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The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Both progestogens and cerclage are individually effective in preterm birth prevention in high risk pregnancies. However, national and international guidelines cite a lack of data available to comment on the potential benefit of concurrent progestogen therapy after cerclage has been placed. Studies to date have been small with mixed results regarding benefit of concurrent progestogen with cerclage leaving uncertainty regarding best clinical practice., Objective: This study aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth in singleton pregnancies., Methods: This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016 to June 2020. Exclusion criteria were lack of documentation regarding whether progestogen was prescribed, unavailable delivery outcome, and pregnancy termination (spontaneous or induced) before 16 weeks' gestation. The exposure of interest was progestogen use with cerclage placement, which included those who continued to use progestogen or who started progestogen after cerclage. The comparison group consisted of those without progestogen use after cerclage placement, which included those who had no progestogen use during the entire pregnancy or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. The primary outcome was spontaneous preterm birth at <37 weeks. The secondary outcomes were spontaneous preterm birth at <34 weeks, gestational age at delivery, and a composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia. There were planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate), preterm birth history, and site. Continuous variables were compared in adjusted analyses with analysis of covariance, and categorical variables were compared with multivariable logistic regression, adjusting for potential confounders with adjusted odds ratio. A Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks., Results: During the study period, a total of 699 singletons met the inclusion criteria: 561 in the progestogen with cerclage group and 138 with cerclage alone. Baseline characteristics were similar, except the higher likelihood of previous spontaneous preterm birth in the progestogen group (61% vs 41%; P<.001). Within the progestogen group, 52% were on 17-hydroxyprogesterone caproate weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of spontaneous preterm birth <37 weeks (31% vs 39%; adjusted odds ratio, 0.59 [0.39-0.89]; P=.01) and <34 weeks (19% vs 27%; adjusted odds ratio, 0.55 [0.35-0.87]; P=.01), increased latency to spontaneous delivery (hazard ratio for spontaneous preterm birth <37 weeks, 0.66 [0.49-0.90]; P=.009), and lower frequency of perinatal death (7% vs 16%; adjusted odds ratio, 0.37 [0.20-0.67]; P=.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a previous preterm birth, those with ultrasound- or examination-indicated cerclage, those who started progestogen therapy before cerclage, and in sites restricted to the United States., Conclusion: Use of progestogen with cerclage was associated with reduced rates of spontaneous preterm birth and early spontaneous preterm birth compared with cerclage alone. Although this study was not sufficiently powered for subgroup analysis, the strength of evidence for benefit appeared greatest for those with ultrasound- or examination-indicated cerclage, and with vaginal progesterone. El resumen está disponible en Español al final del artículo., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thrombotic microangiopathy (TMA) represents a heterogeneous group of disorders characterized by microvascular thrombosis and end-organ damage. Pregnancy-associated thrombotic microangiopathy (p-TMA) has emerged as a distinct clinical entity with unique diagnostic challenges. Identifying the specific form of p-TMA is critical for appropriate and timely management. This review offers a comprehensive overview of the various forms of thrombotic microangiopathies associated with pregnancy, highlighting our current understanding of their pathophysiology and the evolving landscape of diagnosis and treatment for each., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Objective: Our objective was to evaluate if the use of low-dose aspirin (LDA) among pregnant individuals with chronic hypertension (CHTN) reduces the rate of superimposed preeclampsia or other adverse maternal and neonatal outcomes., Study Design: Our study included single-center cohort of pregnant individuals with CHTN who had a live birth after 23 weeks' gestation, between 2013 and 2018. The primary exposure was the use of LDA in pregnancy and the primary outcome was superimposed preeclampsia. LDA use was also evaluated by the timing of initiation, before or after 16 weeks' gestation. Secondary outcomes included preeclampsia subtypes (e.g., preeclampsia with severe features, early-onset disease), as well as adverse maternal and neonatal outcomes. Differences were analyzed by χ 2 , Fisher's exact, or t tests, with logistic regression to adjust for confounders., Results: Of 11,825 deliveries during the study period, 494 (4.2%) occurred in women with CHTN. Among those with CHTN, 174 (35%) were prescribed LDA, most often 81 mg daily (173 out of 174, 99%). Baseline characteristics were similar between groups, but the history of preeclampsia was more common in those prescribed LDA. The rate of superimposed preeclampsia was no different among those with CHTN-prescribed LDA compared with those who were not (36% vs. 30%, p  = 0.2), even when restricting the analysis to those prescribed LDA before 16 weeks' gestation (33 vs. 30%, p  = 0.2). In addition, LDA did not lead to a reduction in the rate of preeclampsia with severe features, early-onset preeclampsia, or other adverse maternal outcomes. However, the composite rate of adverse neonatal outcomes was lower in LDA users versus nonusers (4.0 vs. 13%, p  = 0.002), which persisted after multivariable adjustment (adjusted odds ratio: 0.28, 95% confidence interval: 0.12-0.67)., Conclusion: Among pregnant individuals with CHTN, LDA did not decrease the rate of superimposed preeclampsia. Further studies are warranted to validate our observed reduction in adverse neonatal outcomes and to determine if aspirin is more beneficial at dosages greater than 81 mg daily., Key Points: · Superimposed preeclampsia rates are the same regardless of LDA.. · Decreased rate of adverse neonatal outcomes is seen with LDA.. · No decrease in adverse maternal outcomes is seen with LDA.., Competing Interests: R.M.B. has received speaking fees and research grants from Alexion, AstraZeneca Rare Disease., (Thieme. All rights reserved.)

