Maternal use of folic acid and multivitamin supplements and infant risk of birth defects in Norway, 1999-2013.

The association between folic acid supplementation and birth defects other than neural tube defects (NTD) remains unclear. We used a log-binomial regression model to investigate if periconceptional folic acid and/or multivitamin use was associated with birth defects in Norway with prospectively collected data from the Medical Birth Registry of Norway (MBRN) during 1999-2013. We used the European Surveillance of Congenital Anomalies (EUROCAT) classification system to define eleven organ-specific major birth defect groups (nervous system, eye, ear-face-neck, cardiovascular system, respiratory system, oral clefts, digestive system, abdominal wall, urinary system, genital organs and limb), with additional subgroups. Fetuses or infants whose mothers used folic acid and/or multivitamin supplements before and during pregnancy were classified as exposed. During the years 1999-2013, 888 294 (99·0 %) live-born infants, 6633 (0·7 %) stillborn infants and 2135 (0·2 %) fetuses from terminated pregnancies due to fetal anomalies were registered in the MBRN. Among the live- and stillborn infants of women who used vitamin supplements compared with infants of non-users, the adjusted relative risk (aRR) was 0·94 (95 % CI 0·91, 0·98) for total birth defects (n 18 382). Supplement use was associated with reduced risk of abdominal wall defects (aRR 0·58; 95 % CI 0·42, 0·80, n 377), genital organ defects (aRR 0·81; 95 % CI 0·72, 0·91, n 2299) and limb defects (aRR 0·81; 95 % CI 0·74, 0·90, n 3409). Protective associations were also suggested for NTD, respiratory system defects and digestive system defects although CI included the null value of 1. During the full study period, statistically significant associations between supplement use and defects in the eye, ear-face-neck, heart or oral clefts were not observed.

Recurrence of congenital heart defects among siblings-a nationwide study.

Congenital heart defects (CHD) constitute the largest group of congenital malformations. In most families, only one person has CHD; however, the risk of CHD increases for children born into families already affected. In this study, all births from 1994 through 2009 were identified in the Medical Birth Registry of Norway, including supplemental information on CHD from clinical and administrative registers, as part of the CVDNOR project. By using the unique personal identification number of each parent we were able to link 16,078 pairs of twins, 445,584 pairs of full siblings, and 106,840 pairs of half-siblings. Sibling recurrence risk ratio (RRR) was calculated using CHD status in the oldest sibling as exposure and CHD status in the younger sibling as outcome, adjusted for year of birth, maternal age, and maternal diabetes. Among full sibling pairs with CHD in the older sibling, the younger sibling had CHD in 4.1% compared to 1.1% of the pairs without CHD in the older sibling (adjusted RRR 3.6; 95% confidence interval (CI) 3.1-4.1). In same-sex twins the RRR was 14.0 (95% CI 10.6-18.6), and in opposite-sex twins the RRR was 11.9 (95% CI 7.1-19.9). For half-siblings the RRR was 1.5 (95% CI 0.8-2.8). When restricting to severe types of CHD, the RRR was 6.9 (95% CI 4.9-9.8) for full siblings. In 50% of the pairs with recurrent CHD, the siblings had similar types of CHD. The high relative risk of recurrence indicates that familial risk factors are important in the etiology of CHD.

Plasma Biomarkers of Inflammation, the Kynurenine Pathway, and Risks of All-Cause, Cancer, and Cardiovascular Disease Mortality: The Hordaland Health Study.

