A comprehensive obstetric patient safety program reduces liability claims and payments.

Begun in 2003, the Yale-New Haven Hospital comprehensive obstetric safety program consisted of measures to standardize care, improve teamwork and communication, and optimize oversight and quality review. Prior publications have demonstrated improvements in adverse outcomes and safety culture associated with this program. In this analysis, we aimed to assess the impact of this program on liability claims and payments at a single institution. We reviewed liability claims at a single, tertiary-care, teaching hospital for two 5-year periods (1998-2002 and 2003-2007), before and after implementing the safety program. Connecticut statute of limitations for professional malpractice is 36 months from injury. Claims/events were classified by event-year and payments were adjusted for inflation. We analyzed data for trends as well as differences between periods before and after implementation. Forty-four claims were filed during the 10-year study period. Annual cases per 1000 deliveries decreased significantly over the study period (P < .01). Claims (30 vs 14) and payments ($50.7 million vs $2.9 million) decreased in the 5-years after program inception. Compared with before program inception, median annual claims dropped from 1.31 to 0.64 (P = .02), and median annual payments per 1000 deliveries decreased from $1,141,638 to $63,470 (P < .01). Even estimating the monetary awards for the 2 remaining open cases using the median payments for the surrounding 5 years, a reduction in the median monetary amount per case resulting in payment to the claimant was also statistically significant ($632,262 vs $216,815, P = .046). In contrast, the Connecticut insurance market experienced a stable number of claims and markedly increased cost per claim during the same period. We conclude that an obstetric safety initiative can improve liability claims exposure and reduce liability payments.

IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes.

Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.

Antenatal lamivudine to reduce perinatal hepatitis B transmission: a cost-effectiveness analysis.

OBJECTIVES: This study aimed to determine whether administration of lamivudine to pregnant women with chronic hepatitis B in the third trimester is a cost-effective strategy in preventing perinatal transmission. STUDY DESIGN: We developed a decision analysis model to compare the cost-effectiveness of 2 management strategies for chronic hepatitis B in pregnancy: (1) expectant management or (2) lamivudine administration in the third trimester. We assumed that lamivudine reduced perinatal transmission by 62%. RESULTS: Our Markov model demonstrated that lamivudine administration is the dominant strategy. For every 1000 infected pregnant women treated with lamivudine, $337,000 is saved and 314 quality-adjusted life-years are gained. For every 1000 pregnancies with maternal hepatitis B, lamivudine prevents 21 cases of hepatocellular carcinoma and 5 liver transplants in the offspring. The model remained robust in sensitivity analysis. CONCLUSION: Antenatal lamivudine administration to pregnant patients with hepatitis B is cost-effective, and frequently cost-saving, under a wide range of circumstances.

Comparative analysis of 2-D versus 3-D ultrasound estimation of the fetal adrenal gland volume and prediction of preterm birth.

OBJECTIVE: We aim to test the hypothesis that two-dimensional (2-D) fetal adrenal gland volume (AGV) measurements offer similar volume estimates as volume calculations based on 3-D technique. METHODS: Fetal AGV was estimated by three-dimensional (3-D) ultrasound (VOCAL) in 93 women with signs/symptoms of preterm labor and 73 controls. Fetal AGV was calculated using an ellipsoid formula derived from 2-D measurements of the same blocks (0.523 × length × width × depth). Comparisons were performed by intraclass correlation coefficient (ICC), coefficient of repeatability, and Bland-Altman method. The corrected AGV (cAGV; AGV/fetal weight) was calculated for both methods and compared for prediction of preterm birth (PTB) within 7 days. RESULTS: Among 168 volumes, there was a significant correlation between 3-D and 2-D methods (ICC = 0.979; 95% confidence interval [CI]: 0.971 to 0.984). The coefficient of repeatability for the 3-D was superior to the 2-D method (intraobserver 3-D: 30.8, 2-D:57.6; interobserver 3-D:12.2, 2-D: 15.6). Based on 2-D calculations, cAGV ≥ 433 mm3/kg was best for prediction of PTB (sensitivity: 75%, 95% CI = 59 to 87; specificity: 89%, 95% CI = 82 to 94). Sensitivity and specificity for the 3-D cAGV (cutoff ≥ 420 mm3/kg) was 85% (95% CI = 70 to 94) and 95% (95% CI = 90 to 98), respectively. In receiver-operating-curve curve analysis, 3-D cAGV was superior to 2-D cAGV for prediction of PTB (z = 1.99, p = 0.047). CONCLUSION: 2-D volume estimation of fetal adrenal gland using ellipsoid formula cannot replace 3-D AGV calculations for prediction of PTB.

