Pharmacokinetics and pharmacodynamics of intravenous continuous rate infusion and repeated intramuscular administration of dexmedetomidine in standing horses.

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/h for 15 min then 0.005 mg/kg/h for 60 min) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30-min intervals for 60 min). Clearance and elimination half-life were 134 ± 67.4 ml/kg/min and 44.3 ± 26.3 min, respectively, in the CRI group, and apparent clearance and half-life were 412 ± 306 ml/kg/min (Cl/F) and 38.9 ± 18.6 min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects.

BACKGROUND: There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status. METHODS: We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State; birth year; plurality; and maternal race and ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed younger than 1 year of age. RESULTS: Our dataset included 10 181 074 children: 15 110 diagnosed with cancer, 539 567 diagnosed with birth defects, and 2124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children younger than 1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%). CONCLUSIONS: Our results suggest that birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as a risk factor for childhood cancer.

Causes of Death and Cardiovascular Comorbidities in Adults With Congenital Heart Disease.

Background Little is known about the contemporary mortality experience among adults with congenital heart disease (CHD). The objectives of this study were to assess the age at death, presence of cardiovascular comorbidities, and most common causes of death among adults with CHD in a contemporary cohort within the United States. Methods and Results Patients with CHD who had a healthcare encounter between 2008 and 2013 at 1 of 5 comprehensive CHD centers in North Carolina were identified by International Classification of Diseases, Ninth Revision (ICD-9), code. Only patients who could be linked to a North Carolina death certificate between 2008 and 2016 and with age at death ≥20 years were included. Median age at death and underlying cause of death based on death certificate data were analyzed. The prevalence of acquired cardiovascular risk factors was determined from electronic medical record data. Among the 629 included patients, the median age at death was 64.2 years. Those with severe CHD (n=157, 25%), shunts (n=202, 32%), and valvular lesions (n=174, 28%) had a median age at death of 46.0, 65.0, and 73.3 years, respectively. Cardiovascular death was most common in adults with severe CHD (60%), with 40% of those deaths caused by CHD. Malignancy and ischemic heart disease were the most common causes of death in adults with nonsevere CHD. Hypertension and hyperlipidemia were common comorbidities among all CHD severity groups. Conclusions The most common underlying causes of death differed by lesion severity. Those with severe lesions most commonly died from underlying CHD, whereas those with nonsevere disease more commonly died from non-CHD causes.

Cancer diagnostic profile in children with structural birth defects: An assessment in 15,000 childhood cancer cases.

BACKGROUND: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized. METHODS: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis. RESULTS: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05). CONCLUSIONS: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects. LAY SUMMARY: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable.

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

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

Sharp transection of the suspensory ligament as an alternative to digital strumming during canine ovariohysterectomy.

OBJECTIVE: To compare time efficiency and nociceptive input between digital strumming (DS) and sharp transection (ST) of the suspensory ligament during ovariohysterectomy (OVH). STUDY DESIGN: Randomized controlled trial. ANIMALS: 30 adult female dogs. METHODS: Dogs were randomly assigned to ST or DS procedures. Measures of nociception were assessed through measurements of preoperative and intraoperative heart rate during manipulation of the suspensory ligament. Measures of pain were assessed through preoperative and postoperative pain scores by using the short form Glasgow Composite Pain Scale. Time efficiency was measured through total surgical time and the time to release each suspensory ligament. RESULTS: After body weight was accounted for, the total surgical time was 1.1 minutes (P = .06) faster for ST than for DS, and each additional kilogram of body weight increased total surgical time by 0.1 minutes (P = .02). Digital strumming had 30.6-fold greater odds of taking greater than 1 minute compared with ST (P = .001). The heart rate from baseline to peak was 7.4 beats per minute lower in the ST group than in the DS group (P = .06). No complications were observed, and there was no difference in postoperative pain scores between treatments. CONCLUSION: Sharp transection was faster and generated less intraoperative acceleration in heart rate but did not differ in postoperative outcomes compared with DS. CLINICAL SIGNIFICANCE: Sharp transection is a viable alternative to DS for breakdown of the suspensory ligament during canine OVH. Sharp transection may improve surgical efficiency, especially when performing large volumes in the spay/neuter setting and could influence veterinary student training.