We aimed to evaluate 10 biomarkers related to inflammation and the kynurenine pathway, including neopterin, kynurenine:tryptophan ratio, C-reactive protein, tryptophan, and 6 kynurenines, as potential predictors of all-cause and cause-specific mortality in a general population sample. The study cohort was participants involved in a community-based Norwegian study, the Hordaland Health Study (HUSK). We used Cox proportional hazards models to assess associations of the biomarkers with all-cause mortality and competing-risk models for cause-specific mortality. Of the 7,015 participants, 1,496 deaths were recorded after a median follow-up time of 14 years (1998-2012). Plasma levels of inflammatory markers (neopterin, kynurenine:tryptophan ratio, and C-reactive protein), anthranilic acid, and 3-hydroxykynurenine were positively associated with all-cause mortality, and tryptophan and xanthurenic acid were inversely associated. Multivariate-adjusted hazard ratios for the highest (versus lowest) quartiles of the biomarkers were 1.19-1.60 for positive associations and 0.73-0.87 for negative associations. All of the inflammatory markers and most kynurenines, except kynurenic acid and 3-hydroxyanthranilic acid, were associated with cardiovascular disease (CVD) mortality. In this general population, plasma biomarkers of inflammation and kynurenines were associated with risk of all-cause, cancer, and CVD mortality. Associations were stronger for CVD mortality than for mortality due to cancer or other causes.

Markers of vitamin B6 status and metabolism as predictors of incident cancer: the Hordaland Health Study.

Dietary intake and/or circulating concentrations of vitamin B6 have been associated with risk of cancer, but results are inconsistent and mechanisms uncertain. Pyridoxal 5'-phosphate (PLP) is the most commonly used marker of B6 status. We recently proposed the ratio 3-hydroxykynurenine/xanthurenic acid (HK/XA) as an indicator of functional vitamin B6 status, and the 4-pyridoxic acid (PA) /(pyridoxal (PL) +PLP) ratio (PAr) as a marker of vitamin B6 catabolism during inflammation. We compared plasma PLP, HK/XA and PAr as predictors of cancer incidence in a prospective community-based cohort in Norway. This study included 6,539 adults without known cancer at baseline (1998-99) from the Hordaland Health Study (HUSK). HR and 95% CI were calculated for the risk of overall and site-specific cancers using multivariate Cox proportional hazards regression with adjustment for potential confounders. After a median follow-up time of 11.9 years, 963 cancer cases (501 men and 462 women) were identified. Multivariate-adjusted Cox-regression showed no significant relation of plasma PLP or HK/XA with risk of incident cancer. In contrast, PAr was significantly associated with risk of cancer with HR (95% CI) = 1.31 (1.12-1.52) per two standard deviation (SD) increment (p < 0.01). Further analysis showed that PAr was a particular strong predictor of lung cancer with HR (95% CI) = 2.46 (1.49-4.05) per two SD increment (p < 0.01). The present results indicate that associations of vitamin B6 with cancer may be related to increased catabolism of vitamin B6, in particular for lung cancer where inflammation may be largely involved in carcinogenesis.

Interferon-γ-induced inflammatory markers and the risk of cancer: the Hordaland Health Study.

BACKGROUND: It has been reported that interferon-γ (IFN-γ)-induced inflammatory markers, such as circulating neopterin and kynurenine-to-tryptophan ratio (KTR), are increased in patients with cancer and are also a predictor of poor prognosis. However, whether baseline levels of these makers are associated with subsequent cancer risk in the general population remains unknown. METHODS: We conducted a prospective analysis of the Hordaland Health Study in 6594 adults without known cancer at baseline who were enrolled between April 1998 and June 1999. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariate Cox proportional hazards regression models adjusted for sex, age, body mass index, smoking status, and renal function. RESULTS: A total of 971 incident cancer cases (507 men and 464 women) were identified over a median follow-up time of 12 years. Baseline plasma neopterin, KTR and C-reactive protein (CRP) were significantly associated with an increased risk of overall cancer in models adjusted for covariates (P for trend across quartiles = .006 for neopterin, .022 for KTR, and .005 for CRP). The multivariate-adjusted HR (95% CI) per SD increment in similar models were 1.09 (1.03-1.16) for neopterin, 1.07 (1.01-1.14) for KTR, and 1.04 (0.98-1.10) for CRP. The associations between the inflammatory markers and risk of major specific cancer types were also provided. CONCLUSIONS: Our findings indicate that plasma neopterin, KTR, and CRP are associated with a significantly increased risk of overall cancer. Our study revealed novel evidence regarding the role of IFN-γ-induced inflammation in human carcinogenesis.

