Jamie Bastek

Adverse neonatal outcomes: examining the risks between preterm, late preterm, and term infants

OBJECTIVE There is a relative paucity of data regarding neonatal outcomes in the late preterm cohort (34 to 36 6/7 weeks). This study sought to assess differences in adverse outcomes between infants delivering 32 to 33 6/7, 34 to 36 6/7 weeks, and 37 weeks or later. STUDY DESIGN Data were collected as part of a retrospective cohort study of preterm labor patients (2002-2005). Patients delivering 32 weeks or later were included (n = 264). The incidence of adverse outcomes was assessed. Significant associations between outcomes and gestational age at delivery were determined using chi(2) analyses and Poisson regression modeled cumulative incidence and controlled for confounders. RESULTS Late preterm infants have increased risk of adverse outcomes, compared with term infants. Controlling for confounders, there was a 23% decrease in adverse outcomes with each week of advancing gestational age between 32 and 39 completed weeks (relative risk 0.77, P < .001, 95% confidence interval, 0.71-0.84). CONCLUSION Further investigation regarding obstetrical management and long-term outcomes for this cohort is warranted.

The Role of Inflammation and Infection in Preterm Birth

Much emphasis in recent decades has been devoted to inflammation and infection as a premier causal mechanism of preterm birth. This article explores the epidemiologic, clinical, and animal data that exist to support this conceptual paradigm as well as proposed mechanisms through which to potentially mitigate the adversity of prematurity. Truly successful interventions are not likely to occur until the pathogenesis of preterm birth and the role of inflammation in causing not only parturition but also fetal and neonatal injury is fully elucidated.

miR-210 Inhibits Trophoblast Invasion and Is a Serum Biomarker for Preeclampsia

Preeclampsia is characterized by hypertension and proteinuria in pregnant women. Its exact cause is unknown. Preeclampsia increases the risk of maternal and fetal morbidity and mortality. Although delivery, often premature, is the only known cure, early targeted interventions may improve maternal and fetal outcomes. Successful intervention requires a better understanding of the molecular etiology of preeclampsia and the development of accurate methods to predict women at risk. To this end, we tested the role of miR-210, a miRNA up-regulated in preeclamptic placentas, in first-trimester extravillous trophoblasts. miR-210 overexpression reduced trophoblast invasion, a process necessary for uteroplacental perfusion, in an extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent manner. Conversely, miR-210 inhibition promoted invasion. Furthermore, given that the placenta secretes miRNAs into the maternal circulation, we tested if serum expression of miR-210 was associated with the disease. We measured miR-210 expression in two clinical studies: a case-control study and a prospective cohort study. Serum miR-210 expression was significantly associated with a diagnosis of preeclampsia (P = 0.007, area under the receiver operator curves = 0.81) and was predictive of the disease, even months before clinical diagnosis (P < 0.0001, area under the receiver operator curve = 0.89). Hence, we conclude that aberrant expression of miR-210 may contribute to trophoblast function and that miR-210 is a novel predictive serum biomarker for preeclampsia that can help in identifying at-risk women for monitoring and treatment.

Minor trauma in pregnancy : is the evaluation unwarranted?

OBJECTIVE The purpose of this study was to examine the rate of and risks for abruption and adverse pregnancy outcome after minor trauma in pregnancy. STUDY DESIGN This is a 3-year prospective cohort study of patients after noncatastrophic trauma. Data collected included maternal demographics and history, trauma mechanism, and pregnancy outcome. Examination, lab tests including Kleihauer-Betke (KB), and a minimum of 4 hours of fetal monitoring were performed. The primary outcomes were placental abruption and a composite pregnancy morbidity outcome. Univariate and bivariate analysis were performed. RESULTS Of the 317 patients evaluated for minor trauma, 9 had a positive KB test (2.8%). Delivery information was available on 256 (81%) patients, and there was 1 placental abruption. The 49 cases (19.4%) of composite outcome could not be predicted. CONCLUSION Perhaps it is time to reevaluate the extensive evaluations often done after minor trauma in pregnancy, particularly because none of the commonly used objective measures are predictive of adverse outcomes.

