Marie G. Gantz

Comparison of 2 Transvaginal Surgical Approaches and Perioperative Behavioral Therapy for Apical Vaginal Prolapse: The OPTIMAL Randomized Trial

IMPORTANCEnMore than 300,000 surgeries are performed annually in the United States for pelvic organ prolapse. Sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS) are commonly performed transvaginal surgeries to correct apical prolapse. Little is known about their comparative efficacy and safety, and it is unknown whether perioperative behavioral therapy with pelvic floor muscle training (BPMT) improves outcomes of prolapse surgery.nnnOBJECTIVEnTo compare outcomes between (1) SSLF and ULS and (2) perioperative BPMT and usual care in women undergoing surgery for vaginal prolapse and stress urinary incontinence.nnnDESIGN, SETTING, AND PARTICIPANTSnMulticenter, 2u2009×u20092 factorial, randomized trial of 374 women undergoing surgery to treat both apical vaginal prolapse and stress urinary incontinence was conducted between 2008 and 2013 at 9 US medical centers. Two-year follow-up rate was 84.5%.nnnINTERVENTIONSnThe surgical intervention was transvaginal surgery including midurethral sling with randomization to SSLF (nu2009=u2009186) or ULS (nu2009=u2009188); the behavioral intervention was randomization to receive perioperative BPMT (nu2009=u2009186) or usual care (nu2009=u2009188).nnnMAIN OUTCOMES AND MEASURESnThe primary outcome for the surgical intervention (surgical success) was defined as (1) no apical descent greater than one-third into vaginal canal or anterior or posterior vaginal wall beyond the hymen (anatomic success), (2) no bothersome vaginal bulge symptoms, and (3) no re-treatment for prolapse at 2 years. For the behavioral intervention, primary outcome at 6 months was urinary symptom scores (Urinary Distress Inventory; range 0-300, higher scores worse), and primary outcomes at 2 years were prolapse symptom scores (Pelvic Organ Prolapse Distress Inventory; range 0-300, higher scores worse) and anatomic success.nnnRESULTSnAt 2 years, surgical group was not significantly associated with surgical success rates (ULS, 59.2% [93/157] vs SSLF, 60.5% [92/152]; unadjusted difference, -1.3%; 95% CI, -12.2% to 9.6%; adjusted odds ratio [OR], 0.9; 95% CI, 0.6 to 1.5) or serious adverse event rates (ULS, 16.5% [31/188] vs SSLF, 16.7% [31/186]; unadjusted difference, -0.2%; 95% CI, -7.7% to 7.4%; adjusted OR, 0.9; 95% CI, 0.5 to 1.6). Perioperative BPMT was not associated with greater improvements in urinary scores at 6 months (adjusted treatment difference, -6.7; 95% CI, -19.7 to 6.2), prolapse scores at 24 months (adjusted treatment difference, -8.0; 95% CI, -22.1 to 6.1), or anatomic success at 24 months.nnnCONCLUSIONS AND RELEVANCEnTwo years after vaginal surgery for prolapse and stress urinary incontinence, neither ULS nor SSLF was significantly superior to the other for anatomic, functional, or adverse event outcomes. Perioperative BPMT did not improve urinary symptoms at 6 months or prolapse outcomes at 2 years.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00597935.

Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT).

OBJECTIVEnTo explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Developments Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant.nnnSTUDY DESIGNnThe Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22 months corrected age (CA). Two prespecified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3 days without a cold-were compared for each randomized intervention.nnnRESULTSnOne or more interviews were completed for 918 of the 922 eligible infants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P<.05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P<.05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P<.05) by 18-22 months CA.nnnCONCLUSIONnTreatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18-22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.

