Non-chromosomal Birth Defects Research Articles

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 >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.

Risk of Cancers Increased in Children With Non-Chromosomal Birth Defects

Risk of Cancers Increased in Children With Non-Chromosomal Birth Defects

Childhood cancer risk in those with chromosomal and non-chromosomal congenital anomalies in Washington State: 1984-2013.

BackgroundThe presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies.MethodsRecords of children diagnosed with cancer at <20 years of age during 1984–2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies.ResultsHaving any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28–1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18–1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54–6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75–13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location.ConclusionsNon-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non-chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer.

Advanced Maternal Age and Incidence of Non-Chromosomal Congenital Anomalies: A Population-based Study [35Q

INTRODUCTION: Advanced maternal age (AMA), is associated with an increased risk of aneuploidy, adverse pregnancy outcomes, and infertility. Our study's objective is to assess whether AMA increases the risk of non-chromosomal congenital anomalies. METHODS: A retrospective cohort study was conducted using a linked dataset from Alberta Perinatal Health Program and the Alberta Congenital Anomalies Surveillance System databases. All singleton births and pregnancy terminations greater than 20 weeks gestational age from 2005 to 2013 were included. Pregnancies with aneuploidy were excluded. Maternal age was categorized as less than 35 years and 35 years and greater. Descriptive statistics of maternal demographic characteristics were generated. Multinomial logistic regression models controlled for parity, use of assisted reproductive technology, smoking, and socioeconomic status. RESULTS: There is a significant association between AMA and congenital anomalies in the kidney (P=.004), and reproductive tract (P=.021). The rate of anomalies in the kidney was 2.6 per 1,000 births for women under 20 and rose to 3.0 per 1,000 births for women 35 and older. The rate of anomalies in the reproductive tract was 3.5 per 1,000 births in women under 20, and rose to 4.6 per 1,000 births in women 35 and up. Analysis of the type of anomaly revealed a significant association between AMA and congenital obstructive defects of the renal pelvis (P=.025), other malformations of the kidney (P &lt; .001), undescended testicle (P=.032), congenital deformities of the hip (P &lt; .001) and congenital deformities of the feet (P=.001). CONCLUSION: Advanced Maternal Age appears to be associated with an increased incidence of specific non-chromosomal congenital anomalies, particularly of the renal and genitourinary systems.

Assisted Reproductive Technology and Birth Defects Among Liveborn Infants in Florida, Massachusetts, and Michigan, 2000-2010.

Use of assisted reproductive technology (ART) has been associated with increased risks for birth defects. Variations in birth defect risks according to type of ART procedure have been noted, but findings are inconsistent. To examine the prevalence of birth defects among liveborn infants conceived with and without ART and to evaluate risks associated with certain ART procedures among ART-conceived infants. Used linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan). Methods for ascertaining birth defect cases varied by state. Resident live births during 2000 to 2010 were included, and the analysis was conducted between Feburary 2015 and August 2015. Use of ART among all live births and use of certain ART procedures among ART births. Prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth. Of the 4 618 076 liveborn infants between 2000 and 2010, 64 861 (1.4%) were conceived using ART. Overall, the prevalence of 1 or more of the selected nonchromosomal defects was 58.59 per 10 000 for ART infants (n = 389) vs 47.50 per 10 000 for non-ART infants (n = 22 036). The association remained significant after adjusting for maternal characteristics and year of birth (adjusted risk ratio [aRR], 1.28; 95% CI, 1.15-1.42). Similar differences were observed for singleton ART births vs their non-ART counterparts (63.69 per 10 000 [n = 218] vs 47.17 per 10 000 [n = 21 251]; aRR, 1.38; 95% CI, 1.21-1.59). Among multiple births, the prevalence of rectal and large intestinal atresia/stenosis was higher for ART births compared with non-ART births (aRR, 2.39; 95% CI, 1.38-4.12). Among ART births conceived after fresh embryo transfer, infants born to mothers with ovulation disorders had a higher prevalence of nonchromosomal birth defects (aRR, 1.53; 95% CI, 1.13-2.06) than those born to mothers without the diagnosis, and use of assisted hatching was associated with birth defects among singleton births (aRR, 1.55; 95% CI, 1.10-2.19). Multiplicity-adjusted P values for these associations were greater than .05. Infants conceived after ART had a higher prevalence of certain birth defects. Assisted hatching and diagnosis of ovulation disorder were marginally associated with increased risks for nonchromosomal birth defects; however, these associations may be caused by other underlying factors.

