Practice bulletin #33: diagnosis and management of preeclampsia and eclampsia
Abstract
Hypertensive disease occurs in approximately 12-22% of pregnancies, and it is directly responsible for 17.6% of maternal deaths in the United States (1,2). However, there is confusion about the terminology and classification of these disorders. This bulletin will provide guidelines for the diagnosis and management of hypertensive disorders unique to pregnancy (ie, preeclampsia and eclampsia), as well as the various associated complications. Chronic hypertension has been discussed elsewhere (3).
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Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention
2024, Journal of Reproductive ImmunologyThe prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.
This study compares the angiogenic growth mediators (AGMs), oxidative stress (OS) and haematobiochemical profile as well as foeto-maternal outcomes of preeclampsia (PE) with and without foetal growth restriction (FGR) and the discriminative potential of these markers for identifying these conditions.
This hospital-based case-control study recruited a total of 209 women including 109 PE women without FGR and 48 PE women with FGR as cases whereas 52 normotensive pregnant women were recruited as controls. OS and AGMs and haematobiochemical markers were measured for all participants.
The rates of foetal complications including intrauterine foetal death and foetal distress were more common in PE with FGR than PE without FGR (p < 0.05) but maternal complications were comparable across these groups (p > 0.05). Of the haematobiochemical markers, placental growth factors (PIGF), PIGF/8-Isoprostane, sFlt-1/PIGF (AUC = 0.87, p < 0.001), soluble FMS-tyrosine kinase receptor-1 (sFlt-1) (AUC = 0.85, p < 0.001), total antioxidant capacity, 8-isoprostane (AUC = 0.83, p < 0.001) and lactate dehydrogenase (AUC = 0.70, p < 0.001) were more associated and showed at least an acceptable discrimination for PE with FGR against PE only.
The occurrence of FGR in PE patients does not necessarily indicate a severe maternal presentation of the condition but a tendency for adverse foetal outcomes. Cumulative assessment of OS and AGMs may provide diagnostic usefulness for distinguishing PE with and without FGR.
Placental Inflammation Significantly Correlates with Reduced Risk for Retinopathy of Prematurity
2023, American Journal of PathologyRetinopathy of prematurity (ROP), a blinding condition affecting preterm infants, is an interruption of retinal vascular maturation that is incomplete when born preterm. Although ROP demonstrates delayed onset following preterm birth, representing a window for therapeutic intervention, there are no curative or preventative measures available for this condition. The in utero environment, including placental function, is increasingly recognized for contributions to preterm infant disease risk. The current study identified a protective association between acute placental inflammation and preterm infant ROP development using logistic regression, with the most significant association found for infants without gestational exposure to maternal preeclampsia and those with earlier preterm birth. Expression analysis of proteins with described ROP risk associations demonstrated significantly decreased placental high temperature requirement A serine peptidase-1 (HTRA-1) and fatty acid binding protein 4 protein expression in infants with acute placental inflammation compared with those without. Within the postnatal peripheral circulation, HTRA-1 and vascular endothelial growth factor-A demonstrated inverse longitudinal trends for infants born in the presence of, compared with absence of, acute placental inflammation. An agnostic approach, including whole transcriptome and differential methylation placental analysis, further identify novel mediators and pathways that may underly protection. Taken together, these data build on emerging literature showing a protective association between acute placental inflammation and ROP development and identify novel mechanisms that may inform postnatal risk associations in preterm infants.
Outcomes of induction vs prelabor cesarean delivery at <33 weeks for hypertensive disorders of pregnancy
2023, American Journal of Obstetrics and Gynecology MFMHypertensive disorders of pregnancy are the leading cause of indicated preterm birth; however, the optimal delivery approach for pregnancies complicated by preterm hypertensive disorders of pregnancy remains uncertain.
This study aimed to compare maternal and neonatal morbidity in patients with hypertensive disorders of pregnancy who either went induction of labor or prelabor cesarean delivery at <33 weeks’ gestation. In addition, we aimed to quantify the length of induction of labor and rate of vaginal delivery in those who underwent induction of labor.
This is a secondary analysis of an observational study which included 115,502 patients in 25 hospitals in the United States from 2008 to 2011. Patients were included in the secondary analysis if they were delivered for pregnancy associated hypertension (gestational hypertension or preeclampsia) between 230 and <330 weeks’ gestation; and were excluded for known fetal anomalies, multiple gestation, fetal malpresentation or demise, or a contraindication to labor. Maternal and neonatal adverse composite outcomes were evaluated by intended mode of delivery. Secondary outcomes were duration of labor induction and rate of cesarean delivery in those who underwent labor induction.
