Platelet response to romiplostim amongst patients with newly diagnosed, persistent, and chronic immune thrombocytopenia in routine clinical practice in Denmark, Sweden, and Norway.

Patient characteristics and platelet responses at romiplostim initiation according to the duration of immune thrombocytopenia (ITP) are poorly understood. Amongst romiplostim-exposed adults with ITP lasting ≥6 months during 2009-2018 in Denmark, Sweden, and Norway, we examined characteristics at romiplostim initiation, romiplostim dosage, and durable platelet response (≥75% of measurements ≥50 × 109/L at 14-24 weeks) for subcohorts with newly diagnosed (duration <3 months), persistent (3-12 months), or chronic (>12 months) ITP initiating romiplostim. The 285 romiplostim initiators comprised 81 (28%) with newly diagnosed, 47 (16%) with persistent, and 157 (55%) with chronic ITP. More patients with newly diagnosed ITP than longer ITP duration, had low comorbidity levels, two or more prior ITP therapies, and previous bleeding requiring hospitalisation. The median romiplostim doses were similar across subcohorts. During treatment, median platelet counts were similar across subcohorts (75-76 × 109/L), and the durable platelet response was 64.6%, 52.9%, and 52.7% for newly diagnosed, persistent, and chronic ITP, respectively. After treatment cessation, the median platelet count was 138 × 109/L, 68 × 109/L, and 71 × 109/L, respectively. In conclusion, newly diagnosed patients, compared with romiplostim initiators with longer disease duration, had more severe ITP, higher frequency of durable platelet response, and higher median platelet count after cessation.

Temporal trends in lung cancer survival: a population-based study.

BACKGROUND: Lung cancer is the number one cancer-related cause of death in Sweden and worldwide. In most countries, five-year survival estimates vary between 10% and 20% with evidence of improved survival over time. Over the last decades, the management of lung cancer has changed including the introduction of national guidelines, new diagnostic procedures and treatments. This study aimed to investigate temporal trends in lung cancer survival both overall and in subgroups defined by established prognostic factors (i.e., sex, stage, histopathology and smoking history). MATERIALS AND METHODS: We estimated one-, two-, and five-year relative survival, and excess mortality, in patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016 in Sweden. We used population-based information available in a national lung cancer research database (LCBaSe) generated by cross-linkage between the Swedish National Lung Cancer Register and several Swedish health and sociodemographic registers. RESULTS: We included 36,935 patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016. The overall one-, two- and five-year survival estimates increased between 1995 and 2016, from 38% to 53%, 21% to 37%, and 14% to 24%, respectively. Over the study period, we also found improved survival in subgroups, for example in patients with stages III-IV disease, patients with adenocarcinoma, and never-smokers. The excess mortality decreased over the study period, both overall and in all subgroups. CONCLUSION: Lung cancer survival increased over time in the overall lung cancer population. Of special note was evidence of improved survival in patients with stage IV disease. Our results corroborate a previously observed global trend of improved survival in patients with lung cancer.

Risk factors of hospitalisation for thrombosis in adults with primary immune thrombocytopenia, including disease-specific treatments: a French nationwide cohort study.

We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment.

Antibiotic use prior to a lung cancer diagnosis: a population-based study.

AIM: To examine patterns of recent pre-diagnostic fillings of antibiotics as an indicator of early symptoms of lung cancer. METHODS: Individuals diagnosed with lung cancer (cases) in 2009-2016 were identified in the Swedish National Lung Cancer Register, a population-based register, and randomly matched with up to five individuals free of lung cancer (controls) from the general population. Conditional logistic models were used to estimate odds ratios for the association between lung cancer and a recent history of filled antibiotic prescriptions. RESULTS: The study included 27,017 cases and 129,355 controls. The likelihood of recent exposure was approximately two times higher in cases compared to controls. The magnitude of the effect size became more pronounced with proximity to the diagnosis of lung cancer and an increasing number of filled prescriptions. While the magnitude of the effect size did not differ by sex or educational level, it became attenuated with increasing age. There was no evidence supporting a trend in the magnitude of the effect size for the association between lung cancer and a history of repeated fillings by cancer stage. CONCLUSION: Lung cancer was associated with an increased likelihood of a recent history of filled antibiotic prescriptions. However, there was no evidence of an association between repeated fillings and a diagnostic delay, as reflected by stage. Our findings underscore the importance of clinical reassessment to rule out lung cancer following pneumonia treatment, especially for patients with multiple treatment cycles.

