Congenital anal atresia with rectovestibular fistula, scoliosis, unilateral renal agenesis, and finger defect (VACTERL association) in a patient with partial bicornuate uterus and distal vaginal atresia: A case report.

RATIONALE: Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect (VACTERL) association and Müllerian duct anomalies are rare conditions. We present a rare condition with the co-occurrence of the VACTERL association and Müllerian duct hypoplasia to characterize patients' clinical presentations, outcomes, and treatment. PATIENT CONCERNS: An 11-year-old girl presented to our hospital with severe lower abdominal pain, lower vaginal atresia with enlargement of the upper vagina and a bicornuate uterus with a Y-shaped uterine cavity filled with hematometra on pelvic magnetic resonance imaging. Her medical history included congenital anal atresia with a rectovestibular fistula, congenital right renal deficiency, congenital right thumb malformation, and scoliosis. DIAGNOSES: 1. Congenital genital tract malformations, a partial bicornuate uterus, and distal vaginal atresia (U3aC0V4); 2. VACTERL association (congenital anal atresia with rectovestibular fistula, scoliosis with hemi vertebra and butterfly vertebra, unilateral renal agenesis, and finger defect). INTERVENTIONS: Colpotomy, laparoscopic exploration, pelvic adhesiolysis, and hysteroscopy were performed. OUTCOMES: Two months after surgery, a pelvic examination showed an unobstructed vagina which was 10 cm long and 2 fingers wide, without adhesion or constriction. LESSONS: Clinicians should have a high index of suspicion when evaluating patients with genital malformations associated with VACTERL. Early diagnosis of distal vaginal atresia with appropriate surgical intervention decreases long-term morbidity.

Complexities of Müllerian Anatomy in 46XX Cloacal Exstrophy Patients.

STUDY OBJECTIVE: To characterize Müllerian anatomy in 46,XX cloacal exstrophy patients. DESIGN: Retrospective review of prospectively maintained, institutionally approved exstrophy-epispadias-cloacal exstrophy database. SETTING: Tertiary care, high-volume exstrophy center (Division of Pediatric Urology, The Johns Hopkins Hospital, Baltimore, Maryland). PARTICIPANTS: We included 31 patients who were genetically female with cloacal exstrophy for whom records included detailed evaluation of Müllerian anatomy. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Müllerian structures, method of evaluation, management, and sexual activity. RESULTS: Of our patients, 12.9% (3/31) had no identified abnormalities. Vaginal anatomy was described for 30 patients; 3/30 had vaginal agenesis, 14/30 had a single vagina, and 13/30 had vaginal duplication. Of 14 patients with 1 vagina, 5 had atresia/hypoplasia, and 1 had a lateral displacement. One patient with 2 vaginas also had distal atresia. Of the cervices evaluated, 9/14 were duplicated (2/9 with a solitary vagina), and 19/27 of the uteri were duplicated (6/22 with 1 vagina, 1/22 with no vagina). Five patients required imaging to fully characterize their anatomy, and 7 patients had studies that failed to identify Müllerian structures seen in the operating room or on physical examination. Common reconstructive surgeries included vaginoplasties, incisions of vaginal septa, colporrhaphies, and hysterectomies. Sexual activity was confirmed for 3 patients, 2 of whom had conceived. CONCLUSION: Most female cloacal exstrophy patients exhibit abnormalities of the Müllerian system. Axial imaging and ultrasound are helpful diagnostic adjuncts but do not replace careful physical examination and assessment in the operating room. Further studies of sexual activity and fertility are warranted.

Parental subfertility, fertility treatment, and the risk of congenital anorectal malformations.

BACKGROUND: Fertility treatment seems to play a role in the etiology of congenital anorectal malformations, but it is unclear whether the underlying parental subfertility, ovulation induction, or the treatment itself is involved. Therefore, we investigated the odds of anorectal malformations among children of subfertile parents who conceived with or without treatment compared with fertile parents. METHODS: We performed a case-control study among 380 cases with anorectal malformations treated at 3 departments of pediatric surgery in The Netherlands and 1973 population-based controls born between August 1988 and August 2012. Parental questionnaires were used to obtain information on fertility-related issues and potential confounders. RESULTS: In singletons, increased risks of anorectal malformations were observed for parents who underwent intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment compared with fertile parents (odds ratio = 2.4 [95% confidence interval = 1.0-5.9] and 4.2 [1.9-8.9], respectively). For subfertile parents who conceived after IVF treatment, an elevated risk was also found when they were compared with subfertile parents who conceived without treatment (3.2 [1.4-7.2]). Among children of the latter category of parents, only the risk of anorectal malformations with other major congenital malformations was increased compared with fertile parents (2.0 [1.3-3.3]). No associations were found with intrauterine insemination or use of hormones for ovulation induction. CONCLUSIONS: We found evidence of a role of ICSI and IVF treatments in the etiology of anorectal malformations. However, subfertility without treatment increased only the risk of anorectal malformations with additional congenital malformations.

