Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics.

PURPOSE: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. METHODS: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. RESULTS: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. CONCLUSION: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.

DNA methylation differences at birth after conception through ART.

STUDY QUESTION: Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI? SUMMARY ANSWER: DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI. WHAT IS KNOWN ALREADY: Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey's tests. MAIN RESULTS AND THE ROLE OF CHANCE: We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5-4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences. LIMITATIONS, REASONS FOR CAUTION: We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study. WIDER IMPLICATIONS OF THE FINDINGS: We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI. STUDY FUNDING/COMPETING INTEREST(S): E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union's Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Pediatric use of prescribed melatonin in Sweden 2006-2017: a register based study.

Sleep disturbances are common in the pediatric population and should primarily be treated non-pharmacologically. Most medicines for sleep disturbances are not approved for pediatric use and data on long-term safety is scarce. In Sweden, melatonin is classified as a prescription medicine. The aim of the present study was to characterize the prevalence and incidence of dispensed melatonin prescriptions, long-term treatment, concomitant dispensation of psychotropic medication, and psychiatric comorbidity, in children and adolescents aged 0-17 years living in Sweden during 2006-2017. Data was retrieved by linking the national population-based registers, the Swedish Prescribed Drug register and the National Patient register. In 2017, nearly 2% of the pediatric population 0-17 years was dispensed at least one prescription of melatonin, which was more than a 15-fold increase for girls and a 20-fold increase for boys, when compared to 2006. Among the children in the age group 5-9 who initiated a melatonin treatment in 2009, 15% of girls and 17% of boys were found to be continuously prescribed melatonin 8 years later. Nearly 80% of all children with dispensed melatonin had concomitant dispensations of psychotropic medications. The most common combination was melatonin together with centrally acting sympathomimetic medicines (23% of girls and 43% of boys). About half of the children (47% of girls and 50% of boys) had at least one registered diagnosis of mental or behavioral disorders. The most common diagnosis was attention deficit hyperactive disorder, across all age groups and genders. The continuous increase of use of melatonin in children, often concomitant with other psychotropic medications, together with a high proportion of younger children with prescriptions of melatonin on a long-term basis, suggests the need for further structured follow up studies, in particular of long-term use.

Assisted reproductive technology and risk of ovarian cancer and borderline tumors in parous women: a population-based cohort study.

The study aimed to investigate if assisted reproductive technology (ART) treatment or a diagnosis of infertility were associated with the risk of ovarian cancer or borderline ovarian tumors (BOT) in parous women. In a population-based register study of 1,340,097 women with a first live birth in Sweden 1982-2012, the relationship between ART treatments, infertility and incidence of ovarian cancer or BOT were investigated using Cox regression analysis. In the cohort, 38,025 women gave birth following ART, 49,208 following an infertility diagnosis but no ART and 1,252,864 without infertility diagnosis or ART. During follow-up, 991 women were diagnosed with ovarian cancer and 747 with BOT. Women who gave birth following ART had higher incidence of both ovarian cancer (adjusted hazard ratio [aHR] 2.43, 95% confidence interval [CI] 1.73-3.42) and BOT (aHR 1.91, 95% CI 1.27-2.86), compared to women without infertility. Compared to women with infertility diagnoses and non-ART births, women with ART births also had a higher incidence of ovarian cancer (aHR 1.79, 95% CI 1.18-2.71) and BOT (aHR 1.48, 95% CI 0.90-2.44). Our results suggest that women who have gone through ART have a higher risk of ovarian cancer and BOT. At least part of that risk seems to be due to the underlying infertility and not the treatment per se, since the increased risk was smaller when comparing to other infertile women. As ART treatments are becoming more common and ovarian cancer usually occur in women of advanced age, larger studies with longer follow-up are needed in order to confirm or refute our findings.

The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study.

