Epidemiologic analysis of maternal factors and amniotic band defects

BACKGROUND

The group of defects identified as amniotic bands includes amnion rupture sequence (ARS) and body wall complex (BWC). Little is known about risk factors for either ARS or BWC, except that maternal age has been shown to affect risk inversely.

METHODS

The present analysis used data collected from 1976 to 1998 as part of an ongoing case control study of birth defects in the metropolitan areas of Boston, Philadelphia, and Toronto. There were 73 cases with ARS and 11 cases with BWC. ARS cases were further subdivided according to affected structures: there were 53 with only limbs affected (ARS‐L) and 20 with nonlimb defects with or without limb defects (ARS‐NL). The control group comprised 12,227 subjects with other major malformations. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors.

RESULTS

Multivariate adjusted odds ratios for BWC were increased more than threefold for maternal age < 25 years and maternal education < 12 years, but neither estimate was statistically significant. Corresponding estimates for ARS‐L and ARS‐NL ranged from 1.3 to 1.5 and also were not statistically significant. Cases were less likely to be white non‐Hispanic than controls and the odds ratio for ARS‐NL excluded the null. The multivariate adjusted odds ratio (MVOR) for unplanned pregnancy and BWC was 1.9 (95% confidence interval, 0.5–6.7) compared to 1.2 and 1.0 for ARS‐L and ARS‐NL, respectively. Neither parity nor maternal smoking was associated with any case group. The MVORs for first trimester acetaminophen use in relation to ARS‐L and ARS‐NL risks were 2.1 (1.1–3.9) and 3.4 (1.1–10.3), respectively. Such use was less common among BWC cases (MVOR was 0.4; 0.1–1.4).

CONCLUSIONS

Risk estimates tended to be similar for ARS‐L and ARS‐NL cases but different for BWC cases, suggesting different etiologies. These data suggest that young maternal age, low maternal education, unplanned pregnancy, and non‐white/non‐Hispanic race/ethnicity might increase the risk of BWC in offspring. Increased risks for acetaminophen use should be interpreted with caution because they may be confounded by indication for use. Birth Defects Research (Part A) 67:68–72, 2003. © 2003 Wiley‐Liss, Inc.

     

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND: Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS: As part of the population‐based case‐control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS: Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08–2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11–2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85–1.87; p = 0.124). CONCLUSIONS: Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011. © 2011 Wiley‐Liss, Inc.     

Analysis of birth defects among children 3 years after conception through assisted reproductive technology in China

BACKGROUND : Previous studies inconsistently suggest that assisted reproduction technology (ART) may increase the risk of birth defects in children. METHOD(S) : Live birth infants, conceived by in vitro fertilization fresh embryo transfer (IVF), intracytoplasmic sperm injection fresh embryo transfer (ICSI), or frozen‐thawed embryo transfer (FET) in Reproductive Center of Tongji Hospital (Wuhan, China) between 1997 and 2008, were followed up at birth and after 3 years. Preterm pregnancy, multiple pregnancy, sex ratio (male/female), congenital malformation were compared. RESULT(S) : A total of 4,236 children were born after ART (IVF 2,543, ICSI 908, FET 785). Compared with IVF, the rate of preterm pregnancy and sex ratio in ICSI were lower (p < 0.05); the rate of multiple pregnancy in ICSI and FET were all lower than IVF (p < 0.05). Congenital defects were comparable in all groups at birth. In total, 2,908 children participated in the second follow‐up from 34 months to 60 months with an average of 40 months, and the cases of birth defects had doubled (3 years: 5.16%, birth: 2.22%). The birth defect rate in boys conceived through ICSI was significantly higher than the IVF group after 3‐year follow‐up (ICSI boys: 8.62%, IVF boys: 5.21% [p < 0.05]), even though there was no significant difference at birth. CONCLUSION(S) : Compared with IVF, FET may not increase risk of birth defects. Children conceived through ICSI, especially males, had higher rates of congenital malformations that were inapparent at birth. So longitudinal monitoring may provide insights into the risks of ART. Birth Defects Research (Part A) 97:744–749, 2013. 2013. © 2013 Wiley Periodicals, Inc.     

