Richard M. Burwick

Eculizumab for the treatment of preeclampsia/HELLP syndrome

Severe preeclampsia with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide. Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives: delivery as definitive therapy for maternal health vs. prolongation of pregnancy to avoid prematurity and associated morbidities. We describe a patient presenting with severe preeclampsia/HELLP syndrome at 26 weeks gestation that was treated with Eculizumab, a targeted inhibitor of complement protein C5, which resulted in marked clinical improvement and complete normalization of lab parameters. Pregnancy was prolonged 17 days, likely resulting in a reduction of neonatal morbidity with its associated short and long-term health care costs. Successful use of Eculizumab in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia/HELLP syndrome.

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.

The Complement System and Adverse Pregnancy Outcomes

Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.

Eculizumab fails to inhibit generation of C5a in vivo

To the editor: Eculizumab is a monoclonal antibody (mAb) reputed to block C5 by preventing enzymatic generation of active components C5a and C5b.[1][1] C5a is a proinflammatory mediator whereas C5b combines with C6, C7, C8, and C9 to form the membrane attack complex C5b-9, which contributes to

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.

Pregnancies complicated by both preeclampsia and growth restriction between 34 and 37 weeks' gestation are associated with adverse perinatal outcomes.

Abstract Objective: To determine whether adverse outcomes were more common in late preterm pregnancies complicated by preeclampsia and growth restriction compared to those affected by preeclampsia alone. Methods: This was a retrospective cohort study of 8927 singleton pregnancies with preeclampsia. Pregnancies with small for gestational age (SGA) neonates (birth weight <10th percentile) were compared to those appropriate for gestational age (AGA) neonates. Maternal outcomes included cesarean delivery (CD) rate, CD for fetal heart rate (FHR) abnormalities, abruption, postpartum hemorrhage (PPH), maternal transfusion, acute renal failure, and peripartum cardiomyopathy. Neonatal outcomes studied included respiratory distress syndrome (RDS), jaundice, hypoglycemia, seizure, asphyxia, neonatal death, and intrauterine fetal demise (IUFD). Results: Women with preeclampsia and SGA infants were more likely to experience abruption (5.3% versus 3.0%, p < 0.001), higher CD rate (66.5% versus 55.0%, p < 0.001), and higher likelihood of a CD for FHR abnormalities (21.7% versus 10.0%, p < 0.001). SGA infants were more likely to experience adverse neonatal outcomes including RDS (10.1% versus 4.9%, p < 0.001), jaundice (59.8% versus 39.2%, p < 0.001), hypoglycemia (8.9% versus 3.9%, p < 0.001), asphyxia (0.6% versus 0.2%, p = 0.015), and IUFD (1.5% versus 0.3%, p < 0.001). Conclusions: Preeclamptic women and their neonates were more likely to experience adverse perinatal outcomes when SGA pregnancies were compared to those with AGA neonates.

Maternal, fetal, and neonatal imatinib levels with treatment of chronic myeloid leukemia in pregnancy

BACKGROUND Pregnant women with chronic myeloid leukemia (CML) can be treated effectively with the tyrosine-kinase inhibitor imatinib, but data regarding fetal and neonatal exposure and safety are limited. CASE We present a patient with newly diagnosed CML in early pregnancy. Leukapheresis and interferon-α were initiated in the second trimester with limited benefit. Imatinib was subsequently started at 28 weeks of gestation with complete hematologic response within 4 weeks. No significant maternal or neonatal adverse effects were noted, but imatinib and its primary active metabolite concentrated in maternal breast milk and neonatal urine. CONCLUSION Imatinib is effective for CML in pregnancy, but caution is warranted in light of potentially unrecognized fetal and neonatal effects.

Predictors of eclampsia in California

Abstract Objective: Eclampsia is a rare yet dangerous complication of the hypertensive disorders of pregnancy. The objective was to elucidate the predictors of eclampsia in a large cohort of pregnant women with gestational hypertension or preeclampsia. Methods: This was a retrospective cohort study of 143 093 pregnancies with preeclampsia or gestational hypertension in California during 2005–2008 of which 1719 had eclampsia. Predictors included race/ethnicity, parity, chronic hypertension (CHTN), diabetes mellitus, gestational diabetes mellitus (GDM), preterm delivery <32 weeks, maternal age ≥ 35, maternal age ≤ 20, socioeconomic status, education, and <5 prenatal visits. Univariate and multivariate analyses were performed. Results: Factors that increased the risk of eclampsia included Black (OR 1.46 [1.19–1.80]) and Hispanic race (OR 1.56 [1.35–1.79]), nulliparity (OR 1.59 [1.42–1.77]), maternal age ≤ 20 (OR 1.85 [1.61–2.11]), preterm delivery <32 weeks (OR 1.41 [1.16–1.70]), and <5 prenatal care visits (1.74 [1.46–2.07]). Factors that decreased the risk of eclampsia included CHTN (OR 0.06 [0.03–0.10]), GDM (OR 0.80 [0.67–0.96]), maternal age ≥ 35 (OR 0.70 [0.59–0.82]), and college education (OR 0.83 [0.74–0.94]). Conclusions: Black and Hispanic race, nulliparity, maternal age ≤ 20, preterm delivery <32 weeks, and <5 prenatal care visits increase the risk of eclampsia while CHTN, GDM, maternal age ≥ 35, and college education are protective. The protective effect of CHTN is the most striking. The mechanisms are likely different and warrant further investigation.

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

Abstract 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.