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The colony-stimulating factor 1 receptor (CSF1R) is commonly known as a transmembrane receptor on tumor-associated macrophages, which are essential in the tumor microenvironment. However, the expression pattern and prognosis of CSF1R are still unknown in colorectal cancer (CRC) and are still controversial among various cancers. To clarify the expression pattern and prognosis of CSF1R in CRC, we performed immunohistochemistry on 332 CRC tissue and 283 nontumorous adjacent tissues. We explored the expression pattern of CSF1R and analyzed its relationship with clinical characteristics and prognosis. The positive expression ratio of CSF1R was much higher in nontumorous adjacent tissues, while the positive cytomembrane ratio of CSF1R was much higher in cancer tissue. Furthermore, we found that CSF1R expression, especially in the cytoplasm, acted as a protective factor. However, our findings indicated that CSF1R expression on the cytomembrane decreased its prognostic predictive value. These results emphasize the important role of the localization of CSF1R and may also explain the contrasting effects seen between various cancers.

Background Huntingtin‐interacting protein 1‐related (HIP1R) is a multi‐domain gene that exerts many cellular functions including altering T cell–mediated cytotoxicity and controlling intracellular trafficking. However, its clinical significance and function in gastric cancer (GC) have not been described. Methods The expression levels of HIP1R were tested by the transcriptional and translational expression analysis and immunohistochemistry (IHC) in matched adjacent non‐tumorous vs tumor tissue specimens. The biological function of HIP1R on apoptosis, migration, and proliferation was evaluated by flow cytometry, Transwell, Cell Counting Kit‐8 (CCK‐8) assays, colony formation assays, and EdU labeling assays, respectively. Results We found downregulated HIP1R in GC compared with adjacent non‐tumorous tissue, and HIP1R expression associated with N classification. We further found that the expression of HIP1R could induce apoptosis and inhibit proliferation, migration, invasion of GC cells, possibly through modulating Akt. Conclusions Our data indicate that HIP1R may act as a potential diagnostic biomarker and a tumor suppressor gene in GC, potentially representing a novel therapeutic target for future GC treatment.

Aim: This study aimed to estimate the relative representation of childhood psychiatric diagnoses and use of psychotropic medication in the Danish National Birth Cohort (DNBC) compared to the general population. Methods: The general population was identified as all childbirths in Denmark during 1998?2002 (N=344,160). Linking the DNBC (N=91,442) and the general population to the Danish national health registries, all children were followed until they received an ICD-10 psychiatric diagnosis, had a prescription of psychotropic medication or to the end of follow-up in 2013. The prevalence ratios (PRs) with corresponding 95% confidence intervals (CI) were estimated for each psychiatric diagnosis and by sex. Age at first diagnosis presented as means were compared using the one-sample t-test. Results: In the DNBC, the selected childhood psychiatric diagnoses were underrepresented by 3% (PR=0.97, 95% CI 0.94?0.99), ranging from a 20% underrepresentation for schizophrenia (PR=0.80, 95% CI 0.59?1.09) to a 6% over-representation for anxiety disorder or obsessive-compulsive disorder (PR=1.06, 95% CI 0.97?1.17). The majority of the specific diagnoses were modestly underrepresented in the DNBC compared to the general population, while use of psychotropic medication had similar representation. Girls were generally more underrepresented than boys. Depression was on average diagnosed 0.4 years earlier in the DNBC than in the general population (p=0.023). Conclusions:These findings suggest that the social selection may influence the prevalence of diagnosed childhood psychiatric disorders in the DNBC. AIM:This study aimed to estimate the relative representation of childhood psychiatric diagnoses and use of psychotropic medication in the Danish National Birth Cohort (DNBC) compared to the general population.METHODS:The general population was identified as all childbirths in Denmark during 1998-2002 ( N=344,160). Linking the DNBC ( N=91,442) and the general population to the Danish national health registries, all children were followed until they received an ICD-10 psychiatric diagnosis, had a prescription of psychotropic medication or to the end of follow-up in 2013. The prevalence ratios (PRs) with corresponding 95% confidence intervals (CI) were estimated for each psychiatric diagnosis and by sex. Age at first diagnosis presented as means were compared using the one-sample t-test.RESULTS:In the DNBC, the selected childhood psychiatric diagnoses were underrepresented by 3% (PR=0.97, 95% CI 0.94-0.99), ranging from a 20% underrepresentation for schizophrenia (PR=0.80, 95% CI 0.59-1.09) to a 6% over-representation for anxiety disorder or obsessive-compulsive disorder (PR=1.06, 95% CI 0.97-1.17). The majority of the specific diagnoses were modestly underrepresented in the DNBC compared to the general population, while use of psychotropic medication had similar representation. Girls were generally more underrepresented than boys. Depression was on average diagnosed 0.4 years earlier in the DNBC than in the general population ( p=0.023).CONCLUSIONS:These findings suggest that the social selection may influence the prevalence of diagnosed childhood psychiatric disorders in the DNBC.

