Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate

Maternal cigarette smoking during pregnancy as a risk factor for having a child with cleft lip/palate has been suggested by several epidemiologic studies. However, most of these studies contained small sample sizes, and a clear association between these two factors could not be established. The U.S. Natality database from 1996 and a case-control study design were used to investigate the association between maternal smoking during pregnancy and having a child with cleft lip/palate. The records of 3,891,494 live births from the 1996 U.S. Natality database were extracted to obtain cleft lip/palate cases and random controls. The National Center for Health Statistics collects maternal and newborn demographic and medical data from the birth certificates of all 50 states. New York (excluding New York City), California, Indiana, and South Dakota did not collect smoking data, and the data from these states were excluded from the analysis. A total of 2207 live births with cleft lip/palate cases were identified, and 4414 controls (1:2 ratio) were randomly selected (using the SAS program) from live births with no congenital defects. Odds ratios and 95 percent confidence intervals were determined from logistic regression models, adjusting for confounding variables, including maternal demographic and medical risk factors. A significant association was found between any amount of maternal cigarette use during pregnancy and having a child with cleft lip/palate [unadjusted odds ratio 1.55 (1.36, 1.76), p < 0.001]. Univariate analysis showed that maternal education level, age, race, and maternal medical conditions (diabetes and pregnancy-associated hypertension) were potential confounders. After adjusting for these confounders, the odds ratio remained significant [Mantel-Haenszel odds ratio 1.34 (1.16, 1.54), p < 0.001]. To determine the dose response of cigarette smoking during pregnancy, the cigarette consumption per day was divided into four groups: none, 1 to 10, 11 to 20, and 21 or more. A dose-response relationship was found when comparing each smoking category with the no smoking reference group: 1.50 (1.28, 1.76), 1.55 (1.23, 1.95), and 1.78 (1.22, 2.59), respectively. This means that increased cigarette smoking during pregnancy resulted in increased odds of having a child with cleft lip/palate. This is the largest study to date to test the association between maternal cigarette smoking during pregnancy and having a newborn with cleft lip/palate. The significant trend in the dose-response relationship strongly suggests the association of smoking tobacco and this common congenital deformity. These results emphasize the public health risks associated with smoking during pregnancy. To prevent this devastating craniofacial anomaly, educational initiatives should be considered that will alert expectant mothers to the association between smoking during pregnancy and the occurrence of cleft lip/palate.     

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

Objective

Birth 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 Findings

This 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.

Conclusion

Children 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.     

Additional sex combs‐like family genes are required for normal cardiovascular development

Congenital heart disease (CHD) is the most common birth defect. However, the majority of CHD cases have unknown etiology. Here we report the identification of ASXL2 and ASXL1, two homologous chromatin factors, as novel regulators of heart development. Asxl2^?/? fetuses have reduced body weight and display congenital heart malformations including thickened compact myocardium in the left ventricle, membranous ventricular septal defect, and atrioventricular valval stenosis. Although most Asxl2^?/? animals survive to term, the neonates have patent ductus arteriosus and consequent lung hemorrhage and die soon after birth. Asxl1^?/? fetuses have reduced body weight and display cleft palate, anophthalmia as well as ventricular septal defects and a failure in lung maturation. From these results, we conclude that normal heart development requires both ASXL proteins. In particular, ASXL2 plays an important role in heart morphogenesis and the transition from fetal to postnatal circulation. genesis 52:671–686, 2014. © 2014 Wiley Periodicals, Inc.     

Association between reported venlafaxine use in early pregnancy and birth defects,national birth defects prevention study, 1997–2007

BACKGROUND

Few epidemiologic studies have investigated the use of venlafaxine (Effexor XR capsules, Product Monograph, Wyeth, Montreal, Canada), an antidepressant used to treat major depression and anxiety disorders in adults, during pregnancy. Our objective was to determine whether use of venlafaxine during pregnancy is associated with specific birth defects.

METHODS

We used data from the National Birth Defects Prevention Study (NBDPS), a population‐based, case‐control study in the United States. Our analysis included mothers with pregnancies affected by one of 30 selected birth defects (cases) and babies without birth defects (controls) with estimated dates of delivery between 1997 and 2007. Exposure was any reported use of venlafaxine from 1 month preconception through the third month of pregnancy. We calculated adjusted odds ratios (aORs) and 95% Fisher Exact confidence intervals (CIs) for 24 birth defect groups for which at least 400 case mothers were interviewed. Our adjusted analyses controlled for maternal age and race/ethnicity.