Biomarkers of inflammation and placental dysfunction are associated with subsequent preterm birth

Objective. To assess whether the analysis of high sensitivity C-Reactive Protein (hsCRP), a biomarker of inflammation, and placental growth factor (PlGF), a biomarker of placental dysfunction, could help identify patients at risk for preterm birth (PTB). Methods. We performed a prospective cohort study of women with symptoms of preterm labor (22–33 6/7 weeks). Maternal serum was analyzed for hsCRP and PlGF. Median biomarker values were used as analytic cut-points. We performed chi-square tests of association between biomarkers and PTB, nonparametric tests to compare medians, and logistic regression to determine the odds of PTB associated with biomarker values. Test characteristics of each biomarker were calculated. Results. 56.3% of the cohort (N = 96) delivered preterm. Median hsCRP (N = 78) was 4.34 mg/L, and median PlGF (N = 86) was 558.25 mg/l. In the setting of inflammation (high hsCRP), women with low PlGF had a 6.84-fold (95%CI: 1.57–29.80) increased risk of PTB. In the setting of placental dysfunction (low PlGF), women with high hsCRP had a 5.97-fold (95%CI: 1.52–23.43) increased risk of PTB. Conclusions. Our results suggest an interplay between inflammation and placental dysfunction in the pathogenesis of PTB. Analyzing biomarkers that reflect different pathways of PTB may hold promise for identifying patients at greatest risk.

Evaluating the association between all components of the metabolic syndrome and pre-eclampsia.

Objective. Hypothesising that metabolic syndrome may be associated with or useful in the prediction of pre-eclampsia, we investigated the association between all components of metabolic syndrome and C-reactive protein (CRP) in women with and without pre-eclampsia. Methods. A case–control study was performed. Cases had gestational hypertension or pre-eclampsia and controls were term deliveries. Clinical data and maternal serum was collected. The presence of metabolic syndrome (3/5 variables present) and a metabolic score (continuous 0–5) were investigated. Significant associations were evaluated using t-tests, and Pearson chi-square tests of association. Multivariable logistic regression was used to control for confounders. Results. One-hundred and one cases and 267 controls were evaluated. We observed a higher odds of pre-eclampsia when metabolic syndrome was present (AOR = 2.71 [1.1–6.67], p = 0.03). For every one-unit increase in metabolic score, there was a 39% increased odds of pre-eclampsia (AOR = 1.39 [1.06–1.82], p = 0.017). The odds of pre-eclampsia were nearly four times higher when hs- CRP was >8 (AOR = 3.61 [2.14–6.12], p < 0.001). Conclusions. Metabolic syndrome and hs-CRP are associated with pre-eclampsia. Investigation is crucial to determine if these abnormal lipid and inflammatory pathways observed in women with pre-eclampsia are present pre-pregnancy or develop as a result of the disease process of pre-eclampsia. Further investigation is also warranted to determine whether these abnormalities persist post-pregnancy and if so, their contribution to long-term cardiovascular disease.

Distinct cervical microRNA profiles are present in women destined to have a preterm birth.

OBJECTIVE Although premature cervical remodeling is involved in preterm birth (PTB), the molecular pathways that are involved have not been elucidated fully. MicroRNAs (miRNAs) that are highly conserved single-stranded noncoding RNAs that play a crucial role in gene regulation have now been identified as important players in disease states. The objective of this study was to determine whether miRNA profiles in cervical cells are different in women who are destined to have a PTB compared with a term birth. STUDY DESIGN A nested case-control study was performed. With the use of a noninvasive method, cervical cells were obtained at 2 time points in pregnancy. The cervical cell miRNA expression profiles were compared between women who ultimately had a PTB (n = 10) compared with a term birth (n = 10). MiRNA expression profiles were created with the Affymetrix GeneChip miRNA Array. The data were analyzed with the Significance of Analysis of Microarrays and Principle Components Analyses. A false-discovery rate of 20% was used to determine the most differentially expressed miRNAs. Validation was performed with quantitative polymerase chain reaction. In vitro studies were performed to confirm expression and regulation of select miRNAs. RESULTS With a false-discovery rate of 20% of the 5640 miRNAs that were analyzed on the array, 99 miRNAs differed between those with a PTB vs a term birth. Qualitative polymerase chain reaction validated the array findings. In vitro studies confirmed expression of select miRNAs in cervical cells. CONCLUSION MiRNA profiles in cervical cells may distinguish women who are at risk for PTB months before the outcome. With the large downstream effects of miRNAs on gene expression, these studies provide a new understanding of the processes that are involved in premature cervical remodeling and allow for the discovery of new therapeutic targets.