To investigate the influence of high fat diet-induced obesity (HFDIO) on the differentially methylated region (DMR) of the imprinted gene and global genome methylation of sperm DNA.We performed bisulfite sequencing on the DMR of the imprinted gene and global genome methylation of sperm DNA in the mouse model of HFDIO.No statistically significant differences were found between the HFDIO model and normal control mice in MEG3-IG (93.73 vs 97.26%, P = 0.252), H19 (98.00 vs 97.83%, P = 0.920), IGF2 (97.34 vs 96.25%, P =0.166), IGF2R (1.43 vs 1.11%, P = 0.695), PEG3 (0.19 vs 0.38%, P = 0.537), MEST (0.23 vs 0.68%, P = 0.315), NNAT (0.31 vs 0.00%, P = 0.134), or SNRPN (1.88 vs 3.13%, P = 0.628). A total of 8 942 DMRs were detected across the sperm genome (P0.05). Gene functional enrichment analysis indicated that the enriched terms with the largest numbers of genes were the metabolic process (n = 1 482), RNA synthesis (n = 779), and transcription (n = 767).The methylation level underwent no significant change in the DMRs of the imprinted genes from the mice with HFDIO, but the CG methylation of the genes involved in the metabolic process, RNA synthesis and transcription were significantly altered.目的： 研究高脂饲料诱导的肥胖是否影响小鼠精子印迹基因差异甲基化区域和精子全基因组DNA甲基化水平。方法： 利用高脂饲料诱导的肥胖小鼠模型，进行精子DNA的全基因组甲基化和印迹基因差异甲基化区测序。结果： 高脂饲料诱导的肥胖组印迹基因差异甲基化区甲基化水平与普通饲料对照组无显著差异：MEG3-IG (93.73% vs 97.26%; P=0.252),H19(98.00% vs 97.83%， P=0.920),IGF2(97.34% vs 96.25%，P=0.166),IGF2R(1.43% vs 1.11%，P=0.695), PEG3(0.19% vs 0.38%，P=0.537),MEST(0.23% vs 0.68%，P=0.315), NNAT(0.31% vs 0.00%，P=0.134)和SNRPN(1.88% vs 3.13%，P=0.628)。精子全基因组范围内总共发现8 942个甲基化有显著差异的区域(P0.05)。对差异甲基化区域进行基因功能富集，富集基因数目最多的3项分别为代谢(n=1 482)，RNA合成(n=779)和转录(n=767)。结论： 高脂饲料诱导的肥胖小鼠精子印迹基因差异甲基化区甲基化水平没有发生显著改变，参与代谢、RNA合成以及转录过程基因CG序列甲基化显著改变。.

The objective of the present study was to investigate the effects of for chlorfenuron (FCF) interference with the septin protein on early stage embryos in mice. The 1‑cell embryos were collected and divided into an FCF interference group and a control group. The FCF interference group was cultured in FCF media and the control group was cultured in dimethyl sulphoxide media at 37˚C with 5% CO2 until the desired phase was achieved. Septin2 protein expression was detected using immunofluorescence and western blot analysis. Blastocyst α‑tubulin was stained by immunofluorescence to observe the alterations in spindles and microtubules. The rate of early embryo development into blastocysts was significantly reduced following FCF treatment (P

Aims Accumulating evidence over the past decade has shown that abnormal activation of epithelial to mesenchymal transition (EMT) contributes to tumour progression and metastasis in colorectal cancer (CRC). In this study, we investigated the expression of interleukin-like EMT inducer (ILEI) and EMT-associated markers (E-cadherin, vimentin) in CRC tissues and determined the correlations between ILEI expression and clinicopathological characteristics, prognosis and EMT in CRC. Methods and results In total, 194 patients diagnosed with CRC based on histopathological evaluation and those subjected to surgical resection at the First Hospital of China Medical University between 2003 and 2005 were examined. Immunohistochemical staining for ILEI, vimentin and E-cadherin was performed for each specimen. Cytoplasmic overexpression of ILEI usually accompanied down-regulation of E-cadherin and positive expression of vimentin. Conversely, ILEI was simultaneously down-regulated with overexpression of E-cadherin and negative expression of vimentin. ILEI overexpression was associated significantly with T-stage, N-stage, TNM stage and EMT phenotype (P = 0.024

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

Today, most persons with Down syndrome (DS) survive into middle age, but information on their social conditions as adults is limited. We addressed this knowledge gap using data from national registers in Denmark. We identified a national cohort of 1,998 persons with DS who were born between 1968 and 2007 (1,852 with standard trisomy 21, 80 with Robertsonian translocations and 66 with mosaicism) using the Danish Cytogenetic Register. We followed this cohort from 1980 to 2007. Information on social conditions (education, employment, source of income, marital status, etc.) was obtained by linkages to national registers, including the Integrated Database for Longitudinal Labor Market Research. For those aged 18 and older, more than 80% of persons with DS attended 10 years of primary school, with about 2% completing secondary or post-secondary education. About 4% obtained a full-time job, whereas the remaining mainly received public support from the government. Only a few (1-2%) of persons with DS were married or had a child. No significant differences in these social conditions were seen between males and females. More persons with mosaic DS attended secondary or post-secondary education, had a full-time job, were married, or had a child (18%, 28%, 15%, and 7%, respectively), compared with persons with standard DS (1%, 2%, 1%, and 1%, respectively). These data may provide families with better insight into social conditions and society with a better understanding of the social support needed for persons with DS. © 2013 Wiley Periodicals, Inc.

Aims Recent studies have revealed that glutamate decarboxylase 65 (GAD65) plays important roles in cancer progression. The role of GAD65 in gastric cancer development, progression and prognosis is currently unknown, and we aimed to investigate this. Methods and results Immunohistochemistry revealed that GAD65 expression in 313 gastric cancer tissues was significantly higher than in 60 adjacent non-tumour tissues. Moreover, the expression level of GAD65 significantly correlated with the depth of tumour invasion and TNM stage. GAD65 expression level was a significant prognostic factor in univariate survival analysis, but did not remain an independent prognostic factor following Cox multivariate analysis. For tumours with an intermediate type growth pattern, when those showing low expression of GAD65 were reclassified with expanding type tumours, and those showing high expression with infiltrative type tumours, there was a significant difference in prognosis between these two novel subgroups, and this remained a significant prognostic factor in multivariate analysis. Conclusions Our findings indicate that GAD65 is involved in the development and progression of gastric cancer as a tumour oncoprotein. Further elucidation of the molecular mechanisms underlying the role of GAD65 is warranted.

