Molecular epidemiology of hepatitis B virus infection in Norway.

BACKGROUND: Hepatitis B virus (HBV) infection remains a serious global health challenge. The widespread distribution of HBV is highlighted by multiple HBV genotypes associated with different geographical origin and transmission patterns, as well as, clinical outcomes. Investigating population HBV genotype composition and origin is therefore highly warranted. METHODS: In this molecular epidemiological study we analysed 1157 HBV S-gene sequences collected from patients in Norway, primarily in the period 2004-2011, and linked them to epidemiological data from the Norwegian surveillance system for communicable diseases. RESULTS: Of the patients with reported country of infection (n = 909), 10% (n = 93) were infected in Norway, but the majority (n = 816; 90%) stated that they became infected outside of Norway. Of the patients infected outside of Norway, most became infected in Southeast and East Asia (n = 465; 51%) and Central, West, and North Africa (n = 254; 28%). The distribution of HBV genotypes in Norway is dominated by genotype D (32%) followed by genotype A (22%), B and C (18 and 18%, respectively), and E (7%). Genotype B, C and E were phylogenetically categorized by a majority of sequences originating from distinct geographical regions, either Asia or Africa, whereas genotype A and D originated from multiple geographic regions. However, within genotype A and D, our molecular epidemiology analysis indicated a geographical clustering of sequences depending on their geographical origin. CONCLUSIONS: The majority of HBV patients in Norway became infected outside of Norway and were represented by most common genotypes. Patients stated to have been infected in Norway were found primarily within genotype A and D, and were phylogenetically characterized by both small local clusters and interspersed sequences that clustered with non-Norwegian sequences, indicating that a proportion of the patients assumed to have been infected in Norway likely became infected outside of Norway although assumed the contrary.

Importance of molecular typing in confirmation of the source of a national hepatitis A virus outbreak in Norway and the detection of a related cluster in Germany.

In March 2014, after an increase of notifications of domestically acquired hepatitis A virus infections, an outbreak investigation was launched in Norway. Sequenced-based typing results showed that these cases were associated with a strain that was identical to one causing an ongoing multinational outbreak in Europe linked to frozen mixed berries. Thirty-three confirmed cases with the outbreak strain were notified in Norway from November 2013 to June 2014. Epidemiological evidence and trace-back investigations linked the outbreak to the consumption of a berry mix cake. Identification of the hepatitis A virus outbreak strain in berries from one of the implicated cakes confirmed the cake to be the source. Subsequently, a cluster in Germany linked to the cake was also identified.

Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study.

BACKGROUND: Health authorities in numerous countries recommend periconceptional folic acid supplementation to prevent neural tube defects. The objective of this study was to examine the association of dietary folate intake and folic acid supplementation during different periods of pregnancy with the risk of spontaneous preterm delivery (PTD). METHODS: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 66,014 women with singleton pregnancies resulting in live births in 2002-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until pregnancy week 24. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,755). RESULTS: The median total folate intake was 313 µg/d (interquartile range IQR 167-558) in the overall population and 530 µg/d (IQR 355-636) in the supplement users. Eighty-five percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while only 44% initiated folic acid supplementation before pregnancy. Cox regression analysis showed that the amount of dietary folate intake (hazard ratio HR 1.00; confidence interval 95% CI 0.61-1.65) and supplemental folate intake (HR 1.00; CI 1.00-1.00) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for spontaneous PTD (HR 1.18; CI 1.05-1.32) compared to no folic acid supplementation preconception. There was no significant association with PTD when supplementation was initiated within 8 weeks preconception (HR 0.99; CI 0.87-1.13). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. CONCLUSIONS: Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Preconceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of spontaneous PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.

Intakes of garlic and dried fruits are associated with lower risk of spontaneous preterm delivery.