The effect of vitamin A deficiency during pregnancy on anorectal malformations.

OBJECTIVE: The aim of this study was to study the effect of vitamin A deficiency (VAD) on the embryological development of anorectal malformations (ARMs) and the enteric nervous system. MATERIALS AND METHODS: Female Sprague-Dawley rats were divided into 3 groups: VAD group, normal group (negative control), and ethylene thiourea (ETU) group (positive control) with a normal diet. On day 20 of pregnancy, cesarean section was performed on all rats. The incidence of ARMs in the fetal rats and Protein gene product 9.5 (PGP9.5) and S-100 protein expression by immunohistochemistry were determined. RESULTS: The incidence of ARMs in VAD and ETU groups was 64.8% (59/91) and 45.9% (61/133), respectively (P > .05). Anorectal malformations were not found in the normal group. Protein gene product 9.5 and S-100 protein expression in the non-ARM rectums of the VAD group was lower than the ETU (P = .0156 vs P = .0105) and normal groups (P = .0091 vs P = .0024). There was no significant difference in PGP9.5 and S-100 protein expression between ETU and normal groups. In the ARM rectums, PGP9.5 and S-100 protein expression in the VAD group was lower than the ETU group (P < .0001). Protein gene product 9.5 and S-100 protein expression was also lower in ARM than non-ARM rectums in the VAD and ETU groups (P < .0001, P = .0203, and P = .0122, respectively). CONCLUSION: Vitamin A deficiency during pregnancy may result in the embryological development of ARMs. Enteric nervous system development may be related to ARMs.

Parental risk factors and anorectal malformations: systematic review and meta-analysis.

BACKGROUND: Anorectal malformations (ARM) are rare forms of congenital uro-rectal anomalies with largely unknown causes. Besides genetic factors, prenatal exposures of the parents to nicotine, alcohol, caffeine, illicit drugs, occupational hazards, overweight/obesity and diabetes mellitus are suspected as environmental risk factors. METHODS: Relevant studies published until August 2010 were identified through systematic search in PubMed, EMBASE, ISI Web of Knowledge and the Cochrane Library databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal and paternal smoking, maternal alcohol consumption, underweight (body mass index [BMI] < 18.5), overweight (BMI 25-29.9), obesity (BMI ≥30) and maternal diabetes mellitus with ARM using meta-analyses. RESULTS: 22 studies that reported on the association between prenatal environmental risk factors and infants born with ARM were included in this review. These were conducted in the United States of America (n = 12), Spain (n = 2), Sweden (n = 2), the Netherlands (n = 2), Japan (n = 1), France (n = 1), Germany (n = 1) and Hungary (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, control types and adjustment for covariates. Consistently increased risks were observed for paternal smoking and maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption. In meta-analyses, pooled odds ratios (95% confidence intervals) for paternal smoking, maternal overweight, obesity, pre-gestational and gestational diabetes were 1.53 (1.04-2.26), 1.25 (1.07-1.47), 1.64 (1.35-2.00), 4.51 (2.55-7.97) and 1.81 (1.23-2.65), respectively. CONCLUSION: Evidence on risk factors for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate paternal smoking and maternal overweight, obesity and diabetes to be associated with increased risks. Further, ideally large-scale multicentre and register-based studies are needed to clarify the role of key risk factors for the development of ARM.

[Surgical treatment for cicatrix strictures of anal canal].

Classification of anal canal strictures with gradation of intensity, extent and localization is proposed. In 12 patients with compensated strictures combination of stenosis and anal fissure served as an indication for operation. These patients underwent fissure excision with dosed sphincterotomy. Anoplasty with displacement of island skin flaps to anal canal defects was carried out to 29 patients with sub-or decompensated strictures after dissection of scarry stricture. Good direct results were achieved in 38 patients. Compensated re-stenosis treated conservatively was observed in 3 patients after anoplasty. It is drawn a conclusion about necessity of differential approach to choice of treatment mode for anal scarry strictures. Anoplasty according to proposed method is considered to be optimal for marked strictures.

Maternal and paternal risk factors for anorectal malformations: a Dutch case-control study.