Comorbid disease burden among MS patients 1968-2012: A Swedish register-based cohort study.

BACKGROUND: People with multiple sclerosis (pwMS) have increased comorbid disease (CMD) risk. Most previous studies have not considered overall CMD burden. OBJECTIVE: To describe lifetime CMD burden among pwMS. METHODS: PwMS identified using Swedish registers between 1968 and 2012 (n = 25,476) were matched by sex, age, and county of residence with general-population comparators (n = 251,170). Prevalence, prevalence ratios (PRs), survival functions, and hazard ratios by MS status, age, and time period compared seven CMD: autoimmune, cardiovascular, depression, diabetes, respiratory, renal, and seizures. RESULTS: The magnitude of the PRs for each CMD and age group decreased across time, with higher PRs in earlier time periods. Before 1990, younger age groups had higher PRs, and after 1990, older age groups had higher PRs. Male pwMS had higher burden compared with females. Overall, renal, respiratory, and seizures had the highest PRs. Before 2001, 50% of pwMS received a first/additional CMD diagnosis 20 years prior to people without MS, which reduced to 4 years after 2001. PwMS had four times higher rates of first/additional diagnoses in earlier time periods, which reduced to less than two times higher in recent time periods compared to people without MS. CONCLUSION: Swedish pwMS have increased CMD burden compared with the general population, but this has reduced over time.

Higher body mass index at ages 16 to 20 years is associated with increased risk of a multiple sclerosis diagnosis in subsequent adulthood among men.

BACKGROUND: Evidence for the association between body mass index (BMI) and multiple sclerosis (MS) among men remains mixed. OBJECTIVE AND METHODS: Swedish military conscription and other registers identified MS after age of 20 years and BMI at ages 16-20 years (N = 744,548). RESULTS: Each unit (kg/m2) BMI increase was associated with greater MS risk (hazard ratio and 95% confidence interval = 1.034, 1.016-1.053), independent of physical fitness (1.021, 1.001-1.042). Categorised, overweight and obesity were associated with statistically significant raised MS risk compared to normal weight, but not after adjustment for physical fitness. CONCLUSION: MS risk rises with increasing BMI, across the entire BMI range.

A national Swedish case-control study investigating incidence and factors associated with idiopathic intracranial hypertension.

OBJECTIVE: To study the incidence of idiopathic intracranial hypertension in Sweden and to explore whether previously proposed risk factors are associated with idiopathic intracranial hypertension by investigating the odds of exposure one year prior to diagnosis in patients compared to controls. METHODS: Using Swedish health care registers and validated diagnostic algorithms, idiopathic intracranial hypertension patients diagnosed between 2000-2016 were compared with randomly selected matched controls, five from the general population and five with obesity. RESULTS: We identified 902 idiopathic intracranial hypertension patients and 4510 matched individuals in each control group. Mean incidence among inhabitants ≥18 years of age was 0.71 per 100,000; rising from 0.53 in 2000-2005 to 0.95 in 2012-2016. There were increased odds for idiopathic intracranial hypertension patients compared to general population for exposure to: kidney failure (odds ratio =13.2 (4.1-42.0)), arterial hypertension (odds ratio =17.5 (10.5-29.3)), systemic lupus erythematosus (odds ratio =13.8 (4.3-44.7)), tetracyclines, sulphonamides, lithium, and corticosteroids. In obese controls, odds ratios were also significantly increased for these exposures. Hormonal contraceptive use and exposure to pregnancy did not appear to be associated factors for idiopathic intracranial hypertension development. CONCLUSIONS: The incidence of idiopathic intracranial hypertension in Sweden is lower relative to reports from other countries but is on the rise. This case-control study confirms several previously reported risk factors associated with idiopathic intracranial hypertension.

Predictors for and outcomes after bone marrow biopsy in Scandinavian patients with chronic immune thrombocytopenia.