Thrombotic microangiopathy (TMA) is a pathological lesion that occurs due to endothelial injury. It can be seen in a heterogenous group of disorders, typically characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ ischemia. TMA can also be renal limited with no systemic manifestations. There are multiple etiologies of a TMA with complement activation being a core underlying mechanism, although the nature and extent of complement involvement can vary. A further complicated factor is the cross talk between complement, neutrophils, and coagulation pathways in the pathophysiology of TMAs. Therefore, a thorough and systematic clinical history and laboratory evaluation are critical to establish the cause and pathophysiology of a TMA. Furthermore, TMAs are associated with significant morbidity and mortality, and timely diagnosis is key for appropriate management and to prevent end-stage kidney disease and other associated complications. In this review, we focus on the pathology, mechanisms, diagnostic work up and treatment of TMAs associated with various etiologies. We also define the complement evaluations that should be conducted in these patients and further highlight the currently approved complement therapies as well as others in the pipeline., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Preeclampsia contributes disproportionately to maternal and neonatal morbidity and mortality throughout the world. A critical driver of preeclampsia is angiogenic imbalance, which is often present weeks to months before overt disease. Two placenta-derived angiogenic biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), have proved useful as diagnostic and prognostic tests for preeclampsia. Recently, the U.S. Food and Drug Administration approved the sFlt-1/PlGF assay to aid in the prediction of preeclampsia with severe features among women with hypertensive disorders of pregnancy at 24-34 weeks of gestation. In this narrative review, we summarize the body of work leading to this approval and describe how the sFlt-1/PlGF ratio may be implemented in clinical practice as an adjunctive measure to help optimize care and to reduce adverse outcomes in preeclampsia., Competing Interests: Financial Disclosure Richard Burwick serves on advisory boards for Comanche Biopharma, Roche Diagnostics, and UCB Biosciences and serves on advisory boards and the speakers bureau for Alexion, AstraZeneca Rare Disease. The other author did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The objective of this study was to examine the association between maternal insurance status and maternal and neonatal adverse outcomes in women who had hypertensive disorders in pregnancy. A population-based retrospective cohort study was undertaken using the US Vital Statistics dataset on Period Linked Birth-Infant Data from 2016-2020. The study population was restricted to non-anomalous births from women whose pregnancies were complicated by hypertensive disorders. Insurance status was categorized as private, Medicaid, self-pay and other. The primary outcome was a composite of maternal adverse outcomes, which included admission to the intensive care unit, unplanned hysterectomy, maternal blood transfusion or uterine rupture. We examined the role of prenatal care in these relationships using a mediation analysis with Kotelchuck's Adequacy of Prenatal Care Utilization Index. Multivariable logistic regression models were used to estimate the association between maternal insurance status and adverse outcomes (using adjusted odds ratios [aOR] and 99% confidence interval [CI]). Of the 18,999,865 live births in the five-year study, 1,642,654 (8.6%) met the inclusion criteria. The frequency of the composite maternal adverse outcome was 1.3%. The maternal composite occurred more frequently in women with Medicaid (aOR = 1.11, 99% CI: 1.06, 1.16) or self-pay (aOR = 1.40, 99% CI: 1.25, 1.55) when compared to private insurance. Adjusting for prenatal care slightly attenuated this association, but remained significant. Among women with hypertensive disorders in pregnancy, women with Medicaid insurance or self-pay were more likely to experience maternal and neonatal adverse outcomes than women with private insurance., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The rate of preeclampsia with severe features has increased. Previous studies have shown elevated liver enzymes are an indicator of worsening hypertensive disease of pregnancy and adverse outcomes, therefore leading to their inclusion as a diagnostic criterion for severe features of preeclampsia. Despite this, there are limited data to support an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentration ≥ two times the upper limit of normal as the critical point at which maternal harm from ongoing pregnancy exceeds neonatal harm from delivery. The objective of this study is to evaluate the association between elevated liver enzymes and maternal and neonatal outcomes among patients with preeclampsia with severe features., Methods: Retrospective cohort study among hypertensive patients who delivered ≥23 weeks' gestation at Oregon Health & Science University (October 2013-September 2018). Those with preeclampsia with severe features (including chronic hypertension with superimposed preeclampsia meeting criteria for severe features) were included after a screening of ICD-9 and ICD-10 codes and chart validation. The primary exposure was elevated liver enzymes prior to delivery, according to the American College of Obstetricians and Gynecologists' criteria for severe features of preeclampsia: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2x the upper limit of normal (above threshold liver function tests [LFTs]). Primary outcomes included adverse maternal and neonatal outcomes. Differences were analyzed by Chi-squared, Fisher's exact, t -test, and logistic regression, with α  = 0.05., Results: Of 11,825 deliveries, 319 (2.7%) met inclusion criteria and had preeclampsia with severe features. Of these, 44 (13.8%) had above threshold LFTs. Adverse maternal outcomes were no different in those with above threshold LFTs compared to those with below threshold LFTs. The unadjusted odds of an adverse neonatal outcome were 2.08 times greater in patients with above threshold LFTs (95% CI: 1.04-4.14), and 2.43 times greater when adjusting for maternal characteristics (95% CI: 1.17-5.04) compared to those with below threshold LFTs. However, the association between above threshold LFTs and adverse neonatal outcomes became non-significant after adjustment for gestational age at delivery (OR: 1.54, 95% CI: 0.63-3.76)., Conclusion: Among patients with preeclampsia with severe features, above threshold LFTs are not independently associated with an increased risk of adverse maternal or neonatal outcomes. Adverse neonatal outcomes in patients with preeclampsia with severe features and above threshold LFTs are driven by earlier gestational age at delivery. Prospective studies are needed to guide delivery timing in patients with preeclampsia and elevated liver enzymes., Brief Rationale: The criteria for elevated liver function tests (greater than two times the upper limit of normal) are widely accepted among obstetricians to diagnose a severe feature of preeclampsia. However, these criteria are based on expert opinion and extrapolated from data on patients with HELLP syndrome. Since preterm delivery of the neonate is recommended for preeclampsia with severe features, the threshold used to define severe liver enzyme elevation has a direct impact on neonatal outcomes. Therefore, the goal of our study was to determine if patients with preeclampsia with severe features and a pre-delivery AST or ALT level ≥ two times the upper limit of normal have worse maternal and neonatal outcomes compared to those with an AST and ALT below this level.

