Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway.

BACKGROUND: It is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs. METHODS: We estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference. RESULTS: We included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31-2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35-1.96) to Kliogest®: 2.67 (2.37-3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86-2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83-2.30) than screen-detected (HR 1.33, 95% CI 1.26-1.41) BC in women 50-71 years. HRs for HT use decreased with increasing BMI. CONCLUSIONS: The use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

Low-Dose Aspirin and Prevention of Colorectal Cancer: Evidence From a Nationwide Registry-Based Cohort in Norway.

INTRODUCTION: To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC). METHODS: In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use. RESULTS: We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period. DISCUSSION: In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study.

BACKGROUND: Previous studies assessed the prognostic effect of aspirin, statins, and metformin in breast cancer (BC) patients, with inconclusive results. METHODS: We performed a nationwide population-based cohort study to evaluate if post-diagnostic use of low-dose aspirin, statins, and metformin was associated with BC-specific survival. Women aged ≥ 50 years and diagnosed with BC in 2004-2017, who survived ≥ 12 months after diagnosis (follow-up started 12 months after diagnosis), were identified in the Cancer Registry of Norway. The Norwegian Prescription Database provided information on prescriptions. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between post-diagnostic use and BC-specific survival, overall and by oestrogen receptor (ER) status. RESULTS: A total of 26,190 patients were included. Of these, 5324 (20%), 7591 (29%), and 1495 (6%) were post-diagnostic users of low-dose aspirin, statins, and metformin, respectively. The median follow-up was 6.1 years, and 2169 (8%) patients died from BC. HRs for use, compared to no use, were estimated at 0.96 (95% CI 0.85-1.08) for low-dose aspirin (ER+: HR = 0.97, 95% CI 0.83-1.13; ER-: HR = 0.97, 95% CI 0.73-1.29, p value for interaction = 0.562), 0.84 (95% CI 0.75-0.94) for statins (ER+: HR = 0.95, 95% CI 0.82-1.09; ER-: HR = 0.77, 95% CI 0.60-1.00, p value for interaction = 0.259), and 0.70 (95% CI 0.51-0.96) for metformin (compared to use of non-metformin antidiabetics) (ER+: HR = 0.67, 95% CI 0.45-1.01; ER-: HR = 1.62, 95% CI 0.72-3.62, p value for interaction = 0.077). CONCLUSION: We found evidence supporting an association between post-diagnostic use of statins and metformin and survival, in patients with BC. Our findings indicate potential differences according to ER status.

Real-world effectiveness of HPV vaccination against cervical neoplasia among birth cohorts ineligible for routine vaccination.

Human papillomavirus (HPV) vaccine effectiveness may differ between settings. Here we present the first real-world effectiveness study of HPV vaccination on high-grade cervical lesions from Norway, among women who received HPV vaccine outside the routine program. We performed an observational study of all Norwegian women born 1975 to 1996 and retrieved individual data from nationwide registries on HPV vaccination status and incidence of histologically verified high-grade cervical neoplasia during 2006 to 2016. We estimated the incidence rate ratio (IRR) and 95% confidence intervals (CI) for vaccination vs no vaccination by Poisson regression stratified by age at vaccination <20 years and ≥20 years. The cohort consisted of 832 732 women, of which 46 381 (5.6%) received at least one dose of HPV vaccine by the end of 2016. The incidence rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased with age regardless of vaccination status and was highest at age 25 to 29, at 637/100 000 among unvaccinated women, 487/100 000 among women vaccinated before age 20 and 831/100 000 among women vaccinated at age 20 or older. The adjusted IRR of CIN2+ between vaccinated and unvaccinated women was 0.62 (95% CI: 0.46-0.84) for women vaccinated below age 20, and 1.22 (95% CI: 1.03-1.43) for women vaccinated at age 20 or older. These findings indicate that HPV vaccination among women too old to be eligible for routine HPV vaccination is effective among women who are vaccinated below age 20 but may not have the desired impact among women who are vaccinated at age 20 or older.

Low-dose aspirin and risk of breast cancer: a Norwegian population-based cohort study of one million women.

Several studies evaluated the association between aspirin use and risk of breast cancer (BC), with inconsistent results. We identified women aged ≥ 50 years residing in Norway between 2004 and 2018, and linked data from nationwide registries; including the Cancer Registry of Norway, the Norwegian Prescription Database, and national health surveys. We used Cox regression models to estimate the association between low-dose aspirin use and BC risk, overall and by BC characteristics, women's age and body mass index (BMI), adjusting for sociodemographic factors and use of other medications. We included 1,083,629 women. During a median follow-up of 11.6 years, 257,442 (24%) women used aspirin, and 29,533 (3%) BCs occurred. For current use of aspirin, compared to never use, we found an indication of a reduced risk of oestrogen receptor-positive (ER +) BC (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.92-1.00), but not ER-negative BC (HR = 1.01, 95%CI: 0.90-1.13). The association with ER + BC was only found in women aged ≥ 65 years (HR = 0.95, 95%CI: 0.90-0.99), and became stronger as the duration of use increased (use of ≥ 4 years HR = 0.91, 95%CI: 0.85-0.98). BMI was available for 450,080 (42%) women. Current use of aspirin was associated with a reduced risk of ER + BC in women with BMI ≥ 25 (HR = 0.91, 95%CI: 0.83-0.99; HR = 0.86, 95%CI: 0.75-0.97 for use of ≥ 4 years), but not in women with BMI < 25.Use of low-dose aspirin was associated with reduced risk of ER + BC, in particular in women aged ≥ 65 years and overweight women.

ß-blockers and breast cancer survival by molecular subtypes: a population-based cohort study and meta-analysis.

BACKGROUND: The association between use of ß-blockers and breast cancer (BC) prognosis has been investigated in several observational studies, with conflicting results. We performed a nationwide cohort study and a meta-analysis to investigate the association, and assess if it varied between molecular subtypes of BC. METHODS: We identified women aged ≥50 years with BC diagnosed between 2004 and 2018 in Norway. We used Cox regression models to estimate the association between ß-blocker use at diagnosis and BC-specific survival, overall and by molecular subtype. We performed a meta-analysis of observational studies that reported molecular subtype-specific estimates of this association. RESULTS: We included 30,060 women, of which 4461 (15%) used ß-blockers. After a median follow-up of 5.1 years, 2826 (9%) died of BC. Overall, ß-blocker use was not associated with BC-specific survival (hazard ratio [HR] = 1.07; 95% confidence interval [CI]: 0.97-1.19). We found an association only in triple-negative BC (TNBC) patients (HR = 0.66; 95% CI: 0.47-0.91). This was confirmed in the meta-analysis: ß-blocker use was associated with progression/recurrence-free (HR = 0.58; 95% CI: 0.38-0.89) and BC-specific survival (HR = 0.74; 95% CI: 0.55-1.00) in TNBC patients only. CONCLUSION: In our cohort of BC patients and in the meta-analysis, ß-blocker use was associated with prolonged BC-specific survival only in TNBC patients.