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population-based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR = 1.04; 95% CI: 0.99–1.04) nor fathers (HR = 1.03; 95% CI: 0.98–1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR = 0.76, 95% CI: 0.58–1.00) or fathers (HR = 0.89, 95% CI: 0.66–1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.

Single nucleotide polymorphisms (SNPs) in the promoter regions of non-metastatic cells 1 gene (NME1) may attribute to the changing of promoter activities. In addition, high NME1 protein levels are correlated with negative lymph node metastasis in gastric cancer. This study evaluated possible associations between SNPs in NME1 gene and gastric cancer susceptibility, clinicopathological parameters, or survival. We obtained formalin-fixed paraffin-embedded tissues from 404 gastric cancer patients and blood samples from 404 controls. SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A significant correlation between SNPs and lymph node metastases risk was found. Patients carrying TT genotype in rs16949649, AA genotype in rs3760468, TT genotype in rs3760469, CC genotype in rs2302254, and GG genotype in rs34214448 were correlated to greater numbers of lymph node metastases (P = 0.023 in rs16949649; P = 0.015 in rs3760468; P = 0.043 in rs3760469; P = 0.008 in rs2302254; and P = 0.021 in rs34214448, respectively). Moreover, the haplotype TATCG were associated with positive lymph node metastasis (P = 0.039) and lymphovascular invasion (P = 0.048) compared to the haplotype CTGTT carriers. Furthermore, patients carrying AA genotype in rs3760468 or the haplotype TATCG had poor survival in T4 subgroup (P = 0.038 in univariate and P = 0.014 in multivariate analysis for rs3760468, and P = 0.017 in univariate and P = 0.012 in multivariate analysis for TATCG, respectively). In conclusion, SNPs in NME1 gene may play an important role in regulating lymph node metastasis and, thus, affect survival in T4 subgroup of gastric cancer in a Northern Chinese population.

Background: Studies suggest that children born very preterm have a high risk of developmental coordination disorder (DCD). We examined the relation between the larger spectrum of gestational age at birth and the risk of DCD. Methods: We used the 7-year follow-up data from 22898 singletons in the Danish National Birth Cohort. We calculated a total score from the Developmental Coordination Disorder Questionnaire (DCDQ), incorporated in the 7-year follow-up, and defined children with a score of 46 or below as having probable DCD. Information on gestational age was obtained from the Medical Birth Register. Results: Gestational age at birth was inversely associated with the risk of DCD; a decline in gestational age by a week was associated with a 19% [95% confidence interval 14%, 25%] increased risk of DCD screening positive among children delivered before 40 weeks. No significant increased risk of DCD was seen for children born post-term. Conclusion: Our data indicate that short gestational age at birth in a range up to gestational week 37 is related to an increased risk of DCD.

The bipolar spindle is a complex molecular machinery that drives chromosome congression and segregation. During meiosis in the mouse multiple microtubule organizing centers aggregate to form a bipolar intermediate followed by elongation and establishment of the barrel-shaped acentriolar meiotic spindle. Previous studies have shown that septin1 is localized to spindle poles in mitosis, suggesting its possible involvement in spindle assembly. We, therefore, asked whether perturbation of septin1 will impair the process of spindle assembly and investigated localization and function during mouse oocyte meiotic maturation. Septin1 was localized to the spindle at metaphase and at the midbody during cytokinesis. Disruption of septin1 function using siRNA caused a decrease in PBE and extensive spindle defects. Moreover, the process of chromosome congression was impaired. However, septin1 depletion did not cause aneuploidy in oocyte with an extruded polar body. Taken together, our results show that septin1 is a key player in spindle assembly and chromosome congression in mouse meiosis. Developmental Dynamics 240:2281–2289, 2011. © 2011 Wiley-Liss, Inc.

Objective To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP). Methods The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables. Results Overall, compared with women with no recorded RA (n = 74,255), women with prevalent RA (onset prior to conception) (n = 112) were slightly older (mean ± SD age 30.8 ± 4.3 years versus 29.7 ± 4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken >12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy. Conclusion Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity. Copyright © 2011 by the American College of Rheumatology.

Objective. Increasing use of infertility treatment and a decline in demographic fertility in some countries have raised concern whether human fecundity is declining or has declined over time. A dramatic decline in semen quality over the past half- century has been proposed and widely discussed, but none of the existing studies provide data good enough for coming to any firm conclusion. Results. Results from 19 articles published during the last 5 years on semen quality and fecundity, covering data from the Nordic countries since the year 2000, do not indicate an ongoing decline in fertility. Conclusion. We will probably never know, whether semen quality and fecundity has declined over time, but we may be able to monitor biological fecundity and semen quality over time from now on. There are both research initiatives and interest from official channels that could provide more funding for infertility research.