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies.

Objective:To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA).Methods:This was a population-based case–malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995–2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies.Results:There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73–2.33), isolated OC 1.45 (95% CI 0.80–2.63), isolated cleft palate 1.69 (95% CI 0.69–4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01–3.31) and 1.43 (95% CI 0.66–3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy.Conclusions:The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

The Association of H1N1 Pandemic Influenza with Congenital Anomaly Prevalence in Europe: An Ecological Time Series Study.

In the context of the European Surveillance of Congenital Anomalies (EUROCAT) surveillance response to the 2009 influenza pandemic, we sought to establish whether there was a detectable increase of congenital anomaly prevalence among pregnancies exposed to influenza seasons in general, and whether any increase was greater during the 2009 pandemic than during other seasons. We performed an ecologic time series analysis based on 26,967 pregnancies with nonchromosomal congenital anomaly conceived from January 2007 to March 2011, reported by 15 EUROCAT registries. Analysis was performed for EUROCAT-defined anomaly subgroups, divided by whether there was a prior hypothesis of association with influenza. Influenza season exposure was based on World Health Organization data. Prevalence rate ratios were calculated comparing pregnancies exposed to influenza season during the congenital anomaly-specific critical period for embryo-fetal development to nonexposed pregnancies. There was no evidence for an increased overall prevalence of congenital anomalies among pregnancies exposed to influenza season. We detected an increased prevalence of ventricular septal defect and tricuspid atresia and stenosis during pandemic influenza season 2009, but not during 2007-2011 influenza seasons. For congenital anomalies, where there was no prior hypothesis, the prevalence of tetralogy of Fallot was strongly reduced during influenza seasons. Our data do not suggest an overall association of pandemic or seasonal influenza with congenital anomaly prevalence. One interpretation is that apparent influenza effects found in previous individual-based studies were confounded by or interacting with other risk factors. The associations of heart anomalies with pandemic influenza could be strain specific.

Trends in the prevalences of congenital anomalies and age at motherhood in a southern European region: a population-based study

ObjectivesTo estimate the prevalences of the main groups of congenital anomalies and to assess their trend over time.DesignPopulation-based study of prevalences.SettingThe Basque Country, Spain.ParticipantsAll births and all congenital anomalies diagnosed...