Examining the correlation between placental and serum placenta growth factor in preeclampsia

OBJECTIVE Decreased levels of serum placenta growth factor (PlGF) are associated with preeclampsia. We sought to determine whether serum and placental levels of PlGF (sPlGF and pPlGF) are associated with preeclampsia and whether there is a correlation between serum and placental PlGF levels. STUDY DESIGN These analyses were part of a larger, prospective, case-control study. Cases were women with preeclampsia. Controls were women without preeclampsia who delivered at term. Analyses included nonparametric tests to compare medians, logistic regression to estimate odds, and calculation of correlation coefficients. RESULTS Twenty-four cases (10 preterm, 14 term) were compared with 14 controls. Median levels of PlGF were significantly lower in cases than controls (pPlGF: 232.6 vs 363.4 pg/mL, P = .02; sPlGF: 85.5 vs 274.4 pg/mL, P < .001). Serum and placental PlGF were correlated (overall: 39%, P = .006; cases with preterm preeclampsia and growth restriction: 87%, P = .02). CONCLUSION Serum and placental PlGF are independently associated with preeclampsia and correlated with each other.

Clinical prediction rules for preterm birth in patients presenting with preterm labor.

OBJECTIVE: To develop prediction rules to identify which women with preterm labor are at greatest risk for delivery within 10 days and before 37 weeks of gestation using demographic and clinical risk factors alone. METHODS: We analyzed data collected for a prospective cohort study of singleton pregnancies at 22–33 6/7 weeks of gestation with preterm labor. Potential risk factors were included in multivariable logistic models for each outcome. Using backwards regression, we identified combinations of risk factors that generated the most parsimonious yet predictive models. Adjusted odds ratios of covariates in the final models were used to estimate weights for each risk factor and were summed to generate a predictive score. The score associated with the highest negative predictive value was defined as a positive test result for each outcome. Bootstrapping techniques internally validated the scoring systems. RESULTS: We include data from 583 women. The risk of delivery within 10 days was 15.4% (n=90) and before 37 weeks of gestation it was 35.0% (n=204). The final model for delivery within10 days included initial cervical dilatation, no prenatal care, and tobacco use (area under curve=0.75), and for delivery before 37 weeks of gestation it included initial cervical dilatation, obstetric history, and tobacco use (area under the curve=0.73). A positive test result was associated with 84% sensitivity, 51% specificity, 24% positive predictive value, and 95% negative predictive value in predicting delivery within 10 days and 79% sensitivity, 50% specificity, 46% positive predictive value, and 82% negative predictive value in predicting delivery before 37 weeks of gestation. CONCLUSION: Based on their strong negative predictive values, these prediction rules could identify patients who do not require intensive monitoring when they present with preterm labor. LEVEL OF EVIDENCE: II

Women with preterm birth have a distinct cervicovaginal metabolome

OBJECTIVE Metabolomics has the potential to reveal novel pathways involved in the pathogenesis of preterm birth (PTB). The objective of this study was to investigate whether the cervicovaginal (CV) metabolome was different in asymptomatic women destined to have a PTB compared with term birth. STUDY DESIGN A nested case-control study was performed using CV fluid collected from a larger prospective cohort. The CV fluid was collected between 20-24 weeks (V1) and 24-28 weeks (V2). The metabolome was compared between women with a spontaneous PTB (n = 10) to women who delivered at term (n = 10). Samples were extracted and prepared for analysis using a standard extraction solvent method. Global biochemical profiles were determined using gas chromatography/mass spectrometry and ultra-performance liquid chromatography/tandem mass spectrometry. An ANOVA was used to detect differences in biochemical compounds between the groups. A false discovery rate was estimated to account for multiple comparisons. RESULTS A total of 313 biochemicals were identified in CV fluid. Eighty-two biochemicals were different in the CV fluid at V1 in those destined to have a PTB compared with term birth, whereas 48 were different at V2. Amino acid, carbohydrate, and peptide metabolites were distinct between women with and without PTB. CONCLUSION These data suggest that the CV space is metabolically active during pregnancy. Changes in the CV metabolome may be observed weeks, if not months, prior to any clinical symptoms. Understanding the CV metabolome may hold promise for unraveling the pathogenesis of PTB and may provide novel biomarkers to identify women most at risk.