Several studies have found associations between microbial infections during pregnancy and preterm delivery (PTD). We investigated the influence of food with antimicrobial and prebiotic components on the risk of spontaneous PTD. A literature search identified microbes associated with spontaneous PTD. Subsequently, 2 main food types (alliums and dried fruits) were identified to contain antimicrobial components that affect the microbes associated with spontaneous PTD; they also contained dietary fibers recognized as prebiotics. We investigated intake in 18,888 women in the Norwegian Mother and Child Cohort (MoBa), of whom 950 (5%) underwent spontaneous PTD (<37 gestational weeks). Alliums (garlic, onion, leek, and spring onion) [OR: 0.82 (95% CI: 0.72, 0.94), P = 0.005] and dried fruits (raisins, apricots, prunes, figs, and dates) [OR: 0.82 (95% CI: 0.72, 0.94); P = 0.005] were associated with a decreased risk of spontaneous PTD. Intake of alliums was related to a more pronounced risk reduction in early spontaneous PTD (gestational weeks 28-31) [OR: 0.39 (95% CI: 0.19, 0.80)]. The strongest association in this group was with garlic [OR: 0.47 (95% CI: 0.25-0.89)], followed by cooked onions. Intake of dried fruits showed an association with preterm prelabor rupture of membranes (PPROM) [OR: 0.74 (95% CI: 0.65, 0.95)]; the strongest association in this group was with raisins [OR: 0.71 (95% CI: 0.56, 0.92)]. The strongest association with PPROM in the allium group was with garlic [OR: 0.74 (95% CI: 0.56, 0.97)]. In conclusion, intake of food with antimicrobial and prebiotic compounds may be of importance to reduce the risk of spontaneous PTD. In particular, garlic was associated with overall lower risk of spontaneous PTD. Dried fruits, especially raisins, were associated with reduced risk of PPROM.

Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study.

BACKGROUND: Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD). METHODS: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,628). RESULTS: The median total folate intake was 266 µg/d (interquartile range IQR 154-543) in the overall population and 540 µg/d (IQR 369-651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05-1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. CONCLUSIONS: Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.

No observed association for mitochondrial SNPs with preterm delivery and related outcomes.

BACKGROUND: Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited, creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes and PTD and related outcomes. METHODS: This study combined, through meta-analysis, two case-control, genome-wide association studies: one from the Danish National Birth Cohort Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 wk), very PTD (≤32 wk), and preterm prelabor rupture of membranes (PPROM) were examined. A total of 135 individual single-nucleotide polymorphism (SNP) associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis. RESULTS: After meta-analysis, there were four SNPs for the outcome of PTD below P ≤ 0.10 and two below P ≤ 0.05. For the additional outcomes of very PTD and PPROM, there were three and four SNPs, respectively, below P ≤ 0.10. CONCLUSION: Given the number of tests, no single SNP reached study-wide significance (P = 0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.

Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study.

Probiotics have been suggested to modify placental trophoblast inflammation, systemic inflammation, and blood pressure, all potentially interesting aspects of preeclampsia. The authors examined the association between consumption of milk-based probiotic products in pregnancy and development of preeclampsia and its subtypes. The study was performed in the Norwegian Mother and Child Cohort Study by using a prospective design in 33,399 primiparous women in the years 2002-2008. The intake of milk-based products containing probiotic lactobacilli was estimated from a self-reported food frequency questionnaire. Preeclampsia diagnoses were obtained from the Norwegian Medical Birth Registry. Intake of probiotic milk products was associated with reduced risk of preeclampsia. The association was most prominent in severe preeclampsia (adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.66, 0.96). With probiotic intakes divided into categories representing no, monthly, weekly, or daily intake, a lower risk for preeclampsia (all subtypes) was observed for daily probiotic intake (OR = 0.80, 95% CI: 0.66, 0.96). Lower risks for severe preeclampsia were observed for weekly (OR = 0.75, 95% CI: 0.57, 0.98) and daily (OR = 0.61, 95% CI: 0.43, 0.89) intakes. These results suggest that regular consumption of milk-based probiotics could be associated with lower risk of preeclampsia in primiparous women.

Candidate gene analysis of spontaneous preterm delivery: new insights from re-analysis of a case-control study using case-parent triads and control-mother dyads.

BACKGROUND: Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs. METHODS: The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery. RESULTS: The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways. CONCLUSION: This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.

X-chromosomal maternal and fetal SNPs and the risk of spontaneous preterm delivery in a Danish/Norwegian genome-wide association study.

