The applicability of the central line-associated bloodstream infection (CLABSI) criteria for the evaluation of bacteremia episodes in pediatric oncology patients.

BACKGROUND: The aim of this study was to investigate the applicability of the central line-associated bloodstream infection (CLABSI) criteria of the Centers for Disease Control and Prevention in pediatric oncology patients. METHODS: Bacteremia episodes from 2020 to 2022 from a prospective cohort of pediatric oncology patients with a central venous catheter were included. Episodes were classified by three medical experts following the CLABSI criteria as either a CLABSI or non-CLABSI (i.e., contamination, other infection source, or mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI)). Subsequently, they were asked if and why they (dis)agreed with this diagnosis following the criteria. The primary outcome was the percentage of episodes where the experts clinically disagreed with the diagnosis given following the CLABSI criteria. RESULTS: Overall, 84 bacteremia episodes in 71 patients were evaluated. Following the CLABSI criteria, 34 (40%) episodes were classified as CLABSIs and 50 (60%) as non-CLABSIs. In 11 (13%) cases the experts clinically disagreed with the diagnosis following the CLABSI criteria. The discrepancy between the CLABSI criteria and clinical diagnosis was significant; McNemar's test p < .01. Disagreement by the experts with the CLABSI criteria mostly occurred when the experts found an MBI-LCBI a more plausible cause of the bacteremia than a CLABSI due to the presence of a gram negative bacteremia (Pseudomonas aeruginosa n = 3) and/or mucositis. CONCLUSIONS: A discrepancy between the CLABSI criteria and the evaluation of the experts was observed. Adding Pseudomonas aeruginosa as an MBI pathogen and incorporating the presence of mucositis in the MBI-LCBI criteria, might increase the applicability.

Direct correlation of MR-DWI and histopathology of Wilms' tumours through a patient-specific 3D-printed cutting guide.

OBJECTIVES: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) discourages invasive procedures to determine the histology of paediatric renal neoplasms at diagnosis. Therefore, the histological subtype of Wilms' tumours (WT) is unknown at the start of neoadjuvant chemotherapy. MR-DWI shows potential value as a non-invasive biomarker through apparent diffusion coefficients (ADCs). This study aimed to describe MR characteristics and ADC values of paediatric renal tumours to differentiate subtypes. MATERIALS AND METHODS: Children with a renal tumour undergoing surgery within the SIOP-RTSG 2016-UMBRELLA protocol were prospectively included between May 2021 and 2023. In the case of a total nephrectomy, a patient-specific cutting guide based on the neoadjuvant MR was 3D-printed, allowing a correlation between imaging and histopathology. Whole-tumour volumes and ADC values were statistically compared with the Mann-Whitney U-test. Direct correlation on the microscopic slide level was analysed through mixed model analysis. RESULTS: Fifty-nine lesions of 54 patients (58% male, median age 3.0 years (range 0-17.7 years)) were included. Forty-four lesions involved a WT. Stromal type WT showed the lowest median decrease in volume after neoadjuvant chemotherapy (48.1 cm3, range 561.5-(+)332.7 cm3, p = 0.035). On a microscopic slide level (n = 240 slides) after direct correlation through the cutting guide, stromal areas showed a significantly higher median ADC value compared to epithelial and blastemal foci (p < 0.001). With a cut-off value of 1.195 * 10-3 mm2/s, sensitivity, and specificity were 95.2% (95% confidence interval 87.6-98.4%) and 90.5% (95% confidence interval 68.2-98.3%), respectively. CONCLUSION: Correlation between histopathology and MR-DWI through a patient-specific 3D-printed cutting guide resulted in significant discrimination of stromal type WT from epithelial and blastemal subtypes. CLINICAL RELEVANCE STATEMENT: Stromal Wilms' tumours could be discriminated from epithelial- and blastemal lesions based on high apparent diffusion coefficient values and limited decrease in volume after neoadjuvant chemotherapy. This may aid in future decision-making, especially concerning discrimination between low- and high-risk neoplasms. KEY POINTS: MR-DWI shows potential value as a non-invasive biomarker in paediatric renal tumours. The patient-specific cutting guide leads to a correlation between apparent diffusion coefficient values and Wilms' tumour subtype. Stromal areas could be discriminated from epithelial and blastemal foci in Wilms' tumours based on apparent diffusion coefficient values.

