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In Tanzania, the estimated delivery date (EDD) is mainly determined by the last menstrual period (LMP), presumably leading to inaccurate estimates with a falsely high proportion of post-term and preterm deliveries. The study aimed to compare EDD determination by LMP and ultrasound in pregnant Tanzanian women and examine how the dating method affects the proportions born preterm, at term, and post-term and assess how maternal characteristics relate to wrongly EDD determination by LMP. 1123 women attending antenatal care in Moshi, Tanzania were included. Gestational age (GA) at birth was calculated according to LMP and ultrasound separately. The distribution of preterm (GA 294 days) births was examined separately for LMP and ultrasound. According to LMP, 17.0% of deliveries were preterm and 17.6% post-term. According to ultrasound, 7.7% of deliveries were preterm and 3.4% post-term. Unplanned pregnancy was associated with an increased odds ratio of 3.06 (95% CI: 1.91-4.91) for preterm delivery when LMP was used for EDD determination instead of ultrasound. Parity 3+ was associated with an increased odds ratio of 2.12 (95%CI: 1.16-3.89) for post-term delivery when EDD was assessed by LMP. LMP based EDD increased the preterm birth rate two times and the post-term birth rate five times compared to ultrasound-based EDD. Key words: Gestational age, pregnancy length, last menstrual period (LMP), dating methods, preterm, post term, Africa.

ObjectiveThe objective of the present study was to assess the prevalence and type-specific distribution of cervical high-risk (HR) human papillomavirus (HPV) among women with normal and abnormal cytology, and to describe risk factors for HR HPV among HIV-positive and HIV-negative women in Tanzania.MethodologyA cross-sectional study was conducted in existing cervical cancer screening clinics in Kilimanjaro and Dar es Salaam. Cervical specimens were obtained from women aged 25–60 years. Samples were shipped to Denmark for cytological examination, and to Germany for HR HPV testing (using Hybrid Capture 2) and genotyping (using LiPaExtra). Risk factors associated with HPV were assessed by multivariable logistic regression analysis.ResultAltogether, 4080 women were recruited with 3416 women contributing data for the present paper, including 609 HIV-positive women and 2807 HIV-negative women. The overall HR HPV prevalence was 18.9%, whereas the HR HPV prevalence in women with high-grade squamous intraepithelial lesions (HSILs) was 92.7%. Among HPV-positive women with HSIL, HPV16 (32.5%) and HPV58 (19.3%) were the the most common types followed by HPV18 (16.7%) and HPV52 (16.7%). Factors associated with HR HPV included younger age, increasing number of partners and early age at first intercourse. Similar risk factors were found among HIV-positive and HIV-negative women. In addition, among HIV-positive women, those with CD4 counts 3 had an increased risk of HR HPV (OR 2.2; 95% CI 1.2 to 4.8) compared with individuals with CD4 count ≥500 cells/mm3.ConclusionGiven the HPV distribution among Tanzanian women, the current HPV vaccination in Tanzania using quadrivalent vaccine may be considered replaced by the nonavalent vaccine in the future. In addition, appropriate antiretroviral treatment management including monitoring of viremia may decrease the burden of HR HPV in HIV-positive women.

Purpose: We estimated the association between maternal antidepressant (AD) use in early pregnancy and risk of congenital heart defects. Methods: We applied a case-time-control design with the aim of controlling for confounding from time-invariant factors and compared the results of the design to results from a cohort design in a population of 792 685 singletons born alive in Denmark during 1995-2008. In the case-time-control design, we identified children diagnosed with a congenital heart defect in the first 5 years of life (cases) and compared maternal AD use in the risk period (the first 3 months of pregnancy) and the reference period (gestational months 5-7). A nondiseased control group was included to adjust for time trends of exposure. In the cohort design, we identified children whose mothers redeemed at least one AD prescription in the first 3 months of pregnancy (the exposed) and two other groups including the unexposed children with maternal AD prescriptions in the 12 months before pregnancy. We applied conditional logistic regression and logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results: The case-time-control OR for any congenital heart defect was 1.03 (95% CI, 0.61-1.73), which was similar to the OR (1.09, 95% CI, 0.88-1.35) from the cohort design when we compared the exposed children with the unexposed children with maternal AD use before pregnancy. Conclusions: The case-time-control design provided results similar to the cohort design when the cohort design had a better confounder control strategy. We discussed the strengths and drawbacks of case-time-control design.

Sperm DNA fragmentation index (DFI) can be analyzed by a flow cytometric assay after treatment with acid and acridine orange. In this prospective, cohort study, the value of DFI was determined in a semen analysis collected before fertility treatment (baselineDFI) in 146 couples and during 1–3 intrauterine inseminations (IUI) in 211 couples (511 cycles). The pregnancy rate (PR)/cycle was 9.9% if baselineDFI was &gt, 10 and 21.7% if baselineDFI was ≤10, (p &lt, 0.005). The live birth rate (LBR)/cycle was 5% if baselineDFI was &gt, 10 and 14.2% if baselineDFI was ≤10 (p &lt, 0.005). PR/patient was 23.1% if baselineDFI was &gt, 10 and 45.5% if baselineDFI was ≤10 (p &lt, 0.005). LBR/patient was 12.4% if baselineDFI was &gt, 10 and 34% if baselineDFI was ≤10 (p &lt, 0.005). When isolating non-stimulated IUI cycles and couples with female age &lt, 35, a significant difference in PR and LBR between couples with high DFI and low DFI was seen. Results suggest that DFI &gt, 10 could advice against timed coitus and non-stimulated IUI cycles. Analysis for DFI performed before treatment provides information about PR and LBR after IUI.

INTRODUCTION: Human papillomavirus (HPV) is the causative agent of precancerous lesions and cervical cancer, cervical cancer being the leading cause of deaths in Tanzanian women. Early detection and treatment of precancerous lesions are important in the prevention of cervical cancer cases.MATERIAL AND METHODS: We conducted a cross-sectional study among 3390 Tanzanian women aged 25-60 years. Information on lifestyle habits was collected, and women underwent gynecological examination with collection of cervical cells for conventional cytological and HPV testing. Blood samples were tested for HIV. The association between cervical high-grade cytology (HGC) and potential risk factors was examined using multivariable logistic regression adjusting for age and high-risk HPV (HR-HPV).RESULTS: The prevalence of HGC was 3.6% and of low-grade cytology was 8.3%. In women who were both HR-HPV-positive and HIV-positive, the prevalence of HGC was 28.3%. It increased by age and was 47% among women aged 50-60 years. Women, who had their sexual debut at age 9-15 years and 16-18 years, respectively, had 2.5 and 2.4 times increased odds of HGC compared with women whose sexual debut was at age 21 years and older. HIV-positive women had increased odds of HGC in comparison with HIV-negative women after adjustment for age (odds ratio [OR] 2.95, 95% CI 1.92-4.54). HR-HPV-positive women had nearly 100-fold increased odds of HGC compared with HR-HPV-negative women (OR 96.6, 95% CI 48.0-194), and this estimate was higher among HIV-positive women (OR 152.2, 95% CI 36.1-642.0).CONCLUSIONS: Increasing age, early age at first intercourse, HR-HPV, and HIV infections were associated with a substantially increased risk of HGC.

