Kirsten Cleary

Pravastatin for the prevention of preeclampsia in high-risk pregnant women.

Preeclampsia complicates approximately 3–5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).

Regionalization of care for obstetric hemorrhage and its effect on maternal mortality.

OBJECTIVE: To examine factors that influence the morbidity and mortality of peripartum hysterectomy and analyze the effect of hospital volume on maternal mortality. METHODS: We examined women who underwent peripartum hysterectomy at the time of cesarean delivery in a quality and resource utilization database. Procedure-associated intraoperative, perioperative, and postoperative medical complications, length of stay, intensive care unit use, and maternal mortality were analyzed. Hospitals were stratified into tertiles based on procedure volume and complications and compared using adjusted generalized estimating equations. Results are reported as odds ratios. RESULTS: Maternal mortality among the 2,209 women who underwent peripartum hysterectomy was 1.2%. After adjusting for other clinical and demographic factors, perioperative mortality was 71% (odds ratio 0.29, 95% confidence interval 0.10–0.88) lower in women who underwent operation at high-volume hospitals compared with those treated at low-volume facilities. Hospital volume had no effect on the rates of intraoperative injuries, medical complications, length of stay, or transfusion. In contrast, compared with women treated at low-volume centers, patients who underwent operation at high-volume hospitals had a lower incidence of perioperative surgical complications (odds ratio 0.66, 95% confidence interval 0.47–0.93) and a lower rate of intensive care unit usage (odds ratio 0.53, 95% confidence interval 0.34–0.83). CONCLUSION: Peripartum hysterectomy is associated with substantial morbidity and mortality. Maternal mortality is lower when the procedure is performed in high-volume hospital settings. LEVEL OF EVIDENCE: II

Thromboprophylaxis After Cesarean Delivery: A Decision Analysis

OBJECTIVE: To compare 4 strategies for managing patients after cesarean delivery. METHODS: Using decision analysis, we compared universal subcutaneous (SC) heparin prophylaxis, heparin prophylaxis only for patients with a genetic thrombophilia, use of pneumatic compression stockings (PCS), and no thromboprophylaxis. Outcomes included heparin-induced thrombocytopenia (HIT), HIT-related thrombosis, major maternal bleeding, and venous thromboembolism (VTE). RESULTS: Use of PCS was the strategy with the lowest number of adverse events. With heparin prophylaxis, 13 cases of HIT-induced thrombosis and hemorrhage would occur per VTE prevented. When heparin prophylaxis is administered only to thrombophilia-positive women, 1.2 cases of HIT-induced thrombosis and bleeding would occur per VTE prevented. In sensitivity analyses, the model was stable across virtually all variable ranges. CONCLUSION: Use of PCS after cesarean delivery is the strategy with the lowest number of adverse events. Universal prophylaxis with SC heparin is associated with an excess risk of HIT-induced thrombosis and bleeding per VTE prevented compared with PCS use. Until future studies are completed, postcesarean thromboprophylaxis with PCS should be used if the clinician elects to provide prophylaxis.

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery

BACKGROUND The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section. METHODS In this trial conducted at 14 centers in the United States, we studied 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. We randomly assigned 1019 to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks. RESULTS The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; P<0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P=0.02), wound infection (2.4% vs. 6.6%, P<0.001), and serious maternal adverse events (1.5% vs. 2.9%, P=0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P=0.63). CONCLUSIONS Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; C/SOAP ClinicalTrials.gov number, NCT01235546 .).

Cardiopulmonary Complications of Pre-eclampsia

Pre-eclampsia affects 3 to 8% of all pregnancies. In the USA, pre-eclampsia remains a leading cause of maternal morbidity and mortality, comprising 17% of maternal deaths in advanced gestations in 1999. The pathophysiologic changes associated with pre-eclampsia can have a profound impact on the uteroplacental unit and fetal and neonatal outcome. Equally important are the adverse effects on the maternal hematologic, cardiovascular and pulmonary, neurologic, renal, and gastrointestinal system. This article aims to review complications of pre-eclampsia as they impact on the cardiovascular and pulmonary systems.

Prediction and prevention of ischemic placental disease

Preeclampsia, intrauterine growth restriction (IUGR), and placental abruption are obstetrical conditions that constitute the syndrome of ischemic placental disease or IPD, the leading cause of indicated preterm birth and an important cause of neonatal morbidity and mortality. While the phenotypic manifestations vary significantly for preeclampsia, IUGR, and abruption, these conditions may share a common underlying etiology as evidenced by: (1) shared clinical risk factors, (2) increased recurrence risk across pregnancies as well as increased co-occurrence of IPD conditions within a pregnancy, and (3) findings that suggest the underlying pathophysiologic processes may be similar. IPD is of major clinical importance and accounts for a large proportion of indicated preterm delivery ranging from the periviable to late preterm period. Successful prevention of IPD and resultant preterm delivery could substantially improve neonatal and maternal outcomes. This article will review the following topics: (1) The complicated research literature on aspirin and the prevention of preeclampsia and IUGR. (2) Research evidence on other medical interventions to prevent IPD. (3) New clinical interventions currently under investigations, including statins. (4) Current clinical recommendations for prevention of ischemic placental disease.