Maternal residential exposure to specific agricultural pesticide active ingredients and birth defects in a 2003-2005 North Carolina birth cohort.

BACKGROUND: Previously we observed elevated odds ratios (ORs) for total pesticide exposure and 10 birth defects: three congenital heart defects and structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems. This analysis examines association of those defects with exposure to seven commonly applied pesticide active ingredients. METHODS: Cases were live-born singleton infants from the North Carolina Birth Defects Monitoring Program linked to birth records for 2003-2005; noncases served as controls (total n = 304,906). Pesticide active ingredient exposure was assigned using a previously constructed metric based on crops within 500 m of residence, dates of pregnancy, and likely chemical application dates for each pesticide-crop combination. ORs (95% CI) were estimated with logistic regression for categories of exposure compared to unexposed. Models were adjusted for maternal race/ethnicity, age at delivery, education, marital status, and smoking status. RESULTS: Associations varied by birth defect and pesticide combinations. For example, hypospadias was positively associated with exposures to 2,4-D (OR50th to <90th percentile : 1.39 [1.18, 1.64]), mepiquat (OR50th to <90th percentile : 1.10 [0.90, 1.34]), paraquat (OR50th to <90th : 1.14 [0.93, 1.39]), and pendimethalin (OR50th to <90th : 1.21 [1.01, 1.44]), but not S-metolachlor (OR50th to <90th : 1.00 [0.81, 1.22]). Whereas atrial septal defects were positively associated with higher levels of exposure to glyphosate, cyhalothrin, S-metolachlor, mepiquat, and pendimethalin (ORs ranged from 1.22 to 1.35 for 50th to <90th exposures, and 1.72 to 2.09 for >90th exposures); associations with paraquat were null or inconsistent (OR 50th to <90th: 1.05 (0.87, 1.27). CONCLUSION: Our results suggest differing patterns of association for birth defects with residential exposure to seven pesticide active ingredients in North Carolina.

Study of selected birth defects among American Indian/Alaska Native population: A multi-state population-based retrospective study, 1999-2007.

BACKGROUND: Higher prevalence of selected birth defects has been reported among American Indian/Alaska Native (AI/AN) newborns. We examine whether known risk factors for birth defects explain the higher prevalence observed for selected birth defects among this population. METHODS: Data from 12 population-based birth defects surveillance systems, covering a birth population of 11 million from 1999 to 2007, were used to examine prevalence of birth defects that have previously been reported to have elevated prevalence among AI/ANs. Prevalence ratios (PRs) were calculated for non-Hispanic AI/ANs and any AI/ANs (regardless of Hispanic ethnicity), adjusting for maternal age, education, diabetes, and smoking, as well as type of case-finding ascertainment surveillance system. RESULTS: After adjustment, the birth prevalence of two of seven birth defects remained significantly elevated among AI/ANs compared to non-Hispanic whites (NHWs): anotia/microtia was almost threefold higher, and cleft lip +/- cleft palate was almost 70% higher compared to NHWs. Excluding AI/AN subjects who were also Hispanic had only a negligible impact on adjusted PRs. CONCLUSIONS: Additional covariates accounted for some of the elevated birth defect prevalences among AI/ANs compared to NHWs. Exclusion of Hispanic ethnicity from the AI/AN category had little impact on birth defects prevalences in AI/ANs. NHWs serve as a viable comparison group for analysis. Birth defects among AI/ANs require additional scrutiny to identify modifiable risk and protective factors.

Low carbohydrate diets may increase risk of neural tube defects.