A comprehensive obstetrics patient safety program improves safety climate and culture.

OBJECTIVE: The purpose of this study was to determine the effect of an obstetrics patient safety program on staff safety culture. STUDY DESIGN: We implemented (1) obstetrics patient safety nurse, (2) protocol-based standardization of practice, (3) crew resource management training, (4) oversight by a patient safety committee, (5) 24-hour obstetrics hospitalist, and (6) an anonymous event reporting system. We administered the Safety Attitude Questionnaire on 4 occasions over 5 years (2004-2009) to all staff members that assessed teamwork and safety cultures, job satisfaction, working conditions, stress recognition, and perceptions of management. RESULTS: We observed significant improvements in the proportion of staff members with favorable perceptions of teamwork culture (39% in 2004 to 63% in 2009), safety culture (33% to 63%), job satisfaction (39% to 53%), and management (10% to 37%). Individual roles (obstetrics providers, residents, and nurses) also experienced improvements in safety and teamwork, with significantly better congruence between doctors and nurses. CONCLUSION: Safety programs can improve workforce perceptions of safety and an improved safety climate.

Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth.

OBJECTIVE: The objective of the study was to test whether ultrasound-measured fetal adrenal gland volume (AGV) and fetal zone enlargement (FZE) predicts preterm birth (PTB) better than cervical length (CL). STUDY DESIGN: Three-dimensional and 2-dimensional ultrasound were used prospectively to measure fetal AGV, FZE, and CL in women with preterm labor symptoms. We corrected AGV for fetal weight (cAGV). The ratio between whole gland depth (D) and central fetal zone depth (d) (d/D) was used to measure FZE. Ability of cAGV, d/D, and CL to predict PTB 7 days or less was compared. RESULTS: Twenty-seven of 74 women (36.5%) presenting between 21 and 34 weeks had PTB of 7 days or less. FZE greater than 49.5% was the single best predictor for PTB (sensitivity/specificity 100%/89%) compared with cAGV (81%/87%) and CL (56%/60%; P < .05). Prediction was independent of obstetrics history and tocolytic use. CONCLUSION: The 2-dimensional measurement of the adrenal gland FZE is highly effective performing superior to CL in identifying women at risk for PTB within 7 days.

Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.

Interpretation of 2002 Centers for Disease Control guidelines for group B streptococcus and evolving provider practice patterns.

We investigated if clinicians were altering their care of group B streptococcus (GBS)-positive women in labor to achieve 4 hours of intrapartum antibiotic prophylaxis based on their interpretation of the 2002 Centers for Disease Control (CDC) guidelines on prevention of perinatal GBS disease. We surveyed all clinicians with privileges on the labor floor at our institution about their interpretation and clinical application of the 2002 CDC guidelines. Seventy of 96 eligible clinicians (72.9%) completed our survey. In our survey, only 22.9% of clinicians reported not altering their management of labor in GBS-positive pregnancies that achieved less than 4 hours of prophylaxis. These alterations included "laboring down" or delaying pushing; turning off or decrease an oxytocin infusion; or delaying or avoiding artificial rupture of membranes. Clinicians are altering their management of labor to attempt to achieve 4 hours of intrapartum prophylaxis. The 2002 CDC guidelines do not specifically recommend prolonging labor and are being interpreted differently in the clinical setting than the authors may have intended. The effects and consequences of this interpretation are unknown.

Normative postpartum intraabdominal pressure: potential implications in the diagnosis of abdominal compartment syndrome.