PurposeCervical cancer is a major cause of death among women in Eastern Africa, and the distribution of human papillomavirus (HPV) according to HIV status is inadequately characterised in this region. In order to guide future cervical cancer preventive strategies that involve HPV testing, the Comprehensive Cervical Cancer Prevention in Tanzania (CONCEPT) study was established in 2015. The CONCEPT cohort aims to investigate the natural history of HPV and determine acquisition and persistence patterns of high-risk (HR) HPV among HIV-positive and HIV-negative women. Further, the influence of lifestyle and sexual/reproductive factors will be investigated. The main objective of this article is to describe how the CONCEPT cohort was established.ParticipantsWomen aged 25–60 years were enrolled from cervical cancer screening clinics in Dar-es-Salaam and Moshi, Tanzania. Data were collected at baseline, at 14 months (first follow-up) and at 28 months (second follow-up). Biological samples included two cervical swabs for careHPV DNA testing, cytology, Hybrid Capture 2, genotyping and blood samples for HIV. Visual inspection with acetic acid was performed, and sociodemographic, lifestyle and sexual/reproductive characteristics were collected through a standardised questionnaire.Findings to date4043 women were included in the cohort from August 2015 to May 2017. At baseline, 696 (17.1%) women were HR HPV positive, and among these, 31.6% were HIV positive; 139 women (3.4%) had high-grade squamous intraepithelial lesions. 3074 women (81%) attended the first follow-up. The majority attended after receiving a phone call reminder (35%) or from home via self-samples (41%). At first follow-up, 438 (14.4%) were HR HPV positive and 30.4% of these were HIV positive.Future plansA second follow-up is underway (17 December 2018–October 2020). We plan to integrate our data with a previous cross-sectional HPV study from Tanzania to increase the power of our findings. Researchers interested in collaborating are welcomed, either by extracting data or jointly requesting further investigation from the cohort.

BACKGROUND: Cortisol has been used to capture psychophysiological stress during childbirth and postpartum wellbeing. We explored the effect of a brief antenatal training course in self-hypnosis on salivary cortisol during childbirth and 6 weeks postpartum.METHODS: In a randomized, controlled trial conducted at Aarhus University Hospital Skejby Denmark during the period January 2010 until October 2010, a total of 349 healthy nulliparous women were included. They were randomly allocated to a hypnosis group (n = 136) receiving three one-hour lessons in self-hypnosis with additional audio-recordings, a relaxation group (n = 134) receiving three one-hour lessons in various relaxation methods with audio-recordings for additional training, and a usual care group (n = 79) receiving ordinary antenatal care only. Salivary cortisol samples were collected during childbirth (at the beginning of the pushing state, 30 minutes, and 2 hours after childbirth), and 6 weeks postpartum (at wake up, 30 minutes after wake up, and evening). Cortisol concentrations were compared using a linear mixed-effects model. Correlations between cortisol concentrations and length of birth, experienced pain and calmness during birth were examined by a Spearman rank correlation test.FINDINGS: During childbirth, week correlations were found between cortisol concentrations 30 minutes after childbirth and length of birth. In the beginning of the pushing state and 2 hours after childbirth, we found a tendency towards higher cortisol concentrations in the hypnosis group compared to the other two groups (hypnosis versus relaxation p = 0.02 and 0.03, hypnosis versus usual care p = 0.08 and 0.05). No differences were observed in cortisol concentrations between the groups 30 minutes after childbirth (hypnosis versus relaxation p = 0.08, hypnosis versus usual care 0.10) or 6 weeks postpartum (hypnosis versus relaxation: p = 0.85, 0.51, and 0.68, hypnosis versus usual care: p = 0.85, 0.93, and 0.96).CONCLUSION: Antenatal hypnosis training may increase the release of cortisol during childbirth with no long-term consequences. Further research is needed to help interpret these findings.

AimsThis study aimed to examine the feasibility of a web-based questionnaire when collecting information on alcohol consumption in pregnancy to identify women with risk drinking behaviour, and to describe factors associated with risk drinking behaviour, and the use of specialized care for prenatal risk drinking.MethodsIn 2413 women referred to antenatal care at Odense University Hospital, Denmark, April–October 2018, self-reported alcohol intake was retrieved from a web-based questionnaire. Replies were screened for risk drinking behaviour: current intake of ≥7 drinks/week, ≥3 binge drinking episodes (intake of ≥5 drinks on a single occasion) in pregnancy, binge drinking after recognition of pregnancy and/or a TWEAK-score ≥ 2 points. Women with risk drinking behaviour were called to clarify the need for specialized care. A summary of the interview was obtained from the medical records.ResultsOverall, 2168 (90%) completed the questionnaire. Of 2097 women providing information on alcohol intake, 77 (4%) had risk drinking behaviour. Risk drinking was associated with higher alcohol intake prior to pregnancy, spontaneous conception, younger age, nulliparity and higher level of physical activity in pregnancy. Amongst 47 women with risk drinking behaviour reached by phone, five (11%, 95% CI 4–23%) accepted examinations of the child by paediatrician and child psychologist, and ConclusionsA web-based questionnaire was feasible when collecting information on alcohol consumption in pregnancy to identify risk drinking behaviour. Women with risk drinking behaviour had a low acceptance of referral to specialized care.

BACKGROUND: Limited research has addressed whether maternal alcohol intake in early pregnancy increases the risk of spontaneous preterm birth. In the current study, we examined how alcohol binge drinking and weekly alcohol intake in early pregnancy were associated with spontaneous preterm birth in a contemporary cohort of Danish women.METHODS: We included 15,776 pregnancies of 14,894 women referred to antenatal care at Copenhagen University Hospital, Denmark, between 2012 and 2016. Self-reported alcohol intake in early pregnancy was obtained from a Web-based questionnaire completed prior to the women's first visit at the department. Information on spontaneous preterm birth was extracted from the Danish Medical Birth Register. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of spontaneous preterm birth according to self-reported alcohol binge drinking and weekly intake of alcohol in early pregnancy were derived from Cox regression.RESULTS: Women reporting 1, 2, and ≥ 3 binge drinking episodes had an aHR for spontaneous preterm birth of 0.88 (95% CI 0.68 to 1.14), 1.34 (95% CI 0.98 to 1.82), and 0.93 (95% CI 0.62 to 1.41), respectively, compared to women with no binge drinking episodes. Women who reported an intake of ≥ 1 drink per week on average had an aHR for spontaneous preterm birth of 1.09 (95% CI 0.63 to 1.89) compared to abstainers. When restricting to nulliparous women or cohabiting women with ≥ 3 years of higher education, this estimate was 1.28 (95% CI 0.69 to 2.40) and 1.20 (95% CI 0.67 to 2.15), respectively.CONCLUSION: We found no evidence that maternal alcohol intake in early pregnancy was associated with a higher risk of spontaneous preterm birth, neither for alcohol binge drinking nor for a low average weekly intake of alcohol.

Objective To evaluate the reduction of surgical site infections by prophylactic incisional negative pressure wound therapy compared with standard postoperative dressings in obese women giving birth by caesarean section. Design Multicentre randomised controlled trial. Setting Five hospitals in Denmark. Population Obese women (prepregnancy body mass index (BMI) ≥30 kg/m2) undergoing elective or emergency caesarean section. Method The participants were randomly assigned to incisional negative pressure wound therapy or a standard dressing after caesarean section and analysed by intention‐to‐treat. Blinding was not possible due to the nature of the intervention. Main outcome measures The primary outcome was surgical site infection requiring antibiotic treatment within the first 30 days after surgery. Secondary outcomes included wound exudate, dehiscence and health‐related quality of life. Results Incisional negative pressure wound therapy was applied to 432 women and 444 women had a standard dressing. Demographics were similar between groups. Surgical site infection occurred in 20 (4.6%) women treated with incisional negative pressure wound therapy and in 41 (9.2%) women treated with a standard dressing (relative risk 0.50, 95% CI 0.30–0.84; number needed to treat 22; P = 0.007). The effect remained statistically significant when adjusted for BMI and other potential risk factors. Incisional negative pressure wound therapy significantly reduced wound exudate whereas no difference was found for dehiscence and quality of life between the two groups. Conclusion Prophylactic use of incisional negative pressure wound therapy reduced the risk of surgical site infection in obese women giving birth by caesarean section. Tweetable abstract RCT: prophylactic incisional NPWT versus standard dressings postcaesarean in 876 women significantly reduces the risk of SSI., Tweetable abstract RCT: prophylactic incisional NPWT versus standard dressings postcaesarean in 876 women significantly reduces the risk of SSI.