OBJECTIVES: To examine predictors for bone marrow biopsy (BMB) and the outcome following BMB in patients with chronic immune thrombocytopenia (cITP). METHODS: We identified patients diagnosed with cITP during 2009-2017 and obtained information on BMB, cITP treatment and subsequent thrombotic events, hospitalized bleeding, hematological cancer, and death using data from population-based healthcare databases and medical records in Denmark, Norway, and Sweden. RESULTS: Among 4471 adults (≥18 years) with cITP, 1683 (37.6%) underwent BMB before cITP diagnosis, while cumulative BMB incidence after cITP diagnosis date was 3.1% at 1 year and 7.5% at 5 years. Predictors of having a BMB after cITP diagnosis included older age, male sex, low baseline platelet count, splenectomy, and number of cITP treatments. Compared with patients without BMB, patients with BMB had higher rates of thrombotic events (1 year adjusted hazard ratio [HR] 1.53 [95% CI, 0.92-2.54]), hospitalized bleeding episodes (1 year adjusted HR 1.72 [95% CI, 1.15-2.58]), hematological cancer (1 year adjusted HR 35.26 [95% CI 17.67-70.34]), and all-cause mortality (1 year adjusted HR 1.97 [95% CI, 1.44-2.68]). CONCLUSION: Patients who undergo BMB after cITP diagnosis represent a subset of patients with more severe disease and increased rates of complications as well as hematological malignancies.

Outcomes in patients with lung cancer treated with crizotinib and erlotinib in routine clinical practice: A post-authorization safety cohort study conducted in Europe and in the United States.

PURPOSE: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice. METHODS: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately. RESULTS: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US. CONCLUSIONS: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases.

Infectious and inflammatory disorders might increase the risk of developing idiopathic intracranial hypertension - a national case-control study.

OBJECTIVE: To investigate whether conditions causing inflammatory activation are associated with increased risk of idiopathic intracranial hypertension. METHODS: All newly diagnosed idiopathic intracranial hypertension patients (cases) in Sweden between 2000-2016 were identified using pre-determined algorithms (n = 902) and matched with five controls from the general population and five individuals with an obesity diagnosis (n = 4510) for age, sex, region, and vital status. National health registers provided information on infections, inflammatory disorders and dispensed medications. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. RESULTS: Compared to general population controls, the cases had fourfold increased odds of having an infection (odds ratio = 4.3, 95% confidence interval 3.3-5.6), and threefold increased odds of an inflammatory disorder the year prior to idiopathic intracranial hypertension diagnosis (odds ratio = 3.2, 95% confidence interval 2.4-4.3). Organ specific analyses showed that odds were increased for the study diseases in the respiratory organ, kidney organ and gastrointestinal tract, but not for female genital infections. Similar results were found when comparing idiopathic intracranial hypertension with obese controls though the odds ratios were of lower magnitude. Sub-analyses on exposure to anti-infectious and anti-inflammatory drugs confirmed the increased odds ratios for idiopathic intracranial hypertension patients. CONCLUSIONS: These findings suggest that major inflammatory activation may be a risk factor in idiopathic intracranial hypertension development.

Methods for constructing treatment episodes and impact on exposure-outcome associations.

PURPOSE: To assess the impact on exposure time and outcome misclassifications, and consequent impact on exposure-outcome associations from treatment episode construction. We investigated the dosage assumptions of 1 unit per day, and 1 DDD per day, versus actual prescribed dosage under different handling of gaps and overlaps of prescriptions. METHODS: Data on mirtazapine and citalopram exposure (years 2006-2014) from the Swedish Prescribed Drug register were used. Via a within individuals design we compared method A, based on actual dosage, with methods B and C based on 1 unit of drug per day and 1 DDD per day assumptions, respectively, including consideration of gaps and overlaps. Four outcomes were used, hospitalizations and outpatient visits for all and for psychiatric causes. RESULTS: Relative to method A, both alternative methods lead to misclassification of exposure time. With regard to outcome misclassifications, method B overestimates the effect of the exposure on the outcome in 77% and 100% of exposure definition comparisons for mirtazapine and citalopram respectively, while 23% of the comparisons for mirtazapine results in underestimation of exposure-outcome associations. Conversely, treatment episodes based on DDD (method C) result in underestimation of the exposure-outcome association in 100% and 87.5% of exposure definition comparisons for mirtazapine and citalopram respectively, while 12.5% of the comparisons for citalopram results in overestimation of the exposure-outcome associations. CONCLUSIONS: The study provides results that have consistent clinical relevance. We have showed that a non-accurate construction of exposure time may lead to errors on outcome detection during exposed time, and consequently affect conclusions on safety or efficacy profile of a treatment.

