Prevalence of opioid and benzodiazepine use in adult patients with the exstrophy-epispadias complex.

INTRODUCTION: Bladder exstrophy (BE), cloacal exstrophy (CE), and epispadias (E) are variants of the exstrophy-epispadias complex (EEC). These children require opioids and benzodiazepines to achieve pain management and immobilization for a lifetime of surgeries. It is hypothesized that these children would be sensitized to opiates and benzodiazepines as adults. The objective was to identify incidence of opiate and benzodiazepine use in adult EEC patients. METHODS: A US Health network, TriNetX Diamond was queried from 2009 to 2022. Incidence of prescriptions for benzodiazepines and opioids were calculated for adults aged 18-60 years with a diagnosis of BE, CE, or E. RESULTS: A total of 2627 patients were identified: 337 with CE, 1854 patients with BE, and 436 with E. Of these, 55.5% of CE, 56.4% of BE, and 41.1% of E had received any opioid prescription. Non-EEC controls had lower rates of opioids at 0.3%. E had a lower likelihood than BE or CE of receiving opioids (p < 0.0001, p < 0.0001). Benzodiazepines were prescribed in 30.3% of CE, 24.4% of BE, 18.3% of E, and 0.1% of controls. CE had a higher likelihood of benzodiazepines than both BE and E (p = 0.022, p < 0.001, respectively). E group had the lowest likelihood of benzodiazepine prescription (p = 0.007 when compared to BE) and all groups were significantly higher than controls (p < 0.0001 for all comparisons). For BE, females were more likely to be prescribed opioids (p = 0.039) and benzodiazepines (p = 0.027) than males. Sub-analyses revealed BE females had higher rates of surgical procedures (general, cardiac, gastrointestinal, and maternity) and chronic diagnoses (generalized anxiety disorder, major depressive disorder, chronic pain) compared to males with BE. Older age was associated with higher likelihood of opioid or benzodiazepine prescriptions in BE (p < 0.001), CE (p = 0.004), and E (p = 0.002). DISCUSSION: Across the EEC, adult patients with the most severe anomalies of CE were more likely to have received opioids and benzodiazepines. Females with BE were prescribed more opioid and benzodiazepines than males with BE. Mirroring the US population, female sex and increasing age were associated with higher rates of prescriptions, chronic diagnoses, and surgical procedures. Limitations include the lack of granular data and ability to correlate results with childhood surgeries. CONCLUSION: Adult EEC patients have higher rates of opioid and benzodiazepine prescriptions, with a high percentage of co-prescribing when compared to healthy controls. Across the spectrum, those with more severe anomalies, female sex, and increasing age were more likely to have received prescriptions.

Use of small intestinal submucosa for corporal body grafting in cases of epispadias and epispadias/exstrophy complex.

BACKGROUND: Male epispadias is a rare congenital urogenital anomaly in which the meatus is ectopically located along the dorsal midline of the penile shaft. In cases associated with severe curvature, functional and cosmetic outcomes could be accomplished by lengthening the shorter dorsal surface with the use of corporal grafting. Various graft materials have been used in the past for hypospadias repair including tunica vaginalis, dermis, and small intestinal submucosa (SIS). The use of SIS grafting for corporoplasty during epispadias repair has rarely been described in the literature. OBJECTIVE: To report the experience in the management of dorsal corporal body grafting using SIS in children with severe penile curvature due to epispadias. STUDY DESIGN: The authors retrospectively reviewed the charts of all patients with epispadias or bladder exstrophy/epispadias complex and severe dorsal chordee (>40°) who underwent epispadias repair with single-layer SIS for corporal body grafting. Clinical variables, surgical technique, and outcomes were analyzed. RESULTS: A total of nine consecutive patients underwent staged epispadias repair with dorsal corporal single-layer SIS grafting (summary figure). Of these, four (44.4%) had primary penopubic epispadias, one (11.1%) had mid-shaft epispadias, and four (44.4%) had bladder exstrophy/epispadias complex. The mean age at surgery was 13.4 ± 6 months. After phalloplasty with SIS grafting, there were no reported complications related to the graft during the post-operative period or follow-up visits. DISCUSSION: Although traditional techniques for epispadias repair allow some degree of corporal lengthening, they also result in abrupt medial rotation of the corporal bodies leading to torqueing and potential unsatisfactory cosmetic results. In contrast, the authors use single-layer SIS for corporal body grafting, and this study technique results in a more gradual inward rotation thus allowing more anatomical accuracy. Furthermore, an advantage of the use of SIS over other grafting materials is that there is no need to harvest an autologous graft such as tunica vaginalis or dermis. CONCLUSION: Epispadias repair using single-layer SIS corporal body grafting is an effective, safe, and feasible method, which provides satisfactory cosmesis and correction of dorsal curvature in congenital epispadias in children. Furthermore, a more normal penis appearance, without a decrease in the corporal length or diameter, is achieved with this technique.