BACKGROUND: There is a complex interaction between female and male sex hormones and the risk of epilepsy. Whether prenatal exposure to higher levels of sex hormones affects the development of epilepsy in childhood or later in life is not well known. The sex hormone environment of fetuses may be affected by the sex of the co-twin. We estimated the risk of epilepsy for twins with an opposite-sex (OS) co-twin compared with twins with a same-sex (SS) co-twin.METHODS: From the Danish Twin Registry, we identified OS female twins (n = 11,078), SS female twins (n = 19,186), OS male twins (n = 11,080), and SS male twins (n = 20,207) born between 1977 and 2009. The SS twins include monozygotic twins, dizygotic twins, and twins with unknown zygosity. These children were followed up from day 29 after birth until diagnosis of epilepsy, death, emigration, or end of follow-up (31 December 2011) whichever came first. Information on diagnosis of epilepsy was obtained from the Danish National Patient Registry. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for epilepsy in the OS twins using a Cox proportional hazards regression model compared with the SS twins. To account for the correlation of twins from the same mother when estimating standard errors, we used the cluster option in Stata.RESULTS: We identified 152 OS female twins, 282 SS female twins, 162 OS male twins, and 335 SS male twins diagnosed with epilepsy corresponding to an incidence rate of 9.9 and 9.7 per 10,000 person years for the OS and SS female twins, and 10.6 and 10.9 per 10,000 person years for the OS and SS male twins, respectively. We found a similar risk of epilepsy among the OS and SS female twins [HR = 1.01; 95% CI 0.83-1.24] as well as among the OS and SS male twins [HR = 0.94; 95% CI 0.78-1.14] CONCLUSIONS: In this population-based study of Danish twins, we did not find difference in the risk of epilepsy between twins with an OS co-twin and twins with a SS co-twin. This applied to both female and male twins. The study therefore does not support the hypothesis that subtle hormone difference in fetal life due to co-twin may play a role in the development of epilepsy later in life.

Objective We have previously reported increased long-term morbidity in children of parents with rheumatoid arthritis (RA). Here we assess child mortality and case fatality in the same cohort. Methods All singletons born in Denmark from 1977 to 2008 were identified through linkage of Danish national registries. Cox proportional hazards models were used to calculate hazard ratios (HRs) of death from all causes among children exposed to parental RA, compared to unexposed children. Risk of death after infection or respiratory diseases was also assessed for children below the age of 5 years. Results This study followed 1,917,723 newborns for an average of 16 years. Of these, 13,556 were exposed to maternal RA and 6,330 to paternal RA. Overall mortality rates in children exposed to maternal or paternal RA did not differ from those in unexposed children (HR 0.98 [95% confidence interval (95% CI) 0.84–1.15] and 1.08 [95% CI 0.86–1.36], respectively), nor did the risk of death below the ages of 5 years, 3 years, or 1 year. In the group of children below the age of 5 years, 6,106 children of parents with RA were diagnosed with respiratory diseases and 3,320 with infectious diseases. The case fatality rate in children with these diseases was not significantly higher than in unexposed children (HR 1.11 [95% CI 0.74–1.66] and 0.84 [95% CI 0.52–1.35], respectively). Conclusion Children of parents with RA had similar mortality rates as other children, as well as after diagnoses of respiratory or infectious diseases.

Introduction/Background The oncological safety of minimally invasive techniques versus open access surgery in gynecological cancer is currently debated. Substantial changes in the surgical management of endometrial cancer necessitates evaluation to ensure survival is not compromised and the risk of severe complications is not increased. Methodology A nationwide prospective cohort of all women with early-stage endometrial cancer who underwent surgery between January 1, 2005 and June 30, 2015 were retrieved from the Danish Gynecological Cancer Database. Data were linked with nationwide registers on socioeconomic status, deaths, hospital diagnoses and treatment using each woman´s civil registration number. The cohort was divided according to the time they underwent surgery; group 1 underwent surgery before the introduction of robotic minimally invasive surgery (RMIS) in their respective region, and group 2 underwent surgery after. Women in group 2 were subdivided in total abdominal hysterectomy (TAH), laparoscopic minimally invasive surgery (LMIS), and RMIS. Severe complications encompassed death within 30 days, intraoperative complications, and postoperative complications diagnosed within 90 days. Five-year overall survival was compared by multivariate Cox proportional hazards models stratified by histopathological risk. Odds of severe complications were compared by multivariate logistic regression. Results A total of 5654 women were included. Women in group 1 (n=3091) had significantly higher mortality and odds of severe complications compared with women in group 2 (n=2563; hazard ratio [HR], 1.22; 95%confidence interval [CI], 1.05–1.42 and odds-ratio [OR], 1.39; 95% CI, 1.11–1.74, respectively). In group 2, TAH was associated with higher mortality and increased odds of complications compared with RMIS in adjusted analyses (HR, 1.70; 95%CI 1.31–2.19 and OR, 3.87; 95% CI, 2.52–5.93, respectively). Conclusion The national introduction of RMIS transitioned the surgical approach for early-stage endometrial cancer towards minimally invasive surgery. This change was associated with improved survival and significantly reduced odds of severe complications. Disclosure Nothing to disclose.

Introduction/Background Knowledge on the individual recovery after robotic surgery for endometrial cancer (EC) is sparse but important for optimisation of pre-operative information and for post-operative supportive care. Generic questionnaires measuring quality-of-life are challenged by the diversity of these women, ranging from women who are part of the active workforce in their thirties to retired women in their nineties. The European Organisation of Research and Treatment of Cancer Computer Adaptive Test Core questionnaire (EORTC CAT Core) provides individualised measurements. Methodology 94 consecutive women who underwent robotic minimally invasive surgery for early-stage EC at Odense University Hospital in Denmark were included. The EORTC CAT Core was distributed pre-operatively and every week during the first post-operative month. Repeated measures models were fitted for four domains; physical functioning, role function, fatigue, and pain. Each model was tested for impact of age, ASA score, minor/major surgery, and the individual baseline scores (poorest, intermediate, best). A hypothesis of individual complete recovery of physical health to baseline levels within three post-surgical weeks was evaluated. Results Women with the lowest physical and role functions, and the highest fatigue and pain levels at baseline recovered within three weeks. Women with the highest physical health before surgery did not reach their individual baseline within the first post-operative month but had the most favorable domain-scores three weeks post-operatively. Conclusion The individual woman´s baseline score of physical health is predictive for her postoperative recovery following robotic minimally invasive surgery for early-stage endometrial cancer. Recovery to the individual offset is prolonged in women with the best physical health. The EORTC CAT Core may be a valuable tool for individualised pre-operative information and supportive care during surveillance. Disclosure Nothing to disclose.

OBJECTIVE: To examine the test performance of careHPV, Hybrid Capture2 (HC2) and visual inspection with acetic acid (VIA) for detection of cytologically diagnosed high-grade cervical lesions or cancer (HSIL+).DESIGN: Cross-sectional study.SETTING: Ocean Road Cancer Institute (ORCI) and Kilimanjaro Christian Medical Center (KCMC), Tanzania.POPULATION: Women attending routine cervical cancer screening.METHOD: We enrolled 4080 women (25-60 years) in the study. The women were interviewed on lifestyle habits, and tested for HIV. A cervical specimen for careHPV testing (performed at ORCI and KCMC), and a liquid-based cytology sample for HPV DNA detection using HC2 (performed at Tuebingen University Hospital, Germany) and for cytology assessment (performed at Vejle Hospital, Denmark) were obtained at a gynecological examination. Subsequently, VIA was performed. With cytology as gold standard, the sensitivity and specificity of careHPV, HC2, and VIA for detection of HSIL+ were calculated.RESULTS: Altogether, 23.6% had a positive careHPV test, 19.1% had positive HC2 test, and 6.3% had a positive VIA test. The sensitivity/specificity was 88.9%/78.9% for careHPV and 91.1%/83.7%, for HC2. VIA showed a low sensitivity of 31.1% but a high specificity (94.6%) for detection of HSIL+. The sensitivity of careHPV, HC2 and VIA was higher among younger women, and among HIV positive women. VIA triage of careHPV positive women improved specificity, but sensitivity dropped to 27%.CONCLUSION: Our results confirm the low sensitivity of VIA for detection of HSIL+ and further document that careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions. A suitable triage test has to be identified.

