Xenobiotic Metabolism Genes and Clubfoot

Idiopathic or isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 children worldwide. It is characterized by equinus, varus and adductus deformities of the ankle and foot. Correction of clubfoot involves months of serial manipulations, castings and bracing, with surgical correction needed in forty percent of cases. Multifactorial etiology has been suggested in numerous studies with both environmental and genetic factors playing an etiologic role. Maternal smoking during pregnancy is the only common environmental factor that has consistently been shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot and maternal smoking increases the risk of clubfoot twenty fold. These findings suggest that genetic variation in smoking metabolism genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes, chosen based on their involvement in phase 1 and 2 cigarette smoke metabolism. Twenty-two SNPs and two null alleles in eight genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1 and GSTT1) were genotyped in a dataset composed of nonHispanic white and Hispanic multiplex and simplex families. Only one SNP in CYP1A1, rs1048943, had significantly altered transmission in the aggregate and multiplex NHW datasets (p=0.003 and p=0.009). Perturbation of CYP1A1 by rs1048943 polymorphism causes an increase in the amount of harmful, adduct forming metabolic intermediates. A significant gene interaction between EPHX1 and NAT2 was also found (p=0.007). This interaction may affect the metabolism of harmful metabolic intermediates. Additionally, marginal interactions were found for other xenobiotic genes and these interactions may play a contributory role in clubfoot. Importantly, for CYP1A2, significant maternal (p=0.03; RR=1.24; 95% CI: 1.04-1.44) and fetal (p=0.01; RR=1.33; 95% CI: 1.13-1.54) genotypic effects were identified suggesting that both maternal and fetal genotypes impact normal limb development. No association was found for maternal smoking status and tobacco metabolism genes. Together, these results suggest that xenobiotic metabolism genes may play a contributory role in the etiology of clubfoot regardless of maternal smoking status and may impact foot development through perturbation of tobacco metabolic pathways.

Birth defects among surviving children under seven years of age in Tianjin, China

Birth defects are a leading cause of infant mortality in the developed countries. They are also of increasing concern in many developing countries, such as China. However, prevalence and causes of birth defects in China are inadequately understood.^ The purpose of the present study was to estimated prevalence of birth defects in surviving children under seven years of age in Tianjin, China and investigate determinants of birth defects in the study area.^ The present study took place in Tianjin, China in 1986, involving 22,081 surviving children under seven years of age. Children with birth defects were ascertained through physical examinations by physicians during household visits and ascertainment of birth defects was verified through multiple sources. Of 22,081 surviving children, 524 had birth defects (23.7 per 1,000). The study noted a striking discrepancy in the prevalence of birth defects between urban and rural area. The prevalence of birth defects was 16.3 per 1,000 in the urban and 33.2 per 1,000 in the rural area.^ Using cases of birth defects ascertained from surviving children, a case-control study was carried out. The study observed that first-trimester maternal flu was associated with increased risk of both major and minor birth defects in children after controlling for other maternal factors (adjusted odds ratio (OR) = 8.7, 95% confidence interval (CI) = 4.3-17.3; OR = 3.6, 95% CI = 1.7-7.5). This association could be biased by different reporting of exposure between mothers of children with birth defects and mothers of children without defects. This study indicated that maternal flu was also associated with congenital heart defects and polydactyly after controlling for other maternal factors (adjusted OR = 32.3, 95% CI = 13.3-78.3; adjusted OR = 5.5, 95% CI = 1.1-27.7). The associations remained when affected controls (children with similar birth defects other than congenital heart defects or polydactyly) were used (adjusted OR = 4.3, 95% CI = 1.2-15.3; OR = 1.4, 95% CI = 1.4-7.9). A weak association between first-trimester vaginal bleeding and selected groups of birth defects was found in this study, but the association may be confounded by other factors. Maternal smoking during pregnancy was modestly associated with cleft lip with or without cleft palate (OR = 1.4, 95% = 0.4-4.9), but the association may be due to chance. Some major limitations in this study warrant caution in interpretation of the findings, especially the causal relation. ^

Factors affecting prenatal care use and pregnancy outcome in Texas: A comparative study among and within Black, Anglo, and Hispanic populations