OBJECTIVE: We sought to establish normative values of intraabdominal pressure (IAP) in postpartum women with and without arterial hypertension. STUDY DESIGN: Bladder pressure was measured via a Foley catheter 1 hour following completion of cesarean section in supine and semirecumbent positions in 21 patients. RESULTS: Mean supine IAP (6.4 +/- 5.2 mm Hg) was significantly lower than semirecumbent IAP (11.6 +/- 7.2 mm Hg) (P < .05). Body mass index (BMI) was significantly correlated to IAP regardless of the gestational age (r(2) supine = 0.46, semirecumbent = 0.37; P = .004 for either). Increasing gravidity was associated with decreasing IAP. Patients with arterial hypertension had higher BMI, were delivered earlier, and had higher IAP than patients with normal arterial pressure, either in supine or semirecumbent position. However, these relationships were not significant when results were controlled for BMI. CONCLUSION: Postcesarean section IAP is higher than in the general surgical population. Patients with hypertensive disorders have IAPs approaching to intraabdominal hypertension range.

Acceleration/ejection time ratio in the fetal pulmonary artery predicts fetal lung maturity.

OBJECTIVE: The aim of this study was to determine whether sonographic fetal pulmonary artery flow velocity waveforms correlate with amniotic fluid biomarkers of fetal lung maturity. STUDY DESIGN: We studied women with singleton pregnancies undergoing clinically indicated amniocentesis for fetal lung maturity at Yale-New Haven Hospital. Fetal pulmonary artery flow velocity measurements, including systolic/diastolic ratio, pulsatility index, resistance index, and acceleration-time/ejection-time ratio were obtained using spectral Doppler ultrasound. Pearson's correlation coefficient was used to determine the association between fetal pulmonary artery flow velocity parameters and the lecithin/sphingomyelin ratio. RESULTS: Twenty-nine subjects met study criteria. The acceleration-time/ejection-time ratio was inversely correlated with the lecithin/sphingomyelin ratio (r = -0.76; P < or = .001). This relationship was maintained after controlling for potential confounders. Other fetal pulmonary artery flow velocity measurements were not associated with the lecithin/sphingomyelin ratio. CONCLUSION: There is an inverse correlation between the acceleration-time/ejection-time ratio in the fetal pulmonary artery and the amniotic fluid lecithin/sphingomyelin ratio. This suggests that ultrasound evaluation of fetal pulmonary artery blood flow may be a promising new noninvasive technique to evaluate fetal lung maturity.

Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling.

An abnormally decreased placental weight has been linked to increased perinatal complications, including intrauterine fetal demise (IUFD) and fetal growth restriction (IUGR). Despite its promise, determining placental weight prenatally using three-dimensional systems is time-consuming and requires expensive technology and expertise. We propose a novel method using two-dimensional sonography that provides an immediate estimation of placental volume. Placental volume was calculated in 29 third-trimester pregnancies using linear measurements of placental width, height, and thickness to calculate the convex-concave shell volume within 24 hours of birth. Data were analyzed to calculate Spearman's rho (r (s)) and significance. There was a significant correlation between estimated placental volume (EPV) and actual placental weight (r (s) = 0.80, P < 0.001). Subgroup analysis of preterm gestations ( N = 14) revealed an even more significant correlation of EPV to actual placental weight (r (s) = 0.89, P < 0.001). Placental weight can be accurately predicted by two-dimensional ultrasound with volumetric calculations. This method is simple, rapid, and accurate, making it practical for routine prenatal care, as well as for high-risk cases with decreased fetal movement and IUGR. Routine EPV surveillance may decrease the rates of perinatal complications and unexpected IUFD.

Effect of Implementing a Standardized Shoulder Dystocia Documentation Form on Quality of Delivery Notes.

OBJECTIVES: Complete and accurate documentation by the delivering provider in cases of shoulder dystocia is critical for providing clinical information and care to the patient and protecting providers from litigation risks. Standardized forms improve inclusion of certain data elements in the medical record, but the impact on subsequent narrative notes is unknown. We aimed to determine if implementation of a standardized shoulder dystocia documentation form improves obstetric provider written narrative delivery notes. METHODS: In February 2005, our institution introduced a mandatory, standardized shoulder dystocia form containing 29 discrete data points relevant to shoulder dystocia documentation. We identified all deliveries complicated by shoulder dystocia from 1 year before and 4 years after implementation of this form and analyzed medical records for inclusion of delivery information in both the required form and the narrative delivery notes. RESULTS: We identified 52 cases before and 100 cases after implementation of the standardized form. Inclusion of elements from the form in narrative delivery notes increased significantly after implementation (P = 0.01). Elements present at higher rates included prepregnancy maternal weight (13% before vs 28% after, P = 0.043), total maternal weight gain (19% vs 36%, P = 0.03), estimated fetal weight (60% vs 77%, P = 0.03), duration of active labor (40% vs 65%, P < 0.01), duration of second stage (27% vs 52%, P < 0.01), and time of delivery from head to body (4% vs 30%, P < 0.01). CONCLUSIONS: Use of a mandatory shoulder dystocia documentation form is associated with significant improvement in the comprehensiveness of delivering provider narrative notes and may encourage more complete and accurate charting. Such improvements can allow for more complete and accurate explanation of events to patients and better demonstrate adherence to standards of care in the management of shoulder dystocia and may improve litigation defensibility.