ObjectiveThe objective of this study was to examine whether exposure to Intimate Partner Violence (IPV) is associated with premature termination of Exclusive Breastfeeding (EB). Per WHO recommendations, this was defined as ceasing breastfeeding or supplementing with other foods or liquids before the child was 6 months old.MethodIt is a prospective cohort study set in Moshi, Tanzania consisting of 1128 pregnant women with live singleton births. Women were enrolled during pregnancy and followed up with interviews during pregnancy, after birth and 2-3 years postpartum, using structured questionnaires. Emotional, physical and sexual IPV exerted by the current partner was assessed at 34 weeks gestational age with WHO questionnaires. Months of EB was assessed 2-3 years postpartum. Premature termination of EB was defined as less than 6 months of EB. Analyses were made using a logistic regression model adjusted for maternal age, education, HIV-status, alcohol use during pregnancy and parity. Confounding variables were determined using a theoretical framework approach, i.e. a Directed Acyclic Graph model to minimize bias.ResultsWomen who were exposed to IPV had more than 50% higher odds of terminating EB before the child was 6 months old compared to women who were not exposed (aOR = 1.62, 95%CI: 1.27-2.06). Women exposed to all three types of IPV had twice the odds of early termination of EB (aOR = 1.95, 1.12; 3.37). Furthermore, the odds were tripled if exposure happened specifically during the index pregnancy (aOR = 2.93 95%CI: 1.3; 6.6). Stratified analyses showed the most severely affected groups were the mothers older than 30 and those who gave birth to girls.ConclusionsThe results indicated that exposure to IPV is associated with increased risk of premature termination of EB. The odds increase with multiple types of the IPV, especially when exposed during the index pregnancy.

BACKGROUND: Little is known about maternal alcohol intake in early pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in children beyond 5 years of age. We examined the association between alcohol binge drinking and weekly alcohol intake in early pregnancy and the risk of ADHD in children followed from birth to 19 years of age.METHODS: We included 48,072 children born between 1998 and 2012, whose mothers participated in the Aarhus Birth Cohort. Maternal alcohol intake was obtained from a self-administered questionnaire completed in early pregnancy. ADHD diagnoses were retrieved from the Danish Psychiatric Central Research Register and the Danish National Patient Register. Crude hazard ratio and adjusted hazard ratio (aHR) of ADHD according to alcohol binge drinking or weekly intake of alcohol were calculated using the Cox regression.RESULTS: Compared to children of women with no binge drinking episodes, we observed an aHR for ADHD of 0.91 (95% CI 0.76 to 1.08), 0.73 (95% CI 0.56 to 0.96), and 0.77 (95% CI 0.57 to 1.06) among children of women reporting 1, 2, and 3 or more binge drinking episodes, respectively. Among children of women drinking CONCLUSION: We found no evidence that binge drinking or low alcohol intake in early pregnancy was associated with the risk of ADHD in children.

Objective To assess early recovery of physical health after robotic minimally invasive surgery (RMIS) for early-stage endometrial cancer using the European Organisation of Research and Treatment of Cancer Computer Adaptive Test Core questionnaire (EORTC CAT Core). The EORTC CAT Core provides individualised measurements while maintaining comparability. A hypothesis of individual complete recovery to baseline within three post-surgical weeks was evaluated. Methods Ninety-four women who underwent RMIS for early-stage endometrial cancer were included consecutively. The EORTC CAT Core was distributed before surgery and prospectively every week during the first post-operative month. Repeated measures models were fitted for each of the four domains (physical functioning, role function, fatigue, and pain) and tested for impact of age, ASA score, minor/major surgery, and the individual baseline scores (poorest, intermediate, best). Results Women with the lowest physical functioning, lowest role function, highest fatigue level, and highest pain level at baseline all recovered within three weeks. Women with the highest physical functioning, highest role function, lowest level of fatigue, and lowest level of pain at baseline did not reach their individual baselines within the first post-operative month but had the most favourable domain-scores three weeks post-operatively. Conclusion The individual woman's physical health baseline score is predictive for her postoperative recovery following RMIS for early-stage endometrial cancer. Women with the best physical health had the best postoperative functions and lowest level of symptoms; however their recovery to baseline was prolonged. Computer adaptive testing may be a valuable tool for individualised pre-operative information and supportive care during surveillance.

Objective: To evaluate the cost-effectiveness of incisional negative pressure wound therapy (iNPWT) in preventing surgical site infection in obese women after caesarean section. Design: A cost-effectiveness analysis conducted alongside a clinical trial. Setting: Five obstetric departments in Denmark. Population: Women with a pregestational body mass index (BMI) ≥30 kg/m 2 . Method: We used data from a randomised controlled trial of 876 obese women who underwent elective or emergency caesarean section and were subsequently treated with iNPWT (n = 432) or a standard dressing (n = 444). Costs were estimated using data from four Danish National Databases and analysed from a healthcare perspective with a time horizon of 3 months after birth. Main outcome measures: Cost-effectiveness based on incremental cost per surgical site infection avoided and per quality-adjusted life-year (QALY) gained. Results: The total healthcare costs per woman were €5793.60 for iNPWT and €5840.89 for standard dressings. Incisional NPWT was the dominant strategy because it was both less expensive and more effective; however, no statistically significant difference was found for costs or QALYs. At a willingness-to-pay threshold of €30,000, the probability of the intervention being cost-effective was 92.8%. A subgroup analysis stratifying by BMI shows that the cost saving of the intervention was mainly driven by the benefit to women with a pre-pregnancy BMI ≥35 kg/m 2 . Conclusion: Incisional NPWT appears to be cost saving compared with standard dressings but this finding is not statistically significant. The cost savings were primarily found in women with a pre-pregnancy BMI ≥35 kg/m 2 . Tweetable abstract: Prophylactic incisional NPWT reduces the risk of SSI after caesarean section and is probably dominant compared with standard dressings #healtheconomics.

PurposeThe purpose of the study was to evaluate the association between a nationwide introduction of robotic minimally invasive surgery (RMIS) and survival in women with early-stage endometrial cancer.Materials and methodsProspective data on consecutive women with early-stage endometrial cancer who underwent surgery during January 2005 to June 2015 in Denmark were identified in the nationwide Danish Gynaecological Cancer Database. Data were linked with national registries regarding comorbidity, education, income and death. The cohort was divided according to the time they underwent surgery: Group 1 before RMIS introduction in their respective region and Group 2 after RMIS introduction. Five-year overall survival was compared by multivariate Cox proportional hazards models stratified by histopathological risk between Groups 1 and 2 and between surgical modalities within Group 2: total abdominal hysterectomy (TAH), laparoscopic minimally invasive surgery (LMIS) and RMIS.ResultsWomen in Group 1 (N = 3091) had significantly lower overall survival compared with those in Group 2 (N = 2563; hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.05–1.42). Age, smoking, socioeconomic status, American Society of Anaesthesiologists (ASA) score, comorbidity and histopathological risk influenced the overall survival. Following RMIS adoption, TAH was associated with higher mortality compared with LMIS and RMIS (HR, 1.42; 95% CI 1.02–1.97 and HR, 1.70; 95% CI 1.31–2.19 for LMIS and RMIS, respectively). There was no significant survival difference between RMIS and LMIS (HR, 1.19; 95% CI 0.85–1.68).ConclusionThe national introduction of robotic surgery for early-stage endometrial cancer was associated with improved survival irrespective of age, body mass index, ASA score, comorbidity, smoking, socioeconomic status and histopathological risk.

Importance: Minimally invasive laparoscopic surgery (MILS) for endometrial cancer reduces surgical morbidity compared with a total abdominal hysterectomy. However, only a minority of women with early-stage endometrial cancer undergo MILS. Objective: To evaluate the association between the Danish nationwide introduction of minimally invasive robotic surgery (MIRS) and severe complications in patients with early-stage endometrial cancer. Design, Setting, and Participants: In this nationwide prospective cohort study of 5654 women with early-stage endometrial cancer who had undergone surgery during the period from January 1, 2005, to June 30, 2015, data from the Danish Gynecological Cancer Database were linked with national registers on socioeconomic status, deaths, hospital diagnoses, and hospital treatments. The women were divided into 2 groups; group 1 underwent surgery before the introduction of MIRS in their region, and group 2 underwent surgery after the introduction of MIRS. Women with an unknown disease stage, an unknown association with MIRS implementation, unknown histologic findings, sarcoma, or synchronous cancer were excluded, as were women who underwent vaginal or an unknown surgical type of hysterectomy. Statistical analysis was conducted from February 2, 2017, to May 4, 2018. Exposure: Minimally invasive robotic surgery, MILS, or total abdominal hysterectomy. Main Outcomes and Measures: Severe complications were dichotomized and encompassed death within 30 days after surgery and intraoperative and postoperative complications diagnosed within 90 days after surgery. Results: A total of 3091 women (mean [SD] age, 67 [10] years) were allocated to group 1, and a total of 2563 women (mean [SD] age, 68 [10] years) were allocated to group 2. In multivariate logistic regression analyses, the odds of severe complications were significantly higher in group 1 than in group 2 (odds ratio [OR], 1.39; 95% CI, 1.11-1.74). The proportion of women undergoing MILS was 14.1% (n = 436) in group 1 and 22.2% in group 2 (n = 569). The proportion of women undergoing MIRS in group 2 was 50.0% (n = 1282). In group 2, multivariate logistic regression analyses demonstrated that a total abdominal hysterectomy was associated with increased odds of severe complications compared with MILS (OR, 2.58; 95% CI, 1.80-3.70) and MIRS (OR, 3.87; 95% CI, 2.52-5.93). No difference was found for MILS compared with MIRS (OR, 1.50; 95% CI, 0.99-2.27). Conclusions and Relevance: The national introduction of MIRS changed the surgical approach for early-stage endometrial cancer from open surgery to minimally invasive surgery. This change in surgical approach was associated with a significantly reduced risk of severe complications.

Maternal obesity is associated with impaired fetal and neonatal survival, but underlying mechanisms are poorly understood. We examined how prepregnancy BMI and early gestational weight gain (GWG) were associated with cause-specific stillbirth and neonatal death. In 85,822 pregnancies in the Danish National Birth Cohort (1996–2002), we identified causes of death from medical records for 272 late stillbirths and 228 neonatal deaths. Prepregnancy BMI and early GWG derived from an early pregnancy interview and Cox regression were used to estimate associations with stillbirth or neonatal death as a combined outcome and nine specific cause-of-death categories. Compared to women with normal weight, risk of stillbirth or neonatal death was increased by 66% with overweight and 78% with obesity. Especially deaths due to placental dysfunction, umbilical cord complications, intrapartum events, and infections were increased in women with obesity. More stillbirths and neonatal deaths were observed in women with BMI &lt, 25 and low GWG. Additionally, unexplained intrauterine death was increased with low GWG, while more early stillbirths were seen with both low and high GWG. In conclusion, causes of death that relate to vascular and metabolic disturbances were increased in women with obesity. Low early GWG in women of normal weight deserves more clinical attention.

OBJECTIVE: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy.METHODS: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days-4 years), late childhood (5-15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010).RESULTS: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13-1.60] and 1.26 [95% CI 1.13-1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92-1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81-1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26-2.86] vs HR 1.26 [95% CI 1.03-1.52], respectively [p = 0.16]).CONCLUSIONS: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role. OBJECTIVE: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy.METHODS: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days-4 years), late childhood (5-15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010).RESULTS: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13-1.60] and 1.26 [95% CI 1.13-1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92-1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81-1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26-2.86] vs HR 1.26 [95% CI 1.03-1.52], respectively [p = 0.16]).CONCLUSIONS: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role.

The aim of this paper was to estimate the effect of maternal and paternal smoking on foetal death (miscarriage and stillbirth) and to estimate potential interactions with physical exercise and pre-pregnancy body mass index. We selected 87,930 pregnancies from the population-based Danish National Birth Cohort. Information about lifestyle, occupational, medical and obstetric factors was obtained from a telephone interview and data on pregnancy outcomes came from the Danish population based registries. Cox regression was used to estimate the hazard ratios (adjusted for potential confounders) for predominantly late foetal death (miscarriage and stillbirth). An interaction contrast ratio was used to assess potential effect measure modification of smoking by physical exercise and body mass index. The adjusted hazard ratio of foetal death was 1.22 (95 % CI 1.02-1.46) for couples where both parents smoked compared to non-smoking parents (miscarriage: 1.18, 95 % CI 0.96-1.44; stillbirth: 1.32, 95 % CI 0.93-1.89). On the additive scale, we detected a small positive interaction for stillbirth between smoking and body mass index (overweight women). In conclusion, smoking during pregnancy was associated with a slightly higher hazard ratio for foetal death if both parents smoked. This study suggests that smoking may increase the negative effect of a high BMI on foetal death, but results were not statistically significant for the interaction between smoking and physical exercise.

Socioeconomic factors correlate with mental health and affect individual life chances. However, the influence of specific and cumulative social disadvantages on children's mental health problems has received little attention. Previous studies have primarily used global measures of mental health problems or aggregated indicators of socioeconomic status. We contribute to this research by including multiple indicators of parental social disadvantage to study independent and accumulative effects. The study focuses on the Attention Deficit/Hyperactivity Disorder (ADHD), which is known to affect children's educational and socioeconomic trajectories. ADHD is one of the most common child mental health problems and although heredity has been estimated to 76 percent, research suggests that a large social component remains in the prevalence. We exploit comprehensive high-quality registry data for the entire population of children born 1990–1999 in Denmark (N = 632,725). The ADHD prevalence is 3.68 percent. Estimates from linear probability models show that parental unemployment, relative income poverty, and low educational attainment increase children's risk of ADHD with 2.1 (95% CI 1.8–2.3), 2.3 (95% CI 2.1–2.5), and 3.5 percentage points (95% CI 3.3–3.7), respectively. Children who live with all three disadvantages face an increased risk of 4.9 percentage points., Highlights • Socioeconomic disadvantage correlates with the risk of ADHD. • Yet, the specific and cumulative influence of social disadvantages has received little attention. • Parental unemployment, relative income poverty and low educational attainment increases children's risk of ADHD. • Accumulated social disadvantages add substantially to the risk of ADHD.

An increased amount of DNA fragmentation in the spermatozoa (SDF) is linked to male infertility. The Sperm Chromatin Structure Assay (SCSA) is widely used for analysis of SDF. However, the current software (SCSASoft®) linked to this assay is licensed and often located within larger diagnostic centers. In this study, we present a protocol for using other types of software than SCSASoft® to determine the SDF index (DFI) with clinical relevance. This protocol is engineered after collecting and analyzing 254 samples from fertility patients and sperm donors over a 15-month period. DFI is analyzed using a strict protocol where the spermatozoa are treated with a strong acid (pH 1.2) followed by acridine orange. DFI is determined by a standard flow cytometric software, FACSDiva 6.1.3. Analysis of the outcome of the fertility treatment is included for 137 patients receiving either intrauterine inseminations (IUI) or timed coitus (TC). The results show that the chance of pregnancy declines as DFI increases. We also found that the male DFI affects the chance of pregnancy independent of the female age. We have shown that a standard flow cytometric software can be used when determining a clinical relevant DFI. These findings are a significant step toward implementing the analysis as a part of the routine, in-house diagnosing of the male fertility patient and subsequently optimizing the treatment course of the couple with reduced human and financial costs.

