Purpose-To identify causative non-genetic and genetic risk factors to the bladder exstrophyepispadias complex (BEEC).Materials and Methods-237 BEEC families were invited to participate and information was obtained from 214 families, mainly comprising European countries.Results-Two families showed familial occurrence. Male predominance (p 0.001) was found among all BEEC subgroups comprising epispadias (E), classical exstrophy of the bladder (CBE) or cloacal exstrophy (CE), with male to female ratios of 1.4, 2.8, and 2.0, respectively. No association with parental age, maternal reproductive history or with periconceptional maternal exposure to alcohol, drugs, chemical noxa, radiation or infections was found. However, periconceptional maternal exposure to smoking (p 0.009) was significantly more common for CE patients than for the combined group of E/CBE patients. Only 16.8% of mothers followed the current recommendations *Correspondence to: Michael Ludwig, Ph.D., Dept. of Clinical Biochemistry and Clinical Pharmacology, University of Bonn, SigmundFreud-Str. 25, D-53105 Bonn, Germany. E-mail: E-mail: mludwig@uni-bonn.de. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of periconceptional folic acid supplementation. 17.6% had started supplementation before the 10 th week of gestation. Interestingly, in the latter group, mothers of CE patients were more compliant (p 0.037) than mothers of the combined group of E/CBE patients. Furthermore, mothers of CE children knew significantly more often prenatally that their child would have a congenital malformation (p < 0.0001) than mothers of E/CBE children.Conclusions-Our study corroborates the hypothesis that E, CBE and CE 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 urinary bladders with focus on neural tube defects.

Objective To identify genetic and non-genetic risk factors contributing 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. Patients were divided into three subgroups according to phenotype severity: (i) mild - epispadias (E, n=43); (ii) intermediate - classic bladder exstrophy (CBE, n=366); and (iii) severe - cloacal exstrophy (CE, n=31). These subgroups were then compared to identify factors which 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 CE phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (E). Conclusions Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC.

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