Sindhu K. Srinivas

Rethinking IUGR in preeclampsia: dependent or independent of maternal hypertension?

Objective:Chronic hypertension (CHTN) is a risk factor for both intrauterine growth restriction (IUGR) as well as preeclampsia. This study was performed to: (1) describe the prevalence of IUGR in women with preeclampsia (with and without CHTN) compared with controls, (2) investigate the relationship between preeclampsia and maternal CHTN with IUGR, and (3) investigate the relationship between IUGR and severity of preeclampsia.Study Design:A case–control study was performed. Cases were patients identified with preeclampsia. Controls were patients presenting for delivery at term (⩾37 weeks). IUGR prevalence by case–control status, or severity of disease was evaluated using Pearson χ2 tests. Multivariable logistic regression was used to control for confounders.Result:In all, 430 cases and 568 controls were studied. Preeclamptic women have a 2.7 (CI (1.94 to 3.86)) and 4.3 (CI (2.58 to 7.17)) times increased odds of having a fetus with IUGR at <10 and <5% compared with controls in adjusted analyses. There was a significant interaction between CHTN and IUGR. Therefore, in women without CHTN, women with PEC had increased odds of IUGR, whereas in women with CHTN, there was no difference in odds of IUGR in women with or without preeclampsia. Within the cases, severe preeclampsia was associated with IUGR<10% (AOR=1.82 (1.11 to 2.97)) but not IUGR<5% (AOR=1.6 (0.85 to 2.86)).Conclusion:Preeclampsia is independently associated with the development of IUGR. As suggested earlier, women with CHTN do not have the highest prevalence of IUGR, suggesting disparate pathways by which IUGR develops in women with superimposed preeclampsia compared with preeclampsia alone.

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.

Predicting failure of a vaginal birth attempt after cesarean delivery.

OBJECTIVE: To identify a group of clinical factors that could be used to accurately predict failure in women attempting vaginal birth after cesarean (VBAC). METHODS: We conducted a planned secondary analysis of a retrospective cohort study of women who were offered VBAC from 1996 to 2000 in 17 community and university hospitals. We collected information about maternal history and outcomes of the index pregnancy. We used univariable and multivariable statistical methods to develop a multivariable prediction model for the outcome of VBAC failure. RESULTS: A total of 13,706 patients attempted VBAC, with a failure rate of 24.5%. Six variables were significantly associated with VBAC failure in our final logistic regression model: gestational age at delivery, maternal age, maternal race, labor type (spontaneous, augmented, or induced), history of vaginal delivery, and cephalopelvic disproportion or failed induction (combined variable) as prior cesarean indication. The area under the receiver operating characteristics curve is 0.717. To achieve a sensitivity of approximately 75%, a false-positive rate of approximately 40% would result. CONCLUSION: Our results indicate that significant clinical variables (prelabor and labor) cannot reliably predict VBAC failure. LEVEL OF EVIDENCE: II

Evaluating Risk-Adjusted Cesarean Delivery Rate as a Measure of Obstetric Quality

OBJECTIVE: To validate the risk-adjusted cesarean delivery rate as a measure of obstetric quality through its association with maternal and neonatal outcomes for all pregnancies (model 1) and in primiparous patients with singleton pregnancies (model 2). METHODS: We constructed a population-based cohort of 845,651 patients from 401 hospitals representing all deliveries in California and Pennsylvania between 2004 and 2005. We used linked birth certificate and hospital admission records for mother and neonate to estimate the correlation between risk-adjusted cesarean delivery and a composite of adverse maternal outcomes, adverse neonatal outcomes, and four obstetric patient safety indicators from the Agency for Healthcare Research and Quality (AHRQ). RESULTS: In both models, risk-adjusted cesarean delivery rates were negatively correlated with both the maternal and neonatal composite outcomes and the AHRQ patient safety indicators for birth trauma, injury with instrumented vaginal delivery, and cesarean delivery. Approximately 60% of the 107 hospitals with lower-than-expected risk-adjusted cesarean delivery rates had higher-than-expected rates of at least one of the six adverse outcomes, compared with 19.6% of the hospitals with higher-than-expected risk-adjusted cesarean delivery rates and 36.1% of the hospitals with expected rates (P<.001). CONCLUSION: Lower-than-expected risk-adjusted cesarean delivery rates in all patients or when restricted to a more homogeneous group of primiparous patients with term singleton pregnancies are associated with higher-than-expected adverse maternal or neonatal outcomes. Higher-than-expected risk-adjusted cesarean delivery rates do not result in improved outcomes. LEVEL OF EVIDENCE: II

Serum adiponectin and leptin in relation to risk for preeclampsia: results from a large case-control study.

Conditions resulting in insulin resistance, as well as metabolic, immune, and angiogenic perturbations, have been associated with an increased risk of preeclampsia (PE). Our purpose was to assess whether the adipose tissue-secreted hormones adiponectin, which has immune-modulating, metabolic, and angiogenic properties, and leptin, which reflects overall fat mass, are associated with PE risk. We performed a case-control design study within a hospital-based cohort of 368 pregnant women (106 with PE and 262 controls; mean age, 26.6 ± 6.8 years; mean gestational age at admission, 38.2 ± 2.8 weeks) between March 2005 and August 2007 at the Hospital of Pennsylvania University. Serum adiponectin and leptin were measured by radioimmunoassay. Statistical analysis of data was performed using simple and multiple regression analyses. No significant differences in adiponectin or leptin levels between preeclamptic and control pregnant women emerged in univariate analyses (P = .57 and P = .15, respectively). Among preeclamptic women, there were also no differences in adipokines between those with mild and severe disease. Serum adiponectin and leptin were not associated with higher risk of PE before and after adjustment for maternal age, race, primigravida, smoking status, body mass index at screening, gestational age at admission, history of PE, chronic hypertension, and gestational diabetes (odds ratio, 0.93; 95% confidence interval, 0.83-1.04 and odds ratio, 1; 95% confidence interval, 0.97-1.03, respectively). Maternal serum adiponectin and leptin levels, drawn at the time of PE diagnosis, were not associated with PE.

