Child outcomes after amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a long-term follow-up study of the PROMEXIL-III trial.

OBJECTIVE: To assess the effect of transabdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester prelabour rupture of the membranes (PROM between 16+0/7 -24+0/7  weeks) and oligohydramnios. POPULATION: Follow up of infants of women who participated in the randomised controlled trial: PPROMEXIL-III (NTR3492). METHODS: Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes were measured. Mild delay was defined as -1 standard deviation (SD), severe delay as -2 SD. Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems. RESULTS: In the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60-1.22). Follow-up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy long-term survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53-11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long-term survivor. CONCLUSIONS: In this small sample of women suffering second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay. TWEETABLE ABSTRACT: Healthy long-term survival was comparable for children born after second-trimester PROM and treatment with amnioinfusion or no intervention.

The effects of intrauterine insemination and single embryo transfer or modified natural cycle in vitro fertilization on offspring's health-Follow-up of a randomized clinical trial.

OBJECTIVE: Does ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction affect neurodevelopmental and physical health of the offspring? STUDY DESIGN: Infertile couples were randomly allocated to intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH), modified natural cycle in vitro fertilization (IVF-MNC) or single embryo transfer IVF (IVF-SET). We compared neurodevelopmental and physical health in childhood (4-7 years). We used age-appropriate questionnaires to assess behavioral problems (Child Behavior Check List (CBCL)) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)). We measured body mass index Z-score, waist- and hip-circumference, body fat percentage, blood pressure Z-scores, pulse wave velocity, glucose, insulin, insulin resistance, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, and high sensitivity c-reactive protein. We compared groups by analysis of variance. RESULTS: We examined 191 (57%) of the 333 children born in the study at a mean age of 5.5 years (range 4.0-7.6 years). We found no statistically significant differences between randomization groups in children's neurodevelopmental or physical health indices (all p-values > 0.05). Comparing the outcomes between actual method of conception, including a naturally conceived group, also did not show statistically significant differences. CONCLUSIONS: Although this follow-up study was not powered on childhood outcomes and limited power due to attrition may have hampered detection of subtle effects, we found no indications of differences in neurodevelopmental and physical health between ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction. Future trials should be powered on child outcomes, and aim to optimize follow-up rates to provide answers that are more definitive.

Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta-analysis of animal studies.

Obesity before and during pregnancy leads to reduced offspring cardiometabolic health. Here, we systematically reviewed animal experimental evidence of maternal obesity before and during pregnancy and offspring anthropometry and cardiometabolic health. We systematically searched Embase and Medline from inception until January 2018. Eligible publications compared offspring of mothers with obesity to mothers with a normal weight. We performed meta-analyses and subgroup analyses. We also examined methodological quality and publication bias. We screened 2543 publications and included 145 publications (N = 21 048 animals, five species). Essential methodological details were not reported in the majority of studies. We found evidence of publication bias for birth weight. Offspring of mothers with obesity had higher body weight (standardized mean difference (SMD) 0.76 [95% CI 0.60;0.93]), fat percentage (0.99 [0.64;1.35]), systolic blood pressure (1.33 [0.75;1.91]), triglycerides (0.64 [0.42;0.86], total cholesterol (0.46 [0.18;0.73]), glucose level (0.43 [0.24;0.63]), and insulin level (0.81 [0.61;1.02]) than offspring of control mothers, but similar birth weight. Sex, age, or species did not influence the effect of maternal obesity on offspring's cardiometabolic health. Obesity before and during pregnancy reduces offspring cardiometabolic health in animals. Future intervention studies should investigate whether reducing obesity prior to conception could prevent these detrimental programming effects and improve cardiometabolic health of future generations.

Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3-year follow-up study.

