Statistical methods to detect mother-father genetic interaction effects on risk of infertility: A genome-wide approach.

Infertility is a heterogeneous phenotype, and for many couples, the causes of fertility problems remain unknown. One understudied hypothesis is that allelic interactions between the genotypes of the two parents may influence the risk of infertility. Our aim was, therefore, to investigate how allelic interactions can be modeled using parental genotype data linked to 15,789 pregnancies selected from the Norwegian Mother, Father, and Child Cohort Study. The newborns in 1304 of these pregnancies were conceived using assisted reproductive technologies (ART), and the remainder were conceived naturally. Treating the use of ART as a proxy for infertility, different parameterizations were implemented in a genome-wide screen for interaction effects between maternal and paternal alleles at the same locus. Some of the models were more similar in the way they were parameterized, and some produced similar results when implemented on a genome-wide scale. The results showed near-significant interaction effects in genes relevant to the phenotype under study, such as Dynein axonemal heavy chain 17 (DNAH17) with a recognized role in male infertility. More generally, the interaction models presented here are readily adaptable to the study of other phenotypes in which maternal and paternal allelic interactions are likely to be involved.

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

BACKGROUND: Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian 'Clinical review of the Health of adults conceived following Assisted Reproductive Technologies' (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ('XWASs' hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. RESULTS: In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. CONCLUSIONS: Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

Effectiveness of mRNA Booster Vaccination Against Mild, Moderate, and Severe COVID-19 Caused by the Omicron Variant in a Large, Population-Based, Norwegian Cohort.

BACKGROUND: Understanding how booster vaccination can prevent moderate and severe illness without hospitalization is crucial to evaluate the full advantage of mRNA boosters. METHODS: We followed 85 801 participants (aged 31-81 years) in 2 large population-based cohorts during the Omicron BA.1/2 wave. Information on home testing, PCR testing, and symptoms of coronavirus disease 2019 (COVID-19) was extracted from biweekly questionnaires covering the period 12 January 2022 to 7 April 2022. Vaccination status and data on previous SARS-CoV-2 infection were obtained from national registries. Cox regression was used to estimate the effectiveness of booster vaccination compared to receipt of 2-dose primary series >130 days previously. RESULTS: The effectiveness of booster vaccination increased with increasing severity of COVID-19 and decreased with time since booster vaccination. The effectiveness against severe COVID-19 was reduced from 80.9% shortly after booster vaccination to 63.4% in the period >90 days after vaccination. There was hardly any effect against mild COVID-19. The effectiveness tended to be lower among subjects aged ≥60 years than those aged <50 years. CONCLUSIONS: This is the first population-based study to evaluate booster effectiveness against self-reported mild, moderate, and severe COVID-19. Our findings contribute valuable information on duration of protection and thus timing of additional booster vaccinations.

Association of SARS-CoV-2 Vaccination During Pregnancy With Pregnancy Outcomes.