BACKGROUND: Recent epidemiological studies suggest that the maternal genome is an important contributor to spontaneous preterm delivery (PTD). There is also a significant excess of males among preterm born infants, which may imply an X-linked mode of inheritance for a subset of cases. To explore this, we examined the effect of maternal and fetal X-chromosomal single nucleotide polymorphisms (SNPs) on the risk of PTD in two independent genome-wide association studies and one replication study. METHODS: Participants were recruited from the Danish National Birth Cohort and the Norwegian Mother and Child cohort studies. Data from these two populations were first analyzed independently, and then combined in a meta-analysis. Overall, we evaluated 12,211 SNPs in 1,535 case-mother dyads and 1,487 control-mother dyads. Analyses were done using a hybrid design that combines case-mother dyads and control-mother dyads, as implemented in the Haplin statistical software package. A sex-stratified analysis was performed for the fetal SNPs. In the replication study, 10 maternal and 16 fetal SNPs were analyzed using case-parent triads from independent studies of PTD in the United States, Argentina and Denmark. RESULTS: In the meta-analysis, the G allele at the maternal SNP rs2747022 in the FERM domain containing 7 gene (FRMD7) increased the risk of spontaneous PTD by 1.2 (95% confidence interval (CI): 1.1, 1.4). Although an association with this SNP was confirmed in the replication study, it was no longer statistically significant after a Bonferroni correction for multiple testing. CONCLUSION: We did not find strong evidence in our data to implicate X-chromosomal SNPs in the etiology of spontaneous PTD. Although non-significant after correction for multiple testing, the mother's G allele at rs2747022 in FRMD7 increased the risk of spontaneous PTD across all populations in this study, thus warranting further investigation in other populations.

Association between intake of artificially sweetened and sugar-sweetened beverages and preterm delivery: a large prospective cohort study.

BACKGROUND: Artificially sweetened (AS) and sugar-sweetened (SS) beverages are commonly consumed during pregnancy. A recent Danish study reported that the daily intake of an AS beverage was associated with an increased risk of preterm delivery. OBJECTIVE: We examined the intake of AS and SS beverages in pregnant women to replicate the Danish study and observe whether AS intake is indeed associated with preterm delivery. DESIGN: This was a prospective study of 60,761 pregnant women in the Norwegian Mother and Child Cohort Study. Intakes of carbonated and noncarbonated AS and SS beverages and use of artificial sweeteners in hot drinks were assessed by a self-reported food-frequency questionnaire in midpregnancy. Preterm delivery was the primary outcome, and data were obtained from the Norwegian Medical Birth Registry. RESULTS: Intakes of both AS and SS beverages increased with increasing BMI and energy intake and were higher in women with less education, in daily smokers, and in single women. A high intake of AS beverages was associated with preterm delivery; the adjusted OR for those drinking >1 serving/d was 1.11 (95% CI: 1.00, 1.24). Drinking >1 serving of SS beverages per day was also associated with an increased risk of preterm delivery (adjusted OR: 1.25; 95% CI: 1.08, 1.45). The trend tests were positive for both beverage types. CONCLUSION: This study suggests that a high intake of both AS and SS beverages is associated with an increased risk of preterm delivery.

Intake of probiotic food and risk of spontaneous preterm delivery.

BACKGROUND: Preterm delivery represents a substantial problem in perinatal medicine worldwide. Current knowledge on potential influences of probiotics in food on pregnancy complications caused by microbes is limited. OBJECTIVE: We hypothesized that intake of food with probiotics might reduce pregnancy complications caused by pathogenic microorganisms and, through this, reduce the risk of spontaneous preterm delivery. DESIGN: This study was performed in the Norwegian Mother and Child Cohort on the basis of answers to a food-frequency questionnaire. We studied intake of milk-based products containing probiotic lactobacilli and spontaneous preterm delivery by using a prospective cohort study design (n = 950 cases and 17,938 controls) for the pregnancy outcome of spontaneous preterm delivery (< 37 gestational weeks). Analyses were adjusted for the covariates of parity, maternal educational level, and physical activity. RESULTS: Pregnancies that resulted in spontaneous preterm delivery were associated with any intake of milk-based probiotic products in an adjusted model [odds ratio (OR): 0.857; 95% CI: 0.741, 0.992]. By categorizing intake into none, low, and high intakes of the milk-based probiotic products, a significant association was observed for high intake (OR: 0.820; 95% CI: 0.681, 0.986). CONCLUSION: Women who reported habitual intake of probiotic dairy products had a reduced risk of spontaneous preterm delivery.