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Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 μg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Objective: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA)., Design: Prospective, observational cohort study., Setting: Tertiary maternity hospital in Australia., Population: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32 +0  weeks) and 109 (30.0%) late FGR (≥32 +0  weeks)., Methods: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring., Main Outcome Measures: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained., Results: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46)., Conclusions: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Problem: Preterm birth (PTB) is a leading cause of infant mortality and morbidity. The pathogenesis of PTB is complex and involves many factors, including socioeconomy, inflammation and infection. Asymmetric dimethylarginine, ADMA and symmetric dimethylarginine, SDMA are involved in labor as inhibitors of nitric oxide, a known relaxant of the uterine smooth muscles. Arginines are scarcely studied in relation to PTB and we aimed to investigate arginines (ADMA, SDMA and L-arginine) in women with spontaneous PTB and term birth., Methods of the Study: The study was based on data from the population-based, prospective cohort BASIC study conducted in Uppsala County, Sweden, between September 2009 and November 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at the onset of labor from women with spontaneous PTB (n = 34) and term birth (n = 45). We also analyzed the inflammation markers CRP, TNF-R1 and TNF-R2 and GDF-15., Results: Women with spontaneous PTB had higher plasma levels of ADMA (p < 0.001), and L-Arginine (p = 0.03). In addition, inflammation marker, TNF-R1 (p = 0.01) was higher in spontaneous PTB compared to term birth. Further, in spontaneous PTB, no significant correlations could be observed when comparing levels of arginines with inflammation markers, except ADMA versus CRP., Conclusions: These findings provide novel evidence for the potential involvement of arginines in the pathogenesis of spontaneous PTB and it seems that arginine levels at labor vary independently of several inflammatory markers. Further research is warranted to investigate the potential of arginines as therapeutic targets in the prevention and management of spontaneous PTB., (© 2024 The Author(s). American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Objectives: To identify and internally validate metabolites predictive of spontaneous preterm birth (sPTB) using multiple machine learning methods and sequential maternal serum samples, and to predict spontaneous early term birth (sETB) using these metabolites., Design: Case-cohort design within a prospective cohort study., Setting: Cambridge, UK., Population or Sample: A total of 399 Pregnancy Outcome Prediction study participants, including 98 cases of sPTB., Methods: An untargeted metabolomic analysis of maternal serum samples at 12, 20, 28 and 36 weeks of gestation was performed. We applied six supervised machine learning methods and a weighted Cox model to measurements at 28 weeks of gestation and sPTB, followed by feature selection. We used logistic regression with elastic net penalty, followed by best subset selection, to reduce the number of predictive metabolites further. We applied coefficients from the chosen models to measurements from different gestational ages to predict sPTB and sETB., Main Outcome Measures: sPTB and sETB., Results: We identified 47 metabolites, mostly lipids, as important predictors of sPTB by two or more methods and 22 were identified by three or more methods. The best 4-predictor model had an optimism-corrected area under the receiver operating characteristics curve (AUC) of 0.703 at 28 weeks of gestation. The model also predicted sPTB in 12-week samples (0.606, 95% CI 0.544-0.667) and 20-week samples (0.657, 95% CI 0.597-0.717) and it predicted sETB in 36-week samples (0.727, 95% CI 0.606-0.849). A lysolipid, 1-palmitoleoyl-GPE (16:1)*, was the strongest predictor of sPTB at 12 weeks of gestation (0.609, 95% CI 0.548-0.670), 20 weeks (0.630, 95% CI 0.569-0.690) and 28 weeks (0.660, 95% CI 0.599-0.722), and of sETB at 36 weeks (0.739, 95% CI 0.618-0.860)., Conclusions: We identified and internally validated maternal serum metabolites predictive of sPTB. A lysolipid, 1-palmitoleoyl-GPE (16:1)*, is a novel predictor of sPTB and sETB. Further validation in external populations is required., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Problem: Vitamin D is well-known for having anti-inflammatory