Influenza and congenital anomalies: a systematic review and meta-analysis

Does first trimester maternal influenza infection increase the risk of non-chromosomal congenital anomalies (CA)? First trimester maternal influenza exposure is associated with raised risk of a number of non-chromosomal CA, including neural tube defects, hydrocephaly, congenital heart defects, cleft lip, digestive system defects and limb reduction defects. Hyperthermia is a well-established risk factor for neural tube defects. Previous studies suggest influenza may be a risk factor not only for neural tube defects, but also other CA. No systematic review has previously been undertaken. Systematic review and meta-analysis. A search of EMBASE and PUBMED was performed for English and Dutch studies published up to July 2013. A total of 33 studies (15 case-control, 10 cohort and 8 ecological) were included in the systematic review of which 22 studies were included in the meta-analysis. A total of 29 542 babies with congenital anomaly (1112 exposed) from case-control studies and 1608 exposed pregnancies resulting in 56 babies with congenital anomaly from cohort studies were included in the meta-analysis. Maternal influenza exposure was defined as any reported influenza, influenza-like illness or fever with flu, with or without serological or clinical confirmation during the first trimester of pregnancy. Data for 24 (sub)groups with congenital anomaly available from ≥3 studies were analysed using the DerSimonian-Laird random effects model. The hypothesis of publication bias was assessed using funnel plots and risk of bias of included studies was assessed using a slightly modified version of the Newcastle-Ottawa scale. First trimester maternal influenza exposure was associated with an increased risk of any congenital anomaly [adjusted odds ratio (AOR) 2.00, 95% CI: 1.62-2.48], neural tube defects [odds ratio (OR) 3.33, 2.05-5.40], hydrocephaly (5.74, 1.10-30.00), congenital heart defects (1.56, 1.13-2.14), aortic valve atresia/stenosis (AOR 2.59, 1.21-5.54), ventricular septal defect (AOR 1.59, 1.24-2.14), cleft lip (3.12, 2.20-4.42), digestive system (1.72, 1.09-2.68) and limb reduction defects (2.03, 1.27-3.27). An increased risk for cleft lip (but not for cleft palate) was also reported by ecological studies not included in the meta-analysis. Study outcomes reported for 27 subgroups of congenital anomaly could not be included in the meta-analysis. Visual inspection of funnel plots did not suggest evidence for publication bias. This study enrolled observational studies that can be subject to limitations such as confounding, retrospective maternal exposure reports and non-response of intended participants. Influenza exposed pregnancies can also have been exposed to influenza related medication. Prevention of influenza in pregnant women may reduce congenital anomaly risk, and would be relevant to more than just neural tube defects. More research is needed to determine whether influenza and/or its related medication is teratogenic, to determine the role of hyperthermia in teratogenicity and the role of other environmental factors such as nutritional status in determining susceptibility.

Improved antenatal detection of congenital anomalies in women with pre‐gestational diabetes: population‐based cohort study

To compare antenatal detection of congenital anomaly in women with and without pre-gestational diabetes and their pregnancy outcomes in a regional cohort study. Data from a total of 7148 singleton pregnancies with a congenital anomaly delivered between 1 January 1996 and 31 December 2008 were extracted from the Northern Diabetes in Pregnancy and Northern Congenital Abnormality Surveys. Antenatal ultrasound detection rates of congenital anomaly in pregnancies complicated by major non-chromosomal congenital anomaly and resulting in live birth, stillbirth, late miscarriage (20-23 weeks of gestation) or termination of pregnancy for a congenital anomaly, were compared between women with and without diabetes (120 and 7028, respectively). A significantly higher rate of antenatal detection of congenital anomalies was observed in women with diabetes compared with women without diabetes (50.8 vs. 38.6%, respectively; relative risk 1.32; 95% CI 1.10-1.57; P = 0.003). Cardiovascular anomalies were the only group with a significantly higher antenatal detection rate in women with diabetes (31.8 vs. 10.4%; relative risk 3.05; 95% CI 1.95-4.76; P < 0.00001). This difference remained after excluding cases of ventricular septal defect (52.2 vs. 16.3%; relative risk 3.20; 95% CI 2.13-4.80; P < 0.0001). Among women with diabetes, male fetal sex was the only factor associated with a higher antenatal detection rate. There were no differences in the rates of termination of pregnancy, late miscarriage, stillbirth or infant death between groups. Antenatal detection of cardiovascular anomalies was higher in women with diabetes, suggesting that recommendations for enhanced cardiovascular scanning may improve detection. Greater awareness of the increased risk of anomalies in other organ systems is needed.

Cancer Risk in Children and Adolescents with Birth Defects: A Population-Based Cohort Study

ObjectiveBirth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects.Methods and FindingsThis retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus.ConclusionChildren with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.