Clinical characteristics and survival in non-small cell lung cancer patients by smoking history: a population-based cohort study.

Introduction: Approximately, 10-15% of lung cancer patients have never smoked. Previous epidemiological studies on non-tobacco associated lung cancer have been hampered by selected data from a small number of hospitals or limited numbers of patients. By use of data from large population-based registers with national coverage, this study aims to compare characteristics and survival of patients with non-small cell lung cancer (NSCLC) with different smoking histories.Methods: Swedish national population-based registers were used to retrieve data on patients diagnosed with primary NSCLC between 2002 and 2016. The Kaplan-Meier method and Cox proportional hazard models were used to estimate overall survival and lung cancer-specific survival by smoking history.Results: In total, 41,262 patients with NSCLC were included. Of those, 4624 (11%) had never smoked. Never-smokers were more often women and older compared to ever smokers (current and former). Adenocarcinoma was proportionally more common in never-smokers (77%) compared to current (52%) and former smokers (57%). Stage IV disease was more common in never-smokers (57%) than in current (48%) and former smokers (48%). Epidermal growth factor receptor mutation was observed more in never-smokers (37%) compared to current (5%) and former smokers (9%). Both lung cancer-specific and overall survival were higher for never-smokers compared to current smokers.Conclusions: The observed differences in characteristics between never-smokers and smokers, and the higher survival in never-smokers compared to smokers from this large population-based study provide further evidence that lung cancer in never-smokers is clinically different to tobacco-associated lung cancer. The findings from this study emphasise the need for an improved understanding of genetics, pathogenesis, mechanisms and progression of non-tobacco associated lung cancer that may help prevent lung cancer or identify individually targeted treatments.

Concussion in adolescence and risk of multiple sclerosis.

OBJECTIVE: To assess whether concussion in childhood or adolescence is associated with subsequent multiple sclerosis (MS) risk. Previous research suggests an association, but methodological limitations included retrospective data collection and small study populations. METHODS: The national Swedish Patient Register (hospital diagnoses) and MS Register were used to identify all MS diagnoses up to 2012 among people born since 1964, when the Patient Register was established. The 7,292 patients with MS were matched individually with 10 people without MS by sex, year of birth, age/vital status at MS diagnosis, and region of residence (county), resulting in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 years or from age 11 to 20 years. Conditional logistic regression was used to examine associations with MS. RESULTS: Concussion in adolescence was associated with a raised risk of MS, producing adjusted odds ratios (95% confidence intervals) of 1.22 (1.05-1.42, p = 0.008) and 2.33 (1.35-4.04, p = 0.002) for 1 diagnosis of concussion and >1 diagnosis of concussion, respectively, compared with none. No notable association with MS was observed for concussion in childhood, or broken limb bones in childhood and adolescence. INTERPRETATION: Head trauma in adolescence, particularly if repeated, is associated with a raised risk of future MS, possibly due to initiation of an autoimmune process in the central nervous system. This further emphasizes the importance of protecting young people from head injuries. Ann Neurol 2017;82:554-561.

Methods for time-varying exposure related problems in pharmacoepidemiology: An overview.