Pre-eclampsia and the Kidney

Pre-eclampsia is a multisystem disorder that is unique to pregnancy, affecting at least 5% of all gravidas. The mainstay of this diagnosis is a combination of new-onset hypertension and proteinuria. The kidney deserves particular attention because of the physiologic as well as pathologic changes that can affect this vital organ in pregnancy. In fact, there is a major interplay between renal disease and pre-eclampsia. Proteinuria is universal to all cases of pre-eclampsia, yet some cases can progress to acute renal failure. Furthermore, it is well-established that the latter is more frequent in women with underlying renal disease. This chapter reviews the physiologic changes that the human kidney adapts during pregnancy, the impact of pre-eclampsia on the kidney and its function, and the risk of pre-eclampsia in women with chronic renal disease. Two groups that warrant special consideration are pregnant women with systemic lupus erythematosus and those with history of renal transplantation.

Challenges of studying drugs in pregnancy for off-label indications: Pravastatin for preeclampsia prevention

Statins (3-hydroxy-3 methyl-glutaryl coenzyme-A reductase inhibitors) are the most commonly prescribed cholesterol-lowering medications due to their efficacy in reducing cardiovascular mortality and morbidities, tolerability, and safety profiles. Based on pathophysiologic similarities between cardiovascular disease and preeclampsia, a common and dangerous complication of pregnancy, there is an increasing interest in studying this class of medications during pregnancy to prevent and/or treat preeclampsia. Undergoing such a study, which entails the use of a pregnancy class X medication for an off-label indication in pregnancy, requires intensive multidisciplinary involvement of a group of experts in basic and clinical pharmacology, research methods, pregnancy physiology and maternal-fetal medicine, as well as U.S. Food and Drug Administration (FDA) regulatory guidelines and practice. Issues of potential fetal risk, altered maternal-fetal pharmacokinetics and pharmacodynamics, and regulatory challenges are real, and must be carefully considered in the process of research in this arena.

Pulmonary arterial hypertension in pregnancy

Pulmonary hypertension is a medical condition characterized by elevated pulmonary arterial pressure and secondary right heart failure. Pulmonary arterial hypertension is a subset of pulmonary hypertension, which is characterized by an underlying disorder of the pulmonary arterial vasculature. Pulmonary hypertension can also occur secondarily to structural cardiac disease, autoimmune disorders, and toxic exposures. Although pregnancies affected by pulmonary hypertension and pulmonary arterial hypertension are rare, the pathophysiology exacerbated by pregnancy confers both high maternal and fetal mortality and morbidity. In light of new treatment modalities and the use of a multidisciplinary approach to care, maternal outcomes may be improving.

Patterns of use and predictors of receipt of antibiotics in women undergoing cesarean delivery.

OBJECTIVE: Perioperative antibiotics are recommended during cesarean delivery to reduce the risk of postoperative infections and resulting maternal morbidity. We examined the patterns of use and predictors of receipt of antibiotics in women undergoing cesarean delivery. METHODS: We identified a national cohort of women who underwent a cesarean delivery between 2003 and 2010 using a commercial hospitalization database. Women who received antibiotics on the day of cesarean delivery were classified as having received perioperative antibiotics. Multivariable regression models were developed to account for patient, obstetric, physician, and hospital factors on receipt of antibiotics. Between-hospital variation was calculated using generalized linear mixed models. RESULTS: Among 1,137,804 women who underwent cesarean delivery, 59.5% received perioperative antibiotics. The proportion of patients receiving antibiotics increased over time from 52.5% in 2003 to 63.1% in 2010 (P<.001) and varied significantly by geographic region. Women who did not labor were more likely to receive antibiotics than those who had a cesarean delivery after labor (66% compared with 44%, P<.001). Age, race, and insurance status were not major determinants of the use of perioperative antibiotics. CONCLUSION: Among women undergoing cesarean delivery, compliance with the recommendation for universal perioperative antibiotic prophylaxis is poor. Coordinated efforts are needed to enhance use of guideline-based perioperative antibiotic prophylaxis for women undergoing cesarean delivery. LEVEL OF EVIDENCE: III