R. Katie Morris

An overview of the literature on congenital lower urinary tract obstruction and introduction to the PLUTO trial: Percutaneous shunting in lower urinary tract obstruction

Congenital lower urinary tract obstruction (LUTO) comprises a heterogeneous group of pathologies causing obstruction to the urethra, the most common being posterior urethral valves. Such pathology is often associated with high perinatal mortality and varying degrees of perinatal and infant morbidity. A high proportion of LUTO may be visualised during routine second trimester (and first trimester) ultrasound giving rise to the possibility of determining individual fetal prognosis and treatments such as vesico‐amniotic shunting, with a view to altering pathogenesis. The aims of the percutaneous shunting in low urinary tract obstruction (PLUTO) trial are to determine the effectiveness of these treatments and accuracy of the investigations with the primary outcome measures being perinatal mortality and postnatal renal function.

Long-term renal and neurodevelopmental outcome in infants with LUTO, with and without fetal intervention

Congenital lower urinary tract obstruction (LUTO) is a heterogeneous group of pathologies, the most common being posterior urethral valves (PUV) or urethral atresia. The bladder neck obstruction in utero leads to a spectrum of disease including mild oligohydramnios with normal renal function to a picture of severe oligohydramnios associated with chronic obstructive macro/microcystic renal parenchymal disease leading to chronic renal impairment. These anomalies may be isolated or complex; the latter being associated with other structural or chromosomal abnormalities. If isolated, the congenital bladder neck obstruction may be amenable to in-utero therapy. In a significant proportion of babies affected by LUTO there is severe oligohydramnios (occurring before 20 weeks gestation) and associated with pulmonary hypoplasia, a scenario almost always associated with perinatal death. For those babies that survive the perinatal period there is a significant risk of renal impairment, often necessitating renal dialysis or transplantation in childhood. In addition, there may be other morbidities such as chronic filling anomalies of the bladder that may require treatment.

Systematic review and meta-analysis of the test accuracy of ductus venosus Doppler to predict compromise of fetal/neonatal wellbeing in high risk pregnancies with placental insufficiency

OBJECTIVE To evaluate the test accuracy of ductus venosus Doppler for prediction of compromise of fetal/neonatal wellbeing. STUDY DESIGN The search strategy employed searching of electronic databases (Medline, Embase, Cochrane library, Medion) from inception to May 2009, hand searching of journal and reference lists, contact with experts. Two reviewers independently selected articles in which the results of ductus venosus Doppler were associated with the occurrence of compromise of fetal/neonatal wellbeing. There were no language restrictions applied. Data were extracted on study characteristics, quality and results to construct 2 x 2 tables. Likelihood ratios for positive and negative test results, sensitivity, specificity and their 95% confidence intervals were generated for the different indices and thresholds. RESULTS Eighteen studies, testing 2267 fetuses met the selection criteria, all performed in a high risk population with placental insufficiency in second/third trimester. Meta-analysis showed moderate predictive accuracy. The best result was for the prediction of perinatal mortality, positive likelihood ratio 4.21 (95% CI 1.98-8.96) and negative likelihood ratio 0.43 (95% CI 0.30-0.61). For prediction of adverse perinatal outcome the results were positive likelihood ratio 3.15 (95% CI 2.19-4.54) and negative likelihood ratio 0.49 (95% CI 0.40-0.59). CONCLUSION Abnormal ductus venosus Doppler showed moderate predictive accuracy for compromise of fetal/neonatal wellbeing overall and perinatal mortality in high risk pregnancies with placental insufficiency.

Meta-Analysis of Test Accuracy Studies with Multiple and Missing Thresholds: A Multivariate-Normal Model

Background: When meta-analysing studies examining the diagnostic/predictive accuracy of classifications based on a continuous test, each study may provide results for one or more thresholds, which can vary across studies. Researchers typically meta-analyse each threshold independently. We consider a multivariate meta-analysis to synthesise results for all thresholds simultaneously and account for their correlation. Methods: We assume that the logit sensitivity and logit specificity estimates follow a multivariate-normal distribution within studies. We model the true logit sensitivity (logit specificity) as monotonically decreasing (increasing) functions of the continuous threshold. This produces a summary ROC curve, a summary estimate of sensitivity and specificity for each threshold, and reveals the heterogeneity in test accuracy across studies. Application is made to 13 studies of protein:creatinine ratio (PCR) for detecting significant proteinuria in pregnancy that each report up to nine thresholds, with 23 distinct thresholds across studies. Results: In the example there were large within-study and between-study correlations, which were accounted for by the method. A cubic relationship on the logit scale was a better fit for the summary ROC curve than a linear or quadratic one. Between-study heterogeneity was substantial. Based on the summary ROC curve, a PCR value of 0.30 to 0.35 corresponded to maximal pair of summary sensitivity and specificity. Limitations of the proposed model include the need to posit parametric functions for the relationship of sensitivity and specificity with the threshold, to ensure correct ordering of summary threshold results, and the multivariate-normal approximation to the within-study sampling distribution. Conclusion: The joint analysis of test performance data reported over multiple thresholds is feasible. The proposed approach handles different sets of available thresholds per study, and produces a summary ROC curve and summary results for each threshold to inform decision-making.

