RESUMO
BACKGROUND: Vesico-ureteral reflux (VUR) is a common associated urological anomaly in anorectal malformation (ARM)-patients. High-grade VUR requires antibiotic prophylaxis to prevent urinary tract infections (UTI's), renal scarring and -failure. The exact prevalence of high-grade VUR in ARM patients is unknown. Hence, the aim of this study was determining the incidence of high-grade VUR in ARM-patients, and its associated risk factors. METHODS: A multicenter retrospective cohort study was performed using the ARM-Net registry, including data from 34 centers. Patient characteristics, screening for and presence of renal anomalies and VUR, sacral and spinal anomalies, and sacral ratio were registered. Phenotypes of ARM were grouped according to their complexity in complex and less complex. Multivariable analyses were performed to detect independent risk factors for high-grade (grade III-V) VUR. RESULTS: This study included 2502 patients (50 % female). Renal screening was performed in 2250 patients (90 %), of whom 648 (29 %) had a renal anomaly documented. VUR-screening was performed in 789 patients (32 %), establishing high-grade VUR in 150 (19 %). In patients with a normal renal screening, high-grade VUR was still present in 10 % of patients. Independent risk factors for presence of high-grade VUR were a complex ARM (OR 2.6, 95 %CI 1.6-4.3), and any renal anomaly (OR 3.3, 95 %CI 2.1-5.3). CONCLUSIONS: Although renal screening is performed in the vast majority of patients, only 32 % underwent VUR-screening. Complex ARM and any renal anomaly were independent risk factors for high-grade VUR. Remarkably, 10 % had high-grade VUR despite normal renal screening. Therefore, VUR-screening seems indicated in all ARM patients regardless of renal screening results, to prevent sequelae such as UTI's, renal scarring and ultimately renal failure. TYPE OF STUDY: Observational Cohort-Study. LEVEL OF EVIDENCE: III.
Assuntos
Malformações Anorretais , Sistema de Registros , Refluxo Vesicoureteral , Humanos , Refluxo Vesicoureteral/complicações , Refluxo Vesicoureteral/epidemiologia , Refluxo Vesicoureteral/diagnóstico , Feminino , Masculino , Estudos Retrospectivos , Malformações Anorretais/epidemiologia , Malformações Anorretais/complicações , Malformações Anorretais/diagnóstico , Recém-Nascido , Fatores de Risco , Incidência , Lactente , Anormalidades Múltiplas/epidemiologiaRESUMO
STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: In women with a septate uterus, septum resection does not increase live birth rate nor does it decrease the rates of pregnancy loss or preterm birth, compared with expectant management. WHAT IS KNOWN ALREADY: The septate uterus is the most common uterine anomaly with an estimated prevalence of 0.2-2.3% in women of reproductive age, depending on the classification system. The definition of the septate uterus has been a long-lasting and ongoing subject of debate, and currently two classification systems are used worldwide. Women with a septate uterus may be at increased risk of subfertility, pregnancy loss, preterm birth and foetal malpresentation. Based on low quality evidence, current guidelines recommend removal of the intrauterine septum or, more cautiously, state that the procedure should be evaluated in future studies. STUDY DESIGN, SIZE, DURATION: We performed an international multicentre cohort study in which we identified women mainly retrospectively by searching in electronic patient files, medical records and databases within the time frame of January 2000 until August 2018. Searching of the databases, files and records took place between January 2016 and July 2018. By doing so, we collected data on 257 women with a septate uterus in 21 centres in the Netherlands, USA and UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women with a septate uterus, defined by the treating physician, according to the classification system at that time. The women were ascertained among those with a history of subfertility, pregnancy loss, preterm birth or foetal malpresentation or during a routine diagnostic procedure. Allocation to septum resection or expectant management was dependent on the reproductive history and severity of the disease. We excluded women who did not have a wish to conceive at time of diagnosis. The primary outcome was live birth. Secondary outcomes included pregnancy loss, preterm birth and foetal malpresentation. All conceptions during follow-up were registered but for the comparative analyses, only the first live birth or ongoing pregnancy was included. To evaluate differences in live birth and ongoing pregnancy, we used Cox proportional regression to calculate hazard rates (HRs) and 95% CI. To evaluate differences in pregnancy loss, preterm birth and foetal malpresentation, we used