and immunomodulatory properties. Impaired maternal vitamin D status has been known to increase the risk of adverse pregnancy outcomes like pre-term birth. The present study aims to evaluate the impact of fetal cord serum 25-hydroxyvitamin D-mediated signaling in mediating inflammatory responses in placenta during pre-term birth., Method of Study: For the above purpose, cord serum 25 hydroxyvitamin D 25(OH)D were measured in term (n = 20) and pre-term (n = 20) born babies using ELISA. Vitamin D downstream signaling has also been checked in placenta (VDR, CYP27B1, cathelicidin LL37) along with expression of inflammatory markers (S100A8, HMGB1, TLR2, p-NF-kappaB) using Western blotting and immunohistochemistry. Pearson correlation model was used to do correlation study., Results: Compared with term born babies (59.31 ± 3.476), decline in cord serum 25(OH)D levels is observed in pre-term born babies (22.26 ± 1.083, P = <0.0001) that showed strong positive correlation with gestational age (r = .9368***) and birthweight (r = .9559***). On the other hand, vitamin D signaling markers were found to be downregulated and inflammatory markers were upregulated in placental tissue of pre-term born babies., Conclusion: Thus, our study demonstrated that insufficient cord 25(OH)D levels may disturb the homeostasis of inflammation in placenta. Altered cord serum 25(OH)D mediated anti-inflammatory signaling may be acting as trigger signals in modulating inflammatory responses in placenta and eliciting premature activation of spontaneous labor in pre-term birth., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pregnant women infected with HEV develops adverse pregnancy outcomes like, abortions, intrauterine fetal death, still births, neonatal deaths, preterm delivery and maternal mortality., Aim: To correlate oestrogen and its receptors ESR1α and ESR2β levels with HEV-associated feto-maternal outcomes., Material & Methods: A total of 142 pregnant women with HEV infection and 142 pregnant controls were included in study from Department of Obstetrics & Gynaecology and Department of Medicine, Maulana Azad Medical College (MAMC) and associated Lok Nayak Hospital (LNH), New Delhi. Three millilitre of blood sample was collected in plain for quantification of oestrogen, and its receptors ESR1α and ESR2β using commercially available third-generation ELISA kits., Results: The levels of oestrogen, ESR1α and ESR2β were considerably higher in HEV-infected pregnant women (20.11 ± 18.19 ng/mL, 10.58 ± 3.27 ng/mL, 10.42 ± 4.71 ng/mL respectively) than pregnant controls (11.74 ± 6.42 ng/mL, 9.11 ± 1.63 ng/mL, 9.01 ± 1.18 ng/mL respectively)(P < 0.0001). It was found that oestrogen levels were significantly higher in pregnant women infected with HEV who had preterm delivery, low birth weight babies and fetal loss (19.64 ± 17.60 ng/mL, 19.71 ± 17.63 ng/mL, 33.62 ± 23.20 ng/mL respectively) than who had full term delivery, average birth weight babies and live babies (11.71 ± 8.77 ng/mL, 11.99 ± 9.44 ng/mL, 16.58 ± 14.98 ng/mL respectively)(P < 0.05). A significant negative correlation was observed between baby birth weight and oestrogen levels in HEV-infected pregnant women., Conclusion: The high level of oestrogen plays an important role in preterm delivery, low birth weight babies and fetal mortality in pregnant women with HEV infection through placental dysfunction. Moreover, oestrogen level is a significant predictor for preterm delivery and maternal mortality and ESR2β levels is a significant predictor for maternal mortality in pregnant women infected with HEV., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To estimate the association between lipoprotein particle concentrations in pregnancy and gestational age at delivery., Design: Prospective cohort study., Setting: The study was conducted in the USA at the University of North Carolina., Population: We assessed 715 women enrolled in the Pregnancy, Infection, and Nutrition study from 2001 to 2005., Methods: Fasting blood was collected at two time points (<20 and 24-29 weeks of gestation). Nuclear magnetic resonance (NMR) quantified lipoprotein particle concentrations [low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low density lipoprotein (VLDL)] and 10 subclasses of lipoproteins. Concentrations were assessed as continuous measures, with the exception of medium HDL which was classified as any or no detectable level, given its distribution. Cox proportional hazards models estimated hazard ratios (HR) for gestational age at delivery adjusting for covariates., Main Outcome Measures: Gestational age at delivery, preterm birth (<37 weeks of