Long-term sexual health outcomes in men with classic bladder exstrophy.

OBJECTIVES: To identify the long-term sexual health outcomes and relationships in men born with classic bladder exstrophy (CBE). MATERIALS AND METHODS: A prospectively maintained institutional database comprising 1248 patients with exstrophy-epispadias was used. Men aged ≥18 years with CBE were included in the study. A 42-question survey was designed using a combination of demographic information and previously validated questionnaires. RESULTS: A total of 215 men met the inclusion criteria, of whom 113 (53%) completed the questionnaire. The mean age of the respondents was 32 years. Ninety-six (85%) of the respondents had been sexually active in their lifetime, and 66 of these (58%) were moderately to very satisfied with their sex life. The average Sexual Health Inventory for Men score was 19.8. All aspects of assessment using the Penile Perception Score questionnaire were on average between 'very dissatisfied' and 'satisfied'. Thirty-two respondents (28%) had attempted to conceive with their partner. Twenty-three (20%) were successful in conceiving, while 31 (27%) reported a confirmed fertility problem. A total of 31 respondents (27%) reported undergoing a semen analysis or post-ejaculatory urine analysis. Of these, only four respondents reported azoospermia. CONCLUSION: Patients with CBE have many of the same sexual and relationship successes and concerns as the general population. This is invaluable information to give to both the parents of boys with CBE, and to the boys themselves as they transition to adulthood.

Prospective study on the incidence of bladder/cloacal exstrophy and epispadias in Europe.

OBJECTIVE: On behalf of the European Society of Paediatric Urology (ESPU), a prospective study was designed with the aim of defining the actual number of babies born with bladder exstrophy, cloacal exstrophy, and epispadias in Europe over a 12-month period, and verifying the distribution of the exstrophy patients born during the study period among the different paediatric urology centres in Europe. STUDY DESIGN: The study was structured with a chief investigator and one national investigator for each country enrolled in the study. The national investigators nominated one local investigator for each European centre of paediatric surgery/paediatric urology and urology where the exstrophy complex could potentially be treated. The local investigators were responsible for reporting babies treated in their institutions for bladder/cloacal exstrophy and/or epispadias. During 2010, every 3 months, an electronic survey (Figure) was e-mailed to the local investigators asking them to report babies treated or referred for treatment during the previous 3 months. RESULTS: One-hundred and sixteen centres in 27 European counties were enrolled in the study. The overall response rate for the four online surveys was 79%. Two-hundred and thirty-eight babies were reported to be born with a condition within the bladder exstrophy epispadias complex (BEEC): 71 primary epispadias (66 males), 146 classic bladder exstrophy (97 males) of which two were female bladder exstrophy variant, and 21 cloacal exstrophy (17 males). Two of 67 (3%) male epispadias, 24/146 (16.4%) bladder exstrophy, and 6/21 (28%) cloacal exstrophy were antenatally diagnosed. Associated anomalies were reported in 2/71 (2.8%) epispadias patients, 8/146 (5.5%) bladder exstrophy patients, and 15/21 (71.4%) cloacal exstrophy patients. One-hundred and forty-seven (62%) of the 238 babies born in Europe with a condition within the exstrophy spectrum during 2010 were transferred from other institutions for treatment (36 male epispadias, 97 bladder exstrophy, and 14 cloacal exstrophy). Only 12 centres treated six or more exstrophy and or epispadias patients during the study period; 52 treated between one and five patients, of which 22 treated only one case in 12 months. DISCUSSION: This study provides a contemporary incidence of the BEEC in Europe. It demonstrates also that only a minority (19%) of the European centres involved in the treatment of exstrophy can be considered "high volume" exstrophy centres. CONCLUSION: There is a case for proposing a rationalisation of the treatment of this group of conditions in a small number of exstrophy units around Europe.

New insights into the pathogenesis of bladder exstrophy-epispadias complex.

Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ΔNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.

Lower urinary tract symptoms (LUTS) in patients in adulthood with bladder exstrophy and epispadias.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Many patients with bladder exstrophy or epispadias (BEE) have bladder augmentation or use a catheterisation programme. Of the remainder only some achieve so called '3-h urinary continence'. In addition, some of the patients develop urinary tract infections or bladder stones related to voiding and storage problems. The present study is one of the first to evaluate lower urinary tract symptoms (LUTS) in detail in young adults treated for BEE in childhood by using a validated questionnaire. In addition the patient's own opinion about continence was ascertained. The study shows that both voiding and storage symptoms are frequent in patients with BEE and that most symptoms only become apparent by using a detailed questionnaire. OBJECTIVE: To evaluate lower urinary tract symptoms (LUTS) in patients with bladder exstrophy and epispadias (BEE) who have reached adulthood. PATIENTS AND METHODS: A questionnaire evaluating LUTS was mailed to 52 BEE patients (aged 15-44 years), 32 (62%) returned the questionnaire (19 with bladder exstrophy and 13 with epispadias; 21 males and 11 females). Seven exstrophy patients (37%) had undergone bladder augmentation. Information on LUTS was assessed first with a preliminary question (do you have urinary incontinence?) followed by the Danish Prostatic Symptom Score (DAN-PSS) questionnaire. RESULTS: Of the patients without bladder augmentation or clean intermittent catheterisation, five of 11 patients with exstrophy and 6 of 13 with epispadias considered themselves dry and 13 of 24 (54%) patients had >3 h dry intervals between voiding. According to DAN-PSS questionnaire only two of 11 patients with exstrophy and two of 13 with epispadias were fully continent and could void normally. In addition to storage symptoms, eight of 13 patients with epispadias and 10 of 12 with exstrophy had disturbing voiding symptoms. Moderate or severe LUTS was reported altogether by 12 of 15 (80%) males and by six of nine females. CONCLUSIONS: Continence rates in patients with BEE are very dependent on the evaluation method. Most LUTS become apparent only by using a detailed questionnaire. Moderate or severe LUTS appear to be common amongst patients with BEE.

Assisted reproductive techniques and risk of exstrophy-epispadias complex: a German case-control study.

PURPOSE: We assessed the risk of exstrophy-epispadias complex in children conceived by in vitro fertilization or intracytoplasmic sperm injection. MATERIALS AND METHODS: Data from the German Network for Congenital Uro-REctal malformations were compared to nationwide data from the German In Vitro Fertilization Register and the German Federal Statistical Office. Odds ratios (95% CI) were determined to quantify associations using logistic regression. RESULTS: A total of 123 patients with exstrophy-epispadias complex born in Germany between 1997 and 2011 were recruited through participating departments of pediatric urology and pediatric surgery throughout the country as well as the German self-help organizations Blasenekstrophie/Epispadie e.V. and Kloakenekstrophie. All German live births (10,069,986) between 1997 and 2010 comprised the controls. Overall, 12 subjects (10%) and 129,982 controls (1%) were conceived by in vitro fertilization or intracytoplasmic sperm injection. Conception by assisted reproductive technique was associated with a more than eightfold increased risk of exstrophy-epispadias complex compared to spontaneous conception (OR 8.3, 95% CI 4.6-15.0, p <0.001). Separate analyses showed a significantly increased risk of exstrophy-epispadias complex in children conceived by in vitro fertilization (OR 14.0, 95% CI 6.5-30.0, p <0.0001) or intracytoplasmic sperm injection (OR 5.3, 95% CI 2.2-12.9, p <0.0001). CONCLUSIONS: This study provides evidence that assisted reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are associated with a markedly increased risk of having a child born with exstrophy-epispadias complex. However, it remains unclear whether this finding may be due to assisted reproduction per se and/or underlying infertility/subfertility etiology or parent characteristics.