Some studies have suggested that infertility is a risk factor for endometrial, ovarian and breast cancer. The study aimed to create a comprehensive picture of the association between infertility and the risk of ovarian, endometrial and breast cancer, and whether any association could be explained by ovulatory disturbances, endometriosis or nulliparity. In a population-based cohort of 2,882,847 women, cox regression analysis was used to investigate cancer incidence among infertile women. Overall, infertility was associated with a higher incidence rate of ovarian (adjusted hazard ratio [aHR] 1.53, 95% confidence interval [CI] 1.38-1.71) and endometrial cancer (aHR 1.25, 95% CI 1.11-1.40), but not of breast cancer (aHR 0.96, 95% CI 0.92-1.01). Ovarian cancer incidence was higher in women diagnosed with endometriosis, and in nulliparous women with ovulatory disturbances, compared to women with none of the diagnoses. Endometrial cancer incidence was higher in women with ovulatory disturbances, but not in women with endometriosis. These findings suggest that infertility could have long-term consequences of importance to physicians and public health workers.

A prospective investigation of perceived stress, infertility-related stress, and cortisol levels in women undergoing in vitro fertilization: influence on embryo quality and clinical pregnancy rate.

INTRODUCTION: Women undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self-reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes. MATERIAL AND METHODS: A prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. RESULTS: Ultrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively. CONCLUSIONS: Perceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome.

Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study.

BACKGROUND: Ovarian stimulation drugs, in particular hormonal agents used for controlled ovarian stimulation (COS) required to perform in vitro fertilization, increase estrogen and progesterone levels and have therefore been suspected to influence breast cancer risk. This study aims to investigate whether infertility and hormonal fertility treatment influences mammographic density, a strong hormone-responsive risk factor for breast cancer. METHODS: Cross-sectional study including 43,313 women recruited to the Karolinska Mammography Project between 2010 and 2013. Among women who reported having had infertility, 1576 had gone through COS, 1429 had had hormonal stimulation without COS and 5958 had not received any hormonal fertility treatment. Percent and absolute mammographic densities were obtained using the volumetric method Volpara™. Associations with mammographic density were assessed using multivariable generalized linear models, estimating mean differences (MD) with 95 % confidence intervals (CI). RESULTS: After multivariable adjustment, women with a history of infertility had 1.53 cm(3) higher absolute dense volume compared to non-infertile women (95 % CI: 0.70 to 2.35). Among infertile women, only those who had gone through COS treatment had a higher absolute dense volume than those who had not received any hormone treatment (adjusted MD 3.22, 95 % CI: 1.10 to 5.33). No clear associations were observed between infertility, fertility treatment and percent volumetric density. CONCLUSIONS: Overall, women reporting infertility had more dense tissue in the breast. The higher absolute dense volume in women treated with COS may indicate a treatment effect, although part of the association might also be due to the underlying infertility. Continued monitoring of cancer risk in infertile women, especially those who undergo COS, is warranted.

Cancer risks in twins and singletons from twin and non-twin families.

The unique intrauterine environment has been proposed to put twins at increased risk of certain cancers compared to singletons, still large population comparisons have generally indicated lower risks in twins. To improve the understanding of potential twin influence on cancer we compared twins to their singletons siblings, to target a unique twinning influence. Singletons from twin families were contrasted to singletons from non-twin families to further capture potential twin family influence on risk of cancer. Family relations were identified using the Swedish Multi-Generation Register. Among individuals born between 1932 and 1958, 49,156 twins and N = 35,227 singletons were identified from 18,098 unique twin families. All incident cases of specific cancer types were identified in the National Cancer Register up to the end of 2007. Standardized survival functions were estimated using weighted Cox proportional hazard regression and the corresponding cumulative risks plotted against age. Overall, primary cancers were identified in 9% and 18% of all male and female twins, compared to 11% and 19% of their male and female singleton siblings. When specific cancer sites were compared using standardized cumulative risk plots, no consistent statistically significant differences were noted either between twins and singletons of twin families or between singletons of twin and non-twin families. Despite a different intrauterine experience, twinning does not seem to have any greater negative influence on life-time risks of cancer. The findings also indicate that twin family membership has no substantial influence on cancer risks.

Somatic Comorbidity in Women with Overactive Bladder Syndrome.