logistic regression to calculate odds ratios (OR) with corresponding 95% CI. We adjusted all reproductive outcomes for possible confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 257 women were included in the cohort. Of these, 151 women underwent a septum resection and 106 women had expectant management. The median follow-up time was 46 months. During this time, live birth occurred in 80 women following a septum resection (53.0%) compared to 76 women following expectant management (71.7%) (HR 0.71 95% CI 0.49-1.02) and ongoing pregnancy occurred in 89 women who underwent septum resection (58.9%), compared to 80 women who had expectant management (75.5%) (HR 0.74 (95% CI 0.52-1.06)). Pregnancy loss occurred in 51 women who underwent septum resection (46.8%) versus 31 women who had expectant management (34.4%) (OR 1.58 (0.81-3.09)), while preterm birth occurred in 26 women who underwent septum resection (29.2%) versus 13 women who had expectant management (16.7%) (OR 1.26 (95% CI 0.52-3.04)) and foetal malpresentation occurred in 17 women who underwent septum resection (19.1%) versus 27 women who had expectant management (34.6%) (OR 0.56 (95% CI 0.24-1.33)). LIMITATIONS, REASONS FOR CAUTION: Our retrospective study has a less robust design compared with a randomized controlled trial. Over the years, the ideas about the definition of the septate uterus has changed, but since the 257 women with a septate uterus included in this study had been diagnosed by their treating physician according to the leading classification system at that time, the data of this study reflect the daily practice of recent decades. Despite correcting for the most relevant patient characteristics, our estimates might not be free of residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that septum resection, a procedure that is widely offered and associated with financial costs for society, healthcare systems or individuals, does not lead to improved reproductive outcomes compared to expectant management for women with a septate uterus. The results of this study need to be confirmed in randomized clinical trials. STUDY FUNDING/COMPETING INTEREST(S): A travel for JFWR to Chicago was supported by the Jo Kolk Studyfund. Otherwise, no specific funding was received for this study. The Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, received an unrestricted educational grant from Ferring Pharmaceutical Company unrelated to the present study. BWM reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, other payment from Guerbet and grants from Merck, outside the submitted work. The other authors declare no conficts of interest. TRIAL REGISTRATION NUMBER: N/A.
Assuntos
Nascimento Prematuro , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Países Baixos , Gravidez , Nascimento Prematuro/epidemiologia , Estudos Retrospectivos , Útero/diagnóstico por imagem , Útero/cirurgiaRESUMO
BACKGROUND: The impact of perioperative care interventions on postreconstructive complications and short-term colorectal outcome in patients with anorectal malformation (ARM) type rectovestibular fistula is unknown. METHODS: An ARM-Net consortium multicenter retrospective cohort study was performed including 165 patients with a rectovestibular fistula. Patient characteristics, perioperative care interventions, timing of reconstruction, postreconstructive complications and the colorectal outcome at one year of follow-up were registered. RESULTS: Overall complications were seen in 26.8% of the patients, of which 41% were regarded major. Differences in presence of enterostomy, timing of reconstruction, mechanical bowel preparation, antibiotic prophylaxis and postoperative feeding regimen had no impact on the occurrence of overall complications. However, mechanical bowel preparation, antibiotic prophylaxis ≥48â¯h and postoperative nil by mouth showed a significant reduction in major complications. The lowest rate of major complications was found in the group having these three interventions combined (5.9%). Multivariate analyses did not show independent significant results of any of the perioperative care interventions owing to center-specific combinations. At one year follow-up, half of the patients experienced constipation and this was significantly higher among those with preoperative mechanical bowel preparation. CONCLUSIONS: Differences in perioperative care interventions do not seem to impact the incidence of overall complications in a large cohort of European rectovestibular fistula-patients. Mechanical bowel preparation, antibiotic prophylaxis ≥48â¯h, and postoperative nil by mouth showed the least major complications. Independency could not be established owing to center-specific combinations of interventions. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.