Association of Oxygen Target and Growth Status With Increased Mortality in Small for Gestational Age Infants: Further Analysis of the Surfactant, Positive Pressure and Pulse Oximetry Randomized Trial:

Association of Oxygen Target and Growth Status With Increased Mortality in Small for Gestational Age Infants: Further Analysis of the Surfactant, Positive Pressure and Pulse Oximetry Randomized Trial The Eunice Kennedy Shriver National Institute of Child Health andHumanDevelopmentSurfactant,PositivePressureandPulse Oximetry Randomized Trial (SUPPORT)1 compared the effect of oxygen saturation targets on retinopathy of prematurity or death among infants born at 24 to 27 weeks’ gestational age. One thousand three hundred sixteen infants were randomized to lower (85%-89%) vs higher (91%-95%) target oxygen saturation. Rates of severe retinopathy of prematurity or death were not different (28.3% and 32.1%, respectively; relative risk with lower target, 0.90; 95% CI, 0.76-1.06; P = .21). Lower oxygen targets reduced severe retinopathy of prematurity among survivors (8.6% vs 17.9%; relative risk, 0.52; 95% CI, 0.37-0.73; P < .001). However, an unanticipated and unexplained finding was increased mortality in the lower saturation group (19.9% vs 16.2%; relative risk, 1.27; 95%CI, 1.01-1.60;P = .04). The study included neurodevelopmental assessment at 2 years of age; at that assessment we noted a disproportionate loss of small for gestational age (SGA) infants. This observation promoted us to assess whether there was an interaction between oxygen target group and growth status.

Controlling anal incontinence in women by performing anal exercises with biofeedback or loperamide (CAPABLe) trial: Design and methods

The goals of this trial are to determine the efficacy and safety of two treatments for women experiencing fecal incontinence. First, we aim to compare the use of loperamide to placebo and second, to compare the use of anal sphincter exercises with biofeedback to usual care. The primary outcome is the change from baseline in the St. Marks (Vaizey) Score 24weeks after treatment initiation. As a Pelvic Floor Disorders Network (PFDN) trial, subjects are enrolling from eight PFDN clinical centers across the United States. A centralized data coordinating center supervises data collection and analysis. These two first-line treatments for fecal incontinence are being investigated simultaneously using a two-by-two randomized factorial design: a medication intervention (loperamide versus placebo) and a pelvic floor strength and sensory training intervention (anal sphincter exercises with manometry-assisted biofeedback versus usual care using an educational pamphlet). Interventionists providing the anal sphincter exercise training with biofeedback have received standardized training and assessment. Symptom severity, diary, standardized anorectal manometry and health-related quality of life outcomes are assessed using validated instruments administered by researchers masked to randomized interventions. Cost effectiveness analyses will be performed using prospectively collected data on care costs and resource utilization. This article describes the rationale and design of this randomized trial, focusing on specific research concepts of interest to researchers in the field of female pelvic floor disorders and all other providers who care for patients with fecal incontinence.

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration

Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (SpO2) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures SpO2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. Results A total of 4965 infants were randomized (2480 to the lower SpO2 target range and 2485 to the higher SpO2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower SpO2 target group and 1150 of 2229 infants (51.6%) in the higher SpO2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], Pu2009=u2009.21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower SpO2 target group, and 3 significantly favored the higher SpO2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower SpO2 target group and 418 of 2440 infants (17.1%) in the higher SpO2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], Pu2009=u2009.01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower SpO2 target group and 308 of 2065 infants (14.9%) in the higher SpO2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], Pu2009<u2009.001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower SpO2 target group and 170 of 2465 infants (6.9%) in the higher SpO2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], Pu2009=u2009.003). Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower SpO2 target range compared with a higher SpO2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Markers of Successful Extubation in Extremely Preterm Infants, and Morbidity After Failed Extubation

Objectives To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. Study design This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Networks Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. Results Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5‐minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non‐small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). Conclusions Higher 5‐minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. Trial registration ClinicalTrials.gov: NCT00233324.

Milrinone in congenital diaphragmatic hernia – a randomized pilot trial: study protocol, review of literature and survey of current practices