OBJECTIVE: A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL) < 38 mm. In this follow-up study, the long-term developmental outcome of these children was evaluated at 3 years' corrected age. METHODS: This was a follow-up study of ProTWIN, a multicenter trial conducted between 2009 and 2012 in which asymptomatic women with a multiple pregnancy were randomized to placement of a cervical pessary or no intervention. Current follow-up and analysis were limited to mothers with a mid-trimester CL < 38 mm (78 women (157 children) in the pessary group and 55 women (111 children) in the control group). At 3 years of corrected age, surviving children were invited for a Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) assessment. Death after randomization or neurodevelopmental disability (Bayley-III score of ≤ 85, 1 SD below mean) rates were compared between the pessary and control groups, according to the intention-to-treat principle and using multiple imputation for missing data. Mean Bayley-III scores in surviving children were also assessed. A linear mixed-effects model was used to adjust for correlation between children of one mother. RESULTS: From the time of entry in the ProTWIN trial until follow-up at 3 years of age, a total of 27 children had died (six (5%) in the pessary vs 21 (26%) in the control group; odds ratio (OR), 0.13; 95% CI, 0.04-0.48). Bayley-III outcomes were collected for 173/241 (72%) surviving children (114 (75%) in the pessary vs 59 (66%) in the control group). The cumulative incidence of death or survival with a neurodevelopmental disability was 12 (10%) in the pessary vs 23 (29%) in the control group (OR, 0.26; 95% CI, 0.09-0.73). No statistical or clinically relevant differences were found with respect to cognitive, language and motor development among surviving children between the groups. Comparable results were found after multiple imputation. CONCLUSION: In women with twin pregnancy and a CL < 38 mm, the use of a cervical pessary strongly improved survival of the children without affecting neurodevelopment at 3 years' corrected age. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Sex specific effect of prenatal testosterone on language lateralization in children.

Brain lateralization refers to the division of labour between the two hemispheres in controlling a wide array of functions and is remarkably well developed in humans. Based on sex differences in lateralization of handedness and language, several hypotheses have postulated an effect of prenatal exposure to testosterone on human lateralization development, the topic of a long-standing and unresolved debate. Here we demonstrate a clear relationship between prenatal levels of testosterone as assessed from amniotic fluid of healthy pregnant mothers and language lateralization of their offspring at the age of 6 years. Using focused attention conditions in the dichotic listening task, in which the child is instructed to report information from the left ear or the right ear, we were able to differentiate between potential effects of early testosterone on the left hemisphere and effects on inter-hemispheric connectivity. This provides a new method to distinguish between the claims of the different hypotheses. The results suggest that in girls higher prenatal testosterone exposure facilitates left hemisphere language processing, whereas in boys it reduces the information transfer via the corpus callosum.

[Loss of renal function due to deep infiltrating endometriosis; a complicated consideration in women who wish to have children]. / Nierfunctieverlies bij diep infiltratieve endometriose: tijdige herkenning van ureterobstructie is geboden.

Three nulliparous women, aged 39, 34 and 26 years, who were treated for fertility problems and who were affected by endometriosis, presented with ureteral obstruction caused by deep infiltrating endometriosis. The first two patients had complete unilateral loss of kidney function at the time of diagnosis. They chose to have fertility treatment first and both became pregnant. The third patient still had 24% renal function in the affected left kidney. She was treated by complete surgical resection of the endometriosis and reimplantation of the ureter. Ureteral obstruction is a rare, but serious, complication of deep infiltrating endometriosis. Timely recognition is important, since delay results in unnoticed loss of renal function. Clinical investigation for endometriosis of the posterior vaginal fornix is recommended for all patients with chronic abdominal pain, severe dysmenorrhoea or deep dyspareunia. On diagnosis of deep infiltrating endometriosis, further examination is necessary to detect possible ureteral obstruction and consequent hydronephrosis, which can be demonstrated by ultrasound. MRI is of value to map the extent of disease, which is usually multi-focal. Surgery to relieve ureteral obstruction and remove all endometriotic lesions is the treatment of choice if the kidney is still functional.

Safety and efficacy of a non-steroidal anti-androgen, based on results of a post marketing surveillance of nilutamide.