RESULTS

Among the 27,045 NBDPS participants who met inclusion criteria, 0.17% (14/8002) of control mothers and 0.40% (77/19,043) of case mothers reported any use of venlafaxine from 1 month preconception through the third month of pregnancy. Statistically significant associations were found for anencephaly, atrial septal defect (ASD) secundum, or ASD not otherwise specified, coarctation of the aorta, cleft palate, and gastroschisis.

CONCLUSIONS

Our data suggest associations between periconceptional use of venlafaxine and some birth defects. However, sample sizes were small, CIs were wide, and additional studies are needed to confirm these results. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.     

Paternal age and the occurrence of birth defects

The association between paternal age and the occurrence of birth defects was studied using data collected in Metropolitan Atlanta. Paternal-age information for babies born with defects was obtained from birth certificates, hospital records, and interviews with mothers; for babies born without defects, the information was obtained from birth certificates. Several statistical techniques were used to evaluate the paternal-age-birth-defects associations for 86 groups of defects. Logistic regression analysis that controlled for maternal age and race indicated that older fathers had a somewhat higher risk for having babies with defects, when all types of defects were combined; an equivalent association for older mothers was not found. Logistic regression analyses also indicated modestly higher risks for older fathers for having babies with ventricular septal defects and atrial septal defects and substantially higher risks for having babies with defects classified in the category chondrodystrophy (largely sporadic achondroplasia) and babies with situs inversus. An association between elevated paternal age and situs inversus has not been reported before; the magnitude of the estimated increased risk for situs inversus was about the same as that found in this study for chondrodystrophy.     

Paternal Age and Offspring Congenital Heart Defects: A National Cohort Study

Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1 893 899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox’s proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25–29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17–2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27–30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA).     

Infants with single ventricle: a population-based epidemiological study

BACKGROUND: Single ventricle, a rare congenital cardiac defect, often occurs as part of a complex group of cardiovascular abnormalities. Little is known of its epidemiologic associations. METHODS: Using data from the Baltimore-Washington Infant Study [BWIS], (1981-89), a population based case-control study of cardiovascular malformations, infants with single ventricle were evaluated with respect to infant and family characteristics and maternal and paternal exposures. The cases were analyzed according to presence/absence of abnormal cardio-visceral situs. Controls were 3,572 infants without heart defects randomly selected from the regional cohort of live births. Odds ratios and 95% confidence intervals were used as measures of association. RESULTS: Single ventricle occurred in 1.25% of infants with congenital cardiovascular defects in the BWIS. Fifty-five infants had single ventricle. In 48 families (87.3%) the parents were interviewed. Thirty-three infants had normal situs and 15 had abnormal situs. Paternal alcohol consumption (OR = 2.0, 95% CI 1.1-3.9) and paternal cigarette smoking (OR = 2.4, 95% CI 1.1-5.1) were associated with all cases of single ventricle. These associations were even stronger in the subset of infants with abnormal situs. Maternal history of a previous induced abortion was also associated with infants born with abnormal situs (OR = 3.2, 95% CI 1.1-11.5). Paternal marijuana use was associated with cases of single ventricle in normal situs (OR = 2.2, 95% CI 1.0-5.2). CONCLUSIONS: Potential risk factors included paternal smoking and alcohol consumption, highlighting the need for future studies to consider environmental factors in the pathogenesis of this cardiac defect.     