Objectives: The main objective of this review was to evaluate the methodological design in studies reporting resource use and costs related to robotic surgery in gynecology. Methods: Systematic searches were performed in the databases PubMed, Embase, Scopus, and The Centre for Reviews and Dissemination database for relevant studies before May 2016. The quality of the methodological design was assessed with items regarding methodology from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). The systematic review was reported according to the PRISMA guidelines. Results: Thirty-two relevant studies were included. None of the reviewed studied fully complied with the CHEERS methodological checklist. Background and objectives, Target population and subgroups and Setting and location were covered in sufficient details in all studies whereas the Study perspective, Justification of the time horizon, Discount rate, and Estimating resources and costs were covered in less than 50%. Most of the studies (29/32) used the health care sector perspective whereas the societal perspective was applied in three studies. The time horizon was stated in 18/32 of the studies. Conclusions: The methodological quality of studies evaluating costs of robotic surgery was low. The longest follow-up was 4 months and in general, the use of detailed cost data were lacking in most of the investigations. Key determinants, such as purchasing, maintenance costs of the robotic platform, and the use of surgical equipment, were rarely reported. If health care cost analyses lack transparency regarding cost drivers included it may not provide a true foundation for decision-making.

Background: The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection.Methods: We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end-2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization.Results: 141 359 (18%) mothers had at least one antibiotic prescription during pregnancy, 230 886 (29.4% of those with complete data) in the 18 months before pregnancy. Of 776 657 live-born singletons, 443 546 infection-related hospitalizations occurred in 222 524 (28.6%) children. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.17-1.19]. In mothers prescribed antibiotics only during pregnancy whose child did not receive pre-hospitalization antibiotics, this association was present only in those born vaginally. Higher risks of infection-related hospitalization occurred when pregnancy antibiotic prescriptions were closer to birth and in mothers receiving more pregnancy antibiotics. Children born to mothers exposed to antibiotics before (but not during) pregnancy also had increased risk of infection-related hospitalization (HR 1.10, 95% CI 1.07-1.12).Conclusions: Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms.

Starch is a staple constituent of foodstuffs and energy source in the human diet. In many cases, its practical use is limited because of its lack of versatility to function adequately in the whole range of food product. Functional starch is designated as chemical, physical, or enzymatical modified starch with specific functional properties such as physiological function, healthy benefits, absorption function, sustained slow energy release, and other functions. Functional starches such as slowly digestible starch, resistant starch, porous starch, starch microemulsions, nano-sized starch, and starch copolymers are the dominating varieties that can be used in the food industry. Nowadays, the preparation of functional starch is an ongoing process as there are numerous possibilities, resulting from an evolution of new processing technologies and market trends. This chapter reviewed the current state of knowledge on functional starch. Particular emphasis was placed on the definition, classification, and characterization of functional starch in the food industry. The preparation and application of functional starches were overviewed, which gave a brief introduction for the following chapters.

BACKGROUND: Previous studies have shown an association between prepregnancy BMI and postpartum depression, but little is known about this association beyond one year postpartum and the influence of postpartum weight retention (PPWR).METHODS: We used data from 70355 mothers from the Danish National Birth Cohort to estimate the associations between maternal prepregnancy BMI and PPWR, respectively, and incident depression/anxiety disorders until six years postpartum. Outcome was depression or anxiety diagnosed clinically or filling a prescription for an antidepressant. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Follow-up started at the day of delivery. For the analysis regarding PPWR, follow-up started six months postpartum.RESULTS: Underweight, overweight and obesity were associated with depression and/or anxiety disorders when compared to normal-weight, though the associations were attenuated after adjustments (HR 1.24 [95% CI 1.06-1.45], 1.05 [95% CI 0.96-1.15] and 1.07 [95% CI 0.95-1.21] for underweight, overweight and obese, respectively). Compared to mothers who had returned to their prepregnancy BMI, risk of depression/anxiety disorders was increased for mothers, who from prepregnancy to 6 months postpartum experienced either weight loss >1 BMI unit (HR 1.19 [95% CI 1.06-1.25]), weight gain of 2-3 BMI units (HR 1.23 [95% CI 1.08-1.40]), or weight gain of ≥3 BMI units (HR 1.21 [95% CI 1.05-1.40]).LIMITATION: Causal direction and mechanisms behind the associations are largely unknown.CONCLUSIONS: Low prepregnancy body weight and postpartum weight gain or loss are associated with occurrence of depression and anxiety disorders.

BACKGROUND CONTEXT: Choosing the best surgical treatment for patients with spinal metastases remains a significant challenge for spine surgeons. There is currently no gold standard for surgical treatments. The Aarhus Spinal Metastases Algorithm (ASMA) was established to help surgeons choose the most appropriate surgical intervention for patients with spinal metastases.PURPOSE: The purpose of this study was to evaluate the clinical outcome of stratified surgical interventions based on the ASMA, which combines life expectancy and the anatomical classification of patients with spinal metastases to inform surgical decision making.STUDY DESIGN/SETTING: This is a retrospective study based on a prospective database.PATIENT SAMPLE: A consecutive series of 515 spinal metastatic patients who underwent surgically treatment from December 1992 to June 2012 in Aarhus University Hospital were included prospectively and analyzed in detail retrospectively.OUTCOME MEASURES: Survival time after surgery was determined for all patients. Neurological function was assessed using the Frankel score preoperatively and postoperatively (at the time of discharge). Complete outcome data were retrieved in 97.5% of this cohort.METHODS: Patients with spinal metastases were identified from an institutional database that prospectively collected data since 1992. Survival status data were obtained from a national registry. Neurological function was determined from the same institutional database or local Electronic Patient Journal system. Surgeons evaluated and classified patients into five surgical groups preoperatively by using the revised Tokuhashi score (TS) and the Tomita anatomical classification (TC).RESULTS: The overall median survival time of the cohort was 6.8 (95% confidence interval: 6.1-7.9) months. The median survival times in the five surgical groups determined by the ASMA were 2.1 (TS 0-4, TC 1-7), 5.1 (TS 5-8, TC 1-7), 12.1 (TS 9-11, TC 1-7 or TS 12-15, TC 7), 26.0 (TS 12-15, TC 4-6), and 36.0 (TS 12-15, TC 1-3) months. The 30-day mortality rate was 7.5%. Postoperative neurological function was maintained or improved in 469 patients (92.3%). Overall reoperation rate was 13.5%, commonly because of postoperative hematoma and new limb weakness.CONCLUSIONS: The ASMA recommends at least two surgical options for a particular patient by determining the preoperative life expectancy and anatomical classification of the spinal metastases. This algorithm could help spine surgeons to discriminate the risks of surgeries. The ASMA provides a tool to guild surgeons to evaluate the spinal metastases patients, select potential optimal surgery, and avoid life-threatening risks.

Fetuin-A, also referred to as alpha 2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 mg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 mg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.

Childhood and adulthood exposure to passive smoking associated with increased risk of lung cancerhttp://ow.ly/7kXN30f6aZu

AIM: Although birth asphyxia is a major risk factor for neonatal and childhood morbidity and mortality, it has not been investigated much in relation to attention deficit hyperactivity disorder (ADHD). We examined whether birth asphyxia measured by the pH of the blood in the umbilical artery cord was associated with childhood ADHD.METHOD: A population-based cohort of 295 687 children born in Finland between 1991 and 2002 was followed until December 31, 2007. ADHD was identified by the International Classification of Diseases, 10th edition, as a diagnosis of hyperkinetic disorder. We examined the risk of ADHD with varying pH values using Cox regression, taking time trends into consideration.RESULTS: When compared to the reference group, a pH value below 7.10 was significantly associated with an increased risk of ADHD. The strongest risks were observed among children with a pH value CONCLUSION: Birth asphyxia, defined by low pH value, may predict an increased risk of ADHD in childhood. The association between the pH value and ADHD was homogenous when stratified by gestational age and the Apgar score.

