Pamela K. Burrows

A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele

BACKGROUND Prenatal repair of myelomeningocele, the most common form of spina bifida, may result in better neurologic function than repair deferred until after delivery. We compared outcomes of in utero repair with standard postnatal repair. METHODS We randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function. RESULTS The trial was stopped for efficacy of prenatal surgery after the recruitment of 183 of a planned 200 patients. This report is based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68% of the infants in the prenatal-surgery group and in 98% of those in the postnatal-surgery group (relative risk, 0.70; 97.7% confidence interval [CI], 0.58 to 0.84; P<0.001). Actual rates of shunt placement were 40% in the prenatal-surgery group and 82% in the postnatal-surgery group (relative risk, 0.48; 97.7% CI, 0.36 to 0.64; P<0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (P=0.007) and in improvement in several secondary outcomes, including hindbrain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery. CONCLUSIONS Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00060606.).

Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement

OBJECT The Management of Myelomeningocele Study (MOMS) was a multicenter randomized trial comparing the safety and efficacy of prenatal and postnatal closure of myelomeningocele. The trial was stopped early because of the demonstrated efficacy of prenatal surgery, and outcomes on 158 of 183 pregnancies were reported. Here, the authors update the 1-year outcomes for the complete trial, analyze the primary and related outcomes, and evaluate whether specific prerandomization risk factors are associated with prenatal surgery benefit. METHODS The primary outcome was a composite of fetal loss or any of the following: infant death, CSF shunt placement, or meeting the prespecified criteria for shunt placement. Primary outcome, actual shunt placement, and shunt revision rates for prenatal versus postnatal repair were compared. The shunt criteria were reassessed to determine which were most concordant with practice, and a new composite outcome was created from the primary outcome by replacing the original criteria for CSF shunt placement with the revised criteria. The authors used logistic regression to estimate whether there were interactions between the type of surgery and known prenatal risk factors (lesion level, gestational age, degree of hindbrain herniation, and ventricle size) for shunt placement, and to determine which factors were associated with shunting among those infants who underwent prenatal surgery. RESULTS Ninety-one women were randomized to prenatal surgery and 92 to postnatal repair. The primary outcome occurred in 73% of infants in the prenatal surgery group and in 98% in the postnatal group (p < 0.0001). Actual rates of shunt placement were only 44% and 84% in the 2 groups, respectively (p < 0.0001). The authors revised the most commonly met criterion to require overt clinical signs of increased intracranial pressure, defined as split sutures, bulging fontanelle, or sunsetting eyes, in addition to increasing head circumference or hydrocephalus. Using these modified criteria, only 3 patients in each group met criteria but did not receive a shunt. For the revised composite outcome, there was a difference between the prenatal and postnatal surgery groups: 49.5% versus 87.0% (p < 0.0001). There was also a significant reduction in the number of children who had a shunt placed and then required a revision by 1 year of age in the prenatal group (15.4% vs 40.2%, relative risk 0.38 [95% CI 0.22-0.66]). In the prenatal surgery group, 20% of those with ventricle size < 10 mm at initial screening, 45.2% with ventricle size of 10 up to 15 mm, and 79.0% with ventricle size ≥ 15 mm received a shunt, whereas in the postnatal group, 79.4%, 86.0%, and 87.5%, respectively, received a shunt (p = 0.02). Lesion level and degree of hindbrain herniation appeared to have no effect on the eventual need for shunting (p = 0.19 and p = 0.13, respectively). Similar results were obtained for the revised outcome. CONCLUSIONS Larger ventricles at initial screening are associated with an increased need for shunting among those undergoing fetal surgery for myelomeningocele. During prenatal counseling, care should be exercised in recommending prenatal surgery when the ventricles are 15 mm or larger because prenatal surgery does not appear to improve outcome in this group. The revised criteria may be useful as guidelines for treating hydrocephalus in this group.

Bladder Function After Fetal Surgery for Myelomeningocele

BACKGROUND: A substudy of the Management of Myelomeningocele Study evaluating urological outcomes was conducted. METHODS: Pregnant women diagnosed with fetal myelomeningocele were randomly assigned to either prenatal or standard postnatal surgical repair. The substudy included patients randomly assigned after April 18, 2005. The primary outcome was defined in their children as death or the need for clean intermittent catheterization (CIC) by 30 months of age characterized by prespecified criteria. Secondary outcomes included bladder and kidney abnormalities observed by urodynamics and renal/bladder ultrasound at 12 and 30 months, which were analyzed as repeated measures. RESULTS: Of the 115 women enrolled in the substudy, the primary outcome occurred in 52% of children in the prenatal surgery group and 66% in the postnatal surgery group (relative risk [RR]: 0.78; 95% confidence interval [CI]: 0.57–1.07). Actual rates of CIC use were 38% and 51% in the prenatal and postnatal surgery groups, respectively (RR: 0.74; 95% CI: 0.48–1.12). Prenatal surgery resulted in less trabeculation (RR: 0.39; 95% CI: 0.19–0.79) and fewer cases of open bladder neck on urodynamics (RR: 0.61; 95% CI: 0.40–0.92) after adjustment by child’s gender and lesion level. The difference in trabeculation was confirmed by ultrasound. CONCLUSIONS: Prenatal surgery did not significantly reduce the need for CIC by 30 months of age but was associated with less bladder trabeculation and open bladder neck. The implications of these findings are unclear now, but support the need for long-term urologic follow-up of patients with myelomeningocele regardless of type of surgical repair.