Objective: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia., Design: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls., Setting: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven., Population: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts., Methods: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type., Main Outcome Measures: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations., Results: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V., Conclusions: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Emergent cesarean delivery (CD) carries a high risk for postpartum infection. In cases with a "splash" povidone-iodine (PI) skin preparation, prophylactic postoperative antibiotics (PP-Abx) are sometimes utilized, but the benefit is unclear., Objective: To evaluate if the use of PP-Abx decreases postpartum infection after emergent CD with "splash" PI skin preparation., Study Design: Cohort study of patients undergoing emergent CD with PI skin preparation from July 2012 to April 2020 at a single institution. Cases were identified using a natural language search engine, DEEP-6, with key terms "emergent" and "cesarean delivery." Patients with chorioamnionitis or non-PI skin preparation (e.g. chlorhexidine) were excluded. The primary exposure was use of PP-Abx. The primary outcome was postpartum infection or wound complication, defined as a composite: endometritis, wound infection, cellulitis, seroma, hematoma, or intra-abdominal abscess. Rates of postpartum infection or wound complication were stratified by use of PP-Abx. Demographic and labor characteristics were evaluated as confounders. Statistics by χ 2 , t -test, and logistic regression (α = 0.05)., Results: In total, 481 patients underwent emergent CD; of those, 370 had PI skin preparation and were included. PP-Abx were given in 43% (160/370) of cases, including: cefazolin ( n  = 137), gentamicin/clindamycin ( n  = 18), azithromycin ( n  = 3), and vancomycin ( n  = 2). Those receiving PP-Abx were similar to those who did not, except the PP-Abx group was younger with longer CD duration. The rate of postpartum infection or wound complication was no different in patients who received PP-Abx compared to those who did not (12.6% vs. 9.5%, p  = .34). This finding remained unchanged after multivariable adjustment (aOR 1.2, CI 0.61-2.4, p  = .60). Moreover, the rate of postpartum infection or wound complication did not vary by antibiotic choice., Conclusions: After emergent CD with PI skin preparation, routine use of prophylactic postoperative antibiotics does not appear to reduce the rate of postpartum infection or wound complication, which is important as we consider antibiotic stewardship. More studies are needed to identify treatments that decrease infectious morbidity with emergent CD.

Background: Many providers ignore hypertensive blood pressures (BPs) during epidural placement, attributing them to patient pain or malposition. We aimed to determine if an elevated BP during epidural placement was associated with increased risk for developing a hypertensive disorder of pregnancy (HDP)., Methods: Cohort study of previously normotensive nulliparous, singleton, term patients who received neuraxial analgesia and delivered at our institution in 2016. Primary exposure was BP during epidural window (one hour before and after epidural procedure start time). Primary outcome was HDP (gestational hypertension, preeclampsia, eclampsia, or HELLP syndrome) prior to discharge. Statistics included χ 2 , t-test, and multivariable logistic regression; α  = 0.05., Results: One thousand and eight hundred patients met study criteria. Patients with elevated BP during epidural window ( n  = 566, 31.4%) were more likely to develop HDP than patients who remained normotensive during epidural window (20.1% vs. 6.4%, adjusted OR 3.57 [95% CI 2.61-4.89]). The incidence of HDP increased in association with BP severity during epidural window: 7.3% for maximum systolic blood pressure (SBP) <140 mmHg; 18.4% for maximum SBP 140-159 mmHg (OR 2.9, 95% CI 2.0-4.0); and 29.9% for maximum SBP ≥160 mmHg (OR 5.4, 95% CI 2.9-9.8). The trend was similar for maximum diastolic BP. The magnitude of increased odds for HDP was highest for Black patients with elevated BP during epidural window (40.9% vs. 10.1%, OR 6.1, 95% CI 2.4-16)., Conclusions: Previously normotensive patients with an elevated BP during labor epidural placement are significantly more likely to develop HDP than patients who remain normotensive. Elevated BP during epidural placement should not be disregarded to ensure timely diagnosis and treatment.