Disparities in cesarean delivery rates and associated adverse neonatal outcomes in New York City hospitals.

OBJECTIVE: To examine the primary cesarean delivery rates and associated neonatal outcomes by insurance status in public and private hospitals in New York City. METHODS: We accessed Vital statistics data on all births to women with Medicaid or private insurance from 1996 through 2003, compiling a total of 321,308 nulliparous women who delivered singleton neonates by either normal spontaneous vaginal delivery or primary cesarean delivery. Rates of primary cesarean delivery and adverse neonatal outcomes were examined by hospital type and insurance status while controlling for potential confounders. RESULTS: There were 51,682 and 269,626 women who delivered in public hospitals and private hospitals, respectively. The cesarean delivery rate of women with private insurance delivering in private hospitals was 30.4% compared with a cesarean rate of 21.2% in Medicaid patients delivering in public hospitals (adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.53-1.63). The percent of infants born to women with private insurance and Medicaid delivering in private hospitals with a 5-minute Apgar score less than 7 was 0.6% and 0.8% compared with 1.0% of infants delivering in the public hospital system (adjusted OR 0.59, 95% CI 0.51- 0.68 and adjusted OR 0.73, 95% CI 0.65- 0.82). The neonatal intensive care unit admission rate was also lower in neonates born in private hospitals at 6.7% and 8.5% compared with a 12.8% admission rate in public hospitals (adjusted OR 0.48, 95% CI 0.46-0.51 and adjusted OR 0.59, 95% CI 0.57- 0.62 after controlling for mode of delivery). CONCLUSION: Even when controlling for confounders, there was an association between primary cesarean delivery and insurance status regardless of hospital type. There was also a higher risk of adverse neonatal outcomes in the public hospitals regardless of mode of delivery. LEVEL OF EVIDENCE: III.

The cost-effectiveness of universal screening in pregnancy for subclinical hypothyroidism.

OBJECTIVE: The purpose of this study was to determine whether routine screening for subclinical hypothyroidism during pregnancy would be cost-effective. STUDY DESIGN: We developed a decision analysis model to compare the cost-effectiveness of 2 screening strategies during pregnancy for subclinical hypothyroidism: (1) no routine screening of serum thyroid-stimulating hormone (TSH) levels (standard) and (2) routine screening of TSH levels. In the latter, women with subclinical hypothyroidism received thyroid hormone replacement. We assumed that thyroid hormone replacement could reduce the incidence of an offspring IQ < 85 for pregnancies with subclinical hypothyroidism. The main outcome measure was marginal cost per quality-adjusted life year (QALY) gained. RESULTS: Our model predicts that universal screening is the dominant strategy. For every 100,000 pregnant women who were screened, $8,356,383 are saved, and 589.3 QALYs are gained. When subclinical hypothyroidism prevalence is reduced to 0.25%, screening remains cost-effective at $21,664/QALY gained. CONCLUSION: Screening for subclinical hypothyroidism in pregnancy will be a cost-effective strategy under a wide range of circumstances.

Fetal renal artery impedance as assessed by Doppler ultrasound in pregnancies complicated by intraamniotic inflammation and preterm birth.

OBJECTIVE: The objective of the study was to evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth. STUDY DESIGN: We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (median, 28.1 [interquartile range, 25.3-30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n = 14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio, and presence or absence of end-diastolic blood flow. Proteomic profiling (surface-enhanced laser desorption ionization time-of-flight) was used for assessment of intraamniotic inflammation and biomarker peak corresponding to beta2-microglubin. Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin (IL)-6 and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life. RESULTS: Fetuses delivered by mothers with intraamniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI, RI, S/D ratio, or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6, and status of the membranes. CONCLUSION: The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.