Discrepancy in term calculation from second trimester ultrasound scan versus last menstrual period in women with type 1 diabetes.

OBJECTIVE: To study differences in ultrasound-based compared to menstrual-based term estimation in women with type 1 diabetes. DESIGN: Nationwide register study. SETTING: Norway. POPULATION: Deliveries in Norway 1999-2004 by women registered in the Norwegian Childhood Diabetes Registry (n = 342) and the background population (n = 307 248), with data on both ultrasound-based and menstrual-based gestational age notified in the Birth Registry of Norway. Births with major malformations were excluded. METHODS: Linkage of two nationwide registries, the Medical Birth Registry of Norway and the Norwegian Childhood Diabetes Registry. MAIN OUTCOME MEASURES: Estimated gestational age at delivery based on routine second trimester ultrasound measurements and last menstrual period. RESULTS: In women with type 1 diabetes, the distribution of gestational age at delivery was shifted considerably towards a lower gestational age when using second trimester ultrasound data for estimation, compared with last menstrual period data. The difference between the two estimation methods was larger among women with type 1 diabetes, although also evident in the general population. One in four women with diabetes and a certain last menstrual period date had their ultrasound-calculated term postponed 1 week or more, while one in 10 had it postponed 2 weeks or more. Corresponding numbers in the background population were one in five and one in 20. CONCLUSIONS: We found a systematic postponement of ultrasound-based compared with menstrual-based term estimation in women with type 1 diabetes. Relying solely on routine ultrasound-based term calculation for delivery decision may imply a risk of going beyond an optimal pregnancy length.

Evaluation of the body adiposity index in a Caucasian population: the Hordaland health study.

In this study, we compared the relationships of body mass index (BMI) and body adiposity index (BAI) with body fat percentage (BF%) in a Caucasian, European population. BF% was measured by dual-energy x-ray absorptiometry in a population-based cross-sectional study of 5,193 middle-aged (47-49 years) and elderly (71-74 years) men and women from the Hordaland Health Study in western Norway from 1997 to 1999. In the total population, the correlation between BAI and BF% was stronger (r = 0.78) than the correlation between BMI and BF% (r = 0.56) with similar results in the middle-aged and elderly groups. However, in men and women separately, BMI was a better correlate of BF% (for men, r = 0.76; for women, r = 0.81) than was BAI (for men, r = 0.57; for women, r = 0.72). BMI was also a better correlate of BF% than was BAI assessed by partial correlations adjusted for sex (for BMI-BF%, r = 0.79; for BAI-BF%, r = 0.67). Bland-Altman plots and BF%-stratified analyses showed that BAI tended to overestimate BF% in lean subjects and to underestimate it in those with higher proportions of body fat, but that it predicted BF% well for those whose BMI was in a normal range. At the individual level and in population studies adjusted for sex, BMI outperforms BAI as a predictor of BF%.

Cognitive function in an elderly population: interaction between vitamin B12 status, depression, and apolipoprotein E ε4: the Hordaland Homocysteine Study.

