Bruce B. Feinberg

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. # Novelty and Significance {#article-title-54}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.

Central neuraxial blockade promotes external cephalic version success after a failed attempt.

UNLABELLED External cephalic version (ECV) has been successfully used to decrease the fetal and maternal morbidity and costs of cesarean delivery. As there are limited data regarding the use of central neuraxial blockade in the setting of previously failed ECV attempts, we sought to evaluate the efficacy and safety of spinal and epidural anesthesia in this setting. A retrospective review of all ECV attempts performed by a single experienced obstetrician between 1995 and 1999 was conducted. Standardized tocolytic and anesthetic regimens were used. A total of 77 patients underwent ECV attempts; of these, 37 (48%) were unsuccessful, 15 of which consented to further attempts with anesthesia. Neuraxial anesthesia was associated with frequent ECV success in both multiparous 4/4 (100%) and nulliparous 9/11 (82%) parturients. Overall 5/6 (83%) and 8/9 (89%) (P = NS) ECV attempts were successful with spinal and epidural anesthesia, respectively, with 2/5 (40%) and 6/8 (75%) (P = NS) resulting in vaginal deliveries. One successful ECV in the epidural group had an urgent cesarean delivery for persistent fetal bradycardia with good neonatal and maternal outcomes. We conclude central neuraxial anesthesia promotes successful ECV after previously failed ECV attempts. IMPLICATIONS Our retrospective analysis of central neuraxial techniques, both epidural and spinal anesthesia, noted a significant success rate in the setting of previously failed external cephalic version attempts.

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

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.

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

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.

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, &bgr;2 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.

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.

Cervical hydrosonography in pregnancy to assess cervical length by transabdominal ultrasound.

Background Some womens cervices cannot be evaluated because they are obscured by obesity or vertex-presenting fetuses. Measuring cervical length in these cases is difficult or impossible. Technique We hypothesized that the problem of obscured cervices on transabdominal ultrasound could be resolved by introducing sterile water into the vagina, creating a hydroacoustic window between the vaginal lumen and the cervix. Women with unmeasurable cervices on transabdominal ultrasound had repeat studies after introduction of 60 mL of sterile water into their vaginas, and cervical length measurements taken were compared with those made on transvaginal scans. Experience Six pregnant women were studied (four singleton, one twin, and one triplet pregnancy). In all cases, previously unidentifiable cervices were seen adequately. No complications were noted. Statistical analysis (kappa 0.66) suggested good correlation between transabdominal cervical hydrosonography and transvaginal measurements of cervical length. Conclusion Introducing water into the vagina at transabdominal ultrasound can make an obscured cervix visible and measurable.

Early prenatal sonographic diagnosis of twin triploid gestation presenting with fetal hydrops and theca-lutein ovarian cysts.

The presence of theca‐lutein ovarian cysts in the early second trimester of pregnancy is highly suspicious for a complete hydatidiform molar pregnancy but can be seen in association with a partial mole. Theca‐lutein cysts may occur following hormonal stimulation for assisted reproductive techniques or in association with multiple gestations. Rare causes include immune and nonimmune fetal hydrops, maternal hypothyroidism, and triploid gestations. We report a case of a monochorionic twin gestation in which prenatal sonography demonstrated multiple anomalies and hydrops in each twin and bilateral theca‐lutein ovarian cysts. Triploidy in both twins and a partial hydatidiform mole were confirmed at pathologic examination.

Molar villous fluid suppresses mononuclear cell cytotoxicity

Complete molar pregnancy tissue is an allograft to the mother because all molar chromosomes are of paternal origin. Interactions between molar tissue and the maternal immune system may be important in the natural history of complete molar pregnancy. Molar villous fluid (MVF) has previously been demonstrated to suppress both mitogen and interleukin-2-induced T lymphocyte proliferation. The current study was undertaken to evaluate the potential effect of MVF on the cytotoxic activity of mononuclear cells (MNC) and lymphokine-activated mononuclear cells (LA-MNC). Sera and molar villous fluid were obtained from four women at the time of molar evacuation. K-562 erythroblastoid cells were used as target cells for MNC-mediated lysis, and JEG-3 choriocarcinoma cells were used as targets for LA-MNC-mediated lysis in a 51Cr release assay. Relative to patient sera, all MVF tested significantly inhibited both MNC and LA-MNC lysis of target cells (48.3 and 91% mean inhibition, respectively; P < 0.05). This study provides additional evidence that molar gestational tissue produces factor(s) that suppress maternal immunologic responses. Potential therapies may become available to reduce or eliminate the immunosuppressive effects of molar gestations resulting in a more favorable clinical outcome in patients with complete molar pregnancy and postmolar gestational trophoblastic tumors.