PURPOSE: We explore the influence of co-occurring somatic illnesses on prevalent overactive bladder in women of premenopausal age. MATERIALS AND METHODS: Data for the present study were derived from a nationwide survey on complex diseases among all twins in the Swedish Twin Registry born 1959 to 1985. The present study was limited to female twins participating in the survey (12,850). Generalized estimating equations were used to estimate odds ratios with 95% CIs. Environmental and genetic influences were assessed in co-twin control analysis. RESULTS: Generalized estimating equations analysis showed a significant association between overactive bladder and migraine (OR 1.34, 95% CI 1.15-1.57), fibromyalgia (1.83, 1.54-2.18), chronic fatigue (1.81, 1.49-2.19) and eating disorders (1.56, 1.24-1.96). There was also a significant association with allergic disorders including asthma (1.24, 1.01-1.52) and eczema (1.22, 1.04-1.43). Among reproductive disorders, urinary tract infections (1.60, 1.40-1.84), dysmenorrhea (1.53, 1.33-1.76) and pelvic pain (1.60, 1.31-1.94) showed the strongest association with overactive bladder. Results from co-twin control analysis indicated that the significant associations observed in generalized estimating equations analysis were influenced by environmental and genetic factors without a common pathway model. CONCLUSIONS: Our results suggest a multifactorial and complex pathogenesis of overactive bladder in which associations between various somatic illnesses and overactive bladder may be affected by environmental and genetic factors.

Risk for childhood leukemia associated with maternal and paternal age.

The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies.

Does urinary incontinence have fetal origins? Results from a nationwide twin study.

INTRODUCTION AND HYPOTHESIS: The aim of this study is to evaluate the effect of birth weight and being born small for gestational age (SGA) on urinary incontinence (UI) among premenopausal women. METHODS: In 2005, a total of 14,094 female twins born 1959-1985 who had been included in the Swedish Twin Registry participated in a survey on common exposures and complex diseases, including urinary incontinence. Information regarding birth weight and gestational age was obtained from the Medical Birth Register (for twins born 1973-1985) and from the medical archives (for twins born 1959-1972). A logistic regression model based on generalized estimating equations was used to estimate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: In both crude and adjusted analysis, birth weight and SGA had no effect on UI. An interaction between low birth weight (<2,500 g) and body mass index (BMI) later in life was found for overall and stress UI. Compared with women who were not overweight and had a birth weight above 2,500 g, overweight women (BMI ≥ 25) who had a normal birth weight had a 35 % higher odds of incontinence , while overweight women who had a low birth weight had an approximately 85 % higher odds of UI (OR = 1.84, 95 % CI 1.39-2.45 for overall UI; OR = 1.83, 95 % CI 1.35-2.48 for stress UI). CONCLUSIONS: Birth weight and SGA had no direct effect on urinary incontinence; however, low birth weight in combination with an elevated adult BMI may contribute to the risk of urinary incontinence later in life.

Maternal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births.

This study examines the familial clustering and relative influence of genetic and environmental effects on postterm birth in the Swedish population by considering all full- and half-siblings born in Sweden between 1992 and 2004. Of the eligible 475,429 births, 21% occurred after 41 completed weeks and 5.5% occurred after 42 completed weeks of gestation. Odds of postterm birth increased if mothers were older, heavier, more educated, primiparous, or carrying a male fetus. The highest odds increase was seen in women with a previous postterm birth, both with the same partner (odds ratio = 4.4, 95% confidence interval: 4.0, 4.6) and after a partner change (odds ratio = 3.4, 95% confidence interval: 2.9, 3.9). Sisters of women with a postterm birth were also at increased odds of postterm birth (odds ratio = 1.8, 95% confidence interval: 1.6, 2.0) while brothers' partners were not. Half of the variation in postterm birth could not be explained by factors shared in families, and the remaining half was explained by genetic factors, namely fetal (26%) and maternal (21%) genetic factors. Familial clustering of postterm birth is attributed to genetic effects, and fetal genetic effects have a considerable influence on the liability of postterm birth.

Depression, neuroticism, and urinary incontinence in premenopausal women: a nationwide twin study.