Limb‐body wall defect: Experience of a reference service of fetal medicine from Southern Brazil

Background: Limb‐body wall defect is a rare condition characterized by a combination of large and complex defects of the ventral thorax and abdominal wall with craniofacial and limb anomalies. Methods: The aim of this study was to describe the experience of our fetal medicine service, a reference from Southern Brazil, with prenatally diagnosed patients with a limb‐body wall defect in a 3 years period. Only patients who fulfilled the criteria suggested by Hunter et al. (2011) were included in the study. Clinical data and results of radiological and cytogenetic evaluation were collected from their medical records. Results: Our sample was composed of 8 patients. Many of their mothers were younger than 25 years (50%) and in their first pregnancy (62.5%). It is noteworthy that one patient was referred due to suspected anencephaly and another due to a twin pregnancy with an embryonic sac. Craniofacial defects were verified in three patients (37.5%), thoracic/abdominal abnormalities in 6 (75%) and limb defects in eight (100%). Congenital heart defects were observed in five patients (62.5%). One of them presented a previously undescribed complex heart defect. Conclusion: The results disclosed that complementary exams, such as MRI and echocardiography, are important to better define the observed defects. Some of them, such as congenital heart defects, may be more common than previously reported. This definition is essential for the proper management of the pregnancy and genetic counseling of the family. The birth of these children must be planned with caution and for the prognosis a long survival possibility, despite unlikely and rare, must be considered. Birth Defects Research (Part A) 100:739–749, 2014. © 2014 Wiley Periodicals, Inc.     

The concurrence of ring constrictions in Adams-Oliver syndrome: additional evidence for vascular disruption as common pathogenetic mechanism.

We report on a girl with congenital scalp and acral reduction limb defects, consistent with the diagnosis of Adams-Oliver syndrome. The presence of constriction rings makes the limb anomalies in this case similar to those seen in the amniotic band disruption sequence. Vascular disruption--with or without secondary amniotic rupture--may be responsible for the observed anomalies. Therefore we believe that the present observation adds further evidence for the hypothesis that the Adams-Oliver syndrome is a vascular disruption sequence.     

Maternal severe migraine and risk of congenital limb deficiencies

BACKGROUND: Migraines occurs frequently during pregnancy; however, there are no published data on their possible teratogenic potential in a controlled epidemiological study. Therefore, we examined the risk of congenital abnormalities in infants born to women who had migraines and other headaches during pregnancy. METHODS: Between 1980 and 1996, the Hungarian Case-Control Surveillance of Congenital Abnormalities evaluated 22,843 cases (newborns or fetuses) with congenital abnormalities, 38,151 control newborn infants without any abnormalities, and 834 malformed controls with Down syndrome. RESULTS: Migraines anytime during pregnancy occurred in 565 (2.5%) mothers of the case group compared with 713 (1.9%) mothers in the control group (crude prevalence odds ratio [POR], 1.3; 95% confidence interval [CI], 1.2-1.5) and 24 (2.9%) pregnant women in the malformed control group (crude POR, 0.9; 95% CI, 0.6-1.3) The mothers of 247 cases, 533 controls, and 21 malformed controls had severe migraines during the second and/or third months of pregnancy. There was only 1 congenital abnormality group: limb deficiencies, which had a higher rate of maternal migraines during the second and third months of pregnancy both at the comparison of cases and matched controls (adjusted POR, 2.5; 95% CI, 1.1-5.8) and of cases and malformed controls (adjusted POR, 1.7; 95% CI, 1.3-3.0). There was no association between other headaches and different congenital abnormalities at the comparison of cases and controls. CONCLUSIONS: Our data showed that maternal severe migraines during the second and/or third months of pregnancy were associated with an increased risk of congenital limb deficiencies. A similar association was not detected between congenital anomalies and other headaches during pregnancy. Our study was not based on a prior hypothesis; therefore, these data can be considered only as a signal that needs confirmation by independent data sets.     

Absence of limbs and gross body wall defects: an epidemiological study of related rare malformation conditions.

The study is based on almost 10 million births and reports on 215 infants with two unusual malformations: amelia and gross body wall defect. Amelia without body wall defect was present in 116 cases, 67 had body wall defects without amelia, and 32 had both. The total rate was 2.2 per 100,000 births. The infants were divided into five mutually exclusive groups. There were 40 infants (0.4 per 100,000) with agenesis of the body stalk, 18 with amelia and other types of gross body wall defects (0.2 per 100,000), 56 with amelia and malformations other than gross body wall defects (0.6 per 100,000), 41 with amelia (with or without other limb reduction defects) but no nonlimb malformations (0.4 per 100,000), and 60 infants with gross body wall defects of a type other than agenesis of body stalk and without amelia (0.6 per 100,000). A weak trend of decreasing prevalence of these malformations was found during the observation period. Infants with agenesis of the body stalk and infants with amelia combined with other types of gross body wall defects occurred at an increased rate in infants of young women. This maternal age effect is also found with gastroschisis, but not with omphalocele, and may indicate etiological or pathogenetic similarities between gastroschisis and the two former groups of defect. In infants with amelia, additional limb reduction defects could be of any type: transverse, longitudinal, or intercalary. Therefore, amelia may be the end result of different types of disturbances of limb morphogenesis. There was an increased rate of twinning. The relationship with amniotic band syndrome is discussed.     