Identification of Pediatric Tumors Intraoperatively Using Indocyanine Green (ICG).

BACKGROUND: Fluorescence-guided surgery (FGS) with indocyanine green (ICG) is increasingly applied in pediatric surgical oncology. However, FGS has been mostly reported in case studies of liver or renal tumors. Applying novel technologies in pediatric surgical oncology is more challenging than in adult surgical oncology due to differences in tumor histology, biology, and fewer cases. No consensus exists on ICG-guided FGS for surgically managing pediatric solid tumors. Therefore, we reviewed the literature and discuss the limitations and prospects of FGS. METHODS: Using PRISMA guidelines, we analyzed articles on ICG-guided FGS for childhood solid tumors. Case reports, opinion articles, and narrative reviews were excluded. RESULTS: Of the 108 articles analyzed, 17 (14 retrospective and 3 prospective) met the inclusion criteria. Most (70.6%) studies used ICG to identify liver tumors, but the timing and dose of ICG administered varied. Intraoperative outcomes, sensitivity and specificity, were reported in 23.5% of studies. Fluorescence-guided liver resections resulted in negative margins in 90-100% of cases; lung metastasis was detected in 33% of the studies. In otolaryngologic malignancies, positive margins without fluorescence signal were reported in 25% of cases. Overall, ICG appeared effective and safe for lymph node sampling and nephron-sparing procedures. CONCLUSIONS: Despite promising results from FGS, ICG use varies across the international pediatric surgical oncology community. Underreported intraoperative imaging outcomes and the diversity and rarity of childhood solid tumors hinder conclusive scientific evidence supporting adoption of ICG in pediatric surgical oncology. Further international collaborations are needed to study the applications and limitations of ICG in pediatric surgical oncology.

Sentinel Lymph Node Procedure in Pediatric Patients with Melanoma, Squamous Cell Carcinoma, or Sarcoma Using Near-Infrared Fluorescence Imaging with Indocyanine Green: A Feasibility Trial.

BACKGROUND: Standard sentinel lymph node procedure (SNP) in pediatric cancer consists of a preoperative injection with 99mtechnetium nanocolloid in combination with an optional intraoperative injection with blue dye. However, blue dye has disadvantages, and the detection rate is low, with only 60% of sentinel lymph nodes (SLNs) staining blue. In adult oncology, fluorescence imaging using indocyanine green (ICG) has been shown to be a safe and accurate method for visual detection of SLNs, with a higher sensitivity (up to 97%) compared with blue dye. Therefore, our aim is to determine the feasibility of the addition of ICG to 99mtechnetium nanocolloid (ICG-TC) for visual detection of SLN in pediatric patients. METHODS: A total of 15 pediatric patients with melanoma, squamous cell carcinoma, and sarcoma were prospectively included. Preoperatively, patients were injected with ICG-TC and imaging with lymphoscintigraphy and single-photon emission computed tomography- computed tomography was performed. Intraoperatively, SLN was detected with fluorescence and the gamma probe. Postoperatively, fluorescence was quantified by tumor-to-background ratio (TBR) and surgeons evaluated the use of ICG using a standardized questionnaire. RESULTS: In 10/15 (67%) patients, SLNs were visible transcutaneously. Of all intraoperatively detected SLNs, 35/37 (95%) were fluorescent and 37/37 (100%) were radioactive. Furthermore, ICG-TC led to the identification of six additional SLNs as compared with preoperative imaging. The median TBR in vivo was 6.5 (IQR 5.3). The surgical evaluation showed that ICG assisted in SLN detection and was easy to use. CONCLUSIONS: ICG-TC for the SNP is a feasible procedure in pediatric patients. It showed an accurate detection rate, was helpful for visual guidance, and no adverse events occurred.