Expression and potential clinical significance of urothelial cytodifferentiation markers in the exstrophic bladder.

PURPOSE: We characterize the urothelium from patients with classic bladder exstrophy-epispadias complex for the expression of proteins associated with urothelial differentiation, and discuss a potential impact of urothelial phenotype on the structural and functional properties of the bladder template following bladder closure. MATERIALS AND METHODS: From 2005 to 2010 bladder biopsies from 32 infants with bladder exstrophy-epispadias complex obtained at primary bladder closure were collected. After histological assessment immunochemistry was used to investigate the expression of uroplakin IIIa, cytokeratin differentiation restricted antigens CK13 and CK20, and tight junction protein claudin 4. RESULTS: Overall tissue morphology showed gross alterations with inflammatory, proliferative and metaplastic changes in most specimens. Sections of intact epithelium were present in 78% of biopsies. With respect to urothelial phenotype, CK13 was expressed in all specimens, whereas UPIIIa and CK20 were absent in 76% of the tissues examined. Of the biopsies 52% revealed an irregular expression pattern of tight junction protein Cl-4. CONCLUSIONS: This is the first study to our knowledge to characterize the urothelium from infants with bladder exstrophy-epispadias complex for the expression of urothelial differentiation associated antigens. Our findings suggest urothelial differentiation changes in a majority of exstrophic bladders, at least at primary bladder closure. Although the underlying etiology remains to be established, abnormal urothelial differentiation may result in a dysfunctional urothelial barrier with implications for the structural and functional properties of the bladder template. Despite the study limitations, our preliminary findings provide a platform for further investigation of the significance of the urothelium for the exstrophic bladder.

Congenital renal anomalies in patients with classic bladder exstrophy.

OBJECTIVE: To determine the proportion and type of renal anomalies that occur in children born with classic bladder exstrophy. MATERIAL AND METHODS: All patients in a database of 1044 patients with the bladder exstrophy-epispadias-cloacal exstrophy complex were reviewed. Those with classic bladder exstrophy had their complete medical records reviewed and children with radiographic evidence of congenital renal anomalies were identified and characterized. RESULTS: A total of 674 patients were identified with classic bladder exstrophy, of whom 462 had renal ultrasounds at the authors' institution. In this population, 13/462 (2.8%) had concomitant renal anomalies. The most common malformation was a duplicated collecting system in 6 patients. Hypoplastic or absent kidneys were present in 3 patients, pelvic kidney in 2, ureteropelvic junction obstruction in 1, and multicystic dysplastic kidney in 1 patient. CONCLUSION: Isolated renal anomalies occur at a rate of 2.8% in children born with classic bladder exstrophy. Although uncommon in this rare birth defect, anatomic understanding of the entire genitourinary system is critical for operative planning and long-term follow-up of patients with bladder exstrophy.

Register based study of bladder exstrophy-epispadias complex: prevalence, associated anomalies, prenatal diagnosis and survival.

PURPOSE: We describe the prevalence, associated anomalies, prenatal diagnosis and survival of patients with bladder exstrophy-epispadias complex. MATERIALS AND METHODS: Data were extracted from the Northern Congenital Abnormality Survey for patients delivered during 1985 to 2008. This survey collects data on congenital anomalies in fetuses, stillbirths and live-born infants of mothers residing in Northern England (Northumberland, North Cumbria, Tyne and Wear Durham, Darlington and Teesside). RESULTS: A total of 43 cases were identified from 824,368 registered births for a total prevalence of 5.22 per 100,000 (95% CI 3.77-7.03). Excluding 1 twin with cloacal exstrophy, 42 cases occurred in singleton pregnancies. A total of 29 cases (69%) were isolated and 13 (31%) were associated with other anomalies, of which 11 (26%) were other structural and 2 (5%) were chromosomal. Male-to-female ratio was 2.2:1 for all singleton cases and 1.4:1 for isolated cases. Total prevalence of bladder exstrophy-epispadias complex singleton cases was 5.10 per 100,000 registered births (95% CI 3.67-6.89) and overall live birth prevalence was 4.63 per 100,000 live births (95% CI 3.28-6.36). Total prevalence of isolated cases of bladder exstrophy-epispadias complex was 3.52 per 100,000 births (95% CI 2.36-5.05) and live birth prevalence was 3.29 per 100,000 (95% CI 2.17-4.79). Accuracy of prenatal diagnosis was low, with 4 cases (10%) being detected prenatally by routine ultrasound (bladder exstrophy in 3, cloacal exstrophy in 1). Overall survival of all infants at 1 year was 95%. CONCLUSIONS: This population based study demonstrates a prevalence rate similar to other studies, a low prenatal diagnosis rate and high survival.

Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe.

OBJECTIVE: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). STUDY DESIGN: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were compared with identify factors that contribute to phenotype severity. RESULTS: Males were overrepresented in all subgroups. A relatively high prevalence of cleft lip, with or without cleft palate, was observed. Maternal smoking and medical radiation during the first trimester were associated with the severe cloacal exstrophy phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (epispadias). CONCLUSIONS: Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC.

Aptness and complications of labial mucosa grafts for the repair of anterior urethral defects in children and adults: single centre experience with 115 cases.

PURPOSE: We report a comprehensive review of our experience with labial mucosa graft urethroplasty to evaluate the indications for this kind of substitution urethroplasty, and the possible complications and risk factors for an untoward recipient site outcome both in children and adults. MATERIALS AND METHODS: Complications were retrospectively assessed by chart review. Patients with and without complications were compared with respect to age at surgery, indication for surgery (epispadias vs. hypospadias vs. urethral stricture), graft length and configuration (tube vs. patch). Moreover, in cases with urethral stricture a comparison was made according to the level of the stricture (penile vs. bulbar). RESULTS: After a median follow-up of 36 (6­90) months, the overall success rate was 66%. Complications were observed in 39 (34%) patients, of whom 18 (16%) required additional surgical procedures. Complications appeared to be unrelated to patient age at surgery, indication for surgery, graft length, and the urethral level of the stricture. Use of the graft as a tube was the single factor significantly more frequent in patients experiencing complications, particularly in the urethral defects associated with hypospadias where use of a tube corresponded to an odd ratio of 5.86 (95% CI 1.5­23.4). CONCLUSIONS: Oral grafts harvested from the lower lip are a versatile tissue for the repair of urethral defects associated with either urethral malformations or strictures, both in children and adults. Use of the graft as an on-lay seems preferable particularly in hypospadias repairs.

Bladder exstrophy-epispadias complex.

The bladder exstrophy-epispadias complex (BEEC) represents an anterior midline defect with variable expression comprising a spectrum of anomalies involving the abdominal wall, pelvis, urinary tract, genitalia, and occasionally the spine and anus. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current state of knowledge on this multifactorial disorder, including historical retrospect, phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components. These published lines of evidence argue strongly that BEEC occurs as a result of strong genetic predisposition that is yet to be deciphered.

Paraexstrophy skin flaps for the primary closure of exstrophy in boys: outmoded or updated?

PURPOSE: We evaluated the current application of Duckett paraexstrophy skin flaps for bladder exstrophy reconstruction. MATERIALS AND METHODS: We reviewed the records of cases of classic exstrophy treated at our institution between September 1993 and March 2007. A total of 21 patients were identified in whom modified Duckett paraexstrophy skin flaps were used in bladder closure at our institution. Another 12 patients were referred during the same time after closure with complications with flap use. RESULTS: Of the 21 patients who underwent closure at our institution with our modified version of the Duckett flaps 1 (4%) had a complication, that is urethral stricture. This responded to internal urethrotomy and daily intermittent catheterization for 4 months, and the stricture stabilized. Four of the 12 referred patients responded to multiple urethral dilations, 3 underwent open repair with a buccal graft, 2 received a full-thickness skin graft and 3 underwent internal urethrotomy with daily intermittent catheterization for 4 months. Of our 21 patients with internal treatment 14 underwent bladder neck repair, 5 underwent epispadias repair and 2 were awaiting further reconstruction. Six of the 12 referred patients underwent bladder neck repair, 4 underwent epispadias repair and 2 were awaiting further reconstruction. CONCLUSIONS: By modifying our version of the Duckett paraexstrophy skin flaps we have lowered our complication rate significantly. While overall use of these flaps has continued to decrease, when they are required, these modifications help avoid complicating strictures and their sequelae in the bladder and upper urinary tract.