Assuntos
Malformações Anorretais/cirurgia , Assistência Perioperatória , Complicações Pós-Operatórias/epidemiologia , Fístula Retal/cirurgia , Antibioticoprofilaxia , Humanos , Assistência Perioperatória/métodos , Assistência Perioperatória/estatística & dados numéricos , Estudos RetrospectivosRESUMO
In order to study whether ovarian reserve tests (ORTs) can predict time to ongoing pregnancy, we conducted a prospective cohort study in a cohort of healthy pregnancy planners. A total of 102 pregnancy planners were followed for 1 year, or until ongoing pregnancy occurred, after cessation of contraceptives). A baseline measurement of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH) and antral follicle count (AFC) was conducted. At the end of follow-up, a semen analysis was performed and chlamydia antibody titres were assessed. A univariate prediction model demonstrated age and the AFC to be significantly capable of predicting time to pregnancy (hazard ratio 0.92, 95% CI 0.87-0.98, p = 0.01; 1.04, 95% CI 1.01-1.07, p = 0.02 respectively). In the multivariate model, however, correcting for female age, we found no predictive effect of AMH, basal FSH or the AFC for time to ongoing pregnancy (hazard ratios 1.43, 95% CI 0.84-2.46, p = 0.36; 0.96, 95% CI 0.86-1.06, p = 0.43; 1.03, 95% CI 1.00-1.07, p = 0.08, respectively). This was confirmed by the low C-statistic. We therefore concluded that baseline AMH, AFC or FSH levels do not predict time to ongoing pregnancy in a cohort of healthy pregnancy planners. These results limit the usability of these ORTs in the assessment of current fertility.
Assuntos
Hormônio Antimülleriano/sangue , Fertilidade , Reserva Ovariana , Tempo para Engravidar , Centros Médicos Acadêmicos , Adulto , Estudos de Coortes , Características da Família , Feminino , Hormônio Foliculoestimulante/sangue , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Países Baixos , Ovário/diagnóstico por imagem , Gravidez , Modelos de Riscos Proporcionais , Estudos Prospectivos , UltrassonografiaRESUMO
Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Anormalidades Múltiplas/genética , Cistos/genética , Predisposição Genética para Doença/genética , Humanos , Lábio/anormalidades , Mutação/genética , Mutação de Sentido Incorreto/genética , Análise de Sequência de DNARESUMO
STUDY QUESTION: Do ovarian reserve tests (ORTs) predict age at natural menopause (ANM) in a cohort of healthy women with a regular menstrual cycle? SUMMARY ANSWER: Of the ORTs researched, anti-Müllerian hormone (AMH) alone predicts age at menopause. However, its predictive value decreased with increasing age of the woman, prediction intervals were broad and extreme ages at menopause could not be predicted. WHAT IS KNOWN ALREADY: A fixed interval is hypothesized to exist between ANM and age at loss of natural fertility. Therefore, if it is possible to predict ANM, one could identify women destined for early menopause and thus at higher risk for age-related subfertility. Of ORTs researched in the prediction of ANM, AMH is the most promising one. STUDY DESIGN, STUDY SIZE AND DURATION: A long-term, extended follow-up study was conducted, results of the first follow-up round were previously published. Two hundred and sixty-five normo-ovulatory women (21-46 years) were included between 1992 and 2001, 49 women (18.5%) could not be reached in the current follow-up round. PARTICIPANTS, SETTING, METHODS: Two hundred and sixty-five healthy normo-ovulatory women were included, recruited in an Academic hospital. We measured baseline AMH, follicle-stimulating hormone and the antral follicle count (AFC). At follow-up (2009 and 2013), menopausal status was determined via questionnaires. Cox regression analysis calculated time to menopause (TTM) using age and ORT. A check of (non-) proportionality of the predictive effect of AMH was performed. A Weibull survival model was used in order to predict individual ANM. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 155 women were available for analyses. Eighty-one women (37.5%) had become post-menopausal during follow-up. Univariable Cox regression analysis demonstrated age and ORTs to be significantly correlated with TTM. Multivariable Cox regression analysis, adjusting for baseline age and smoking; however, demonstrated AMH alone to be an independent predictor of TTM (Hazard Ratio 0.70, 95% Confidence Interval 0.56-0.86, P-value <0.001). A (non-)proportionality analysis of AMH over time demonstrated AMH's predictive effect to decline over time. LIMITATIONS, REASON FOR CAUTION: The observed predictive effect of AMH became less strong with increasing age of the woman. Individual AMH-based age at menopause predictions did not cover the full range of menopausal ages, but did reduce the variation around the predicted ANM from 20 to 10.1 years. WIDER IMPLICATIONS OF THE FINDINGS: Age-specific AMH levels are predictive for ANM. Unlike in our previous publication however, a declining AMH effect with increasing age was observed. This declining AMH effect is in line with recent long-term follow-up data published by others. Moreover, the accompanying predictive inaccuracy observed in individual age at menopause predictions based on AMH, makes this marker currently unsuitable for use in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No external funds were used for this study. M.D., M.J.C.E, S.L.B., G.J.S. and I.A.J.R. have nothing to declare. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, MSD, Organon, Serono and Schering Plough. F.J.M.B. receives monetary compensation: member of the external advisory board for Merck Serono, the Netherlands; consultancy work for Gedeon Richter, Belgium; educational activities for Ferring BV, the Netherlands; strategic cooperation with Roche on automated AMH assay development.
Assuntos
Hormônio Antimülleriano/sangue , Menopausa/sangue , Reserva Ovariana , Adulto , Fatores Etários , Feminino , Seguimentos , Humanos , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos ProspectivosRESUMO
PURPOSE: Outcomes of patients with an ARM-type rectovesical fistula are scarcely reported in medical literature. This study evaluates associated congenital anomalies and long-term colorectal and urological outcome in this group of ARM-patients. METHODS: A retrospective Dutch cohort study on patients treated between 1983 and 2014 was performed. Associated congenital anomalies were documented, and colorectal and urological outcome recorded at five and ten years of follow-up. RESULTS: Eighteen patients were included, with a mean follow-up of 10.8years. Associated congenital anomalies were observed in 89% of the patients, 61% considered a VACTERL-association. Total sacral agenesis was present in 17% of our patients. At five and ten years follow-up voluntary bowel movements were described in 80% and 50%, constipation in 80% and 87%, and soiling in 42% and 63% of the patients, respectively. Bowel management was needed in 90% and one patient had a definitive colostomy. PSARP was the surgical reconstructive procedure in 83%. Urological outcome showed 14 patients (81%) to be continent. No kidney transplantations were needed. CONCLUSION: In our national cohort of ARM-patients type rectovesical fistula that included a significant proportion of patients with major sacral anomalies, the vast majority remained reliant on bowel management to be clean after ten years follow-up, despite "modern" PSARP-repair. Continence for urine is achieved in the majority of patients, and end-stage kidney failure is rare.
Assuntos
Malformações Anorretais/cirurgia , Colostomia , Fístula Retal/cirurgia , Fístula da Bexiga Urinária/cirurgia , Anormalidades Múltiplas/cirurgia , Canal Anal/anormalidades , Anus Imperfurado/cirurgia , Pré-Escolar , Constipação Intestinal/etiologia , Defecação , Esôfago/anormalidades , Feminino , Seguimentos , Cardiopatias Congênitas , Humanos , Rim/anormalidades , Deformidades Congênitas dos Membros , Masculino , Países Baixos , Complicações Pós-Operatórias , Estudos Retrospectivos , Coluna Vertebral/anormalidades , Traqueia/anormalidadesRESUMO
BACKGROUND: Pediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process. METHODS: Relevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted. RESULTS: European legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe. CONCLUSIONS: Establishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.
Assuntos
Canal Anal/anormalidades , Anus Imperfurado/cirurgia , Instalações de Saúde/normas , Reto/anormalidades , Canal Anal/cirurgia , Malformações Anorretais , União Europeia , Humanos , Qualidade da Assistência à Saúde , Reto/cirurgiaRESUMO
The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup.