Importance: Data about the safety of vaccines against SARS-CoV-2 during pregnancy are limited. Objective: To examine the risk of adverse pregnancy outcomes after vaccination against SARS-CoV-2 during pregnancy. Design, Setting, and Participants: This registry-based retrospective cohort study included 157 521 singleton pregnancies ending after 22 gestational weeks from January 1, 2021, until January 12, 2022 (Sweden), or January 15, 2022 (Norway). The Pregnancy Register in Sweden and the Medical Birth Registry of Norway were linked to vaccination and other registries for identification of exposure and background characteristics. Exposures: Data on mRNA vaccines-BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-and 1 viral vector vaccine-AZD1222 (AstraZeneca)-were collected from national vaccination registries. Main Outcomes and Measures: The risk of preterm birth and stillbirth was evaluated using Cox regression models, with gestational day as the time metric and vaccination as a time-dependent exposure variable. The risk of small for gestational age, low Apgar score, and neonatal care admission was evaluated using logistic regression. Random-effects meta-analysis was used to combine results between countries. Results: Among the 157 521 singleton births included in the study (103 409 in Sweden and 54 112 in Norway), the mean maternal age at the time of delivery was 31 years, and 28 506 (18%) were vaccinated against SARS-CoV-2 (12.9% with BNT162b2, 4.8% with mRNA-1273, and 0.3% with AZD1222) while pregnant. A total of 0.7%, 8.3%, and 9.1% of individuals delivering were vaccinated during the first, second, and third trimester, respectively. Vaccination against SARS-CoV-2 was not significantly associated with increased risk of preterm birth (6.2 vs 4.9 per 10 000 pregnancy days; adjusted hazard ratio [aHR], 0.98 [95% CI, 0.91 to 1.05]; I2 = 0%; P for heterogeneity = .60), stillbirth (2.1 vs 2.4 per 100 000 pregnancy days; aHR, 0.86 [95% CI, 0.63 to 1.17]), small for gestational age (7.8% vs 8.5%; difference, -0.6% [95% CI, -1.3% to 0.2%]; adjusted OR [aOR], 0.97 [95% CI, 0.90 to 1.04]), low Apgar score (1.5% vs 1.6%; difference, -0.05% [95% CI, -0.3% to 0.1%]; aOR, 0.97 [95% CI, 0.87 to 1.08]), or neonatal care admission (8.5% vs 8.5%; difference, 0.003% [95% CI, -0.9% to 0.9%]; aOR, 0.97 [95% CI, 0.86 to 1.10]). Conclusions and Relevance: In this population-based study conducted in Sweden and Norway, vaccination against SARS-CoV-2 during pregnancy, compared with no SARS-CoV-2 vaccination during pregnancy, was not significantly associated with an increased risk of adverse pregnancy outcomes. The majority of the vaccinations were with mRNA vaccines during the second and third trimesters of pregnancy, which should be considered in interpreting the findings.

Wavelet Screening: a novel approach to analyzing GWAS data.

BACKGROUND: Traditional methods for single-variant genome-wide association study (GWAS) incur a substantial multiple-testing burden because of the need to test for associations with a vast number of single-nucleotide polymorphisms (SNPs) simultaneously. Further, by ignoring more complex joint effects of nearby SNPs within a given region, these methods fail to consider the genomic context of an association with the outcome. RESULTS: To address these shortcomings, we present a more powerful method for GWAS, coined 'Wavelet Screening' (WS), that greatly reduces the number of tests to be performed. This is achieved through the use of a sliding-window approach based on wavelets to sequentially screen the entire genome for associations. Wavelets are oscillatory functions that are useful for analyzing the local frequency and time behavior of signals. The signals can then be divided into different scale components and analyzed separately. In the current setting, we consider a sequence of SNPs as a genetic signal, and for each screened region, we transform the genetic signal into the wavelet space. The null and alternative hypotheses are modeled using the posterior distribution of the wavelet coefficients. WS is enhanced by using additional information from the regression coefficients and by taking advantage of the pyramidal structure of wavelets. When faced with more complex genetic signals than single-SNP associations, we show via simulations that WS provides a substantial gain in power compared to both the traditional GWAS modeling and another popular regional association test called SNP-set (Sequence) Kernel Association Test (SKAT). To demonstrate feasibility, we applied WS to a large Norwegian cohort (N=8006) with genotypes and information available on gestational duration. CONCLUSIONS: WS is a powerful and versatile approach to analyzing whole-genome data and lends itself easily to investigating various omics data types. Given its broader focus on the genomic context of an association, WS may provide additional insight into trait etiology by revealing genes and loci that might have been missed by previous efforts.

A fast wavelet-based functional association analysis replicates several susceptibility loci for birth weight in a Norwegian population.