Downstaging and survival after Neoadjuvant chemotherapy for bladder cancer in Norway; a population-based study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) before radical cystectomy is associated with pathological downstaging (DS) and improved overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC). Population-based studies have not unequivocally shown improved survival. The aim of this population-based study was to evaluate the effect of NAC on DS and OS in Norwegian patients with MIBC. METHODS: Patients in the Cancer Registry of Norway undergoing radical cystectomy (2008-2015) with or without NAC diagnosed with MIBC between 2008 and 2012 were included. Follow-up data were available until 31 December 2019. Logistic regression estimated the odds of DS with NAC, and a Cox model investigated the effect of DS on OS. Cox models, a mediator analysis and an instrumental variable approach were used to investigate the effect of NAC on OS. RESULTS: A total of 575 patients were included. NAC was administered to 82 (14%) patients. Compared to cystectomy only, NAC increased the proportion (43% vs. 22%) and the odds of DS (OR 2.51, CI 1.37-4.60, p = 0.003). Independent of NAC, the proportion of pN0 was higher in patients with DS (89% vs. 60%) and DS yielded a 78% mortality risk reduction (HR 0.22, CI 0.15-0.34, p = 1.9∙10-12), compared to patients without DS. We did not find an association between NAC and OS, neither by Cox regression (HR 1.16, CI 0.80-1.68, p = 0.417) nor by an instrumental variable approach (HR = 0.56, CI = 0.07-4.57, p = 0.586). The mediation analysis (p = 0.026) confirmed an indirect effect of NAC on OS through DS. Limitations include limited information of the primary tumour, details of NAC treatment and treatment indications. CONCLUSIONS: NAC increases the probability of DS and is indirectly associated to OS. DS is related to the absence of regional lymph node metastases and is associated with an OS benefit. Improved staging and biomarkers are needed to identify patients most likely to achieve DS and to benefit from NAC.

Metformin use and lung cancer survival: a population-based study in Norway.

BACKGROUND: We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS: The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS: Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS: Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Use of non-cancer drugs and survival among patients with pancreatic adenocarcinoma: a nationwide registry-based study in Norway.

BACKGROUND: The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. MATERIAL AND METHODS: The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. RESULTS: In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. CONCLUSION: The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.

Robust estimation of the effect of an exposure on the change in a continuous outcome.

BACKGROUND: The change in two measurements of a continuous outcome can be modelled directly with a linear regression model, or indirectly with a random effects model (REM) of the individual measurements. These methods are susceptible to model misspecifications, which are commonly addressed by applying monotonic transformations (e.g., Box-Cox transformation) to the outcomes. However, transforming the outcomes complicates the data analysis, especially when variable selection is involved. We propose a robust alternative through a novel application of the conditional probit (cprobit) model. METHODS: The cprobit model analyzes the ordered outcomes within each subject, making the estimate invariant to monotonic transformation on the outcome. By scaling the estimate from the cprobit model, we obtain the exposure effect on the change in the observed or Box-Cox transformed outcome, pending the adequacy of the normality assumption on the raw or transformed scale. RESULTS: Using simulated data, we demonstrated a similar good performance of the cprobit model and REM with and without transformation, except for some bias from both methods when the Box-Cox transformation was applied to scenarios with small sample size and strong effects. Only the cprobit model was robust to skewed subject-specific intercept terms when a Box-Cox transformation was used. Using two real datasets from the breast cancer and inpatient glycemic variability studies which utilize electronic medical records, we illustrated the application of our proposed robust approach as a seamless three-step workflow that facilitates the use of Box-Cox transformation to address non-normality with a common underlying model. CONCLUSIONS: The cprobit model provides a seamless and robust inference on the change in continuous outcomes, and its three-step workflow is implemented in an R package for easy accessibility.

Psychological effect of cervical cancer screening when changing primary screening method from cytology to high-risk human papilloma virus testing.

From 2015, Norway has implemented high-risk human papilloma virus (hrHPV) testing in primary screening for cervical cancer. Women aged 34-69 years, living in four counties, have been pseudo-randomly assigned (1:1 randomization) to either hrHPV testing every 5 years (followed by cytology if hrHPV is positive), or cytology testing every 3 years (followed by hrHPV testing if low-grade cytology is detected). We compared anxiety and depression scores among participants by screening arm and results. In total, 1,008 women answered a structured questionnaire that included the validated Patient Health Questionnaire-4 (PHQ-4). The Relative Risk Ratio (RRR) of mild vs. normal anxiety and depression scores, and moderate/severe vs. normal anxiety and depression scores, were estimated by multinomial logistic regression with 95% confidence intervals (95% CIs). Compared to women who were screened with cytology, women randomized to hrHPV testing were not more likely to have mild anxiety and depression scores (RRR 0.96, CI 0.70-1.31) nor more likely to have moderate/severe anxiety and depression scores (RRR 1.14, CI 0.65-2.02). Women with five different combinations of abnormal screening test results were not more likely to have mild or moderate/severe vs. normal anxiety and depression scores than women with normal screening results. The likelihood of having abnormal long-term (4-24 months after the screening) anxiety or depression scores among women 34 years and older was not affected by screening method or screening results. The results of our study suggest that a change to hrHPV testing in primary screening would not increase psychological distress among participants.

