Brett C. Young

Pathogenesis of preeclampsia.

Preeclampsia is a systemic syndrome that occurs in 3 to 5% of pregnant women and classically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. The only known cure is delivery of the placenta. Recent discoveries, however, have led to important advances in understanding the pathogenesis of the condition. Placental antiangiogenic factors are upregulated and disrupt the maternal endothelium. This change in the normal angiogenic balance toward an antiangiogenic state can result in hypertension, proteinuria, glomerular endotheliosis, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and cerebral edema-the clinical signs of preeclampsia and eclampsia. The regulation of these antiangiogenic factors in the placenta is unknown. The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic targets for amelioration of the clinical disease.

Pathogenesis of Preeclampsia

Purpose of reviewPreeclampsia is a gestational kidney disease characterized by glomerular endothelial injury, leading to maternal hypertension and proteinuria. If not addressed promptly, there is significant maternal and fetal morbidity and mortality. When severe, this disorder can cause hepatic and neurologic dysfunction. Understandably, this placental disease enters the focus of the obstetrician first; however, with progression, the nephrologist can also be enlisted. Typical complications include acute kidney injury, refractory hypertension, and acute pulmonary edema. This review summarizes recent literature on the pathogenesis of this condition and will highlight new diagnostic and therapeutic options for preeclampsia. Recent findingsOver the past decade, the role of soluble vascular factors in preeclampsia has shed light on the mechanism underlying this disease. During the last 2 years, several new therapeutics have been developed that target implicated circulating angiogenic factors, including soluble fms-like tyrosine kinase 1, an endogenous vascular endothelial growth factor inhibitor. Serum levels of angiogenic factors have been correlated with a constellation of hemodynamic and pathophysiologic changes. Thus, circulating levels of these factors may serve both diagnostic and prognostic purposes. SummaryOverall, our understanding of preeclampsia has developed significantly and the future holds promise for mechanism-based novel diagnostics and therapeutics.

The use of angiogenic biomarkers to differentiate non-HELLP related thrombocytopenia from HELLP syndrome

OBJECTIVE Preeclampsia (PE) is diagnosed using clinical criteria and in atypical cases the diagnosis may be inaccurate as there are no specific tests to confirm or exclude PE. This study sought to evaluate the utility of angiogenic biomarkers, sFlt1, sEng and PlGF to distinguish patients with gestational thrombocytopenia and immune thrombocytopenic purpura (ITP) from patients with thrombocytopenia resulting from the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, a complication of severe PE. METHODS Serum was collected and the angiogenic biomarkers of patients with ITP and gestational thrombocytopenia (N = 9) were compared to patients with HELLP (N = 11) and PE (N = 11). Circulating levels of these angiogenic biomarkers were also compared by gestational age to 1564 randomly selected normotensive women from the Calcium for Preeclampsia Prevention study. RESULTS Patients with non-HELLP thrombocytopenia had lower sFlt1 (7.3 +/- 3.8 ng/ml vs. 15.5 +/- 5 ng/ml, P < 0.001), lower sEng (8.7 +/- 3.6 vs. 34 +/- 17, P < 0.001) and higher PlGF (484 +/- 412 vs. 66.3 +/- 44, P = 0.003) than patients with HELLP syndrome. Angiogenic factor abnormalities in patients with PE were similar to patients with HELLP syndrome, suggesting a common pathogenesis. Patients with non-HELLP thrombocytopenia had angiogenic profiles similar to normotensive controls, whereas patients with HELLP syndrome had levels higher than the 90th percentile for sFlt1 and sEng and lower than the 10th percentile for PlGF. CONCLUSIONS Angiogenic biomarkers may be useful in excluding conditions that mimic PE.