In Case You Missed It: Cancer Risk in Children With Birth Defects

In a study published in June 2012, Carrozza et al reviewed data from Texas registries on cancer and birth defects to assess whether specific birth defects increase the risk of childhood cancer.1 Within the cohort of 3 million children born over a 10-year period, these investigators identified 115,686 children with birth defects and 2,351 cases of cancer. Children with an identified birth defect had a threefold increased risk of developing cancer (incidence rate ratio [IRR] = 3.05; 95% CI, 2.65-3.50). This increased risk was most pronounced in the following subgroups: germ cell tumors (IRR = 5.19), retinoblastomas (IRR = 2.34), soft-tissue sarcomas (IRR = 2.12), and leukemias (IRR = 1.39). With the exception of musculoskeletal birth defects, all birth defect groups had increased cancer incidence. The strongest association was seen in children with chromosomal defects (IRR = 15.52), due to the high incidence of leukemia among Down syndrome children (51 of 55 trisomy cancer cases were children with trisomy 21 and leukemia).Previous studies have demonstrated an increased risk of developing cancer for children with identified birth defects.24 This study provides additional convincing data to support that association, and new data about risk stratification based on type of birth defect. The large size of the study cohorts made a revealing subgroup analysis feasible. The data analysis convincingly demonstrates that in this cohort, children with birth defects were at increased risk for cancer development compared to those without birth defects.The strong association between trisomy 21 and leukemia has been cited as responsible for much of the increased risk of cancer in children with birth defects.5 Although the data are not presented in the article, the authors report that they also analyzed the study cohort after excluding any child with a chromosomal anomaly. This resulted in a lower incidence rate for both leukemias and total cancers, but unchanged or increased risk for all other cancer categories. This information greatly strengthens support for the association between nonchromosomal birth defects and cancer risk.The authors acknowledge several weaknesses of the study, including the lack of death certificate linkage, which prevented adjustment for person-year contributions for children who died before the end of the study. The maximum follow-up time was 10 years, resulting in a likely underrepresentation of cancers that occur more commonly or exclusively in late childhood or beyond. In addition, minor structural birth defects may go undiagnosed in otherwise healthy children, but are more likely to be diagnosed in children with serious underlying illness, leading to a potential bias. Finally, the study was not designed to stratify infants with isolated versus multiple defects, and the authors point out that correlation of multiple birth defects and cancer risk could be informative.Although it was not within the scope of this study to determine a causal relationship between birth defects and cancer, the authors speculate about several possibilities that might explain the observed association. They postulate that birth defects may confer genetic susceptibility to environmental exposures, or that the developmental genes responsible for body plan formation during embryogenesis may be linked to cancer development.6 Well-designed, comprehensive studies such as this one can provide insights into these important connections between birth defects and childhood cancer.

Maternal age and birth defects after the use of assisted reproductive technology in Japan, 2004-2010.

BackgroundOlder mothers are becoming more common in Japan. One reason for this is the widespread use of assisted reproductive technology (ART). This study assesses the relationship between maternal age and the risk of birth defects after ART.MethodsNationwide data on ART between 2004 and 2010 in Japan were analyzed. Diseases that were classified as code Q00-Q99 (ie, congenital malformations, deformations, and chromosomal abnormalities) in the International Classification of Diseases, tenth edition, were selected. There were 219,185 pregnancies and 153,791 live births in total ART. Of these, 1943 abortions, stillbirths, or live births with birth defects were recorded. Percentage of multiple birth defects in total birth defects, the prevalence, crude relative risk and 95% confidence interval per 10,000 pregnancies and per 10,000 live births were analyzed according to the maternal age class (ie, 25–29, 30–34 (reference), 35–39, and 40+ years).ResultsMultiple birth defects were observed among 14% of the 25–29 year old class, and 8% among other classes when chromosomal abnormalities were excluded. The prevalence of chromosomal abnormalities per pregnancy and per live birth became significantly and rapidly higher in mothers in the age classes of 30–35 and 40+ years. Nonchromosomal birth defects per pregnancy decreased linearly with advanced maternal age, while the number of nonchromosomal birth defects per live birth formed a gradual U-shaped distribution. The prevalence per pregnancy of congenital malformations of the nervous system was significantly lower with advanced maternal age. The relative risk per live birth was significant regarding congenital malformations of the circulatory system for a maternal age of 40+ years. Some other significant associations between maternal age and birth defects were observed.ConclusionMaternal age is associated with several birth defects; however, older maternal age in itself does not produce noticeable extra risk for nonchromosomal birth defects overall.

