Producing valid statistics when legislation, culture, and medical practices differ for births at or before the threshold of survival: Report of a European workshop

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Downloa

Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?

Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. Study Design We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). Conclusion Evidence for gene-smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene-environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures. Key Points Maternal and fetal genotype may differentially influence preeclampsia. Smoking-related genes did not strongly modify smoking-preeclampsia association. Smoking cessation reduced strength of gene by smoking interactions

Factors associated with non-attendance, opportunistic attendance and reminded attendance to cervical screening in an organized screening program: a cross-sectional study of 12,058 Norwegian women

<p>Abstract</p> <p>Background</p> <p>Cervical cancer incidence and mortality may be reduced by organized screening. Participant compliance with the attendance recommendations of the screening program is necessary to achieve this. Knowledge about the predictors of compliance is needed in order to enhance screening attendance.</p> <p>Methods</p> <p>The Norwegian Co-ordinated Cervical Cancer Screening Program (NCCSP) registers all cervix cytology diagnoses in Norway and individually reminds women who have no registered smear for the past three years to make an appointment for screening. In the present study, a questionnaire on lifestyle and health was administered to a random sample of Norwegian women. The response rate was 68%. To address the predictors of screening attendance for the 12,058 women aged 25-45 who were eligible for this study, individual questionnaire data was linked to the cytology registry of the NCCSP. We distinguished between non-attendees, opportunistic attendees and reminded attendees to screening for a period of four years. Predictors of non-attendance versus attendance and reminded versus opportunistic attendance were established by multivariate logistic regression.</p> <p>Results</p> <p>Women who attended screening were more likely than non-attendees to report that they were aware of the recommended screening interval, a history of sexually transmitted infections and a history of hormonal contraceptive and condom use. Attendance was also positively associated with being married/cohabiting, being a non-smoker and giving birth. Women who attended after being reminded were more likely than opportunistic attendees to be aware of cervical cancer and the recommended screening interval, but less likely to report a history of sexually transmitted infections and hormonal contraceptive use. Moreover, the likelihood of reminded attendance increased with age. Educational level did not significantly affect the women's attendance status in the fully adjusted models.</p> <p>Conclusions</p> <p>The likelihood of attendance in an organized screening program was higher among women who were aware of cervical screening, which suggests a potential for a higher attendance rate through improving the public knowledge of screening. Further, the lower awareness among opportunistic than reminded attendees suggests that physicians may inform their patients better when smears are taken at the physician's initiative.</p

The Stringent Response and Cell Cycle Arrest in Escherichia coli

The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes upon arrest. Nucleoids of these cells are decondensed; in the absence of the ability to synthesize ppGpp, nucleoids become highly condensed, similar to that seen after treatment with the translational inhibitor chloramphenicol. After induction of the stringent response, while regions corresponding to the origins of replication segregate, the termini remain colocalized in wild-type cells. In contrast, cells arrested by rifampicin and cephalexin do not show colocalized termini, suggesting that the stringent response arrests chromosome segregation at a specific point. Release from starvation causes rapid nucleoid reorganization, chromosome segregation, and resumption of replication. Arrest of replication and inhibition of colony formation by ppGpp accumulation is relieved in seqA and dam mutants, although other aspects of the stringent response appear to be intact. We propose that DNA methylation and SeqA binding to non-origin loci is necessary to enforce a full stringent arrest, affecting both initiation of replication and chromosome segregation. This is the first indication that bacterial chromosome segregation, whose mechanism is not understood, is a step that may be regulated in response to environmental conditions

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: A European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors