC count at admission. Our study demonstrates that upregulation of C19MC microRNAs is a characteristic phenomenon of PTB. PPROM pregnancies have a tendency to produce lower levels of miR‑525‑5p. All examined C19MC microRNAs displayed decreased expression with advancing gestational age in PPROM group.

• MeSH
• C-reaktivní protein metabolismus   MeSH
• dospělí MeSH
• down regulace genetika   MeSH
• gestační stáří MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• multigenová rodina * MeSH
• novorozenec MeSH
• placenta metabolismus   MeSH
• porodní děj * MeSH
• předčasný odtok plodové vody krev   genetika   MeSH
• předčasný porod krev   genetika   MeSH
• stanovení celkové genové exprese * MeSH
• těhotenství MeSH
• upregulace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• C-reaktivní protein MeSH
• mikro RNA MeSH

OBJECTIVE: Concerns about differences in registration practices across countries have limited the use of routine data for international very preterm birth (VPT) rate comparisons. DESIGN: Population-based study. SETTING: Twenty-seven European countries, the United States, Canada and Japan in 2010. POPULATION: A total of 9 376 252 singleton births. METHOD: We requested aggregated gestational age data on live births, stillbirths and terminations of pregnancy (TOP) before 32 weeks of gestation, and information on registration practices for these births. We compared VPT rates and assessed the impact of births at 22-23 weeks of gestation, and different criteria for inclusion of stillbirths and TOP on country rates and rankings. MAIN OUTCOME MEASURES: Singleton very preterm birth rate, defined as singleton stillbirths and live births before 32 completed weeks of gestation per 1000 total births, excluding TOP if identifiable in the data source. RESULTS: Rates varied from 5.7 to 15.7 per 1000 total births and 4.0 to 11.9 per 1000 live births. Country registration practices were related to percentage of births at 22-23 weeks of gestation (between 1% and 23% of very preterm births) and stillbirths (between 6% and 40% of very preterm births). After excluding births at 22-23 weeks, rate variations remained high and with a few exceptions, country rankings were unchanged. CONCLUSIONS: International comparisons of very preterm birth rates using routine data should exclude births at 22-23 weeks of gestation and terminations of pregnancy. The persistent large rate variations after these exclusions warrant continued surveillance of VPT rates at 24 weeks and over in high-income countries. TWEETABLE ABSTRACT: International comparisons of VPT rates should exclude births at 22-23 weeks of gestation and terminations of pregnancy.

• Klíčová slova
• Euro-Peristat, international comparisons, preterm birth, stillbirths, very preterm,
• MeSH
• gestační stáří MeSH
• lidé MeSH
• novorozenec MeSH
• porodnost * MeSH
• předčasný porod epidemiologie   MeSH
• těhotenství MeSH
• výsledek těhotenství epidemiologie   MeSH
• vyspělé země MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Japonsko epidemiologie   MeSH
• Kanada epidemiologie   MeSH
• Spojené státy americké epidemiologie   MeSH

OBJECTIVE: Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level. METHODS: We used national aggregate birth data on multiple pregnancies, maternal age, gestational age (GA), stillbirth and neonatal death collected in the Euro-Peristat project (29 countries in 2010, N = 5 074 643 births). We also used European Society of Human Reproduction and Embryology (ESHRE) data on assisted conception and single embryo transfer (SET). The impact of MBR on outcomes was studied using meta-analysis techniques with random-effects models to derive pooled risk ratios (pRR) overall and for four groups of country defined by their MBR. We computed population attributable risks (PAR) for these groups. RESULTS: In 2010, the average MBR was 16.8 per 1000 women giving birth, ranging from 9.1 (Romania) to 26.5 (Cyprus). Compared to singletons, multiples had a nine-fold increased risk (pRR 9.4, 95% Cl 9.1-9.8) of preterm birth (<37 weeks GA), an almost 12-fold increased risk (pRR 11.7, 95% CI 11.0-12.4) of very preterm birth (<32 weeks GA). Pooled RR were 2.4 (95% Cl 1.5-3.6) for fetal mortality at or after 28 weeks GA and 7.0 (95% Cl 6.1-8.0) for neonatal mortality. PAR of neonatal death and very preterm birth were higher in countries with high MBR compared to low MBR (17.1% (95% CI 13.8-20.2) versus 9.8% (95% Cl 9.6-11.0) for neonatal death and 29.6% (96% CI 28.5-30.6) versus 17.5% (95% CI 15.7-18.3) for very preterm births, respectively). CONCLUSIONS: Wide variations in MBR and their impact on population outcomes imply that efforts by countries to reduce MBR could improve perinatal outcomes, enabling better long-term child health.

