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Background: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known.Objective: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion.Study Design: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion.Results: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions.Conclusion: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. [ABSTRACT FROM AUTHOR]

Objective: Clinical and histologic chorioamnionitis have recently been identified as risk factors for cerebral palsy. Proinflammatory cytokines have been implicated in the mechanisms that are responsible for brain injury in cases of intrauterine infection. The purpose of this study was to determine whether clinical chorioamnionitis, which is a maternal syndrome, is associated with an elevation in the fetal plasma interleukin-6 (IL-6) that is indicative of fetal inflammation.Study Design: A cross-sectional study was designed to determine plasma concentrations of IL-6 in umbilical venous blood from patients with clinical chorioamnionitis (n = 26) and a control group (n = 111). Umbilical cord blood was obtained at the time of delivery. Plasma concentrations of IL-6 were measured with a sensitive and specific immunoassay. Nonparametric statistics were used for analysis.Results: Plasma concentrations of IL-6 were detectable in all samples of umbilical venous plasma. The median concentration of plasma IL-6 was higher in neonates born to mothers with clinical chorioamnionitis than in neonates born to mothers in the control group (clinical chorioamnionitis: median, 27.46 pg/mL; range, 1.3-5550.0 pg/mL; vs control: median, 2.13 pg/mL; range, 0.6-812.3 pg/mL; P <.001). Sixty-two percent of neonates (16/26) who were born to women with clinical chorioamnionitis had fetal plasma concentrations of IL-6 >11 pg/mL and 54% (14/26) had fetal plasma concentrations of IL-6 >18 pg/mL (these cutoff points have been used previously to define the fetal inflammatory response syndrome).Conclusion: Umbilical vein plasma concentrations of interleukin-6 are elevated in the neonates who were born to mothers with clinical chorioamnionitis, which suggests that the inflammatory process that is responsible for the maternal syndrome of clinical chorioamnionitis frequently involves the human fetus. [ABSTRACT FROM AUTHOR]

Background: Placental lesions consistent with maternal vascular underperfusion (MVU) are thought to be pathogenically linked to preeclampsia, small-for-gestational-age newborns, fetal death, and spontaneous preterm labor and delivery; yet, these lesions cannot be diagnosed antenatally. We previously reported that patients with such conditions and lesions have an abnormal profile of the angiogenic placental growth factor (PlGF) and antiangiogenic factors (eg, soluble vascular endothelial growth factor receptor [sVEGFR]-1).Objective: The objectives of this study were to: (1) examine the relationship between the maternal plasma PlGF/sVEGFR-1 concentration ratio (referred to herein as angiogenic index-1) and the burden of histologic placental features consistent with MVU; and (2) test the hypothesis that angiogenic index-1 can identify patients in the midtrimester who are destined to deliver before 34 weeks of gestation with multiple (ie, ≥3) histologic placental features consistent with MVU.Study Design: A 2-stage case-cohort sampling strategy was used to select participants from among 4006 women with singleton gestations enrolled from 2006 through 2010 in a longitudinal study. Maternal plasma angiogenic index-1 ratios were determined using enzyme-linked immunosorbent assays. Placentas underwent histologic examination according to standardized protocols by experienced pediatric pathologists who were blinded to clinical diagnoses and pregnancy outcomes. The diagnosis of lesions consistent with MVU was made using criteria proposed by the Perinatal Section of the Society for Pediatric Pathology. Weighted analyses were performed to reflect the parent cohort; "n*" is used to reflect weighted frequencies.Results: (1) Angiogenic index-1 (PlGF/sVEGFR-1) concentration ratios were determined in 7560 plasma samples collected from 1499 study participants; (2) the prevalence of lesions consistent with MVU was 21% (n* = 833.9/3904) and 27% (n* = 11.4/42.7) of women with ≥3 MVU lesions delivered before 34 weeks of gestation; (3) a low angiogenic index-1 (<2.5th quantile for gestational age) in maternal plasma samples obtained within 48 hours of delivery had a sensitivity of 73% (n* = 8.3/11.4; 95% confidence interval [CI], 47-98%), a specificity of 94% (n* = 3130.9/3316.2; 95% CI, 94-95%), a positive likelihood ratio of 12.2, and a negative likelihood ratio of 0.29 in the identification of patients who delivered placentas with ≥3 MVU lesions at <34 weeks; (4) prospectively, at 20-23 weeks of gestation, a maternal plasma concentration of angiogenic index-1 <2.5th quantile identified 70% (n* = 7.2/10.3; 95% CI, 42-98%) of patients who delivered placentas with ≥3 MVU lesions before 34 weeks (specificity, 97% [n* = 2831.3/2918; 95% CI, 96-98%]; positive likelihood ratio, 23; negative likelihood ratio, 0.31); and (5) among women without obstetrical complications who delivered at term, angiogenic index-1 was lower in women with than without placental lesions consistent with MVU (P < .05).Conclusion: Maternal plasma angiogenic index-1 (PlGF/sVEGFR-1) is the first biomarker for the burden of placental lesions consistent with MVU. We propose that an accumulation of these lesions in placentas delivered before 34 weeks is a histologic counterpart of an antiangiogenic profile. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify differential expression of microRNAs (miRNAs) in chorioamniotic membranes with advancing gestation, labor, and inflammation. Study Design: Expression profiles of 157 miRNAs in the chorioamniotic membranes were obtained from patients in the following groups: 1) term not in labor (n = 10); 2) term in labor (n = 10); 3) preterm labor with histologic chorioamionitis (n = 9); and 4) without histologic chorioamnionitis (n = 10). Results: More than 95% of the miRNAs screened were expressed. Gestational age-dependent changes in expression were observed for 13 miRNAs. No differences in miRNA expression were observed between women without labor and women in labor. Membranes with chorioamnionitis displayed increased expression of miR-223 and miR-338. Gene Ontology analysis of genes targeted by differentially expressed miRNAs revealed enrichment for specific biological process categories. Conclusion: Chorioamniotic membranes with advancing gestational age and chorioamnionitis are associated with the differential expression of a subset of miRNAs. [Copyright &y& Elsevier]