gestation), and spontaneous preterm birth., Results: At <20 weeks of gestation, three lipoproteins were associated with later gestational ages at delivery [large LDL NMR (HR 0.78, 95% CI 0.64-0.96), total VLDL NMR (HR 0.77, 95% CI 0.61-0.98), and small VLDL NMR (HR 0.78, 95% CI 0.62-0.98], whereas large VLDL NMR (HR 1.19, 95% CI 1.01-1.41) was associated with a greater hazard of earlier delivery. At 24-28 weeks of gestation, average VLDL NMR (HR 1.25, 95% CI 1.03-1.51) and a detectable level of medium HDL NMR (HR 1.90, 95% CI 1.19-3.02) were associated with earlier gestational ages at delivery., Conclusion: In this sample of pregnant women, particle concentrations of VLDL NMR , LDL NMR , IDL NMR , and HDL NMR were each independently associated with gestational age at delivery for all deliveries or spontaneous deliveries <37 weeks of gestation. These findings may help formulate hypotheses for future studies of the complex relationship between maternal lipoproteins and preterm birth., Tweetable Abstract: Nuclear magnetic resonance spectroscopy may identify lipoprotein particles associated with preterm delivery., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Low plasma cholesterol may be associated with preterm birth; however, results are mixed and limited primarily to high-income countries. Our objective was to determine whether maternal plasma lipid concentrations are associated with pregnancy duration. We performed a nested cohort (n = 320) study of pregnant Ghanaian women enrolled in a randomized controlled trial. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and triglyceride concentrations were analyzed in plasma at ≤20and 36 weeks gestation as continuous variables and also categorized into low, referent, or high (<10th, 10th-90th, >90th percentile). At ≤20 weeks, plasma lipid concentrations were not associated with pregnancy duration. At 36 weeks, total cholesterol and triglyceride concentrations were not associated with pregnancy duration. Higher HDL-C at 36 weeks was associated with a longer pregnancy duration (adjusted β-coefficient ± standard error: 0.05 ± 0.02 days mg -1 /dL, p = .02); pregnancy duration was 5.9 ± 2.0 (mean ± standard error) days shorter among women with low HDL-C compared with the referent group (10th-90th percentile) (p = .02) and 8.6 ± 2.6 days shorter when compared with the high HDL-C group (p = .003). Pregnancy duration was 4.9 ± 2.1 days longer among women with low low-density lipoprotein cholesterol at 36 weeks gestation when compared with the referent group (p = .051). Our data suggest that low HDL-C in the third trimester of pregnancy is associated with a shorter duration of pregnancy in this study population but do not support the hypothesis that low total cholesterol is associated with a shorter pregnancy duration., (© 2016 John Wiley & Sons Ltd.)

Antenatal iron and multiple micronutrient supplementation has been shown in randomized trials to improve birthweight, although mechanisms are unknown. We examined late pregnancy serum erythropoietin (EPO) and cortisol concentrations in relation to maternal micronutrient supplementation and iron status indicators (haemoglobin, serum ferritin, soluble transferrin receptor) in 737 rural Nepalese women to explore evidence of stress or anaemia-associated hypoxia. A double-masked randomized control trial was conducted from December 1998 to April 2001 in Sarlahi, Nepal, in which women received vitamin A alone (as control), or with folic acid (FA), FA + iron, FA + iron + zinc and a multiple micronutrient supplement. In a substudy, we collected maternal blood in the first and third trimester for biochemical assessments. Generalized estimating equations linear regression analysis was used to examine treatment group differences. EPO was ∼ 14-17 mIU mL(-1) lower (P < 0.0001) in late pregnancy in groups receiving iron vs. the control group, with no difference in the FA-only group. Cortisol was 1.3 μg dL(-1) lower (P = 0.04) only in the micronutrient supplement group compared with the control group. EPO was most strongly associated with iron status indicators in groups that did not receive iron, and in the non-iron groups cortisol was positively correlated with EPO (r = 0.15, P < 0.01) and soluble transferrin receptor (sTfR, r = 0.19, P < 0.001). In adjusted analyses, third trimester EPO was associated with a reduction in low birthweight, whereas cortisol was negatively associated with length of gestation and higher risk of preterm birth. Iron and multiple micronutrient supplementation may enhance birth outcomes by reducing mediators of maternal stress and impaired erythropoiesis., (© 2014 John Wiley & Sons Ltd.)