Udgivelsesdato: 2010-Nov-2 BACKGROUND Children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of cerebral palsy (CP), perhaps due to the higher frequency of preterm birth, multiple births or vanishing embryo in the pregnancies. However, it has been suggested that the underlying infertility may be part of the pathway. In this study, we examined whether untreated subfecundity (measured by time to pregnancy) or infertility treatment was associated with an increased risk of CP in the offspring. METHODS Using the Danish National Birth Cohort (1997-2003), we compared children born after 0-2 months of waiting time to pregnancy (n = 35 848) with those born after a time to pregnancy of 3-5 months (n = 15 361), 6-12 months (n = 11 528) and >12 months (n = 7387), as well as those born after IVF/ICSI (n = 3617), ovulation induction with or without intrauterine insemination (n = 3000), and unplanned pregnancies (n = 13 462). CP cases were identified through the Danish CP Register. RESULTS In total, 165 (0.18%) children were diagnosed with CP in the entire cohort. We found no significant association between time to pregnancy and the risk of CP in children conceived spontaneously. Children born after IVF/ICSI had an increased risk of CP, even after adjustment for preterm birth and multiplicity (hazard ratio 2.30, 95% confidence interval 1.12-4.73). CONCLUSIONS Subfecundity per se did not appear to be associated with the risk of CP in children, whereas being born after IVF/ICSI conferred an increased risk.

To understand the relationship between rice sowing date and occurrence of the rice small brown planthopper (SBPH) Laodelphax striatellus Fallen and the epidemics of the planthopper-transmitted rice stripe viral (RSV) disease, four sowing dates of rice were evaluated in 2006 and 2007. The results showed that the peak density of SBPH and RSV incidence in the nursery and in the transplanted field decreased with the delay of sowing date in single crop of japonica rice in north Zhejiang Province of China. The relationship between seedling RSV incidence at the end of the nursery trial with sowing date was well described by Weibull equation. The area under the curve of population dynamics (AUCPD or planthopper-day accumulation) or the peak density of the planthopper in the nursery could be summarized by a logistic equation. RSV incidence in the transplanted fields could be characterized quantitatively by a multivariate regression equation, including the variables of sowing date, peak density of the vector, and RSV incidence at the end of the nursery trial. That the descriptive model excluded the AUCPD in transplanted field implies that this variable is not necessary in forecasting disease epidemics in the field. The 2-year experiments sufficiently indicated that suitable sowing of rice could be used as one of the effective measures to control the vector population and therefore the planthopper-transmitted RSV on a larger scale. The optimal sowing date for the single-cropped transplanted japonica rice is recommended from late May to early June in north Zhejiang, China.

Udgivelsesdato: 2009-Feb OBJECTIVES: To compare two post-abortion family planning (FP) service packages on contraceptive use and repeat abortion rate among young women in three cities in China. METHODS: In this cluster-randomized trial, one FP service package included provision of limited information and referral to existing FP services, and the other, more comprehensive, package consisted--in addition to the above simple package--of individual counselling, free provision of contraceptive materials, and involvement of the male partner. Eight matched pairs of hospitals were certified by centralized randomization. Women undergoing abortion were followed up for six months, and data were collected in two rounds, before and after the intervention. RESULTS: We followed a total of 2336 women younger than 25 years (555 before and 555 after the simple intervention package; 634 before and 592 after the comprehensive intervention package). Both packages increased use of any contraceptive method, but the comprehensive approach also increased use of more effective methods. Odds ratios for consistent and correct use of condoms were 2.32 (95% confidence interval 1.55-3.46) and 2.78 (1.81-4.26), respectively, compared with the simple package. The rates of unwanted pregnancies and repeat abortions were somewhat reduced for both packages, with no significant statistical difference between them. CONCLUSION: Couples who received the comprehensive post-abortion FP service appear to use more effective contraceptive methods and show better compliance.

Background Conventional cohort studies have consistently shown that exposure to maternal smoking in pregnancy is associated with about twice the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. However, recent studies using alternative designs to disentangle the effect of social and genetic confounders have suggested that confounding may account for the association. In this study we aimed to estimate the association by a sibling design. Methods We used a design with half and full siblings in a Danish national register-based cohort on all singletons born between January 1991 and December 2006 and followed until January 2011. Data were available for 90% (N = 968,665) of the singleton live births in the period. We used the combination of the International Classification of Diseases (10th version) diagnosis of hyperkinetic disorder (HKD) and ADHD medication to identify children. We used sibling-matched (conditional) Cox regression to control social and genetic confounding. Results Using conventional cohort analyses, we found the expected association between pregnancy smoking and offspring ADHD (adjusted HR 2.01, 95% CI 1.94–2.07). In the sibling analysis, however, we did not detect such a strong association (adjusted HR 1.07, 95% CI 0.94–1.22). There was no difference between results for half- and full sibling analyses. The link between pregnancy smoking and low birth weight remained robust in the sibling design (adjusted OR 1.68, 95% CI 1.33–2.12). Conclusions We found no support for prenatal smoking as a strong causal factor in ADHD. Our findings suggest that the strong association found in most previous epidemiological studies is likely to be due to a strong link between maternal smoking and maternal ADHD genetics or shared family environment. Pregnant women should still be encouraged to stop smoking because of other risks, but we have no reason to believe that this would reduce the risk of ADHD in the offspring.

Objective To examine the timing of reaching developmental milestones in children born post-term. Design Cohort study. Setting The Danish National Birth Cohort: children born between 1997 and 2003. Population Data were obtained from a cohort of 92 892 pregnancies participating in the first pregnancy interview. All singletons born in gestational weeks 39–45 were identified. The study was then restricted to children who participated in an interview at the age of approximately 18 months and had information on at least one developmental milestone. We excluded children of mothers with chronic diseases from the final analysis. The remaining study population constituted of 43 915 singletons (27 503 born at term; 16 412 born post-term). Methods Logistic regression was used to calculate odds ratios of late achievement of these developmental milestones, adjusted for potential confounding factors. Main outcome measures Achieving developmental milestones at the time of interview or at a certain age. Results More children born post-term achieved the assessed developmental milestones compared with children born at term (39–40 weeks). A test for trend for gestational ages 39, 40, and 41 weeks also showed a positive trend at achieving developmental milestones with gestational age at birth in nine out of 14 milestone items. Conclusions Children born post-term appear to reach the main developmental milestones at an earlier age than children born at term. The association could also result from bias related to a longer time between conception and interviewing, misclassification of end points, or selection bias.