Impact of a comprehensive patient safety strategy on obstetric adverse events.

OBJECTIVE: We implemented a comprehensive strategy to track and reduce adverse events. STUDY DESIGN: We incrementally introduced multiple patient safety interventions from September 2004 through November 2006 at a university-based obstetrics service. This initiative included outside expert review, protocol standardization, the creation of a patient safety nurse position and patient safety committee, and training in team skills and fetal heart monitoring interpretation. We prospectively tracked 10 obstetrics-specific outcome. The Adverse Outcome Index, an expression of the number of deliveries with at least 1 of the 10 adverse outcomes per total deliveries, was analyzed for trend. RESULTS: Our interventions significantly reduced the Adverse Outcome Index (linear regression, r(2) = 0.50; P = .01) (overall mean, 2.50%). Concurrent with these improvements, we saw clinically significant improvements in safety climate as measured by validated safety attitude surveys. CONCLUSION: A systematic strategy to decrease obstetric adverse events can have a significant impact on patient safety.

Timing of fetal meconium absorption by amnionic macrophages.

This study sought to determine the time interval from fetal defecation to membrane staining and subsequent meconium uptake by amnionic macrophages. Pieces of external membranes were fastened to Teflon rings to create a well. The amnionic surface was exposed to meconium and amniotic fluid for 1 to 48 hours and analyzed microscopically for the presence of free meconium and meconium-laden amnionic macrophages. In each of the experiments, prior to the 12-hour time point, few meconium-laden macrophages were present in the membrane layers. A significant rise in the number of meconium-laden macrophages and a concomitant increase in staining intensity was noted in the membranes at 24 and 48 hours. Contrary to previous reports, our in vitro model of meconium incorporation into placental membranes demonstrated that significant numbers of meconium-laden macrophages were only observed after 24 and 48 hours.

Fetal adrenal gland volume and cortisol/dehydroepiandrosterone sulfate ratio in inflammation-associated preterm birth.

OBJECTIVE: Fetal adaptation to stress is regulated in part by the pituitary-adrenocortical system. The stress hormones dehydroepiandrosterone sulfate (DHEAS) and cortisol have opposing effects: cortisol suppresses while DHEAS enhances immune functions. We sought to estimate the impact of intraamniotic inflammation on fetal adrenal gland volume and cortisol-to-dehydroepiandrosterone sulfate ratio (fetal stress ratio) in pregnancies complicated by preterm birth. METHODS: Fifty-one consecutive singleton fetuses of mothers who had an indicated amniocentesis to rule out infection were analyzed. Intraamniotic inflammation was assessed by proteomic profiling of amniotic fluid for the biomarkers of the Mass Restricted score. The Mass Restricted score ranges from 0 (biomarkers absent) to 4 (all biomarkers present), with Mass Restricted scores of 3 or 4 indicating severe intraamniotic inflammation. Fetal adrenal gland volume was assessed by three-dimensional ultrasonography and corrected for estimated fetal weight. Interleukin-6 (IL-6), cortisol, and DHEAS were measured by immunoassay. RESULTS: Women with intraamniotic inflammation delivered earlier (27.8+/-3.4 weeks, n=16, compared with 32.3+/-3.0 weeks, n=35, P<.001), and their fetuses had higher cord blood IL-6 (P=.011) and higher corrected adrenal gland volumes (P=.027). Cord blood IL-6 levels were in direct relationship with corrected adrenal volume (r=0.372, P=.019), fetal cortisol (r=0.428, P=.010), and DHEAS (r=0.521, P<.001). However, fetuses exposed to intraamniotic inflammation had an overall lower fetal stress ratio (P=.034). These results maintained after adjusting for gestational age, uterine contractions, and steroid exposure. CONCLUSION: Fetuses exposed to intraamniotic inflammation have higher adrenal gland volumes and lower cortisol-to-DHEAS ratios, suggesting that the fetal adrenocortical axis plays a role in the intrauterine adaptation to inflammation.

Fractional excretion of tumor necrosis factor-alpha in women with severe preeclampsia.