BackgroundCongenital diaphragmatic hernia (CDH) is commonly associated with pulmonary hypoplasia and pulmonary hypertension (PH). PH associated with CDH (CDH-PH) is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO) possibly due to right and left ventricular dysfunction. Milrinone is an intravenous inotrope and lusitrope with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PH. We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ≥36xa0weeks postmenstrual age (PMA) with CDH.Methods/designData on pulmonary vasodilator management and outcome of CDH patients was collected from 18 university NICUs affiliated with the Neonatal Research Network (NRN) from 2011 to 2012. The proposed pilot will be a masked, placebo–controlled, multicenter, randomized trial of 66 infants with CDH with an oxygenation index (OI) ≥10 or oxygen saturation index (OSI) ≥5. The primary outcome is the oxygenation response, as determined by change in OI at 24xa0h after initiation of study drug. As secondary outcomes, we will determine oxygenation at 48xa0h and 72xa0h post-infusion, right ventricular pressures on echocardiogram and the incidence of systemic hypotension, arrhythmias, intracranial hemorrhage, survival without extracorporeal membrane oxygenation, and chronic lung disease (oxygen need at 28xa0days postnatal age). Finally, we will evaluate the pulmonary and nutritional status at 4, 8 and 12xa0months of age using a phone questionnaire.ResultsThree hundred thirty-seven infants with CDH were admitted to NRN NICUs in 2011 and 2012 of which 275 were ≥36xa0weeks PMA and were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%). ECMO was required in 36% of patients. Survival to discharge was 71%.DiscussionCDH is an orphan disease with high mortality with few randomized trials evaluating postnatal management. Intravenous milrinone is a commonly used medication in neonatal/pediatric intensive care units and is currently used in 17% of patients with CDH within the NRN. This pilot study will provide data and enable further studies evaluating pulmonary vasodilator therapy in CDH.Trial registrationClinicalTrials.gov; NCT02951130; registered 14 October 2016.

The urinary microbiome in women with mixed urinary incontinence compared to similarly aged controls

Introduction & hypothesisPrevious studies have suggested that women with urinary incontinence have an altered urinary microbiome. We hypothesized that the microbiome in women with mixed urinary incontinence (MUI) differed from controls and tested this hypothesis using bacterial gene sequencing techniques.MethodsThis multicenter study compared the urinary microbiome in women with MUI and similarly aged controls. Catheterized urine samples were obtained; v4–6 regions of the 16S rRNA gene were sequenced to identify bacteria. Bacterial predominance (> 50% of an individual’s genera) was compared between MUI and controls. Bacterial sequences were categorized into “community types” using Dirichlet multinomial mixture (DMM) methods. Generalized linear mixed models predicted MUI/control status based on clinical characteristics and community type. Post-hoc analyses were performed in women < 51 andu2009≥u200951xa0years. Sample size estimates required 200 samples to detect a 20% difference in Lactobacillus predominance with Pu2009<u20090.05.ResultsOf 212 samples, 97.6% were analyzed (123 MUI/84 controls, mean age 53u2009±u200911xa0years). Overall Lactobacillus predominance did not differ between MUI and controls (45/123u2009=u200936.6% vs. 36/84u2009=u200942.9%, Pu2009=u20090.36). DMM analyses revealed six community types; communities differed by age (Pu2009=u20090.001). A High-Lactobacillus (89.2% Lactobacillus) community had a greater proportion of controls (19/84u2009=u200922.6%, MUI 11/123u2009=u20098.9%). Overall, bacterial community types did not differ in MUI and controls. However, post-hoc analysis of women < 51xa0years found that bacterial community types distinguished MUI from controls (Pu2009=u20090.041); Moderate-Lactobacillus (aOR 7.78, CI 1.85–32.62) and Mixed (aOR 7.10, CI 1.32–38.10) community types were associated with MUI. Community types did not differentiate MUI and controls in women ≥ 51xa0years (Pu2009=u20090.94).ConclusionsWomen with MUI and controls did not differ in overall Lactobacillus predominance. In younger women, urinary bacterial community types differentiated MUI from controls.

Methodological issues in the design and analyses of neonatal research studies: Experience of the NICHD Neonatal Research Network

Impressive advances in neonatology have occurred over the 30 years of life of The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). However, substantial room for improvement remains in investigating and further developing the evidence base for improving outcomes among the extremely premature. We discuss some of the specific methodological challenges in the statistical design and analysis of randomized trials and observational studies in this population. Challenges faced by the NRN include designing trials for unusual or rare outcomes, accounting for and explaining center variations, identifying other subgroup differences, and balancing safety and efficacy concerns between short-term hospital outcomes and longer-term neurodevelopmental outcomes. In conclusion, the constellation of unique patient characteristics in neonates calls for broad understanding and careful consideration of the issues identified in this article for conducting rigorous studies in this population.

Metabolites and microbial composition of stool of women with fecal incontinence: Study design and methods

This paper aims to report the rationale, design, and the specific methodology of an ongoing nested observational study that will determine the association of the metabolite and microbial composition of stool with fecal incontinence (FI).