The use, tolerability and efficacy of the non-steroidal anti-androgen nilutamide (Anandron(R)) in daily clinical practice was investigated in this 5-y project. In total 725 patients were recruited from 27 Dutch centres. The investigated population was very heterogeneous and different therapeutic options were reported. We may conclude that in general good results have been obtained, especially in first line combination therapy combined with luteinising hormone releasing hormone (LHRH) agonists. Patients with a good performance status at inclusion seem to benefit more from nilutamide combination therapy.Prostate Cancer and Prostatic Diseases (2001) 4, 112-117

[Appropriate treatment of benign prostatic hyperplasia; refining the indications for treatment by systematic analysis of expert opinion]. / Passende behandeling bij benigne prostaathyperplasie; verfijning van de indicatiestelling door systematische analyse van klinische expertise.

OBJECTIVE: To assess systematically the opinion of urology experts regarding the appropriateness of indications for treatment of benign prostatic hyperplasia (BPH) and to evaluate the potential use of these expert opinions for the refinement of treatment guidelines. DESIGN: Modified Delphi procedure. METHODS: A panel of 12 Dutch urologists judged the appropriateness of three common treatments (surgery, alpha-adrenergic antagonists, finasteride) for 1152 hypothetical cases of BPH. These cases consisted of all combinations of 9 diagnostic characteristics considered relevant to treatment choice. The study population was restricted to patients for whom current (evidence-based) guidelines do not provide clear indications on the most appropriate treatment. The panel members individually rated the appropriateness of the three active treatments using a 1 to 9 scale, each in comparison with 'watchful waiting'. By combining the results on agreement and appropriateness, aggregate panel judgements were calculated for each indication (appropriate, inappropriate, uncertain). The relationship between diagnostic characteristics and panel opinions was studied using logistic regression methods. RESULTS: For patients without previous treatment for BPH, surgery was considered appropriate in 44% of cases. For alpha-blocking drugs and finasteride, these values were 70% and 3% respectively. Logistic regression analysis revealed a strong and consistent relationship between the several diagnostic characteristics and the panel judgement 'appropriate indication'. CONCLUSION: Systematic analysis of clinical expertise can offer a meaningful contribution to the refinement of indications for BPH treatments.

Treatment choice for benign prostatic hyperplasia: a matter of urologist preference?

PURPOSE: New treatment modalities for benign prostatic hyperplasia (BPH) have considerably altered the decision making process in daily clinical practice. Guidelines provide a framework for treatment choice but leave much room for physician personal opinions. We identified and quantified determinants of treatment choice for BPH among urologists focusing on urologist treatment preferences. MATERIALS AND METHODS: The study population consisted of 670 consecutive patients with BPH 50 years old or older newly referred to 1 of 39 urologists in a stratified sample of 13 hospitals throughout The Netherlands. Data on patient characteristics were retrieved from patient questionnaires (symptomatology, bothersomeness, sexual function), medical records (diagnostic outcomes, co-morbidity) and urologist questionnaire (initial treatment choice and main considerations for this decision). Urologist treatment preferences were inventoried using a mailed questionnaire. Polychotomous logistic regression analysis was used to study the impact of patient characteristics and urologist preferences on treatment choice. RESULTS: Among the patient characteristics maximum flow rate, residual urine and prostate volume were strongly associated with the probability of surgery and watchful waiting. However, the influence of urologist preferences on actual decisions was also significant. Adjusted for case mix the differences in low and high preferences revealed a 2.2 times greater probability of surgery. For alpha-blockers and finasteride these ratios were 1.8 and 9.4, respectively. An additional independent effect was seen for urologist extent of experience. CONCLUSIONS: The influence of urologist personal preferences on treatment choice in BPH is considerable. Given the different efficacy and side effects of the various treatments, further consensus development is needed to enhance appropriate treatment decisions and eliminate undue costs.

Utility of ultrasound of the upper urinary tract in elderly men with indicators of obstructive symptoms or abnormal flow: how often can silent hydronephrosis be detected in general practice?