Pregnancy is a well-established trigger for a first episode or relapse of immune thrombotic thrombocytopenic purpura (iTTP). Other outcomes of subsequent pregnancy after a diagnosis of iTTP are less well described. We conducted this retrospective cohort study to evaluate maternal and fetal outcomes of pregnancy in women with prior iTTP from the Johns Hopkins Thrombotic Microangiopathy Cohort. Of 168 women in the cohort, 102 were of reproductive age at diagnosis. Fourteen pregnancies (in 9 women) that occurred after the initial iTTP episode were included in the analysis. iTTP relapse occurred in 9 (64%) pregnancies. Out of the 9 instances of relapse, 5 relapses occurred in 2 women. Seven pregnancies (50%) ended in fetal death or miscarriage in the setting of iTTP relapse and three were electively terminated due to fear of relapse. Four pregnancies (50% of the 8 that progressed beyond 20 weeks) were complicated by preeclampsia or HELLP syndrome, which is over ten-fold higher than that of the general population. No maternal deaths occurred. Only 4 pregnancies resulted in live births, of which, 2 were pre-term. Pregnancy in women with prior iTTP is associated with a substantial risk of iTTP relapse and fetal loss. Preeclampsia and HELLP syndrome is also more common than that in the general population. ADAMTS13 monitoring and preemptive therapy may improve pregnancy outcomes, which needs to be evaluated prospectively., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the association between the use of low-dose aspirin for preeclampsia prophylaxis and risks of gestational diabetes (primary outcome), neonatal hypoglycemia, macrosomia, large for gestational age, birth trauma, and shoulder dystocia (secondary outcomes)., Data Sources: We searched Ovid MEDLINE, Embase, CINAHL, and Cochrane/CENTRAL for studies published between January 1, 1989, and April 24, 2021., Study Selection: Randomized controlled trials (RCTs) or cohort studies of any size conducted in any setting were included., Data Extraction and Synthesis: We assessed risk of bias using the Cochrane Risk of Bias tool 2.0 (for RCTs) and the Newcastle-Ottawa Scale (for cohort studies). We meta-analyzed relative risks (RRs) using random-effects models., Conclusions: Our search retrieved 4441 records, of which 9 studies (6 RCTs with 1932 patients and 3 cohort studies with 313 837 patients) met inclusion criteria. We rated only 4 of the 6 RCTs and 1 of the 3 cohort studies at low risk of bias. Low-dose aspirin in pregnancy for preeclampsia prophylaxis was not associated with a greater risk of gestational diabetes (RR 1.18; 95% confidence interval 0.80-1.74). No studies reported data for the secondary outcomes. In summary, the use of low-dose aspirin does not appear associated with risk of gestational diabetes. The poor quality and small number of studies limit the interpretation of these results., (Copyright © 2022 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to determine if soluble levels of C5b-9, the terminal complement complex, correlate with end-organ injury in preeclampsia., Study Design: Project COPA (Complement and Preeclampsia in the Americas), a multi-center observational study in Colombia from 2015 to 2016, enrolled hypertensive pregnant women into four groups: chronic hypertension, gestational hypertension, preeclampsia, and preeclampsia with severe features. Trained coordinators collected clinical data, blood and urine. End-organ injury was defined by serum creatinine ≥ 1.0 mg/dl, aspartate transaminase ≥ 70U/L, platelet count < 150,000/µl, or lactate dehydrogenase ≥ 500 U/L. Data were analyzed by χ 2 or Fisher's exact test with significance at P < 0.05., Main Outcome Measure: C5b-9 concentrations in plasma and urine, using enzyme linked immunosorbent assays., Results: In total, 298 hypertensive participants were enrolled. Plasma and urine C5b-9 levels were measured in all participants and stratified by quartile (Q1-4), from lowest to highest C5b-9 concentration. Participants with low plasma C5b-9 levels (Q1) were more likely to have end-organ injury compared to those with higher levels (Q2-Q4) [platelet count < 150,000/μl (20.8% vs. 8.4%, P = 0.01); elevated serum creatinine ≥ 1.0 mg/dl (14.9% vs. 4.5%, P = 0.009)]. In contrast, participants with high urinary C5b-9 levels (Q4) were more likely to have end-organ injury compared to those with lower levels (Q1-Q3) [platelet count < 150,000/μl (19.7% vs. 7.4%, P = 0.003); elevated serum creatinine ≥ 1.0 mg/dl (12.3% vs. 4.4%, P = 0.025)]., Conclusion: We identified a pattern of increased urine and low plasma C5b-9 levels in patients with preeclampsia and end-organ injury. Soluble C5b-9 levels may be used to identify complement-mediated end-organ injury in preeclampsia., (Copyright © 2022. Published by Elsevier B.V.)

Problem: We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals., Method of Study: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19. Participants enrolled at our center from August 2020 to February 2021. Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement. Eculizumab was administered on day 1 (1200 mg IV) with additional doses if still hospitalized (1200 mg IV on Days 4 and 8; 900 mg IV on Days 15 and 22; optional doses on Days 12 and 18). The primary outcome was survival at Day 15. Secondary outcomes included survival at Day 29, need for mechanical ventilation, and duration of hospital stay. We evaluated pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes., Results: Eight participants were enrolled at the Cedars-Sinai Medical Center, six during pregnancy (mean 30 ± 4.0 weeks) and two in the postpartum period. Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask. The median number of doses of eculizumab was 2 (range 1-3); the median time to hospital discharge was 5.5 days (range 3-12). All participants met the primary outcome of survival at Day 15, and all were alive and free of mechanical ventilation at Day 29. In three participants we demonstrated that free C5 and soluble C5b-9 levels decreased following treatment. There were no serious adverse maternal or neonatal events attributed to eculizumab at 3 months., Conclusion: We describe use of eculizumab to treat severe COVID-19 in a small series of pregnant and postpartum adults. A larger, controlled study in pregnancy is indicated., (© 2022 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Background: Marijuana has vasoconstrictive properties and its use has been associated with increased blood pressure in the general population. Yet, there are limited data on marijuana use and adverse outcomes among women with hypertension in pregnancy, even though these disorders are associated with severe maternal and fetal morbidity and mortality. Since marijuana is currently the most commonly used illicit drug in pregnancy, there is an urgent need to better understand the potential association between marijuana use and hypertension in pregnancy., Objective: To determine the adverse prenatal effects of marijuana use in women with hypertension in pregnancy., Study Design: We conducted a retrospective cohort study among individuals with hypertension in pregnancy that delivered ≥23 weeks' gestation at Oregon Health & Science University (October 2013-September 2018). The primary exposure assessed was marijuana use, identified by chart review of documented patient self-report or positive urine toxicology screen. Individuals were stratified into two groups by marijuana use: use during pregnancy versus never used. Primary outcomes included composite adverse maternal and neonatal outcomes. Secondary outcomes included individual maternal outcomes, rarer neonatal outcomes and severe features of preeclampsia. Differences were analyzed by Fisher's exact, t-test, and logistic regression. Significance was determined by alpha = 0.05 for primary outcomes and alpha = 0.01 for secondary outcomes., Results: From 11,825 deliveries, 1,613 (13.6%) were classified with hypertension in pregnancy. A total of 117 individuals (7.3%) used marijuana during pregnancy, 1,110 (68.2%) had never used marijuana and 396 (24.6%) had unknown marijuana use and were excluded, leaving 1,217 individuals in this analysis. Women using marijuana in pregnancy were more likely to be younger, non-Hispanic White, publicly insured and using other substances compared to women who did not use marijuana. There were no differences in the overall distribution of hypertensive disorders, including preeclampsia with severe features, in women who used marijuana versus those who did not ( p  = .80). In multivariable analyses, after adjusting for maternal factors and other substance use, marijuana use was not associated with adverse maternal (aOR 1.23, 95% CI 0.43-3.50, p  = .69) or neonatal (aOR 0.90, 95% CI 0.28-2.89, p  = .86) outcomes., Conclusions: Marijuana use in pregnancy was not associated with maternal or neonatal outcomes or worsened hypertensive disease among women with hypertension in pregnancy after adjusting for maternal characteristics, including use of other substances. Our data highlight the need to consider use of other substances when evaluating the association between marijuana use in pregnancy and adverse pregnancy outcomes.