Using marginal standardisation to estimate relative risk without dichotomising continuous outcomes.

BACKGROUND: Although criticisms regarding the dichotomisation of continuous variables are well known, applying logit model to dichotomised outcomes is the convention because the odds ratios are easily obtained and they approximate the relative risks (RRs) for rare events. METHODS: To avoid dichotomisation when estimating RR, the marginal standardisation method that transforms estimates from logit or probit model to RR estimate is extended to include estimates from linear model in the transformation. We conducted a simulation study to compare the statistical properties of the estimates from: (i) marginal standardisation method between models for continuous (i.e., linear model) and dichotomised outcomes (i.e., logit or probit model), and (ii) marginal standardisation method and distributional approach (i.e., marginal mean method) applied to linear model. We also compared the diagnostic test for probit, logit and linear models. For the real dataset analysis, we applied these analytical approaches to assess the management of inpatient hyperglycaemia in a pilot intervention study. RESULTS: Although the RR estimates from the marginal standardisation method were generally unbiased for all models in the simulation study, the marginal standardisation method for linear model provided estimates with higher precision and power than logit or probit model, especially when the baseline risks were at the extremes. When comparing approaches that avoid dichotomisation, RR estimates from these approaches had comparable performance. Assessing the assumption of error distribution was less powerful for logit or probit model via link test when compared with diagnostic test for linear model. After accounting for multiple thresholds representing varying levels of severity in hyperglycaemia, marginal standardisation method for linear model provided stronger evidence of reduced hyperglycaemia risk after intervention in the real dataset analysis although the RR estimates were similar across various approaches. CONCLUSIONS: When compared with approaches that do not avoid dichotomisation, the RR estimated from linear model is more precise and powerful, and the diagnostic test from linear model is more powerful in detecting mis-specified error distributional assumption than the diagnostic test from logit or probit model. Our work describes and assesses the methods available to analyse data involving studies of continuous outcomes with binary representations.

Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role?

The association between use of menopausal hormone therapy (HT) and occurrence of skin malignant melanoma (SMM) is controversial. We investigated the issue in a nationwide cohort of 684,696 Norwegian women, aged 45-79 years, followed from 2004 to 2008. The study was based on linkage between Norwegian population registries. Multivariable Poisson regression models were used to estimate the effect of HT use, different HT types, routes of administration and doses of estrogen and progestin on the risk of SMM. During the median follow-up of 4.8 years, 178,307 (26%) women used HT, and 1,476 incident SMM cases were identified. Current use of HT was associated with increased risk of SMM (rate ratios (RR) = 1.19; 95% confidence interval (CI) 1.03-1.37). Plain estrogen therapy was associated with an increased risk of SMM (RR 1.45; 95% CI 1.21-1.73), both for oral (RR 1.45; 95% CI 1.09-1.93) and vaginal (RR 1.44; 95% CI 1.14-1.84) formulations, while combined estrogen and progestin therapy (EPT) was not (RR 0.91; 95% CI 0.70-1.19). We performed a dose-response analysis of estrogen and progestin in women using tablets, and found that use of estrogens was associated with increased risk (RR 1.24; 95% CI 1.00-1.53 per 1 mg/day) and use of progestins with decreased risk (RR 0.71; 95% CI 0.57-0.89 per 10 mg/month) of SMM. In conclusion, estrogens were associated with increased risk of SMM, while combinations of estrogens and progestins were not. Our results suggest that estrogens and progestins might affect the risk of SMM in opposite ways.

Hyperemesis gravidarum and maternal cancer risk, a Scandinavian nested case-control study.