Objective: To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes., Design: Population-based cohort., Setting: California, United States of America., Population: From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included., Methods: Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results., Main Outcome Measure: PTB by subtype., Results: In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2)., Conclusions: Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies., Tweetable Abstract: Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Problem: Previous studies have investigated the utility of inflammation markers as predictors of preterm birth, but none have compared trends in levels between uncomplicated and preterm pregnancy., Method of Study: We explored longitudinal changes in plasma cytokines, including IL-1β, IL-6, IL-10, and TNF-α, as well as C-reactive protein in pregnant women from a nested case-control study., Results: IL-6 was associated with increased odds of spontaneous preterm birth, defined by presentation of spontaneous preterm labor and/or preterm premature rupture of the membranes. Associations were strongest later in pregnancy. IL-10 was associated with increased odds of placentally mediated preterm birth, defined by presentation with preeclampsia or intrauterine growth restriction, and odds ratios were also highest near the end of pregnancy., Conclusion: Maternal inflammation markers were associated with increased risk of preterm birth, and relationships differed by etiology of preterm delivery and gestational age at sample collection., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To assess the performance of clinical risk factors, uterine artery Doppler and angiogenic markers to predict preterm pre-eclampsia in nulliparous women., Design: Predictive test accuracy study., Setting: Prospective multicentre cohort study Screening for Pregnancy Endpoints (SCOPE)., Methods: Low-risk nulliparous women with a singleton pregnancy were recruited. Clinical risk factor data were obtained and plasma placental growth factor (PlGF), soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 14-16 weeks of gestation. Prediction models were developed using multivariable stepwise logistic regression., Main Outcome Measure: Preterm pre-eclampsia (delivered before 37(+0)  weeks of gestation)., Results: Of the 3529 women recruited, 187 (5.3%) developed pre-eclampsia of whom 47 (1.3%) delivered preterm. Controls (n = 188) were randomly selected from women without preterm pre-eclampsia and included women who developed other pregnancy complications. An area under a receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.67-0.84) was observed using previously reported clinical risk variables. The AUC improved following the addition of PlGF measured at 14-16 weeks (0.84; 95% CI 0.77-0.91), but no further improvement was observed with the addition of uterine artery Doppler or the other angiogenic markers. A sensitivity of 45% (95% CI 0.31-0.59) (5% false-positive rate) and post-test probability of 11% (95% CI 9-13) were observed using clinical risk variables and PlGF measurement., Conclusions: Addition of plasma PlGF at 14-16 weeks of gestation to clinical risk assessment improved the identification of nulliparous women at increased risk of developing preterm pre-eclampsia, but the performance is not sufficient to warrant introduction as a clinical screening test. These findings are marker dependent, not assay dependent; additional markers are needed to achieve clinical utility., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

Background and Objective: A low-grade systemic inflammatory status originating from periodontal infection has been proposed to explain the association between periodontal disease and systemic conditions, including adverse obstetric outcomes. The aim of this study was to evaluate the effect of periodontal therapy during pregnancy on the gingival crevicular fluid and serum levels of six cytokines associated with periodontal disease and preterm birth., Material and Methods: A subsample of 60 women (18-35 years of age) up to 20 gestational weeks, previously enrolled in a larger randomized clinical trial, was recruited for the present study. Participants were randomly allocated to receive either comprehensive nonsurgical periodontal therapy before 24 gestational weeks (n = 30, test group) or only one appointment for supragingival calculus removal (n = 30, control group). Clinical data, and samples of blood and gingival crevicular fluid, were collected at baseline, at 26-28 gestational weeks and 30 d after delivery. The levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-α were analyzed by flow cytometry., Results: After treatment, a major reduction in periodontal inflammation was observed in the test group, with bleeding on probing decreasing from 49.62% of sites to 11.66% of sites (p < 0.001). Periodontal therapy significantly reduced the levels of IL-1β and IL-8 in gingival crevicular fluid (p < 0.001). However, no significant effect of therapy was observed on serum cytokine levels. After delivery, the levels of IL-1β in the gingival crevicular fluid of the test group were significantly lower than were those in the control group (p < 0.001), but there were no significant differences between test and control groups regarding serum cytokine levels., Conclusion: Although periodontal therapy during pregnancy successfully reduced periodontal inflammation and gingival crevicular fluid cytokine levels, it did not have a significant impact on serum biomarkers., (© 2012 John Wiley & Sons A/S.)

Objective: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption., Design: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth., Setting: Fourteen academic health centres in the USA., Population: Women with prior spontaneous preterm birth., Methods: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment., Main Outcome Measures: Recurrent preterm birth at <37 and <32 weeks of gestation., Results: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01)., Conclusions: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth., (© Published 2012. This article is a U.S. Government work and is in the public domain in the USA. © 2012 RCOG.)

Problem: This study investigates whether affectivity differs between mothers delivering preterm and term and whether maternal and umbilical cord serum cytokines differ between these groups. Further, whether there are associations between mothers' emotions and maternal and cord cytokines at preterm and term birth., Method of Study: Twenty-seven mothers delivering preterm and 37 mothers delivering at term reported positive/negative affect and previous depressive symptoms during pregnancy. Blood samples from mothers in labor and cord samples (23 preterm and 33 term) were analyzed for cytokines., Results: Maternal IL-8 was lower at preterm delivery compared with term. In the preterm group only, associations were found between negative emotions and maternal IL-6, IL-8 and cord IL-6, IL-8, IL-10, IL-13, and IL-18., Conclusion: The findings indicate associations in preterm delivery between negative emotions and both maternal and neonate immune activity. Future studies should investigate whether such associations are part of the etiology of preterm delivery., (© 2011 John Wiley & Sons A/S.)

Objective: To analyse whether specific proteins in maternal serum and cervical length, alone or in combination, can predict the likelihood that women with intact membranes with threatened preterm labour will deliver spontaneously within 7 days of sampling., Design: Cohort study., Setting: Sahlgrenska University Hospital, Gothenburg, Sweden., Population: Women at between 22 and 33 weeks of gestation with threatened preterm labour (n = 142) admitted to the Sahlgrenska University Hospital, Gothenburg, Sweden, in 1995-2005., Methods: Maternal serum was tested for 27 proteins using multiplex xMAP technology. Individual levels of each protein were compared, and calculations were performed to investigate potential associations between different proteins, cervical length and spontaneous preterm delivery. Receiver operating characteristic curves were used to find the best cut-off values for continuous variables in relation to spontaneous preterm delivery within 7 days of sampling. Prediction models were created based on a stepwise logistic regression using binary variables., Main Outcome Measure: Spontaneous preterm delivery within 7 days., Results: In order to determine the best prediction model, we analysed models of serum proteins alone, cervical length alone, and the combination of serum proteins and cervical length. We found one multivariable combined model through the data analysis that more accurately predicted spontaneous preterm delivery within 7 days. This model was based on serum interleukin-10 (IL-10) levels, serum RANTES levels and cervical length (sensitivity 74%, specificity 87%, positive predictive value 76%, negative predictive value 86%, likelihood ratio 5.8 and area under the curve 0.88)., Conclusions: A combination of maternal serum proteins and cervical length constituted the best prediction model, and would help determine whether women with threatened preterm labour are likely to deliver within 7 days of