Thrombotic microangiopathies (TMAs) have in common a terminal phenotype of microangiopathic hemolytic anemia with end-organ dysfunction. Thrombotic thrombocytopenic purpura results from von Willebrand factor multimerization, Shiga toxin-mediated hemolytic uremic syndrome causes toxin-induced endothelial dysfunction, while atypical hemolytic uremic syndrome results from complement system dysregulation. Drug-induced TMA, rheumatological disease-induced TMA, and renal-limited TMA exist in an intermediate space that represents secondary complement activation and may overlap with atypical hemolytic uremic syndrome clinically. The existence of TMA without microangiopathic hemolytic features, renal-limited TMA, represents an undiscovered syndrome that responds incompletely and inconsistently to complement blockade. Hematopoietic stem cell transplant-TMA represents another more resistant form of TMA with different therapeutic needs and clinical course. It has become apparent that TMA syndromes are an emerging field in nephrology, rheumatology, and hematology. Much work remains in genetics, molecular biology, and therapeutics to unravel the puzzle of the relationships and distinctions apparent between the different subclasses of TMA syndromes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Remdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir., Methods: The reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2-10, given intravenously)., Results: Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day 1 [range, 0-3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths., Conclusions: Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: For unvaccinated individuals with mild-to-moderate coronavirus disease 2019 (COVID-19), monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) decrease the risk of severe disease and hospitalization. We describe the use of the monoclonal antibodies casirivimab and imdevimab for COVID-19 in pregnancy., Case: Two unvaccinated pregnant individuals presented with moderate COVID-19, one in the second trimester and one in third trimester; both met criteria for outpatient management. To decrease the risk for severe disease, they were treated with casirivimab and imdevimab. Neither experienced an adverse drug reaction, and neither progressed to severe disease., Conclusion: Monoclonal antibodies such as casirivimab and imdevimab, approved under an emergency use authorization, should be considered in unvaccinated pregnant individuals with mild-to-moderate COVID-19 to decrease the risk of severe disease., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

[Figure: see text].

Female carriers are more common than males with hemophilia and unrecognized factor VIII or IX deficiency is associated with intrauterine growth retardation, epidural hematomas, blood transfusion, and peripartum hemorrhage. A review was conducted to assess the evidence for professional society recommendations for > 50% factor levels during labor. Two searches of Pubmed, CINAHL, Cochrane, and Google Scholar were completed in October 2019. The first for case reports and series described neuraxial techniques in patients with hemophilia-regardless of sex, age, or pregnant status. The second for case reports and series described bleeding outcomes of parturients with hemophilia. Primary outcomes were diagnosis of neuraxial hematoma (first search) and postpartum bleeding complications (second search). Thirteen articles (n = 134) described neuraxial techniques in patients with hemophilia. Neuraxial hematoma with paraplegia occurred in 3/134 patients-all had a factor level of 1%. Nineteen articles (2712 deliveries in 2657 women) described bleeding outcomes. Postpartum hemorrhage occurred in 7.1% (193/2712) of deliveries, of which 60% necessitated blood transfusion. Postpartum bleeding complications were twice as likely (51.0% [25/49] vs. 25.6% [52/203], P < 0.001) with factor activity < 50%. Therefore, factor levels should be assessed and increased above 50% prior to neuraxial technique and delivery.Trial registration: PROSPERO 2018 CRD42018110215.

Competing Interests: Alexion Pharmaceuticals has supported speaking fees (AL and RB) and research grants (RB) in the past. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: There are limited data regarding treatment options for pregnant women with severe coronavirus disease 2019 (COVID-19)., Case: A 35-year-old primigravid patient at 22 weeks of gestation presented with 7 days of fever, cough, anosmia, and dyspnea. Nasopharyngeal swab was positive for the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a chest X-ray demonstrated bilateral patchy infiltrates. Laboratory evaluation was notable for marked elevation of interleukin-6 and C-reactive protein concentrations. On hospital day 3, owing to increased dyspnea and oxygen requirement, the patient was treated with tocilizumab followed by 5 days of remdesivir. She responded well, recovered to room air, and was discharged home after a 9-day hospitalization., Conclusion: Tocilizumab and remdesivir may be effective for treatment of severe COVID-19 in pregnancy, but additional data are needed to guide risk-benefit considerations.