OBJECTIVE: To investigate the cross-sectional relation between metabolic markers of vitamin B(12) status and cognitive performance, and possible effect modification by the presence of depression and apolipoprotein E (ApoE) ε4. METHODS: This is a population-based study of 1935 participants, aged 71 to 74 years, from Norway. Participants were administered a cognitive test battery, and vitamin B(12) status was assessed by measurements of plasma vitamin B(12), holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine. RESULTS: The geometric mean (95% confidence interval) for vitamin B(12) was 348 pM (341-354), whereas 5.9% of participants had vitamin B(12) levels lower than 200 pM. In linear regression analyses, holoTC (p = .039) and the holoTC/vitamin B(12) ratio (p = .013) were positively related, whereas MMA (p = .010) was inversely related, to global cognition, after adjustment for sex, education, ApoE status, plasma creatinine, and history of diabetes, cardiovascular disease, hypertension, and depression. Among those positive for ApoE ε4, but not among those without the ε4 allele, plasma vitamin B(12) was positively associated with global cognition (p = .015), whereas MMA was inversely related to global cognition (p = .036) and executive function (p = .014). In participants with depression, MMA was inversely associated with global cognition (p < .001) and episodic memory (p = .001). CONCLUSIONS: Among the well-nourished elderly, low vitamin B(12) status is associated with cognitive deficit, particularly in those with the ApoE ε4 allele or with depression.

Exposure to antiepileptic drugs in utero and child development: a prospective population-based study.

PURPOSE: Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development. METHODS: From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight. KEY FINDINGS: A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range. SIGNIFICANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Plasma free choline, betaine and cognitive performance: the Hordaland Health Study.

Choline and betaine are nutrients involved in one-carbon metabolism. Choline is essential for neurodevelopment and brain function. We studied the associations between cognitive function and plasma concentrations of free choline and betaine. In a cross-sectional study, 2195 subjects (55 % women), aged 70-74 years, underwent extensive cognitive testing including the Kendrick Object Learning Test (KOLT), Trail Making Test (part A, TMT-A), modified versions of the Digit Symbol Test (m-DST), Block Design (m-BD), Mini-Mental State Examination (m-MMSE) and Controlled Oral Word Association Test (COWAT). Compared with low concentrations, high choline (>8·4 µmol/l) was associated with better test scores in the TMT-A (56·0 v. 61·5, P=0·004), m-DST (10·5 v. 9·8, P=0·005) and m-MMSE (11·5 v. 11·4, P=0·01). A generalised additive regression model showed a positive dose-response relationship between the m-MMSE and choline (P=0·012 from a corresponding linear regression model). Betaine was associated with the KOLT, TMT-A and COWAT, but after adjustments for potential confounders, the associations lost significance. Risk ratios (RR) for poor test performance roughly tripled when low choline was combined with either low plasma vitamin B12 (≤257 pmol/l) concentrations (RR(KOLT)=2·6, 95 % CI 1·1, 6·1; RR(m-MMSE)=2·7, 95 % CI 1·1, 6·6; RR(COWAT)=3·1, 95 % CI 1·4, 7·2) or high methylmalonic acid (MMA) (≥3·95 µmol/l) concentrations (RR(m-BD)=2·8, 95 % CI 1·3, 6·1). Low betaine (≤31·1 µmol/l) combined with high MMA was associated with elevated RR on KOLT (RR(KOLT)=2·5, 95 % CI 1·0, 6·2). Low plasma free choline concentrations are associated with poor cognitive performance. There were significant interactions between low choline or betaine and low vitamin B12 or high MMA on cognitive performance.

Dietary intake of protein is positively associated with percent body fat in middle-aged and older adults.

Data on associations between dietary intake of macronutrients and body composition in the general population are sparse. This population-based, cross-sectional study of 4478 middle-aged (47-49 y) and elderly (71-74 y) men and women from the Hordaland Health Study in western Norway was conducted using a validated FFQ and measurements by dual-energy X-ray absorptiometry. The relation between macronutrient intake [percentage of total energy intake (E%)] and percent body fat was investigated in the total population and in a subgroup with intermediate BMI and stable weight (BMI within the 25th-75th percentile and weight change <5% during the last 6 y; n = 975). In the total population, protein intake (E%) was associated with higher percent body fat (partial r = 0.11; P < 0.001) in multivariate linear regression analysis. In the subgroup with intermediate BMI and stable weight, there was no association between protein intake (E%) and percent body fat. Fat intake (E%) was positively associated (partial r = 0.07) whereas carbohydrate intake (E%) was inversely associated (partial r = -0.07) with percent body fat (P = 0.042 for both) in the subgroup with intermediate BMI and stable weight. Both in the total population and in the stable weight group, physical activity was inversely related to adiposity (partial r = -0.15 and -0.12, respectively; P < 0.001). Our results may explain some of the conflicting data on the effects of macronutrients in different populations and suggest the potential importance of protein intake as a factor in obesity.

Long- and short-term effects of tobacco smoking on circulating concentrations of B vitamins.

BACKGROUND: Smoking is associated with decreased concentrations of several antioxidant vitamins. We sought to determine the relation between circulating concentrations of selected B vitamins and smoking status, with particular attention to longitudinal associations. METHODS: We used baseline data from 2 B-vitamin intervention trials that included 6837 patients with ischemic heart disease. Smoking habits were ascertained by interview. Vitamins and metabolites, including the nicotine metabolite cotinine, were measured in plasma and serum by microbiological assays or gas/liquid chromatography-tandem mass spectrometry. RESULTS: The highest circulating concentrations of folate and pyridoxal 5'phosphate (PLP) and lowest concentrations of total plasma homocysteine, a functional marker of folate status, were observed for self-reported never smokers, followed by self-reported ex-smokers and current smokers (P(trend) < 0.001). Cobalamin and its functional marker methylmalonic acid were not associated with smoking status. Based on their low cotinine concentrations, we were able to identify a group of smokers that had abstained from smoking for 3 days or more. Compared with smokers with high plasma cotinine, smokers with low cotinine had significantly higher circulating concentrations of folate, PLP, and riboflavin (all P < 0.005), and this trend continued for ex-smokers, with increasing time since smoking cessation. CONCLUSIONS: Smoking lowered circulating concentrations of folate, PLP, and riboflavin, but concentrations increased significantly after a few days of smoking cessation. We propose that short-term effects may be related to acute smoking-induced oxidative stress, whereas the longer-lasting effects among ex-smokers may reflect changes in diet and/or restoration of vitamin concentrations in tissue during the first few months to years after smoking cessation.

Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004.

OBJECTIVE: To estimate the risk of congenital anomalies in offspring of women with type 1 diabetes in Norway during recent years. DESIGN: Nationwide population-based study using the Medical Birth Registry of Norway and the Norwegian type 1 Diabetes Registry. SETTING: All birth clinics in Norway. PARTICIPANTS: All births in Norway during 1999-2004 (N = 350,961), of which 1,583 were births by a mother registered with pregestational type 1 diabetes. MAIN OUTCOME MEASURE: Congenital anomalies, excluding minor anomalies according to the EUROCAT system. RESULTS: Anomalies were registered in 5.7% of offspring of women with type 1 diabetes, and in 2.9% among the background population (odds ratio 2.1, 95% CI: 1.7-2.6). Cardiovascular anomalies were registered in 3.2% in the diabetes group and 0.94% in the background population (odds ratio 3.5, 95% CI: 2.7-4.7). Results were similar when restricted to women identified with type 1 diabetes through the Diabetes Registry. CONCLUSIONS: Women in Norway with type 1 diabetes experience a significantly higher risk of congenital anomalies in their babies compared with the background population.

Heart failure in Norway, 2000-2014: analysing incident, total and readmission rates using data from the Cardiovascular Disease in Norway (CVDNOR) Project.

