Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome.

The complement system is critical to human health owing to its central role in host defense and innate immunity. During pregnancy, the complement system must be appropriately regulated to allow for immunologic tolerance to the developing fetus and placenta. Although some degree of complement activation can be seen in normal pregnancy, the fetus seems to be protected in part through the placental expression of complement regulatory proteins, which inhibit complement activation at different steps along the complement activation cascade. In women who develop preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, there is a shift toward increased complement activation and decreased complement regulation. There is an increase in placental deposition of C5b-9, which is the terminal effector of classical, lectin, and alternative complement pathways. C5b-9 deposition stimulates trophoblasts to secrete soluble fms-like tyrosine kinase-1, which sequesters vascular endothelial growth factor and placental growth factor. Pathogenic mutations or deletions in complement regulatory genes, which predispose to increased complement activation, have been detected in women with preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Before the disease, biomarkers of alternative complement pathway activation are increased; during active disease, biomarkers of terminal complement pathway activation are increased. Urinary excretion of C5b-9 is associated with preeclampsia with severe features and distinguishes it from other hypertensive disorders of pregnancy. Taken together, existing data link preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome with increased activation of the terminal complement pathway that, in some cases, may be influenced by genetic alterations in complement regulators. These findings suggest that the inhibition of the terminal complement pathway, possibly through C5 blockade, may be an effective strategy to treat preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, but this strategy warrants further evaluation in clinical trials.

Clinical and Demographic Risk Factors for COVID-19 during Delivery Hospitalizations in New York City.

OBJECTIVE: This study was aimed to review 4 weeks of universal novel coronavirus disease 2019 (COVID-19) screening among delivery hospitalizations, at two hospitals in March and April 2020 in New York City, to compare outcomes between patients based on COVID-19 status and to determine whether demographic risk factors and symptoms predicted screening positive for COVID-19. STUDY DESIGN: This retrospective cohort study evaluated all patients admitted for delivery from March 22 to April 18, 2020, at two New York City hospitals. Obstetrical and neonatal outcomes were collected. The relationship between COVID-19 and demographic, clinical, and maternal and neonatal outcome data was evaluated. Demographic data included the number of COVID-19 cases ascertained by ZIP code of residence. Adjusted logistic regression models were performed to determine predictability of demographic risk factors for COVID-19. RESULTS: Of 454 women delivered, 79 (17%) had COVID-19. Of those, 27.9% (n = 22) had symptoms such as cough (13.9%), fever (10.1%), chest pain (5.1%), and myalgia (5.1%). While women with COVID-19 were more likely to live in the ZIP codes quartile with the most cases (47 vs. 41%) and less likely to live in the ZIP code quartile with the fewest cases (6 vs. 14%), these comparisons were not statistically significant (p = 0.18). Women with COVID-19 were less likely to have a vaginal delivery (55.2 vs. 51.9%, p = 0.04) and had a significantly longer postpartum length of stay with cesarean (2.00 vs. 2.67days, p < 0.01). COVID-19 was associated with higher risk for diagnoses of chorioamnionitis and pneumonia and fevers without a focal diagnosis. In adjusted analyses, including demographic factors, logistic regression demonstrated a c-statistic of 0.71 (95% confidence interval [CI]: 0.69, 0.80). CONCLUSION: COVID-19 symptoms were present in a minority of COVID-19-positive women admitted for delivery. Significant differences in obstetrical outcomes were found. While demographic risk factors demonstrated acceptable discrimination, risk prediction does not capture a significant portion of COVID-19-positive patients. KEY POINTS: · COVID-19 symptoms were present in a minority of COVID-19-positive women admitted.. · COVID-19 symptomatology did not appear to differ before or after the apex of infection in New York.. · Demographic risk factors are unlikely to capture a significant portion of COVID-19-positive patients..

Evaluation of Hemolysis as a Severe Feature of Preeclampsia.

