Sergey Krikov

Case-control study of self reported genitourinary infections and risk of gastroschisis: findings from the national birth defects prevention study, 1997-2003

Objective To assess the association between genitourinary infections in the month before conception to the end of the first trimesterand gastroschisis. Design Case-control study with self reported infections from a computer assisted telephone interview. Setting National birth defects prevention study, a multisite, population based study including 10 surveillance systems for birth defects in the United States. Participants Mothers of 505 offspring with gastroschisis and 4924 healthy liveborn infants as controls. Main outcome measure Adjusted odds ratios for gastroschisis with 95% confidence intervals. Results About 16% (n=81) of case mothers and 9% (n=425) of control mothers reported a genitourinary infection in the relevant time period; 4% (n=21) and 2% (n=98) reported a sexually transmitted infection and 13% (n=67) and 7% (n=338) reported a urinary tract infection, respectively. Case mothers aged <25 years reported higher rates of urinary tract infection alone and in combination with a sexually transmitted infection compared with control mothers. In women who reported both types of infection, there was a greater risk of gastroschisis in offspring (adjusted odds ratio 4.0, 95% confidence interval 1.4 to 11.6). Conclusion There is a significant association between self reported urinary tract infection plus sexually transmitted infection just before conception and in early pregnancy and gastroschisis.

Acetaminophen Use in Pregnancy and Risk of Birth Defects: Findings From the National Birth Defects Prevention Study

OBJECTIVE: To investigate whether exposure during the first trimester of pregnancy to single-ingredient acetaminophen increases the risk of major birth defects. METHODS: Data from the National Birth Defects Prevention Study, a population-based, case–control study, were used. Women who delivered between January 1, 1997, and December 31, 2004, and participated in the telephone interview were included. Type and timing of acetaminophen use were assigned based on maternal report. Women reporting first-trimester acetaminophen use in a combination product were excluded, resulting in a total of 11,610 children in the case group and 4,500 children in the control group for analysis. RESULTS: The prevalence of first-trimester single-ingredient–acetaminophen use was common: 46.9% (n=5,440) among women in the case group and 45.8% (n=2,059) among women in the control group (P=.21). Overall, acetaminophen was not associated with an increased risk of any birth defect. Among women reporting a first-trimester infection and fever, use of acetaminophen was associated with a statistically significantly decreased odds ratio (OR) for anencephaly or craniorachischisis (adjusted OR 0.35, 95% confidence interval [CI] 0.08–0.80), encephalocele (adjusted OR 0.17, 95% CI 0.03–0.87), anotia or microtia (adjusted OR 0.25, 95% CI 0.07–0.86), cleft lip with or without cleft palate (adjusted OR 0.44, 95% CI 0.26–0.75), and gastroschisis (adjusted OR 0.41, 95% CI 0.18–0.94). CONCLUSION: Single-ingredient–acetaminophen use during the first trimester does not appear to increase the risk of major birth defects. It may decrease the risk of selected malformations when used for a febrile illness. LEVEL OF EVIDENCE: II

Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi‐site case‐control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non‐white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extra‐cardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non‐tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy‐Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left‐right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

Effect of donors' intravenous drug use, cigarette smoking, and alcohol dependence on kidney transplant outcome.

Background. The shortage of organ donors for kidney transplants has made the expansion of the kidney donor pool a clinically significant issue. Previous studies suggest that kidneys from donors with a history of intravenous (IV) drug, cigarette, and/or alcohol use are considered to be a risky choice. However, these kidneys could potentially be used and expand the kidney supply pool if no evidence shows their association with adverse transplant outcomes. Methods. This study analyzed the United Network for Organ Sharing dataset from 1994 to 1999 using Kaplan-Meier survival analysis and Cox modeling. The effects on transplant outcome (graft and recipient survival) were examined with respect to the donors’ IV drug use, cigarette smoking, and alcohol dependency. Covariates including the recipient variables, the donor variables, and the transplant procedure variables were included in the Cox models. Results. The results show that the donors’ history of cigarette smoking is a statistically significant risk factor for both graft survival (hazard ratio = 1.05, P < 0.05) and recipient survival (1.06, P<0.05), whereas neither IV drug use nor alcohol dependency had significant adverse impact on graft or recipient survival. Conclusions. Assuming that adequate testing for potential infections is performed, there is no evidence to support avoiding the kidneys from donors with IV drug use or alcohol dependency in transplantation. Utilizing these kidneys would clearly expand the potential pool of donor organs.

