Objective The prognosis of coronary artery disease (CAD) is related to its severity and cardiovascular risk factors in both sexes. In women, social isolation, marital stress, sedentary lifestyle and ...depression predicted CAD progression and outcome within 3 to 5 years. We hypothesised that these behavioral factors would still be associated with all-cause mortality in female patients after 26 years. Methods We examined 292 patients with CAD and 300 healthy controls (mean age of 56 ± 7 y) within the Fem-Cor-Risk-Study at baseline. Their cardiac, behavioral, and psychosocial risk profiles, exercise, smoking, and dietary habits were assessed using standardized procedures. Physiological characteristics included a full lipid profile, the coagulation cascade and autonomic dysfunction (heart rate variability, HRV). A new exploratory analysis using machine-learning algorithms compared the effects of social and behavioral mechanisms with standard risk factors. Results: All-cause mortality records were completed in 286 (97.9%) patients and 299 (99.7%) healthy women. During a median follow-up of 26 years, 158 (55.2%) patients and 101 (33.9%) matched healthy controls died. The annualized mortality rate was 2.1% and 1.3%, respectively. After controlling for all available confounders, behavioral predictors of survival in patients were social integration (HR 0.99, 95% CI 0.99–1.0) and physical activity (HR 0.54, 95% CI 0.37–0.79). Smoking acted as a predictor of all-cause mortality (HR 1.56, 95% CI 1.03–2.36). Among healthy women, moderate physical activity (HR 0.42, 95% CI 0.24–0.74) and complete HRV recordings (≥50%) were found to be significant predictors of survival. Conclusions CAD patients with adequate social integration, who do not smoke and are physically active, have a favorable long-term prognosis. The exact survival times confirm that behavioral risk factors are associated with all-cause mortality in female CAD patients and healthy controls.
Objective
High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases ...remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.
Methods
Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease‐matched women and a group of women without autoimmune diseases (neither group was exposed to MTX).
Results
The study sample included 324 MTX‐exposed pregnancies (188 exposed post‐conception, 136 exposed pre‐conception), 459 disease‐matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post‐conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval 95% CI 29.2–58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 6.6%) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 2.9%) (adjusted odds ratio OR 3.1 95% CI 1.03–9.5) and the disease‐matched cohort (14 of 393 3.6%) (adjusted OR 1.8 95% CI 0.6–5.7). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% 95% CI 8.0–25.3) nor the risk of major birth defects (4 of 114 3.5%) was increased in the pre‐conception cohort. Elective termination rates were increased in both of the MTX‐exposed cohorts. There were no other significant differences among groups in other study end points.
Conclusion
Post‐conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre‐conception cohort.
The prognosis of coronary artery disease (CAD) is related to its severity and cardiovascular risk factors in both sexes. In women, social isolation, marital stress, sedentary lifestyle and depression ...predicted CAD progression and outcome within 3 to 5 years. We hypothesised that these behavioral factors would still be associated with all-cause mortality in female patients after 26 years.
We examined 292 patients with CAD and 300 healthy controls (mean age of 56 ± 7 y) within the Fem-Cor-Risk-Study at baseline. Their cardiac, behavioral, and psychosocial risk profiles, exercise, smoking, and dietary habits were assessed using standardized procedures. Physiological characteristics included a full lipid profile, the coagulation cascade and autonomic dysfunction (heart rate variability, HRV). A new exploratory analysis using machine-learning algorithms compared the effects of social and behavioral mechanisms with standard risk factors. Results: All-cause mortality records were completed in 286 (97.9%) patients and 299 (99.7%) healthy women. During a median follow-up of 26 years, 158 (55.2%) patients and 101 (33.9%) matched healthy controls died. The annualized mortality rate was 2.1% and 1.3%, respectively. After controlling for all available confounders, behavioral predictors of survival in patients were social integration (HR 0.99, 95% CI 0.99-1.0) and physical activity (HR 0.54, 95% CI 0.37-0.79). Smoking acted as a predictor of all-cause mortality (HR 1.56, 95% CI 1.03-2.36). Among healthy women, moderate physical activity (HR 0.42, 95% CI 0.24-0.74) and complete HRV recordings (≥50%) were found to be significant predictors of survival.