AIMS: To examine trends in heart failure (HF) hospitalization rates and risk of readmissions following an incident HF hospitalization. METHODS AND RESULTS: During 2000-2014, we identified in the Cardiovascular Disease in Norway Project 142 109 hospitalizations with HF as primary diagnosis. Trends of incident and total (incident and recurrent) HF hospitalization rates were analysed using negative binomial regression models. Changes over time in 30-day and 3-year risk of HF recurrences or cardiovascular disease (CVD)-related readmissions were analysed using Fine and Grey competing risk regression, with death as competing events. Age-standardized rates declined on average 1.9% per year in men and 1.8% per year in women for incident HF hospitalizations (both Ptrend < 0.001) but did not change significantly in either men or women for total HF hospitalizations. In men surviving the incident HF hospitalization, 30-day and 3-year risk of a HF recurrent event increased 1.7% and 1.2% per year, respectively. Similarly, 30-day and 3-year risk of a CVD-related hospitalization increased 1.5% and 1.0% per year, respectively (all Ptrend < 0.001). No statistically significant changes in the risk of HF recurrences or CVD-related readmissions were observed among women. In-hospital mortality for a first and recurrent HF episode declined over time in both men and women. CONCLUSIONS: Incident HF hospitalization rates declined in Norway during 2000-2014. An increase in the risk of recurrences in the context of reduced in-hospital mortality following an incident and recurrent HF hospitalization led to flat trends of total HF hospitalization rates.

Determinants of plasma methylmalonic acid in a large population: implications for assessment of vitamin B12 status.

BACKGROUND: Methylmalonic acid (MMA) in plasma or serum is widely used for assessment of vitamin B(12) status. However, data are sparse regarding factors, besides renal function, that may influence MMA concentrations. We searched for important determinants of plasma MMA in the general population. METHODS: In 6946 middle-aged (47-49 years) and elderly (71-74 years) individuals from the Hordaland Homocysteine Study in Norway, we collected anthropometric measurements, lifestyle data, and plasma MMA, vitamin B(12), and creatinine measurements. For 5820 individuals, we also collected dietary data. RESULTS: Age and plasma creatinine were positively associated with plasma MMA, whereas plasma vitamin B(12) was negatively associated. These variables together with sex were the strongest determinants of plasma MMA, accounting for 16% of the variation (R(2) = 0.16). Addition of anthropometric measures and lifestyle and dietary factors only gave slight improvement (total R(2) = 0.167). Increased plasma MMA was seen when plasma vitamin B(12) was <400 pmol/L. In individuals with vitamin B(12) >or =400 micromol/L (vitamin B(12)-replete), the 2.5th-97.5th percentile reference limits for MMA were 0.10-0.28 micromol/L (middle-aged) and 0.10-0.36 micromol/L (elderly). When plotted against creatinine (nomograms), the 97.5th percentile of MMA was similar in men and women but approximately 0.15 micromol/L higher in elderly than middle-aged individuals. Vitamin B(12)-replete participants had MMA upper limits approximately 0.1 micromol/L (elderly) and 0.04 micromol/L (middle-aged) below those of the unselected population at all creatinine concentrations. CONCLUSIONS: Identified determinants accounted for <17% of the overall variation in plasma MMA. The difference in MMA between middle-aged and elderly individuals is only partly explained by creatinine and vitamin B(12) concentrations.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study.

The authors investigated a possible association of supplemental folic acid and multivitamin use with placental abruption by using data on 280,127 singleton deliveries recorded in 1999-2004 in the population-based Medical Birth Registry of Norway. Odds ratios, adjusted for maternal age, marital status, parity, smoking, pregestational diabetes, and chronic hypertension, were estimated with generalized estimating equations for logistic regression models. Use of folic acid and/or multivitamin supplements before or any time during pregnancy was reported for 36.4% of the abruptions (0.38% of deliveries) and 44.4% of the nonabruptions. Compared with no use, any supplement use was associated with a 26% risk reduction of placental abruption (adjusted odds ratio = 0.74, 95% confidence interval: 0.65, 0.84). Women who had taken folic acid alone had an adjusted odds ratio of 0.81 (95% confidence interval: 0.68, 0.98) for abruption, whereas multivitamin users had an adjusted odds ratio of 0.72 (95% confidence interval: 0.57, 0.91), relative to supplement nonusers. The strongest risk reduction was found for those who had taken both folic acid and multivitamin supplements (adjusted odds ratio = 0.68, 95% confidence interval: 0.56, 0.83). These data suggest that folic acid and other vitamin supplementation during pregnancy may be associated with reduced risk of placental abruption.