Objectives: Dysregulation of CD59 may lead to increased complement-mediated end-organ injury in preeclampsia. We sought to determine if soluble CD59 concentrations are altered in preeclampsia with severe features., Study Design: Observational case-control study, which enrolled subjects prospectively from six centers in Colombia from 2015 to 2016. Cases had preeclampsia with severe features and controls were either healthy or had chronic hypertension, gestational hypertension, or preeclampsia without severe features. Trained coordinators collected clinical data, blood and urine. Analyses were by test of medians and Spearman's correlation., Main Outcome Measures: Soluble CD59 concentration in plasma and urine, using enzyme linked immunosorbent assays., Results: In total, 352 subjects were enrolled (104 cases; 248 controls). Compared to healthy women or those with other hypertensive disorders of pregnancy, women with preeclampsia with severe features had increased concentration of CD59 in plasma (P < 0.001) and decreased CD59 in urine (P = 0.01). In sub-group analyses, plasma CD59 concentrations were increased in preeclampsia with severe features compared to healthy controls (P < 0.001) or controls with either chronic hypertension (P = 0.002) or gestational hypertension (P = 0.02). Increased plasma CD59 concentrations correlated with decreased platelet count and increased lactate dehydrogenase, creatinine, aspartate transaminase, urine protein/creatinine ratio, systolic blood pressure and diastolic blood pressure (P < 0.01, all correlations)., Conclusion: In women with preeclampsia with severe features, soluble CD59 concentrations were increased in plasma and decreased in urine, and plasma levels correlated with increased blood pressure and end-organ injury. Soluble CD59 concentrations may help identify a subset of women with preeclampsia that have altered regulation of terminal complement proteins., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To assess whether mild thrombocytopenia (platelet count 100-149 k/microliter) is associated with an increased risk of postpartum hemorrhage., Methods: Nulliparous women with term, singleton, vertex pregnancies undergoing labor at our institution between August 2016 and September 2017 were included. The primary exposure was mild thrombocytopenia, defined as platelet count 100-149 k/microliter, and the comparator was normal platelet count (150 k/microliter or greater). Those with severe thrombocytopenia (platelet count less than 100 k/microliter) were excluded from analysis. The primary outcome was postpartum hemorrhage, determined by International Classification of Diseases, Tenth Revision codes and the hospital discharge problem list. Secondary outcomes included use of uterotonic agents (methylergonovine maleate or carboprost tromethamine), total blood loss 1,000 mL or greater, and blood transfusion. Data were analyzed by t test, χ or Fisher exact test, and multivariable logistic regression, with significance at α <0.05., Results: We evaluated 2,845 eligible women, of whom 2,579 (90.2%) had normal platelet count 150 k/microliter or greater, 266 (9.3%) had platelet count 100-149 k/microliter (mild thrombocytopenia), and 13 (0.5%) had platelet count less than 100 k/microliter (severe thrombocytopenia). Compared with women with normal platelet count, those with mild thrombocytopenia had a higher rate of postpartum hemorrhage (16.9% vs 8.5%, P<.001) and were more likely to have total blood loss 1,000 mL or greater (4.5% vs 1.7%, P=.002) and receive methylergonovine maleate (10.5% vs 5.9%, P=.003) or carboprost tromethamine (6.0% vs 1.6%, P<.001) or both (3.8% vs 1.0%, P<.001), but rates of blood transfusion were no different (1.9% vs 1.5%, P=.59). The association between mild thrombocytopenia and postpartum hemorrhage persisted after multivariable adjustment for potential confounders (adjusted odds ratio 2.2, 95% CI 1.5-3.2, P<.001)., Conclusion: Among nulliparous women with term, singleton, vertex pregnancies undergoing labor, those with mild thrombocytopenia (platelet count 100-149 k/microliter) had a twofold greater likelihood of postpartum hemorrhage compared with those with normal platelet count.

Objective: Hypertension in pregnancy is associated with adverse maternal and neonatal outcomes. Previous studies have demonstrated disparities in the risk of preeclampsia based on race, educational attainment, census tract income level and household income. Yet, data on the association of insurance type, classification of hypertension in pregnancy and outcomes have not been well described. We sought to compare outcomes in women with hypertensive disorders of pregnancy, by private versus public insurance. Study design: This was a retrospective cohort study of subjects with a hypertensive disorder of pregnancy that delivered ≥23-week gestation at Oregon Health & Science University (October 2013-December 2017). The cohort began with the 2013 American College of Obstetricians and Gynecologists Executive Summary on Hypertension in Pregnancy, which advised surveillance for severe features of disease in women with hypertension. Utilizing ICD-9 and ICD-10 discharge codes, followed by individual chart review, subjects were stratified into two groups by insurance status: Medicaid (public insurance), or individual or group health insurance (private insurance). As primary outcomes, we assessed severe features of preeclampsia, adverse maternal or neonatal outcomes (composite), and final hypertensive diagnosis: (i) chronic hypertension; (ii) gestational hypertension; (iii) preeclampsia without severe features and, (iv) preeclampsia with severe features. Differences in demographic and outcome data were analyzed by chi-square, t -test, and logistic regression. Results: Among 10 132 deliveries, 1335 (13.2%) were delivered with a hypertensive disorder of pregnancy. Medicaid covered 54.1% (722) of these deliveries; 44.1% (589) were covered by private insurance, and 1.8% (24) had unknown insurance. There was a similar percentage of subjects with Medicaid or private insurance in each hypertensive group ( p  = .08). However, compared to subjects with private insurance, those with Medicaid had more severe blood pressure (BP) elevations (systolic BP ≥160 mmHg, p  = .001) and more cases of eclampsia ( p  = .04), while neonates of subjects with Medicaid had more intensive care unit admissions ( p  = .02), and preterm births ( p  < .001). The association between Medicaid insurance and severe BP elevation, or adverse neonatal outcomes, persisted after multivariable adjustment. Conclusion: Medicaid was not associated with a particular hypertensive disorder in pregnancy, yet those with Medicaid experienced more severe BP elevations and higher rates of adverse neonatal outcomes. More research is needed to understand potential risk factors and ways to improve outcomes for those with publicly funded insurance.

Objective: To evaluate disease presentation, diagnosis, treatment, and clinical outcomes in pregnancy-associated atypical hemolytic uremic syndrome (aHUS)., Data Sources: We searched PubMed, MEDLINE, Cochrane Library, ClinicalTrials.gov, Web of Science, EMBASE and Google Scholar, from inception until March 2018., Methods of Study Selection: We included English-language articles describing aHUS in pregnancy or postpartum. The diagnosis of aHUS was characterized by hemolysis, thrombocytopenia, and renal failure and was distinguished from typical diarrhea-associated hemolytic uremic syndrome. Patients were excluded if individual data could not be obtained, the diagnosis was unclear, or an alternative etiology was more likely, such as thrombotic thrombocytopenic purpura or Shiga toxin-producing Escherichia coli. Reports were appraised by two reviewers, with disagreements adjudicated by a third reviewer., Tabulation, Integration, and Results: The search identified 796 articles. After review of titles, abstracts, and full text, we identified 48 reports describing 60 unique cases of pregnancy-associated aHUS, with 66 pregnancies. Twelve cases involved pregnancy in women with known aHUS, and 54 cases involved first-episode pregnancy-associated aHUS. Women with known aHUS, particularly those with baseline creatinine at or above 1.5 mg/dL, had a high rate of adverse pregnancy outcomes. For first-episode pregnancy-associated aHUS, diagnosis most often occurred postpartum (94%), after a cesarean delivery (70%), in nulliparous women (58%). Preceding obstetric complications were common and included fetal death, preeclampsia, and hemorrhage. Diagnosis was usually made clinically, based on the triad of microangiopathic hemolysis, thrombocytopenia, and renal failure. Additional testing included renal biopsy, complement genetic testing, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) testing. Treatment modalities included corticosteroids, plasma exchange, dialysis, and eculizumab. More women with first-episode pregnancy-associated aHUS achieved disease remission when treated with eculizumab, compared with those not treated with eculizumab (88% vs 57%, P=.02)., Conclusion: Pregnancy-associated aHUS usually presents in the postpartum period, often after a pregnancy complication, and eculizumab is effective for achieving disease remission., Systematic Review Registration: PROSPERO, CRD42019129266.