This is a pre-print of an article published in European Journal of Epidemiology. The final authenticated version is available online at: https://doi.org/10.1007/s10654-017-0262-y. Higher levels of circulating adiponectin have been related to lower risk of colorectal cancer in several prospective cohort studies, but it remains unclear whether this association may be causal. We aimed to improve causal inference in a Mendelian Randomization meta-analysis using nested case–control studies of the European Prospective Investigation into Cancer and Nutrition (EPIC, 623 cases, 623 matched controls), the Health Professionals Follow-up Study (HPFS, 231 cases, 230 controls) and the Nurses’ Health Study (NHS, 399 cases, 774 controls) with available data on pre-diagnostic adiponectin concentrations and selected single nucleotide polymorphisms in the ADIPOQ gene. We created an ADIPOQ allele score that explained approximately 3% of the interindividual variation in adiponectin concentrations. The ADIPOQ allele score was not associated with risk of colorectal cancer in logistic regression analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable analysis (based on previously published data) with higher statistical power, no association between genetically determined twofold higher adiponectin and risk of colorectal cancer was observed (0.99, 95% CI 0.93, 1.06 in women and 0.94, 95% CI 0.88, 1.01 in men). Thus, our study does not support a causal effect of circulating adiponectin on colorectal cancer risk. Due to the limited genetic determination of adiponectin, larger Mendelian Randomization studies are necessary to clarify whether adiponectin is causally related to lower risk of colorectal cancer.

Background: Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. Methods: We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Results: Compared with the 4th season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the 2nd and 3rd quartiles (median 39.9 and 51.5 nmol/L) compared with the 4th quartile, with HRs of 0.63 (95% CI 0.41 to 0.98) and 0.58 (0.38 to 0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for 2nd and 3rd quartiles: 0.40 (0.22 to 0.72) and 0.50 (0.27 to 0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52 to 1.75) and 0.60 (0.32 to 1.10)]. Conclusions: Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution. This is a pre-print of an article published in [European Journal of Epidemiology]. The final authenticated version is available online at: https://doi.org/10.1007/s10654-017-0324-1

Objective To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA). Methods Through linkage of Danish national registries, we identified all children born in Denmark between 1977 and 2008. We used general linear regression models to estimate mean differences in indicators of fetal growth among children with a parent with RA compared to unexposed children. Odds ratios (ORs) and 95% confidence intervals (95% CIs) of preterm birth were calculated using a logistic regression model. Results Of the 1,917,723 children included, a total of 13,556 children were exposed to maternal RA or maternal preclinical RA. Children exposed to maternal RA (n = 2,101) had approximately similar length, head circumference, and abdominal circumference at birth compared with children of mothers without RA. Birth weight was 87 gm lower (mean difference −87.04 gm [95% CI −111.23, −62.84]) and placenta weight was 14 gm lower (−13.45 gm [95% CI −21.46, −5.43]) than those in children of mothers without RA. Rather similar results were found in children exposed to maternal preclinical RA (n = 11,455). Compared with unexposed children, a higher risk of preterm birth was found in children exposed to maternal RA (OR 1.48 [95% CI 1.20, 1.84]) and preclinical RA (OR 1.32 [95% CI 1.07, 1.64]). No associations were found with paternal RA. Conclusion Children exposed to either maternal RA or maternal preclinical RA are more often born preterm. However, indicators of fetal growth measured at birth were only slightly lower than those in unexposed children.

Background: Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated. Methods: Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730). Results: Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04–11.86) and in the urinary system 2.73 (1.22–6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs). Conclusions: We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Study design We conducted a retrospective cohort study of 151 patients with breast cancer spinal metastases. Objective To investigate the influence of breast cancer subtypes on survival duration of patients with breast cancer spinal metastases, and to aid spine surgeons in selecting treatments on a more precise basis. Summary of background data There is lack of knowledge about specific prognosis of patients with spinal metastases in various breast cancer subtypes. Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (Her-2) status are the key factors in determining breast cancer subtypes and predicting patients' response to adjuvant treatments. Methods Until August 2013, we retrieved 151 surgically treated patients with breast cancer spinal metastases and followed up all the patients for at least 2 years. Survival duration analysis and Cox proportional hazards regression model unadjusted and adjusted by age were used. Results Patients with ER-negative (-) breast cancer had 11 months shorter median survival duration (10.6 vs. 21.5 mo) and 48% higher mortality risk (P=0.03) than those with ER-positive (+) breast cancer. Patients with PgR (-) status had 59% higher mortality risk than those with PgR (+) status (P=0.02). Hormone receptor (HR) status is a combination of ER and PgR status. Patients with HR (-) status had an 11-month shorter median survival duration and 52% higher mortality risk (P=0.01) than patients with HR (+) status. Human epidermal growth factor receptor 2 subtypes had similar median survival duration and mortality risk. Patients with triple-negative breast cancer had a median survival duration of only 9.9 months. Conclusion Patients with spinal metastases with ER/HR (-) status and triple-negative breast cancer could be downgraded from score "5" to "3" in Tokuhashi scoring system and from "slow growth" to "moderate growth" in Tomita scoring system. Spine surgeons should be critical before performing high-risk extensive surgery in patients with ER/HR (-) status, and especially, in those with triple-negative status. Level of evidence 3.

Purpose Studies on the safety of drugs used during pregnancy are necessary and important but prone to bias. Using cases as their own controls can reduce bias. We used a case-crossover design and a case-time-control design to estimate the risk of congenital malformation (CM) for children born to mothers who redeemed a trimethoprim prescription shortly before pregnancy. Methods The study was based on all live born singletons (N = 685 600) in Denmark whose mothers had available information on prescriptions in the Danish National Prescription Registry between 1996 and 2008. We defined 1–3 months before pregnancy as a potential risk period and 13–15 months before pregnancy as a reference period. Two other reference periods were used (7–9 months before pregnancy and months 4–6 of pregnancy). The case-crossover design is dependent on the assumption of a stable trimethoprim prescription over the study period in the source population. To estimate the trend of trimethoprim prescriptions, we used a control group comprising children without CMs. Results Both study designs showed children had a higher risk of overall CM [odds ratio of 1.66, 95% confidence interval (CI): 1.10–2.53 and 1.50, 95%CI: 0.66–3.38, respectively] if their mothers had a trimethoprim prescription in the 3 months before pregnancy and subtypes of CM for example in the musculoskeletal system, which were consistent to the previous findings from a cohort study. Conclusions This study corroborates that trimethoprim is a potential teratogen when used 3 months before pregnancy and demonstrates the value of case-only approaches for studying, for example, adverse effects of antibiotics in reproductive epidemiology. Copyright © 2014 John Wiley & Sons, Ltd.

High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP-score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.

Objective To examine the association between maternal hyper- and hypothyroidism and the risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in the child. Design A population-based cohort study. Setting Singletons liveborn in Denmark between 1991 and 2004. Population A total of 857 014 singletons alive and living in Denmark at the age of 3 years. Methods Information on the diagnosis and/or treatment of maternal thyroid disease and the neurodevelopmental disorders ADHD and ASD in the child was obtained from Danish nationwide registers. The Cox proportional hazards model was used to estimate the hazard ratio (HR) with 95% confidence interval (95% CI) for risk of ADHD and ASD in children born to mothers with thyroid dysfunction, adjusting for potential confounding factors. Main outcome measures ADHD and ASD in the child. Results Altogether, 30 295 singletons (3.5%) were born to mothers with thyroid dysfunction. Maternal hyperthyroidism diagnosed and treated for the first time after the birth of the child increased the risk of ADHD in the child (adjusted HR 1.23; 95% CI 1.05–1.44), whereas hypothyroidism increased the risk of ASD (adjusted HR 1.34; 95% CI 1.14–1.59). No significant association was seen for maternal diagnosis and treatment prior to the birth of the child. Conclusions Children born to mothers diagnosed and treated for the first time for thyroid dysfunction after their birth may have been exposed to abnormal levels of maternal thyroid hormone already present during the pregnancy, and this untreated condition could increase the risk of specific neurodevelopmental disorders in the child.