This research project is a study in the field of public health to test the relationships of demographic, socioeconomic, behavioral, and biological factors with (1) prenatal care use and (2) pregnancy outcome, measured by birth weight. It has been postulated that demographic, socioeconomic, and behavioral factors are associated with differences in the use of prenatal care services. It has also been postulated that differences in demographic, socioeconomic, behavioral, and biological factors result in differences in birth weight. This research attempts to test these two basic conceptual frameworks. At the same time, an attempt is made to determine the population groups and subgroups that are at increased risk (1) of using fewer prenatal care visits, and (2) of displaying a higher incidence of low birth weight babies. An understanding of these relationships of the demographic, socioeconomic, behavioral, and biological factors in the use of prenatal care visits and pregnancy outcome, measured by birth weight, will potentially offer guidance in the planning and policy development of maternal and child health services. The research considers four major components of maternal characteristics: (1) Demographic factors. Ethnicity, household size, maternal parity, and maternal age; (2) Socioeconomic factors. Maternal education, family income, maternal employment, health insurance coverage, and household dwelling; (3) Behavioral factors. Maternal smoking, attendance at child development classes, mother's first prenatal care visit, total number of prenatal care visits, and adequacy of care; and, (4) Biological factors. Maternal weight gain during pregnancy.^ The research considers 16 independent variables and two dependent variables.^ It was concluded that: (1) Generally, differences in demographic, socioeconomic, and behavioral factors were associated with differences in the average number of prenatal care visits between and within population groups and subgroups. The Hispanic mothers were the lowest users of prenatal care services. (2) In some cases, differences in demographic, socioeconomic, behavioral, and biological factors demonstrated differences in the average birth weight of infants between and within population groups and subgroups. (3) Differences in demographic, socioeconomic, behavioral, and biological factors resulted in differences in the rates of low birth weight babies between and within population groups and subgroups. The Black mothers delivered the highest incidence of low birth weight infants.^ These findings could provide guidance in the formulation of public health policies such as MCH services, an increase in the use of prenatal care services by prospective mothers, resulting in reduction of the incidence of low birth weight babies, and consequently aid in reducing the rates of infant mortality. ^

Sudden Infant Death disparities: A systematic review on health education and policy recommendations for decreasing Sudden Infant Death in the African-American community

Objective: To perform a systematic review of the literature on SIDS and SUID deaths concentrated in the African-American community, describe health education and policy recommendations and recommend a new approach that may aid in decreasing the disparity of infant mortality in the African-American community. ^ Methods: The PubMed database was systematically searched to identify relevant articles for final review and analysis. Using the CASP 2006 system to critique literature, twelve articles were found that met inclusion and exclusion criteria. ^ Results: Evidence in the literature confirmed there was a current disparity among African Americans' infant mortality rates in comparison to other US ethnic groups. The underlying reasons for these disparities included the following maternal and infant characteristics: mothers younger than eighteen, having more than one live infant, having a high school education or less, never been married, and have infants born preterm or with low birth weight. Maternal smoking, substance abuse, and breastfeeding did not have a significant impact on infant sleep environments among African Americans. ^ Conclusion: Tailored health education programs at the community level, better access to pre-pregnancy and prenatal care, and increased maternal perception of risk that is relevant to the infants sleeping environment are all possible solutions that may decrease African American infant mortality rates.^

Effect of maternal weight status on the relationship between prenatal smoking and infant birth weight

The purpose of this study was to assess the effect of maternal pre-pregnancy weight status on the relationship between prenatal smoking and infant birth weight (IBW). Prenatal cigarette smoking and maternal weight exert opposing effects on IBW; smoking decreases birth weight while maternal pre-pregnancy weight is positively correlated with birth weight. As such, mutual effect modification may be sufficiently significant to alter the independent effects of these two birth weight correlates. Finding of such an effect has implications of prenatal smoking cessation education. Perception of risk is an important determinant of smoking cessation, and reduced or low birth weight (LBW) as a smoking-associated risk predominates prenatal smoking counseling and education. In a population such as the US, where obesity is becoming epidemic, particularly among minority and low-income groups, perception of risk may be lowered should increased maternal size attenuate the effect of smoking. Previous studies have not found a significant interaction effect of prenatal smoking and maternal pre-pregnancy weight on IBW; however, use of self-reported smoking status may have biased findings. Reliability of self-reported smoking status reported in the literature is variable, with deception rates ranging from a low of 5% to as high as 16%. This study, using data from a prenatal smoking cessation project, in which smoking status was validated by saliva cotinine, was an opportunity to assess effect modification of smoking and maternal weight using biochemically determined smoking status in lieu of self report. Stratified by saliva cotinine, 151 women from a prenatal smoking cessation cohort, who were 18 years and older and had full-term, singleton births, were included in this study. The effect of smoking in terms of mean birth weight across three levels of maternal pre-pregnancy weight was assessed by general linear modeling procedures, adjusting for other known correlates of IBW. Effect modification was marginally significant, p = .104, but only with control for differential effects among racial/ethnic groups. A smaller than planned sample of nonsmokers, or women who quit smoking during the pregnancy, prohibited rejection of the null hypothesis of no difference in the effect of smoking across levels of pre-pregnancy weight. ^

Ultrasound feedback and motivational interviewing targeting smoking cessation in the second and third trimesters of pregnancy.