Assuntos
Anus Imperfurado/diagnóstico , Anus Imperfurado/cirurgia , Anormalidades Múltiplas/cirurgia , Malformações Anorretais , Anus Imperfurado/classificação , Europa (Continente) , Feminino , Humanos , Recém-Nascido , Masculino , Procedimentos de Cirurgia Plástica/normas , Fístula Retal/cirurgiaRESUMO
PURPOSE: This systematic review aims to give an overview of available evidence concerning the influence of anorectal malformations (ARM) on fertility. METHODS: We conducted a search in PubMed, EMBASE and Cochrane Library conformed to the PRISMA standards. All studies reporting on fertility and ARM were included. RESULTS: 2,905 studies were identified. Based on title, abstract and full text, nine articles on 429 patients remained to answer the research question. Childbirth rate was the only reported outcome parameter to describe fertility. An overall childbirth rate of 27 % (range 0-57 %) was found. Mean age at time of study ranged from 23 to 35 years. There was no statistical significant difference in childbirth rate between female and male patients, based on seven studies (p = 0.45). Patients with a more complex type of ARM (imperforated anus without fistula, rectourethral bulbar and prostatic fistulas, rectobladderneck fistulas and cloacal malformations) had a lower childbirth rate compared to healthy controls, whereas in patients with a less complex ARM (rectoperineal or rectovestibular fistula) the childbirth rate was similar to healthy controls. Patients with a more complex type of ARM had a significant lower childbirth rate than patients with a less complex type of ARM (18 vs 47 %, respectively) (p = 0.0001). When further dividing these patients by gender, this difference was only seen in female patients (p = 0.04). CONCLUSION: In patients with a more complex type of ARM a lower childbirth rate was found compared to healthy controls and patients with a less complex type of ARM. The latter was only seen in female patients. However, conclusions concerning fertility in ARM patients have to be taken with caution due to limited quality of the studies. Further investigation is recommended.
Assuntos
Canal Anal/anormalidades , Anus Imperfurado/complicações , Fertilidade , Infertilidade/etiologia , Reto/anormalidades , Malformações Anorretais , Anus Imperfurado/epidemiologia , Feminino , Saúde Global , Humanos , Incidência , Infertilidade/epidemiologia , Masculino , Prevalência , Fatores de RiscoRESUMO
STUDY QUESTION: In the prediction of time to menopause (TTM), what is the added value of anti-Müllerian hormone (AMH) when mother's age at natural menopause (ANM) is also known? SUMMARY ANSWER: AMH is a more accurate predictor of individual TTM than mother's age at menopause. WHAT IS KNOWN ALREADY: Mother's ANM is considered a proxy for daughter's ANM although studies on its predictive accuracy are non-existent. AMH is a biomarker with a known capacity to predict ANM. However, its added value on top of known predictors, like mother's ANM, is unknown. STUDY DESIGN, SIZE, DURATION: Population-based cohort studies were used. To assess any additive predictive value of mother's ANM, 164 mother-daughter pairs were used (Group 1). To assess the added value of AMH, a second group of 150 women in whom AMH and mother's ANM were recorded prior to a 12-year follow-up period during which daughter's ANM was assessed was used (Group 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Group 1 consisted of participants of the DOM cohort (an ongoing breast cancer study). Group 2 was a pooled cohort of women with regular menstrual cycles from two independent published studies. Cox proportional hazards analysis estimated uni- and multivariate regression coefficients for female age at study entry, mother's ANM and AMH in the prediction of TTM. Discrimination of models was assessed with C-statistics. Clinical added value of AMH was quantified with a net reclassification index (NRI). MAIN RESULTS AND THE ROLE OF CHANCE: A model with female age and mother's ANM had a c-statistic of 79 and 85% in groups 1 and 2, respectively. Both age and mother's ANM were significantly associated with TTM (HR 1.54 and HR 0.93 for age and mother's ANM in Cohort 1 and HR 1.59 and HR 0.89 in Group 2, respectively. P-value for all <0.001). In Group 2, the multivariate model with age, mother's ANM and AMH had a c-statistic of 92%, and only female age and AMH remained significantly associated with TTM (HR 1.41 P < 0.0001; HR 0.93 P = 0.08 and HR 0.06 P < 0.0001 for age, mother's ANM and AMH, respectively). The mean weighted NRI suggests that a 47% improvement in predictive accuracy is offered by adding AMH to the model of age and mother's ANM. In conclusion, AMH and mother's ANM both have added value in forecasting TTM for the daughter based on her age. In comparison, AMH is a more accurate added predictor of TTM than mother's ANM. LIMITATIONS, REASONS FOR CAUTION: The cohort of women is relatively small and different cohorts of women were pooled. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that AMH is a more accurate predictor of ANM than mother's ANM. However, before achieving clinical applicability, the certainty with which a woman's prediction is made must improve. The association between mother's ANM and TTM in daughters did not appear to be influenced by whether ANM was recorded by mothers or daughters--an important finding because in the clinical setting daughters usually provide this information. STUDY FUNDING/COMPETING INTEREST(S): No funding was received and there were no competing interests in direct relation to this study.