Physicians' Knowledge of Future Vascular Disease in Women with Preeclampsia

Objective. Preeclampsia, a hypertensive disorder of pregnancy, affects 5–8% of women. Large studies demonstrate a strong association between preeclampsia and future cardiovascular disease (CVD). Despite CVD being the leading cause of mortality for women, there has been little education for internal medicine physicians or obstetrician-gynecologists (ob-gyns) about this association; published guidelines do not include preeclampsia as a risk factor for future CVD. Therefore, women with a history of preeclampsia may not receive adequate risk-reduction counseling for CVD. It is unclear whether primary care physicians are aware of the association; thus, we sought to determine whether primary care providers at our institution were aware of preeclampsias association with future CVD and whether they were providing appropriate counseling. Methods. An anonymous online survey was sent to all internists and (ob-gyns) at our hospital. Results. Although most internists (95%) and (ob-gyns) (70%) provide routine cardiovascular risk-reduction counseling, a substantial proportion of them were unaware of any health risk associated with a history of preeclampsia. Many internists were unsure or did not know whether preeclampsia is associated with ischemic heart disease (56%), stroke (48%), and decreased life expectancy (79%). The corresponding proportions for (ob-gyns) were 23, 38, and 77%, respectively. Only 9% of internists and 38% of obstetrician-gynecologists were providing cardiovascular risk-reduction counseling to women with a history of preeclampsia. Conclusion. There is limited knowledge of the association between preeclampsia and future CVD; this deficiency may limit the application of this risk factor to clinical care.

Effects of twin gestation on maternal morbidity.

As the incidence of twin gestation increases, it is important to consider the maternal risks associated with carrying multiples. Compared with singleton gestation, there are increased risks to the mother during the antepartum, intrapartum, and postpartum periods. Certain pregnancy complications are more likely to occur during a twin gestation, including preeclampsia and other hypertensive disorders, antepartum hospitalization for preterm labor or abnormal bleeding, nutritional deficiencies, cesarean delivery, and postpartum hemorrhage. Women carrying twins may benefit from early education regarding these issues, close maternal monitoring as well as physical therapy sessions, and nutrition counseling during their pregnancies.

Evaluation of a rapid, real-time intrapartum group B streptococcus assay.

OBJECTIVE We sought to evaluate an intrapartum nucleic acid amplification test (NAAT) for group B streptococcus (GBS). STUDY DESIGN This was a prospective cohort study of 559 women comparing intrapartum GBS culture with antepartum culture and intrapartum NAAT. RESULTS GBS prevalence was 19.5% by antepartum culture and 23.8% by intrapartum culture. Compared with intrapartum culture, antepartum culture had 69.2% sensitivity (60.6-76.9%) and 96.0% specificity (93.7-97.7%). The NAAT demonstrated sensitivity of 90.8% (84.6-95.2%), specificity of 97.6% (95.6-98.8%), and predictive values >92%. The incidence of discordant cultures was 10.4%. Of the women with negative antepartum and positive intrapartum cultures, only 1 (2.4%) received intrapartum antibiotics. Compared with white women, black (P = .02) and Hispanic (P = .02) women were more likely to have discordant cultures. CONCLUSION This intrapartum NAAT has excellent characteristics. It may be superior to antepartum culture for detecting intrapartum GBS-allowing more accurate management of laboring mothers and reducing neonatal GBS sepsis.

Dendritic cells in the circulation of women with preeclampsia demonstrate a pro-inflammatory bias secondary to dysregulation of TLR receptors

Toll-like receptors (TLRs) are central components of the innate immune system that recognize both microbial ligands and host products released during tissue damage. Data from epidemiologic studies and animal models suggest that inappropriate activation of the immune system plays a critical role in the development of preeclampsia. This study evaluates in a systematic fashion the expression and function of TLRs in the circulation of patients with preeclampsia compared to healthy pregnant controls. We evaluated TLR expression and function in primary dendritic cells (DCs) of 30 patients with preeclampsia and 30 gestational age-matched healthy pregnant controls. DCs were stimulated with the different TLR ligands engaging TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9. The expression of TLR-induced production of TNF-α, IFN-α, IL-6, and IL-12 were measured by multicolor flow cytometry. Basal expression of TLR3, TLR4 and TLR9 was significantly increased in DCs isolated from women with preeclampsia. Preeclamptic DCs also expressed significantly higher basal levels of cytokines. In contrast, preeclamptic DCs demonstrated a less robust response to stimulation with various TLR ligands as compared with healthy pregnant controls. Under basal conditions, DCs from preeclamptic individuals express higher levels of select TLRs and produce more pro-inflammatory cytokines as compared with healthy controls. As such, the ability of these cells to mount an inflammatory reaction in response to a TLR ligand is limited. These data demonstrate a dysregulated pattern of TLR expression and cytokine production in DCs from PE patients that may limit further activation by TLR engagement.