BACKGROUND: Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS: In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS: A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS: This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well.

Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia: National Birth Defects Prevention Study 1997-2003.

.Anorectal atresia is a congenital anomaly with mostly unknown risk factors. Studies have provided evidence of teratogenic effects of alcohol and tobacco, and animal studies have suggested that caffeine may potentiate their teratogenicity. However, it is unclear how these factors affect the risk of anorectal atresia. We analysed data from maternal telephone interviews in a multistate case-control study with 464 infants with anorectal atresia and 4940 infants with no major birth defects. We used unconditional logistic regression to determine the association of exposure to smoking, environmental tobacco smoke (ETS), alcohol or caffeine with anorectal atresia. Effect modification by caffeine intake was assessed on additive and multiplicative scales. There was no association with alcohol intake in this analysis. However, there was some evidence of an association between anorectal atresia and maternal exposure to tobacco smoke and caffeine. Compared with non-smokers not exposed to ETS, the crude odds ratio (OR) and 95% confidence interval [CI] for cigarette smoking was 1.2 [95% CI 1.0, 1.5]. The association with anorectal atresia for non-smokers exposed to ETS at home and work was OR = 2.3 [95% CI 1.2, 4.1]. Compared with the lowest level of caffeine intake (<10 mg/day), the association for the highest caffeine intake (> or =300 mg/day) was OR = 1.5 [95% CI 1.0, 2.2]. Results did not change after adjustment for covariates. This study found evidence of associations between anorectal atresia and caffeine intake, cigarette smoking and exposure to ETS. Because there are currently few additional data to support these results, further study is needed.

Combined effects of cigarette smoking and alcohol consumption on perinatal outcome.

BACKGROUND: An increase in various congenital abnormalities associated with cigarette smoking and the use of alcohol during pregnancy has been reported in many studies. These exposures also increase the risk of pregnancy complications such as abruptio placentae, unexplained stillbirth, preterm labor and intrauterine growth restriction. However, very few studies have addressed the combined effect of smoking and drinking on pregnancy outcomes. METHODS: In this review, the adverse effects of smoking or drinking on pregnancy were obtained from publications in which both substances were addressed in the same study population. A special effort was made to find studies in which the combined effect of these substances was investigated. RESULTS: Preterm labor occurred more frequently in women who drank and smoked during pregnancy. This increased odds ratio was more than the sum of the effects of either smoking or drinking, indicating that the use of both substances by the same woman has a synergistic effect that increases the risk of preterm labor. This synergistic effect was also found for low birth weight and growth restriction. CONCLUSIONS: As most of the women who drink during pregnancy also smoke cigarettes, attention should be given to the prevention or reduced use of both substances during pregnancy.

Single umbilical artery and the VATER-animal model.

BACKGROUND/PURPOSE: Vascular disruption is recognized as a cause of congenital malformations. The authors analyzed the significance of single umbilical artery (SUA) in the Adriamycin-animal model to find out if it was associated with organ malformations. METHODS: Pregnant SD rats were injected with Adriamycin intraperitoneally at a dose of 2 mg/kg on days 6 through 9 of gestation. Serial transverse sections of full-term fetuses were analyzed by light microscopy. Embryos also were removed on different gestational days during organogenesis, and serial transverse histologic sections were examined and compared with suitable controls. RESULTS: In experimental embryos (n = 47), presence of a SUA resulted from either persistence of the primitive umbilical arteries that joined each other ventral to the hind gut to give rise to one umbilical artery or from secondary atrophy of one of the definitive umbilical arteries. Malformations such as intestinal atresia were associated with anomalous fusion between the dorsal aorta and the persistent primitive umbilical arteries. CONCLUSIONS: SUA is a prominent feature of the Adriamycin-animal model. No obvious association was found between malformations and SUA that resulted from atrophy of one of the definitive umbilical arteries; however, it was associated with anomalies such as intestinal atresia when it resulted from persistence of the primitive umbilical arteries.

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) in triplet pregnancy after IVF and CVS.

BACKGROUND: Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a rare sporadic condition. CASE: We identified an infant with major malformations resembling OEIS. He was the product of a 30-week triplet pregnancy conceived by in vitro fertilization (IVF) and evaluated by chorionic villi sampling (CVS). In this article, we review the possible pathogenetic mechanisms in this case, including IVF, multiple gestation, trauma to the uterus or uterine vessels following CVS, and placenta accreta. CONCLUSIONS: We conclude that the cumulative effects of all or some of these factors may have resulted in uteroplacental insufficiency adequate to produce this phenotype. This case provides additional evidence for the uterine vascular pathogenesis of OEIS complex in humans.