PURPOSE: Lack of control for time-varying exposures can lead to substantial bias in estimates of treatment effects. The aim of this study is to provide an overview and guidance on some of the available methodologies used to address problems related to time-varying exposure and confounding in pharmacoepidemiology and other observational studies. The methods are explored from a conceptual rather than an analytical perspective. METHODS: The methods described in this study have been identified exploring the literature concerning to the time-varying exposure concept and basing the search on four fundamental pharmacoepidemiological problems, construction of treatment episodes, time-varying confounders, cumulative exposure and latency, and treatment switching. RESULTS: A correct treatment episodes construction is fundamental to avoid bias in treatment effect estimates. Several methods exist to address time-varying covariates, but the complexity of the most advanced approaches-eg, marginal structural models or structural nested failure time models-and the lack of user-friendly statistical packages have prevented broader adoption of these methods. Consequently, simpler methods are most commonly used, including, for example, methods without any adjustment strategy and models with time-varying covariates. The magnitude of exposure needs to be considered and properly modelled. CONCLUSIONS: Further research on the application and implementation of the most complex methods is needed. Because different methods can lead to substantial differences in the treatment effect estimates, the application of several methods and comparison of the results is recommended. Treatment episodes estimation and exposure quantification are key parts in the estimation of treatment effects or associations of interest.

Opium use during pregnancy and infant size at birth: a cohort study.

BACKGROUND: The reported positive association between opiatic drug use during pregnancy and adverse pregnancy outcomes might be confounded by other factors related to high-risk behaviors, including the use of other harmful substances. In rural areas of Iran, opium use during pregnancy is relatively common among women who otherwise do not have a hazardous lifestyle, which reduces the risk of residual confounding and increasing the possibility to identify its effects. We aimed to examine the association of antenatal exposure to opium with risks of small for gestational age, short birth length, and small head circumference at birth. METHOD: In this cohort study in the rural area of the Golestan province, Iran, we randomly selected 920 women who were exposed to opium during pregnancy and 920 unexposed women during 2008-2010. Log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for the associations between prenatal exposure to opium and risks of small for gestational age, short birth length, and small head circumference at birth. RESULTS: Compared with non-use of opium and tobacco during pregnancy, using opium only and dual use of opium and tobacco were associated with increased risks of small for gestational age at births (RR = 1.71; 95% CI 1.34-2.18 and RR = 1.62; 95% CI 1.13-2.30, respectively). Compared with non-use of opium and tobacco, exposure to only opium or dual use of opium and tobacco were also associated with more than doubled increased risks of short birth length, and small head circumference in term infants. CONCLUSION: Maternal opium use during pregnancy is associated with increased risks of giving birth to a small for gestational age infant, as well as a term infant with short birth length or small head circumference.

Use of drugs for ADHD among adults-a multinational study among 15.8 million adults in the Nordic countries.

PURPOSE: The use of ADHD drugs among adults is controversial and has until recently not been approved for use in adults in most countries. The aim was to investigate use of ADHD drugs (stimulants and atomoxetine) among the entire adult population in the Nordic countries. METHODS: We conducted a multinational population-based prescription register study based on the entire adult population in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). All users of ADHD drugs aged 18-64 years during 2008-2012 were included, which for 2012 comprised 76,896 drug users among 15.8 million adult inhabitants. RESULTS: Annual prevalence of drug use increased during the study period for both genders and all age groups. The overall prevalence increased from 2.4 to 5.3 per 1000 men and 1.8 to 4.4 per 1000 women. Incidence also increased, but to a lesser extent in the last part of the study period. Methylphenidate was used by 88 % of drug users. Treatment was discontinued within the first year by 21 % of new drug users. Among all users of ADHD drugs, 53 % of men and 64 % of women concurrently used other psychotropic drugs, most frequently antidepressants and hypnotics. Psychotropic co-medication increased with age and was more pronounced among women than men. CONCLUSIONS: Use of ADHD drug among adults more than doubled over a 5-year period, and a majority were concurrently treated with other psychotropics. Adults constitute a substantial proportion of persons treated with ADHD drugs. Thus, evidence for long-term efficacy and safety in adults is urgently needed.

Suicide risk and antipsychotic side effects in schizophrenia: nested case-control study.