Assuntos
Hormônio Antimülleriano/sangue , Menopausa , Mães , Adulto , Fatores Etários , Hormônio Antimülleriano/genética , Feminino , Previsões , Humanos , Pessoa de Meia-Idade , Característica Quantitativa HerdávelRESUMO
OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.
Assuntos
Anormalidades Múltiplas/epidemiologia , Anus Imperfurado/epidemiologia , Epilepsia/epidemiologia , Febre/epidemiologia , Pré-Eclâmpsia/epidemiologia , Gravidez de Gêmeos/estatística & dados numéricos , Técnicas de Reprodução Assistida/estatística & dados numéricos , Aborto Induzido/estatística & dados numéricos , Malformações Anorretais , Estudos de Casos e Controles , Epilepsia/complicações , Europa (Continente)/epidemiologia , Feminino , Febre/complicações , Humanos , Recém-Nascido , Razão de Chances , Paridade , Gravidez , Complicações na Gravidez , Técnicas de Reprodução Assistida/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias. METHODS: Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995. RESULTS: The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent. CONCLUSIONS: Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.
Assuntos
Interação Gene-Ambiente , Hipospadia/etiologia , Mutação/genética , Polimorfismo Genético , Efeitos Tardios da Exposição Pré-Natal/etiologia , Feminino , Genes Homeobox , Humanos , Hipospadia/genética , Masculino , Pré-Eclâmpsia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genéticaRESUMO
CONTEXT: It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma. OBJECTIVE: The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause. DESIGN AND SETTING: We conducted a long-term follow-up study at an academic hospital. PARTICIPANTS: A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria. INTERVENTIONS: Anti-Müllerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried. MAIN OUTCOME MEASURES: Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause. RESULTS: A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level. CONCLUSIONS: AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.
Assuntos
Hormônio Antimülleriano/sangue , Fertilidade/fisiologia , Menopausa/metabolismo , Adulto , Fatores Etários , Biomarcadores/metabolismo , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Ovulação/fisiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
INTRODUCTION: Tenascin-X (TNX) is an extracellular matrix (ECM) glycoprotein, the absence of which in humans leads to a recessive form of Ehlers-Danlos syndrome (EDS), a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. A mouse model of TNX-deficient type EDS has been used to characterize the dermatological, orthopedic, and obstetrical features. The growing insight in the clinical overlap between myopathies and inherited connective tissue disorders asks for a study of the muscular characteristics of inherited connective tissue diseases. Therefore, this study aims to define the muscular phenotype of TNX knockout (KO) mice. MATERIALS AND METHODS: We performed a comprehensive study on the muscular phenotype of these TNX KO mice, consisting of standardized clinical assessment, muscle histology, and gene expression profiling of muscle tissue. Furthermore, peripheral nerve composition was studied by histology and electron microscopy. RESULTS: The main findings are the presence of mild muscle weakness, mild myopathic features on histology, and functional upregulation of genes encoding proteins involved in ECM degradation and synthesis. Additionally, sciatic nerve samples showed mildly reduced collagen fibril density of endoneurium. DISCUSSION: The muscular phenotype of TNX KO mice consists of mild muscle weakness with histological signs of myopathy and of increased turnover of the ECM in muscle. Furthermore, mildly reduced diameter of myelinated fibers and reduction of collagen fibril density of endoneurium may correspond with polyneuropathy in TNX-deficient EDS patients. This comprehensive assessment can serve as a starting point for further investigations on neuromuscular function in TNX KO mice.