Previous studies have found that major depression and neuroticism are positively associated with urinary incontinence (UI). However, the genetic contribution to these associations has never been investigated. In 2005, a total of 14,094 female twins born 1959-1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on UI, depressive symptoms, major depression, and neuroticism. A logistic regression model based on generalized estimating equations (GEE) was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Environmental and genetic influences were assessed in co-twin control analyses and quantitative genetic analyses, which were also used to determine the proportion of the phenotypic correlation explained by familial factors. Major depression, depressive symptoms, and neuroticism were positively associated with all UI subtypes (overall, stress, urge, and mixed UI). In a trivariate Cholesky model with neuroticism, depressive symptoms (or depression), and UI a modest genetic correlation was found between indicators of depression and overall, or stress, UI. The majority of this correlation was independent from neuroticism. In contrast, the genetic factors shared between indicators of depression and urge or mixed UI were entirely in common with neuroticism. In conclusion, depression and neuroticism are associated with UI among premenopausal women: the associations are in part determined by genetic factors in common to the disorders.

Autism and mental retardation among offspring born after in vitro fertilization.

IMPORTANCE: Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. OBJECTIVE: To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. DESIGN, SETTING, AND PARTICIPANTS: A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered. MAIN OUTCOMES AND MEASURES: Relative risks (RRs) for autistic disorder and mental retardation and rates per 100,000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons. RESULTS: Of the more than 2.5 million infants born, 30,959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 children (1.5%) with autistic disorder and 180 of 15,830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% CI, 0.94-1.39; 19.0 vs 15.6 per 100,000 person-years). The RR for mental retardation was 1.18 (95% CI, 1.01-1.36; 46.3 vs 39.8 per 100,000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons. Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR, 4.60 [95% CI, 2.14-9.88]; 135.7 vs 29.3 per 100,000 person-years); for mental retardation following ICSI using surgically extracted sperm and fresh embryos (RR, 2.35 [95% CI, 1.01-5.45]; 144.1 vs 60.8 per 100,000 person-years); and following ICSI using ejaculated sperm and fresh embryos (RR, 1.47 [95% CI, 1.03-2.09]; 90.6 vs 60.8 per 100,000 person-years). When restricting the analysis to singletons, the risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100,000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100,000 person-years). CONCLUSIONS AND RELEVANCE: Compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small.

Birth weight predicts risk of cardiovascular disease within dizygotic but not monozygotic twin pairs: a large population-based co-twin-control study.

BACKGROUND: The widely reported inverse association between birth weight and risk of cardiovascular disease (CVD) has sparked theories about early life determinants of adult disease. Within-twin-pair analysis provides a unique opportunity to investigate whether factors shared within twin pairs influence the association. METHODS AND RESULTS: In a population-based cohort of like-sexed twins with known zygosity born in Sweden from 1926 to 1958, disease-discordant twin pairs were identified through linkage to the National Inpatient and Cause of Death registers between 1973 and 2006. Co-twin-control analyses were performed on twins discordant for cardiovascular disease (n=3884), coronary heart disease (n=2668), and stroke (n=1372). Overall, inverse associations between birth weight and risk of cardiovascular diseases were seen within dizygotic but not monozygotic twin pairs. In dizygotic twins, the odds ratios for a 1-kg within-pair increase in birth weight were 0.74 (95% confidence interval, 0.56 to 0.98) for coronary heart disease and 0.57 (95% confidence interval, 0.37 to 0.88) for stroke. Conversely, no statistically significant associations were found within monozygotic twins (for coronary heart disease: odds ratio, 1.10; 95% confidence interval, 0.73 to 1.68; for stroke: odds ratio, 0.92; 95% confidence interval, 0.48 to 1.80). CONCLUSIONS: We found an association between birth weight and risk of cardiovascular disease within disease-discordant dizygotic but not monozygotic twin pairs. This indicates that the association between birth weight and cardiovascular disease could be a result of common causes, and that factors that vary within dizygotic but not monozygotic twin pairs may help identify them.

Perinatal characteristics and risk of polio among Swedish twins.