OBJECTIVE: This study explores suicide risk in schizophrenia in relation to side effects from antipsychotic medication. METHODS: Among patients with a first clinical discharge diagnosis of schizophrenia or schizoaffective disorder in Stockholm County between 1984 and 2000 (n = 4000), those who died by suicide within 5 years from diagnosis were defined as cases (n = 84; 54% male). For each case, one individually matched control was identified from the same population. Information on antipsychotic side effects, including extrapyramidal symptoms (EPS) and akathisia, as well as prescriptions of anticholinergic medication, was retrieved from clinical records in a blinded fashion. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of the association between suicide and side effects as well as anticholinergic medication were estimated using conditional logistic regression. RESULTS: A lower suicide risk was found in patients with a history of EPS (aOR 0.33, 95% CI 0.12-0.94). There was no statistically significant association between akathisia or anticholinergic medication use and the suicide risk. CONCLUSIONS: A lower suicide risk identified among patients with EPS could potentially reflect higher antipsychotic adherence, exposure to higher dosage, or polypharmacy among these patients. Copyright © 2016 John Wiley & Sons, Ltd.

Maternal haemoglobin concentrations before and during pregnancy and stillbirth risk: a population-based case-control study.

BACKGROUND: Results of previous studies on the association between maternal haemoglobin concentration during pregnancy and stillbirth risk are inconclusive. It is not clear if haemoglobin concentration before pregnancy has a role. Using prospectively collected information from pre-pregnancy and antenatal visits, we investigated associations of maternal haemoglobin concentrations before and during pregnancy and haemoglobin dilution with stillbirth risk. METHODS: In a population-based case-control study from rural Golestan, a province in northern Iran, we identified 495 stillbirths (cases) and randomly selected 2,888 control live births among antenatal health-care visits between 2007 and 2009. Using logistic regression, we estimated associations of maternal haemoglobin concentrations, haemoglobin dilution at different stages of pregnancy, with stillbirth risk. RESULTS: Compared with normal maternal haemoglobin concentration (110-120 g/l) at the end of the second trimester, high maternal haemoglobin concentration (≥140 g/l) was associated with a more than two-fold increased stillbirth risk (OR = 2.31, 95 % CI [1.30-4.10]), while low maternal haemoglobin concentration (<110 g/l) was associated with a 37 % reduction in stillbirth risk. Haemoglobin concentration before pregnancy was not associated with stillbirth risk. Decreased haemoglobin concentration, as measured during pregnancy (OR = 0.61, 95 % CI [0.46, 0.80]), or only during the second trimester (OR = 0.75, 95 % CI [0.62, 0.90]), were associated with reduced stillbirth risk. The associations were essentially similar for preterm and term stillbirths. CONCLUSIONS: Haemoglobin concentration before pregnancy is not associated with stillbirth risk. High haemoglobin level and absence of haemoglobin dilution during pregnancy could be considered as indicators of a high-risk pregnancy.

Consanguineous marriage, prepregnancy maternal characteristics and stillbirth risk: a population-based case-control study.

INTRODUCTION: Consanguineous marriage is associated with increased risks for congenital anomalies, low birthweight, and other adverse perinatal outcomes. In this population-based, case-control study we investigated the association between consanguineous marriage (first-cousin marriage) and stillbirth risk, using prospectively collected information from prepregnancy visits. MATERIAL AND METHODS: From 2007 to 2009, we identified 283 stillbirths (cases) and 2088 randomly selected live control births through prepregnancy visits in rural Golestan, Iran. The associations between consanguinity and prepregnancy maternal characteristics and stillbirth risk were examined using multivariate logistic regression. RESULTS: The rate of consanguineous marriage was 19.4% among cases and 13.6% among controls. Consanguinity was associated with increased stillbirth risk [odds ratio (OR) 1.53; 95% CI 1.10-2.14]. The association was significantly increased for preterm stillbirth (< 37 gestational weeks) (OR 2.43; 95% CI 1.46-4.04) but not for term stillbirth (≥ 37 weeks) (OR 1.14; 95% CI 0.75-1.74). Low and high maternal age, underweight, obesity, nulliparity, a history of infertility or miscarriage, previous obstetric complications (preeclampsia, preterm delivery, and stillbirth in previous pregnancies) were also associated with increased stillbirth risks. CONCLUSIONS: Consanguineous marriage is associated with increased risk of stillbirth, particularly preterm stillbirth. Findings for other maternal risk factors for stillbirth in rural Iran are consistent with previously reported findings from high-income countries.