The Management of Myelomeningocele Study: Obstetrical Outcomes and Risk Factors for Obstetrical Complications Following Prenatal Surgery

BACKGROUND The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published. OBJECTIVE In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair. STUDY DESIGN Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture ≤34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at ≤34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using χ2 and Wilcoxon tests and multivariable logistic regression. RESULTS A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01-2.22; and odds ratio, 2.96, 95% confidence interval, 1.05-8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19-38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35-10.05). CONCLUSION Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery.

Recruitment for a clinical trial of drug treatment for benign prostatic hyperplasia

OBJECTIVES To evaluate the effectiveness of various recruitment strategies for a 6-year multicenter clinical trial of medical therapy for benign prostatic hyperplasia, the Medical Therapy of Prostatic Symptoms Trial. METHODS How participants learned about the trial was obtained during initial contact with clinical centers and at the first screening visit. The yield of randomized participants from the initial contact and first screening visit was calculated for each of the recruitment techniques. RESULTS During a period of 28 months, 16,723 potential trial participants made an initial contact with the 17 clinical centers, and 2931 men were randomized. An average of four initial contacts were required for each first screen visit and six per randomized participant. Newspaper (29.9%) and mail (26.7%) were the two leading sources of randomized participants. Medical sources (9.6%), radio (8.8%), and newsletters (8.4%) were also important sources. All clinical centers achieved or exceeded their recruitment goals. CONCLUSIONS Mass mail and newspaper were the most effective recruitment techniques to enlist the interest of men with urinary symptoms for a long-term trial of drug therapy for benign prostatic hyperplasia.

Cross-Sectional and Longitudinal Associations of Sexual Function with Lower Urinary Tract Symptoms in Men with Benign Prostatic Hyperplasia

PURPOSE We examine the cross-sectional associations between baseline characteristics and sexual function and the longitudinal associations between change in lower urinary tract symptoms and change in sexual function among men with benign prostatic hyperplasia. MATERIALS AND METHODS We studied lower urinary tract symptoms assessed by the AUA-SI and sexual function determined by the BMSFI in men enrolled in the MTOPS study. The cross-sectional cohort included 2,916 men who completed the BMSFI at baseline. The longitudinal cohort included 672 men who were randomized to placebo and had completed the BMSFI at baseline and at least once during a 4-year followup. Multiple adjusted linear modeling for each domain of the BMSFI was performed to assess associations of sexual function with lower urinary tract symptoms. RESULTS After adjustment for baseline demographic and clinical characteristics, increased age, less education, obesity and severe lower urinary tract symptoms were each significantly associated with poorer sexual drive, erectile function, ejaculatory function, sexual problem assessment and overall satisfaction in the cross-sectional cohort. However, none of these baseline characteristics predicted change in sexual function in the longitudinal cohort. Decline in sexual function in all sexual function domains associated with worsening of lower urinary tract symptoms in this group was small. CONCLUSIONS Increased age, less education, obesity and more severe lower urinary tract symptoms were individually associated cross-sectionally, but not longitudinally, with poorer sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia. The decline in sexual function associated with worsening of lower urinary tract symptoms in men assigned to placebo was small.

PNFLBA-04 RANDOMIZED CLINICAL TRIAL OF TREATMENT WITH TAMSULOSIN BEGUN IN THE EMERGENCY DEPARTMENT TO PROMOTE PASSAGE OF URINARY STONES