Direct correlation of MRI with histopathology in pediatric renal tumors through the use of a patient-specific 3-D-printed cutting guide: a feasibility study.

BACKGROUND: Pediatric renal tumors are often heterogeneous lesions with variable regions of distinct histopathology. Direct comparison between in vivo imaging and ex vivo histopathology might be useful for identification of discriminating imaging features. OBJECTIVE: This feasibility study explored the use of a patient-specific three-dimensional (3D)-printed cutting guide to ensure correct alignment (orientation and slice thickness) between magnetic resonance imaging (MRI) and histopathology. MATERIALS AND METHODS: Before total nephrectomy, a patient-specific cutting guide based on each patient's preoperative renal MRI was generated and 3-D printed, to enable consistent transverse orientation of the histological specimen slices with MRI slices. This was expected to result in macroscopic slices of 5 mm each. The feasibility of the technique was determined qualitatively, through questionnaires administered to involved experts, and quantitatively, based on structured measurements including overlap calculation using the dice similarity coefficient. RESULTS: The cutting guide was used in eight Wilms tumor patients receiving a total nephrectomy, after preoperative chemotherapy. The median age at diagnosis was 50 months (range: 4-100 months). The positioning and slicing of the specimens were rated overall as easy and the median macroscopic slice thickness of each specimen ranged from 5 to 6 mm. Tumor consistency strongly influenced the practical application of the cutting guide. Digital correlation of a total of 32 slices resulted in a median dice similarity coefficient of 0.912 (range: 0.530-0.960). CONCLUSION: We report the feasibility of a patient-specific 3-D-printed MRI-based cutting guide for pediatric renal tumors, allowing improvement of the correlation of MRI and histopathology in future studies.

Central venous catheter-associated complications in pediatric patients diagnosed with Hodgkin lymphoma: implications for catheter choice.

PURPOSE: The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. METHODS: A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06-2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. RESULTS: A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76-9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68-53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18-45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45-33.57). CONCLUSION: The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors.

Value of the Sentinel Node Procedure in Pediatric Extremity Rhabdomyosarcoma: A Systematic Review and Retrospective Cohort Study.

BACKGROUND: Our aim is to show whether the sentinel node procedure (SNP) is recommendable for pediatric patients with extremity rhabdomyosarcoma (RMS). Lymph node metastases are an important prognostic factor in pediatric patients with extremity RMS. Accurate nodal staging is necessary to treat the patient accordingly. An alternative to the current recommended lymph node sampling is the sentinel node procedure (SNP). METHODS: A systematic review was performed summarizing all published cases of SNP in addition to 13 cases from our hospital and 8 cases from two other hospitals that have not been published before. RESULTS: For all patients (n = 55), at least one SLN was identified, but the SNP technique used was not uniform. The SNP changed the nodal classification of eight patients (17.0%) and had a false-negative rate of 10.5%. CONCLUSIONS: The SNP is recommendable for pediatric patients with extremity RMS. It can change lymph node status and can be used to sample patients in a more targeted way than nodal sampling alone. Therefore, we recommend use of the SNP in addition to clinical and radiological nodal assessment for pediatric patients with extremity RMS.

Use of quality indicators in neuroblastoma treatment: A feasibility assessment.

