Amniocentesis in the second trimester and congenital talipes equinovarus in the offspring: a population-based record linkage study in Scotland.

BACKGROUND: To investigate whether amniocentesis in the second trimester is associated with congenital talipes equinovarus (CTEV) in the offspring. METHODS: Case-control study nested within a population-based cohort, developed through linkage of the Scottish Congenital Anomalies Linked Database with records of amniocentesis from cytogenetics laboratories, including 564,299 singleton births 1992-2001. Odds ratios and 95% confidence intervals for CTEV in the offspring (isolated, non-isolated, total) were calculated using logistic regression, adjusting for maternal age, year of birth and health board of birth. RESULTS: There was a modest positive association between total CTEV and amniocentesis at any time (OR = 1.27, 95% CI 0.99-1.65) and at >or= 15 weeks (OR = 1.25, 95%CI 0.95-1.64). The association was strongest for non-isolated CTEV (amniocentesis any time: OR = 1.68, 95%CI 1.08-2.61; amniocentesis >or= 15 weeks: OR = 1.81, 95%CI 1.16-2.83). Amniocentesis at >or= 20 weeks was associated with increased risk of total (OR = 5.87, 95% CI 3.38-10.21), non-isolated (OR = 13.17, 95% CI 6.49-26.74) and isolated CTEV (OR = 3.10, 95% CI 1.28-7.49). There were no associations in mothers aged >or= 35 years. CONCLUSIONS: The modest association observed is most likely accounted for by amniocenteses conducted because of an earlier abnormal prenatal test. Thus, second trimester amniocentesis is unlikely to contribute to the development of CTEV in the offspring.

Folate and clefts of the lip and palate--a U.K.-based case-control study: Part I: Dietary and supplemental folate.

OBJECTIVES: We sought to determine the associations between nonsyndromic cleft lip with or without cleft palate (CL-P) and cleft palate only (CP) and maternal intake of dietary folate and supplemental folic acid, in an area where the prevalence at birth of neural tube defects has been high and flour is not fortified with folic acid. METHODS: Interviews regarding periconceptional dietary intake and supplement use were completed with the mothers of 112 CL-P cases, 78 CP cases, and 248 unaffected infants. The data were analyzed by logistic regression methods. RESULTS: There was no overall association between CL-P and CP and either energy-adjusted total folate intake or supplemental folic acid use, irrespective of dosage. CONCLUSION: Overall, higher intakes of total folate do not appear to prevent oral clefts in this population.

Folate and clefts of the lip and palate--a U.K.-based case-control study: Part II: Biochemical and genetic analysis.

OBJECTIVE: To investigate associations between nonsyndromic oral clefts and biochemical measures of folate status and the MTHFR C677T variant in the United Kingdom, where there has been no folic acid fortification program. METHOD: Dietary details were obtained from the mothers of 112 cases of cleft lip with or without cleft palate (CL+/-P), 78 cleft palate only (CP) cases, and 248 unaffected infants. Infant and parental MTHFR C677T genotype was determined. Red blood cell (RBC) and serum folate and homocysteine levels were assessed in 12-month postpartum blood samples from a subset of mothers. The data were analyzed by logistic and log-linear regression methods. RESULTS: There was an inverse association between CL+/-P and maternal MTHFR CT (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.31-0.95) and TT (OR = 0.6, 95% CI = 0.21-1.50) genotypes, with similar risk estimates for CP. There was no clear association with infant MTHFR genotype. Higher levels of maternal postpartum RBC and serum folate were associated with a lower risk for CL+/-P and an increased risk for CP. Higher levels of serum homocysteine were associated with a slightly increased risk for both CL+/-P and CP. CONCLUSION: While the inverse relation between the mother's having the MTHFR C677T variant and both CL+/-P and CP suggests perturbation of maternal folate metabolism is of etiological importance, contrasting relations between maternal postpartum levels of RBC and serum folate by type of cleft are difficult to explain.

Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case-control study.

BACKGROUND: Congenital talipes equinovarus (CTEV) is a common developmental disorder of the foot, affecting between 1 and 4.5 per 1000 live births. The aetiology is not well elucidated. While both genetic and environmental factors are implicated, no specific genes have been identified and little is known about environmental risk factors. METHODS: We conducted a case-control study of idiopathic congenital talipes equinovarus (ICTEV) in the United Kingdom. 194 cases and 60 controls were recruited. Pedigrees were obtained for 167 cases. RESULTS: The rank of the index pregnancy, maternal education and caesarean delivery were significantly associated with ICTEV risk in a multivariate model. There were suggestions that maternal use of folic acid supplements in the three months before the pregnancy decreased ICTEV risk, and that parental smoking during the pregnancy increased risk, although the associations were not statistically significant. One quarter of pedigrees showed a family history of CTEV, and autosomal dominant inheritance was suggested in some of these. CONCLUSION: Uterine restriction did not appear to have a strong influence on ICTEV development in our study. Large population-based studies are needed to clarify the aetiology of this common developmental disorder.