Early pregnancy azathioprine use and pregnancy outcomes

BACKGROUND: Azathioprine (AZA) is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation. Previous studies have demonstrated potential risks. METHODS: The Swedish Medical Birth Register was used to identify 476 women who reported the use of AZA in early pregnancy. The effect of AZA exposure on pregnancy outcomes was studied after adjustment for maternal characteristics that could act as confounders. RESULTS: The most common indication for AZA use was IBD. The rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98–2.04). An association between early pregnancy AZA exposure and ventricular/atrial septal defects was found (adjusted OR: 3.18, 95% CI: 1.45–6.04). Exposed infants were also more likely to be preterm, to weigh <2500 gm, and to be small for gestational age compared to all infants born. This effect remained for preterm birth and low birth weight when infants of women with IBD but without AZA exposure were used as a comparison group. A trend toward an increased risk of congenital malformations was found among infants of women with IBD using AZA compared to women with IBD not using AZA (adjusted OR: 1.42, 95% CI: 0.93–2.18). CONCLUSIONS: Infants exposed to AZA in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects. There is also an increased risk of growth restriction and preterm delivery. These associations may be confounded by the severity of maternal illness. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Epidemiologic Characteristics and Risk Factors for Congenital Hypothyroidism from 2009 to 2018 in Xiamen,China

Objective: Early diagnosis and treatment of children with congenital hypothyroidism (CH) through newborn screening can effectively prevent delayed development. This study was designed to investigate the pathogenesis and factors that influence CH in urban areas of China between 2009 and 2018.Methods: A retrospective analysis of newborn screening data and diagnosis and treatment information for CH diagnosed in the information database of the neonatal disease screening center in one of China's five special economic zones from 2009 to 2018.Results: Of the 947,258 newborns screened between 2009 and 2018, 829 (406 girls) were diagnosed with CH at birth (1 diagnosis/1,136 births). Among the 608 cases of CH diagnosed at birth and re-evaluated at the age of 3 years, 487 were permanent congenital hypothyroidism (PCH, 1/1,429), and 121 were transient congenital hypothyroidism (TCH, 1/5,882). A total of 83.2% of infants with PCH (405/487) underwent thyroid imaging in the neonatal period, of which thyroid dysgenesis accounted for 28.64% (116/405) and functional defects accounted for 71.36% (289/405). The incidence of CH changed significantly in infants with initial serum thyroid-stimulating hormone concentrations of 41 to 100 mIU/L and ≥100 mIU/L, whereas the incidence of mild CH showed a slight increase. The incidence of CH was significantly higher in postterm infants (1/63) and low-birth-weight infants (1/370).Conclusion: In the past decade, the incidence of CH has increased, mainly due to the increase in the incidence of PCH and TCH. The incidence of mild CH has increased slightly. Postterm birth and low birth weight are important factors affecting the incidence of CH.Abbreviations: CH = congenital hypothyroidism; FT4 = free thyroxine; L-T4 = levothyroxine sodium; PCH = permanent congenital hypothyroidism; TCH = transient congenital hypothyroidism; TSH = thyroid-stimulating hormone; TT4 = total thyroxine     

On the symmetry of limb deficiencies among children with multiple congenital anomalies

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.     

Bending of DNA segments with Saccharomyces cerevisiae autonomously replicating sequence activity, isolated from basidiomycete mitochondrial linear plasmids