BACKGROUND: Birth weight (BW) is one of the most widely studied anthropometric traits in humans because of its role in various adult-onset diseases. The number of loci associated with BW has increased dramatically since the advent of whole-genome screening approaches such as genome-wide association studies (GWASes) and meta-analyses of GWASes (GWAMAs). To further contribute to elucidating the genetic architecture of BW, we analyzed a genotyped Norwegian dataset with information on child's BW (N=9,063) using a slightly modified version of a wavelet-based method by Shim and Stephens (2015) called WaveQTL. RESULTS: WaveQTL uses wavelet regression for regional testing and offers a more flexible functional modeling framework compared to conventional GWAS methods. To further improve WaveQTL, we added a novel feature termed "zooming strategy" to enhance the detection of associations in typically small regions. The modified WaveQTL replicated five out of the 133 loci previously identified by the largest GWAMA of BW to date by Warrington et al. (2019), even though our sample size was 26 times smaller than that study and 18 times smaller than the second largest GWAMA of BW by Horikoshi et al. (2016). In addition, the modified WaveQTL performed better in regions of high LD between SNPs. CONCLUSIONS: This study is the first adaptation of the original WaveQTL method to the analysis of genome-wide genotypic data. Our results highlight the utility of the modified WaveQTL as a complementary tool for identifying loci that might escape detection by conventional genome-wide screening methods due to power issues. An attractive application of the modified WaveQTL would be to select traits from various public GWAS repositories to investigate whether they might benefit from a second analysis.

Growth in children conceived by ART.

STUDY QUESTION: Is the growth pattern of children conceived by ART different compared to naturally conceived children. SUMMARY ANSWER: Both ART and underlying parental subfertility may contribute to differences in early childhood growth between children conceived with and without the use of ART. WHAT IS KNOWN ALREADY: Children conceived by ART weigh less and are shorter at the time of delivery. The extent to which differences in growth according to mode of conception persist during childhood, and the role of underlying parental subfertility, remains unclear. STUDY DESIGN, SIZE, DURATION: We conducted a prospective study population-based study. We studied 81 461 children participating in the Norwegian Mother, Father and Child Cohort Study (MoBa) and 544 113 adolescents screened for military conscription. PARTICIPANTS/MATERIALS, SETTING, METHODS: Conception by ART as registered in the Medical Birth Registry. We compared maternally reported length/height and weight among children in MoBa from mid-pregnancy to age 7 according to mode of conception using mixed-effects linear regression. Differences in self-reported height and weight at 17 years of age at screening for military conscription were assessed with linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: At birth, children conceived by ART were shorter (boys -0.3 cm; 95% CI, -0.5 to -0.1), girls -0.4 cm; 95% CI, -0.5 to -0.3) and lighter (boys -113 grams; 95% CI, -201 to -25, girls -107 grams; 95% CI, -197 to -17). After birth, children conceived by ART grew more rapidly, achieving both greater height and weight at age 3. Children conceived by ART had a greater height up to age 7, but did not have a greater height or weight by age 17. Naturally conceived children of parents taking longer time to conceive had growth patterns similar to ART children. Children born after frozen embryo transfer had larger ultrasound measures and were longer and heavier the first 2 years than those born after fresh embryo transfer. LIMITATIONS, REASONS FOR CAUTIONS: Selection bias could have been introduced due to the modest participation rate in the MoBa cohort. Our reliance on self-reported measures of length/height and weight could have introduced measurement error. WIDER IMPLICATIONS OF THE FINDINGS: : Our findings provide reassurance that offspring conceived by ART are not different in height, weight or BMI from naturally conceived once they reach adolescence. STUDY FUNDING/COMPETING INTEREST(S): Research Council of Norway; Medical Research Council; National Institute of Environmental Health Sciences. The authors have no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Heritability curves: A local measure of heritability in family models.

Classical heritability models for family data split the phenotype variance into genetic and environmental components. For instance, the ACE model in twin studies assumes the phenotype variance decomposes as a2 + c2 + e2 , representing (additive) genetic effects, common (shared) environment, and residual environment, respectively. However, for some phenotypes it is biologically plausible that the genetic and environmental components may vary over the range of the phenotype. For instance, very large or small values of the phenotype may be caused by "sporadic" environmental factors, whereas the mid-range phenotype variation may be more under the control of common genetic factors. This article introduces a "local" measure of heritability, where the genetic and environmental components are allowed to depend on the value of the phenotype itself. Our starting point is a general formula for local correlation between two random variables. For estimation purposes, we use a multivariate Gaussian mixture, which is able to capture nonlinear dependence and respects certain distributional constraints. We derive an analytical expression for the associated correlation curve, and show how to decompose the correlation curve into genetic and environmental parts, for instance, a2 (y) + c2 (y) + e2 (y) for the ACE model, where we estimate the components as functions of the phenotype y. Furthermore, our model allows switching, for instance, from the ACE model to the ADE model within the range of the same phenotype. When applied to birth weight (BW) data on Norwegian mother-father-child trios, we conclude from the model that low and high BW are less heritable traits than medium BW. We also demonstrate switching between the ACE and ADE model when studying body mass index in adult monozygotic and dizygotic twins.