BACKGROUND: Quality indicators (QIs) may be used to monitor the quality of neuroblastoma (NBL) care during treatment, in addition to survival and treatment toxicity, which can only be evaluated in the years after treatment. The present study aimed to assess the feasibility of a new set of indicators for the quality of NBL therapy. PROCEDURE: Seven QIs have been proposed based on literature and consensus of experts: (a) duration of complete diagnostic work-up, (b) prescription of thyroid prophylaxis before metaiodobenzylguanidine imaging, (c) treatment intensity, (d) use of tumor board meetings, (e) number of outpatient visits and sedation procedures during follow-up, (f) protocolled follow-up, and (g) required apheresis sessions. A retrospective data analysis from October 2014 to November 2017 including all patients with NBL in the centralized Princess Máxima Center in the Netherlands was performed to assess these parameters and determine practicality of measurement. RESULTS: A total number of 72 patients (aged between 2 weeks and 15 years) were analyzed. Adherence to all QIs could be determined for all eligible patients using their electronic medical records. Three indicators were compared over time, and an increase in adherence was observed. CONCLUSIONS: Assessment of QIs in neuroblastoma treatment is feasible. Seven new QIs were found to be feasible to measure and showed improvement over time for three indicators. Monitoring of these QIs during treatment may provide tools for quality improvement activities and comparisons of treatment quality over time or between centers. Further study is required to investigate their association with long-term outcomes.

Diagnostic accuracy of image-guided core needle biopsy of non-central nervous system tumors in children.

BACKGROUND AND AIMS: Core needle biopsies (CNB) are less invasive, cause less morbidity, and have lower costs than open biopsies (OB). However, the number of studies reporting CNB accuracy in pediatric tumors is limited and series are small. The aim of this study is to investigate if CNB diagnosis is concordant with the final diagnosis in pediatric solid non-central nervous system (CNS) tumors. METHODS: Data from all patients treated in a single center between November 2014 and December 2019 were collected from the national pathology database and from local medical records. Data collection included age, sex, CNB diagnosis, final diagnosis, number of cores obtained, number of cores used for histology, cumulative core length, greatest dimension of the lesion, lesion volume, and complications. RESULTS: Out of 361 CNB, 95.6% (345/361) provided a diagnosis. A resection or follow-up biopsy was performed in 201 cases. The final diagnosis was concordant with the CNB in 100% (201/201) of cases. The age, number of cores used for histology, and the greatest dimension of the lesion did not significantly differ between diagnostic and nondiagnostic CNB. The cumulative core length of diagnostic CNB was significantly higher than in the nondiagnostic group (24.72 mm vs. 13.37 mm, p-value .022). Complications occurred in 2.1% (7/337) of CNB procedures. Molecular analysis was successful in 228/233 (98%) of cases in which it was performed. CONCLUSIONS: CNB diagnosis is highly concordant with the final diagnosis and the diagnostic rate is high. The complication rate in CNB is low.

Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical presentation, treatment modalities, and factors associated with survival in pediatric MPNST using Dutch nationwide databases. METHODS: Data were obtained from the Netherlands Cancer Registry (NCR) and the Dutch Pathology Database (PALGA) from 1989 to 2017. All primary MPNSTs were collected. Demographic differences were analyzed between adult and pediatric (age ≤18 years) MPNST. In children, demographic and treatment differences between neurofibromatosis type 1 (NF1) and non-NF1 were analyzed. A Cox proportional hazard model was constructed for localized pediatric MPNSTs. RESULTS: A total of 70/784 MPNST patients were children (37.1% NF1). Children did not present differently from adults. In NF1 children, tumor size was more commonly large (> 5 cm, 92.3% vs 59.1%). Localized disease was primarily resected in 90.6%, and radiotherapy was administered in 37.5%. Non-NF1 children tended to receive chemotherapy more commonly (39.5% vs 26.9%). Overall, estimated five-year survival rates of localized NF1-MPNST was 52.4% (SE: 10.1%) compared with 75.8% (SE: 7.1%) in non-NF1 patients. The multivariate model showed worse survival in NF1 patients (HR: 2.98; 95% CI, 1.17-7.60, P = 0.02) and increased survival in patients diagnosed after 2005 (HR: 0.20; 95% CI, 0.06-0.69, P = 0.01). No treatment factors were independently associated with survival. CONCLUSION: Pediatric MPNSTs have presentations similar to adult MPNSTs. In children, NF1 patients present with larger tumors, but are treated similarly to non-NF1 MPNSTs. In localized pediatric MPNST, NF1 is associated with worse survival. Promisingly, survival has increased for pediatric MPNSTs after 2005.

