Pediatric cancer risk in association with birth defects: A systematic review

PLOS ONE, Jul 2017

Background Many epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association. Methods We used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer subtypes. Results A total of 14,778 article citations were identified, of which 80 met inclusion criteria. Pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types. Conclusions Some children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy.

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Pediatric cancer risk in association with birth defects: A systematic review

A total of Pediatric cancer risk in association with birth defects: A systematic review Kimberly J. Johnson 0 1 2 Jong Min Lee 1 2 Kazi Ahsan 1 2 Hannah Padda 1 2 Qianxi Feng 1 2 Sonia Partap 2 Susan A. Fowler 1 2 Todd E. Druley 0 2 Jeffrey S Chang, National Health Research 0 Department of Pediatrics, Washington University School of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America, 3 Department of Neurology, Stanford University , Palo Alto , California, United States of America, 4 Division of Pediatric Hematology and Oncology, Washington University School of Medicine , Washington University in St. Louis, St. Louis, Missouri , United States of America 1 Brown School , Washington University in St. Louis, St. Louis, Missouri , United States of America 2 Institutes , TAIWAN Methods from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This review was supported by the Arlene Rubin Stiffman Junior Faculty Research Award, an internal award at the Brown School at Washington University. The funder of this award had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Background Methods cancer subtypes. Results Many epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association. We used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles Conclusions Some children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy. Introduction Pediatric cancer is diagnosed in >14,000 U.S. children per year from the ages of 0±19 years and is the leading cause of disease-related death among children aged 1±14 years [1, 2]. Although a few risk factors have been conclusively identified, including exposure to high dose radiation and certain genetic syndromes, the etiology underlying most cases remains unknown. Evidence accumulated over several decades suggests positive associations between birth defects (BDs) and pediatric malignancy. BDs affect ~1 in 33 U.S. children and are defined as ªstructural changes present at birth that can affect almost any part or parts of the bodyº [3]. BDs are often categorized as major and minor with major anomalies generally considered those having ªan adverse effect on the individual's health, functioning or social acceptabilityº and minor anomalies considered those having ªlimited social or medical significanceº. Major anomaly examples include spina bifida, cleft lip palate, and Down Syndrome [4]. Minor anomaly examples include low set ears, epicanthal folds, and simian crease [5]. Although certain genetic syndromes are known to increase pediatric cancer risk (e.g. Down Syndrome and leukemia), other BDs (including major and minor), independent of known cancer predisposition syndromes, may also be associated with an increased risk. Recent evidence suggests that 8.5% of children with cancer harbor germline mutations in well-known cancer genes that predispose them to the development of early-onset malignancy [6]. However, when considering a more broad predisposition definition including family history, co-morbidities, and types of pediatric cancer, up to about a third of children with cancer may have a genetic predisposition [7]. Many pediatric cancer predisposition syndromes involve defects in normal development and many pediatric cancers arise from immature cell types (e.g. the ªblastomasº). Thus, identifying and understanding connections between abnormal fetal or childhood development and the risk of developing cancer will have implications for surveillance, prognosis, risk stratification and potential personalized therapeutics. To summarize evidence on associations between pediatric malignancy and BDs, we conducted a systematic literature review to identify articles reporting primary human epidemiological research. This work provides a foundation for future studies and may help to identify high risk populations for malignancy among individuals with BDs that will enable improved surveillance, mechanistic research, targeted treatment and outcomes. Methods Abbreviations used in this review are provided in Table 1. Our review followed the 2009 Preferred Reporting Method for Systematic Reviews (PRISMA) guidelines [8] (See S1 Checklist). A summary of the review protocol is provided below. Search strategy We identified relevant articles in the Medline PubMed [9] and Embase [10] databases on 9/10/ 2015 and 10/12/2015 using librarian designed search strategies. The review was updated on 5/ 12/2017 using the PubMed database. (S1 Table). We also examined each article's reference list from those included in the review and consulted a well-known review published by the International Agency for Cancer Research in 1999 for any additional studies [11]. Finally, the senior 2 / 56 Abbreviation MDS MPD NB NHL NOS NA ND NR NRCT NWTS OR OS PNET PRISMA RB RB RDD RMS RMS RR SNS STS WAGR syndrome WT UPDB author conducted a few PubMed literature searches based on her expert opinion to identify additional qualifying articles. Eligibility criteria and review process The citation lists obtained from each database search were evaluated for initial eligibility by at least two coauthors (KA, JL, and KJ). We excluded review articles, editorial commentaries, meeting abstracts, articles focused solely on syndromes with known genetic etiologies, on treatment or clinical outcomes, solely on adults ( 18 years), and articles not providing information on risks specific to children with the exception of the Gelberg et al. study that reported risks for osteosarcoma from 0±24 years [12]. In addition, lab-based studies and case reports/series without external comparison groups were excluded. Reviewers classified each article initially based on title review (and abstract if eligibility was unclear from the title) as: 1) eligible, 2) unclear eligibility, and 3) ineligible. Following reconciliation of articles with coding disagreement by the senior author and reviewers, articles assigned to category one were abstracted. Data collection Data were abstracted from each article using a pre-designed form that captured: study population, study design and description, sources of information on BDs and cancer, study inclusion 3 / 56 and exclusion criteria, age groups studied, birth years, cancer diagnosis years, BD case definition, BD types examined, cancer types examined, subject numbers, analysis method, measure of association reported, and key findings. Any additional information relevant to interpretation of study results was captured in a comment field. To the extent possible, we abstracted the number of subjects for each comparison group and included this information where the numbers were reported directly or required minimum assumptions to calculate. Any articles that were identified as ineligible during the abstraction phase were subsequently excluded. During our update of the review, we also abstracted information where reported on classification of major and minor anomalies, maximum age at which BDs were ascertained, and cancer risks by age. We did not attempt to reclassify anomalies from the original reports for summary purposes. Quality assessment We employed a modified Newcastle-Ottawa Scale (NOS), designed for quality assessment of observational studies [13], that uses a star assignment system to determine overall quality for case-control, nested case-control, case-cohort, and cohort studies. Case series studies with external comparison groups were not evaluated. Evaluation criteria are described briefly below. Case-control, nested case-control, and case-cohort studies. A) Selection. Up to four stars were awarded to studies based on: 1) adequate case definition, 2) representativeness of cases, 3) control selection, and 4) adequate control definition. A case definition was considered adequate if cases were defined based on either clinical and/or histopathological validation of their cancer diagnosis or were identified through cancer registry data. Cancer cases were considered representative if they were community/population-based versus hospital-based. For control selection, a star was given if controls were selected from the same population as cases. The control definition was considered adequate if the authors provided information to indicate that controls did not have a history of the outcome. B) Comparability between the groups. Up to two stars were awarded to studies matching on or adjusting for maternal age and child's sex, potential confounders of the association between pediatric malignancy and BDs. C) Ascertainment of the exposure. Up to three stars were awarded to studies if: 1) BDs were ascertained through medical