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.

Predicting Kidney Transplant Survival Using Tree-based Modeling

Predicting the outcome of kidney transplantation is clinically important and computationally challenging. The goal of this project was to develop the models predicting probability of kidney allograft survival at 1, 3, 5, 7, and 10 years. Kidney transplant data from the United States Renal Data System (January 1, 1990, to December 31, 1999, with the follow-up through December 31, 2000) were used (n = 92,844). Independent variables included recipient demographic and anthropometric data, end-stage renal disease course, comorbidity information, donor data, and transplant procedure variables. Tree-based models predicting the probability of the allograft survival were generated using roughly two-thirds of the data (training set), with the remaining one-third left aside to be used for models validation (testing set). The prediction of the probability of graft survival in the independent testing dataset achieved a good correlation with the observed survival (r = 0.94, r = 0.98, r = 0.99, r = 0.93, and r = 0.98) and relatively high areas under the receiving operator characteristic curve (0.63, 0.64, 0.71, 0.82, and 0.90) for 1-, 3-, 5-, 7-, and 10-year survival prediction, respectively. The models predicting the probability of 1-, 3-, 5-, 7-, and 10-year allograft survival have been validated on the independent dataset and demonstrated performance that may suggest implementation in clinical decision support system.

Self‐reported maternal smoking during pregnancy by source in Utah, 2003–2007

BACKGROUND Maternal self-report is the most common method for assessment of past cigarette exposure to assess birth defect risk. This study compared maternal smoking prior to and during pregnancy based on self-reports obtained from the medical records abstracted for the Utah Birth Defect Network (UBDN), the birth certificate, and the computer-assisted telephone interview (CATI) in the National Birth Defects Prevention Study (NBDPS). The study also investigated how the different sources for maternal smoking data affect estimates in an empirical study. METHODS A total of 1774 case and 618 control mothers who had participated in the NBDPS and whose live born infants were delivered between January 1, 2003, and December 31, 2007, were included in this study. Among the case mothers, we compared data from all three sources, whereas for control mothers only two data sources were available for comparison (i.e., birth certificate and CATI). RESULTS Smoking prevalence was highest in the CATI. Compared to the CATI, data from the UBDN had a higher sensitivity (61.3%) and better agreement (kappa = 0.63) than birth certificates (51.8%; kappa = 0.56). Adjusted odds ratios for all and specific birth defects (i.e., holoprosencephaly, hydrocephalus, anophthalmia/microphthalmia, anotia/microtia, total anomalous pulmonary venous return/partial anomalous pulmonary venous return [TAPVR/PAPVR], heterotaxy, and gastroschisis) were different between the birth certificate and CATI. The change in the effect estimates between the two sources ranged from 19% to 56%. CONCLUSIONS Based on our findings, maternal smoking exposure from interview data was shown to be of higher quality with less misclassification compared to data obtained from medical records or birth certificates.

Is gastroschisis truly a sporadic defect? Familial cases of gastroschisis in Utah, 1997 to 2008†‡