Objective: Patients with an episode of preterm labor that subsides in response to tocolysis and who, subsequently, deliver at term are considered to have false preterm labor. However, the episode of “preterm labor” may represent the uterine response (ie, uterine contractions) to an insult not severe enough to trigger preterm parturition, but which may put the fetus at risk for additional pregnancy complications, including growth restriction. The objective of this study was to compare the frequency of small-for-gestational-age (SGA) neonates among patients with an episode of increased uterine contractility who delivered at term and those who delivered preterm. Study Design: This retrospective cohort study included 849 patients. Inclusion criteria were (1) regular uterine contractions that required hospitalization, (2) intact membranes, and (3) gestational age between 20 and 36 weeks. SGA was defined as a birth weight of <10th percentile for gestational age. Placental pathologic evidence was reviewed, and the results were used to classify patients into an inflammatory cluster, vascular cluster, or both. Contingency tables, Mann-Whitney U test, and multivariate logistic regression were used for statistical analyses. A probability value of <.05 was considered significant. Results: The prevalence of SGA neonates in the study population was 16.1% (124/772). Patients who delivered at term had a significantly higher frequency of SGA neonates than those who delivered preterm (21.5% [64/298] vs 12.7% [60/474]; P = .001); the results of placental pathologic evidence were available in 63.7% (492/772) of the patients. Patients who delivered at term had a higher frequency of fetal or maternal vascular lesions without histologic evidence of inflammation than those who delivered preterm (29.1 % [43/148] vs 18.9% [65/344]; P = .01). Term delivery after an episode of regular preterm uterine contractions was associated with an odds ratio of 2.22 (95% CI, 1.28-3.85) to deliver an SGA neonate after the statistics were controlled for confounding variables. A subanalysis limited to patients who received tocolysis showed similar results. Conclusion: Patients with an episode of increased uterine contractility that subsided and who deliver at term are at risk for delivering an SGA neonate, which suggests that an episode of false preterm labor is not a benign condition. We propose that insults to the fetoplacental unit may be resolved by either irreversible preterm parturition or restriction of fetal growth. [Copyright &y& Elsevier]