National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001

BACKGROUND: In the United States, birth defects affect approximately 3% of all births, are a leading cause of infant mortality, and contribute substantially to childhood morbidity. METHODS: Population-based data from the National Birth Defects Prevention Network were combined to estimate the prevalence of 21 selected defects for 1999-2001, stratified by surveillance system type. National prevalence was estimated for each defect by pooling data from 11 states with active case-finding, and adjusting for the racial/ethnic distribution of US live births. We also assessed racial/ethnic variation of the selected birth defects. RESULTS: National birth defect prevalence estimates ranged from 0.82 per 10,000 live births for truncus arteriosus to 13.65 per 10,000 live births for Down syndrome. Compared with infants of non-Hispanic (NH) white mothers, infants of NH black mothers had a significantly higher birth prevalence of tetralogy of Fallot, lower limb reduction defects, and trisomy 18, and a significantly lower birth prevalence of cleft palate, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, gastroschisis, and Down syndrome. Infants of Hispanic mothers, compared with infants of NH white mothers, had a significantly higher birth prevalence of anencephalus, spina bifida, encephalocele, gastroschisis, and Down syndrome, and a significantly lower birth prevalence of tetralogy of Fallot, hypoplastic left heart syndrome, cleft palate without cleft lip, and esophageal atresia/tracheoesophageal fistula. CONCLUSIONS: This study can be used to evaluate individual state surveillance data, and to help plan for public health care and educational needs. It also provides valuable data on racial/ethnic patterns of selected major birth defects.     

Defective sumoylation pathway directs congenital heart disease

Congenital heart defects (CHDs) are the most common of all birth defects, yet molecular mechanism(s) underlying highly prevalent atrial septal defects (ASDs) and ventricular septal defects (VSDs) have remained elusive. We demonstrate the indispensability of "balanced" posttranslational small ubiquitin-like modifier (SUMO) conjugation-deconjugation pathway for normal cardiac development. Both hetero- and homozygous SUMO-1 knockout mice exhibited ASDs and VSDs with high mortality rates, which were rescued by cardiac reexpression of the SUMO-1 transgene. Because SUMO-1 was also involved in cleft lip/palate in human patients, the previous findings provided a powerful rationale to question whether SUMO-1 was mutated in infants born with cleft palates and ASDs. Sequence analysis of DNA from newborn screening blood spots revealed a single 16 bp substitution in the SUMO-1 regulatory promoter of a patient displaying both oral-facial clefts and ASDs. Diminished sumoylation activity whether by genetics, environmental toxins, and/or pharmaceuticals may significantly contribute to susceptibility to the induction of congenital heart disease worldwide. Birth Defects Research (Part A) 2011. ? 2011 Wiley-Liss, Inc.     

Cooperation between the PDGF receptors in cardiac neural crest cell migration

Neural crest cells (NCCs) are essential components of the sympathetic nervous system, skin, craniofacial skeleton, and aortic arch. It has been known for many years that perturbation of migration, proliferation, and/or differentiation of these cells leads to birth defects such as cleft palate and persistent truncus arteriosus (PTA). Previously, we had shown that disruption of the platelet-derived growth factor receptor (PDGFR) alpha in NCCs resulted in defects in craniofacial and aortic arch development, the latter with variable penetrance. Because we observed ventricular septal defects in embryos that are null for the PDGFRbeta, we hypothesized that both PDGF receptors are involved in NCC formation. Here, we show that both receptors are expressed in cardiac NCCs and that the combined loss of the PDGFRalpha and PDGFRbeta in NCCs resulted in NCC-related heart abnormalities, including PTA and a ventricular septal defect (VSD). Using NCC lineage tracing, we observed that loss of PDGF receptor signaling resulted in reduced NCCs in the conotruncus region, leading to defects in aortic arch septation. These results indicate that while PDGFRalpha plays a predominant role in NCC development, the PDGFRbeta is expressed by and functions in cardiac NCCs. Combined PDGF receptor signaling is required for sufficient recruitment of cardiac NCCs into the conotruncal region and for formation of the aortico-pulmonary and ventricular septum.     

Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study

BACKGROUND: Observational studies and clinical trials have suggested that periconceptional use of folic acid can reduce the risk of birth defects other than neural tube defects (NTDs). Using data reported by states to the National Birth Defects Prevention Network, we examined whether folic acid fortification might have decreased the prevalence of other specific birth defects. METHODS: For each of 16 birth defect categories selected for study, birth prevalence for two time periods was calculated with data submitted from a number of states in 1995-1996 ("pre-fortification") and 1999-2000 ("post-fortification"). Changes in birth prevalence between the two time periods were assessed by calculating prevalence ratios and 95% confidence intervals for each defect, and compared by maternal race/ethnicity and availability of prenatally diagnosed cases. RESULTS: We confirmed previously reported reductions in the birth prevalence of NTDs. In addition, we found modest, yet statistically significant, decreases in the birth prevalence for transposition of the great arteries(12%), cleft palate only (12%), pyloric stenosis (5%), upper limb reduction defects (11%), and omphalocele (21%). More substantial subgroup decreases were observed for renal agenesis among programs that conduct prenatal surveillance (28%), for common truncus among Hispanics (45%), and for upper limb reduction defects among Hispanics (44%). There were modest yet significant increases in the prevalence of obstructive genitourinary defects (12%) and Down syndrome (7%), but not among programs conducting prenatal surveillance for these defects. CONCLUSIONS: These results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non-NTD birth defects.     

Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts

BACKGROUND: Periconceptional supplementation of multivitamins that include folic acid have been shown to prevent several birth defects, including neural tube defects and orofacial clefts. We investigated whether polymorphic variants of fetal acetyl-N-transferase 1 (NAT1), an enzyme involved in the catabolism of folates, differentially interacted with maternal multivitamin use during early pregnancy to alter the risk of delivering an infant with an orofacial cleft malformation. METHODS: Using a large population-based case-control study, we genotyped 421 California infants born with an isolated cleft and 299 controls for two NAT1 polymorphisms. RESULTS: Compared to the homozygous wild-type genotypes, odds ratios for isolated cleft lip with/without cleft palate were slightly increased among infants who were homozygous for the variant alleles of NAT1 1088 and 1095. For isolated cleft palate, no similar associations with these two NAT1 variants were observed. For NAT1 1088 genotypes, we did not observe any differential risks for clefts related to maternal multivitamin intake. For NAT1 1095 genotypes, however, we found a two-fold higher risk for isolated cleft lip with/without cleft palate among infants who were homozygous for the variant allele and whose mothers did not take multivitamins during early pregnancy. CONCLUSIONS: We found evidence suggestive of an interaction between the NAT1 1095 polymorphism and lack of maternal multivitamin use that increased risks of isolated cleft lip with/without cleft palate.     

Essential role for ADAM19 in cardiovascular morphogenesis

Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19(-/-) animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects.     

Birth prevalence of cleft lip and palate in British Columbia between 1952 and 1986: stability of rates.

We examined the birth prevalence of cleft lip with or without cleft palate and of isolated cleft palate in British Columbia between 1952 and 1986 using the data of the BC Health Surveillance Registry. The rates fluctuated over the study period, but linear trend analysis showed no increase or decrease for cleft lip with or without cleft palate; however, there was a significant increase for isolated cleft palate, attributed to improved ascertainment around 1963-66. Given the possible effects of newer agents used in both silviculture and agriculture, as well as the general concern over drugs and other environmental agents, such a long-term monitoring program is important. Furthermore, if significant clustering occurs, good background data are essential for comparison. The general public''s perception is that the rates of birth defects are increasing. Our findings should give some reassurance with respect to orofacial clefts.     

National rates of birth defects among hospitalized newborns

BACKGROUND: The Healthcare Cost and Utilization Project (HCUP) family of hospital discharge databases offer an unprecedented opportunity to generate national estimates of newborn infants with birth defects. This report estimates national hospital admissions for newborn infants diagnosed with birth defects computed from HCUP and compares them to pooled prevalence figures computed from state birth defect surveillance systems. METHODS: HCUP-derived rates of 36 birth defects from 1997 through 2001 were compared to rates derived from pooled data reported by 26 state-based surveillance systems stratified by inclusion of elective terminations in case definitions. Rate ratios (RRs) were calculated for each birth defect by dividing the rate derived from HCUP by the rate derived from the relevant surveillance systems. RESULTS: HCUP newborn hospitalization rates for birth defects closely approximate pooled birth defect rates for surveillance systems that do not include elective terminations. HCUP rates were not significantly different for 35 of 36 defects. Overall, 20 HCUP rates were within 10% of state rates, 11 more were within 20% of state rates, and only 1 differed by more than 50%. HCUP rates compared most closely to state rates for cardiovascular (VSD RR = 0.98, ASD = 0.96, pulmonary valve atresia and stenosis = 0.92), orofacial (cleft palate RR = 1.10, cleft lip = 1.06), and genitourinary defects (obstructive genitourinary RR = 1.01, bladder exstrophy = 0.97). HCUP rates compared less favorably to rates derived from surveillance systems that included elective terminations. CONCLUSIONS: HCUP data approximate state-based surveillance system data for defects that are easily recognized in the newborn period and infrequently a cause for elective termination. HCUP data can be used to examine the impact of public health efforts on the number of infants born with birth defects as well as the cost and consequences of variations in the hospital management of birth defects.     

Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies

BACKGROUND: This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring. METHODS: Data were drawn from a population‐based case‐control study of fetuses and live‐born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live‐born controls. RESULTS: Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6‐ to 2.1‐fold higher risk of NTDs (95% CI: 0.9, 2.6), d‐transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1). CONCLUSIONS: This study observed that maternal alcohol intake increased the risk for d‐transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Palatogenesis: engineering, pathways and pathologies

Cleft palate represents the second most common birth defect and carries substantial physiologic and social challenges for affected patients, as they often require multiple surgical interventions during their lifetime. A number of genes have been identified to be associated with the cleft palate phenotype, but etiology in the majority of cases remains elusive. In order to better understand cleft palate and both surgical and potential tissue engineering approaches for repair, we have performed an in-depth literature review into cleft palate development in humans and mice, as well as into molecular pathways underlying these pathologic developments. We summarize the multitude of pathways underlying cleft palate development, with the transforming growth factor beta superfamily being the most commonly studied. Furthermore, while the majority of cleft palate studies are performed using a mouse model, studies focusing on tissue engineering have also focused heavily on mouse models. A paucity of human randomized controlled studies exists for cleft palate repair, and so far, tissue engineering approaches are limited. In this review, we discuss the development of the palate, explain the basic science behind normal and pathologic palate development in humans as well as mouse models and elaborate on how these studies may lead to future advances in palatal tissue engineering and cleft palate treatments.     

Socioeconomic measures,orofacial clefts,and conotruncal heart defects in California

OBJECTIVE : To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects. DESIGN : Data were from a recent population‐based case‐control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls. RESULTS : The odds ratio for the worst versus best score on a household‐level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9–3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood‐level SES was also not associated with increased risk of the studied defects. CONCLUSIONS : This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Association of paternal age with prevalence of selected birth defects

BACKGROUND: Unlike maternal age, the effect of paternal age on birth defect prevalence has not been well examined. We used cases from the Texas birth defect registry, born during 1996-2002, to evaluate the association of paternal age with the prevalence of selected structural birth defects. METHODS: Poisson regression was used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs) associated with paternal age for each birth defect, adjusting for maternal age, race/ethnicity, and parity. RESULTS: Relative to fathers ages 25-29 years, fathers 20-24 years of age were more likely to have offspring with gastroschisis (PR 1.47, 95% CI: 1.12-1.94), and fathers 40+ years old were less likely to have offspring with trisomy 13 (PR 0.40, 95% CI: 0.16-0.96). No association was seen between paternal age and prevalence of anencephaly and encephalocele. A selection bias was observed for the other birth defects in which cases of younger fathers were more often excluded from study. CONCLUSIONS: In studies of birth defect risk and paternal age, the source of information may affect the validity of findings.     

Genetic approaches to identify disease genes for birth defects with cleft lip/palate as a model

BACKGROUND: Understanding the etiology of birth defects is an important step toward developing improved treatment and preventive strategies. Most birth defects have an underlying genetic basis, ranging from single genes playing dominant or recessive roles in Mendelian disorders to a mixture of contributions from multiple genes and environmental triggers in complex traits. The purpose of this article is to provide an overview of genetic approaches to identifying disease genes for genetically complex birth defects. METHODS: A review of the literature describing successes and limitations for identifying disease genes for complex traits was conducted. RESULTS: Cleft lip and cleft palate are common congenital anomalies with significant medical, psychological, social, and economic ramifications. The Online Mendelian Inheritance in Man catalog (OMIM; http://www3.ncbi.nlm.nih.gov/Omim) lists more than 400 single-gene causes of clefts of the lip and/or palate. Genetic causes of clefting also include chromosomal rearrangements, genetic susceptibility to teratogenic exposures, and complex genetic contributions of multiple genes. CONCLUSIONS: Genetic causes of birth defects can be identified using an increasingly powerful combination of careful sample collection, molecular analytic methods, and statistical evaluations. We will describe a range of approaches to search for genetic factors of birth defects and use our own work with cleft lip and palate as a model.