Blood-based epigenetic estimators of chronological age in human adults using DNA methylation data from the Illumina MethylationEPIC array.

BACKGROUND: Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age. RESULTS: We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set. CONCLUSIONS: Our ABECs predicted adults' chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.

Design efficiency in genetic association studies.

Selecting the best design for genetic association studies requires careful deliberation; different study designs can be used to scan for different genetic effects, and each design has its own set of strengths and limitations. A variety of family and unrelated control configurations are amenable to genetic association analyses, including the case-control design, case-parent triads, and case-parent triads in combination with unrelated controls or control-parent triads. Ultimately, the goal is to choose the design that achieves the highest statistical power using the lowest cost. For given parameter values and genotyped individuals, designs can be compared directly by computing the power. However, a more informative and general design comparison can be achieved by studying the relative efficiency, defined as the ratio of variances of two different parameter estimators, corresponding to two separate designs. Using log-linear modeling, we derive the relative efficiency from the asymptotic variance of the parameter estimators and relate it to the concept of Pitman efficiency. The relative efficiency takes into account the fact that different designs impose different costs relative to the number of genotyped individuals. We show that while optimal efficiency for analyses of regular autosomal effects is achieved using the standard case-control design, the case-parent triad design without unrelated controls is efficient when searching for parent-of-origin effects. Due to the potential loss of efficiency, maternal genes should generally not be adjusted for in an initial genome-wide association study scan of offspring genes but instead checked post hoc. The relative efficiency calculations are implemented in our R package Haplin.

Haplin power analysis: a software module for power and sample size calculations in genetic association analyses of family triads and unrelated controls.

BACKGROUND: Log-linear and multinomial modeling offer a flexible framework for genetic association analyses of offspring (child), parent-of-origin and maternal effects, based on genotype data from a variety of child-parent configurations. Although the calculation of statistical power or sample size is an important first step in the planning of any scientific study, there is currently a lack of software for genetic power calculations in family-based study designs. Here, we address this shortcoming through new implementations of power calculations in the R package Haplin, which is a flexible and robust software for genetic epidemiological analyses. Power calculations in Haplin can be performed analytically using the asymptotic variance-covariance structure of the parameter estimator, or else by a straightforward simulation approach. Haplin performs power calculations for child, parent-of-origin and maternal effects, as well as for gene-environment interactions. The power can be calculated for both single SNPs and haplotypes, either autosomal or X-linked. Moreover, Haplin enables power calculations for different child-parent configurations, including (but not limited to) case-parent triads, case-mother dyads, and case-parent triads in combination with unrelated control-parent triads. RESULTS: We compared the asymptotic power approximations to the power of analysis attained with Haplin. For external validation, the results were further compared to the power of analysis attained by the EMIM software using data simulations from Haplin. Consistency observed between Haplin and EMIM across various genetic scenarios confirms the computational accuracy of the inference methods used in both programs. The results also demonstrate that power calculations in Haplin are applicable to genetic association studies using either log-linear or multinomial modeling approaches. CONCLUSIONS: Haplin provides a robust and reliable framework for power calculations in genetic association analyses for a wide range of genetic effects and etiologic scenarios, based on genotype data from a variety of child-parent configurations.

Intake of sucrose-sweetened soft beverages during pregnancy and risk of congenital heart defects (CHD) in offspring: a Norwegian pregnancy cohort study.