Prenatal exposure to adverse environmental conditions is related to increased adult mortality in regions where infections are highly prevalent, yet there is little evidence of the impact of perinatal conditions on the risk of severe infections throughout life. Using prospectively collected data from 21 604 like-sexed Swedish twins of known zygosity born in 1926-1958, we examined the risk of polio in relation to perinatal characteristics using cohort and nested co-twin case-control analyses. Polio incidence was determined through an interview in 1998, and linkage with the Swedish national inpatient and death registries. There were 133 cases of polio. In the cohort analysis, birth length, birthweight and head circumference were positively associated with polio risk. After adjustment for sex, birth year, gestational age at birth and within-twin pair correlations, twins of shortest length (<44 cm) had a 67% ([95% CI: 6%, 88%]; P=0.04) lower risk of polio compared with the reference group (47-49 cm). After additional adjustment for birth length, every 100-g increase in birthweight was related to a 34% increased risk of polio ([95% CI: -1%, 82%]; P=0.06), and every 10-mm increase in head circumference was related to a 17% greater risk of polio ([95% CI: 5%, 31%]; P=0.004). In co-twin control analyses among 226 disease-discordant twins, birth length, birthweight and head circumference were 0.3 cm (P=0.19), 84 g (P=0.07) and 3 mm (P=0.08) higher in cases than controls, respectively. Similar associations were observed among monozygotic (n=84) and dizygotic (n=142) twins. These findings suggest that early intrauterine growth restriction may be inversely related to the incidence of polio.

Maternal smoking during pregnancy and risks of suicidal acts in young offspring.

Obstetric and neonatal complications have been associated with completed and attempted suicide (suicidal acts) in young offspring. Maternal smoking is one of the most important risk factors for obstetric complications, but the association between prenatal smoking exposure and offspring risk of suicidal acts is unknown. We performed a population-based study of 1,449,333 single births born in Sweden between 1983 and 1996, derived from linked registry data. Maternal smoking and risks of suicidal acts in offspring were estimated using hazard ratios, derived from proportional-hazard models, controlling for potential confounding of parental socio-demographic factors and psychiatric care in first degree relatives. To control for unmeasured familial confounding, a matched case-control analysis of suicidal acts was performed within sibling pairs discordant for prenatal smoking exposure. In the cohort analysis, the adjusted hazard ratio for completed suicide among offspring to women smoking 1-9 cigarettes and at least 10 cigarettes per day were 1.67, 95% confidence interval (CI), 1.29-2.16, and 1.54, 95% CI, 1.12-2.10. For suicidal acts, corresponding hazard ratios were 1.28, 95% CI 1.21-1.35 and 1.48, 95% CI 1.39-1.57, respectively. However, in sibling pairs discordant for suicidal acts and prenatal smoking exposure, we found no evidence that prenatal smoking exposure increased the risk of suicidal acts. We conclude that the association between prenatal smoking exposure and offspring risk of suicidal acts is probably confounded by unmeasured familial factors.

Evidence for an effect of fetal growth on the risk of tuberculosis.

We examined the risk of tuberculosis in relation to birth weight and ponderal index among 21,596 Swedish twins born from 1926 through 1958. Using a cohort design, tuberculosis risk was 11% lower for every 500 g of birth weight (P = .05) and 8% lower for every 0.2 of ponderal index, calculated as birth weight in grams multiplied by 100 and divided by the cube of birth length in centimeters (P = .08). The association between birth weight and tuberculosis was stronger in male individuals than in female individuals. In co-twin control analyses among disease-discordant monozygotic twins, tuberculosis risk was 46% lower for every 500 g of birth weight (P = .05). The association was stronger in male individuals (87% risk reduction; P = .02) than it was in female individuals (16% reduction; P = .62). A similarly stronger relation with male sex, compared with female sex, was found for ponderal index. Because associations among monozygotic twins are largely independent of shared genetic or environmental factors, we postulate that fetal growth may play a causal role in susceptibility to tuberculosis, possibly through early programming of immunity.

Rheumatoid arthritis, treatment with corticosteroids and risk of malignant lymphomas: results from a case-control study.

BACKGROUND: Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk. OBJECTIVE: To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma. METHODS: In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression. RESULTS: A total duration of oral steroid treatment of <2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment >2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94). CONCLUSION: In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.