Spectrum of congenital anomalies in pregnancies with pregestational diabetes

Maternal pregestational diabetes is a well-known risk factor for congenital anomalies. This study analyses the spectrum of congenital anomalies associated with maternal diabetes using data from a large European database for the population-based surveillance of congenital anomalies. Data from 18 population-based EUROCAT registries of congenital anomalies in 1990-2005. All malformed cases occurring to mothers with pregestational diabetes (diabetes cases) were compared to all malformed cases in the same registry areas to mothers without diabetes (non-diabetes cases). There were 669 diabetes cases and 92,976 non diabetes cases. Odds ratios in diabetes pregnancies relative to non-diabetes pregnancies comparing each EUROCAT subgroup to all other non-chromosomal anomalies combined showed significantly increased odds ratios for neural tube defects (anencephaly and encephalocele, but not spina bifida) and several subgroups of congenital heart defects. Other subgroups with significantly increased odds ratios were anotia, omphalocele and bilateral renal agenesis. Frequency of hip dislocation was significantly lower among diabetes (odds ratio 0.15, 95% CI 0.05-0.39) than non-diabetes cases. Multiple congenital anomalies were present in 13.6 % of diabetes cases and 6.1 % of non-diabetes cases. The odds ratio for caudal regression sequence was very high (26.40,95% CI 8.98-77.64), but only 17% of all caudal regression cases resulted from a pregnancy with pregestational diabetes. The increased risk of congenital anomalies in pregnancies with pregestational diabetes is related to specific non-chromosomal congenital anomalies and multiple congenital anomalies and not a general increased risk.

Cancer in Children with Nonchromosomal Birth Defects

To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies. We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies. Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors. Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.

Congenital anomalies in newborns to women employed in jobs with frequent exposure to organic solvents - a register-based prospective study

BackgroundThe foetal effects of occupational exposure to organic solvents in pregnancy are still unclear. Our aim was to study the risk of non-chromosomal congenital anomalies at birth in a well-defined population of singletons born to women employed as painters and spoolers in early pregnancy, compared to women in non-hazardous occupations.MethodThe study population for this prospective cohort study was singleton newborns delivered to working mothers in the industrial community of Mončegorsk in the period 1973-2005. Occupational information and characteristics of the women and their newborns was obtained from the local population-based birth register.ResultsThe 597 women employed as painters, painter-plasterers or spoolers had 712 singleton births, whereof 31 (4.4%) were perinatally diagnosed with 37 malformations. Among the 10 561 newborns in the group classified as non-exposed, 397 (3.9%) had one or more malformations. The overall prevalence in the exposed group was 520/10 000 births [95% confidence limits (CL): 476, 564], and 436/10 000 births (95% CL: 396, 476) in the unexposed. Adjusted for young maternal age, smoking during pregnancy, maternal congenital malformation and year of birth, the odds ratio (OR) was 1.24 (95% CL: 0.85, 1.82); for multiple anomalies it was 1.54 (95% CL: 0.66, 3.59).The largest organ-system specific difference in prevalence between the two groups was observed for malformations of the circulatory system: 112/10 000 (95% CL: 35, 190) in the exposed group, and 42/10 000 (95% CL: 29, 54) in the unexposed, with an adjusted OR of 2.03 (95% CL: 0.85, 4.84). The adjusted ORs for malformations of the genital organs and musculoskeletal system were 2.24 (95% CI: 0.95, 5.31) and 1.12 (95% CI: (0.62, 2.02), respectively.ConclusionThere appeared to be a higher risk of malformations of the circulatory system and genital organs at birth among newborns to women in occupations with organic solvent exposure during early pregnancy (predominantly employed as painters). However, the findings were not statistically conclusive. Considering that these two categories of malformations are not readily diagnosed perinatally, the difference in prevalence between the exposed and unexposed may have been underestimated.

Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls

BACKGROUNDThere is uncertainty over whether maternal smoking is associated with birth defects. We conducted the first ever comprehensive systematic review to establish which specific malformations are associated with smoking.METHODSObservational studies published 1959–2010 were identified (Medline), and included if they reported the odds ratio (OR) for having a non-chromosomal birth defect among women who smoked during pregnancy compared with non-smokers. ORs adjusted for potential confounders were extracted (e.g. maternal age and alcohol), otherwise unadjusted estimates were used. One hundred and seventy-two articles were used in the meta-analyses: a total of 173 687 malformed cases and 11 674 332 unaffected controls.RESULTSSignificant positive associations with maternal smoking were found for: cardiovascular/heart defects [OR 1.09, 95% confidence interval (CI) 1.02–1.17]; musculoskeletal defects (OR 1.16, 95% CI 1.05–1.27); limb reduction defects (OR 1.26, 95% CI 1.15–1.39); missing/extra digits (OR 1.18, 95% CI 0.99–1.41); clubfoot (OR 1.28, 95% CI 1.10–1.47); craniosynostosis (OR 1.33, 95% CI 1.03–1.73); facial defects (OR 1.19, 95% CI 1.06–1.35); eye defects (OR 1.25, 95% CI 1.11–1.40); orofacial clefts (OR 1.28, 95% CI 1.20–1.36); gastrointestinal defects (OR 1.27, 95% CI 1.18–1.36); gastroschisis (OR 1.50, 95% CI 1.28–1.76); anal atresia (OR 1.20, 95% CI 1.06–1.36); hernia (OR 1.40, 95% CI 1.23–1.59); and undescended testes (OR 1.13, 95% CI 1.02–1.25). There was a reduced risk for hypospadias (OR 0.90, 95% CI 0.85–0.95) and skin defects (OR 0.82, 0.75–0.89). For all defects combined the OR was 1.01 (0.96–1.07), due to including defects with a reduced risk and those with no association (including chromosomal defects).CONCLUSIONSBirth defects that are positively associated with maternal smoking should now be included in public health educational materials to encourage more women to quit before or during pregnancy.

Survival and Morbidity Outcomes for Very Low Birth Weight Infants With Down Syndrome

Our objective was to compare survival and neonatal morbidity rates between very low birth weight (VLBW) infants with Down syndrome (DS) and VLBW infants with non-DS chromosomal anomalies, nonchromosomal birth defects (BDs), and no chromosomal anomaly or major BD. Data were collected prospectively for infants weighing 401 to 1500 g who were born and/or cared for at one of the study centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network in 1994-2008. Risk of death and morbidities, including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late-onset sepsis (LOS), retinopathy of prematurity, and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups. Infants with DS were at increased risk of death (adjusted relative risk: 2.47 [95% confidence interval: 2.00-3.07]), PDA, NEC, LOS, and BPD, relative to infants with no BDs. Decreased risk of death (relative risk: 0.40 [95% confidence interval: 0.31-0.52]) and increased risks of NEC and LOS were observed when infants with DS were compared with infants with other non-DS chromosomal anomalies. Relative to infants with nonchromosomal BDs, infants with DS were at increased risk of PDA and NEC. The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for anticipating the need for enhanced surveillance for prevention of these morbidities.

