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

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

Evaluation of Low-Dose Aspirin to Prevent Preeclampsia in Pregnant People with Chronic Hypertension.

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..

Compassionate Use of Remdesivir in Pregnant Women With Severe Coronavirus Disease 2019.

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.

Situs inversus totalis and prenatal diagnosis of a primary ciliary dyskinesia.

Situs inversus, a condition in which the major visceral organs are reversed from their normal positions in the body, can be detected by prenatal ultrasonography. Often benign, it may be associated with primary ciliary dyskinesia, an autosomal recessive disorder characterized by chronic respiratory disease. Yet, prenatal diagnosis of primary ciliary dyskinesia has not been reported. We describe a pregnancy in which situs inversus was diagnosed by fetal ultrasound at 20 weeks gestation. Prenatal testing for primary ciliary dyskinesia led to the discovery that both parents were asymptomatic carriers of a pathogenic mutation in the CCDC103 gene, with an affected neonate.

Delivery and neuraxial technique outcomes in patients with hemophilia and in hemophilia carriers: a systematic review.

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.

Assessment of blood-brain barrier integrity and neuroinflammation in preeclampsia.

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 (Qalb) 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 Qalb 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. Qalb values were not increased in preeclampsia cases compared with healthy or hypertensive control subjects (Qalb 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, Qalb values were not increased in the subset of women with preeclampsia with severe features (n=8) compared with those without severe features (n=8; Qalb 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.

Successful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease.

BACKGROUND: Atypical hemolytic uremic syndrome is a rare group of disorders that have in common underlying complement amplifying conditions. These conditions can accelerate complement activation that results in a positive feedback cycle. The known triggers for complement activation can be diverse and include, infection, autoimmune disease, and malignancy. Recent reports suggest that certain autoimmune and rheumatological triggers of complement activation may result in atypical hemolytic uremic syndrome that does not resolve despite treating the underlying disorder. Specifically, patients with systemic lupus erythematosus and microangiopathic hemolysis may not respond to treatment of their underlying rheumatological trigger but responded to complement blockade. CASE PRESENTATIONS: We report two patients with inflammatory bowel disease complicated by development of atypical hemolytic uremic syndrome. In both cases, patients were on treatment for inflammatory bowel disease, that was not well controlled/flaring at the time. The first patient is a male who developed Crohn's disease and microangiopathic hemolysis at age 5 and was treated with eculizumab successfully. Discontinuation of the medication led to multiple relapses, and the patient currently is being treated with eculizumab and has normal hematological and stable renal parameters. The second patient is a 49-year-old female with Ulcerative Colitis treated with 6-Mercaptopurine. She developed acute kidney injury and microangiopathic hemolysis. Prompt diagnosis and treatment with eculizumab resulted in the recovery of kidney injury along with a complete hematological response. CONCLUSIONS: These two cases are the fifth and sixth patients to be published in the literature with atypical hemolytic uremic syndrome and inflammatory bowel disease treated with complement blockade. This confirms that C5 complement blockade is effective in treating complement mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome when it is triggered in patients with inflammatory bowel disease.

Treatment of Iron Deficiency Anemia in Pregnancy with Intravenous versus Oral Iron: Systematic Review and Meta-Analysis.

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.

The Complement System and Preeclampsia.

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.

The risk of fetal death in nonanomalous pregnancies affected by polyhydramnios.

OBJECTIVE: The objective of the study was to evaluate the ongoing risk of intrauterine fetal demise (IUFD) in nonanomalous pregnancies affected by polyhydramnios. STUDY DESIGN: We analyzed a retrospective cohort of all singleton, nonanomalous births in California between 2005 and 2008 as recorded in a statewide birth certificate registry. We included all births between 24+0 and 41+6 weeks' gestational age, excluding multiple gestations, major congenital anomalies, and pregnancies affected by oligohydramnios. Polyhydramnios was identified by International Classification of Diseases, ninth revision, codes. χ(2) tests were used to compare the dichotomous outcomes, and multivariable logistic regression analyses were then performed to control for potential confounders. We analyzed the data for pregnancies affected and unaffected by polyhydramnios. The IUFD risk was expressed as a rate per 10,000. RESULTS: The risk of IUFD in pregnancies affected by polyhydramnios was greater at every gestational age compared with unaffected pregnancies. The IUFD risk in pregnancies affected by polyhydramnios was more than 7 times higher than unaffected pregnancies at 37 weeks at a rate of 18.0 (95% confidence interval [CI], 9.0-32.6) vs 2.4 (95% CI, 2.0-2.5) and was 11-fold higher by 40 weeks' gestational age at a rate of 66.3 (95% CI, 10.8-68.6) vs 6.0 (95% CI, 5.1-6.3) in unaffected pregnancies. When adjusted for multiple confounding variables, the presence of polyhydramnios remained associated with an increased odds of IUFD in nonanomalous singleton pregnancies, with an adjusted odds ratio of 5.5 (95% CI, 4.1-7.6). CONCLUSION: Ongoing risk of IUFD is greater in low-risk pregnancies affected by polyhydramnios at all gestational ages compared with unaffected pregnancies with the greatest increase in risk at term. Although further study is needed to explore the underlying etiology of polyhydramnios in these cases, the identification of polyhydramnios alone may warrant increased antenatal surveillance.

Angiogenic Biomarkers in Preeclampsia.

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.

Elevated liver enzymes and adverse outcomes among patients with preeclampsia with severe features.

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.

Prophylactic postoperative antibiotics after emergent cesarean delivery and risk of postpartum infection or wound complication.

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 χ2, 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.

Marijuana use and pregnancy outcomes among women with hypertension in pregnancy.

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.

Elevated blood pressures during epidural placement are associated with increased risk of hypertensive disorders of pregnancy.

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 χ2, 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.

Soluble concentrations of the terminal complement complex C5b-9 correlate with end-organ injury in preeclampsia.

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 χ2 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.

Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series.

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.