Udgivelsesdato: 2006-Apr OBJECTIVE: We conducted a follow-up study to examine whether exposure to pesticides during pregnancy had an adverse effect on pregnancy outcomes among Danish gardeners and farmers. METHODS: Using data from the National Birth Cohort in Denmark, we identified 226 pregnancies of gardeners and 214 pregnancies of farmers during 1997 through 2003. Work activities and exposure to pesticides were reported in an interview (around 16 weeks of gestation). Totally, 62,164 other workers in the cohort served as a reference group. Pregnancy outcomes were obtained by linkage to the national registers. Cox regression was applied to analyze late fetal loss and congenital malformations, and logistic regression was used to analyze preterm birth and small for gestational age. RESULTS: There were no significant differences in the studied pregnancy outcomes between gardeners or farmers and all other workers, except for an increased risk of very preterm birth for gardeners and a favorable birth weight for farmers. With the exception of biologic approach used in gardening, neither work activities nor exposure to pesticides showed a significant increased risk of adverse birth outcomes among gardeners or farmers. CONCLUSIONS: Our data suggest little effect of occupational exposures to pesticides on pregnancy outcomes among gardeners or farmers in Denmark. The results may not apply to other countries.

BACKGROUND: Early parental separation may be a stress factor causing a long-term alteration in the hypothalamic-pituitary-adrenal-axis activity possibly impacting on the susceptibility to develop overweight and obesity in offspring. We aimed to examine the body mass index (BMI) and the risk of overweight and obesity in children whose parents lived separately before the child was born.METHODS: A follow-up study was conducted using data from the Aarhus Birth Cohort in Denmark and included 2876 children with measurements of height and weight at 9-11-years-of-age, and self-reported information on parental cohabitation status at child birth and at 9-11-years-of-age. Quantile regression was used to estimate the difference in median BMI between children whose parents lived separately (n = 124) or together (n = 2752) before the birth. We used multiple logistic regression to calculate odds ratio (OR) for overweight and obesity, adjusted for gender, parity, breast feeding status, and maternal pre-pregnancy BMI, weight gain during pregnancy, age and educational level at child birth; with and without possible intermediate factors birth weight and maternal smoking during pregnancy. Due to a limited number of obese children, OR for obesity was adjusted for the a priori confounder maternal pre-pregnancy BMI only.RESULTS: The difference in median BMI was 0.54 kg/m2 (95% confidence intervals (CI): 0.10; 0.98) between children whose parents lived separately before birth and children whose parents lived together. The risk of overweight and obesity was statistically significantly increased in children whose parents lived separately before the birth of the child; OR 2.29 (95% CI: 1.18; 4.45) and OR 2.81 (95% CI: 1.05; 7.51), respectively. Additional, adjustment for possible intermediate factors did not substantially change the estimates.CONCLUSION: Parental separation before child birth was associated with higher BMI, and increased risk of overweight and obesity in 9-11-year-old children; this may suggest a fetal programming effect or unmeasured difference in psychosocial factors between separated and non-separated parents.

Fatal Occupational Events in a Development Area in East China: 1991 to 1997: Jinliang ZHU, et al. School of Public Health, Shanghai Medical University-We analyzed 383 occupational fatal events in a new development area in east China during the period 1991-1997. Most of the events took place during the period 1994-1997, because many large projects related to infrastructure development were ratified and implemented during that period. Extra working shifts on weekends were one of the risk factors in occupational fatalities. Falls, collisions, objects struck against, excavation cave-ins and electrocution were most important types of injury and accounted for the majority of the multiple incident accident types. The most common equipment or environment involved was the work surface, structures being built, cranes, and electric and electronic devices. The most common setting was construction and most incidents occurred in construction. We suggest that the prevention and control of occupational fatalities requires a comprehensive approach which includes improvement of product design, modification of the man-made environment, safety training, enforcement of relevant regulations and ergonomic controls.

Fatal occupational injuries in a new development region in Shanghai in east China are described. All occupational deaths in the East Pujiang New Area during the period 1991 through 1997 were abstracted from multiple, overlapping source documents. There were 426 deaths and a crude mortality rate of 9.1 per 100,000 workers. The death rate was highest in 1995 (14.6%), when expansion in the area was most rapid. The construction sector accounted for 55% of the deaths, followed by manufacturing (23%) and transport, storage, and telecommunications (11%). Falls, collisions, struck by/against incidents, and electrocutions accounted for 80% of all deaths. Falls led all other causes of deaths (33%) and were particularly prevalent in the construction industry (46% of all deaths in construction). The development of ongoing, comprehensive injury surveillance systems in the People's Republic of China will be essential to target and evaluate injury prevention activities in the future.

Two hundred thirty-five work-related deaths occurred in the construction industry in a new economic development area in eastern China between 1991 and 1997. These fatalities represented 55% of all occupational deaths. The average annual mortality rate was 51.5 per 100,000 construction workers. Falls were the leading cause of death (46.4%). Falls, collisions, struck by/against something, electrocutions, and excavation cave-ins were the main fatality antecedents, accounting for nearly 93.6% of all fatalities. The most common antecedents for incidents with multiple fatalities were falls, crane-related events, poisoning, and fire. These categories of antecedents were similar to those encountered in the construction industry in the United States. These data suggest that organizations need to focus on these event types when planning their prevention activities. Moreover, improved surveillance systems including computerized databases with narrative descriptions of injury events, antecedent factors, and person-time at-risk data are needed to target interventions more precisely.