BACKGROUND: Folic acid fortification significantly reduced the prevalence of neural tube defects (NTDs) in the United States. The popularity of "low carb" diets raises concern that women who intentionally avoid carbohydrates, thereby consuming fewer fortified foods, may not have adequate dietary intake of folic acid. METHODS: To assess the association between carbohydrate intake and NTDs, we analyzed data from the National Birth Defects Prevention Study from 1,740 mothers of infants, stillbirths, and terminations with anencephaly or spina bifida (cases), and 9,545 mothers of live born infants without a birth defect (controls) conceived between 1998 and 2011. Carbohydrate and folic acid intake before conception were estimated from food frequency questionnaire responses. Restricted carbohydrate intake was defined as ≤5th percentile among controls. Odds ratios were estimated with logistic regression and adjusted for maternal race/ethnicity, education, alcohol use, folic acid supplement use, study center, and caloric intake. RESULTS: Mean dietary intake of folic acid among women with restricted carbohydrate intake was less than half that of other women (p < .01), and women with restricted carbohydrate intake were slightly more likely to have an infant with an NTD (AOR = 1.30, 95% CI: 1.02, 1.67). CONCLUSIONS: This is the first study to examine the association between carbohydrate intake and NTDs among pregnancies conceived postfortification. We found that women with restricted carbohydrate intake were 30% more likely to have an infant with anencephaly or spina bifida. However, more research is needed to understand the pathways by which restricted carbohydrate intake might increase the risk of NTDs.

Geographic distribution of live births with tetralogy of Fallot in North Carolina 2003 to 2012.

BACKGROUND: Geographic variation in congenital heart disease is not well-described. This study uses geographic information systems (GIS) to describe the spatial epidemiology of tetralogy of Fallot (TOF), in North Carolina (NC) and to compare travel time for cases to congenital heart centers in NC. METHODS: Using the NC Birth Defects Monitoring Program database, live births with TOF born between 2003 and 2012 were identified. Birth certificates provided demographic variables. A denominator of live births/zip code was obtained from the NC live births database. ArcGIS® software was used to illustrate TOF prevalence by zip code, and SatScanTM was used to identify spatial clusters of TOF cases and to identify changes in cluster location over time. Driving time to each of five NC congenital heart centers was predicted based on road systems information. RESULTS: A total of 496 infants were born with TOF between 2003 and 2012. The prevalence was 4.2/10,000 live births. A large cluster (330 zip codes, 306 cases) was identified in northeastern NC. Average driving time for each case to closest congenital heart center was: University of North Carolina 37 min, Vident Medical Center 64 min, Duke University 58 min, Carolina's Medical Center 89 min, and Wake Forest Baptist Health 57 min. Overall, average predicted driving time to the nearest congenital heart center was 61 min. CONCLUSION: Approximately 50 infants/year were born with TOF in NC. One cluster was identified. Further study is necessary to explore potential explanations for the observed case cluster. As interest in regionalization of congenital heart surgery grows, GIS and spatial analysis can become increasingly useful tools for health care planning. Birth Defects Research (Part A) 106:881-887, 2016. © 2016 Wiley Periodicals, Inc.

Nasal Airway Dysfunction in Children with Cleft Lip and Cleft Palate: Results of a Cross-Sectional Population-Based Study, with Anatomical and Surgical Considerations.

BACKGROUND: The aesthetic aspects of the cleft lip nasal deformity have been appreciated for over a century, but the functional implications have remained largely underappreciated or misunderstood. This study describes the frequency and severity of nasal obstructive symptoms among children with cleft lip and/or cleft palate, addressing the hypotheses that age, cleft type, and severity are associated with the development of nasal obstructive symptoms. METHODS: Children with nonsyndromic cleft lip and/or cleft palate and a comparison group of unaffected children born from 1997 to 2003 were identified through the North Carolina Birth Defects Monitoring Program and birth certificates. Nasal airway obstruction was measured using the validated Nasal Obstruction Symptom Evaluation scale. RESULTS: The survey was completed by parental proxy for 176 children with cleft lip and/or cleft palate and 333 unaffected children. Nasal obstructive symptoms were more frequently reported in cleft lip with cleft palate compared with unaffected children (p < 0.0001); children who had isolated cleft lip with or without alveolus and isolated cleft palate were not statistically different from unaffected children. Patients with unilateral cleft lip with cleft palate were found to be more severely affected than bilateral cases. Nasal obstruction was observed in early childhood, although severity worsened in adolescence. CONCLUSIONS: This population-based study reports a high prevalence of nasal obstructive symptoms in children with cleft lip and/or cleft palate based on type and severity of the cleft. The authors encourage cleft teams to consider using this or similar screening methods to identify which children may benefit from functional rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, I.

Maternal residential exposure to agricultural pesticides and birth defects in a 2003 to 2005 North Carolina birth cohort.

BACKGROUND: Birth defects are responsible for a large proportion of disability and infant mortality. Exposure to a variety of pesticides have been linked to increased risk of birth defects. METHODS: We conducted a case-control study to estimate the associations between a residence-based metric of agricultural pesticide exposure and birth defects. We linked singleton live birth records for 2003 to 2005 from the North Carolina (NC) State Center for Health Statistics to data from the NC Birth Defects Monitoring Program. Included women had residence at delivery inside NC and infants with gestational ages from 20 to 44 weeks (n = 304,906). Pesticide exposure was assigned using a previously constructed metric, estimating total chemical exposure (pounds of active ingredient) based on crops within 500 meters of maternal residence, specific dates of pregnancy, and chemical application dates based on the planting/harvesting dates of each crop. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for four categories of exposure (<10(th) , 10-50(th) , 50-90(th) , and >90(th) percentiles) compared with unexposed. Models were adjusted for maternal race, age at delivery, education, marital status, and smoking status. RESULTS: We observed elevated ORs for congenital heart defects and certain structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems (e.g., OR [95% confidence interval] [highest exposure vs. unexposed] for tracheal esophageal fistula/esophageal atresia = 1.98 [0.69, 5.66], and OR for atrial septal defects: 1.70 [1.34, 2.14]). CONCLUSION: Our results provide some evidence of associations between residential exposure to agricultural pesticides and several birth defects phenotypes. Birth Defects Research (Part A) 106:240-249, 2016. © 2016 Wiley Periodicals, Inc.

Assessed occupational exposure to chlorinated, aromatic and Stoddard solvents during pregnancy and risk of fetal growth restriction.

OBJECTIVES: Previous experimental and epidemiological research suggests that maternal exposure to some organic solvents during pregnancy may increase the risk of fetal growth restriction (FGR). We evaluated the association between expert-assessed occupational solvent exposure and risk of small for gestational age (SGA) infants in a population-based sample of women in the National Birth Defects Prevention Study. METHODS: We analysed data from 2886 mothers and their infants born between 1997 and 2002. Job histories were self-reported. Probability of exposure to six chlorinated, three aromatic and one petroleum solvent was assessed by industrial hygienists. SGA was defined as birthweight<10th centile of birthweight-by-gestational age in a national reference. Logistic regression was used to estimate ORs and 95% CIs to assess the association between SGA and exposure to any solvent(s) or specific solvent classes, adjusting for maternal age and education. RESULTS: Approximately 8% of infants were SGA. Exposure prevalence to any solvent was 10% and 8% among mothers of SGA and non-SGA infants, respectively. Among women with ≥ 50% probability of exposure, we observed elevated but imprecise associations between SGA and exposure to any solvent(s) (1.71; 0.86 to 3.40), chlorinated solvents (1.70; 0.69 to 4.01) and aromatic solvents (1.87; 0.78 to 4.50). CONCLUSIONS: This is the first population-based study in the USA to investigate the potential association between FGR and assessed maternal occupational exposure to distinct classes of organic solvents during pregnancy. The potential associations observed between SGA and exposure to chlorinated and aromatic solvents are based on small numbers and merit further investigation.

Maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot.

BACKGROUND: Clubfoot is associated with maternal cigarette smoking in several studies, but it is not clear if this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. METHODS: The present study used data from a population-based case-control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. RESULTS: More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling in risk, after controlling for demographic factors, parity, obesity, and specific medication exposures. Adjusted odds ratios for women who drank >3 servings of alcohol or coffee per day throughout early pregnancy were 2.38 and 1.77, respectively, but the numbers of exposed women were small and odds ratios were unstable. CONCLUSIONS: Clubfoot risk appears to be increased for offspring of women who smoke cigarettes, particularly those who continue smoking after pregnancy is recognisable, regardless of amount. For alcohol and coffee drinkers, suggested increased risks were only observed in higher levels of intake.

Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study.

BACKGROUND: Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. METHODS: A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile). RESULTS: Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). CONCLUSIONS: These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects.

Geographic analysis of individual and environmental risk factors for hypospadias births.