Objective: To evaluate whether women with protracted active phase labor longer than 6 hours have an increased risk of adverse maternal and neonatal outcomes after the implementation of new labor management guidelines., Methods: This was a retrospective study of nulliparous, term, singleton, vertex deliveries at Cedars Sinai Medical Center from August 2016 to September 2017. Women were included if they progressed to active phase labor, defined by cervical dilation of 6 cm or more. Women then were divided into three groups based on the time course of cervical change between 6 and 10 cm: 1) normal active phase: cervical change 1 cm or more within 4 hours throughout active labor; 2) mildly protracted active phase: cervical change 1 cm or less over 4-6 hours; and 3) very protracted active phase: cervical change 1 cm or less over 6 hours. Rate of change was assessed between cervical examinations. Primary outcome was a composite of maternal morbidity by study group. Secondary outcome was a composite of neonatal morbidity. We hypothesized that women with very protracted active phase had higher rates of adverse outcomes when compared with normal active phase. Regression analyses were performed to compare maternal and neonatal outcomes by study group., Results: There were 2,559 deliveries, of which 2,378 (90.8%) were vaginal deliveries. Composite maternal and neonatal morbidity was higher with longer labor. Maternal morbidity-very protracted active phase (42.0%) compared with normal active phase (22.6%) adjusted odds ratio (aOR) 2.15 (95% CI 1.62-2.86); mildly protracted active phase (39.5%) compared with normal active phase (22.6%) aOR 2.18 (95% CI 1.67-2.84). Neonatal morbidity: very protracted active phase (19.8%) compared with normal active phase (13.8%) aOR 1.38 (95% CI 0.98-1.96); mildly protracted active phase (19.4%) compared with normal active phase (13.8%) aOR 1.44; (95% CI 1.04-1.99). Composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups., Conclusion: Composite maternal morbidity was greater in women with cervical change consistent with mildly protracted (4-6 hours) and very protracted (more than 6 hours) labor compared with cervical change in the normal active phase (less than 4 hours) group. However, composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups.

Background: Although blood-brain barrier integrity is intact under normal pregnancy conditions, animal studies suggest that blood-brain barrier impairment occurs in preeclampsia. Yet, human data are limited, and the integrity of the blood-brain barrier has not been assessed in women with preeclampsia., Objective: We sought to test the hypothesis that the integrity of the blood-brain barrier is impaired and that neuroinflammation is increased in women with preeclampsia., Study Design: We performed an observational case-control study in pregnant women >24 weeks gestation who underwent spinal anesthesia for elective cesarean delivery or combined spinal epidural analgesia for labor. Cases were women with preeclampsia, and control subjects were women with either healthy pregnancy, chronic hypertension, or gestational hypertension. Paired samples of blood, urine, and cerebrospinal fluid were collected from each subject before delivery. We measured albumin, C5a, C5b-9, tumor necrosis factor-α, and interleukin-6 concentrations in plasma and cerebrospinal fluid, and albumin, C5a, and C5b-9 concentrations in urine, using colorimetric or enzyme-linked immunosorbent assays. The ratio of albumin in cerebrospinal fluid to plasma (Q alb ) was used as a surrogate for maternal blood-brain barrier integrity. Cerebrospinal fluid concentrations of C5a, C5b-9, tumor necrosis factor-α, and interleukin-6 were used as surrogate markers of neuroinflammation. Differences in Q alb and cerebrospinal fluid protein concentrations between groups were assessed by nonparametric test of medians., Results: Forty-eight subjects were enrolled, which included 16 cases with preeclampsia, 16 control subjects with healthy pregnancy, and 16 control subjects with either chronic or gestational hypertension. Q alb values were not increased in preeclampsia cases compared with healthy or hypertensive control subjects (Q alb median, 3.5 [interquartile range, 2.9-5.1] vs 3.9 [interquartile range, 3.0-4.8] vs 3.9 [interquartile range, 3.0-4.8]; P=.78]. Moreover, Q alb values were not increased in the subset of women with preeclampsia with severe features (n=8) compared with those without severe features (n=8; Q alb median, 3.5 [interquartile range, 3.3-4.9] vs 3.7 [interquartile range, 2.3-5.5]; P=.62]. Cerebrospinal fluid concentrations of C5a, C5b-9, tumor necrosis factor-α and interleukin-6 were not increased in cases of preeclampsia, compared with control subjects with either healthy pregnancy, chronic hypertension, or gestational hypertension (P>.05, all comparisons). In contrast to the negative findings in cerebrospinal fluid, plasma concentrations of both C5b-9 and interleukin-6 and urine concentrations of C5a and C5b-9 were increased in cases of preeclampsia., Conclusion: Through measurements of albumin, complement proteins, and cytokines in paired samples of blood and cerebrospinal fluid at the time of delivery, we found no evidence of blood-brain barrier impairment or neuroinflammation in preeclampsia. Larger studies that will investigate a wider range of proteins are suggested to validate our findings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Atypical hemolytic uremic syndrome (aHUS) is a diagnosis that has captured the interest of specialists across multiple fields. The hallmark features of aHUS are microangiopathic hemolysis and thrombocytopenia, which creates a diagnostic dilemma because of the occurrence of these findings in a wide variety of clinical disorders., Recent Findings: In most of the instances, aHUS is a diagnosis of exclusion after ruling out causes such as Shigella toxin, acquired or genetic a disintegrin and metalloproteinase thrombospondin motif 13 deficiency (thrombotic thrombocytopenic purpura), and vitamin B12 deficiency. In the purest sense, aHUS is a genetic condition that is activated (or unmasked) by an environmental exposure. However, it is now evident that complement activation is a feature of many diseases. Variants in complement regulatory genes predispose to microangiopathic hemolysis in many rheumatologic, oncologic, and drug-induced vascular, obstetric, peritransplant, and infectious syndromes., Summary: Many 'hemolysis syndromes' overlap clinically with aHUS, and we review the literature on the treatment of these conditions with complement inhibition. New reports on the treatment of C3 glomerulopathy, Shiga toxin-related classic hemolytic uremic syndrome, and medication-related thrombotic microangiopathy will be reviewed as well.