The authors carried out a descriptive analysis of acute chemical intoxication in a large petrochemical corporation with 38,000 employees, located in a suburban district of Shanghai, China, to determine the chemicals involved and the primary causes of the incidents. Between 1977 and 1997, 350 cases of acute chemical-intoxication were recorded, resulting in a total of 541 workers with symptoms. Of these, 483 were male and 58, female, with over half the victims under 30 years old. Two hundred and seventy-five cases were serious enough to necessitate hospital admission. There were 266 cases of chemical irritation or inhalation responses (49.2%), 215 cases of mild chemical poisoning (39.7%), 31 cases of moderate poisoning (5.7%), and 29 cases resulting in critical injury (5.4%), including eight deaths (1.5%). The main causes of injury reported by patients were lack of training about safety (63%) and equipment failure (23%). The chemicals involved were asphyxiating gases (302 cases; 55.8%), irritating gases (111 cases; 20.5%), and other toxins. Intervention strategies for the prevention of acute chemical exposures were suggested to the corporation.

To explore the possible oxidative stress induced by lead, heparinized whole blood and urine of 66 secondary smelter lead workers (46 for Comet assay) and 28 controls were collected. The concentrations of blood lead (BPb) and urinary lead (UPb) and alpha-aminolevulinic acid (alpha-ALA), indices of lead exposure level of the body, were determined. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity of plasma were also measured. Single-cell gel (SCG, Comet assay) was used to measure the DNA damage of peripheral blood cells. There was a positive correlation between the presence of Pb in blood and significant increases in MDA levels and SOD activity. Alcohol consumption and smoking with increased exposure to Pb was associated with enhanced DNA damage. A positive correlation was found between MDA and DNA damage.

OBJECTIVES: It has been suggested that maternal emotional stress during cardiogenesis may be a risk factor for congenital heart defects (CHD). We examined this association using bereavement around the time of conception as an indicator of maternal exposure to stress in a large registry-based study. METHODS: We identified 1 770 878 singletons born in Denmark from January 1, 1978, to December 31, 2008. Of these, 44 820 children were born to mothers who had lost a first-degree relative during the time period from 1 year before their last menstrual period until delivery (6080 mothers lost a child or partner, and 38 740 mothers lost a parent or sibling). CHD diagnoses were identified from the Danish Registry of Congenital Heart Disease. We used logistic regression models to calculate prevalence odds ratios (ORs) of CHD for exposed children compared with unexposed children. RESULTS: Exposed children had a slightly higher prevalence of CHD than unexposed children (0.94% vs 0.82%; adjusted OR = 1.11, 95% confidence interval 1.00–1.22). The association was most marked for children of mothers who had lost a child or partner (1.15% vs 0.82%; adjusted OR = 1.32, 1.04–1.67). CONCLUSIONS: Prenatal exposure to severe emotional stress may slightly increase the prevalence of CHD in offspring.

Aims Mesenchyme forkhead 1 (FoxC2) is an epithelial–mesenchymal transition (EMT)-inducing factor. Previous studies have demonstrated that FoxC2 binds directly to the promoter region of p120-catenin (p120ctn). The aim of this study was to investigate the clinical significance of FoxC2 expression and the inter-relationship between FoxC2 and p120ctn, in gastric cancer. Methods and results Immunohistochemistry was used to examine the expression of FoxC2 and p120ctn proteins in 325 gastric cancer samples. Staining for FoxC2 in cancer tissues was markedly stronger than in normal tissues. High FoxC2 expression was associated significantly with differentiation, invasion depth, lymph node metastasis and tumour stage. Patients with high FoxC2 expression or low p120ctn expression had a poor prognosis. In the high p120ctn expression group, the prognosis for patients with low FoxC2 expression was better than for the high FoxC2 group. Moreover, stepwise Cox regression showed that p120ctn was an independent prognostic factor, but FoxC2 in combination with p120ctn was not correlated significantly with survival. Conclusions We found that FoxC2 and p120ctn play important roles in the progression and prognosis of gastric cancer. Moreover, FoxC2 and p120ctn should be evaluated further as novel biomarkers and therapeutic targets for gastric cancer treatment.

Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype. A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51–7.08), 8.94 (8.32–9.60), and 10.23 (7.50–13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes. Genet Med 2013:15(1):64–69

To investigate the role of immunity-related medical conditions in the etiology of pancreatic cancer, we analyzed data from a population-based case-control study of pancreatic cancer conducted in Shanghai during 1992 and 1993. Information on prior histories of selected auto-immune diseases and allergic conditions was obtained from 108 incident pancreatic-cancer cases and 275 age- and gender-frequency matched controls by face-to-face interviews using a structured questionnaire. A prior history of auto-immune diseases was associated with a 2-fold elevated risk of pancreatic cancer (95% CI = 1.0-4.2), with an indication of a dose-response relation for the number of reported diseases. In contrast, a prior history of allergic condition was related to reduced risk (OR = 0.6, 95% CI = 0.4-1.1). With the possible exception of drug allergy, such an inverse association was seen for virtually all allergic conditions., although none of the OR was statistically significant. This study suggests that host immune function may be involved in the etiology of pancreatic cancer. Further investigations into the mechanism of these observed associations are warranted.

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population-based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR=1.04; 95% CI: 0.99-1.04) nor fathers (HR=1.03; 95% CI: 0.98-1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR=0.76, 95% CI: 0.58-1.00) or fathers (HR=0.89, 95% CI: 0.66-1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.