BACKGROUND: Intimate partner violence (IPV) is a global problem that affects one-third of all women. The present study aims to develop and determine the validity of a screening instrument for the detection of IPV in pregnant women in Tanzania and Vietnam and to determine the minimum number of questions needed to identify IPV.METHOD: An IPV screening instrument based on eight questions was tested on 1,116 Tanzanian and 1,309 Vietnamese women who attended antenatal care before 24 gestational weeks. The women were re-interviewed during their 30th-34th gestational week where the World Health Organization (WHO) IPV questionnaire was used as the gold standard. In all, 255 combinations of eight different questions were first tested on the Tanzanian study population where sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. In the evaluation of the performance of the question combinations, different IPV types and the frequency of abusive acts were considered. The question combinations that performed best in Tanzania were subsequently evaluated in the Vietnamese study population.RESULTS: In Tanzania, a combination of three selected questions including one question on emotional IPV, one on physical IPV and one on sexual IPV was found to be most effective in identifying women who are exposed to at least one type of IPV during pregnancy (sensitivity = .80; specificity = .74). The performance of the identified combination was slightly less effective in Vietnam (sensitivity = .74; specificity = .68). Focusing on different IPV types, the best performance was found for exposure to physical IPV in both Tanzania (sensitivity = .93; specificity = .70) and Vietnam (sensitivity = .96; specificity = .55). In both countries, the sensitivity increased with the frequency of abuse whereas the specificity decreased.CONCLUSION: By asking pregnant women three simple questions we were able to identify women who were exposed to IPV during pregnancy in two different countries. The question combination performed best in assessing physical IPV where it identified 93% and 96% of Vietnamese and Tanzanian women, respectively, who were exposed to physical IPV.

BACKGROUND: Maternal emotional stress during pregnancy has previously been associated with congenital neural malformations, but most studies are based on data collected retrospectively. The objective of our study was to investigate associations between antenatal maternal bereavement due to death of a close relative and neural tube defects (NTDs) in the offspring.METHODS: We performed a register-based cohort study including all live-born children (N = 1,734,190) from 1978-2008. Exposure was bereavement due to loss of a close relative from one year before conception to the end of the first trimester of pregnancy. The outcome was NTDs in the offspring according to the International Classification of Disease. We used multivariate logistic regression to estimate prevalence odds ratios (ORs).RESULTS: A total of 2% children were born to mothers who lost a close relative prenatally. During 30 years of follow-up, 1,115 children were diagnosed with any NTDs: spina bifida (n = 889), anencephaly (n = 85) and encephalocele (n = 164). And 23 children were diagnosed with two types of NTDs. Overall, when comparing bereaved mothers to non-bereaved mothers, no significant increased prevalence of NTDs in the offspring was seen (OR = 0.84; 95% confidence interval: 0.52-1.33).CONCLUSION: Overall maternal bereavement in the antenatal period was not related to NTDs in liveborn offspring.

Objective To assess whether mothers who lost a child from stillbirth or in the first week of life have an increased overall mortality and cause-specific mortality. Design A population based follow-up study. Setting Data from Danish national registers. Population All mothers in Denmark were included in the cohort at time of their first delivery from 1 January 1980 to 31 December 2008 and followed until 31 December 2009 or death, whichever came first. Methods The association between perinatal loss and total and cause-specific mortality in mothers was estimated with hazard ratios (HR) and 95% confidence intervals (95% CI) calculated using Cox proportional hazards regression analyses. Main outcome measures Overall mortality and cause-specific mortality. Results During the follow-up period, 838 331 mothers in the cohort gave birth to one or more children and 7690 mothers (0.92%) experienced a perinatal loss. During follow-up, 8883 mothers (1.06%) died. There was an increased overall mortality for mothers who experienced a perinatal loss adjusted for maternal age and educational level, hazard ratio (HR) 1.83 [95% confidence interval (CI) 1.55–2.17]. The strongest association was seen in mortality from cardiovascular diseases (CVD) with an HR of 2.29 (95% CI 1.48–3.52) adjusted for CVD at time of delivery. We found no association between a perinatal loss and mortality from traumatic causes. Conclusions Mothers who experience a perinatal loss have an increased mortality, especially from CVD.

Purpose Cancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied. Methods From singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry. Results We identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR = 2.61, 95%CI:1.60–4.27) or in the eye, ear, face, or neck (HR = 2.47, 95%CI: 1.46–4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR = 1.87, 95%CI: 0.98–3.56). Conclusions Children who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half-sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources.

STUDY DESIGN.: A risk factor analysis study. OBJECTIVE.: To identify the causative factors for postoperative trunk shift in Lenke 1C scoliosis and investigate how to prevent it. SUMMARY OF BACKGROUND DATA.: When selective thoracic fusion is performed, postoperative trunk shift is a significant problem in the management of Lenke 1C scoliosis. It is often accompanied by unsatisfactory clinical outcomes and a risk of reoperation. METHODS.: We reviewed all the patients with adolescent idiopathic scoliosis (AIS) surgically treated in our institution from 2002 through 2008. Inclusion criteria were as follows: (1) patients with Lenke 1C curves who were treated with selective thoracic fusion using posterior pedicle screw-only constructs; (2) the lowest instrumented vertebra (LIV) ending at L1 level or above; and (3) 2-year radiographical follow-up. Eighteen radiographical parameters were chosen as potential risk factors. The 18 parameters measured (1) amount of correction obtained by surgery; (2) preoperative position of LIV; (3) magnitude of major thoracic and thoracolumbar/lumbar (MT and TL/L) curves and ratio of MT: TL/L curve; and (4) curve flexibility. Both comparative and correlation analyses were performed. Those parameters that had shown highest correlation with the 2-year thoracic apical vertebra-center sacral vertical line (AV-CSVL) distance were selected to form a linear regression model, by which the correlations were quantified. RESULTS.: Of the 278 patients reviewed, 44 met the inclusion criteria. The parameters that measured the preoperative position of LIV and ratio of MT: TL/L curve showed high correlation with the 2-year thoracic AV-CSVL distance. With regard to the parameters that measured the amount of correction obtained by surgery, only the correction of the thoracic AV-T1 distance showed low correlation. Among the 18 parameters, preoperative lowest instrumented vertebra-lower end vertebra (LIV-LEV) difference and ratio of MT: TL/L Cobb angle were selected to form a formula to help predict postoperative trunk shift. The formula was as follows: 2-year thoracic AV-CSVL distance = -26.6 + 22.7 (ratio of MT: TL/L Cobb angle) - 3.9 (preoperative LIV-LEV difference). The model R = 0.55. CONCLUSION.: Both LIV selection and ratio of MT: TL/L curve were found to be highly correlated with the onset of postoperative trunk shift in Lenke 1C scoliosis. Amount of correction obtained by surgery, however, did not seem to be an independent causative factor. Postoperative trunk shift is less likely to occur when selecting LEV as LIV and the ratio of MT: TL/L Cobb angle of 1.2° or more.

Objective: To examine the effect of an alternative wound closure method after tumor arthroplasty of the hip compared to routine wound closure with skin staples. Method: Single center, frequency matched cohort study. We reviewed all patients who underwent tumor resection and endoprosthetic reconstruction of the proximal femur for pathologic fracture due to metastatic bone disease or malignant hematologic bone disease at our center between 2010 and 2014. All patients treated with occlusive wound closure (OWC), a combination of intradermal suture, Steri-Strips™, and an occlusive skin adhesive, during this period ( n = 35), were compared to an equally sized frequency matched group of patients having undergone routine wound closure with conventional skin staples. Results: Patients with OWC were significantly faster to achieve dry wound status and consequently had significantly shorter administration of antibiotics and hospital stay. Compared to the patients with conventional wound closure with staples, their wounds were already dry after a mean 3.4 days (vs. 6.7 days [95%CI: 3–3.8 vs. 5.5–7.9], p < 0.0001), they received antibiotics for a mean 4.2 days (vs. 6.8 days [95%CI: 3.7–4.8 vs. 5.5–8.0], p < 0.0003) and their mean hospital stay was 6.3 days (vs. 8.0 days [95%CI: 5.5–7 vs. 6.8–9.3], p < 0.015). Prolonged wound discharge (PWD) for 7 days or more was observed in 34% of patients ( n = 12) in the conventional group, whereas this complication was completely absent ( n = 0) in the investigational group. For every three patients treated with OWC, one complication of PWD over 7 days is avoided (number needed to treat = 3). Conclusion: Compared to conventional staples, OWC appears to significantly reduce wound complications, use of antibiotics, and hospital stay in patients undergoing tumor arthroplasty procedures of the hip. As such, it may also contribute to a reduction of the substantially increased risk for prosthetic joint infection in this patient population.