Summary Previous studies have indicated that DNA bending is a general structural feature of sequences (ARSs) from cellular DNAs of yeasts and nuclear and mitochondrial genomic DNAs of other eukaryotes that are capable of autonomous replication in Saccharomyces cerevisiae. Here we showed that bending activity is also tightly associated with S. cerevisiae ARS function of segments cloned from mitochondrial linear DNA plasmids of the basidiomycetes Pleurotus ostreatus and Lentinus edodes. Two plasmids, designated pLPO2-like (9.4 kb), and pLPO3 (6.6 kb) were isolated from a strain of P. ostreatus. A 1029 by fragment with high-level ARS activity was cloned from pLPO3 and it contained one ARS consensus sequence (A/T)TTTAT(A/G)TTT(A/T) indispensable for activity and seven dispersed ARS consensus-like (10/11 match) sequences. A discrete bent DNA region was found to lie around 500 by upstream from the ARS consensus sequence (T-rich strand). Removal of the bent DNA region impaired ARS function. DNA bending was also implicated in the ARS function associated with a 1430 by fragment containing three consecutive ARS consensus sequences which had been cloned from the L. edodes plasmid pLLE1 (11.0 kb): the three consecutive ARSs responsible for high-level ARS function occurred in, and immediately adjacent to, a bent DNA region. A clear difference exists between the two plasmid-derived ARS fragments with respect to the distance between the bent DNA region and the ARS consensus sequence(s).     

Are selective serotonin reuptake inhibitors cardiac teratogens? Echocardiographic screening of newborns with persistent heart murmur

BACKGROUND : Selective serotonin reuptake inhibitors (SSRIs) have been suspected of cardiac teratogenicity, but reports have been inconsistent. Our aim was to investigate the rate of nonsyndromic congenital heart defects in newborns exposed in utero to SSRIs compared with unexposed controls. METHODS : This prospective study of women who gave birth at our tertiary center from 2000 to 2007 yielded 235 women who reported first‐trimester SSRI use during pregnancy. All newborns born during the study period and found to have a persistent cardiac murmur on day 2 or 3 of life were referred for examination by a pediatric cardiologist and by echocardiography. The findings were compared between the newborns who were exposed to SSRIs and those who were not. RESULTS : Nonsyndromic congenital heart defects were identified by echocardiography in 8 of 235 (3.40%) newborns exposed in utero to SSRIs and in 1083 of 67,636 (1.60%) non‐exposed newborns. The difference in prevalence between the two groups was significant (relative risk, 2.17; 95% confidence interval, 1.07–4.39). The prevalence rates for paroxetine and fluoxetine exposure were 4.3% and 3.0%, respectively. All cardiac defects in the study group were mild: ventricular septal defect (6), bicuspid aortic valve (1) and right superior vena cava to coronary sinus (1). CONCLUSIONS : Newborns exposed in utero to SSRIs, have a twofold higher risk of mild nonsyndromic heart defects than unexposed infants. The data suggest that women who require SSRI treatment during pregnancy can be reassured that the fetal risk is low and possible cardiac malformations will probably be mild. Late‐targeted ultrasound and fetal echocardiography at 22 to 23 weeks' gestation are recommended in this patient group. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Hirschsprung's disease prevalence in Europe: A register based study

Background: Hirschsprung's disease is a congenital gut motility disorder, characterised by the absence of the enteric ganglion cells along the distal gut. The aim of this study was to describe the epidemiology of Hirschsprung's disease, including additional congenital anomalies, total prevalence, trends, and association with maternal age. Methods: Cases of Hirschsprung's disease delivered during 1980 to 2009 notified to 31 European Surveillance of Congenital Anomaly registers formed the population‐based case‐series. Prevalence rates and 95% confidence intervals were calculated as the number of cases per 10,000 births. Multilevel Poisson regression was performed to investigate trends in prevalence, geographical variation and the association with maternal age. Results: There were 1,322 cases of Hirschsprung's disease among 12,146,210 births. The total prevalence was 1.09 (95% confidence interval, 1.03–1.15) per 10,000 births and there was a small but significant increase in prevalence over time (relative risk = 1.01; 95% credible interval, 1.00–1.02; p = 0.004). There was evidence of geographical heterogeneity in prevalence (p < 0.001). Excluding 146 (11.0%) cases with chromosomal anomalies or genetic syndromes, there were 1,176 cases (prevalence = 0.97; 95% confidence interval, 0.91–1.03 per 10,000 births), of which 137 (11.6%) had major structural anomalies. There was no evidence of a significant increased risk of Hirschsprung's disease in cases born to women aged ≥35 years compared with those aged 25 to 29 (relative risk = 1.09; 95% credible interval, 0.91–1.31; p = 0.355). Conclusion: This large population‐based study found evidence of a small increasing trend in Hirschsprung's disease and differences in prevalence by geographic location. There was also no evidence of an association with maternal age. Birth Defects Research (Part A), 100:695–702, 2014. © 2014 Wiley Periodicals, Inc.     