OBJECTIVE: Proinflammatory cytokines of placental or systemic origin are thought to play a central role in the pathophysiology of preeclampsia. We sought to estimate the fractional excretion of tumor necrosis factor (TNF)-alpha in relationship to proteinuria in women with severe preeclampsia. METHODS: In a cross-sectional study, we evaluated the serum and urine levels of TNF-alpha in 45 women diagnosed with severe preeclampsia (mean+/-standard error of the mean, gestational age 29.1+/-0.5 weeks). Forty-five healthy pregnant women matched for parity, maternal age, and gestational age at recruitment (30.1+/-0.4 weeks) made up the control group. Urinary concentrations were normalized to creatinine. The fractional excretion of TNF-alpha was interpreted in relationship to that of total proteins and soluble fms-like tyrosine kinase-1 (sFlt-1). RESULTS: We found that the women with preeclampsia had significantly higher serum TNF-alpha concentrations compared with the women in the control group (mean+/-standard error of the mean, preeclampsia: 1.39+/-0.09 versus control: 0.93+/-0.07 pg/mL, P<.001). In contrast, urinary levels of TNF-alpha were significantly decreased in the women with preeclampsia compared with the healthy women (median [interquartile range], preeclampsia: 0.26 [0.10-0.91] versus control: 0.58 [0.21-1.29] pg/mg creatinine, P=.003), even though the hypertensive women had higher levels of proteinuria. In contrast to sFlt-1, urinary TNF-alpha did not correlate with the degree of proteinuria. Additionally, in preeclampsia, the fractional excretion of TNF-alpha was significantly lower (preeclampsia: 1.92% [0.46-4.20] versus control: 7.2% [2.44-12.07], P<.001). CONCLUSION: The fractional excretion of TNF-alpha is significantly reduced in women with severe preeclampsia despite proteinuria. The decreased clearance and altered renal excretion of this cytokine may contribute to the exaggerated inflammatory response observed in preeclampsia. LEVEL OF EVIDENCE: II.

Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia.

OBJECTIVE: The cause of preeclampsia remains unknown and the diagnosis can be uncertain. We used proteomic-based analysis of urine to improve disease classification and extend the pathophysiologic understanding of preeclampsia. STUDY DESIGN: Urine samples from 284 women were analyzed by surface-enhanced laser desorption/ionization. In the exploratory phase, 59 samples were used to extract the proteomic fingerprint characteristic of severe preeclampsia requiring mandated delivery and to develop a diagnostic algorithm. In the challenge phase, we sought to prospectively validate the algorithm in 225 women screened for a variety of high- and low-risk conditions, including preeclampsia. Of these, 19 women were followed longitudinally throughout pregnancy. The presence of biomarkers was interpreted relative to clinical classification, need for delivery, and other urine laboratory measures (ratios of protein to creatinine and soluble fms-like tyrosine kinase-1 to placental growth factor). In the translational phase, biomarker identification by tandem mass spectrometry and validation experiments in urine, serum, and placenta were used to identify, quantify, and localize the biomarkers or related proteins. RESULTS: We report that women with preeclampsia appear to present a unique urine proteomic fingerprint that predicts preeclampsia in need of mandated delivery with highest accuracy. This characteristic proteomic profile also has the ability to distinguish preeclampsia from other hypertensive or proteinuric disorders in pregnancy. Pregnant women followed longitudinally who developed preeclampsia displayed abnormal urinary profiles more than 10 weeks before clinical manifestation. Tandem mass spectrometry and de novo sequencing identified the biomarkers as nonrandom cleavage products of SERPINA1 and albumin. Of these, the 21 amino acid C-terminus fragment of SERPINA1 was highly associated with severe forms of preeclampsia requiring early delivery. In preeclampsia, increased and aberrant SERPINA1 immunoreactivity was found in urine, serum, and placenta, in which it localized predominantly to placental villi and placental vascular spaces adherent to the endothelium. In addition, significant perivascular deposits of misfolded SERPINA1 aggregates were exclusively identified in preeclamptic placentae. CONCLUSION: Proteomics-based characterization of urine in preeclampsia identified a proteomic fingerprint composed of SERPINA1 and albumin fragments, which can accurately diagnose preeclampsia and shows promise to discriminate it from other hypertensive proteinuric diseases. These findings provide insight into a novel pathophysiological mechanism of preeclampsia related to SERPINA1 misfolding, which may offer new therapeutic opportunities in the future.