records, physical exam, or birth certificate data, 2) they used the same method of BD ascertainment for cases and controls, and 3) they reported a similar non-response rate for both cases and controls (<10% difference) or the study used registry data for BD ascertainment. Cohort studies. A) Selection. Up to four stars were awarded to studies based on: 1) representativeness of the exposed cohort, 2) selection of the non-exposed cohort, 3) ascertainment of exposure, and 4) demonstration that the outcome of interest was not present at the start of the study. Studies were given one star each if the exposed cohort registry/population included all children from a defined geographic region was representative of the community, if the nonexposed cohort was drawn from the same community as the exposed cohort, if medical records or BD registry information was used to identify exposed subjects or if the exposure was based on birth certificate data, and if it was indicated that cancer was not present at the start of the study. B) Comparability. Comparability criteria were the same as for case-control studies. C) Outcome. Up to two stars were awarded based on: 1) assessment of the outcome and 2) follow-up length. One star was awarded if the outcome was assessed independently or through medical records or record linkage (i.e. through administrative data through ICD codes). One 4 / 56 star was given if the follow-up period was long enough for outcomes to occur (we set this at 6 years with consideration for the age distribution of pediatric cancer). Statistical methods Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for casecontrol studies where authors provided data for calculations but did not include these measures of association. To summarize the individual quality of each study, we computed the total quality points by summing the number of stars received. To compare overall quality of cohort studies vs. other study designs that differed in their maximum achievable quality points (8 for cohort vs. 9 for case-control, nested case-control, and case-cohort studies), we calculated a mean total percent quality for each study design category by dividing the mean total quality points by the total quality points possible. Results A total of 14,407 article citations, 9,672 from Embase and 4,735 from PubMed, were initially identified. After removing 851 non-unique citations (844 in both PubMed and Embase and 7 contained in Embase twice), 13,556 citations remained. With the addition of 371 articles identified through the reference lists of selected articles, the IARC publication [11], additional PubMed searches, and the updated systematic search in PubMed, 13,927 records were screened for eligibility of which 13,789 were excluded. One hundred thirty-eight full-text articles were abstracted and 80 were included (Fig 1). We organized our review with summaries of the characteristics of included studies followed by their results for pediatric cancer types using the International Classification of Childhood Cancer third edition major diagnostic categories [14]. Within each major cancer type, results are summarized by study design with overall associations generally reported first followed by findings for specific abnormalities/subgroups. Characteristics of studies included (Table 2) Studies from 17 countries (Australia, Brazil Canada, China, Croatia, Denmark, France, Germany, Hungary, Italy, the Netherlands, Norway, Sweden, Switzerland, Turkey, the United Kingdom, and the United States) were published from 1958±2017. Study designs included 13 cohort, 58 case-control, 3 case-cohort, 3 nested case-control and 3 case series with external comparison groups. BDs were measured through a variety of methods including interviews, questionnaires, medical records, physical exams, administrative data linkages and from physician interview/report. Cancers were most commonly ascertained through hospital or population-based tumor registries and death certificates. Pediatric cancers overall (Table 3) We identified 24 articles reporting findings for associations between pediatric cancer overall and BDs. Case-control studies (n = 12). Three studies reported ~2±4.5 fold increased odds of childhood cancer in association with any/BDs or major BDs [15±17], while one reported no association [18]. For minor anomalies, four studies reported increased odds of varying magnitude for minor anomalies overall (ORs = 4.25 and 44.6 [19, 20]), and specific minor anomalies (OR >2-fold [21, 22]). One study reported positive associations ranging from 2.6±14.5 for a number of BD types [17]. Finally, four studies reported generally positive associations between rib anomalies and childhood cancer with ORs ranging from 1.44 to 5.49 [23±26]. 5 / 56 Fig 1. PRISMA flow diagram. The number of records screened is equal to the sum of the number of records initially identified in PubMed and Embase after removing overalapping citations and the number of studies with citations identified through other sources shown in the upper most right text box. After exclusions of non-relevant articles during the screening phase, 138 full-text text articles were abstracted, 58 of which were excluded leaving a total of 80 articles that were included in the review. Cohort studies (n = 12). Consistently elevated risks ranging from 1.8±3.05 were reported for associations between any BDs/major BDs and pediatric cancers [27±35]. Increased cancer risks were within the same range or lower when children with chromosomal anomalies were excluded [32, 34±36]. One cohort study reported increased risks in children with different BD types ranging from 1.69±15.52 with the exception of musculoskeletal abnormalities and limb reduction defects [31]. Janitz et al. reported increased risks for CNS, eye/ear, cardiovascular, orofacial, gastrointestinal, genitourinary, and musculoskeletal abnormalities with stronger risks at younger ages (except orofacial where results were not reported) and when individuals with chromosomal BDs were excluded [35]. Birthmarks (not including nevus simplex or pigmented nevi or cafeÂ-au-lait spots <3 cm or fewer than 6) were positively associated with 6 / 56 Maternal interview/medical record Leukemia, 0±4 years, 1953±1957 (died verification. The authors note that of leukemia), Minnesota death ªlesser conditions, such as nevi, were certificates not recordedº. (Continued) 7 / 56 NB, 0±14 years, 1964±1978 (died of NB), Two controls per case were randomly Texas death certificates selected from birth certificates matched to cases on birth year. Overall, leukemia, solid tumors, 1.6±22 years, NR, Swiss University Children's Hospitals of Basel and Zurich Oncologic Departments WT, 0±14 years, 1970±1983, three Philadelphia-area hospitals: Children's Hospital of Philadelphia, St. Christopher's Hospital for Children, and Wilmington Medical Center CNS, 0±14, deaths from 1964±1980, Texas Department of Health death certificates Leukemia, 0±14 years, 7/1/1974-6/30/ 1986, Shanghai Cancer Institute Tumor Registry CNS, 0±14 years, 1/1/1968-12/31/1977, New York State Cancer Registry NB, 0±8.9 years, cases born since 1969, Four controls per case were selected hospital review of NB cases seen in from live births in Minnesota matched Minnesota and bordering states to cases on birth year. Magnani et al., 1990 [47] (Italy) Interview of parents/closest relatives Kajta r et al., 1990 [79] (Hungary) Zack et al., 1991 [40] (Sweden) Examinations of spine for vertebral WT, NR, NR, Department of Pediatrics, anomalies on i.v. pyelograms in cases University Medical School, Hungary and X-rays in controls The Swedish Medical Birth Registry (ICD-8 codes 740±759) Schumacher et al., 1992 [23] (Germany) Chest X-ray examination for rib anomalies Mann et al., 1993 [16] (United Kingdom) Parental interview/medical record verification (ICD-9 coded) Savitz et al., 1994 [15] (U.S.) Cordier et al., 1994 [61] (Ile de France, France) Maternal interview or alternate respondent. BDs were recorded verbatim and blindly classified as major, minor, or not a defect. Overall, ALL, brain, lymphoma, STS, 0±14 years, 1/1/1976-12/31/1983, primary data sources were the Colorado Central Cancer Registry and the Colorado Department of Health [106] Maternal interview. The authors noted Brain, 0±15 years, 7/1/1985-6/30/1987, excluding "minor anomalies such as medical record abstractions from the nevi or birthmarks". neurosurgery, neurology, pediatric, pediatric oncology, or radiology departments at 13 hospitals Gold et al., 1994 [64] (U.S.) Parental interview Brain, 0±17 years, 1/1/1977-12/31/1981 from eight Surveillance, Epidemiology, and End Results tumor registries CNS, 0±14 years, 1980±1983 from Two sets of controls were regional pediatric oncology centers, West ascertained from general practitioner Midlands Regional Cancer Registry, lists and hospitals matched to cases Manchester Children's Tumor Registry, on sex and age. The second set Yorkshire Regional Cancer Registry excluded children with "a genetic or other constitutional disease or malformation known to be associated with increased risk of cancer" and any other major malformation or chronic disease. ALL, AML, NHL, NR, 1974±1984, Pediatric Hospital in Turin Overall, ALL, other leukemia, HL, other Two sets of controls were selected lymphomas, CNS, STS, bone tumors, from general practitioner lists and WT, NB, RB, HB, GCT, epithelial tumors, hospitals matched to cases on sex Other neoplasms, 0±14 years, 1980± and age. The second set excluded 1983, regional pediatric oncology children with "a genetic or other centers, West Midlands Regional Cancer constitutional disease or Registry, Manchester Children's Tumor malformation known to be associated Registry, Yorkshire Regional Cancer with increased risk of cancer" and any Registry other major malformation or chronic disease. Controls were a random sample of children hospitalized at the same hospital as cases. Controls were children with X-ray for acute abdomen or trauma. Five controls per case were selected from the Swedish Medical Birth Registry matched to cases on sex, birth year and month. Chest roentgenograms from patients without cancer with a similar age distribution as cases (15 months-14 years) were reviewed for comparison. Controls were selected through RDD and frequency matching on location, sex, and age within 3 years. Controls were selected from the general population through sampling households on a representative list provided by the census bureau and telephone books at random matched to cases on birth year. Three controls per case were identified through a variety of methods including RDD, lists of noninstitutionalized individuals maintained by the Hawaii Department of Health and through a random sample of households (Pierce County, Washington). Controls were individually matched to cases on age, sex, and mother's racial/ethnic classification. McCredie et al., 1994 [65] (Australia) Yang et al., 1995 [86] (U.S.) Shu et al., 1995 [89] (U.S., Canada, Australia) Cnattingius et al., 1995 [49] (Sweden) Cnattingius et al., 1995 [41] (Sweden) Adami et al., 1996 [54] (Sweden) Altmann et al., 1998 [17] (Victoria Australia) Gelberg et al., 1997 [12] (New York State, U.S., excluding New York City) Telephone interview with the subject and/or parents, birth certificates and school and medical records OS, 0±24 years, 1978±1988, the New York State Cancer Registry Swedish Medical Birth Register (ICD- Lymphatic leukemia, 0±14 years who 8 to 1986 and ICD-9 after). were born between 1973 and 1989, Registration was completed upon diagnoses through 1989, National mother and child leaving the hospital. Cancer Register Swedish Medical Birth Register Myeloid leukemia, 0±14 years who were (ICD-8 to 1986 and ICD-9 after). born between 1973 and 1989, diagnoses Registration completed when mother through 1989, National Cancer Register and child leave the hospital. Swedish Medical Birth Register (ICD- NHL, 0±14 years who were born between Same as Cnattingius et al., 1995 [49] 8 to 1986 and ICD-9 after). 1973 and 1989, diagnoses through 1989, the National Cancer Register Five controls per case were selected from the source population who were alive at the case diagnosis and who were matched on sex, birth year and month. Same as Cnattingius et al., 1995 [49] Controls were ascertained from New York live birth records and matched to cases at a 1:1 ratio on birth year and sex. Four live born controls per who survived the neonatal period were selected from Victorian births at random and matched to cases on date of birth within 6 months. The Victorian Perinatal Data Overall, leukemia (ALL, AML), CNS Collection Unit Congenital (astrocytoma), SNS (NB), lymphoma, Malformations/BDs Register (BDs STS (RMS), renal (WT), RB, germ cell/ coded according to the British gonadal, bone, and hepatic, 0±14 years, Pediatric Association's modification of 1/1/1984 to 12/31/1993, the Victorian the ICD-9). The authors noted that Cancer Registrar "the register collects information on both structural defects and chromosomal anomalies at birth. . .The register excludes certain trivial malformations, such as birth marks, skin tags and hydroceles." BDs were ascertained up to the age of 15 years. Me hes et al., 1998 [52] (Germany) Physical exam for mild errors of morphogenesis Leukemia, 7 months-14 years, NR, the Department of Pediatrics, University Medical School of Pe cs and the University Children's Hospital, TuÈbingen, Germany There were two control comparison groups: 1) children with acute infectious diseases and 2) siblings. Mertens et al., 1998 [43] (U.S., Maternal interview (ICD-9 coded 740± ALL, AML, cases from three different Controls were selected from regional Canada, Western Australia) 759). Some minor BDs were included. leukemia studies diagnosed at 0±18 populations by a modified RDD months (CCG-E09), 0±17 years method and matched on telephone (CCG-E14), 0±14 years, 1983±1994 exchange, age, and race (for E14 and (CCG-E15), the Children's Cancer Group E15). Buck et al., 2001 [68] (New York State, U.S., excluding New York City) Parental telephone interview/ supplemented with data from birth certificates NB, 0±5 years, 1976±1987, the New York Controls were randomly selected State Cancer Registry from live birth registries and frequency matched to cases on birth year. (Continued) 9 / 56 Infante-Rivard et al., 2001 [42] Parental interview for major BDs (QueÂbec, Canada) (ICD-9 coded 751±754) Roganovic et al., 2002 [50] (Rijeka, Croatia) Me hes et al., 2003 [80] (P eÂcs, Hungary) NR (minor BDs ascertained) Abdominal roentgenograms and WT, 2 months to 9 years for cases, NR, anteroposterior radiographs for cases; Department of Pediatrics, University radiography for trauma or acute Medical School of Pe cs, Pe cs, Hungary abdomen in controls; physical exam for both cases and controls. Spinal dysraphism ascertained. Controls were selected from family allowance files and were individually matched to cases on age within 3 months, sex, and region of residence at diagnosis. Controls were healthy children that were the same age and gender as cases. Controls were children with radiography for trauma or acute abdomen ranging in age from 1±10 years. One control per case was selected by RDD individually matched to cases on date of birth within 6 months for cases aged <3 years and 1 year for cases aged >3 years. Controls aged 0±18 years were selected from patient chest radiographs ordered by general practitioners and pediatricians in the outpatient ward and emergency room physicians. Ten controls without leukemia per case were randomly selected from the birth certificate records and were frequency matched to cases on birth year. Two controls per case were randomly selected from birth certificates matched to cases on birth date and gender. Controls were replaced if they died younger than their matched case's diagnosis age. Ten controls without NB per case were randomly ascertained and were frequency matched on year of delivery. Controls were randomly selected using phone numbers representative of the French population frequency matched to cases on age and gender. A similar sized control group identified from the Radiology Department logs was selected from children admitted at the same hospital for polytrauma. Maternal telephone interview (ICD-10 NB, 0±14 years, 1/1/2003-12/31/2004, coded Q00-Q99). BDs were classified the National Registry of Hematological as minor and major according to the Cancer and the National Registry of European Surveillance of Congenital Childhood Solid Tumors Anomalies. Loder et al., 2007 [25] (Indiana, U.S.) Chest radiographs were reviewed for rib number. Overall, solid, lymphoproliferative, and neural, 1±12 years, malignancies cared for from 2001±2005, Riley's Children's Hospital Pediatric Tumor Registry Merks et al., 2008 [21] (Amsterdam, Netherlands) Controls were selected from the French population by sampling from 60,000 representative addresses taken from the French national telephone directory plus unlisted phone numbers generated randomly. Age and gender quotas were applied. Controls were recruited from the city of Haarlem and the surrounding semirural and rural area. The control group was recruited through RDD and frequency was matched to cases on sex and birth year within 1 year at ratios of approximately 1:2 for males and 1:1 for females. Phase one controls (5/1999-10/2002) were sampled from the population through RDD. Phase two controls (10/2003-3/2008) were selected from state birth registries. Controls were frequency matched to cases on birth year and region of residence based on the phase one case distribution. The control group was randomly recruited from the Pediatric Outpatient Service at the Ege University Medical Faculty. Four controls that matched to each case on birth date and sex were selected from the California birth certificate database. The control group consisted of healthy children of the same age, gender, and ethnicity. Controls were recruited at random from the telephone directory using gender and age quotas in eight strata reflecting the expected distribution of all the cases. Controls were selected from individuals seen at the healthy child clinic of Mersin University Hospital and Mersin Obstetric, Gynecology and Children Hospital, Department of Pediatric Hematology and Oncology who were within the same age range, sex, and ethnicity as cases. Two medical geneticists qualified in pediatric genetic dysmorphology examined patients for ageindependent minor BDs by using the London Dysmorphology database. Overall, hematopoetic, CNS, WT/GCT, RMS, OS, NR, NR, Cases were diagnosed at Ege University Faculty of Medicine, Izmir, Turkey Overall, all acute leukemia, ALL, AML, Controls were randomly selected lymphoma, CNS, NB, renal, bone tumors, pediatric patients who received a sarcomas, 0±19 years, 2003±2009, the chest X-ray at Fairview Ridges University of Minnesota Medical Center- Hospital in Burnsville, MN. Fairview All acute leukemia, ALL, AML, 0±14 years, 2003±2004, the National Registry of Childhood Hematopoietic Malignancies Overall, lymphoma, solid tumors, 0.1±18 years, NR, "2 different institutions" HB, 0±5 years, 2000±2008, the The discovery control group was Children's Oncology Group (COG) for the identified from the birth registries discovery cohort, the UPDB linked to the from 32 states and matched to cases State Cancer Registry from 1978±2010 on birth weight, gender, birth year, for the validation cohort and region. The validation control group was selected randomly from the Utah population and matched 10:1 to cases on gender and birth year. Brain tumors, NR (childhood), 2005± 2010, 10 Australian oncology centers Solid tumors (clear cell renal cell carcinoma, CNS, EWS, fibrosarcoma, GCT, HB, OS, RB, RMS, synovial sarcoma, STS, WT), 0±18, NR, NR Controls were recruited through random digit dialing and matched to childhood CBT cases on age, sex, and state of residence at a 3:1 ratio [108]. Cases were from Rio De Janeiro and Sao Paulo. The control group was comprised of school children from Rio de Janeiro without a diagnosis of cancer or a predisposing syndrome. Parodi et al., 2014 [72] (Italy) Venkatramani et al., 2014 [84] Maternal interview/ the Utah (U.S.) Population Database (UPDB, ICD-9 codes 740±759) Greenop et al., 2014 [60] (Australia) Mailed exposure questionnaire Santos et al., 2016 [109] (Brazil) Exam for cafeÂ-au-lait spots by two trained dysmorphologists Rios et al., 2016 [74] (France) Hall et al.c, 2017 [90] (California, U.S.) Bailey et al., 2017 [59] (France) Cohort studies Windham et al., 1985 [27] (Norway) Mili et al., 1993 [28] (Georgia, U.S.) Mili et al., 1993 [29] (Iowa, U. S.) Maternal telephone interview (ICD-10 NB, <6 years, 2003±2004 (ESCALE) and The analysis was based on pooled coded). Minor BDs or unspecified BDs 2010±2011 (ESTELLE), French National data from two French case-control were excluded according to the Registry of Childhood Cancer studies (ESTELLE and ESCALE). European Surveillance of Congenital Controls were frequency matched to Anomalies. cases on sex and age so that there would be at least one control per case. California birth certificates Maternal telephone interview Medical Birth Registry (ICD-8 codes 740±759) GCT, yolk sac tumors, teratomas, 5 years, 1988±2013, California Cancer Registry Brain tumors, 0±14 years, 2003±2004 (ESCALE) and 2010±2011 (ESTELLE), French National Registry of Childhood Cancer Overall, leukemia, nervous system tumors, renal cancer, eye cancer, NB, 0±13 years, 1967±1980, the Norwegian Cancer Registry Controls were randomly selected from California birth records frequency matched to cases on birth year. Same as Rios et al., 2016 [74]. Individuals without BDs from the Norwegian Medical Birth Registry comprised the unexposed group. The Metropolitan Atlanta Congenital Overall, leukemia, brain tumors, NB, WT, The expected number of cancer Defects Program (major BDs, six-digit RB, 0±14, 1/1/1975-12/31/1988, the cases was calculated based on code for reportable BDs, a Georgia Center for Cancer Statistics at Atlanta Surveillance Epidemiology modification of the British Pediatric Emory University and End Results rates. Association Code, which uses a modification of ICD-9 codes). BDs were captured in the first year of life. Overall, leukemia, brain tumors, NB, The expected number of cancer sarcoma, 0±7 years, 1/1/1983-12/31/ cases was calculated based on Iowa 1989, the State Health Registry of Iowa's Surveillance Epidemiology and End Cancer Registry (a SEER registry) Results rates. The Iowa Birth Defects Registry (only major BDs, six-digit code for reportable BDs, a modification of the British Pediatric Association Code, which uses a modification of ICD-9 codes). BDs were captured in the first year of life. (Continued) 12 / 56 Agha et al., 2005 [33] (Ontario, Canadian Congenital Anomalies Canada) Surveillance System (ICD-9 codes 740.0±759.9). BDs were captured in the first year of life. Overall, leukemia, lymphoma, CNS, sympathetic nervous system, RB, renal tumors, bone tumors, STS, GCT, trophoblastic and other gonadal carcinoma, and malignant epithelial, 0±19 years, 1979±1996, the Ontario Cancer Registry Overall, 0±8 years, 1959±1966, the Collaborative Perinatal Project (CPP) subject population Children without BDs were selected from the Birth Certificate File of Ontario. For every child with a BD, one child without BDs was selected matched on birth year, maternal age, birth order, mother's marital status, and parent's place of birth (Ontario vs. other). Children without birthmarks in the CPP cohort were used as the comparison group. NB, 0±14 years, 1967±2004, the Cancer The comparison group included all Registry of Norway live born children in Norway during 1967±2004 without reported congenital malformations. Northern Congenital Abnormality Survey (ICD-10 coded BDs). The authors note including only "major congenital anomaly subtypes" BDs were captured in the first year of life. Overall, ALL, AML, other leukemia, HL and NHL, brain, NB, WT, RB, RMS, and others, NR, 1985±2001, the Northern Region Young Persons Malignant Disease Registry Children without BDs born in the Northern Region were used as the comparison group. Texas Birth Defects Registry (1979 Overall, leukemia, lymphoma, CNS, NB, All children live born in Texas and not British Pediatric Association RB, renal tumors, hepatic tumors, registered in the Texas Birth Defects Classification of Diseases and the malignant bone tumors, STS, GCT, other Registry who were identified through 1979 ICD-9-CM, as modified by the U. epithelial, 0±14 years, 1996±2005, the birth certificates were included as the S. CDC and the Texas Department of Texas Cancer Registry controls. State Health Services). Major structural and chromosomal BDs were included. More minor defects were included if the individual also had a major BD. BDs were captured in the first year of life. The California Birth Defects Overall, leukemia, lymphoma, CNS, NB, Children without major BDs born from Monitoring Program and birth WT, Non-CNS germ cell, RMS, 0±14 1988±2004 were used as the certificates (major BDs were classified years, 1988±2006, the California Cancer comparison group. based on the British Pediatric Registry Association Classification of Diseases codes, as modified by the CDC). BDs were captured in the first year of life. State Birth Defect Surveillance Program (selected major BDs as defined by the National Birth Defect Prevention Network); BD's were captured up to 15 years of age. Danish National Hospital Register (Danish version of ICD-8 codes from 1977±1993: 740±743, 746±747, 759, ICD-10 codes from 1994 onwards Q00-07, Q20-28, Q90-99) Overall, leukemia, MDS/MPD, lymphoma, brain tumor, NB spectrum, RB, kidney tumor, liver tumor, sarcoma, germ cell, trophoblastic and gonadal tumor, 0±14 years, 1968±2005 for AZ, 1983±2005 for IA, 1994±2008 for Utah, Arizona and Utah state cancer registries Overall, CNS, mesothelial and soft tissue, skin, lymphatic and haematopoietic, other systems, 0±19 years, 1/1/1977-12/31/2007, Danish Cancer Registry The comparison group included individuals without BDs selected randomly from state birth certificates who were frequency matched 3:1 to the cases by birth year. The comparison group consisted of all children without BDs live born in Denmark between 1977±2007 after excluding missing data, adopted children, twins, and chromosomal anomalies. Western Australian Register of Overall, leukemia, lymphoma, CNS, NB, The comparison group included all Development Anomalies (British RB, renal tumors, hepatic, bone, STS, live born children with > 90 days of Pediatric Association Classification of gonadal and germ cell, other epithelia/ follow-up born in Western Australia Diseases, a five-digit extension of melanoma, >90 days-14 years, 1982± from 1982±2007 BDs. ICD-9). BDs were captured in the first 2007, Western Australia Cancer Registry year of life. (Continued) 13 / 56 Janitz et al., 2016 [35] (Oklahoma, U.S.) Case-cohort studies Johnson et al., 2008 [76] (Minnesota, U.S.) Puumala et al., 2008 [82] (Minnesota, U.S.) Spector et al., 2008 [85] (Minnesota, U.S.) Nested case-control studies Wanderas et al., 1998 [92] (Norway) Overall, leukemia, lymphoma, CNS, hepatic tumors, STS, GCT, 0±12 years, 1/1/1997-3/31/2009, Oklahoma Central Cancer Registry Case series studies with external comparison groups Breslow et al., 1982 [83] (The National Wilms' Tumor Study (NWTS))[110] The NWTS registration form (ICD-9 codes 741±759) Ruymann et al., 1988 [87] (Ohio, U.S.) Autopsy reports (major and minor ascertained) Narod et al., 1997 [53] (United Kingdom) A postal questionnaire to family physicians of children diagnosed with cancer and who were alive at the end of 1988 (ICD-9 codes 7400±7599) WT, 0±15 years, 10/1969±3/1981, the Survey findings were compared to NWTS Statistical Center; histologic the CPP and results from the CDC confirmation was available for 75% of the Surveillance system on BDs. patients RMS, NR, NR, Autopsy results from children in the Intergroup Rhabdomyosarcoma Studies I and II Leukemia, lymphoma, brain and spinal cord, NB, RB, WT, liver, OS, ES, STS, gonadal and germ cell, 0±14 years, 1971±1986, National Registry of Childhood Tumors childhood cancers (HRs 2.81 and 2.03 for those diagnosed at 0±8 and 1±8 years respectively) [37]. Botto et al. examined a number of specific BD types in children without chromosomal anomalies observing that a majority increased risk [32]. Finally, Sun et al. reported BDs of both the circulatory and nervous system were positively associated with pediatric cancer with 14 / 56 Comparison group 1¥ Overall case-control studies Stewart et al., 1,416 (25) 1958 [18] Me hes et al., 104 (72) 1985 [19] Schumacher et al., 1992 [23] Cases and controls were examined by two different observers. Although the authors report that "11% of controls and 7% of patients were scored independently by 2 observers, resulting in high scores", they do not report the data associated with this comment. Comments Individuals with suspected birthmarks were excluded. The authors note that none of the individuals were recorded as having a genetic syndrome. Four cases of DS were observed in the cohort. 1.58 (1.33±1.87)e Children with leukemia were excluded 12.44 (10.10±15.32)e from the non-chromosomal analysis. Results for specific BDs exclude - children with chromosomal anomalies. (Continued ) Certain congenital musculoskeletal deformities (754) Other BD of limbs (755) Certain congenital musculoskeletal anomaly (756, excluding 754) BD of integument (757) Other and unspecified BD (759) Any BD Non-chromosomal Brain Neural tube defects, all Spina bifida w/out anencephalus Encepahalocele Microcephaly Holoprosencephaly Hydrocephalus (no spina bifida) Eye Anophtalmia/ microphthalmia Congenital cataract Aniridia Ear (anotia/microtia) Craniosynotosis Heart Complex heart defects Common truncus Transposition of great arteries Tetralogy of Fallot Atrioventricular septal defect (AV canal) Total anomalous pulmonary venous return Pulmonary valve atresia Tricuspid valve atresia and stenosis Ebstein anomaly Hypoplastic left heart syndrome Coarctation of the aorta Aortic valve stenosis Other major congenital heart defects Pulmonary valve stenosis Ventricular septal defect, membranous Ventricular septal defect, NOS Atrial septal defect Risk estimate (95% CI) 2.56 (1.70±3.86)e Renal tumors case series with an external comparison group studies WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT HB HB HB HB HB HB HB HB HB HB HB HB HB WT WT WT WT WT WT WT Renal carcinoma HB Hepatic Comments Hepatic tumors case series with an external comparison group studies Malignant bone tumors case-control studies OS ES OS Bone OS Bone Bone Bone ES and related sarcomas of bone Other specified and unspecified malignant bone Abnormal ribs Abnormal ribs Abnormal ribs Abnormal ribs 2.0 (NRCT); 4.7 (BC) Two hundred seventy-five cases with an 2.1; 1.9 established genetic cause were removed; authors report RRs but do not 0; 0 define the RR abbreviation. Malignant bone tumors cohort studies 6 (45,200) NA Malignant bone tumors case series with an external comparison group studies Soft tissue and other extraosseous sarcomas case-control studies Soft tissue and other extraosseous sarcomas cohort studies 2 ( 10,891 ) 18 (241,473) Sarcoma NA NA NA NA NA NA NA NA NA NA NA NA NA NA 9 (115) 13 (115) 4 (115) 5 (115) NR (115) NR (115) NR (115) 1,248 (18) 1,248 ( 3 ) NR NR 10.47 (1.43±76.58)e Children with chromosomal anomalies were excluded. Estimates adjusted for 24.22 (3.30±177.63)e calendar year and sex. Any BD (w/chromosomal) 3.7 (1.3±10.6)e Soft tissue and other extraosseous sarcomas case series studies with an external comparison group studies Excluded syndromes known to be associated with cancer (e.g. DS) (N category). The exact number of STS cases was suppressed. Authors presented rates for two external comparison groups: 1) the NWTS and 2) the CPP. Rate ratios were calculated as the ratio of the rate in study population to the rate in the external comparison group. Two hundred seventy-five cases with an established genetic cause were removed; authors report RRs but do not define the RR abbreviation. (Continued ) 39 / 56 Germ cell tumors, trophoblastic tumors, and neoplasms of gonads case-control studies Germ cell tumors, trophoblastic tumors, and neoplasms of gonads cohort studies 181 (0) 216 (19) 216 ( 7 ) 8 (59,258) 1 ( 6,327 ) 6 (44,151) 6 (23,368) 6 (22,109a) NR NR 6 (147, 940) Any BD (w/chromosomal) 13.6 (5.0±36.7)e Non-chromosomal 14.3 (5.3±38.7)e Large/multiple birthmarks 1.0 (0.2±4.1)b; 1.4 (0.6±2.9)b NR 281 (55) 281 (28) 5 (22,856) 1 (45,200) Other and unspecified malignant tumors case-control studies Germ cell tumors, trophoblastic tumors, and neoplasms of gonads nested case-control studies Germ cell tumors, trophoblastic tumors, and neoplasms of gonads case series studies with an external comparison group studies Other and unspecified malignant tumors cohort studies Solitary cafeÂ-au-lait spots Multiple cafe -au-lait spots 1.51 (0.75±3.06)a,b (Continued ) Other and unspecified case series studies with an external comparison group studies ¥For case-control and nested case-control studies the total number of cancer cases (comparison group 1) and non-cancer cases (comparison group 2) is shown in columns 2±3 with the number in parentheses indicating the number of individuals with BDs in each comparison group. For cohort studies, comparison group 1 is noted as above; comparison group 2 shows the number of cancer cases among the number without BDs in parentheses. For casecohort studies, comparison group 1 is the same as for other study designs; comparison group 2 shows the total number of individuals with cancer among the total number of individuals in the sub-cohort in parentheses. *p<0.05; **p<0.01; ***p<0.001; bOdds Ratio; cRate Ratio aCalculated based on information; dStandardized Incidence Ratio; eHazard Ratio; fIncidence Rate Ratio; gO/E ratio; hRelative Risk 42 / 56 generally weaker associations for older children and when the follow-up period started at the time of BD diagnosis [38]. Leukemia (Table 3) We identified 36 articles reporting findings for associations between leukemia and hematological malignancies and BDs. Case-control studies (n = 24). Risk estimates ranged from 1.07 to 11.6 [15±17, 39±47] for associations between any/major BDs and leukemia overall or specific leukemia subtypes. Shu et al. observed no leukemia cases with BDs other than one case with Down syndrome [48]. Studies excluding DS cases from overall or sub-analyses generally reported weaker associations [39±41, 44±46, 49]. Several studies reported positive associations between minor BDs and leukemia/hematological malignancies ranging from 1.48 to 67.48 [19, 20, 45, 50±52]. Cleft lip or palate was inconsistently associated with lymphatic and myeloid leukemia [40, 43, 49]. Several studies observed positive associations between hematologic malignancies and birthmarks [43, 46, 50] and rib anomalies [23±26]. Minor BDs of the hand, foot, eye, nose, mouth, and ear were all positively associated with hematological malignancies in one study [20]. Finally, inconsistent results were reported for a number of other specific BDs [41, 43, 45, 46, 53]. Cohort studies (n = 11). In six studies, positive associations were observed between leukemias and any BDs/major BDs ranging from 1.1±21.97 [27±31, 33]. Associations were generally weaker in studies/analyses with DS cases were excluded [27±29, 31, 32, 34±36]. Rankin et al. noted, however, that ªthe association between congenital anomalies and childhood leukemia remained after exclusion of Down Syndrome casesº [30]. Notably, Dawson et al. reported a positive association between other leukemias (types other than ALL or AML) and non-chromosomal BDs [34]. Finally, Sun et al. examined nervous and circulatory system BDs and risk of lymphatic and haematopoietic tissue malignancies in children without chromosomal anomalies and reported positive associations that were stronger for infants versus children 1±15 years. Associations were generally weaker when follow-up time was counted from the BD diagnosis rather than from birth [38]. Case series with an external comparison group studies (n = 1). Narod et al. examined a number of specific abnormalities and did not report any consistently increased risks for leukemia [53]. Lymphoma (Table 3) We identified 17 articles reporting findings for associations between lymphoma and BDs. Case-control studies (n = 9). Four studies reported inconsistent associations between lymphoma/lymphoma subtypes and any BDs/major BDs with ORs ranging from 0.7±4.43 [15±17, 54]. Based on 19 lymphoma cases, Mangani et al. reported 0 lymphoma cases with BDs [47]. Rib anomalies specifically were inconsistently associated with lymphoma subtypes [23, 24, 26]; however, one study combining lymphoma with leukemia in their analysis reported a significant OR of 2.0 [25]. Cohort studies (n = 7). Lymphoma was positively associated with any BD in three of four cohort studies [30, 31, 33, 35]. Fisher et al. and Janitz et al. reported positive associations between non-chromosomal anomalies and lymphoma [35, 36], while both Botto et al. and Dawson et al. observed risks for lymphoma/lymphoma subtypes in both directions in children with non-chromosomal BDs and those not known to be related to cancer [32, 34]. Certain musculoskeletal anomalies were associated with lymphoma in one study [33]. 43 / 56 Case series with an external comparison group studies (n = 1). Narod et al. reported findings for cardiac septal defects, genitourinary abnormalities, and spine and rib abnormalities with a significant positive association for spine and rib abnormalities for the British Columbia registry comparison group only [53]. CNS and miscellaneous intracranial and intraspinal neoplasms (Table 3) We identified 31 articles reporting findings for associations between CNS tumors and BDs. Case-control and nested case-control studies (n = 19). Risk estimates for associations between CNS tumors and any BDs/major BDs ranged from 1.0 to 4.7 [15±17, 55±60]. Two studies did not report risk estimates; however, one reported no association and the other reported a decreased frequency of BDs (excluding minor BDs) in cases versus controls [61, 62]. Altmann et al. reported an increased odds of astrocytoma in children with any BD [17]. However, three studies [58, 59, 63] found weak to no evidence that children with any BD/ major BDs have an increased risk for specific CNS subtypes with the exception of other gliomas [58] where a 2±3 fold increased risk was reported. Importantly, these results were unchanged after excluding seven CNS tumor cases with Neurofibromatosis Type 1 [58]. Partap et al.'s results contrast with these findings by showing increased odds of a BD history for MBs and PNETs compared to controls and inverse associations for gliomas [57]. Gold et al. reported a strong positive association only between brain tumors and club foot [64]. Another study reported universally positive associations for hand, foot, eye, nose, mouth, and ear minor BDs [20]. Birthmarks/deformities were not associated with brain tumors in one study [65]. Altmann et al. reported highly significant and strong associations between CNS tumors and nervous system and eye/face/neck abnormalities [17]. Finally, several investigators reported that brain tumor cases with varying subtypes had higher odds of rib abnormalities than controls [23±26]. Cohort studies (n = 11). Six studies reported positive associations for any BD and CNS tumors ranging from 1.11 to 2.9 [27±31, 33]. Fisher et al. reported increased HRs for CNS tumors in both children with and without chromosomal BDs of 1.87 and 1.80 [36]. Botto et al. reported an increased brain tumor incidence in children with structural BDs that was stronger for other brain tumors [32]. Dawson et al. reported a weak imprecise association of 1.26 between BDs not known to be related to cancer and CNS tumors [34]. Janitz et al. reported increased risks in children with non-chromosomal BDs that decreased with increasing age [35]. For specific BD types, nervous system abnormalities were strongly associated with CNS tumors in three studies [27, 33, 38]. Finally, circulatory system malformations were positively associated with CNS tumors in one study [38]. Case series with an external comparison group studies (n = 1). Narod et al. reported inconsistent or inverse associations for total BD and most specific abnormalities with the exception of hydrocephalus where both RRs were positive and significant [53]. Neuroblastoma and other peripheral nervous cell tumors (Table 3) We identified 26 articles reporting findings for associations between NB and BDs. Case-control studies (n = 14). Risk estimates from 11 studies reporting associations between any BDs/physical anomalies and NB/sympathetic nervous system tumors ranged from 1.0 to 8.61 [16, 17, 66±74]. Major and minor BDs were positively associated with NB in four [69±71, 74] and two studies, respectively [69, 71]. Several studies examining specific BDs generally observed positive associations [69±71], particularly for digestive system/gastrointestinal and genitourinary anomalies [17, 69, 71, 74] and during infancy [69]. Rib anomalies were 44 / 56 positively associated with NB/other peripheral nerve tumors in three studies to varying degrees [23, 24, 26]. Cohort and case-cohort studies (n = 11). Children with any BD had a consistently higher risk of NB across studies with RRs from 1.1±20.3 [27±31, 33, 75]. Fisher et al. and Botto et al. [32, 36] also reported that non-chromosomal BDs were associated with NB and other peripheral nervous system tumors with individuals in the BD group having a >2-fold higher risk, while Dawson et al. reported a lower risk estimate of 1.41 for individuals with BDs not known to be related to cancer [34]. Finally, a case-cohort study reported a similar percentage of cases and sub-cohort members had BDs recorded in their birth records [76]. For specific anomalies, Agha et al. reported more observed than expected cases of SNS tumors in those with other anomalies of the digestive system [33]. Case series with an external comparison group studies (n = 1). Narod et al. reported results that were imprecise and in opposite directions for total BD. Generally positive associations were observed for specific BDs, particularly for cardiac and gastrointestinal abnormalities [53]. Retinoblastoma and eye tumors (Table 3) We identified 10 articles reporting findings for associations between RB/eye tumors and BDs. Case-control studies (n = 2). Results were mixed with Mann et al. finding no BDs in RB cases and Altmann et al. reporting a strong positive OR of 15.0 [16, 17]. For specific BDs, strong associations were reported for chromosomal anomalies in a single study. Cohort and case-cohort studies (n = 7). Of seven studies, six reported positive associations ranging from 2.2±4.7 between BDs overall or those that excluded individuals with chromosomal anomalies [27, 28, 30±33]. Dawson et al. reported no RB cases [34]. Chromosomal and eye anomalies were strongly associated with RB in one study [33]. Case series with an external comparison group studies (n = 1). Narod et al. reported inconsistent results for associations between RB and BDs and strong associations between RB and cataracts and ventricular septal defects [53]. Renal tumors (Table 3) We identified 21 articles reporting findings for associations between renal tumors and BDs. Case-control and nested case-control studies (n = 10). Wilkins et al. reported similar frequencies of any BD in WT cases and controls [77], while two other groups reported positive associations [16, 17]. Stronger associations were reported for non-WT associated BDs than WT-associated BDs in one study [78]. Two studies reported significant positive associations between WT and spina bifida [79, 80]. WT was also reported as positively associated with eye/ face/neck BDs and chromosomal BDs [17]. WT/renal carcinomas were positively associated with rib abnormalities in three studies [23, 24, 26]. Finally, Lindblad et al. reported that associations between BDs and WT were not confirmed in a nested case-control study [81]. Cohort and case-cohort studies (n = 9). Risk estimates for cohort and case-cohort studies examining associations between any BD and WT or renal tumors ranged from 1.0±3.2 [27, 28, 30, 31, 33, 82]. Fisher et al. reported significant risks for WT only in children with chromosomal BDs [36]. In two studies excluding children with chromosomal anomalies and syndromes known to predispose toward cancer, results were mixed [32, 34]. Case series with an external comparison group studies (n = 2). Breslow et al. compared the rate of different BD types in a case series to two external comparison groups and observed consistent strongly increased rates of aniridia, double-collecting system, and hemihypertrophy [83]. Narod et al. reported consistent findings across the two different comparison groups for 45 / 56 genitourinary and reproductive organ associated BDs. Renal carcinomas were strongly associated with spine and rib malformations in one study [53]. Hepatic tumors (Table 3) We identified 10 articles reporting associations between hepatic tumors and BDs. Case-control studies (n = 3). There was no significant association between HB and any BDs in one study [16], while another reported a non-significant 9.3-fold increased odds of BDs in hepatic tumor cases versus controls [17]. For specific abnormalities, both spina bifida and genitourinary conditions were positively associated with HB in one study [84]. Other abnormalities were examined only in single studies. Cohort and case-cohort studies (n = 6). One study reported three hepatic tumor cases in individuals with BDs and none in the comparison group [33]. Carozza et al. reported no association between liver tumors and any BD [31], while Spector et al. reported an almost 6-fold increased risk of HB in association with any BD [85]. Both Botto et al. and Dawson et al. reported strongly increased IRRs for liver tumors in individuals with BDs after exclusion of children with chromosomal BDs and syndromes known to be associated with cancer [32, 34]. In the Janitz et al. study, there were too few hepatic tumor cases to examine statistical associations [35]. Digestive and chromosomal anomalies were positively associated with hepatic tumors in one study [33]. Case series with an external comparison group studies (n = 1). Narod et al. reported positive associations between spina bifida and genitourinary abnormalities and HB [53]. Malignant bone tumors (Table 3) We identified 12 articles reporting associations between BDs and bone tumors. Case-control studies (n = 7). One study reported no association between OS and any BDs [12]. Two studies reported positive but imprecise associations (ORs = 1.56 and 23.2) between bone cancer and any BD [16, 17]. Minor BDs were associated with OS in one study (OR = 12.4) [20]. One study reported a positive association between bone tumors and chromosomal anomalies [17]. Finally, three studies reported inconsistent associations between rib anomalies and bone cancer (OS or ES) [23, 24, 26]. Cohort studies (n = 4). Mixed results were reported for any BD/BDs not known to be related to cancer and bone cancer in three studies [31, 33, 34]. Botto et al. reported a two-fold non-significant increased incidence of ES in individuals with non-chromosomal structural BDs [32]. An ~ 4-fold excess of bone tumors was reported in children with other musculoskeletal BDs in one study [33]. Case series with an external comparison group studies (n = 1). Narod et al. reported consistently strong associations using two different comparison groups between bone tumors overall and spina bifida; however, the association was based on only one case. Strong positive associations were also reported between osteodystrophy and cataracts and ES using both comparison groups [53]. Soft tissue and other extraosseous sarcomas (Table 3) We identified 19 articles reporting associations between BDs and soft tissue and other extraosseous sarcomas. Case-control studies (n = 8). Four studies reported positive associations between any BDs/major BDs and STS/RMS ranging from 1.3 to 7.9 [15±17, 86]. Minor BDs were observed in 100% of RMS cases and only 35% of controls in one study [20]. Further evidence for a positive association between genitourinary malformations and STS was reported for RMS [17]. 46 / 56 Three studies examined associations between rib anomalies and STS/RMS reporting inconsistent associations [23, 24, 26]. Minor BDs were not positively associated with RMS [86]. Cohort studies (n = 9). Five cohort studies examined associations between any BDs and STS/RMS, with all finding positive associations ranging from 1.9 to 4.1 [29±31, 33, 35]. Three studies reported positive associations between RMS and non-chromosomal (structural) BDs, while one study reported a non-significant inverse for STS for BDs not known to be related to cancer [32, 34±36]. Finally Sun et al., reported strong positive associations between nervous system BDs and mesothothelial and soft tissue cancers across age groups and weaker associations for circulatory system BDs [38]. Case series with an external comparison group studies (n = 2). One study reported markedly higher rates of CNS anomalies, upper alimentary tract/digestive systems, cardiopulmonary anomalies, and accessory spleens in the RMS cohort than in the two comparison groups [87]. Narod et al. reported that genitourinary and spine and rib malformations were positively associated with STS but this was inconsistent across comparison groups used for RR calculations. Cardiac septal defects were not significantly associated with RMS [53]. Germ cell tumors (GCT), trophoblastic tumors, and neoplasms of gonads (Table 3) We identified 16 articles reporting associations between BDs and GCTs, trophoblastic tumors, and neoplasms of gonads. Case-control and nested case-control studies (n = 9). Several studies reported positive associations between any BDs and gonadal tumors/GCTs ranging from 1.1 to 9.12 [16, 17, 88± 90]. Genitourinary defects and inguinal hernias were positively associated with testicular tumors [91]. Johnson et al. reported a strong association with cryptorchidism in males [88]. Merks et al. reported an ~3-fold increased odds of cervical anomalies in GCT cases compared to controls [26]. Hall et al. reported an increased odds of ear/face/neck anomalies in GCT cases and those with teratomas specifically [90]. In a nested case-control study, no cases had BDs in the 0±4 year old age group [92]. Cohort studies (n = 6). Among two cohort studies, Agha et al. reported no association between germ cell, trophoblastic and other gonadal carcinoma and any BD, while Carozza et al. reported a significant 5-fold increased risk [31, 33]. Fisher et al., Botto et al., and Janitz et al. reported significant positive associations between GCTs/Gonadal and GCT and nonchromosomal BDs, while Dawson et al. reported a weak positive association for BDs not known to be related to cancer [32, 34±36]. GCTs were strongly associated with other musculoskeletal anomalies in one study [33]. Case series with an external comparison group studies (n = 1). Narod et al. reported consistent increased risks between gonadal and GCT tumors and total BDs and weak non-significant associations between these tumors and genitourinary defects. Musculoskeletal, spinal, and spine and rib malformations were consistently positively associated with [53]. Other tumors (Table 3) Several studies examined other childhood cancers and various subtype groupings for their association with BDs. For completeness, we include these results; however, given the heterogeneous nature of the BDs/cancer types and outcomes examined, we do not summarize the findings. 47 / 56 Quality assessment (S2 and S3 Tables) The mean percent total quality point score was higher for cohort (88% ± 13%) than case-control (62% ± 19%) studies. The three case-cohort study reports that were based on the same parent study were of high quality each receiving 89% of the total quality points, while the three nested case-control studies received a mean of ~85% ± 6% of the total quality points (data not shown). Discussion Associations between BDs and pediatric cancer have been extensively studied. Overall conclusions on pediatric cancer risk in children with BDs are limited by heterogeneity in study design, subject selection (including inclusion/exclusion criteria), measurement, definitions, and length of follow-up for ascertaining BDs, as well as covariate adjustment in models. For example, in studies ascertaining individuals with BDs from BD surveillance systems, standardized definitions using published classification schemes were used to group individuals with BDs according to BD type (e.g. major, minor, and specific BD types), while for studies ascertaining BDs through parental questionnaire, coding schemes were often elusive. We strongly emphasize that future studies on this topic should employ and clearly report in their methods a standardized classification system such as that reported by Rasmussen et al. for the National Birth Defects Prevention Study [93], which will facilitate pooling and meta-analysis studies that are needed to more precisely quantify pediatric cancer risk in children with BDs. In spite of the differences in methodology used by studies on this topic that limit overall conclusions, several noteworthy findings emerged from this review. An increased risk for pediatric cancer overall in association with BDs clearly exists with most case-control and cohort studies reporting positive associations. A seminal Nordic study of 5.2 million individuals, not included in our review because it did not present pediatric cancer specific risk estimates, linked medical birth and cancer registries to examine cancer risk in children with BDs [94]. Cancer risk was significantly increased in individuals with nonchromosomal BDs by ~1.4±1.5 fold, with stronger risks at younger ages, which was also reported in several studies included in this review [34, 35, 38]. Moreover, a strong association was observed in both Norway and Sweden (>8 fold) between nervous system abnormalities and CNS tumors [94]. Collectively, our review and the Nordic data provide strong evidence for an overall increased cancer risk in children with BDs. For leukemia, most studies excluding DS cases reported relatively weak or no evidence for an increased risk of leukemia in children with any BD/major BDs. For example, when considering the results from several cohort studies with overall higher quality than case-controls studies, generally weak associations were reported between BDs and leukemia when DS cases were excluded [28, 29, 32, 34±36] with the exception of one study [30]. It is noteworthy that consistent associations with rib anomalies and minor malformations have been reported in several studies [19, 20, 23±26, 50, 52]. These data suggest that minor BDs may be linked to leukemia development but most of the observed positive associations between major BDs and leukemia are likely explained by inclusion of DS cases. For CNS tumors, strong consistent associations with CNS abnormalities were reported in several studies [17, 27, 33, 38, 53]. When interpreting these results, it is important to consider the timing of the BD diagnosis. BDs detected only as a result of tests or procedures associated with the tumor diagnosis may lead to over-ascertainment of BDs in cases compared to controls, a potential issue raised by Altmann et al. [17]. In addition, it is also important to consider whether the abnormality occurred secondary to the tumor, a concern noted by Narod et al. for the association between brain/spinal tumors and hydrocephalus [53]. Evidence against these 48 / 56 possibilities was provided by Sun et al. who reported a strong positive association between nervous system abnormalities and CNS tumors when follow-up was initiated at the point of the BD diagnosis (i.e. prior to the cancer diagnosis) [38]. For NB, many studies reported consistent positive associations with BDs overall, although there was inconsistency for specific BD types [17, 26, 28±34, 36, 53, 66±75] with the possible exception of gastrointestinal BDs [17, 53, 69, 71]. It is important to note that some of the observed anomalies were noted as secondary to the tumor [67, 71]. Further research is needed to clarify specific abnormalities associated with NB and to confirm the timing of the abnormality as congenital. For RB/eye tumors, most cohort studies reported consistent positive associations with any BD and structural defects [27, 28, 30±33], some of which may be explained if cases with partial monosomy 13q were included that is associated with a number of anomalies and an increased RB risk [95]. Since ~ 40% of RB tumors arise from a germline mutation [96], there is biological plausibility for developmental abnormalities associated with RB haploinsufficiency. However, despite mouse studies demonstrating lethality for embryos with Rb1-/- genotypes as well as neural and hematopoietic abnormalities; heterozygotes did not have any observable defects [97]. WT was associated with a number of abnormalities, some of which are due to known syndromic causes of WT including Beckwith-Wiedemann and WAGR (Wilms tumor, Aniridia, Genitourinary anomalies and intellectual disability) syndromes. WAGR syndrome is caused by a chromosome 11p deletion and is associated with genitourinary abnormalities and aniridia (absence of the colored part of the iris) [98]. In two recent cohort studies excluding children with chromosomal anomalies, associations between BDs and WT were weak and imprecise [32, 36]. It is interesting to note, however, that a greater frequency of non-WT associated BDs were observed in children with WT versus controls in one study [78], a finding that could suggest an underlying genetic predisposition. For liver cancer, where most cases are HBs, most studies provided evidence of a positive association with any BD [17, 32, 34, 85] that may stem from genitourinary abnormalities that were positively associated with HB in three different study populations [53, 84]. It is unclear if inclusion of Beckwith-Wiedemann Syndrome or Familial Adenomatous Polyposis cases in some of studies explains the observed associations. Although a three studies detected positive associations between BDs (especially for bone BDs) and bone tumors or bone tumor subtypes [16, 17, 53], cohort study results are mixed and based on small numbers [31±34]. For STSs, increased risks in children with BDs are evident from most case-control and cohort studies [15±17, 20, 29±33, 35, 36, 86]. However, as with other cancer types, conclusions about particular abnormalities associated with risk are limited by the heterogeneous nature of BDs observed/assessed in different studies. For germ cell and other gonadal tumors, there is a relatively consistent pattern of an increased risk in association with BDs across studies [16, 17, 31, 32, 34±36, 53, 88, 89] that could be partially be due to cryptorchidism but only one study provided risk estimates in males [88]. Although not completely consistent, one of the most intriguing findings is the observed association between rib anomalies and many different childhood cancer types [23±26]. Although some of these associations could be due to detection bias as a result of diagnostic tests for malignancy, the Zierhut et al. study was not subject to this type of bias [24]. The biology underlying associations between pediatric cancer and BDs is poorly understood. If the observed statistical associations are causal, a leading theory is that a common genetic abnormality impairing normal development may subsequently predispose toward both BDs and malignancy [99±103]. Since family history is absent in most individuals with 49 / 56 non-syndromic BDs, genetic aberrations could arise through de novo mutations in the parental germline or through somatic mutations or epimutations arising early in development. For example, Beckwith-Wiedemann syndrome, can result from genetic and epigenetic mosaicism accompanied by a variably increased risk of malignancy (typically HB or WT) in the affected tissues depending on the causative genetic lesion [104]. The striking number of studies showing an association between rib abnormalities and pediatric/adolescent cancer risk may provide an important clue to underlying genetic commonalities. The finding has frequently been attributed to possible mutations in homeobox genes [25, 53] but no genetic cause has been identified so far explaining this statistical observation. Our study is the first systematic and most comprehensive review on this topic to date. However, there are limitations to consider. At the expense of specificity, we used broad search terms to capture articles examining associations between BDs and pediatric cancers, identifying >14,000 articles. To be as comprehensive as possible, we identified additional relevant articles through review of article references lists, IARC's review [11], and PubMed searches. Despite these efforts, it is still possible that we missed some eligible articles; however, it seems unlikely that they are systematically missing and therefore their exclusion should not bias our overall conclusions. In addition, we did not include gray literature [105] (e.g. meeting abstracts and PhD theses) and therefore publication bias may influence general conclusions. Conclusions and future directions Clear positive associations exist between BDs and pediatric cancer with evidence for increased risks for specific cancer/BD type combinations such as CNS abnormalities and CNS cancer, rib anomalies and a number of cancer types, and genitourinary abnormalities and HB. With advances in mutation detection through next generation sequencing technologies it may be possible to identify genetic causes underlying some of these cases, which will provide insight into overlaps between genes impacting both development and malignancy and provide a basis for identification of high risk populations among children with congenital abnormalities. Supporting information S1 Checklist. PRISMA 2009 checklist. (DOC) S1 Table. Search strategy. aSearch run without the english language limit. (DOCX) S2 Table. Quality metrics for case-control, nested case-control, and case-cohort studies. aCase-cohort study bNested case-control study (DOCX) S3 Table. Quality metrics for cohort studies. (DOCX) Acknowledgments We are grateful to the support of our expert Washington University librarians, Lori Siegel, MLS, Sylvia Toombs, MLS, and Susan Fowler, MLIS who assisted us with the design and implementation of Pubmed and Embase database searches. This review was supported by the Washington University Brown School Arlene Rubin Stiffman Junior Faculty Research Award. The funder of this award had no role in the review. 50 / 56 Author Contributions Conceptualization: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Data curation: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Formal analysis: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Funding acquisition: Kimberly J. Johnson. Investigation: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Methodology: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan, Sonia Partap, Susan A. Fowler, Todd E. Druley. Project administration: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan, Susan A. Fowler. Resources: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Software: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan. Supervision: Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan, Sonia Partap, Susan A. Fowler, Todd E. Druley. Validation: Kimberly J. 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Kimberly J. Johnson, Jong Min Lee, Kazi Ahsan, Hannah Padda, Qianxi Feng, Sonia Partap, Susan A. Fowler, Todd E. Druley. Pediatric cancer risk in association with birth defects: A systematic review, PLOS ONE, 2017, DOI: 10.1371/journal.pone.0181246