The quality of reporting of primary test accuracy studies in obstetrics and gynaecology: application of the STARD criteria

BackgroundIn obstetrics and gynaecology there has been a rapid growth in the development of new tests and primary studies of their accuracy. It is imperative that such studies are reported with transparency allowing the detection of any potential bias that may invalidate the results. The objective of this study was to determine the quality of reporting in diagnostic test accuracy studies in obstetrics and gynaecology using the Standards for Reporting of Diagnostic Accuracy - STARD checklist.MethodsThe included studies of ten systematic reviews were assessed for compliance with each of the reporting criteria. Using appropriate statistical tests we investigated whether there was an improvement in reporting quality since the introduction of the STARD checklist, whether a correlation existed between study sample size, country of origin of study and reporting quality.ResultsA total of 300 studies were included (195 for obstetrics, 105 for gynaecology). The overall reporting quality of included studies to the STARD criteria was poor. Obstetric studies reported adequately > 50% of the time for 62.1% (18/29) of the items while gynaecologic studies did the same 51.7% (15/29). There was a greater mean compliance with STARD criteria in the included obstetric studies than the gynaecological (p < 0.0001). There was a positive correlation, in both obstetrics (p < 0.0001) and gynaecology (p = 0.0123), between study sample size and reporting quality. No correlation between geographical area of publication and compliance with the reporting criteria could be demonstrated.ConclusionsThe reporting quality of papers in obstetrics and gynaecology is improving. This may be due to initiatives such as the STARD checklist as well as historical progress in awareness among authors of the need to accurately report studies. There is however considerable scope for further improvement.

Meta-analysis of test accuracy studies: an exploratory method for investigating the impact of missing thresholds

BackgroundPrimary studies examining the accuracy of a continuous test evaluate its sensitivity and specificity at one or more thresholds. Meta-analysts then usually perform a separate meta-analysis for each threshold. However, the number of studies available for each threshold is often very different, as primary studies are inconsistent in the thresholds reported. Furthermore, of concern is selective reporting bias, because primary studies may be less likely to report a threshold when it gives low sensitivity and/or specificity estimates. This may lead to biased meta-analysis results. We developed an exploratory method to examine the potential impact of missing thresholds on conclusions from a test accuracy meta-analysis.MethodsOur method identifies studies that contain missing thresholds bounded between a pair of higher and lower thresholds for which results are available. The bounded missing threshold results (two-by-two tables) are then imputed, by assuming a linear relationship between threshold value and each of logit-sensitivity and logit-specificity. The imputed results are then added to the meta-analysis, to ascertain if original conclusions are robust. The method is evaluated through simulation, and application made to 13 studies evaluating protein:creatinine ratio (PCR) for detecting proteinuria in pregnancy with 23 different thresholds, ranging from one to seven per study.ResultsThe simulation shows the imputation method leads to meta-analysis estimates with smaller mean-square error. In the PCR application, it provides 50 additional results for meta-analysis and their inclusion produces lower test accuracy results than originally identified. For example, at a PCR threshold of 0.16, the summary specificity is 0.80 when using the original data, but 0.66 when also including the imputed data. At a PCR threshold of 0.25, the summary sensitivity is reduced from 0.95 to 0.85 when additionally including the imputed data.ConclusionsThe imputation method is a practical tool for researchers (often non-statisticians) to explore the potential impact of missing threshold results on their meta-analysis conclusions. Software is available to implement the method. In the PCR example, it revealed threshold results are vulnerable to the missing data, and so stimulates the need for advanced statistical models or, preferably, individual patient data from primary studies.

Fetal therapy for the treatment of congenital bladder neck obstruction

Lower urinary tract obstruction (LUTO) comprises a heterogeneous group of pathologies associated with early-onset oligohydramnios and cystic renal disease that have high rates of perinatal morbidity (from renal disease) and mortality (from pulmonary hypoplasia). The use of prenatal detailed ultrasonography and fetal urine analysis has been only partially successful in identifying fetuses with LUTO with relatively good prognosis that would benefit from in utero therapy. The most common prenatal therapy is vesicoamniotic shunting. Newer techniques, such as fetal cystoscopy, have potential for enhancing prenatal triage and simultaneously delivering treatment. Vesicoamniotic shunting seems to improve perinatal survival, but whether this treatment or conservative management is used, the surviving children have a high rate of end-stage renal failure requiring dialysis and transplantation. Further investigation of long-term outcomes of vesicoamniotic shunting and fetal cystoscopy is hoped to delineate the risks and benefits of these prenatal treatments and inform management strategies.

Prenatal Diagnosis of Isolated Right Pulmonary Agenesis Using Sonography Alone Case Study and Systematic Literature Review

Pulmonary agenesis is a rare congenital anomaly, estimated to complicate around 1 per 15,000 pregnancies, in which there is complete absence or severe hypoplasia of one or both lungs, frequently associated with other abnormalities. A prospective prenatal diagnosis is a challenge, and a substantial proportion of cases are diagnosed by fetal magnetic resonance imaging, postnatal computed tomography, or postmortem. Thus, there are only a few reported cases of prenatal diagnosis in the literature. We report the prenatal diagnosis of isolated right lung agenesis diagnosed with sonography alone at a relatively early gestational age. We also present a systematic review of the literature for this condition to accompany this case study.

Advances in fetal therapy

• Fetal medicine is a rapidly developing subspecialty. • The mainstay of treatment for fetal alloimmune thrombocytopenia remains maternal immunoglobulin therapy. • Stem cell transplantation and gene therapy have advanced over the last decade but must still be considered experimental. • Laser coagulation is the best treatment for all stages of twin‐to‐twin transfusion syndrome presenting before 26 weeks of gestation. • Fetoscopic endoluminal tracheal occlusion appears to improve prognosis in severe congenital diaphragmatic hernia.

Association of serum PAPP‐A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta‐analysis

To determine association, and predictive ability, of first trimester maternal serum pregnancy associated plasma protein A (PAPP‐A) with adverse pregnancy outcomes.