BACKGROUND Gastroschisis remains an epidemiologic and pathogenetic dilemma, with genetics not thought to play a significant role in its etiology. The purpose of this study was to determine which gastroschisis cases in the Utah Birth Defect Network (UBDN) were related and the excess familial risk among multigenerational families. METHODS Gastroschisis cases born from 1997 through 2008 were identified from the statewide population-based UBDN and linked with the Utah Population Database (UPDB) to access multigenerational pedigrees. We analyzed these pedigrees using the familial standardized incidence ratio (FSIR). RESULTS Of the 284 UBDN gastroschisis cases, one in 40 (n = 7; 2.5%) were reported to have another affected family member. Among these seven cases, three had affected sib pairs and four reported either a distant cousin, paternal uncle, maternal half-uncle, or paternal cousin with gastroschisis. UBDN-UPDB-linked cases resulted in many multigenerational pedigrees with the same affected descendents through marriage. We selected 30 pedigrees for repeated analysis based on two parameters: highest FSIRs with a p ≤ 0.01 and ≥2 cases. In these 30 pedigrees, FSIRs ranged from 3.7 to 93.5 (p < 0.009), each with two to eight distantly related cases (n = 64 distinct cases, representing 23% of the 284). CONCLUSIONS We found a statistically significant excess risk for gastroschisis because of familial factors. Similar to many other birth defects, gastroschisis may fit a multifactorial model of inheritance. The UBDN-UPDB linkage provides a robust approach to investigating genetic factors. Genetic susceptibility should be further investigated because it may have a greater role in the etiology of gastroschisis than currently appreciated.

Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects

BACKGROUND While associations between secondhand smoke and a few birth defects (namely, oral clefts and neural tube defects) have been noted in the scientific literature, to our knowledge, there is no single or comprehensive source of population-based information on its associations with a range of birth defects among nonsmoking mothers. OBJECTIVE We utilized data from the National Birth Defects Prevention Study, a large population-based multisite case-control study, to examine associations between maternal reports of periconceptional exposure to secondhand smoke in the household or workplace/school and major birth defects. STUDY DESIGN The multisite National Birth Defects Prevention Study is the largest case-control study of birth defects to date in the United States. We selected cases from birth defect groups having >100 total cases, as well as all nonmalformed controls (10,200), from delivery years 1997 through 2009; 44 birth defects were examined. After excluding cases and controls from multiple births and whose mothers reported active smoking or pregestational diabetes, we analyzed data on periconceptional secondhand smoke exposure-encompassing the period 1 month prior to conception through the first trimester. For the birth defect craniosynostosis, we additionally examined the effect of exposure in the second and third trimesters as well due to the potential sensitivity to teratogens for this defect throughout pregnancy. Covariates included in all final models of birth defects with ≥5 exposed mothers were study site, previous live births, time between estimated date of delivery and interview date, maternal age at estimated date of delivery, race/ethnicity, education, body mass index, nativity, household income divided by number of people supported by this income, periconceptional alcohol consumption, and folic acid supplementation. For each birth defect examined, we used logistic regression analyses to estimate both crude and adjusted odds ratios and 95% confidence intervals for both isolated and total case groups for various sources of exposure (household only; workplace/school only; household and workplace/school; household or workplace/school). RESULTS The prevalence of secondhand smoke exposure only across all sources ranged from 12.9-27.8% for cases and 14.5-15.8% for controls. The adjusted odds ratios for any vs no secondhand smoke exposure in the household or workplace/school and isolated birth defects were significantly elevated for neural tube defects (anencephaly: adjusted odds ratio, 1.66; 95% confidence interval, 1.22-2.25; and spina bifida: adjusted odds ratio, 1.49; 95% confidence interval, 1.20-1.86); orofacial clefts (cleft lip without cleft palate: adjusted odds ratio, 1.41; 95% confidence interval, 1.10-1.81; cleft lip with or without cleft palate: adjusted odds ratio, 1.24; 95% confidence interval, 1.05-1.46; cleft palate alone: adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.63); bilateral renal agenesis (adjusted odds ratio, 1.99; 95% confidence interval, 1.05-3.75); amniotic band syndrome-limb body wall complex (adjusted odds ratio, 1.66; 95% confidence interval, 1.10-2.51); and atrial septal defects, secundum (adjusted odds ratio, 1.37; 95% confidence interval, 1.09-1.72). There were no significant inverse associations observed. CONCLUSION Additional studies replicating the findings are needed to better understand the moderate positive associations observed between periconceptional secondhand smoke and several birth defects in this analysis. Increased odds ratios resulting from chance (eg, multiple comparisons) or recall bias cannot be ruled out.

Congenital heart defects after maternal fever

OBJECTIVE The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use. STUDY DESIGN From a multistate population-based case-control study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders. RESULTS First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period. CONCLUSION The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.