measurement., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To examine the relationship between hyperuricaemia, haemoconcentration and maternal and fetal outcomes in hypertensive pregnancies., Design: Retrospective analysis of a database of hypertensive pregnancies., Setting: St George Hospital, a major obstetric unit in Australia., Population: A cohort of 1880 pregnant women without underlying hypertension or renal disease, referred for management of pre-eclampsia or gestational hypertension., Methods: Demographic, clinical and biochemical data at time of referral and delivery were collected for each pregnancy. Women were grouped according to diagnosis (pre-eclampsia or gestational hypertension) and logistic regression analysis was used to determine the relationship between uric acid, haemoglobin, haematocrit and adverse outcomes; an α level of P < 0.01 was used for statistical significance., Main Outcome Measures: Composites of adverse maternal and fetal outcomes., Results: In women with 'benign' GH (without proteinuria or any other maternal clinical feature of pre-eclampsia) gestation-corrected hyperuricaemia was associated with increased risk of a small-for-gestational-age infant (OR 2.5; 95% CI 1.3-4.8) and prematurity (OR 3.2; 95% CI 1.4-7.2), but not with adverse maternal outcome. In the whole cohort of hypertensive pregnant women (those with pre-eclampsia or gestational hypertension) the risk of adverse maternal outcome (OR 2.0; 95% CI 1.6-2.4) and adverse fetal outcome (OR 1.8; 95% CI 1.5-2.1) increased with increasing concentration of uric acid. Hyperuricaemia corrected for gestation provided additional strength to these associations. Haemoglobin and haematocrit were not associated with adverse pregnancy outcome., Conclusions: Hyperuricaemia in hypertensive pregnancy remains an important finding because it identifies women at increased risk of adverse maternal and particularly fetal outcome; the latter, even in women with gestational hypertension without any other feature of pre-eclampsia., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To document racial disparity in biomarker concentrations in maternal/fetal plasma and amniotic fluid between African Americans and European Americans with spontaneous preterm birth (PTB; cases) and normal term birth (controls), and their contribution to distinct pathophysiological pathways of PTB., Design: Nested case-control study., Setting: The Perinatal Research Center, Nashville, Tennessee, USA., Sample: Maternal and fetal plasma and amniotic fluid samples were collected from 105 cases (59 African American and 46 European American) and 86 controls (40 African American and 46 European American)., Methods: Thirty-six biomarkers were analysed using the protein microarray approach., Main Outcome Measures: Differences in biomarker concentrations between cases and controls of different races in maternal, fetal and intra-amniotic compartments, and the risk of PTB. Dysregulated biomarker-induced PTB pathways associated with PTB in each race were determined using ingenuity pathway analysis (IPA)., Results: Racial disparity was observed in biomarker concentrations in each compartment between cases and controls: amniotic fluid, IL8 and MIP1α differed between case and controls in European Americans, whereas ANGPT2, Eotaxin, ICAM-1, IL-1β, IL1RA, RANTES and TNFα differed between case and controls in African Americans. In both races the FAS ligand, MCP-3 and TNFR-I differed between cases and controls. For fetal plasma, ANGPT2, Eotaxin, FGF basic, ICAM-1, IGF-I, IL10, IL-1β, IL2, IP10 KGF, MCP-3, MIP1α, PDGF-BB, TGFα, TGFβ1, TIMP1, TNFα, TNFR-I, TNFR-II and VEGF differed between cases and controls in European Americans, whereas only MMP7 differed between cases and controls in African Americans. IL-8 differed between cases and controls in both races. For maternal plasma, IL1RA, MMP7 and VEGF differed between cases and controls in European Americans, whereas ANGPT2, FGF basic, IL-1β, IL5, IL6R, KGF, MCP-3, MIP1α, TIMP1 and TNFα differed between cases and controls in African Americans. ANG, IL8 and TNFR-I differed between cases and controls in both races., Conclusions: We conclude that: (1) biomarker concentrations in maternal, fetal and intra-amniotic compartments differ between cases and controls; (2) there is racial disparity in the biomarker profile in each of the compartments; (3) substantial numbers of dysregulated fetal plasma biomarkers contribute to PTB in European Americans, whereas maternal plasma biomarkers contribute to PTB in African Americans; and (4) both inflammation and haematological functions are associated with PTB in European Americans, but maternal proinflammatory changes dominate PTB in African Americans. Biomarker analyses document racial disparity and the distinct pathophysiological contributions from different compartments that can determine pregnancy outcome., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