Nek9 (also known as Nercc1), a member of the NIMA (never in mitosis A) family of protein kinases, regulates spindle formation, chromosome alignment and segregation in mitosis. Here, we showed that Nek9 protein was expressed from germinal vesicle (GV) to metaphase II (MII) stages in mouse oocytes with no detectable changes. Confocal microscopy identified that Nek9 was localized to the spindle poles at the metaphase stages and associated with the midbody at anaphase or telophase stage in both meiotic oocytes and the first mitotic embyros. Depletion of Nek9 by specific morpholino injection resulted in severely defective spindles and misaligned chromosomes with significant pro-MI/MI arrest and failure of first polar body (PB1) extrusion. Knockdown of Nek9 also impaired the spindle-pole localization of γ-tubulin and resulted in retention of the spindle assembly checkpoint protein Bub3 at the kinetochores even after 10 h of culture. Live-cell imaging analysis also confirmed that knockdown of Nek9 resulted in oocyte arrest at the pro-MI/MI stage with abnormal spindles, misaligned chromosomes and failed polar body emission. Taken together, our results suggest that Nek9 may act as a MTOC-associated protein regulating microtubule nucleation, spindle organization and, thus, cell cycle progression during mouse oocyte meiotic maturation, fertilization and early embryo cleavage.

Studies suggest that children born very preterm have a high risk of developmental coordination disorder (DCD). We examined the relation between the larger spectrum of gestational age at birth and the risk of DCD. We used the 7-year follow-up data from 22898 singletons in the Danish National Birth Cohort. We calculated a total score from the Developmental Coordination Disorder Questionnaire (DCDQ), incorporated in the 7-year follow-up, and defined children with a score of 46 or below as having probable DCD. Information on gestational age was obtained from the Medical Birth Register. Gestational age at birth was inversely associated with the risk of DCD; a decline in gestational age by a week was associated with a 19% [95% confidence interval 14%, 25%] increased risk of DCD screening positive among children delivered before 40 weeks. No significant increased risk of DCD was seen for children born post-term.Our data indicate that short gestational age at birth in a range up to gestational week 37 is related to an increased risk of DCD.

Summary Epidemiological studies have raised concern about the reproductive consequences of prenatal cigarette smoking exposure, possibly affecting semen quality and onset of pubertal development of the offspring. The aim of this study was to further investigate pubertal development in young men exposed to cigarette smoking in foetal life. In a Danish pregnancy cohort, information on maternal smoking during pregnancy was available from questionnaires administered in 1984–1987, and information on pubertal development, assessed by age at first nocturnal emission, acne, voice break and regular shaving, was obtained from a follow-up questionnaire administered in 2005 to the young men (age: 18–21). We found no significant association between prenatal cigarette smoking exposure and earlier onset of puberty, but we did observe a tendency towards earlier age of first nocturnal emission, acne and voice break, indicating an accelerated age of pubertal development. Men exposed to ≥15 cigarettes/day had 3.1 months (95% CI: −6.4; 0.2) earlier age at acne and 2.2 months (95% CI: −7.3; 3.0) earlier age at first nocturnal emission, 1.2 months (95% CI: −4.6; 2.2) earlier age at voice break, however, 1.3 months (95% CI: −1.6; 4.3) later age at regular shaving, compared with unexposed men. Prenatal cigarette smoking exposure may induce an earlier age at onset of puberty in young men, but larger studies with prospectively collected data on pubertal development are needed to explore this hypothesis further.

Objective At present, only the number of metastatic lymph nodes (LNs+) is used for the pN category of AJCC TNM system for colon cancer. Recently, the ratio of metastatic to examined lymph nodes (LNR) has been reported to represent powerful independent predictive capacity in colon cancer. We sought to propose a novel category (nLN) which intergrades LNR and LNs+ into the AJCC staging system for colon cancer. Design 34476 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) dataset with stage III colon cancer were reviewed. Harrell's C statistic was used to evaluate the predictive capacity. The Cox proportional hazards model was used to construct a novel category. Results The LNR category had more predictive capacity than the pN category in whole groups of patients (Harrell's C index: 0.6194 vs 0.6113, p = 0.003). Subgroup analysis showed that the LNR category was not better than pN category in predictive capacity if the number of lymph nodes examined was more than 13. We also found that there was significant survival heterogeneity among different pN categories at the same LNR category (P

BackgroundHuman heparanase plays an important role in cancer development and single nucleotide polymorphisms (SNPs) in the heparanase gene (HPSE) have been shown to be correlated with gastric cancer. The present study examined the associations between individual SNPs or haplotypes in HPSE and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China.Methodology/principal findingsGenomic DNA was extracted from formalin-fixed, paraffin-embedded normal gastric tissue samples from 404 patients and from blood from 404 healthy controls. Six SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A chi-square (χ2) test and unconditional logistic regression were used to analyze the risk of gastric cancer; a Log-rank test and Cox proportional hazards model were used to produce survival analysis and a Kaplan-Meier method was used to map survival curves. The mean genotyping success rates were more than 99% in both groups. Haplotype CA in the block composed of rs11099592 and rs4693608 had a greater distribution in the group of Borrmann types 3 and 4 (P = 0.037), the group of a greater number of lymph node metastases (N3 vs N0 group, P = 0.046), and moreover was correlated to poor survival (CG vs CA: HR = 0.645, 95%CI: 0.421-0.989, P = 0.044). In addition, genotypes rs4693608 AA and rs4364254 TT were associated with poor survival (P = 0.030, HR = 1.527, 95%CI: 1.042-2.238 for rs4693608 AA; P = 0.013, HR = 1.546, 95%CI: 1.096-2.181 for rs4364254 TT). There were no correlations between individual SNPs or haplotypes and gastric cancer risk.Conclusions/significanceA functional haplotype in HPSE was found, which included the important SNP rs4693608. SNPs in HPSE play an important role in gastric cancer progression and survival, and perhaps may be a molecular marker for prognosis and treatment values.