Studies report increased risk of congenital heart defects (CHD) in the offspring of mothers with diabetes, where high blood glucose levels might confer the risk. We explored the association between intake of sucrose-sweetened soft beverages during pregnancy and risk of CHD. Prospective cohort data with 88,514 pregnant women participating in the Norwegian Mother and Child Cohort Study was linked with information on infant CHD diagnoses from national health registers and the Cardiovascular Diseases in Norway Project. Risk ratios were estimated by fitting generalized linear models and generalized additive models. The prevalence of children with CHD was 12/1000 in this cohort (1049/88,514). Among these, 201 had severe and 848 had non-severe CHD (patent ductus arteriosus; valvular pulmonary stenosis; ventricular septal defect; atrial septal defect). Only non-severe CHD was associated with sucrose-sweetened soft beverages. The adjusted risk ratios (aRR) for non-severe CHD was 1.30 (95% CI 1.07-1.58) for women who consumed 25-70 ml/day and 1.27 (95% CI 1.06-1.52) for women who consumed ≥ 70 ml/day when compared to those drinking ≤ 25 ml/day. Dose-response analyses revealed an association between the risk of non-severe CHD and the increasing exposure to sucrose-sweetened soft beverages, especially for septal defects with aRR = 1.26 (95% CI 1.07-1.47) per tenfold increase in daily intake dose. The findings persisted after adjustment for maternal diabetes or after excluding mothers with diabetes (n = 19). Fruit juices, cordial beverages and artificial sweeteners showed no associations with CHD. The findings suggest that sucrose-sweetened soft beverages may affect the CHD risk in offspring.

Parent-of-origin-environment interactions in case-parent triads with or without independent controls.

With case-parent triad data, one can frequently deduce parent of origin of the child's alleles. This allows a parent-of-origin (PoO) effect to be estimated as the ratio of relative risks associated with the alleles inherited from the mother and the father, respectively. A possible cause of PoO effects is DNA methylation, leading to genomic imprinting. Because environmental exposures may influence methylation patterns, gene-environment interaction studies should be extended to allow for interactions between PoO effects and environmental exposures (i.e., PoOxE). One should thus search for loci where the environmental exposure modifies the PoO effect. We have developed an extensive framework to analyze PoOxE effects in genome-wide association studies (GWAS), based on complete or incomplete case-parent triads with or without independent control triads. The interaction approach is based on analyzing triads in each exposure stratum using maximum likelihood estimation in a log-linear model. Interactions are then tested applying a Wald-based posttest of parameters across strata. Our framework includes a complete setup for power calculations. We have implemented the models in the R software package Haplin. To illustrate our PoOxE test, we applied the new methodology to top hits from our previous GWAS, assessing whether smoking during the periconceptional period modifies PoO effects on cleft palate only.

Estimation of fetal weight in pregnancies past term.

INTRODUCTION: The aim of the study was to investigate the accuracy of estimating fetal weight with ultrasound in pregnancies past term, using the eSnurra algorithm. MATERIAL AND METHODS: In all, 419 women with pregnancy length of 290 days, attending a specialist consultation at Stavanger University Hospital, Norway, were included in a prospective observational study. Fetal weight was estimated using biparietal diameter (BPD) and abdominal circumference (AC). The algorithm implemented in an electronic calculation (eSnurra) was used to compute estimated fetal weight (EFW). Results were compared with birthweight (BW). RESULTS: The mean interval between the ultrasound examination and birth was 2 days (SD 1.4). The median difference between BW and EFW was -6 g (CI -40 to +25 g) and the median percentage error was -0.1% (95% CI -1.0 to 0.6%). The median absolute difference was 190 g (95% CI 170-207 g). The BW was within 10% of EFW in 83% (95% CI 79-87%) of cases and within 15% of EFW in 94% (95% CI 92-96%) of cases. Limits of agreement (95%) were from -553 g to +556 g. Using 5% false-positive rates, the sensitivity in detecting macrosomic and small for gestational age fetuses was 54% (95% CI 35-72%) and 49% (95% CI 35-63%), respectively. CONCLUSION: The accuracy of fetal weight estimation was good. Clinicians should be aware of limitations related to prediction at the upper and lower end, and the importance of choosing appropriate cut-off levels.

Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.