1. Patent ductus arteriosus (PDA) is a common congenital heart defect in premature infants. The present study was designed to determine the role of the prostaglandin (PG) E(2) pathway in the process of ductus arteriosus (DA) maturation and functional closure. 2. Changes in PGE(2) pathway-related enzymes and receptors in DA in preterm and term rabbits were examined at both the mRNA and protein levels. In addition, responses of DA rings to Po(2) and PGE(2) were determined. 3. Circulating PGE(2) levels remained high until 2 h after birth. High levels of the EP(4) receptor were found in preterm DA. These tissues were sensitive to PGE(2), which caused vessel dilation, but were insensitive to increased Po(2). In contrast, DA tissues from term rabbits exhibited an immediate contractile response to increased Po(2) and PGE(2) treatment resulted in vasoconstriction, which was associated with increased EP(3) and decreased EP(4) receptor expression in term DA. 4. In conclusion, the preterm PDA is maintained by high levels of PGE(2), which mainly binds to the EP(4) receptor under conditions of hypoxia. In contrast, in the term DA, in which levels of the EP(3) receptor are higher than in preterm DA, exposure to PGE(2) resulted in vasoconstriction under normoxic conditions. These findings suggest that blocking the EP(4) receptor may represent a more selective treatment for the preterm PDA, whereas activating the EP(3) receptor may be more suitable for the treatment of the term PDA.

Problem: Human Leukocyte Antigen (HLA)-G is a class Ib gene located in the human major histocompatibility complex (MHC). Several lines of investigation indicate that the HLA-G molecule is involved in the maternal acceptance of the semi-allogenic fetus during pregnancy and in the development of tolerance. Expression of soluble HLA-G (sHLA-G) is positively correlated with successful in vitro fertilization (IVF) treatments, and aberrant expression of HLA-G in certain complications of pregnancy, such as pre-eclampsia and spontaneous abortion, has been reported. The main purpose of this study was to investigate the levels of different soluble HLA-G isoforms in maternal plasma in early and late pregnancy., Method of Study: Soluble HLA-G (sHLA-G) can be detected in maternal blood, and in this study, two different isoforms of sHLA-G, namely sHLA-G1 generated by shedding of membrane-bound HLA-G1 and HLA-G generated by specific HLA-G transcripts, have been investigated early [median of 16.4 weeks of gestation (GW)] and late (median: 38.9 GW) in pregnancy in an original cohort of 580 pregnant Caucasian women., Results: Lower concentrations of sHLA-G1 were found late in pregnancy (>32 GW) in a group of women with severe pre-eclampsia compared with controls with uncomplicated pregnancies (P = 0.029, P(C) = 0.09; Mann-Whitney; Logistic regression analysis: P = 0.024, OR = 0.920, 95% CI: 0.855-0.989). However, this was not the case with HLA-G5, and significantly more of the cases with severe pre-eclampsia had detectable plasma HLA-G5 compared with that of the control group (P = 0.013, P(C) = 0.04; Mann-Whitney). Similar findings were not observed in women with gestational hypertension or existing hypertension continuing into pregnancy. Furthermore, there was a trend toward lower maternal plasma sHLA-G1 in a group of women with premature birth (<37 GW) compared with that of the control group (P = 0.028, P(C) = 0.17; Mann-Whitney). On the contrary, HLA-G5 was lower in the control group compared with that in the premature group (P = 0.004, P(C) = 0.02; Mann-Whitney)., Conclusion: This study shows in line with other published studies that a high, detectable soluble HLA-G concentration in maternal plasma or serum is not mandatory for a successful pregnancy. However, complications during pregnancy, such as (severe) pre-eclampsia, spontaneous abortion, IUGR, and premature birth, are associated with a low or undetectable level of soluble HLA-G in the maternal blood circulation. Also, this study indicates that sHLA-G1 is the interesting soluble HLA-G isoform in pre-eclampsia, and that low or undetectable levels of HLA-G5 at the end of pregnancy seem to be associated with an uncomplicated normal pregnancy, whereas in severe pre-eclampsia and possibly other pregnancy complications, such as preterm birth and IUGR, the level of HLA-G5 is higher.

