Angiogenic Biomarkers for Risk Stratification in Women with Preeclampsia.

BACKGROUND: Preeclampsia is a leading cause of maternal and neonatal mortality and morbidity worldwide. Diagnosis of the condition is currently limited to utilization of nonspecific signs and symptoms. However, identification of potential pathogenic biomarkers may support earlier diagnosis and ultimately improved prognosis. CONTENT: The current models of preeclampsia suggest that the disease has components of abnormal placentation, a degree of angiogenic imbalance and endothelial dysfunction. Angiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin increase while placental growth factor concentrations decrease in the circulation weeks before the onset of the disease. Multiple studies have looked at the capacity of angiogenic factors for the prediction of preeclampsia and adverse pregnancy outcomes. SUMMARY: The goal of this review is to focus on the role of angiogenic factors in the pathogenesis of preeclampsia and use of angiogenic biomarkers for risk stratification, diagnosis, and prognosis of the disease.

Perinatal and obstetric outcomes of dichorionic vs trichorionic triplet pregnancies.

BACKGROUND: Clinical management and outcome of multiple gestation can be affected by chorionicity. In triplet pregnancies, fetal death has been associated with dichorionic (DC) and monochorionic placentation. Studies evaluating triplet pregnancy outcomes in relation to chorionicity have been few and may not reflect contemporary antenatal and neonatal care. OBJECTIVE: The objective of this study was to compare obstetric and perinatal outcomes in DC and trichorionic (TC) triplet pregnancies. STUDY DESIGN: We performed a retrospective cohort study of triplet pregnancies that delivered at ≥20 weeks' gestation at 2 Chicago area hospitals from January 1999 through December 2010. Chorionicity was determined by pathology specimen. Maternal and infant charts were reviewed for obstetric and perinatal outcomes. RESULTS: The study population included 159 pregnancies (477 neonates) of which 108 were TC (67.9%) and 51 were DC (32.1%). Over 94% of mothers in this study had all 3 infants survive to discharge regardless of chorionicity. No difference was found in perinatal mortality rate between DC and TC triplets (3.3% vs 4.6%; P = .3). DC triplets were significantly more likely to be very low birthweight (41.8% vs 22.2%; odds ratio, 2.2; 95% confidence interval, 1.2-4.2; P = .02) and to deliver at <30 weeks (25.5% vs 8.3%; odds ratio, 6.1; 95% confidence interval, 1.9-19.4; P = .002) compared to TC triplets. Criteria for twin-twin transfusion syndrome (TTTS) were present in 3 DC triplet pregnancies (5.9%). Neonates in pregnancies complicated by TTTS were less likely to survive 28 days as compared to neonates from DC pregnancies that were not affected by TTTS (P = .02) or TC neonates (P = .02) Neonatal survival was similar in DC pregnancies not affected by TTTS and TC pregnancies (98.6% and 96.6%; P = .7). CONCLUSION: Although perinatal mortality did not correlate with chorionicity, DC pregnancies were more likely to deliver <30 weeks' gestational age and have very low birthweight neonates. Neonatal mortality appears to be mediated by the presence or absence of TTTS as 28-day survival was worse in DC pregnancies complicated by TTTS, but similar between DC pregnancies not affected by TTTS and TC pregnancies.

Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states.

OBJECTIVES: With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. STUDY DESIGN: In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient's medical records. MAIN OUTCOME MEASURES: Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP were evaluated. RESULTS: A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0 % vs 50.2 %, p = 0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (pg/ml) (3168 [IQR: 2160-4945] vs 2678 [IQR: 1752-4271]; p = 0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs 12 [IQR: 5-30]; p = 0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. CONCLUSIONS: Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a covariate when studying angiogenic factors in normotensive pregnant patients.

Prevalence and management of severe intrapartum hypertension in patients with preeclampsia at an urban tertiary care medical center.

OBJECTIVES: Data on management of severe intrapartum hypertension is lacking. The aim of this study is to explore the proportion of timely interventions in severe, persistent intrapartum hypertension treatment by exploring the prevalence and management of intrapartum hypertension trends. STUDY DESIGN: This was a retrospective case-control study of pregnant women who delivered at the University of Chicago between January 2015 and March 2017. Patients with severe preeclampsia who underwent labor (either induced or spontaneous) were stratified into two groups: severe intrapartum hypertension and no severe intrapartum hypertension. MAIN OUTCOME MEASURES: Type of treatment and timing to treatment of severe hypertensive episodes were explored as well as prevalence of maternal adverse outcomes. RESULTS: A total of 95 patients with severe preeclampsia in labor were identified. In patients with persistent severe intrapartum hypertension (n = 52), 15 (28.9%) received treatment. Patients experiencing greater than three episodes of blood pressure elevation were more likely to receive treatment as compared to those with fewer episodes. There was no significant difference in severe maternal morbidity (SMM) between those treated within 60 min compared to those untreated or treated after 60 min (16.7% vs 27.5%; p = 0.71). CONCLUSIONS: Management protocols of intrapartum hypertensive episodes are variable or not universally implemented. Inadequately treated episodes of severe intrapartum hypertension trend towards higher rates of SMM.