Reproductive factors have been shown to influence cancer risk. Several pathological conditions during pregnancy have also been associated with subsequent altered cancer risk in the mother. Hyperemesis gravidarum (hyperemesis) is an early pregnancy condition characterized by severe nausea and vomiting resulting in weight loss and metabolic disturbances. Studies have reported associations between hyperemesis and cancer, but results are inconsistent. In this nested case-control study we linked the population-based medical birth registries and cancer registries in Norway, Sweden and Denmark in order to examine overall cancer risk and risk of specific cancer types in women with a history of hyperemesis, using conditional logistic regression. In total, 168,501 cases of cancer in addition to up to 10 cancer-free controls per case were randomly sampled, matched on year of birth and birth registry (n = 1,721,626). Hyperemesis was defined through the International Classification of Diseases. Analyses were adjusted for potential confounders. Hyperemesis was inversely associated with overall cancer risk with adjusted relative risk (aRR) of 0.93 (95% CI: 0.88-0.99), with cancer in the lungs (aRR: 0.60, 95% CI: 0.44-0.81), cervix (aRR: 0.66, 95% CI: 0.49-0.91) and rectum (aRR: 0.48, 95% CI: 0.29-0.78). Thyroid cancer was positively associated with hyperemesis (aRR 1.45, 95% CI: 1.06-1.99) and risk increased with more than one hyperemetic pregnancy (aRR 1.80, 95% CI: 1.23-2.63). Hormonal factors, in particular human chorionic gonadotropin, are likely to be involved in mediating these effects. This study is the first to systematically address these associations and provides valuable knowledge on potential long-term consequences of hyperemesis.

Hyperemesis gravidarum and risk of cancer in offspring, a Scandinavian registry-based nested case-control study.

BACKGROUND: Hyperemesis gravidarum is a serious condition affecting 0.8-2.3% of pregnant women and can be regarded as a restricted period of famine. Research concerning potential long-term consequences of the condition for the offspring, is limited, but lack of nutrition in-utero has been associated with chronic disease in adulthood, including some cancers. There is growing evidence that several forms of cancer may originate during fetal life. We conducted a large study linking the high-quality population-based medical birth- and cancer registries in Norway, Sweden and Denmark, to explore whether hyperemesis is associated with increased cancer risk in offspring. METHODS: A registry-based nested case-control study. Twelve types of childhood cancer were selected; leukemia, lymphoma, cancer of the central nervous system, testis, bone, ovary, breast, adrenal and thyroid gland, nephroblastoma, hepatoblastoma and retinoblastoma. Conditional logistic regression models were applied to study associations between hyperemesis and risk of childhood cancer, both all types combined and separately. Cancer types with five or more exposed cases were stratified by age at diagnosis. All analysis were adjusted for maternal age, ethnicity and smoking, in addition to the offspring's Apgar score, placental weight and birth weight. Relative risks with 95% confidence intervals were calculated. RESULTS: In total 14,805 cases and approximately ten controls matched on time, country of birth, sex and year of birth per case (147,709) were identified. None of the cancer types, analyzed combined or separately, revealed significant association with hyperemesis. When stratified according to age at diagnosis, we observed a RR 2.13 for lymphoma among adolescents aged 11-20 years ((95% CI 1.14-3.99), after adjustment for maternal ethnicity and maternal age, RR 2.08 (95% CI 1.11-3.90)). The finding was not apparent when a stricter level of statistical significance was applied. CONCLUSIONS: The main finding of this paper is that hyperemesis does not seem to increase cancer risk in offspring. The positive association to lymphoma may be by chance and needs confirmation.

Inverse probability weighting in nested case-control studies with additional matching--a simulation study.