Evaluation of heterogeneity in the association between congenital heart defects and variants of folate metabolism genes: conotruncal and left-sided cardiac defects

BACKGROUND: Genetic variation in the folate metabolic pathway may influence the risk of congenital heart defects. This study was undertaken to assess the associations between the inherited and maternal genotypes for variants in folate‐related genes and the risk of a composite heart phenotype that included two component phenotypes: conotruncal heart defects (CTDs) and left‐sided cardiac lesions (LSLs). METHODS: Nine folate‐related gene variants were evaluated using data from 692 case‐parent triads (CTD, n = 419; LSL, n = 273). Log‐linear analyses were used to test for heterogeneity of the genotype‐phenotype association across the two component phenotypes (i.e., CTD and LSLs) and, when there was no evidence of heterogeneity, to assess the associations of the maternal and inherited genotypes with the composite phenotype. RESULTS: There was little evidence of heterogeneity of the genotype‐phenotype association across the two component phenotypes or of an association between the genotypes and the composite phenotype. There was evidence of heterogeneity in the association of the maternal MTR A2756G genotype (p = 0.01) with CTDs and LSLs. However, further analyses suggested that the observed associations with the maternal MTR A2756G genotype might be confounded by parental imprinting effects. CONCLUSIONS: Our analyses of these data provide little evidence that the folate‐related gene variants evaluated in this study influence the risk of this composite congenital heart defect phenotype. However, larger and more comprehensive studies that evaluate parent‐of‐origin effects, as well as additional folate‐related genes, are required to more fully explore the relation between folate and congenital heart defects. Birth Defects Research (Part A) 2011. © 2011 Wiley‐Liss, Inc.     

Microarray analysis of murine limb bud ectoderm and mesoderm after exposure to cadmium or acetazolamide

BACKGROUND: A variety of drugs, environmental chemicals, and physical agents induce a common limb malformation in the offspring of pregnant mice exposed on day 9 of gestation. This malformation, postaxial, right‐sided forelimb ectrodactyly, is thought to arise via an alteration of hedgehog signaling. METHODS: We have studied two of these teratogens, acetazolamide and cadmium, using the technique of microarray analysis of limb bud ectoderm and mesoderm to search for changes in gene expression that could indicate a common pathway to postaxial limb reduction. RESULTS: Results indicated a generalized up‐regulation of gene expression after exposure to acetazolamide but a generalized down‐regulation due to cadmium exposure. An intriguing observation was a cadmium‐induced reduction of Mt1 and Mt2 expression in the limb bud mesoderm indicating a lowering of embryonic zinc. CONCLUSIONS: We propose that these two teratogens and others (valproic acid and ethanol) lower sonic hedgehog signaling by perturbation of zinc function in the sonic hedgehog protein. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Analysis of chromosomal structural variation in patients with congenital left‐sided cardiac lesions

Background: We sought to characterize the landscape of structural variation associated with the subset of congenital cardiac defects characterized by left‐sided obstruction. Methods: Cases with left‐sided cardiac defects (LSCD) and pediatric controls were uniformly genotyped and assessed for copy number variant (CNV) calls. Significance testing was performed to ascertain differences in overall CNV incidence, and for CNV enrichment of specific genes and gene functions in LSCD cases relative to controls. Results: A total of 257 cases of European descent and 962 ethnically matched, disease‐free pediatric controls were included. Although there was no difference in CNV rate between cases and controls, a significant enrichment in rare LSCD CNVs was detected overall (p = 7.30 × 10^?3, case/control ratio = 1.26) and when restricted either to deletions (p = 7.58 × 10^?3, case/control ratio = 1.20) or duplications (3.02 × 10^?3, case/control ratio = 1.43). Neither gene‐based, functional nor knowledge‐based analyses identified genes, loci or pathways that were significantly enriched in cases as compared to controls when appropriate corrections for multiple tests were applied. However, several genes of interest were identified by virtue of their association with cardiac development, known human conditions, or reported disruption by CNVs in other patient cohorts. Conclusion: This study examines the largest cohort to date with LSCD for structural variation. These data suggest that CNVs play a role in disease risk and identify numerous genes disrupted by CNVs of potential disease relevance. These findings further highlight the genetic heterogeneity and complexity of these disorders. Birth Defects Research (Part A) 100:951–964, 2014. © 2014 Wiley Periodicals, Inc.     