Racial Differences in Readmissions in Hypertensive Disorders of Pregnancy.

Hypertensive disorders of pregnancy (HDP) are associated with maternal and neonatal morbidity as well as postpartum hospital readmission. This study seeks to characterize differences among patients with postpartum readmissions related to HDP. This is a retrospective study of patients with HDP admitted at an urban tertiary care center from January 2019 to November 2019 following the implementation of a standardized readmission workflow for patients with HDP at a single institution. Medical information up to 6 weeks postpartum was collected by chart review. The primary outcome was readmission. Secondary outcomes included reason for readmission, location of initial evaluation, and blood pressure values at time of readmission. A total of 729 patients with HDP delivered over the study period, 79.7% (N = 581) of whom were Black and 11.0% (N = 80) of all patients were readmitted within 6 weeks of delivery. Patients who were older, privately insured, and with chronic hypertension/cardiac disease were more likely to be readmitted. There was no difference in readmission rate by race. However, Black patients were more likely to be readmitted for preeclampsia with severe features (43.3% vs 10.0% non-Black, p = 0.01). Black patients who were readmitted were more likely to be initially evaluated in the emergency room compared to non-Black patients (43.3% vs 15.0%, p = 0.03). Our results suggest although readmission rates did not differ by race, there are significant differences at the patient and system level between Black and non-Black patients readmitted to the hospital after a pregnancy affected by HDP.

The interval between births and the risk of recurrent preeclampsia among predominantly high risk women in urban tertiary care center.

INTRODUCTION: Women with a history of preeclampsia have a higher risk of recurrent preeclampsia. This study sought to ascertain the relationship between the interbirth interval and the risk of recurrent preeclampsia and difference in angiogenic markers between the two groups. METHODS: Data was collected from an ongoing cohort study of women with hypertensive disorders of pregnancy (HDP) enrolled at the admission to the labor and delivery floor. From this dataset, multigravida women with a prior diagnosis of preeclampsia were identified and compared to women with no prior history of preeclampsia. RESULTS: Of the 375 women with HDP who were predominantly African American, 245 were multigravida and 44 (18.0%) had a prior history of preeclampsia. Women with prior preeclampsia had an earlier gestational age of delivery, higher rates of preterm delivery and a higher incidence of preeclampsia with severe features (56.8% vs 29.8%) in the index pregnancy (p-values ≤ 0.001) than those without. The median number of years between history of preeclampsia in previous pregnancy and current pregnancy was 6 years (IQR 3, 8). Among patients with a prior history of preeclampsia, the interbirth interval was not associated with severe preeclampsia (p = 0.60) and there was no difference in angiogenic factors between patients with a prior history of preeclampsia compared to those without. CONCLUSIONS: In this study, the duration of the interbirth interval was not identified as a risk factor of developing severe preeclampsia in a subsequent pregnancy and angiogenic factors are not a reflection of maternal predisposition to recurrent preeclampsia.

Furosemide for Accelerated Recovery of Blood Pressure Postpartum in women with a hypertensive disorder of pregnancy: A Randomized Controlled Trial.

[Figure: see text].

Use of the angiogenic biomarker profile to risk stratify patients with fetal growth restriction.

BACKGROUND: Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exist in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers. OBJECTIVE: The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 to placental growth factor ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a 2-week time period. STUDY DESIGN: This was a prospective observational cohort study performed in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks' gestation were evaluated using serial 2-week encounters from the time of enrollment to delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia laboratory tests and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for soluble fms-like tyrosine kinase-1 and placental growth factor after delivery in a double-blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes. RESULTS: A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14-33.57) weeks. Patients were divided into low-risk (ratio of <38) and high-risk (ratio of ≥38) groups. Baseline characteristics of patients did not show any marked differences, including preeclampsia labs or ultrasound parameters, between the 2 groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when soluble fms-like tyrosine kinase-1 to placental growth factor ratio was ≥38 (P=.02 and P=.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks gestation, smaller neonatal birthweight, and a shorter time to delivery from testing to delivery. CONCLUSION: Among patients with fetal growth restriction, the soluble fms-like tyrosine kinase-1 to placental growth factor ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery.

Postpartum blood pressure trends are impacted by race and BMI.