Nested case-control designs are inevitably less efficient than full cohort designs, and it is important to use available information as efficiently as possible. Reuse of controls by inverse probability weighting may be one way to obtain efficiency improvements, and it can be particularly advantageous when two or more endpoints are analyzed in the same cohort. The controls in a nested case-control design are often matched on additional factors than at risk status, and this should be taken into account when reusing controls. Although some studies have suggested methods for handling additional matching, a thorough investigation of how this affects parameter estimates and weights is lacking. Our aim is to provide such a discussion to help developing guidelines for practitioners. We demonstrate that it is important to adjust for the matching variables in regression analyses when the matching is broken. We present three types of estimators for the inverse sampling probabilities accounting for additional matching. One of these estimators was somewhat biased when the cases and controls were matched very closely. We investigated how additional matching affected estimates of interest, with varying degree of association between the matching variables and exposure/outcome. Strong associations introduced only a small bias when the matching variables were properly adjusted for. Sometimes, exposure variables, for example, blood samples, are analyzed in batches. Rather, strong batch effects had to be present before this introduced much bias when the matching was broken. All simulations are based on a study of prostate cancer and vitamin D.

Hyperemesis gravidarum and pregnancy outcomes in the Norwegian Mother and Child Cohort - a cohort study.

BACKGROUND: Hyperemesis gravidarum (HG) characterized by excessive nausea and vomiting in early pregnancy, is reported to be associated with increased risks for low birthweight (LBW), preterm birth (PTB), small-for-gestational-age (SGA) and perinatal death. Conflicting results in previous studies underline the necessity to study HG's potential effect on pregnancy outcomes using large cohorts with valid data on exposure and outcome measures, as well as potential confounders. This study aims to investigate associations between HG and adverse pregnancy outcomes using the Norwegian Mother and Child Cohort Study (MoBa). METHODS: All singleton pregnancies in MoBa from 1998 to 2008 were included. Multivariable regression was used to estimate relative risks, approximated by odds ratios, for PTB, LBW, SGA and perinatal death. Linear regression was applied to assess differences in birthweight and gestational age for children born to women with and without HG. Potential confounders were adjusted for. RESULTS: Altogether, 814 out of 71,468 women (or 1.1%) had HG. In MoBa HG was not associated with PTB, LBW or SGA. Babies born to women with HG were born on average 1 day earlier than those born to women without HG; (-0.97 day (95% confidence intervals (CI): -1.80 - -0.15). There was no difference in birthweight when maternal weight gain was adjusted for; (23.42 grams (95% CI: -56.71 - 9.86). Babies born by women with HG had lower risk for having Apgar score < 7 after 1 minute (crude odds ratio was 0.64 (95% CI: 0.43 - 0.95)). No differences between the groups for Apgar score < 7 after 5 minutes were observed. Time-point for hospitalisation slightly increased differences in gestational age according to maternal HG status. CONCLUSIONS: HG was not associated with adverse pregnancy outcomes. Pregnancies complicated with HG had a slightly shorter gestational length. There was no difference in birth weight according to maternal HG-status. HG was associated with an almost 40% reduced risk for having Apgar score < 7 after 1 minute, but not after 5 minutes. The clinical importance of these statistically significant findings is, however, rather limited.

Antimuscarinics and lung cancer survival: A Norwegian population-based cohort study.

OBJECTIVES: Epidemiological studies have reported an association between antimuscarinics and reduced risk of cancer, including lung cancer (LC). However, the potential association between antimuscarinic use and LC prognosis has not previously been assessed. In a large population-based cohort, we aimed to investigate the association between the use of antimuscarinics and LC-specific survival. MATERIALS AND METHODS: Norwegian residents, aged ≥ 50 years, and diagnosed with LC between 2005 and 2018, were identified in the Cancer Registry of Norway, and information on filled prescriptions was obtained from the Norwegian Prescription Database. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between peri-diagnostic and post-diagnostic use of antimuscarinics and LC-specific survival. RESULTS: We included 26,693 patients with incident primary invasive LC. Of these, 466 (1.7 %) were peri-diagnostic users, and 877 (3.3 %) were post-diagnostic users of antimuscarinics, respectively. During a median follow-up of nine months, 18,088 (67.8 %) patients died due to LC. In the overall LC population, the HRs for the association between the use of antimuscarinics, compared to no use, were estimated at 1.01 (95 %CI: 0.90-1.12) for peri-diagnostic use, and 0.84 (95 %CI: 0.77-0.92) for post-diagnostic use. The association with post-diagnostic use was observed in many subgroups defined by sex, age, smoking status, histopathology, and stage, except for patients with unspecified or other histopathology than small cell LC and non-small cell LC, and for patients with local disease. The association was observed in patients treated with chemotherapy (HR = 0.75, 95 %CI: 0.64-0.88), but not in those not treated with chemotherapy (HR = 1.00, 95 %CI: 0.86-1.17; p for interaction: 0.007). CONCLUSION: Our results suggest a possible association between use of antimuscarinics and longer LC-specific survival. More studies are warranted to investigate the use of antimuscarinics to possibly prolong LC prognosis.