BACKGROUND AND OBJECTIVE: While the prevalence of hydronephrosis is very low in obduction studies, a prevalence of 3-13% is reported for patients with an obstruction who are listed for prostatectomy. In order to evaluate the usefulness of transabdominal ultrasound in primary care, we determined the occurrence of hydronephrosis in males with symptoms of urinary obstruction in a general practice setting. METHOD: A micturition questionnaire (a modified Boyarsky) was sent to all men of 55 years or more who were registered in 10 general practices in Maastricht, and was followed by an examination at their general practice. Men with obstructive symptoms and/or with a free-flow abnormality were examined in the hospital with transabdominal ultrasound in order to detect dilatation of the upper urinary tract. This ultrasound was repeated approximately 15 months later. RESULTS: At the first measurement, none of the examined men (n = 178) had hydronephrosis, and this was still the case for 94 men 15 months later. CONCLUSION: Renal ultrasound is not necessary in general practice for men with uncomplicated obstructive complaints.

Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: a randomized, multicenter study of orchiectomy alone versus orchiectomy plus estramustine phosphate. The Dutch Estracyt Study Group.

OBJECTIVES: Based on the theory that hormone-resistant cells are present in all metastatic patients, early administration of chemotherapy appears to be logical and its use is supported by experimental studies. Therefore, trials with combined hormonal and cytotoxic treatment as primary therapy should be conducted. In the present trial, the efficacy and tolerance of estramustine phosphate (EMP) as a chemotherapeutic agent in addition to hormonal treatment (orchiectomy) was studied in patients with metastatic and nonmetastatic prostate cancer not previously treated. EMP was chosen because it produces few serious adverse reactions and no cumulative toxicity. METHODS: Four hundred nineteen patients were included in a 1.5-year period starting in January 1989. Patients with locally advanced prostate cancer or with bone metastases were randomized to orchiectomy (O) or orchiectomy followed by EMP (O + E), given until progression. RESULTS: Analysis of the total group showed no significant difference in time to progression between the treatment groups. Because the course of the disease is different in patients with either T4 tumor only or with lymph node metastases only (M0) as compared with patients with bone metastases (M1) and because the number of progressions in the M0 patients was low, corresponding analyses were performed for these subgroups as well. In the M1 patients, there was a tendency for a longer time to progression in the O + E group than in the O group, but there was no indication of a difference between the groups with regard to survival. In the M0 patients, there was no indication of any difference in results between the treatments. Multivariate analysis of prognostic factors showed pain, alkaline phosphatase, metastasis status, and tumor stage to be significant factors. There was a relation between age and drug treatment in that a significant beneficial effect of EMP in terms of prolonged progression-free interval as well as survival was evident in younger patients (aged less than 73 years) with metastatic disease. Tumor stage was also of importance for the drug effect; T0 to T3 patients who received EMP survived longer than those who were treated with orchiectomy only. The most common adverse reaction was nausea in the O + E group, which led to discontinuation of the drug in 7 patients. Cardiovascular problems are not uncommon in this age group, and there was a higher incidence of cardiovascular events, predominantly cardiac failure, in the O + E group, leading to treatment interruption in 16 patients. CONCLUSIONS: Our results indicate that future studies of hormono/chemotherapy should focus on younger patients with bone metastases.

Interpretation of uroflowmetry curves by urologists.

PURPOSE: Uroflowmetry has become a routine investigation in patients with symptoms of the lower urinary tract. Little is known about the variation in the use of uroflowmetry and in the interpretation of its outcomes. We investigated the diagnostic value of uroflowmetry as a freestanding test, and examined the interobserver and intra-observer variation in the interpretation of uroflowmetry curves. MATERIALS AND METHODS: A representative panel of 58 urologists was questioned about the relevance of visual inspection and flow parameters for interpretation. In addition, they individually assessed 25 randomly selected uroflowmetry curves (from patients with no abnormalities and those with various lower urinary tract symptoms) regarding normal findings and the most likely diagnosis. To investigate intra-observer agreement 4 of these curves were studied twice. RESULTS: Voided volume (81%), visual inspection (77%) and maximum flow rate (77%) were most frequently mentioned as relevant for interpretation. Large differences existed between panel opinions and actual case information. For 43% of the normal cases the panel members considered the curves as abnormal. Of the abnormal cases 6% of the curves were regarded as normal. The urologists predicted correctly the actual diagnosis in 36% of all cases. Interobserver agreement was moderate for normalcy (kappa 0.46, standard error 0.087) and poor for the most likely diagnosis (kappa 0.30, standard error 0.043). Intra-observer agreement was also not satisfactory. On average, for the 4 cases studied twice 29% of the panel members chose another option for normalcy, while 41% mentioned another diagnosis the second time. CONCLUSIONS: These results necessitate reconsideration of the diagnostic use of uroflowmetry in daily urological practice.