Mortality after long-term sickness absence: prospective cohort study.

BACKGROUND: The study estimated the excess mortality after long-term sickness absence (LTSA), and identified socio-demographic and diagnostic risk factors of death. METHODS: Prospective cohort study during 1994-2003 in a Norwegian county with 256,654 inhabitants aged 16-62 years. A representative sample of 3386 persons with a spell of sickness absence >8 weeks was compared with the total county population with respect to all cause mortality. Comparative mortality figures (CMF) for the total sample and standardized mortality rates for diagnostic groups were calculated. RESULTS: The CMFs were 1.5 (95% CI 1.1-1.9) for the female and 2.0 (95% CI 1.7-2.4) for the male sample. Among women, persons' sickness certified with cancer contributed with 43% of all deaths and standardized mortality ratios (SMR) was 16.1 (11.2-23.2). The respective figure for the men was 27% and SMR was 8.0 (5.7-11.1). SMR for men with mental diagnoses was 1.7 (95% CI 1.1-2.9) and for 'other' (respiratory, neurological, digestive) 1.8 (95% CI 1.3-2.7). Musculoskeletal cases had not elevated SMRs. Cox proportional hazard analysis with musculoskeletal cases as reference adjusted for age and income showed very high hazard ratios (HR) for cases with cancer diagnoses. Among the men, mental and 'other' diagnoses had also HR above unity. CONCLUSION: The study verified findings from Finland and the UK of excess mortality after LTSA, also when compared with the total population of the same age. Among women, cancer cases explained all the excess mortality, whereas other cases outside the musculoskeletal group also contributed among men.

The PAr index, an indicator reflecting altered vitamin B-6 homeostasis, is associated with long-term risk of stroke in the general population: the Hordaland Health Study (HUSK).

Background: Vitamin B-6 homeostasis is altered during inflammation and immune activation. It is unknown whether altered vitamin B-6 homeostasis is associated with the risk of stroke. Objective: We investigated the relation between the ratio plasma 4-pyridoxic acid: (pyridoxal + pyridoxal-5'-phosphate) (PAr) as an indicator of altered vitamin B-6 homeostasis and the risk of stroke in the general population. Design: We conducted a prospective analysis of the community-based Hordaland Health Study (HUSK) in 6891 adults (born during 1925-1927 and 1950-1951) without known stroke at baseline (1998-1999). Participants were followed via linkage to the CVDNOR (Cardiovascular Disease in Norway) project and the Cause of Death Registry. HRs and 95% CIs were calculated using Cox proportional hazards analyses. Results: A total of 390 participants (193 men and 197 women) developed stroke over a median follow-up period of 11 y. Study participants with elevated PAr experienced a higher risk of incident stroke in an essentially linear dose-response fashion. The HR (95% CI) for the highest compared with the lowest quartile of PAr was 1.97 (1.42, 2.73; P-trend <0.001) for total stroke and 2.09 (1.42, 3.09; P-trend <0.001) for ischemic stroke after adjustment for age, sex, body mass index (BMI), smoking, education, physical activity, estimated glomerular filtration rate, hypertension, diabetes, total cholesterol, and statin use. PAr had greater predictive strength than did C-reactive protein, current smoking, diabetes, hypertension, estimated glomerular filtration rate, and physical activity. The associations were similar in subgroups stratified by age group, sex, BMI, current smoking, hypertension, diabetes, and statin use at baseline. Conclusions: Higher plasma PAr was independently associated with increased risk of incident stroke in all participants and across all subgroups stratified by conventional risk predictors. Our novel findings point to and expand the range of inflammation and immune activation processes that may be relevant for the pathogenesis and prevention of stroke. This trial was registered at clinicaltrials.gov as NCT03013725.