Problem: The rate of pre-term birth in the United States continues to rise despite several interventions. Induction of pro-inflammatory cytokines and chemokines has been implicated in the activation of the cascade of events resulting in pre-term labor. To date, no comprehensive panel of the cytokine profile in PTL has been published., Method of Study: To address cytokine profiles in pre-term labor, levels of 19 plasma and amniotic fluid cytokines were measured using a multiplex immunoassay in an inflammation-induced murine model of pre-term labor., Results: Pro-inflammatory mediators, RANTES, KC, IL-6, and IL-12p40 were increased by 3 hr and remained high at 15 hr. Concentrations of KC, IL-6, IL-1beta, and MIP-1alpha were increased in the amniotic fluid at 15 hr. Plasma levels of anti-inflammatory mediators IL-10 and IL-13 at 15 hr were unchanged and decreased respectively., Conclusion: These results suggest that stimulation of several pro-inflammatory cytokines occurs very early in the cascade of events and remains increased, whereas anti-inflammatory cytokines are either unchanged or decreased until the onset of delivery in an inflammation-induced mouse model of pre-term labor.

Objective: The aim of this study was to characterize the lymphocyte and the hematopoietic stem and progenitor cell (HPC) subsets of cryopreserved premature cord blood (PCB) compared to term cord blood (TCB) by flow cytometry, to study the influence of birth conditions, and to assess its availability for transplantation., Materials and Methods: Four-color flow cytometric analysis was performed on 43 PCB and 40 TCB cryopreserved samples using a panel of 24 different mAbs, directed against lymphoid and HPC surface markers. The CB volume was estimated by the weight of the newborn to determine the absolute MNC and CD34(+) cell content/CB sample. Clinical and obstetrical data were recovered. Statistical comparisons and a multiple regression analysis were performed., Results: No consistent differences were found in the mononuclear cell (MNC) or CD34(+) cell concentration (x10(6)/L) between PCB and TCB. The percentage of primitive HPC (CD34(+)CD38(-), CD34(+)CD38(-)CD90(-)HLA-DR(-), CD34(+)CD38(-)CD90(-)HLA-DR(+)) and primitive lymphoid progenitors (CD34(+)CD7(+), CD34(+)CD7(+)CD19(-)CD117(-)) were higher in PCB than in TCB. Correspondingly, TCB had an increased percentage of committed HPC. No sample of PCB contained >2 x 10(7) MNC/kg (and only 48% had >1 x 10(5) CD34(+) cells) for a recipient of 20 kg body wt, as the minimum threshold recommended for CB transplantation. Obstetrical factors modulated mainly lymphocyte subsets and fewer HPC subpopulations. Acute fetal distress increased CD34(+) cells, especially the immature subsets. Maternal treatment with dexamethasone and intrauterine growth retardation decreased CD3(+) cells. No other obstetrical factors played a detrimental effect on CB cells if used for transplantation., Conclusion: PCB is richer in immature cells both in lymphocyte and HPC populations, and its use for transplantation, at least in special cases, should be reconsidered.