Longitudinal expression of Toll-like receptors on dendritic cells in uncomplicated pregnancy and postpartum

OBJECTIVE Toll-like receptors (TLRs) are integral parts of the innate immune system and have been implicated in complications of pregnancy. The longitudinal expression of TLRs on dendritic cells in the maternal circulation during uncomplicated pregnancies is unknown. The objective of this study was to prospectively evaluate TLRs 1-9 as expressed on dendritic cells in the maternal circulation at defined intervals throughout pregnancy and postpartum. STUDY DESIGN This was a prospective cohort of 30 pregnant women with uncomplicated pregnancies and 30 nonpregnant controls. TLRs and cytokine expression was measured in unstimulated dendritic cells at 4 defined intervals during pregnancy and postpartum. Basal expression of TLRs and cytokines was measured by multicolor flow cytometry. The percent-positive dendritic cells for each TLRs were compared with both nonpregnant and postpartum levels with multivariate linear regression. RESULTS TLRs 1, 7, and 9 were elevated compared with nonpregnant controls with persistent elevation of TLR 1 and interleukin-12 (IL-12) into the postpartum period. Concordantly, levels of IL-6, IL-12, interferon alpha, and tumor necrosis factor alpha increased during pregnancy and returned to levels similar to nonpregnant controls during the postpartum period. The elevated levels of TLR 1 and IL-12 were persistent postpartum, challenging notions that immunologic changes during pregnancy resolve after the prototypical postpartum period. CONCLUSION Normal pregnancy is associated with time-dependent changes in TLR expression compared with nonpregnant controls; these findings may help elucidate immunologic dysfunction in complicated pregnancies.

Triggers of spontaneous preterm delivery--why today?

BACKGROUND Our goal is to study the triggers of spontaneous preterm delivery using a case-crossover design. METHODS In a pilot study, we enrolled 50 women with spontaneous preterm labour (PTL) and 50 with preterm premature rupture of membranes (PPROM) between 2011 and 2012. To assess non-transient risk factors, we also enrolled a control group of 158 pregnant women at their regular prenatal care visits matched to cases by gestational age and calendar time. The index time was defined as the onset of PTL/PPROM (for cases) or interview (for controls). Detailed data were collected through structured interviews regarding factors of interest during the 72 h that preceded the index time. Within case subjects, we compared the frequency of transient factors from 0 to 24 h before index time with that from 48 to 72 h before index time, and estimated matched odds ratios (OR) and 95% confidence intervals (CI). RESULTS Previously hypothesised chronic risk factors for spontaneous preterm delivery, including mood disorders and stressful events, were more common among cases than among controls. Within cases, skipped meals [OR 4.3, 95% CI 1.2, 15.2], disturbed sleep [OR 4.5, 95% CI 1.5, 13.3], sexual activity [OR 6.0, 95% CI 0.7, 69.8], and intake of spicy foods [OR 7.0, 95% CI 1.6, 30.8] were associated with an increased risk for PTL/PPROM within the subsequent 24 h. For physical exertion and other potential risk factors evaluated, the OR was close to the null. CONCLUSION Skipping meals and disturbed sleep may be associated with imminent PTL/PPROM; sexual activity and spicy food may trigger PTL/PPROM in susceptible women. Larger case-crossover studies will be able to evaluate the impact of modifiable risk factors and acute predictors of PTL/PPROM, and might help guide obstetrical management.

Rupture of the Posterior Cul-De-Sac During Spontaneous Labor

BACKGROUND: Women with genital anomalies are at increased risk of labor dysfunction. Rupture of the posterior cul-de-sac causing an intraabdominal delivery is a rare complication of labor that may be related to a congenitally atretic vagina. CASE: A nulliparous woman at 28 weeks of gestation with a known short vagina presented with preterm labor; her cervix could not be palpated or visualized. At cesarean delivery, the cervix was intraabdominal and the fetal head was delivered in the abdomen. A large rent in the posterior cul-de-sac required repair to restore correct anatomical positioning. The uterus was intact. CONCLUSION: Rupture of the posterior cul-de-sac is a rare event that can cause significant maternal and fetal morbidity.