Association between use of low-dose aspirin and detection of colorectal polyps and cancer in a screening setting.

BACKGROUND: The possible protective effect of aspirin on risk of colorectal cancer (CRC) is still highly debated. METHODS: We used data from Bowel Cancer Screening in Norway, a trial randomizing individuals from general population, aged 50-74 years, to flexible sigmoidoscopy or faecal immunochemical test (FIT), to study the association between aspirin use and detection of CRC and two CRC precursors: adenomas and advanced serrated lesions (ASL). Prescriptions of low-dose aspirin were obtained from Norwegian prescription database. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 64,889 screening participants (24,159 sigmoidoscopy, 40,730 FIT), 314 (0.5%) had CRC, 6,208 (9.6%) adenoma and 659 (1.0%) ASL. Overall and short-term use (<3 years) of low-dose aspirin, versus no use, were not associated with any colorectal lesion. Long-term use (≥3 years) was associated with lower detection of CRC (overall OR 0.66, 95%CI 0.46-0.93; sigmoidoscopy: 0.56, 0.33-0.97; FIT: 0.72, 0.45-1.15), adenomas in sigmoidoscopy arm (overall OR 0.95, 95%CI 0.87-1.03; sigmoidoscopy: 0.89, 0.80-0.99; FIT: 1.03, 0.89-1.18), but not ASLs. We did not observe significant differences in the effect of aspirin according to the location of colorectal lesions. CONCLUSION: Our results suggest that long-term use of aspirin might have a protective effect against adenomas and colorectal cancer, but not ASLs.

Night shift work and risk of aggressive prostate cancer in the Norwegian Offshore Petroleum Workers (NOPW) cohort.

BACKGROUND: Night shift work may acutely disrupt the circadian rhythm, with possible carcinogenic effects. Prostate cancer has few established risk factors though night shift work, a probable human carcinogen, may increase the risk. We aimed to study the association between night shift work and chlorinated degreasing agents (CDAs) as possible endocrine disrupters in relation to aggressive prostate cancer as verified malignancies. METHODS: We conducted a case-cohort study on 299 aggressive prostate cancer cases and 2056 randomly drawn non-cases in the Norwegian Offshore Petroleum Workers cohort (1965-98) with linkage to the Cancer Registry of Norway (1953-2019). Work history was recorded as years with day, night, and rollover (rotating) shift work, and CDA exposure was assessed with expert-made job-exposure matrices. Weighted Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for aggressive prostate cancer, adjusted for education and year of first employment, stratified by 10-year birth cohorts, and with 10, 15, and 20 years of exposure lag periods. RESULTS: Compared with day work only, an increased hazard of aggressive prostate cancer (HR = 1.86, 95% CI 1.18-2.91; P-trend = 0.046) was found in workers exposed to ≥19.5 years of rollover shift work. This persisted with longer lag periods (HR = 1.90, 95% CI 0.92-3.95; P-trend = 0.007). The exposure-hazard curve for a non-linear model increased linearly (HRs ≥1.00) for 18-26 years of rollover shift work. No association was found with CDA exposure. CONCLUSIONS: Long-term exposure to rollover shift work may increase the hazard of aggressive prostate cancer in offshore petroleum workers.