Surgical treatment of childhood hepatoblastoma in the Netherlands (1990-2013).

BACKGROUND: Achievement of complete surgical resection plays a key role in the successful treatment of children with hepatoblastoma. The aim of this study is to assess the surgical outcomes after partial liver resections for hepatoblastoma, focusing on postoperative complications, resection margins, 30-day mortality, and long-term survival. METHOD: Chart reviews were carried out on all patients treated for hepatoblastoma in the Netherlands between 1990 and 2013. RESULTS: A total of 103 patients were included, of whom 94 underwent surgery. Partial hepatectomy was performed in 76 patients and 18 patients received a liver transplant as a primary procedure. In 42 of 73 (58 %) patients, one or more complications were reported. In 3 patients, information regarding complications was not available. Hemorrhage necessitating blood transfusion occurred in 33 (45 %) patients and 9 (12 %) patients developed biliary complications, of whom 8 needed one or more additional surgical interventions. Overall, 5-year disease-specific survival was 82, 92 % in the group of patients who underwent partial hepatectomy, and 77 % in the group of patients who underwent liver transplantation. CONCLUSIONS: Partial hepatectomy after chemotherapy in children with hepatoblastoma offers good chances of survival. This type of major surgery is associated with a high rate of surgical complications (58 %), which is not detrimental to survival.

Adnexal masses in children, adolescents and women of reproductive age in the Netherlands: A nationwide population-based cohort study.

OBJECTIVE: To provide an accurate incidence of adnexal masses in children and young women which can significantly improve the performance of current risk prediction models. METHODS: We used the PALGA database, a nationwide network and registry of histopathology and cytopathology, as the primary source of our study. Reports on ovarian histology of girls, years 1991-2014, and women aged 21-39, years 2011-2013, were included. Reports were labeled using the WHO-classification and classified as benign, borderline malignant, or malignant. Surgical procedure was scored separately. RESULTS: Included were 11,595 patients. The incidence of adnexal masses increased exponentially with age, from 0.43 per 100,000womenyears at age 1 to 152 per 100,000womenyears at age 35. A (borderline) malignancy was found in 898 (7.7%) patients, ratios between benign and malignant masses varied with age and were lowest in premenarchal children. Histology varied widely with surface epithelial tumors (35.1%), germ cell tumors (29.8%), and other cysts, tumors and tumorlike lesions (32.8%) being evenly distributed while sex cord stromal tumors were rare and only represented 2.3%. The proportion of malignancies was 6.3% in germ cell tumors while the type of malignant germ cell tumor was dependent on age. Oophorectomy was more often performed in the premenarchal age group and in women approaching the end of their reproductive age. CONCLUSION: Our results show that adnexal masses in different age groups do not only differ in histological subgroups but also in malignancy rate which is of high value in presurgical risk evaluation.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.

Patient-Reported Defecation and Micturition Problems Among Adults Treated for Sacrococcygeal Teratoma During Childhood--The Need for New Surveillance Strategies.

BACKGROUND: To evaluate defecation and micturition complaints in adults treated for sacrococcygeal teratoma (SCT) during childhood and to identify risk factors for soiling, urinary incontinence, and constipation beyond childhood. PROCEDURE: Records of patients aged ≥18 treated for SCT during infancy in the Netherlands were retrospectively reviewed. Frequency and severity of soiling, constipation, and urinary incontinence were evaluated using questionnaires designed in line with the Krickenbeck classification. Problems during childhood were compared to outcomes at adult age in part of the cohort. Associations between patient- and disease-related factors with complaints beyond childhood were analyzed with the chi-square test or Fisher's exact test, when appropriate. RESULTS: Of 47 included patients (mean age 26.2 years, SD ±6.5), 49% reported at least one defecation or micturition complaint. Urinary incontinence was present in 30% and had a greater negative impact than soiling (24%). Ten patients (21%) reported constipation; five found this severely bothering. Three patients reported social restrictions due to defecation or micturition complaints (6.4%). While sex and tumor histology were not identified as risk factors, a tumor diameter of >10 cm and Altman type I or type II SCT were associated with constipation during adulthood. CONCLUSIONS: One-third of the patients treated for SCT during childhood reported urinary and defecation problems beyond childhood. In only a minority of cases, these led to social restrictions. A greater tumor diameter was associated with a higher risk of constipation during adulthood. Prolonged surveillance strategies are advised for all patients with SCT.

Evaluation of chemotherapeutic sequelae and quality of life in survivors of malignant sacrococcygeal teratoma.

PURPOSE: The impact of chemotherapeutic sequelae on long-term quality of life (QoL) for survivors of malignant sacrococcygeal teratoma (SCT) is unknown. The incidence of chemotherapeutic toxicity in patients treated for malignant SCT and possible effects on the QoL were analyzed. METHODS: Retrospective chart review of patients ≥18 years treated for SCT in the Netherlands was performed. Present QoL was evaluated using the SF-36 questionnaire. The results of survivors of malignant SCT were compared to those of patients treated for benign SCT. RESULTS: Fifty-one of 76 traceable patients consented to participate. The results of 47 (92.2 %), 9 men and 38 women (median age 25.4 years, range 18.3-41.2), were analyzed. Eleven had been treated for malignancy; 63.6 % suffered from at least one chemotherapeutic sequel with hearing loss as the most common one. Results for both groups were similar on all but one SF-36 subcategory; those treated for malignant tumor scored significantly lower on the subcategory physical functioning (p = 0.02). CONCLUSION: Despite the high incidence of chemotherapeutic sequelae among survivors of malignant SCT, their QoL does not differ from that of those treated for benign SCT. Even though their physical functioning is restricted, daily activities and psychosocial functioning of survivors of malignant SCT are not restricted.

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.

No major role for periconceptional folic acid use and its interaction with the MTHFR C677T polymorphism in the etiology of congenital anorectal malformations.

BACKGROUND: Both genetic and nongenetic factors are suggested to be involved in the etiology of congenital anorectal malformations (ARM). Maternal periconceptional use of folic acid supplements were inconsistently suggested to play a role in the prevention of ARM. Therefore, we investigated independent associations and interactions of maternal periconceptional folic acid supplement use and the infant and maternal MTHFR (methylenetetrahydrofolate reductase) C677T polymorphisms with the risk of ARM and subgroups of ARM. METHODS: A case-control study was conducted among 371 nonsyndromic ARM cases and 714 population-based controls born between 1990 and 2012 using maternal questionnaires and DNA samples from mother and child. Cases were treated for ARM at departments of Pediatric Surgery of the Radboud university medical center, Sophia Children's Hospital-Erasmus MC Rotterdam, and the University Medical Center Groningen in The Netherlands and hospitals throughout Germany. RESULTS: No association with folic acid use was present (odds ratio = 1.1; 95% confidence interval: 0.8-1.4) for ARM as a group. Infant and maternal MTHFR C677T polymorphisms were weakly associated with isolated ARM in particular. Lack of folic acid supplement use in combination with infants or mothers carrying the MTHFR C677T polymorphism did not seem to increase the risk of ARM or subgroups of ARM. The relative excess risks due to interaction did not clearly indicate interaction on an additive scale either. CONCLUSION: This first study investigating interactions between periconceptional folic acid supplement use and infant and maternal MTHFR C677T polymorphisms in the etiology of ARM did not provide evidence for a role of this gene-environment interaction.