Complications of primary closure of classic bladder exstrophy.

PURPOSE: We report the urological, orthopedic and neurological complications of primary closure of classic bladder exstrophy using modern staged repair of exstrophy. MATERIALS AND METHODS: An approved database identified 137 males and 57 females with classic bladder exstrophy who underwent primary repair by 1 of 2 surgeons in 23 years. A total of 185 patients underwent primary closure using modern staged repair of exstrophy with or without osteotomies, whereas 9 underwent delayed primary closure with epispadias repair at age 12 months. Of the patients 63 received osteotomies. Mean age at closure was 60 days and mean followup was 9 years. RESULTS: There were 14 major complications (11%) and 27 minor complications (14%). Major urological complications included bladder prolapse or dehiscence in 6 male patients (3%), which was successfully reclosed. Major orthopedic complications, including osteotomy nonunion in 2 cases, leg length inequality in 1 and persistent joint pain in 1, developed in 4 of the 63 patients (6%) who underwent osteotomy. Major neurological complications included femoral nerve palsy in 4 patients (2%). There were 21 minor urological complications (11%), including posterior bladder outlet obstruction in 4 cases, urethrocutaneous fistula in 2, suprapubic tube removal in 2, intrapubic stitch erosion in 4, febrile urinary tract infection in 6 and surgical site infection in 3. Six patients (3%) had minor orthopedic complications, including pelvic osteomyelitis in 1, pin site infection in 3 and a pressure sore from immobilization in 1. CONCLUSIONS: Closure of bladder exstrophy is a safe surgery with an acceptable risk of complications. A critical review of outcomes provides insight to further refine the technique and manage complications when they develop.

Epidemiological survey of 214 families with bladder exstrophy-epispadias complex.

PURPOSE: We sought to identify causative nongenetic and genetic risk factors for the bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 237 families with the bladder exstrophy-epispadias complex were invited to participate in the study, and information was obtained from 214 families, mainly from European countries. RESULTS: Two families showed familial occurrence. Male predominance was found among all subgroups comprising epispadias, classic bladder exstrophy and cloacal exstrophy, with male-to-female ratios of 1.4:1, 2.8:1 and 2.0:1, respectively (p = 0.001). No association with parental age, maternal reproductive history or periconceptional maternal exposure to alcohol, drugs, chemical noxae, radiation or infections was found. However, periconceptional maternal exposure to smoking was significantly more common in patients with cloacal exstrophy than in the combined group of patients with epispadias/classic bladder exstrophy (p = 0.009). Only 16.8% of mothers followed the current recommendations of periconceptional folic acid supplementation, and 17.6% had started supplementation before 10 weeks of gestation. Interestingly, in the latter group mothers of patients with cloacal exstrophy were more compliant with folic acid supplementation than were mothers of the combined group of patients with epispadias/classic bladder exstrophy (p = 0.037). Furthermore, mothers of children with cloacal exstrophy knew significantly more often prenatally that their child would have a congenital malformation than did mothers of children with epispadias/classic bladder exstrophy (p <0.0001). CONCLUSIONS: Our study corroborates the hypothesis that epispadias, classic bladder exstrophy and cloacal exstrophy are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full bladders with a focus on neural tube defects.

Recent advances in external genitalia.

In the last decade, significant progress in the knowledge and management of external genital anomalies has been achieved, including an improved understanding of epidemiology and pathophysiology of these anomalies, the identification of etiologic genetic defects, and significant improvements in surgical approaches that have decreased complications and improved cosmetic outcomes. We highlight the most clinically important advances of the commonly encountered external genital anomalies.