Jeff M. Szychowski

Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length

OBJECTIVE The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix. STUDY DESIGN Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm. RESULTS Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks (P = .09). In planned analyses, birth less than 24 weeks (P = .03) and perinatal mortality (P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks (P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum. CONCLUSION In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm.

Cerclage for Short Cervix on Ultrasonography in Women With Singleton Gestations and Previous Preterm Birth: A Meta-Analysis

OBJECTIVE: To estimate if cerclage prevents preterm birth and perinatal mortality and morbidity in women with previous preterm birth, singleton gestation, and short cervical length in a meta-analysis of randomized trials. DATA SOURCES: MEDLINE, PUBMED, EMBASE, and the Cochrane Library were searched using the terms “cerclage,” “short cervix,” “ultrasound,” and “randomized trial.” METHODS OF STUDY SELECTION: We included randomized trials of cerclage in women with short cervical length on transvaginal ultrasonography, limiting the analysis to women with previous spontaneous preterm birth and singleton gestation. TABULATION, INTEGRATION, AND RESULTS: Patient-level data abstraction and analysis were accomplished by two independent investigators. Five trials met inclusion criteria. In women with a singleton gestation, previous spontaneous preterm birth, and cervical length less than 25 mm before 24 weeks of gestation, preterm birth before 35 weeks of gestation was 28.4% (71/250) in the cerclage compared with 41.3% (105/254) in the no cerclage groups (relative risk 0.70, 95% confidence interval 0.55–0.89). Cerclage also significantly reduced preterm birth before 37, 32, 28, and 24 weeks of gestation. Composite perinatal mortality and morbidity were significantly reduced (15.6% in cerclage compared with 24.8% in no cerclage groups; relative risk 0.64, 95% confidence interval 0.45–0.91). CONCLUSION: In women with previous spontaneous preterm birth, singleton gestation, and cervical length less than 25 mm, cerclage significantly prevents preterm birth and composite perinatal mortality and morbidity.

The Secondary Prevention of Small Subcortical Strokes (SPS3) study.

Background Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Methods Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n=3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Conclusions Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.

Vaginal progesterone, cerclage or cervical pessary for preventing preterm birth in asymptomatic singleton pregnant women with a history of preterm birth and a sonographic short cervix

To compare the outcome of pregnancy in cohorts of women with singleton pregnancy and history of preterm birth and sonographic short cervix managed with different treatment protocols, namely cerclage, vaginal progesterone or cervical pessary.

Surgical Staples Compared With Subcuticular Suture for Skin Closure After Cesarean Delivery A Randomized Controlled Trial

OBJECTIVE: To compare the risk of cesarean wound disruption or infection after closure with surgical staples compared with subcuticular suture. METHODS: Women with viable pregnancies at 24 weeks of gestation or greater undergoing scheduled or unscheduled cesarean delivery were randomized to wound closure with surgical staples or absorbable suture. Staples were removed at postoperative days 3–4 for low transverse incisions and days 7–10 for vertical incisions. Standardized wound evaluations were performed at discharge (days 3–4) and 4–6 weeks postoperatively. The primary outcome was a composite of wound disruption or infection within 4–6 weeks. Secondary outcomes included operative time, highest pain score on analog scale, cosmesis score, and patient scar satisfaction score. Analyses were by intent to treat. RESULTS: Of 398 patients, 198 were randomized to staples and 200 to suture (but four received staples). Baseline characteristics including body mass index, prior cesarean delivery, labor, and type of skin incision were similar by group. The primary outcome incidence at hospital discharge was 7.1% for staples and 0.5% for suture (P<.001, relative risk 14.1, 95% confidence interval [CI] 1.9–106). Of 350 (87.9%) with follow-up at 4–6 weeks, the cumulative risk of the primary outcome at 4–6 weeks was 14.5% for staples and 5.9% for suture (P=.008, relative risk 2.5, 95% CI 1.2–5.0). Operative time was longer with suture closure (median time of 58 versus 48 minutes; P<.001). Pain scores at 72–96 hours and at 6 weeks, cosmesis score, and patient satisfaction score did not differ by group. CONCLUSION: Staples closure compared with suture is associated with significantly increased composite wound morbidity after cesarean delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01008449. LEVEL OF EVIDENCE: I

Long-term mortality after community-acquired sepsis: a longitudinal population-based cohort study

Objective Prior studies have concentrated on the acute short-term outcomes of sepsis, with little focus on its long-term consequences. The objective of this study was to characterise long-term mortality following a sepsis event. Design Population-based data from the 30 239 community-dwelling individuals in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Setting USA. Participants Community-dwelling adults ≥45 years of age. Sepsis was defined as hospitalisation or emergency department treatment for a serious infection with the presence of ≥2 systemic inflammatory response syndrome criteria. Outcomes 6-year all-cause mortality. The analysis utilised a time-varying Cox model adjusted for participants age, demographic factors, health behaviours and chronic medical conditions. Results The participants were observed for a median of 6.1 years (IQR 4.5–7.1). During this period, 975 individuals experienced a sepsis event. Sepsis hospital mortality was 8.9%. One-year, 2-year and 5-year all-cause mortality among individuals with sepsis were 23%, 28.8% and 43.8%, respectively, compared with death rates of 1%, 2.6% and 8.3% among those who never developed sepsis. On multivariable analysis, the association of sepsis with increased all-cause mortality persisted for up to 5 years, after adjustment for confounders; year 0.00–1.00, adjusted HR (aHR) 13.07 (95% CI 10.63 to 16.06); year 1.01–2.00 aHR 2.64 (1.85 to 3.77); year 2.01–3.00 aHR 2.18 (1.43 to 3.33); year 3.01–4.00 aHR 1.97 (1.19 to 3.25); year 4.01–5.00 aHR 2.08 (1.14 to 3.79); year 5.01+ aHR 1.41 (0.67 to 2.98). Conclusions Individuals with sepsis exhibited increased rates of death for up to 5 years after the illness event, even after accounting for comorbidities. Sepsis is independently associated with increased risk of mortality well after hospital treatment.

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 .).

Cervical funneling: effect on gestational length and ultrasound-indicated cerclage in high-risk women

OBJECTIVE The purpose of this study was to assess funnel type and pregnancy duration in women with previous spontaneous preterm birth and cervical length <25 mm. STUDY DESIGN We performed a secondary analysis of a multicenter randomized trial of cerclage. At the randomization scan that documented short cervix, the presence and type of funnel (U or V) were recorded. RESULTS One hundred forty-seven of 301 women (49%) had funneling: V-shaped funnel, 99 women; U-shaped funnel, 48 women. U-shaped funnel was associated significantly with preterm birth at <24, <28, <35, and <37 weeks of gestation. In multivariable models that controlled for randomization cervical length and cerclage, women with U-shaped funnel delivered earlier than women with either V-shaped funnel or no funnel. Interaction between cerclage and U-shaped funnel was observed, and analyses that were stratified by cerclage showed that women with a U-shaped funnel and cerclage delivered at a mean of 33.8 +/- 6.6 weeks of gestation, compared with women who did not receive cerclage (28.9 +/- 6.9 weeks of gestation). CONCLUSION U-shaped funnels in high-risk women with a short cervix are associated with earlier birth.

A Randomized Clinical Trial Testing the Anti-Inflammatory Effects of Preemptive Inhaled Nitric Oxide in Human Liver Transplantation

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were

Patient Death as a Censoring Event or Competing Risk Event in Models of Nursing Home Placement

1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.