[Variation in the diagnosis and treatment of benign prostatic hyperplasia in urological practice]. / Variatie in diagnostiek en behandeling van benigne prostaathyperplasie in de urologische praktijk.

OBJECTIVE: To analyse practice variation among urologists and its determinants with respect to diagnostics and therapy choice in benign prostatic hyperplasia (BPH). DESIGN: Cross-sectional. SETTING: Stratified sample of 12 urological practices throughout the Netherlands. METHODS: On 670 consecutive, newly referred BPH patients > or = 50 years, data were collected about symptomatology, discomfort and sexual functioning (patient questionnaire), diagnostic procedures and outcomes (medical record), and (considerations for) therapy choice (urologist questionnaire). Characteristics of patients as well as of urologists were integrally studied to explain the variation. RESULTS: With respect to diagnostics, highest variation (interquartile ranges) was found for ultrasonography of the prostate (19-86%), kidneys (19-68%), and bladder (42-91%), and lowest variation for digital rectal examination (97-100%) and blood tests and urinalysis (88-100% and 86-99% respectively). For therapy choice, interquartile ranges were 24-42% (surgery), 32-49% (watchful waiting), 5-29% (alpha-blockers), and 0-17% (5-alpha-reductase-inhibitor). Variation in diagnostics was associated with characteristics of urologists and work setting as well as of patients. For differences in therapy choice, symptomatology, discomfort, sexual activity, peak flow, volume of residual urine, prostate volume, comorbidity, experience of the urologist, and the type of hospital were the most important explanatory variables. CONCLUSION: Variation in both diagnostics and therapy choice is considerable. This variation is associated with characteristics of patients as well as of urologists and work setting.

The symptom questionnaire for benign prostatic hyperplasia: an ambiguous indicator for an ambiguous disease.

OBJECTIVE: To assess the criterion validity of the American Urological Association (AUA) symptom index for benign prostatic hyperplasia (BPH) in urological practice. PATIENTS AND METHODS: The study comprised 1414 consecutive men > or = 50 years of age, newly referred to a urologist in a stratified sample of 12 hospitals throughout the Netherlands, who completed the AUA symptom questionnaire at their first visit. The 39 urologists completed a questionnaire on the diagnosis. The discriminative power of the index for BPH versus other urological diagnoses was calculated by receiver operating characteristic (ROC) analysis. Subsequently, criterion sensibility was studied by assessing the effect of particular variables on the probability of the diagnosis of BPH. RESULTS: ROC areas were low for BPH versus prostate cancer (0.57, SE 0.04), chronic prostatitis/prostatodynia (0.65, SE 0.03), and other diseases of the lower urinary tract (0.57, SE 0.04). Satisfactory to good values were found for BPH versus diseases of the upper urinary tract (0.79, SE 0.03), impotence/infertility (0.79, SE 0.04), penile-scrotal diseases (0.85, SE 0.02), and no abnormalities (0.84, SE 0.03). The diagnosis of BPH, as made by urologists in daily practice, appeared to be a weak criterion. Irrespective of other characteristics, the chance of being diagnosed with BPH was affected by differences in definition and the type of hospital. CONCLUSION: Although the AUA index discriminated fairly well between BPH and diseases of the upper urinary tract, as well as genital diseases, it has no potential for distinguishing BPH from other diseases of the lower urinary tract. In addition, the lack of consensus in defining clinical BPH underscores the weakness of the index as a tool in the diagnostic process of this disease.