INTRODUCTION: Cigarette smoking during pregnancy is associated with poor maternal and child health outcomes. Effective interventions to increase smoking cessation rates are needed particularly for pregnant women unable to quit in their first trimester. Real-time ultrasound feedback focused on potential effects of smoking on the fetus may be an effective treatment adjunct, improving smoking outcomes. METHODS: A prospective randomized trial was conducted to evaluate the efficacy of a smoking cessation intervention consisting of personalized feedback during ultrasound plus motivational interviewing-based counseling sessions. Pregnant smokers (N = 360) between 16 and 26 weeks of gestation were randomly assigned to one of three groups: Best Practice (BP) only, Best Practice plus ultrasound feedback (BP+US), or Motivational Interviewing-based counseling plus ultrasound feedback (MI+US). Assessments were conducted at baseline and end of pregnancy (EOP). RESULTS: Analyses of cotinine-verified self-reported smoking status at EOP indicated that 10.8% of the BP group was not smoking at EOP; 14.2% in the BP+US condition and 18.3% who received MI+US were abstinent, but differences were not statistically significant. Intervention effects were found conditional upon level of baseline smoking, however. Nearly 34% of light smokers (< or =10 cigarettes/day) in the MI+US condition were abstinent at EOP, followed by 25.8% and 15.6% in the BP+US and BP conditions, respectively. Heavy smokers (>10 cigarettes/day) were notably unaffected by the intervention. DISCUSSION: Future research should confirm benefit of motivational interviewing plus ultrasound feedback for pregnant light smokers and explore mechanisms of action. Innovative interventions for pregnant women smoking at high levels are sorely needed.

Content of prenatal care and spontaneous preterm birth: Findings from the 1988 National Maternal and Infant Health Survey

The purposes of this study were to examine (1) the relationship between selected components of the content of prenatal care and spontaneous preterm birth; and (2) the degree of comparability between maternal and caregivers' responses regarding the number of prenatal care visits, selected components of the content of prenatal care, and gestational age, based on analyses of the 1988 National Maternal and Infant Health Survey conducted by the National Centers for Health Statistics. Spontaneous preterm birth was subcategorized into very preterm and moderately preterm births, with term birth as the controls. The study population was limited to non-Hispanic Anglo- and African-American mothers. The racial differences in terms of birth outcomes were also compared.^ This study concluded that: (1) there was not a high degree of comparability (less than 80%) between maternal and prenatal care provider's responses regarding the number of prenatal care visits and the content of prenatal care; (2) there was a low degree of comparability (less than 50%) between maternal and infant's hospital of delivery responses regarding gestational age at birth; (3) there were differences in selected components of the content of prenatal care between the cases and controls, overall and stratified by ethnicity (i.e., hemoglobin/hematocrit test, weight measurement, and breast-feeding counseling), but they were confounded with missing values and associated preterm delivery bias; (4) there were differences in selected components of the content of prenatal care between Anglo- and African-American cases (i.e., vitamin/mineral supplement advice, weight measurement, smoking cessation and drug abuse counseling), but they, too, were difficult to interpret definitively due to item nonresponse and preterm delivery biases; (5) no significant predictive association between selected components of the content of prenatal care and spontaneous preterm birth was found; and (6) inadequate/intermediate prenatal care and birth out of wedlock were found to be associated with moderately preterm birth.^ Future research is needed to examine the validity of maternal and prenatal care providers' responses and identify the sources of disagreement between their responses. In addition, further studies are needed to examine the relationship between the quality of prenatal care and preterm birth. Finally, the completeness and quality of patient and provider data on the utilization and content of prenatal care needs to be strengthened in subsequent studies. ^

The relationship of maternal low birthweight and infant low birthweight among African-American women at term delivery: Findings from the 1988 National Maternal and Infant Health Survey

A cohort study study design was used to study the relationship of maternal low birthweight and infant low birthweight among African American women delivering full term infants. The cohort consisted of 3,157 mother-infant pairs drawn from the 1988 National Maternal and Infant Health Survey conducted by the National Center for Health Statistics. The objectives of the study were (1) to determine if low birthweight, African American mothers delivering term infants experienced higher rates of infant low birthweight and (2) to examine the role of selected contributory variables in the relationship of maternal low birthweight and infant low birthweight. Contributory risk factors examined included maternal marital status, maternal age, maternal education, maternal height, maternal prepregnant weight, birth order, history of a prior low birthweight delivery, timing of prenatal care, number of prenatal visits, gestational length, infant gender, and behavioral factors of smoking, alcohol, and illicit drug use during pregnancy.^ Using logistic regression analysis, risk of infant low birthweight among maternal low birthweight mothers increased after controlling for less than a high school education, less than 20 years of age, prepregnant weight less than 100 lbs, history of a prior low birthweight delivery, birth order, smoking during pregnancy, and use of alcohol and illicit drugs during pregnancy, but was not statistically significant. Loss of statistical significance was attributed to a large reduction in cases available for analysis after including illicit drug use in the model.^ This study demonstrated a consistent pattern of increased rates of infant low birthweight among low birthweight mothers. The force of history remains, hence women with this trait should be carefully monitored and advised during pregnancy to decrease risk of a low birthweight infant, in order to decrease the chain of events leading to future generations of low birthweight mothers. ^