Improvements in US maternal obstetrical outcomes from 1992 to 2006.

Background:Over 4 million women give birth annually in the United States, making delivery one of the most common reasons for hospital care. Objective:We examined 15-year trends in risk-adjusted maternal complications following childbirth. Research Design:We examined maternal obstetrical outcomes from 1992–2006 among women undergoing cesarean delivery (CD) and vaginal delivery (VD). A composite measure of major maternal complications including infection, hemorrhage, laceration, and other major operative and thrombotic complications was evaluated. Subjects:Population-based sample of over 6 million women from Florida and New York hospital discharge data. Measures:Obstetric procedures and maternal complications postdelivery. Results:During the 15-year time period, the CD rate decreased from 24.7% in 1992 to 23% in 1996 and increased to 34.7% in 2006. The risk-adjusted rate of any major complication declined from 14.7% in 1992 to 10.7% in 2006 for all deliveries; from 14.4% to 11.6% for VD; and from 15.7% to 8.5% for CD. During 1992 to 2006, the average number of comorbidities increased from 0.65 to 0.93 for patients overall, from 0.43 to 0.58 for VD patients, and 1.34 to 1.59 for CD patients. Conclusion:As evidenced by New York and Florida, the US has seen large reductions in major maternal complications over the past 15 years. Concurrently, the average number of comorbidities increased. These results reflect substantial improvements in maternal delivery 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.

Allelic variations in angiogenic pathway genes are associated with preeclampsia

OBJECTIVE This study investigates the association of allelic variation in angiogenic pathway genes and preeclampsia. STUDY DESIGN Data for cases with preeclampsia and term control subjects were collected prospectively. Maternal DNA was extracted, and 124 tagging single nucleotide polymorphisms in 6 genes (vascular endothelial growth factor A, B, and C; fms-like tyrosine kinase 1 and 4; endoglin) were genotyped. Multivariable logistic regression was used to evaluate the association between tagging single nucleotide polymorphisms and preeclampsia; data were controlled for age. All models were evaluated in black women and white women separately. Haplotype analyses were performed. RESULTS We analyzed data from 606 women (489 black women [184 cases] and 117 white women [32 cases]). In black women, the fms-like tyrosine kinase 1 rs12584067 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.01-2.36; P=.05) and rs7335588 (OR, 1.61; 95% CI, 1.06-2.43; P=.01) and the vascular endothelial growth factor C rs1485766 (OR, 1.56; 95% CI, 1.05-2.30; P=.03) and rs6838834 (OR, 1.60; 95% CI, 1.05-2.45; P=.03) single nucleotide polymorphisms were associated with preeclampsia. In white women, the fms-like tyrosine kinase 1 rs722503 (OR, 2.12; 95% CI, 1.07-4.19; P=.03), fms-like tyrosine kinase 4 rs307826 (OR, 3.06; 95% CI, 1.18-7.91; P=.01), and vascular endothelial growth factor C rs7664413 (OR, 2.04; 95% CI, 0.99-4.17; P=.04) single nucleotide polymorphisms were associated with preeclampsia. CONCLUSION Allelic variations in the fms-like tyrosine kinase 1 and vascular endothelial growth factor C genes are associated with preeclampsia in both ethnic groups.

Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study

BackgroundPreeclampsia affects 3-8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This complex disorder is characterized by alterations in the immune and vascular systems and involves multiple organs. There is strong evidence for a genetic contribution to preeclampsia. Two different single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene were recently reported to be associated with increased risk for preeclampsia in two different populations. ERAP2 is expressed in placental tissue and it is involved in immune responses, inflammation, and blood pressure regulation; making it is an attractive preeclampsia candidate gene. Furthermore, ERAP2 expression is altered in first trimester placentas of women destined to develop preeclampsia.MethodsA case-control design was used to test for associations between two SNPs in ERAP2, rs2549782 and rs17408150, and preeclampsia status in 1103 Chilean maternal-fetal dyads and 1637 unpaired African American samples (836 maternal, 837 fetal).ResultsWe found that the fetal minor allele (G) of rs2549782 was associated with an increased risk for preeclampsia in the African American population (P = 0.009), but not in the Chilean population. We found no association between rs17408150 and risk for preeclampsia in the Chilean population. Association between rs17408150 and risk for preeclampsia was not tested in the African American population due to the absence of the minor allele in this population.ConclusionsWe report an association between fetal ERAP2 and preeclampsia in an African American population. In conjunction with previous studies, which have found maternal associations with this gene in an Australian/New Zealand population and a Norwegian population, ERAP2 has now been associated with preeclampsia in three populations. This provides strong evidence that ERAP2 plays a role in the development of preeclampsia.

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.