Behavioural patterns in children of infertile couples may be influenced by both the underlying causes of infertility and stress in the couples. Treatment procedures, such as culture media and manipulation of gametes and embryos, may also result in developmental problems. We examined behavioural problems in children as a function of infertility and infertility treatment, using data from three population-based birth cohorts in Denmark (Aalborg-Odense Birth Cohort, Aarhus Birth Cohort and Danish National Birth Cohort). Information on time to pregnancy and infertility treatment was collected during pregnancy. Children aged between 7 and 21 years were assessed using the Strengths and Difficulties Questionnaire (SDQ). The SDQ was completed by mothers in all cohorts and, in addition, by teachers in the Aarhus cohort and by children themselves in the Aalborg-Odense cohort. Children born after a time to pregnancy of >12 months and no infertility treatment had a behavioural pattern similar to children of fertile parents. Teachers reported a higher total difficulties score for children born after infertility treatment, but no significant differences were seen on any subscales of the teachers' report, and neither the mothers nor the children reported any differences on the total difficulties score and the prosocial behaviour score. Our results are thus overall reassuring regarding behavioural problems in children born to infertile couples, regardless of infertility treatment.

Aims: To explore the relation between employment status, type of unemployment and pregnancy outcomes. Methods: A cohort study of 7,282 pregnancies of unemployed women and 56,014 pregnancies among women in paid jobs was performed within the Danish National Birth Cohort. Pregnancy outcomes were ascertained and information about lifestyle, occupational, medical, and obstetric factors was obtained. Logistic regression was used to calculate odds ratios (OR) for fetal loss, congenital anomalies, multiple births, sex ratio, preterm and very preterm birth and small for gestational age status, adjusting for lifestyle, medical and obstetric factors. Results: There were no differences in pregnancy outcomes between employed and unemployed women but women receiving unemployment benefit had an increased risk of preterm birth (adjusted OR (aOR) 1.16, 95% confidence interval (95% CI) 1.03—1.31) and having a small for gestational age child (aOR 1.08, 95% CI 1.00—1.19) compared with employed women. Women receiving sickness or maternity benefit had an increased risk of multiple birth (aOR 1.70, 95% CI 1.43—2.04), preterm (aOR 1.47, 95% CI 1.22—1.77) and very preterm birth (aOR 1.88, 95% CI 1.22—2.89), while those receiving an unreported type of support had an increased risk of preterm birth (aOR 1.40, 95% CI 1.02—1.93). Conclusions: We found no indication that being unemployed during pregnancy benefits or endangers the health of the child. Within the subgroups of unemployed women, we observed that women receiving unemployment and sickness or maternity benefits were at higher risk for some adverse pregnancy outcomes. © 2011, the Nordic Societies of Public Health. All rights reserved.

In mitosis, centrosomes nucleate microtubules that capture the sister kinetochores of each chromosome to facilitate chromosome congression. In contrast, during meiosis chromosome congression on the acentrosomal spindle is driven primarily by movement of chromosomes along laterally associated microtubule bundles. Previous studies have indicated that septin2 is required for chromosome congression and cytokinesis in mitosis, we therefore asked whether perturbation of septin2 would impair chromosome congression and cytokinesis in meiosis. We have investigated its expression, localization and function during mouse oocyte meiotic maturation. Septin2 was modified by SUMO-1 and its levels remained constant from GVBD to metaphase II stages. Septin2 was localized along the entire spindle at metaphase and at the midbody in cytokinesis. Disruption of septins function with an inhibitor and siRNA caused failure of the metaphase I /anaphase I transition and chromosome misalignment but inhibition of septins after the metaphase I stage did not affect cytokinesis. BubR1, a core component of the spindle checkpoint, was labeled on misaligned chromosomes and on chromosomes aligned at the metaphase plate in inhibitor-treated oocytes that were arrested in prometaphase I/metaphase I, suggesting activation of the spindle assembly checkpoint. Taken together, our results demonstrate that septin2 plays an important role in chromosome congression and meiotic cell cycle progression but not cytokinesis in mouse oocytes.

Udgivelsesdato: 2010-Feb-6 BACKGROUND It has previously been reported that children born after infertility treatment had a slight delay in early motor milestones. In this study, we examined whether children of infertile couples with or without infertility treatment had a higher risk of developmental coordination disorder (DCD). METHODS We used data on parental infertility and DCD among 23 167 singletons from the Danish National Birth Cohort (1996-2002). Data on time to pregnancy (TTP) and infertility treatment were collected early in pregnancy. Data on DCD in children were collected using the Developmental Coordination Disorder Questionnaire, filled in by the mothers during follow-up when the children were 7 years old. We used the recommended cut-off for the age group to classify children. RESULTS Compared with children born of fertile couples, children conceived after a waiting TTP of longer than 12 months had a slightly higher risk of DCD [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.03-1.77], but the estimated OR was not significant in children born after infertility treatment (OR 1.19, 95% CI 0.86-1.66). None of the individual treatment procedures was significantly associated with a higher risk of DCD. Children of parents who had not planned their pregnancy showed no elevated risk. CONCLUSIONS Our findings are overall reassuring, although it is possible that low fecundity may be associated with a modestly increased risk of DCD.