Objective: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the benefits of intravenous (IV) iron in pregnancy., Study Design: Systematic review was registered with PROSPERO and performed using PRISMA guidelines. PubMed, MEDLINE, Web of Science, ClinicalTrials.gov, Cochrane Library, and Google Scholar were searched. Eleven RCTs, comparing IV to oral iron for treatment of iron-deficiency anemia in pregnancy, were included. Meta-analyses were performed with Stata software (College Station, TX), utilizing random effects model and method of DerSimonian and Laird. Outcomes were assessed by pooled odds ratios (OR) or pooled weighted mean difference (WMD). Sensitivity analyses were performed for heterogeneity., Results: We found that pregnant women receiving IV iron, compared with oral iron, had the following benefits: (1) Achieved target hemoglobin more often, pooled OR 2.66 (95% confidence interval [CI]: 1.71-4.15), p  < 0.001; (2) Increased hemoglobin level after 4 weeks, pooled WMD 0.84 g/dL (95% CI: 0.59-1.09), p  < 0.001; (3) Decreased adverse reactions, pooled OR 0.35 (95% CI: 0.18-0.67), p  = 0.001. Results were unchanged following sensitivity analyses., Conclusion: In this meta-analysis, IV iron is superior to oral iron for treatment of iron-deficiency anemia in pregnancy. Women receiving IV iron more often achieve desired hemoglobin targets, faster and with fewer side effects., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To assess the incidence and severity of preeclampsia in pregnancies complicated by fetal hydrops., Methods: We performed a retrospective cohort study of singleton gestations from 2005 to 2008 in California. The primary predictor was fetal hydrops and the primary outcome was preeclampsia. Selected adverse maternal and neonatal events were assessed as secondary outcomes. Potential confounders examined included fetal anomalies, polyhydramnios, race/ethnicity, nulliparity, chronic hypertension, and gestational or pregestational diabetes mellitus., Results: We identified 337 pregnancies complicated by fetal hydrops, 70.0% had a concomitant fetal anomaly and 39.8% had polyhydramnios. Compared to the general population, hydrops was associated with an increased risk for severe preeclampsia (5.26 versus 0.91%, p < .001) but not mild preeclampsia (2.86 versus 2.02%, p = .29). In multivariable analysis, fetal hydrops remained an independent risk factor for severe preeclampsia (as adjusted odds ratios (aOR) 3.13, 1.91-5.14). Hydrops was also associated with increased rates of eclampsia, acute renal failure, pulmonary edema, postpartum hemorrhage, blood transfusion, preterm birth, and neonatal death., Conclusions: We find that fetal hydrops is an independent risk factor for severe preeclampsia. In light of serious concerns for maternal and neonatal health, heightened surveillance for signs and symptoms of severe preeclampsia is warranted in all pregnancies complicated by fetal hydrops.

Objective: To evaluate whether C5b-9 concentrations in blood and urine are increased in preeclampsia with severe features., Methods: The Complement and Preeclampsia in the Americas study is a prospective, multicenter case-control study performed at six centers in Colombia from November 2015 to July 2016. The case group included women with preeclampsia with severe features, and the control group included women who were healthy or had chronic hypertension, gestational hypertension, or preeclampsia without severe features. We enrolled two women in the control group for every woman in the case group. Soluble C5b-9 concentrations were measured by enzyme-linked immunosorbent assays in blood and urine. The primary outcome was C5b-9 concentrations in women in the case group compared with all women in the control group, and the secondary outcome was C5b-9 levels in women in the case group compared with individual control subgroups. Differences were assessed by test of medians, and associations were further evaluated by receiver operating characteristic curve analysis and logistic regression with α=0.05., Results: Three hundred fifty-two patients were enrolled. Plasma C5b-9 concentrations did not differ significantly between women in the case group and those in the control group, but urine C5b-9 concentrations were higher in women in the case group (median [interquartile range] 9.9 [1.6-43.7] vs 1.8 [0.54-4.1] ng/mL, P<.001). In subgroup analysis, plasma C5b-9 concentrations were increased in women in the case group compared with healthy women in the control group (median [interquartile range] 2,778 [1,633-4,230] vs 1,374 [1,064-2,332] ng/mL, P<.001), and urine C5b-9 concentrations were increased in women in the case group compared with all control subgroups (P<.001). Using receiver operating characteristic analysis, urine C5b-9 concentrations differentiated preeclampsia with severe features from hypertensive women in the control group (area under the receiver operating characteristic curve 0.74, 95% CI 0.68-0.80). Urine C5b-9 22 ng/mL or greater (range 0-158.4 ng/mL) was the optimal cut point for diagnosis of preeclampsia with severe features with adjusted odds ratio of 10.0 (95% CI 3.5-28.8, P<.001)., Conclusion: Urinary excretion of terminal complement effector C5b-9 is higher in women with preeclampsia with severe features compared with women with other hypertensive disorders of pregnancy and women without hypertension.

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 χ 2 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., (© 2018 American Heart Association, Inc.)

Purpose of Review: Preeclampsia affects 3-4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed., Recent Findings: Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities and/or the maternal symptoms which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction, and angiogenic imbalance, thus informing future human studies. Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved, and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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.