OBJECTIVE: Our objective was to evaluate postpartum blood pressure trends, and time to resolution of hypertension among women with hypertensive disorders of pregnancy, specifically focusing on impact of race and BMI on these trends. METHODS: We performed a secondary analysis of a randomized trial that utilized a text-message based home blood pressure monitoring system. BPs for this study included both inpatient postpartum BPs as well as home BPs obtained from the text-based program. Women were followed from 12 h of delivery to 16 days postpartum. Outcomes were: (1) postpartum BP trend summaries from a linear mixed-effects regression model and (2) time to resolution of hypertension (defined as ≥ 48 h of BPs < 140/90) depicted using Kaplan Meier survival curves with hazard ratio estimates of association using Cox models. RESULTS: Eighty-four women were included, of which 63% were black. Non-black women with a BMI < 35 kg/m2 had steady decreases in systolic BP whereas other groups peaked around 6.5 days postpartum. BPs for women in the BMI < 35 group, regardless of race, remained in the normotensive range. Conversely, women with a BMI ≥ 35 had a systolic BP peak into the hypertensive range prior to declining. Diastolic BP peaked at an average of 8.5 days postpartum. Time to resolution of BPs differed by race and BMI groups (p = 0.012). Non-black women with a BMI < 35 had the shortest time to resolution and 81% of these women had resolution of hypertension. Only 49% of black women with a BMI < 35 had resolution of hypertension and approximately 40% of both black and non-black women with BMI ≥ 35 had resolution of hypertension. CONCLUSION: We identified race and BMI to be determinants of postpartum BP trends and hypertension resolution. Further study is needed to determine if race and BMI targeted postpartum hypertension interventions may lead to faster blood pressure recovery and lower maternal morbidity postpartum.

Angiogenic Factor Estimation as a Warning Sign of Preeclampsia-Related Peripartum Morbidity Among Hospitalized Patients.

Preeclampsia-related morbidity and mortality is rising predominantly because of delayed identification of patients at risk for preeclampsia with severe features and associated complications. This study explored the association between angiogenic markers (sFlt1 [soluble fms-like tyrosine kinase-1]) and PlGF [placental growth factor]) and preeclampsia-related peripartum complications. Normotensive women or those with hypertensive disorders of pregnancy were enrolled. Blood samples were collected within 96 hours before delivery, and angiogenic markers were measured on an automated platform. Our study included 681 women, 375 of which had hypertensive disorders. Of these, 127 (33.9%) had severe preeclampsia, and 71.4% were black. Compared with normotensive women, women with severe preeclampsia had higher levels of sFlt1 (9372.5 versus 2857.0 pg/mL; P<0.0001), lower PlGF (51.0 versus 212.0 pg/mL; P<0.0001), and a high sFlt1/PlGF (212.0 versus 14.0; all P<0.0001). A similar trend in sFlt1, PlGF, and sFlt1/PlGF was found in those women with complications secondary to preeclampsia (all P<0.001). The highest tertile of sFlt1/PlGF was strongly associated with severe preeclampsia in a multivariable analysis. Among patients with a hypertensive disorder of pregnancy, 340 (90.7%) developed postpartum hypertension, of which 50.4% had mild, and 40.3% had severe postpartum hypertension. The sFlt1/PlGF ratio was significantly higher for severe and mild postpartum hypertension compared with women with normal postpartum blood pressures (73.5, 46.0, and 13.0, respectively; P values<0.0001). Furthermore, the highest tertile of antepartum sFlt1/PlGF was associated with postpartum hypertension ( P=0.004). This study demonstrates a significant association between an abnormal angiogenic profile before delivery and severe preeclampsia and peripartum complications.

Abnormal mid-trimester cardiac strain in women with chronic hypertension predates superimposed preeclampsia.

BACKGROUND: Chronic hypertension (cHTN) affects 7% of all pregnancies. We hypothesized that cHTN during pregnancy would be associated with abnormal myocardial strain patterns and adverse perinatal outcomes. METHODS: This was a retrospective cohort study of patients seen in a high-risk obstetrics clinic with cHTN. Parturients with a singleton pregnancy who had undergone an echocardiogram as part of routine clinical care were eligible. Clinical and demographic information was collected from medical records. Global peak longitudinal strain (GLS) was measured using automated software from stored echocardiographic images. RESULTS: 60 patients were included in this analysis, of which 48 (80.0%) were African American. The median BMI was 40.6, age was 34 years, and the gestational age was 20.4 weeks at the time of the echo and 37.9 weeks at delivery. Thirty-four patients (56.7%) demonstrated abnormal strain, defined as a GLS <= -19%. Patients with abnormal strain were similar in age and BMI to patients with normal cardiac function. When compared to women with normal strain, those with abnormal strain had lower stroke volume (69.0 ml vs 81.5 ml; p = .001) and ejection fraction (49.6% vs 57.5%; p < .0001). Rates of superimposed preeclampsia were higher (38.2% vs 11.5%, p-value = .02) and a higher proportion of patients in the abnormal strain group delivered before 37 weeks (44.1% vs 19.2%; p = .04). CONCLUSION: In a population of parturients with cHTN, we found that more than one-half demonstrated subclinical abnormal cardiac function. The presence of abnormal cardiac strain predates superimposed preeclampsia and preterm delivery. Further studies are needed to validate these findings.