A total of 471 patients met inclusion criteria, of whom 271 (58%) underwent induction of labor and 200 (42%) underwent prelabor cesarean delivery. Composite maternal morbidity was 10.2% in the induction group and 21.1% in the cesarean delivery group (unadjusted odds ratio, 0.42 [0.25–0.72]; adjusted odds ratio, 0.44 [0.26–0.76]). Neonatal morbidity in the induction group vs the cesarean delivery was 51.9% and 63.8 %, respectively (unadjusted odds ratio, 0.61 [0.42–0.89]; adjusted odds ratio, 0.71 [0.48–1.06]). The frequency of vaginal delivery in the induction group was 53% (95% confidence interval, 46.8–58.7) and the median duration of labor was 13.9 hours (interquartile range, 8.7–22.2). The frequency of vaginal birth was higher in patients at or beyond 29 weeks (39.9% at 240–286 weeks, 56.3% at 290–<330 weeks; P=.01).
Among patients delivered for hypertensive disorders of pregnancy <330 weeks, labor induction compared with prelabor cesarean delivery is associated with significantly lower odds of maternal but not neonatal morbidity. More than half of patients induced delivered vaginally, with a median duration of labor induction of 13.9 hours.
Preeclampsia at term can be classified into 2 clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood
2023, American Journal of Obstetrics and GynecologyAn antiangiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are used in the risk assessment of this syndrome, particularly of early disease. The role of an antiangiogenic state in late preeclampsia is unclear.
This study aimed to determine the prevalence, characteristics, and clinical significance of angiogenic/antiangiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery.
Two studies were conducted: (1) a longitudinal nested case–control study comprising women with preeclampsia (n=151) and a control group (n=540); and (2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis. Plasma concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 expressed as a multiple of the median <10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia who had an abnormal angiogenic profile was determined in the case-series participants and stratified by gestational age at delivery into early (≤34 weeks), intermediate (34.1–36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of women with preeclampsia with and without an abnormal angiogenic profile were compared.
The prevalence of an abnormal angiogenic profile was higher in preterm than in term preeclampsia (for early, intermediate, and term in the case–control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively). Women with preeclampsia at term who had an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, P<.05) than those without an abnormal profile. Women with preeclampsia at term who had a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to have class ≥2 obesity (41% vs 23%) than those with an abnormal profile (both, P<.05).
Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such abnormalities. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, on the basis of mechanisms of disease, into 2 clusters, which have different demographics, clinical characteristics, and risks of adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research.
Perturbations in kinetics of the thrombin generation assay identify women at risk of preeclampsia in the first trimester and provide the rationale for a preventive approach
2023, American Journal of Obstetrics and GynecologyActivation of the coagulation system and increased thrombin generation have been implicated in the pathophysiology of preeclampsia, and this rationale supports the administration of low-molecular-weight heparin to prevent this syndrome in patients at risk. Yet, randomized trials of this prophylactic measure have yielded contradictory results. A possible explanation is that only a subset of patients with preeclampsia have excessive thrombin generation and would benefit from the administration of low-molecular-weight heparin. Therefore, the key questions are whether and when patients who subsequently develop preeclampsia present evidence of abnormal thrombin generation.
This study aimed to determine (1) the kinetics of thrombin generation throughout gestation in women with a normal pregnancy and in those with early and late preeclampsia, and (2) the diagnostic performance of in vivo thrombin generation parameters to predict the development of preeclampsia.
This retrospective, nested case–control study was based on a prospective longitudinal cohort of singleton gestations. Cases comprised women who developed preeclampsia (n=49), and controls consisted of patients with a normal pregnancy (n=45). Preeclampsia was classified into early-onset (n=24) and late-onset (n=25). Longitudinal changes in the parameters of the thrombin generation assay (lag time, time to peak thrombin concentration, peak thrombin concentration, endogenous thrombin generation, and velocity index) throughout gestation were compared between the study groups, and normal pregnancy percentiles were derived from the control group. We tested whether a single parameter or a combination of parameters, derived from the kinetics of thrombin generation, could identify patients who subsequently developed preeclampsia. Time-related parameters <10th percentile were considered short, and concentration-related parameters >90th percentile were considered high.
(1) Patients who developed preeclampsia (early- and late-onset) had abnormal thrombin generation kinetics as early as 8 to 16 weeks of pregnancy; (2) patients with a combination of a short lag time and high peak thrombin concentration at 8 to 16 weeks of pregnancy had an odds ratio of 43.87 for the subsequent development of preeclampsia (area under the curve, 0.79; sensitivity, 56.8%; specificity, 92.7%; positive likelihood ratio, 7.76); (3) at 16 to 22 weeks of gestation, patients with a combination of a short lag time and a high velocity index had an odds ratio of 16 for the subsequent development of preeclampsia (area under the curve, 0.78; sensitivity, 62.2%; specificity, 92.5%; positive likelihood ratio, 8.29).
During early pregnancy, the thrombin generation assay can identify the subset of patients at a greater risk for the development of preeclampsia owing to accelerated and enhanced production of thrombin. This observation provides a rationale for testing the efficacy of low-molecular-weight heparin in this subset of patients. We propose that future research on the efficacy of low-molecular-weight heparin and other interventions targeting the coagulation system to prevent preeclampsia should be focused on patients with abnormal kinetics of thrombin generation.