BPH. Gilling et al. reported a prospective single-arm multicenter trial at 3 centers in Australia and New Zealand with 1-year follow-up on 21 men with a similar profile as WATER. Prostate volume dropped from 57 ml at baseline to 35 ml (P<0.0001). Mean IPSS score improved from 23.0 at baseline to 6.8 at 12 months (P<0.0001) and maximum urinary flow increased from 8.7 mL/sec to 18.3 mL/sec (P<0.0001). There were no important perioperative adverse events. No subject developed urinary incontinence and sexual function was preserved postoperatively. In this report, we compared the safety and efficacy of prostate resection using a high-pressure waterjet vs. electrocautery from the WATER study. METHODS: In this randomized, double-blind, multicenter phase III trial, patients with moderate-to-severe lower urinary tract symptoms related to benign prostatic hyperplasia were assigned to transurethral resection of the prostate using either standard electrosurgery (TURP) or robotic waterjet (Aquablation). The trial has a co-primary safety and efficacy endpoint designed to show non-inferiority. With a minimum enrollment of 177, the estimated power for safety was 99% and efficacy was 80%. The primary safety endpoint is the occurrence of ClavienDindo persistent grade 1 or Grade 2 or higher operative complications at 3 months. The primary efficacy endpoint is the reduction at 6 months in IPSS score. RESULTS: The geographic enrollment from the OUS (Australia, New Zealand, United Kingdom) sites and US sites was 91 and 93 subjects, respectively. The baseline IPSS score (TURP 22.2, Aquablation 22.9, p1⁄40.47), demographic profile (Table 1), and prostate volume (TURP 52.0 mL, Aquablation 54.3 mL, p1⁄40.31) were similar in both arms. Operative time was equivalent between the two groups, but resection time was lower in the Aquablation group (28 vs. 4 minutes, p<.0001). The length of stay and length of stay by geography was similar for both arms that averaged 1.4 days. CONCLUSIONS: The first report of the primary safety and efficacy endpoints will be available and ready for presentation at AUA in May 2017.

Design and challenges of a randomized clinical trial of medical expulsive therapy (tamsulosin) for urolithiasis in the emergency department.

Urolithiasis or urinary stone disease has been estimated to affect about 1 in 11 Americans. Patients with urinary stone disease commonly present to the emergency department for management of their acute pain. In addition to providing analgesia, administration of drug (medical expulsive therapy) is often prescribed to assist passage of the urinary stone. In this methodology paper, we describe the design of a prospective, multi-center, randomized, double-blind placebo controlled clinical trial of the alpha-adrenergic blocker, tamsulosin, to evaluate its effectiveness as medical expulsive therapy. In addition, we describe the unique challenges of conducting a trial of this type within the setting of the emergency department.

Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones: A Randomized Clinical Trial

Importance Urinary stone disease is a common presentation in the emergency department, and &agr;-adrenergic receptor blockers, such as tamsulosin, are commonly used to facilitate stone passage. Objective To determine if tamsulosin promotes the passage of urinary stones within 28 days among emergency department patients. Design, Setting, and Participants We conducted a double-blind, placebo-controlled clinical trial from 2008 to 2009 (first phase) and then from 2012 to 2016 (second phase). Participants were followed for 90 days. The first phase was conducted at a single US emergency department; the second phase was conducted at 6 US emergency departments. Adult patients were eligible to participate if they presented with a symptomatic urinary stone in the ureter less than 9 mm in diameter, as demonstrated on computed tomography. Interventions Participants were randomized to treatment with either tamsulosin, 0.4 mg, or matching placebo daily for 28 days. Main Outcomes and Measures The primary outcome was stone passage based on visualization or capture by the study participant by day 28. Secondary outcomes included crossover to open-label tamsulosin, time to stone passage, return to work, use of analgesic medication, hospitalization, surgical intervention, and repeated emergency department visit for urinary stones. Results The mean age of 512 participants randomized to tamsulosin or placebo was 40.6 years (range, 18-74 years), 139 (27.1%) were female, and 110 (22.8%) were nonwhite. The mean (SD) diameter of the urinary stones was 3.8 (1.4) mm. Four hundred ninety-seven patients were evaluated for the primary outcome. Stone passage rates were 50% in the tamsulosin group and 47% in the placebo group (relative risk, 1.05; 95.8% CI, 0.87-1.27; P = .60), a nonsignificant difference. None of the secondary outcomes were significantly different. All analyses were performed according to the intention-to-treat principle, although patients lost to follow-up before stone passage were excluded from the analysis of final outcome. Conclusions and Relevance Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised. Trial Registration ClinicalTrials.gov Identifier: NCT00382265

The Management of Myelomeningocele Study: full cohort 30-month pediatric outcomes

Background Previous reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30‐month outcomes were only available at the time of initial publication in 134 mother‐child dyads. Data from the complete cohort for the 30‐month outcomes are presented here. Maternal and 12‐month neurodevelopmental outcomes for the full cohort were reported previously. Objective The purpose of this study is to report the 30‐month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study. Study Design Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair <26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley Scales of Infant Development, Second Edition. We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30‐month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30‐month motor outcomes. Results The data for the full cohort of 183 patients corroborate the original findings of Management of Myelomeningocele Study, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 ± 80.5 vs 166.7 ± 76.7, P = .004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% vs 23.9%, P = .004), WeeFIM self‐care score (20.8 vs 19.0, P = .006), functional level at least 2 better than anatomic level (26.4% vs 11.4%, P = .02), and mean Bayley Scales of Infant Development, Second Edition, psychomotor development index (17.3% vs 15.1%, P = .03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and psychomotor development index. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of ≤L3 were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement. Conclusion The full cohort data of 30‐month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning.