Non-chromosomal Birth Defects Research Articles

Assisted Reproductive Technologies: A New Player in the Foetal Programming of Childhood and Adult Diseases?

Assisted reproductive technology (ART) is an emerging field in medicine that incorporates complex procedures and has profound ethical, moral, social, religious, and economic implications not just for the individuals who have access to this method but also for society. In this narrative review, we summarise multiple aspects of ART procedures and the possible consequences on the mother and newborn. Moreover, we provide an overview of the possible long-term consequences of ART procedures on the health of newborns, although longitudinal evidence is particularly scant. Users should be informed that ART procedures are not risk-free to prepare them for the possible negative outcomes that may occur in the perinatal period or even in childhood and adulthood. Indeed, risk estimates point to increased liability for major nonchromosomal birth defects; cardiovascular, musculoskeletal, and urogenital (in male newborns) defects; and any other birth defects. Less certainty is present for the risk of neuropsychiatric sequelae in children conceived through ART. Thus, its application should be accompanied by adequate counselling and psychological support, possibly integrated into specific multidisciplinary clinical programmes.

Abstract 6370: Evaluating the risk of carcinomas among children with congenital anomalies: A population-based study of 21 million births

Abstract Background: Carcinomas in childhood are rare, limiting our understanding of their epidemiology. While congenital anomalies are one of the strongest risk factors for childhood cancer overall, their association with carcinomas is understudied. We evaluated the associations between chromosomal and non-chromosomal congenital anomalies and risk of carcinoma through age 18 years. Methods: We leveraged the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Cohort, which includes linked data from population-based birth defects and cancer registries for 21 million births between 1990-2018 in nine U.S. states. We used Cox regression to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the hazard of carcinomas among children with major congenital anomalies relative to children without these conditions, adjusting for sex, state of birth, and maternal age. We performed sensitivity analyses excluding cases diagnosed with carcinomas during the first 2 years of life to assess the potential impact of incidental discovery of anomalies during cancer diagnosis or treatment on our findings. Results: Our study population numbered 21,829,628 children, including 635,632 with major anomalies and 879 with carcinomas (incidence rate: 4.2 per million person-years). Mean follow-up time was 9.6 years. The most common diagnoses were thyroid (N=600 cases) and hepatocellular carcinoma (HCC; N=68 cases). Prevalence of major anomalies was 4.0% in children with carcinomas and 2.9% in children without carcinomas. The hazard of carcinomas was increased for both children with chromosomal or genetic syndromes (HR 5.3, CI 2.6-10.6; N=8) and children with non-syndromic anomalies (HR 1.6, CI 1.2-2.4; N=31). When we evaluated carcinomas by type, we observed associations between 1) chromosomal or genetic syndromes and renal cell carcinoma (HR 57.8, CI 20.7-161.3; N<5), 2) non-syndromic congenital anomalies and HCC (HR 3.8, CI 1.6-8.8; N=6), and to a lesser degree, 3) non-syndromic congenital anomalies and thyroid carcinoma (HR 1.4, CI 0.9-2.2; N=17). Notably, sensitivity analyses suggested associations were not attributable to incidental discovery of anomalies during cancer diagnosis or treatment. Discussion: In this comprehensive assessment of congenital anomalies and carcinomas in children, we report novel associations. The observed associations between congenital anomalies and carcinoma could be due to factors including: 1) common genetic pathways; 2) in utero exposures that lead to both conditions; or 3) postnatal exposures among children with congenital anomalies. Ultimately, our findings could yield new insights into the etiologies of carcinomas in childhood and inform clinical surveillance practices for children with congenital anomalies. Citation Format: Jeremy M. Schraw, Tania A. Desrosiers, Tiffany M. Chambers, Michael E. Scheurer, Charles J. Shumate, Wendy N. Nembhard, Mahsa M. Yazdy, Eirini Nestoridi, Amanda E. Janitz, Jean Paul Tanner, Russell S. Kirby, Jason L. Salemi, Chad D. Huff, Sharon E. Plon, Philip J. Lupo. Evaluating the risk of carcinomas among children with congenital anomalies: A population-based study of 21 million births [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6370.

Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies.

Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility. We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants. A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes. We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer. Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk. Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. Information on cases (n=517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n=784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those<15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

Reducing the Risk of Birth Defects Associated with Maternal Influenza: Insights from a Hungarian Case—Control Study

Influenza viruses can cause several complications during pregnancy. Therefore, we aimed to investigate the effects of influenza on the development of congenital abnormalities (CAs) by analyzing the database of the Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA). In our multicenter, case–control, population-based study, we processed clinician-reported outcomes and diagnoses collected in the HCCSCA. The case group included newborns with different non-chromosomal birth defects, while the controls were newborns without CAs. Maternal influenza, as a risk factor for CAs, was analyzed by using a logistic regression model and odds ratios with 95% confidence intervals (CIs). Our results showed that maternal influenza in the first trimester was associated with increased odds of developing non-chromosomal CAs (OR: 1.41, CI: 1.28–1.55). There were increased odds of neural tube defects (OR: 2.22, CI: 1.78–2.76), orofacial clefts (OR: 2.28, CI: 1.87–2.78), and congenital heart defects (OR: 1.28, CI: 1.10–1.49) after influenza infection. In all cases, we found a protective effect of folic acid supplementation in the first trimester. In summary, the odds of non-chromosomal birth defects are higher after maternal influenza in the first trimester, and folic acid or pregnancy vitamin supplementation and antipyretic therapy may reduce the effect of maternal influenza during the first trimester.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Educational achievement of children with selected major congenital anomalies and associated factors: a Finnish registry-based study.

Children with major congenital anomalies may be at risk of poor educational outcomes. We aimed to evaluate the educational achievement of children born with major congenital anomalies compared with children without major congenital anomalies in relation to sociodemographic factors. We performed a registry-based study including 401544 children in Finland, graduates of the compulsory school who applied to secondary education. We used health data from the Finnish Register of Congenital Malformations for children born from 1995 to 2002 linked with education data from the Finnish Ministry of Education and Culture. We used generalized linear regression to compare the mean grade differences of children with specific major congenital anomalies and 'All anomalies' subgroup (major congenital anomalies, chromosomal syndromes, and multiple anomalies) with reference children. Children with major congenital anomalies were less likely to apply for further education than reference children (88.0% vs. 96.8%; odds ratio = 4.13; 95% confidence interval, 3.92-4.36). For most non-chromosomal congenital anomalies, children born with congenital anomalies had similar educational achievement to the reference children. For the 'All anomalies' subgroup, children with congenital anomalies had lower educational achievement than reference children. Among children with congenital anomalies, male sex, lower maternal educational levels and younger maternal age were associated with lower educational achievement. For children applying to further education, most non-chromosomal congenital anomalies were not associated with lower educational achievement. Nevertheless, efforts are needed to improve educational achievement in children with major congenital anomalies associated with maternal sociodemographic background.

Maternal age is highly associated with non-chromosomal congenital anomalies: Analysis of a population-based case-control database.

The role of maternal age in the development of non-chromosomal congenital anomalies (NCAs) is under debate. Therefore, the primary aim of this study was to identify the age groups at risk for NCAs. The secondary aim was to perform a detailed analysis of the relative frequency of various anomalies. National population-based study. The Hungarian Case-Control Surveillance of Congenital Anomalies (CAs) between 1980 and 2009. A cohort of 31 128 cases with confirmed NCAs was compared with Hungary's total of 2 808 345 live births. Clinicians prospectively reported cases after delivery. Data were analysed by non-linear logistic regression. Risk-increasing effect of young and advanced maternal age was determined by each NCA group. These were the total number of NCAs: cleft lip and palate, circulatory, genital, musculoskeletal, digestive, urinary, eye, ear, face, and neck, nervous system, and respiratory system anomalies. The occurrence of NCAs in our database was lowest between 23 and 32 years of maternal age at childbirth. The relative risk (RR) of any NCA was 1.2 (95% CI 1.17-1.23) and 1.15 (95% CI 1.11-1.19) in the very young and advanced age groups, respectively. The respective results for the circulatory system were RR=1.07 (95% CI 1.01-1.13) and RR=1.33 (95% CI 1.24-1.42); for cleft lip and palate RR=1.09 (95% CI 1.01-1.19) and RR=1.45 (95% CI 1.26-1.67); for genital organs RR=1.15 (95% CI 1.08-1.22) and RR=1.16 (95% CI 1.04-1.29); for the musculoskeletal system RR=1.17 (95% CI 1.12-1.23) and RR=1.29 (95% CI 1.14-1.44); and for the digestive system RR=1.23 (95% CI 1.14-1.31) and RR=1.16 (95% CI 1.04-1.29). Very young and advanced maternal ages are associated with different types of NCAs. Therefore, screening protocols should be adjusted for these risk groups.

The Risks of Birth Defects and Childhood Cancer With Conception by Assisted Reproductive Technology

ABSTRACT As the proportion of births conceived with assisted reproductive technology (ART) continues to increase, a growing body of literature continues to examine the risks involved such as the higher risk of birth defects. Recently, several studies have suggested that ART-conceived children may have a greater risk of childhood cancer. This population-based cohort study aimed to evaluate the risk of childhood cancer as a function of birth defect status and method of conception. Data were obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, birth certificates (2004–2013), birth defect registries, and cancer registries in 4 states. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System contains comprehensive information on ART procedures from 86% of all clinics and more than 92% of all ART cycles in the United States. Assisted reproductive technology cycles reported from January 2004 to December 2017 that resulted in live births were included in this study. For each ART-conceived delivery, the subsequent 10 deliveries were selected as the non-ART comparison group, and siblings of each ART birth were selected as the ART sibling group. The ART group was divided into 4 subgroups based on the combination of oocyte source (autologous or donor) and embryo state (fresh or thawed). A host of independent variables with established associations on birth defects, cancer, and/or ART were selected a priori for inclusion in statistical models. The total study population included 165,125 ART-conceived children, 31,524 non-ART siblings, 12,451 children born as a result of infertility treatment without ART (ovulation induction/intrauterine insemination [OI/IUI]), and 1,353,440 naturally conceived children. A total of 29,571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect. Compared with naturally conceived children, risks for defects were increased for all other groups for nonchromosomal (adjusted odds ratios [AORs] ranged from 1.20 to 1.24, except for donor-fresh), blastogenesis (AORs, 1.22–1.74), cardiovascular (AORs, 1.04–1.26), gastrointestinal (AORs, 1.28–2.01), musculoskeletal (AORs, 1.10–1.48), and genitourinary among male children (AORs, 1.15–1.40, except for donor-fresh). Orofacial defects were increased in the OI/IUI and autologous-fresh and autologous-thawed groups (AORs, 1.26–1.42). The risk of any cancer was increased among ART autologous-fresh and non-ART siblings (hazard ratios [HRs], 1.31 and 1.34, respectively). A total of 127 children had both birth defects and cancer, with 53 (42%) of these children having leukemia. A Cox proportional hazards regression model identified 2 components for the risk of cancer: method of conception and type and number of birth defects. The presence of chromosomal defects was strongly associated with cancer risk (HRs, 8.70 for all cancers and 21.90 for leukemia), and this was further increased in the presence of both chromosomal and nonchromosomal defects (HRs, 21.29 for all cancers, 64.83 for leukemia, and 4.71 for embryonal tumors). The results of this study demonstrate that compared with naturally conceived children a significantly increased risk of nonchromosomal birth defects was found among children conceived with infertility treatment and that the risk of cancer was increased by greater than 30% among non-ART siblings and ART children born from autologous-fresh cycles. Among both naturally conceived and ART-conceived children, the presence of birth defects was associated with a greater risk of cancer.

First-Trimester Influenza Infection Increases the Odds of Non-Chromosomal Birth Defects: A Systematic Review and Meta-Analysis.

Viral infections during pregnancy raise several clinical challenges, including birth defects in the offspring. Thus, this systematic review and meta-analysis aims to prove and highlight the risk of birth defects after first-trimester maternal influenza infection. Our systematic search was performed on 21 November 2022. Studies that reported maternal influenza infection in the first trimester and non-chromosomal congenital abnormalities were considered eligible. We used odds ratios (OR) with 95% confidence intervals (CIs) to measure the effect size. Pooled ORs were calculated with a random effects model. Heterogeneity was measured with I² and Cochran's Q tests. We found that first-trimester maternal influenza was associated with increased odds of developing any type of birth defects (OR: 1.5, CI: 1.30-1.70). Moreover, newborns were more than twice as likely to be diagnosed with neural tube defects (OR: 2.48, CI: 1.95-3.14) or cleft lip and palate (OR: 2.48, CI: 1.87-3.28). We also found increased odds of developing congenital heart defects (OR: 1.63, CI: 1.27-2.09). In conclusion, influenza increases the odds of non-chromosomal birth defects in the first trimester. The aim of the present study was to estimate the risk of CAs in the offspring of mothers affected by first-trimester influenza infection.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth

Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

Cancer risk in individuals with major birth defects: large Nordic population based case-control study among children, adolescents, and adults

ObjectiveTo examine associations between birth defects and cancer from birth into adulthood.DesignPopulation based nested case-control study.SettingNationwide health registries in Denmark, Finland, Norway, and Sweden.Participants62 295 cancer cases (0-46 years) and...

The risk of birth defects with conception by ART.

The risk of birth defects with conception by ART.

Cancer Risk by Attained Age among Children with Birth Defects in Arkansas

BackgroundFew studies have evaluated associations between birth defects and risk of pediatric cancers by age of attainment. Therefore, we assessed the risk of cancer among children with and without birth defects by age at attainment. MethodsWe examined cancer risk in children ≤14 years with and without birth defects born between 1996 and 2011 by linking data from the Arkansas Reproductive Health Monitoring System, Arkansas Central Cancer Registry, and birth certificates. Age of attainment for cancer was calculated as person-years from birth to cancer diagnosis, death, or end of study period, whichever occurred first. Using Cox proportional hazards models, we evaluated associations by attained age groups (<1, 1-4, 5-9, and 10-14 years) between: (1) groups of birth defects (any, chromosomal, and non-chromosomal) and any cancer; (2) non-chromosomal birth defects by organ system and any cancer; and (3) non-chromosomal birth defects and subtypes of cancer. ResultsIn the cohort of 629,086 children, 23,341 (3.7%) children had birth defects and 1,037 (0.2%) children had cancer. For children with non-chromosomal birth defects, specifically cardiovascular and genitourinary, highest risk of any cancer was observed in first year of life (Hazard Ratio [HR] 18.5; 95% confidence interval [CI] 10.1-33.8). For children with chromosomal birth defects, increased cancer risk was observed among those 1-4 years-old (HR 20.0; 95% CI 8.3-48.4). ConclusionOverall, cancer risk among children with birth defects was highest among those <5 years-old. Our findings, consistent with previous studies, may inform surveillance strategies for children with birth defects.

Mother’s age as a risk factor of birth defects

Objective. To analyze the age structure of the mothers of children with birth defects and to assess the age-related risks of chromosomal and non-chromosomal congenital anomalies.Material and methods. The authors analyzed the data from 23 regional registers of birth defects from 2011 to 2018. There were total 5 047 468 births during this period. The authors calculated the incidence and relative risks of chromosomal and non-chromosomal birth defects in different age groups of mothers: under 20, from 20 to 34, from 35 to 39, 40–44, and above 45 years old.Results. The incidence of chromosomal abnormalities significantly increases with the mother’s age. The relative risk (RR) of chromosomal abnormalities in different age groups: 4,67 (95% CI 4,44–4,92) in Group 35-39, 15,00 (95% CI 14,10–15,96) in Group 40–44, and 26,49 (95% CI 21,89–32,07) in Group ≥45 as compared with the main age group of 20–34 years old. The authors also revealed the dependence of the non-chromosomal birth defects on the age of the mother: RR 1,15 (95% CI 1,08–1,23) in Group &lt;20 years, RR 1,18 (95% CI 1,13–1,23) in Group 35–39, RR 1,35 (95% CI 1,24–1,47) in Group 40–44, and RR 2,03 (95% CI 1,47–2,79) in Group ≥ 45 years old.Conclusion. The study demonstrates the dependence of chromosomal and non-chromosomal birth defects on the mother’s age.

Growing up with spina bifida: bridging the gaps in the transition of care from childhood to adulthood.

Spina bifida is the most common nonchromosomal birth defect, resulting in permanent disability of multiple organ systems, yet compatible with long-term survival. Important advances across various disciplines have now improved survival among the spina bifida population. Although the majority of individuals living with spina bifida are now adults, there are few publications in the neurosurgical literature regarding the care of adults with spina bifida, associated medical conditions, surgical interventions, and long-term complications. The major goals for transitioning adult patients with spina bifida are preservation of function and promotion of independence as well as general overall health. Nevertheless, many gaps exist in our knowledge and understanding of the complex needs of this aging patient population. The goal of this paper was to provide a comprehensive updated review of the literature regarding the challenges and considerations involved in the transitional care to adulthood for patients with spina bifida. Unique to this review, the authors provide a first-hand personal communication and interview with an adult patient with spina bifida that discusses many of these challenges with transition.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. Paediatric HIV clinics. Live-born infants born in Canada to WLWH between 2007 and 2017. Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. Congenital anomalies. Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

Association Between Birth Defects and Cancer Risk Among Children and Adolescents in a Population-Based Assessment of 10 Million Live Births

Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects. This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019. Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries. Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk. Compared with children without any birth defects, children with chromosomal anomalies were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.3-6.4) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma. Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

Abstract LB-161: A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births

Abstract Purpose: While cancer risk is increased among children with chromosomal birth defects, less is known about associations between specific non-chromosomal structural birth defects and specific childhood cancers. To investigate these, we established a population-based retrospective cohort of &amp;gt;10 million children by pooling statewide registry data from four U.S. states (Texas, Michigan, North Carolina, and Arkansas) for the period 1992-2013. Methods: Individual level data from birth certificates, birth defects registries, and cancer registries were linked in each state; demographic and diagnostic variables were harmonized; and the data were pooled for the overall analysis. We used Cox proportional hazards models to evaluate associations between 60 birth defects and 31 childhood cancers when there were five or more comorbid cases. A hazard ratio (HR) and 95% confidence interval (CI) was calculated for each birth defect-childhood cancer (BD-CC) pairwise combination, adjusted for maternal age, infant sex, and state. The false discovery rate (FDR) was computed via the Benjamini-Hochberg procedure to account for multiple comparisons. Results: We identified 517,548 children with non-chromosomal structural birth defects and 14,774 children with cancer. The risk of any cancer was increased among children with any non-chromosomal structural defect compared to children without any birth defect (HR=2.6, 95% CI 2.4-2.7). Of 2,511 potential BD-CC combinations, we tested 606 where there were ≥5 comorbid cases and identified 496 BD-CC associations with significantly elevated HRs at a 5% FDR. No significant inverse associations were identified for any BD-CC combination. Notably, hepatoblastoma, astrocytoma, ependymoma, and extracranial germ cell tumors were each strongly associated with several birth defects. For example, the risk of hepatoblastoma was increased among children with atrial septal defects (HR=12.5, 95% CI 7.9-19.7) and craniosynostosis (HR=15.4, 95% CI 7.6-31.3). Astrocytoma and ependymoma were associated with central nervous system (CNS) defects (HR=6.7, 95% CI 4.6-9.8 and HR=7.4, 95%CI 3.5-15.7, respectively). Elevated risk of extracranial germ cell tumors was observed among children with CNS defects (HR=22.5, 95% CI 10.9-46.4) and obstructive genitourinary defects (HR=32.4, 95% CI 16.2-64.6). Conclusions: By pooling registry data across four U.S. states, we were able to evaluate specific BD-CC patterns and report several novel associations. Our findings suggest that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. These findings may inform research into the etiologies of childhood cancer, as well as new cancer surveillance protocols for children with non-chromosomal birth defects. This work was supported by the Cancer Prevention Research Institute of Texas. Citation Format: Jeremy M. Schraw, Tania A. Desrosiers, Wendy N. Nembhard, Glenn Copeland, Robert E. Meyer, Austin L. Brown, Tiffany M. Chambers, Heather E. Danysh, Saumya Sisoudiya, Chunqiao Luo, Amir Mian, Michael E. Scheurer, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-161.