BACKGROUND: Hypospadias is a relatively common birth defect affecting the male urinary tract. We explored the etiology of hypospadias by examining its spatial distribution in North Carolina and the spatial clustering of residuals from individual and environmental risk factors. METHODS: We used data collected by the North Carolina Birth Defects Monitoring Program from 2003 to 2005 to estimate local Moran's I statistics to identify geographic clustering of overall and severe hypospadias, using 995 overall cases and 16,013 controls. We conducted logistic regression and local Moran's I statistics on standardized residuals to consider the contribution of individual variables (maternal age, maternal race/ethnicity, maternal education, smoking, parity, and diabetes) and environmental variables (block group land cover) to this clustering. RESULTS: Local Moran's I statistics indicated significant clustering of overall and severe hypospadias in eastern central North Carolina. Spatial clustering of hypospadias persisted when controlling for individual factors, but diminished somewhat when controlling for environmental factors. In adjusted models, maternal residence in a block group with more than 5% crop cover was associated with overall hypospadias (odds ratio = 1.22; 95% confidence interval = 1.04-1.43); that is living in a block group with greater than 5% crop cover was associated with a 22% increase in the odds of having a baby with hypospadias. Land cover was not associated with severe hypospadias. CONCLUSION: This study illustrates the potential contribution of mapping in generating hypotheses about disease etiology. Results suggest that environmental factors including proximity to agriculture may play some role in the spatial distribution of hypospadias. Birth Defects Research (Part A) 100:887-894, 2014. © 2014 Wiley Periodicals, Inc.

Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring.

Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007-2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2-4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)(2)), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21-1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.

Classification, epidemiology, and genetics of orofacial clefts.

Orofacial clefts (OFCs) include a broad range of facial conditions that differ in cause and disease burden. In the published literature, there is substantial ambiguity in both terminology and classification of OFCs. This article discusses the terminology and classification of OFCs and the epidemiology of OFCs. Demographic, environmental, and genetic risk factors for OFCs are described, including suggestions for family counseling. This article enables clinicians to counsel families regarding the occurrence and recurrence of OFCs. Although much of the information is detailed, it is intended to be accessible to all health professionals for use in their clinical practices.

An evaluation of metrics for assessing maternal exposure to agricultural pesticides.

We evaluate the use of three different exposure metrics to estimate maternal agricultural pesticide exposure during pregnancy. Using a geographic information system-based method of pesticide exposure estimation, we combine data on crop density and specific pesticide application amounts/dates to create the three exposure metrics. For illustration purposes, we create each metric for a North Carolina cohort of pregnant women, 2003-2005, and analyze the risk of congenital anomaly development with a focus on metric comparisons. Based on the results, and the need to balance data collection efforts/computational efficiency with accuracy, the metric which estimates total chemical exposure using application dates based on crop-specific earliest planting and latest harvesting information is preferred. Benefits and drawbacks of each metric are discussed and recommendations for extending the analysis to other states are provided.

Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts.

OBJECTIVES: Though toxicological experiments demonstrate the teratogenicity of organic solvents in animal models, epidemiologic studies have reported inconsistent results. Using data from the population-based National Birth Defects Prevention Study, the authors examined the relation between maternal occupational exposure to aromatic solvents, chlorinated solvents and Stoddard solvent during early pregnancy and neural tube defects (NTDs) and orofacial clefts (OFCs). METHODS: Cases of NTDs (anencephaly, spina bifida and encephalocoele) and OFCs (cleft lip ± cleft palate and cleft palate alone) delivered between 1997 and 2002 were identified by birth defect surveillance registries in eight states; non-malformed control infants were selected using birth certificates or hospital records. Maternal solvent exposure was estimated by industrial hygienist review of self-reported occupational histories in combination with a literature-derived exposure database. ORs and 95% CIs for the association between solvent class and each birth defect group and component phenotype were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, folic acid supplement use and smoking. RESULTS: The prevalence of exposure to any solvent among mothers of NTD cases (n = 511), OFC cases (n = 1163) and controls (n = 2977) was 13.1%, 9.6% and 8.2%, respectively. Exposure to chlorinated solvents was associated with increased odds of NTDs (OR = 1.96, CI 1.34 to 2.87), especially spina bifida (OR = 2.26, CI 1.44 to 3.53). No solvent class was strongly associated with OFCs in these data. CONCLUSIONS: The findings suggest that maternal occupational exposure to chlorinated solvents during early pregnancy is positively associated with the prevalence of NTDs in offspring.