Hemolysis predisposes to adverse pregnancy outcomes. Yet, there are limited data on hemolysis in hypertensive disorders of pregnancy other than hemolysis, elevated liver enzymes, and low platelet count syndrome. To evaluate the prevalence and impact of hemolysis in hypertensive disorders of pregnancy, we performed a retrospective cohort study at a single center (October 2013-May 2017), among women screened for hemolysis using lactate dehydrogenase (LDH) levels. We compared LDH levels by hypertensive disorder (chronic hypertension, gestational hypertension, preeclampsia, and preeclampsia with severe features) and evaluated impact on adverse pregnancy outcomes. Data were analyzed by χ2 or t test, ANOVA, test of medians, and logistic regression. Among 8645 deliveries, 1188 (13.7%) had a hypertensive disorder. Of these, 812 (68.4%) had LDH measurement before delivery: chronic hypertension (n=152); gestational hypertension (n=209); preeclampsia (n=216); and preeclampsia with severe features (n=235). LDH ≥400 U/L (≥1.6× normal) was more common in preeclampsia with severe features compared with other hypertensive disorders of pregnancy (9.8% versus 2.3%; P<0.001); adjusted odds ratio 4.52 (95% confidence interval, 2.2-9.2; P<0.001). LDH ≥400 U/L was associated with adverse maternal outcomes (41.7% versus 15.3%; P<0.001), adjusted odds ratio 3.05 (95% confidence interval, 1.4-6.7; P=0.006), and adverse neonatal outcomes (eg, preterm birth 59.4% versus 22.5%; P<0.001). We find that elevated LDH levels are associated with adverse maternal and neonatal outcomes in hypertension and preeclampsia, independent of hemolysis, elevated liver enzymes, and low platelet count syndrome. Therefore, elevated LDH levels (≥1.6× normal or ≥400 U/L) may be considered a severe feature of preeclampsia.

Maternal and feto-placental phenotypes of early-onset severe preeclampsia.

OBJECTIVE: To characterize maternal and feto-placental phenotypes of severe preeclampsia that trigger early-onset delivery. METHODS: A retrospective cohort review of pregnant women receiving care from 2000 to 2010. Subjects with early-onset severe preeclampsia delivering between 20 and 32 weeks were identified excluding multiple gestations or major anomalies. We defined indications for delivery as maternal (i.e. severe headache or abnormal laboratory parameters), feto-placental (i.e. non-reassuring tracing) or mixed (i.e. both maternal and feto-placental factors). To characterize the groups, demographic, clinical, laboratory, ultrasound and pathology data were abstracted. Statistical analysis was conducted. RESULTS: We identified 164 subjects meeting inclusion criteria. Indications for delivery were maternal (57.3%), feto-placental (29.9%) or mixed (12.8%). Compared to neonates delivered for maternal indications, birthweight was significantly lower among neonates delivered for feto-placental or mixed indications (p < 0.001). While placental findings were largely similar between groups, abnormal cord insertion was more common in subjects delivered for feto-placental factors (p = 0.02). Women delivered for maternal indications had more significant lab abnormalities than women delivered for feto-placental or mixed indications. CONCLUSION: In attempting to classify early-onset severe preeclampsia by delivery indication, we found patterns to suggest that feto-placental and maternal phenotypes of disease may have distinct pathophysiologic underpinnings.

Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia.

PROBLEM: Severe preeclampsia has been independently linked to complement dysregulation and angiogenic imbalance; however, the relationship between complement and angiogenic factors in human pregnancy is unclear. METHOD OF STUDY: Utilizing existing biomarkers, our study sought to better understand this relationship in active disease. We performed a case-control study, enrolling 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension. Levels of complement components (C3a, C5a, and C5b-9) and angiogenic markers [basic fibroblast growth factor (bFGF), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)] were measured simultaneously. RESULTS: Compared to both hypertensive and non-hypertensive controls, severe preeclampsia was associated with increased plasma sFlt-1, decreased plasma VEGF and PlGF, decreased urinary PlGF, and increased urinary C5b-9. Urinary marker C5b-9 correlated strongly with the anti-angiogenic condition. In subjects with detectable urinary excretion of C5b-9, median plasma levels of sFlt-1 were significantly greater (32,029 versus 4556 pg/mL, P < 0.0001) and levels of PlGF (15.6 versus 226 pg/mL, P < 0.0001) and VEGF (119 versus 153 pg/mL, P = 0.001) were significantly lower. CONCLUSION: More so than plasma complement markers, urinary C5b-9 may a useful measure to link complement dysregulation with angiogenic imbalance in severe preeclampsia.

Complement activation and kidney injury molecule-1-associated proximal tubule injury in severe preeclampsia.

Kidney injury with proteinuria is a characteristic feature of preeclampsia, yet the nature of injury in specific regions of the nephron is incompletely understood. Our study aimed to use existing urinary biomarkers to describe the pattern of kidney injury and proteinuria in pregnancies affected by severe preeclampsia. We performed a case-control study of pregnant women from Brigham and Women's Hospital from 2012 to 2013. We matched cases of severe preeclampsia (n=25) 1:1 by parity and gestational age to 2 control groups with and without chronic hypertension. Urinary levels of kidney injury molecule-1 and complement components (C3a, C5a, and C5b-9) were measured by enzyme-linked immunosorbent assay, and other markers (albumin, ß2 microglobulin, cystatin C, epithelial growth factor, neutrophil gelatinase-associated lipocalin, osteopontin, and uromodulin) were measured simultaneously with a multiplex electrochemiluminescence assay. Median values between groups were compared with the Wilcoxon signed-rank test and correlations with Spearman correlation coefficient. Analysis of urinary markers revealed higher excretion of albumin and kidney injury molecule-1 and lower excretion of neutrophil gelatinase-associated lipocalin and epithelial growth factor in severe preeclampsia compared with chronic hypertension and healthy controls. Among subjects with severe preeclampsia, urinary excretion of complement activation products correlated most closely with kidney injury molecule-1, a specific marker of proximal tubule injury (C5a: r=0.60; P=0.001; and C5b-9: r=0.75; P<0.0001). Taken together, we describe a pattern of kidney injury in severe preeclampsia that is characterized by glomerular impairment and complement-mediated inflammation and injury, possibly localized to the proximal tubule in association with kidney injury molecule-1.

Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy.

The complement cascade is activated in normal pregnancy, and excessive complement activation propagates the systemic inflammatory response in severe preeclampsia. Consequently, biomarkers of complement dysregulation may be useful for prediction or treatment of disease. Because renal damage with proteinuria is a characteristic pathological feature of preeclampsia, we hypothesized that complement markers in urine, rather than plasma, could better reflect complement dysregulation in disease. To investigate this, we performed a case-control study of pregnant women, enrolling 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension matched by gestational age and parity. Subjects were recruited from the Brigham and Women's Hospital from March 2012 to March 2013. Urine and blood samples were collected on the day of enrollment, with complement activation (C3a, C5a, and C5b-9) measured by ELISA. Severe preeclampsia was associated with marked elevations in urinary C5b-9 (median [interquartile range], 4.3 [1.2-15.1] ng/mL) relative to subjects with chronic hypertension (0 [0-0]) and healthy controls (0 [0-0]; P<0.0001). Urinary excretion of C5b-9 was detected in 96% of cases with severe preeclampsia, 12% of controls with chronic hypertension, and 8% of healthy controls. Cases were also notable for significantly greater urinary excretion of C3a and C5a. Plasma levels of C5a and C5b-9, but not C3a, were increased in the cases with severe preeclampsia compared with healthy controls; however, they did not distinguish preeclampsia from chronic hypertension, supporting our hypothesis that complement markers in urine, rather than plasma, better reflect complement dysregulation. Complement inhibition is an intriguing treatment option for patients with severe preeclampsia.

Preeclampsia: the death of Goliath.

In this review, a novel and unifying pathophysiologic mechanism of preeclampsia is presented whereby a minimal excess of placental immune complex production versus removal causes a proinflammatory autoamplification cascade of trophoblast apoptosis/necrosis and oxidative stress, culminating in clinical preeclampsia. This concept immediately leads to a plethora of new and robust therapeutic strategies.

Low erythrocyte complement receptor type 1 (CR1, CD35) expression in preeclamptic gestations.

PROBLEM: Erythrocyte complement receptor type 1 (E-CR1) is the main immune complex clearance mechanism in humans. Decreased E-CR1 expression is noted in certain inflammatory disorders. Recent evidence implicates inflammation in the pathogenesis of preeclampsia. We investigated whether E-CR1 is decreased in preeclampsia. METHOD OF STUDY: E-CR1 protein expression was quantified by radioimmunoassay. Plasma concentration of soluble CR1 was quantified using a specific enzyme linked immunosorbent assay. Quantitative genotypes were evaluated by HindIII restriction fragment length polymorphism analysis. RESULTS: E-CR1 expression was reduced in patients with preeclampsia. Lack of neoantigen expression (indicative of enzymatic cleavage of CR1) or elevated plasma-soluble CR1 was evidence against an acquired loss of E-CR1. Genotype analysis revealed a higher frequency of a CR1 allele associated with low E-CR1 expression in preeclampsia when compared with normal pregnant controls. CONCLUSIONS: E-CR1 expression is decreased in preeclamptic patients and levels correlate with severity of disease. This condition may have a genetic basis in some patients.

Detection of fetal lactate with two-dimensional-localized proton magnetic resonance spectroscopy.

BACKGROUND: Antenatal surveillance is inefficient for accurately detecting fetal compromise. A noninvasive technique for assessing fetal metabolic status would be useful for clinical management. CASE: Fetal magnetic resonance spectroscopy was performed at 20 weeks in a pregnancy complicated by severe intrauterine growth restriction to determine if lactate, a metabolite associated with fetal hypoxia, was present. Two-dimensional, single-slice proton magnetic resonance spectroscopy was carried out at 1.5 T using a volume-selective, double-spin echo technique. Lactate was detected in fetal back muscle. Fetal death occurred the next day. CONCLUSIONS: Although this initial report is purely experimental, further development of this technique may prove to be a valuable noninvasive tool in the management of suspected fetal hypoxia.