Reoperative surgery for anorectal anomalies.

Complications occur during the repair of anorectal malformations relatively frequently. Unfortunately, these complications are often preventable. Furthermore, the consequences of these complications are significant. Not only do patients experience unnecessary pain and suffering, but a secondary operation always renders less optimal functional results. A 20-year experience in the care of children with anorectal malformations was retrospectively analyzed. Patients who previously underwent surgical repair at other institutions, and subsequently required secondary surgery by the primary author were evaluated; 334 patients were identified. Reasons for reoperation included fecal incontinence in 77 patients; dehiscence and retraction in 96; recto-genito-urinary fistulae in 55; persistent urogenital sinus in 31 cloaca patients; acquired vaginal atresia in 21; acquired urethral atresia in 9; posterior urethral diverticulum in 20; and overflow pseudo incontinence in 25 patients. Except for fecal incontinence, all other complications are considered preventable. The source of the complications in almost all other settings are technical errors at the time of the primary repair. Recommendations are presented to help prevent these complications, and suggestions are made on how to treat them when they occur.

Renal anomalies in the VATER animal model.

BACKGROUND PURPOSE: Renal anomalies are a prominent feature of the VATER association. Administration of Adriamycin to timed-pregnant rats resulted in a spectrum of anomalies similar to the human VATER association. The aim of this study is to describe the renal anomalies in the Adriamycin animal model. METHODS: Timed-pregnant Sprague-Dawley rats were injected with Adriamycin intraperitoneally at a dose of 2 mg/kg on days 6 through 9 of gestation. Full-term fetuses were fixed in Bouin's solution and serial transverse sections were analyzed by light microscopy. All specimens were compared with suitable controls. RESULTS: In experimental animals, renal anomalies were found in 98% of the examined fetuses. Bilateral hydroureteronephrosis with kinking of the ureters was obvious. Ureteric atresia led to obstructive uropathy. Bladder agenesis occurred in all experimental animals. Mesonephric ducts were seen joining a proximally blind-ending urethra in male animals. In females both paramesonephric ducts ended blindly after joining each other, and this resulted in vaginal atresia. In association with imperforate anus, a recto-urethral and a recto-urogenital fistula was seen in male and female fetuses, respectively. CONCLUSIONS: Bladder agenesis was an important feature in the Adriamycin animal model. Bilateral hydronephrosis resulted from blind-ending ureters.

OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases.

OEIS complex refers to a combination of defects consisting of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. Possible embryologic mechanisms proposed for these findings have included: a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. Fourteen cases with OEIS complex and related malformations were reviewed for demographic features, prenatal and family histories, and clinical, radiological and pathological findings including the frequency and types of associated anomalies. The pathogenetic mechanisms causing OEIS complex and related malformations, such as anorectal and spinal defects, are discussed. The findings in these cases illustrate the spectrum of defects that can occur in the embryologic development of the cloaca and the urorectal septum. Differences in the timing and extent of mesenchymal ingrowth as well as cloacal membrane rupture may account for these variable findings. A developmental field defect involving the intraembryonic mesoderm suggests a possible etiologic role for homeobox genes, such as HLXB9 with mutations, resulting in anorectal and spine abnormalities, or retinoic acid receptors. OEIS complex with its mostly sporadic occurrence suggests etiologic heterogeneity with a possible role for environmental and genetic causes.

Anal atresia: effect of smoking and drinking habits during pregnancy.

Using data compiled from 216,707 births from the population-based Kanagawa Birth Defects Monitoring Program (KAMP), we conducted a case-control study to evaluate the effect of maternal smoking and/or drinking during pregnancy on the risk of infants' anal atresia in 1989-1994. The frequency of maternal smoking (including passive smoking) and/or maternal drinking during pregnancy among 84 infants with anal atresia was compared with 174 matched controls. The 84 anal atresias include 49 cases of isolated anal atresia and 35 cases of syndromal anal atresia. Our findings suggest that maternal drinking during early pregnancy is associated with an increased risk of isolated anal atresia (OR = 4.8, 95% CI 1.2 to 19.1, p < 0.05). A slightly increased trend was also observed in the association of maternal smoking during pregnancy with both in the pooled groups of anal atresia (OR = 1.4, 95% CI 0.5 to 3.6).

Anal agenesis associated with rectal atresia.

The authors report an unusual case of anal agenesis associated with rectal atresia. Such an anomaly has been reported only once before. Coincidentally, this patient also had a rarely encountered skeletal anomaly--unilateral cleft foot.