CYP17 gene polymorphisms: prevalence and associations with hormone levels and related factors. a HuGE review.

The cytochrome P-450c17alpha (CYP17 ) gene, located on chromosome 10q24.3, encodes the enzyme cytochrome P-450c17alpha, which functions at key branch points in steroid hormone biosynthesis. Three polymorphisms have been described, but only the single base-pair change in the 5'-untranslated region (5'-UTR) has been investigated to any great extent. In single studies, the variant was associated with reduced messenger RNA level in ovarian cells but not with messenger RNA level in breast tissue. Homozygosity for the 5'-UTR variant is most common in East Asian (32%) and Japanese (22%) populations and is less common among White (mainly European and North American (14%)) and Black (mainly African-American (13%)) populations, but selection biases are likely to have affected these frequency estimates. Genotype appears to influence circulating estrogen levels in premenopausal women, while studies of relations with hormone levels in men have produced inconclusive results. However, relatively few studies have been conducted. Seven of 11 retrospective studies suggested a modest association between genotype and age at menarche. Random error in recall of age at menarche is likely to have attenuated this relation. Associations between genotype and postmenopausal estrogen use and bone mass have been observed in single studies. Further investigation of relations between genotype and hormone levels, exogenous hormone use, and markers of hormonal status may advance understanding of hormonally mediated diseases.

Smoking and orofacial clefts: a United Kingdom-based case-control study.

OBJECTIVE: To investigate the association between smoking and orofacial clefts in the United Kingdom. DESIGN: Case-control study in which the mother's exposure to tobacco smoke was assessed by a structured interview. SETTING: Scotland and the Manchester and Merseyside regions of England. PARTICIPANTS: One hundred ninety children born with oral cleft between September 1, 1997, and January 31, 2000, and 248 population controls, matched with the cases on sex, date of birth, and region. MAIN OUTCOME MEASURE: Cleft lip with or without cleft palate and cleft palate. RESULTS: There was a positive association between maternal smoking during the first trimester of pregnancy and both cleft lip with or without cleft palate (odds ratio 1.9, 95% confidence interval 1.1 to 3.1) and cleft palate (odds ratio 2.3, 95% confidence interval 1.3 to 4.1). There was evidence of a dose-response relationship for both types of cleft. An effect of passive smoking could not be excluded in mothers who did not smoke themselves. CONCLUSION: The small increased risk for cleft lip with or without cleft palate in the offspring of women who smoke during pregnancy observed in this study is in line with previous evidence. In contrast to some previous studies, an increased risk was also apparent for cleft palate. In these U.K. data, there was evidence of a dose-response effect of maternal smoking for both types of cleft. The data were compatible with a modest effect of maternal passive smoking, but the study lacked statistical power to detect or exclude such an effect with confidence. It may be useful to incorporate information on the effects of maternal smoking on oral clefts into public health campaigns on the consequences of maternal smoking.

Influence of socioeconomic conditions on growth in infancy: the 1921 Aberdeen birth cohort.

OBJECTIVES: To identify environmental influences on infant growth using data from a birth cohort established in 1921. DESIGN: A longitudinal cohort study. SETTING: Aberdeen 1921-22. SUBJECTS: Five hundred and sixteen individuals (263 boys and 253 girls) born in Aberdeen during 1921. Health visitor assessments ranged from two to 40 (47% received at least 10 visits). No records were available for infants who died. Individuals were grouped as those who did not breast feed, those who breast fed initially but not at 6 months, and those who were continuing to breast feed at 6 months. MAIN OUTCOME MEASURE: Rate of weight gain over the 1st year of life. A random effects model was used to identify environmental factors and conditions contributing to rate of weight gain in the 1st year of life. RESULTS: Breast feeding rates were about 80% and 50% at 10 days and 6 months, respectively. Breast fed infants were significantly heavier than bottle fed infants at 28 days but this difference disappeared by 12 months. Significant negative effects on rate of weight gain, independent of initial body weight, were found for overcrowding in family homes and maternal parity, whereas social class had no effect. CONCLUSION: Studies based on historical cohorts that have controlled socioeconomic variables only in terms of social class (derived from parental occupation) may have been subject to residual confounding. Growth in the 1st year of life is likely to reflect a number of environmental influences, some of which may continue to have effects throughout early life and beyond.

A novel mechanism for cyclosporine: inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model.

BACKGROUND: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. METHODS: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. RESULTS: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. CONCLUSIONS: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.