Maternal Age-Specific Risk of Nonchromosomal Anomalies

With a continuing rise in the average maternal age in industrialized societies, accurate data are needed on maternal age-related obstetric risks. Although it is well known that the risk of fetal aneuploidy increases along with maternal age, it is unclear whether older mothers are at increased risk of having a fetus with nonchromosomal congenital anomalies (NCA). Much of the data on the risk data for NCA among older European mothers are either difficult to interpret or come from studies with small sample size, and little data are available on the overall risk of NCA in younger (teenage) mothers. This population-based prevalence study compared the age-specific risk of NCA among mothers in 15 European countries. Data from 1.75 million infants born between 2000 and 2004 were obtained from the EUROCAT database, a network of population-based congenital anomaly registers in 15 European countries. The primary outcome measures were the prevalence of NCA at increasing maternal ages and the relative risk (RR) of any NCA and 84 standard NCA subgroups. Included among the 38,958 cases of NCA were live births, fetal deaths ≥20 weeks’ gestation, and pregnancy terminations following prenatal diagnosis of malformation. The highest crude prevalence of all NCAs was among mothers <20 years old (26.5 per 1000 births). With increasing maternal age, the overall prevalence of NCA decreased: the crude prevalence per 1000 births for mothers 20 to 24, 25 to 29, 30 to 34, 35 to 39, and 40 to 44 years was 23.8, 22.5, 21.5, 21.4, and 22.6, respectively. Compared to mothers age 25 to 29, the RR of NCA adjusted for country was 1.11 (95% confidence interval [CI], 1.06–1.17) for mothers age <20 years, 0.99 (95% CI, 0.96–1.02) for mothers age 35 to 39, and 1.01 (95% CI, 0.95–1.07) for mothers age 40 to 44. There was significant variation in the pattern of maternal age-related risk between countries: the RR was higher for teenage mothers in France, Ireland, and Portugal, whereas the RR was higher for older mothers in Germany and Poland. The maternal age-specific RR was also different for specific NCAs among the 84 subgroups analyzed. Mothers <20 years old were at a significantly greater risk of nervous system abnormalities including anencephaly, tricuspid atresia, digestive system anomalies including gastroschisis, and maternal infection syndromes. Older mothers aged from 35 to 39 and 40 to 44 years were at a significantly greater risk of encephalocele, esophageal atresia, thanatophoric dwarfism, and fetal alcohol syndrome (all values P < 0.01). These findings indicate that, while teenage mothers are at increased risk of having offspring with NCAs, older maternal age is a negligible risk factor for NCAs overall, although the risk of a few specific anomalies appears to increase with age.

Maternal age‐specific risk of non‐chromosomal anomalies

Objectives To determine the excess risk of non‐chromosomal congenital anomaly (NCA) among teenage mothers and older mothers.Design and setting Population‐based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004.Participants A total of 38 958 cases of NCA that were live births, fetal deaths with gestational age ≥20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly.Main outcome measures Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25–29.Results The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (&lt;20 years), 23.8 for mothers 20–24 years, 22.5 for mothers 25–29 years, 21.5 for mothers 30–34 years, 21.4 for mothers 35–39 years and 22.6 for mothers 40–44 years. The RR adjusted for country for teenage mothers was 1.11 (95% CI 1.06–1.17); 0.99 (95% CI 0.96–1.02) for mothers 35–39; and 1.01 (95% CI 0.95–1.07) for mothers 40–44. The pattern of maternal age‐related risk varied significantly between countries: France, Ireland and Portugal had higher RR for teenage mothers, Germany and Poland had higher RR for older mothers. The maternal age‐specific RR varied for different NCAs. Teenage mothers were at a significantly greater risk (P &lt; 0.01) of gastroschisis, maternal infection syndromes, tricuspid atresia, anencephalus, nervous system and digestive system anomalies while older mothers were at a significantly greater risk (P &lt; 0.01) of fetal alcohol syndrome, encephalocele, oesophageal atresia and thanatophoric dwarfism.Conclusions Clinical and public health interventions are needed to reduce environmental risk factors for NCA, giving special attention to young mothers among whom some risk factors are more prevalent. Reassurance can be given to older mothers that their age in itself does not confer extra risk for NCA.