Assuntos
Músculos/patologia , Tenascina/deficiência , Animais , Modelos Animais de Doenças , Síndrome de Ehlers-Danlos/patologia , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Atividade Motora , Músculo Esquelético/fisiopatologia , Músculos/fisiopatologia , Nervo Isquiático/patologiaRESUMO
BACKGROUND/OBJECTIVES: Riboflavin is a cofactor for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme involved in the homocysteine pathway. The aim of this study was to investigate the effects of maternal riboflavin intake and two MTHFR polymorphisms (677C>T; Ala222Val and 1298A>C; Glu429Ala substitutions) on the biomarkers of the homocysteine pathway, and investigate the risk of having offspring with an orofacial cleft (OFC). SUBJECTS/METHODS: In a case-control study design, dietary riboflavin intake and the MTHFR 677C>T and 1298A>C polymorphisms were evaluated in 123 OFC and 108 control mothers by using food frequency questionnaires and blood samples. Homocysteine (tHcy), folate and vitamin B12 concentrations in blood were analyzed in 70 cases and 68 controls. Linear and logistic regression analyses were applied. RESULTS: At 14 months postpartum riboflavin intake and MTHFR 677C>T and 1298A>C genotypes were not significantly different between cases and controls. The 677TT genotype showed lower folate concentrations compared to C-allele carriers with a mean difference of 2.8 nmol/l in serum and 174 nmol/l in red blood cell (both P's=0.01). Every mg per day increase of dietary riboflavin intake was positively associated with increase in vitamin B12 concentration by 52.1% (P<0.01). This effect was most pronounced in MTHFR 677TT homozygotes (205.1%, P=0.03). The riboflavin-adjusted MTHFR 677TT and 1298CC genotypes showed a trend toward an increasing risk for OFC, adjusted odds ratio 1.7 (confidence interval (95% CI), 0.7-4.5) and 1.6 (95% CI, 0.7-4.2), respectively. CONCLUSIONS: Maternal riboflavin intake is significantly associated with biomarkers of the homocysteine pathway, with the strongest effects in MTHFR 677TT homozygotes. The maternal risk of having OFC offspring, however, is not associated with dietary riboflavin intake.
Assuntos
Homocisteína/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Riboflavina/administração & dosagem , Biomarcadores/sangue , Estudos de Casos e Controles , Fenda Labial/enzimologia , Fenda Labial/epidemiologia , Fenda Labial/genética , Fissura Palatina/enzimologia , Fissura Palatina/epidemiologia , Fissura Palatina/genética , Feminino , Ácido Fólico/sangue , Predisposição Genética para Doença , Genótipo , Homocisteína/sangue , Humanos , Modelos Lineares , Modelos Logísticos , Nutrigenômica , Razão de Chances , Riboflavina/sangue , Fatores de Risco , Inquéritos e Questionários , Vitamina B 12/sangueRESUMO
Marfan syndrome is a clinically and allelic heterogeneous, heritable connective tissue disorder with infrequently reported neuromuscular features. This study is the first to delineate these symptoms in a non-selected population. Neuromuscular involvement was evaluated in 10 Marfan patients through a standardized questionnaire, physical examination, nerve conduction study (NCS), needle electromyography (EMG), muscle ultrasound, laboratory investigation, and muscle biopsy. Existing neuroimages were screened for dural ectasia and spinal meningeal cysts. Twenty healthy controls with similar age distribution completed the questionnaire. The results showed that various neuromuscular symptoms occur more frequently in the patients. Four older patients reported muscle weakness, five patients had a mild-to-moderate reduction in vibration sense, and all older patients mentioned mild functional impairments. NCS showed axonal polyneuropathy in four and EMG myopathic and neurogenic changes in all patients. Increased echo intensity and atrophy on muscle ultrasound was found in more than half of the patients. Muscle biopsies obtained in two patients showed myopathic changes in the older, female patient. In conclusion, the majority of Marfan patients exhibited neuromuscular symptoms characterized as myopathy or polyneuropathy or both, and signs of lumbosacral radiculopathy, with symptoms being most pronounced in the older patients. Although meriting corroboration, these findings indicate a need to further the awareness of neuromuscular involvement in this population.