CAD patients with adequate social integration, who do not smoke and are physically active, have a favorable long-term prognosis. The exact survival times confirm that behavioral risk factors are associated with all-cause mortality in female CAD patients and healthy controls.
Spontaneous abortion rates are of general interest when investigating pregnancy outcome. In most studies observations are left truncated as pregnant women enter with a delay of several weeks after ...conception. Apart from spontaneous abortion pregnancy may end in induced abortion or live birth. These outcomes are considered as competing events (risks). Although statistical methods for handling this setting are available since more than 10 years, studies on pregnancy outcome after drug exposure usually report crude rates of spontaneous abortions, ignoring left truncation and competing risks.
The authors propose simple methods which remove bias inherent to crude rates. The probability of spontaneous abortion is estimated using an event-history based approach for the subdistribution of competing risks that handles left truncation appropriately. Variance estimation enables the construction of approximate confidence intervals and of a simple test-statistic for comparing rates between different cohorts. The proposed methods are applied to a comparative prospective study on the association of spontaneous abortion and exposure to coumarin derivatives.
The naive analysis using crude rates gives substantially different results than those based on the proposed methods, with up to a twofold change. Correctly incorporating left truncation into the analysis may increase the variance of the estimators, relative to an ideal sample where all pregnancies are followed from the time of conception. The consequences of such truncation for study design are discussed.
Combining corrections for left truncation and competing risks offers a powerful method for analyzing miscarriage risk.
Objective
Apart from thalidomide, retinoids like isotretinoin are the strongest teratogens in humans known today. The overall risk of birth defects is estimated as up to 30% after exposure during ...embryogenesis. In spite of well established pregnancy prevention programs, pregnancies still occur during isotretinoin therapy in many countries including Germany. A detailed investigation of the incidence and outcome of these pregnancies would fill an important gap.
Methodology
The Berlin Institute for Clinical Teratology documents prospectively the course of drug-exposed pregnancies when contacted for individual drug risk assessment. Datasets of isotretinoin exposed pregnancies recorded between 1993 and 2008 were evaluated as to the outcome of pregnancy.
Results
A total of 108 pregnancies exposed to systemic isotretinoin (median dosage 20 mg/day) during the contraindicated period were registered. 76% (69/91) of the pregnancies with known outcome were electively terminated—mainly for fear of medication risk. No terminations due to abnormal prenatal ultrasound findings were reported. Spontaneous abortions occurred in five pregnancies. Of 18 live births including 1 pair of twins 1 major birth defect (small ventricular septal defect) was observed. None of the infants showed symptoms of retinoid embryopathy. 70% (48/69) of the patients with data on contraception did not use any method, in 30% contraception failed. There was no evidence that poor maternal education was a major cause for the omission of contraception documented in 48 women.
Conclusion
Inadvertent isotretinoin exposure during the first 2 weeks post conception does not necessarily require discussion of termination of pregnancy, as the risk of major birth defects appears to be much lower than it becomes beyond this period. Nevertheless, additional efforts are required to improve the effectiveness of contraception while on isotretinoin treatment considering psycho-social aspects such as improved self-confidence, unexpected new partnership and sexual activity and incorrect perception of infertility.
Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), ...observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.