BACKGROUND/AIMS: Maternal and offspring cell contact at the site of placentation presents a plausible setting for maternal-fetal genotype (MFG) interactions affecting fetal growth. We test hypotheses regarding killer cell immunoglobulin-like receptor (KIR) and HLA-C MFG effects on human birth weight by extending the quantitative MFG (QMFG) test. METHODS: Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these interactions, we developed the extended QMFG test, a linear mixed-effect model that can use multi-locus genotype data from families. RESULTS: We demonstrate the extended QMFG test's statistical properties. We also show that if an offspring-only model is fit when MFG effects exist, associations can be missed or misattributed. Furthermore, imprecisely modeling the effects of both KIR and HLA-C could result in a failure to replicate if these loci's allele frequencies differ among populations. To further illustrate the extended QMFG test's advantages, we apply the extended QMFG test to a UK cohort study and the Norwegian Mother and Child Cohort (MoBa) study. CONCLUSION: We find a significant KIR-HLA-C interaction effect on birth weight. More generally, the QMFG test can detect genetic associations that may be missed by standard genome-wide association studies for quantitative traits.

Symphysis-fundus measurement - the predictive value of a new reference curve. / Symfyse-fundus-mål ­ prediktiv verdi av ny referansekurve.

BACKGROUND: Symphysis-fundus measurement is used in pregnancy care to detect poor fetal growth. Symphysis-fundus measurement curves (percentile curves) and prediction of fetuses with a birth weight below the10th percentile have been published previously. The percentile curves show the distribution of symphysis-fundus measurements in the reference population and are recommended as the national standard. This article discusses the predictive value of this method for identification of neonates who are small for gestational age (SGA). MATERIAL AND METHOD: This is a population-based registry study of pregnant women who gave birth at Sahlgrenska University Hospital in Gothenburg in the period 2005 ­ 2010. Diagnostic accuracy was analysed using ROC curves and presented with the area under the curve (AUC) from gestational week 24 to 42. Sensitivity, specificity, and positive and negative predictive value were calculated. RESULTS: A total of 42 018 pregnant women carrying a single fetus were included. The AUC values showed that a symphysis-fundus measurement late in pregnancy was a stronger predictor for determining fetuses that are small for gestational age than a measurement early in pregnancy. The AUC value increased from 0.61 in week 24 to 0.74 in week 40. With a threshold value at the 10th percentile, symphysis-fundus measurement has a total sensitivity of 47 % and a specificity of 79 %. A positive total test was defined as at least one measurement below the 10th percentile curve in the course of the pregnancy. INTERPRETATION: Symphysis-fundus measurement may be important for the identification of high-risk pregnancies, but should preferably be used in conjunction with other clinical variables.

Risk of fetal death after pandemic influenza virus infection or vaccination.

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination. METHODS: We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. RESULTS: There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). CONCLUSIONS: Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.).

Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.

Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤ 5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p = 0.005, n = 1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). Thus, maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight, the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA.

Extensive variation and low heritability of DNA methylation identified in a twin study.

Disturbance of DNA methylation leading to aberrant gene expression has been implicated in the etiology of many diseases. Whereas variation at the genetic level has been studied extensively, less is known about the extent and function of epigenetic variation. To explore variation and heritability of DNA methylation, we performed bisulfite sequencing of 1760 CpG sites in 186 regions in the human major histocompatibility complex (MHC) in CD4+ lymphocytes from 49 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs. Individuals show extensive variation in DNA methylation both between and within regions. In addition, many regions also have a complex pattern of variation. Globally, there appears to be a bimodal distribution of DNA methylation in the regions, but a significant fraction of the CpG sites are also heterogeneously methylated. Classification of regions into CpG islands (intragenic and intergenic), 5' end of genes not associated with a defined CpG island, conserved noncoding regions, and random CpG sites shows region-type differences in variation and heritability. Analyses revealed slightly lower intra-pair differences among MZ than among DZ pairs, suggesting some genetic influences on DNA methylation variation, with most of the variance attributed to nongenetic factors. Overall, heritability estimates of DNA methylation were low. Our heritability estimates are, however, somewhat deflated due to the presence of batch effects that artificially inflate the estimates of shared environment.