Assuntos
Síndrome de Marfan/complicações , Síndrome de Marfan/fisiopatologia , Doenças Neuromusculares/complicações , Doenças Neuromusculares/fisiopatologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Eletromiografia , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Dinamômetro de Força Muscular , Músculos/anormalidades , Músculos/patologia , Condução Nervosa , Exame Físico , Radiografia , UltrassonografiaRESUMO
OBJECTIVES: Fertility problems are an increasing public health issue in industrialised countries. Exposure to exogenous agents with endocrine disrupting properties, such as some pesticides, are potential risk factors for subfertility. The aim of this study was to determine whether time-to-pregnancy (TTP) is prolonged in male greenhouse workers exposed to pesticides in comparison with a non-exposed reference group. METHODS: Data were collected through self-administrated questionnaires with detailed questions on TTP, as well as on lifestyle (for example, smoking habits, coffee and alcohol consumption), work tasks, and occupational exposures of the men and their partners in the six months before conception of the most recent pregnancy. TTP was compared between male greenhouse workers (n = 694) and a non-exposed reference group (n = 613) by means of discrete proportional hazards regression analysis. RESULTS: The crude analyses did not show a decreased overall fecundability among greenhouse workers compared to the non-exposed reference group. However, when fecundability was assessed for primigravidous couples, duogravidous couples, and multigravidous couples separately, greenhouse workers were found to be less fecund when trying to conceive their first pregnancy (FR = 0.65; 95% CI 0.46 to 0.92), which is also the most valid analysis in which pregnancy planning issues were avoided. Among couples who already experienced one or more pregnancies, no association was seen between pesticide exposure and TTP after adjustment for confounders. CONCLUSION: A prolonged time-to-pregnancy was observed in male greenhouse workers exposed to pesticides before conception of their first pregnancy.
Assuntos
Jardinagem , Infertilidade Masculina/induzido quimicamente , Exposição Ocupacional , Exposição Paterna , Praguicidas/toxicidade , Adulto , Estudos de Casos e Controles , Fatores de Confusão Epidemiológicos , Feminino , Fertilização , Humanos , Masculino , Análise Multivariada , Razão de Chances , Paridade , Gravidez , Fatores de TempoRESUMO
BACKGROUND: Attempted suicide is a frequent occurrence, even in mental health institutions (mhis). The World Health Organization strongly supports the development and implementation of guidelines for dealing with cases of attempted suicide in mhis. aim To check on the existence, content and quality of guidelines for dealing with persons attempting suicide within mhis in the Netherlands and to compare these guidelines with those available in university and general hospitals. METHOD: A questionnaire was sent to all mhis. Criteria for assessing the content of existing guidelines were derived from the literature. The quality of the guidelines was then assessed on the basis of the Appraisal of Guidelines for Research and Evaluation (agree), a tool developed to evaluate guideline quality. results Thirty-eight out of 48 (72.2%) psychiatric institutions responded, giving us access to 12 sets of guidelines. The content and quality of these guidelines were compared with the content and quality of the guidelines available in university and general hospitals; there were several differences, but on the whole the mhi-guidelines were better. CONCLUSION: Guidelines were only available in a limited number of mhis. Most of the guidelines were adequate with regard to content, but some of the mhi-guidelines lacked some important elements. The quality of the mhi-guidelines was rather low but nevertheless better that that of the hospital guidelines.