Motivation: Several authors have studied expression in gene sets with specific goals: overrepresentation of interesting genes in functional groups, predictive power for class membership and searches ...for groups where the constituent genes show coordinated changes in expression under the experimental conditions. The purpose of this article is to follow the third direction. One important aspect is that the gene sets under analysis are known a priori and are not determined from the experimental data at hand. Our goal is to provide a methodology that helps to identify the relevant structural constituents (phenotypical, experimental design, biological component) that determine gene expression in a group. Results: Gene-wise linear models are used to formalize the structural aspects of a study. The full model is contrasted with a reduced model that lacks the relevant design component. A comparison with respect to goodness of fit is made and quantified. An asymptotic test and a permutation test are derived to test the null hypothesis that the reduced model sufficiently explains the observed expression within the gene group of interest. Graphical tools are available to illustrate and interpret the results of the analysis. Examples demonstrate the wide range of application. Availability: The R-package GlobalAncova (http://www.bioconductor.org) offers data and functions as well as a vignette to guide the user through specific analysis steps. Contact: hummel@ibe.med.uni-muenchen.de
Both delayed study entry (left‐truncation) and competing risks are common phenomena in observational time‐to‐event studies. For example, in studies conducted by Teratology Information Services (TIS) ...on adverse drug reactions during pregnancy, the natural time scale is gestational age, but women enter the study after time origin and upon contact with the service. Competing risks are present, because an elective termination may be precluded by a spontaneous abortion. If left‐truncation is entirely random, the Aalen‐Johansen estimator is the canonical estimator of the cumulative incidence functions of the competing events. If the assumption of random left‐truncation is in doubt, we propose a new semiparametric estimator of the cumulative incidence function. The dependence between entry time and time‐to‐event is modeled using a cause‐specific Cox proportional hazards model and the marginal (unconditional) estimates are derived via inverse probability weighting arguments. We apply the new estimator to data about coumarin usage during pregnancy. Here, the concern is that the cause‐specific hazard of experiencing an induced abortion may depend on the time when seeking advice by a TIS, which also is the time of left‐truncation or study entry. While the aims of counseling by a TIS are to reduce the rate of elective terminations based on irrational overestimation of drug risks and to lead to better and safer medical treatment of maternal disease, it is conceivable that women considering an induced abortion are more likely to seek counseling. The new estimator is also evaluated in extensive simulation studies and found preferable compared to the Aalen‐Johansen estimator in non–misspecified scenarios and to at least provide for a sensitivity analysis otherwise.
Objective
The objective of our study is to assess the impact of triptan exposure on pregnancy outcome.
Methods
We performed a prospective observational cohort study with 432 pregnant women exposed to ...triptans and enrolled by the German Embryotox system. Pregnancy outcomes were compared with a migraine and a non-migraine comparison cohort. Primary objectives were major birth defects and spontaneous abortion; secondary endpoints were preterm delivery, birth weight, pregnancy complications and the rate of electively terminated pregnancies.
Results
Compared to a non-migraine cohort the rates of major birth defects (ORadj 0.84; 95% CI 0.4–1.9), spontaneous abortions (ORadj 1.20; 95% CI 0.9–1.7), preterm delivery (ORadj 1.01; 95% CI 0.7–1.5), and preeclampsia (ORadj 1.33; 95% CI 0.7–2.5) were not increased in triptan-exposed pregnancies.
Conclusions
Our findings support the evidence that triptans are not major teratogens. When compellingly needed during pregnancy, sumatriptan as the best studied triptan appears an acceptable treatment option. A detailed fetal ultrasound should be offered in cases of first trimester exposure to less well-studied triptans.
Trial registration number in German Clinical Trials Register: DRKS00007660
There is increasing awareness of the potential impact of paternal exposures on pregnancy outcome. In particular this applies to MTX, which is used in low doses for the treatment of RA and other ...inflammatory diseases. MTX is associated with a specific pattern of malformations in fetuses of exposed women, but there is uncertainty concerning the risk of paternal low-dose MTX. The aim of this study was to investigate whether paternal low-dose MTX therapy around conception has an unfavourable effect on pregnancy outcome.
We performed a prospective observational cohort study involving pregnancies fathered by men who were treated with low-dose MTX around conception. Pregnancies were identified through our Teratology Information Service. Pregnancy outcomes were compared with a cohort neither exposed to MTX nor to other teratogens. Outcomes evaluated were major birth defects, spontaneous abortion (SAB), elective termination of pregnancy, gestational age at delivery, and birth weight.
A total of 113 pregnancies with paternal low-dose MTX treatment were compared with 412 non-exposed pregnancies. Neither the rate of major birth defects odds ratio (OR) 1.02, 95% CI 0.05, 7.0) nor the risk of SAB (hazard ratio 1.19, 95% CI 0.65, 2.17) was increased. Gestational age at delivery and birth weights did not differ significantly between groups. The rate of electively terminated pregnancies was increased in the MTX-exposed patients compared with controls.
Our study does not confirm an increased risk of adverse pregnancy outcome after paternal low-dose MTX therapy. The reassuring findings do not support the necessity of a 3-month MTX-free interval until conception. In the case of unavoidable paternal MTX therapy, it seems reasonable not to postpone family planning.
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