Maternal caffeine intake during pregnancy and orofacial clefts

BACKGROUND: Moderate caffeine intake during pregnancy is common, but little is known about its potential association with birth defects. METHODS: The National Birth Defects Prevention Study is a population‐based, case‐control study of major birth defects, excluding infants with single‐gene disorders and chromosomal abnormalities. This analysis includes infants with cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), excluding infants whose cleft was secondary to holoprosencephaly or amniotic band sequence. Mothers reported dietary caffeine intake from coffee, tea, sodas, and chocolate in the year before pregnancy and reported intake of medications containing caffeine during pregnancy. We assessed the association between dietary caffeine intake, frequency of consuming each type of caffeinated beverage, medications containing caffeine, and CL/P or CPO among infants born from October 1997 through December 2004. RESULTS: This analysis included 1531 infants with CL/P, 813 infants with CPO, and 5711 infants with no major birth defects (controls). Examining dietary sources among control mothers, 11% reported consuming at least 300 mg of caffeine per day and 17% reported consuming less than 10 mg of caffeine per day; high consumption (≥3 servings per day) was reported by 8% (coffee), 4% (tea), and 15% (sodas); medications containing at least 100 mg caffeine/dose were reported by less than 1%. Although some effect estimates were elevated for moderate caffeine intake from all beverages, estimates were closer to the null for high caffeine levels. Isolated CL/P was associated with use of medications containing at least 100 mg of caffeine per dose. CONCLUSIONS: Our data do not suggest an association between maternal dietary caffeine intake and orofacial clefts, but caffeine‐containing medications merit further study. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Experimental evaluation of calcein and alizarin red S for immersion marking of silver carp Hypophthalmichthys molitrix (Valenciennes, 1844)

Calcein (CAL) and alizarin red S (ARS) at concentrations of 50–200 and 150–300 mg/L, respectively, were used for immersion marking of juvenile silver carp Hypophthalmichthys molitrix (79.65 ± 2.11 mm total length, mean ± SD). The marked fish were kept in separate tanks (0.012 individuals per litre, rearing temperature 18.4–25.7°C) for 360 days. Each experimental treatment group consisted of three replicates (16 individuals per replicate). Immersion for 24 h produced detectable marks in the sagittae, lateral line and non‐lateral line scales, and fin rays (dorsal, pectoral, ventral, anal, and caudal) at 360 days post‐marking. Acceptable marks in the sagittae were observed for CAL at concentrations of 150–200 mg/L and for ARS at concentrations of 200–300 mg/L. Fluorescent marks were poorly visible in all non‐lateral line scales from both the CAL‐ and ARS‐treated groups. Acceptable fluorescent marks in the lateral line scales and fin rays were detected for CAL at concentrations of 150–200 and 100–200 mg/L, respectively, and for ARS at concentrations of 200–300 and 150–300 mg/L, respectively. In particular, optimal marks were observed at the highest concentrations investigated in lateral line scales (200 mg/L CAL, 300 mg/L ARS) and fin rays (200 mg/L CAL, 200–300 mg/L ARS). There was no significant difference in the survival or growth of marked fish compared to controls throughout the experiment (P > 0.05).     

Do infants with major congenital anomalies have an excess of macrosomia?

BACKGROUND: Infants that develop congenital anomalies may also have an excess prevalence of macrosomia (birth weight > or =4,000 g). This may indicate that abnormalities of glycemic control play a role in the etiology of birth defects. This study was undertaken to determine whether all infants with congenital anomalies have an excess of macrosomia and whether it is confined to specific types of anomalies. METHODS: A case-control study was conducted, comparing the birth weights of 8,226 infants with congenital anomalies ascertained by the Texas Birth Defects Monitoring Division with those of 965,965 infants without birth defects. Odds ratios were calculated to determine the association between birth weight and congenital anomalies, for 45 specific defects, and for all these defects combined. RESULTS: For all 45 defects combined, a significant association occurred only in the highest birth weight category. Infants with congenital anomalies were more likely than infants without birth defects to have a birth weight > or =4,500 g (OR = 1.65; 95% CI = 1.39-1.96). Infants born with ventricular septal defects, atrial septal defects, ventricular hypertrophy, or anomalies of the great vessels were 1.5-2.5 times more likely to weigh > or =4,000 g than were infants without birth defects. Based on small numbers, a stronger excess of macrosomia was observed for infants with encephalocele, holoprosencephaly, anomalies of the corpus callosum, preaxial polydactyly, and omphalocele. CONCLUSIONS: Our data suggest that infants with specific congenital anomalies are more likely to be macrosomic than are infants without an anomaly. If these findings are confirmed, associations between macrosomia and specific types of birth defects may help to identify birth defects that are caused by alterations in glycemic control.