• MeSH
• dospělí MeSH
• fetální úmrtnost MeSH
• kojenec MeSH
• kojenecká mortalita MeSH
• lidé MeSH
• narození mrtvého plodu epidemiologie   MeSH
• novorozenec MeSH
• odumření plodu MeSH
• perinatální smrt * MeSH
• porodnost MeSH
• předčasný porod epidemiologie   mortalita   MeSH
• těhotenství mnohočetné * MeSH
• těhotenství MeSH
• věk matky MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

BACKGROUND: Hypothyroidism and/or autoimmune thyroid disorders (AITD) may contribute to spontaneous abortions (SpA). Cost-effectiveness analyses of thyroid screening in women after SpA are lacking. Our aim was to evaluate the cost-effectiveness of screening for AITD and/or hypothyroidism and their treatment in women after SpA with regard to their reproductive health. METHODS: We performed a cross-sectional non-randomized study with follow-up in 2008-2011 in the settings of Departments of Endocrinology and Obstetrics/Gynecology of a university hospital. We enrolled 258 women after SpA before the 12th gestational week and followed them for a median of 3 years. At enrollment, serum concentrations of thyroid stimulatory hormone (TSH), antibodies to thyroid peroxidase (TPOAb) and free thyroxine (FT4) were measured and thyroid ultrasound performed. Women with overt hypothyroidism were treated with levothyroxine (n = 45; 61.6%) and women with subclinical hypothyroidism or euthyroid AITD were treated (n = 28; 38.4%) or left untreated (n = 38; 14.7%). Euthyroid women without signs of AITD served as controls (n = 147; 57.0%). RESULTS: Of the 38 untreated women with AITD and/or subclinical hypothyroidism, 8 (21.1%) reported secondary infertility as compared to 16/147 (10.9%) controls and 3/73 (4.1%) treated women (p = 0.021). Treatment was associated with an increased rate of successfully completed subsequent pregnancies (increment of 6 newborns/100 women) and a savings of €19,539/100 women. Total costs per successfully completed pregnancy were €1,189 in controls, €1,564 in the treated, and €2,488 in the untreated women. CONCLUSIONS: Screening for thyroid disorders in women after SpA and treatment with levothyroxine is cost-saving and it improves the subsequent pregnancy rate.

• MeSH
• analýza nákladů a výnosů MeSH
• autoimunitní nemoci komplikace   diagnóza   farmakoterapie   MeSH
• autoprotilátky krev   MeSH
• dospělí MeSH
• hypotyreóza komplikace   diagnóza   farmakoterapie   MeSH
• jodidperoxidasa imunologie   MeSH
• lidé MeSH
• následné studie MeSH
• plošný screening ekonomika   MeSH
• průřezové studie MeSH
• samovolný potrat etiologie   MeSH
• těhotenství MeSH
• thyreotropin krev   MeSH
• thyroxin krev   ekonomika   terapeutické užití   MeSH
• úhrn těhotenství na počet žen v reprodukčním věku MeSH
• ženská infertilita etiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• jodidperoxidasa MeSH
• thyreotropin MeSH
• thyroxin MeSH