Early childhood respiratory tract infections according to parental subfertility and conception by assisted reproductive technologies.

STUDY QUESTION Are children conceived by ART or born to subfertile parents more susceptible to upper or lower respiratory tract infections (URTI, LRTI)? SUMMARY ANSWER ART-conceived children had a higher frequency of and risk of hospitalization for respiratory infections up to age 3, which was only partly explained by parental subfertility. WHAT IS KNOWN ALREADY Some studies report increased risks of infections in children conceived by ART. Results for URTIs and LRTIs are inconclusive, and the contribution of underlying parental subfertility remains unclear. STUDY DESIGN, SIZE, DURATION We included 84 102 singletons of the Norwegian Mother, Father and Child Cohort Study (MoBa) born between 1999 and 2009. Mothers reported time-to-pregnancy at recruitment and child history of, frequency of and hospitalization for, respiratory infections when the child was 6, 18 and 36 months old by questionnaires. Subfertility was defined as having taken 12 or more months to conceive. The Medical Birth Registry of Norway (MBRN) provided information on ART. URTI included throat and ear infections, while LRTI included bronchitis, bronchiolitis, respiratory syncytial virus and pneumonia. PARTICIPANTS/MATERIALS, SETTING, METHODS We used log-binomial regression to estimate risk ratios (RR) and 95% CI of any respiratory tract infection and hospitalization, and negative-binomial regression to calculate incidence rate ratios (IRR) and 95% CI for number of infections. We compared children conceived by ART, and naturally conceived children of subfertile parents, to children of fertile parents (<12 months to conceive) while adjusting for maternal age, education, BMI and smoking during pregnancy and previous livebirths. We accounted for dependency between children born to the same mother. MAIN RESULTS AND THE ROLE OF CHANCE A total of 7334 (8.7%) singletons were naturally conceived by subfertile parents and 1901 (2.3%) were conceived by ART. Between age 0 and 36 months, 41 609 (49.5%) of children experienced any URTI, 15 542 (18.5%) any LRTI and 4134 (4.9%) were hospitalized due to LRTI. Up to age 3, children conceived by ART had higher frequencies of URTI (adjusted IRR (aIRR) 1.16; 95% CI 1.05-1.28) and hospitalizations due to LRTI (adjusted RR (aRR) 1.25; 95% CI 1.02-1.53), which was not seen for children of subfertile parents. Children conceived by ART were not at higher risks of respiratory infections up to age 18 months; only at age 19-36 months, they had increased risk of any LRTI (aRR 1.16; 95% CI 1.01-1.33), increased frequency of LRTIs (IRR 1.22; 95% CI 1.02-1.47) and a higher risk of hospitalization for LRTI (aRR 1.35; 95% CI 1.01-1.80). They also had an increased frequency of URTIs (aIRR; 1.19; 95% CI 1.07-1.33). Children of subfertile parents only had a higher risk of LRTIs (aRR 1.09; 95% CI 1.01-1.17) at age 19-36 months. LIMITATIONS, REASONS FOR CAUTION Self-reported time-to-pregnancy and respiratory tract infections by parents could lead to misclassification. Both the initial participation rate and loss to follow up in the MoBa limits generalizability to the general Norwegian population. WIDER IMPLICATIONS OF THE FINDINGS ART-conceived children might be more susceptible to respiratory tract infections in early childhood. This appears to be only partly explained by underlying parental subfertility. Exactly what aspects related to the ART procedure might be reflected in these associations need to be further investigated. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Swiss National Science Foundation (P2BEP3_191798), the Research Council of Norway (no. 262700), and the European Research Council (no. 947684). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A

Effect of interpregnancy interval on gestational diabetes: a retrospective matched cohort study

© 2019 The Authors Purpose: To examine the association between interpregnancy interval (IPI) and gestational diabetes using both within-mother and between-mother comparisons. Methods: A retrospective cohort study of 103,909 women who delivered three or more consecutive singleton births (n = 358,046) between 1 January 1980 and 31 December 2015 in Western Australia. The association between IPI and gestational diabetes was estimated using conditional logistic regression, matching pregnancies to the same mother and adjusted for factors that vary within-mother across pregnancies. For comparison with previous studies, we also applied unmatched logistic regression (between-mother analysis). Results: The conventional between-mother analysis resulted in adjusted odds ratios (aOR) of 1.13 (95% CI, 1.06–1.21) for intervals of 24–59 months and 1.51 (95% CI, 1.33–1.70) for intervals of 120 or more months, compared with IPI of 18–23 months. In addition, short IPIs were associated with lower odds of gestational diabetes with (aOR: 0.89; 95% CI, 0.82–0.97) for 6–11 months and (aOR: 0.92; 95% CI, 0.85–0.99) for 12–17-month. In comparison, the adjusted within-mother matched analyses showed no statistically significant association between IPIs and gestational diabetes. All effect estimates were attenuated using the within-mother matched model. Conclusion: Our findings do not support the hypothesis that short IPI (<6 months) increases the risk of gestational diabetes and suggest that observed associations in previous research might be attributable to confounders that vary between mothers

The regulatory landscape of plastic governance - a Norwegian perspective

In this report we co-produced a matrix of governance fragmentation in the Norwegian plastic value chain to assess where there are overlaps, interplay and synergies to be aligned. This also included an assessment of the global level of plastic regulatory fragmentation as it relates to the upcoming negotiations for a global treaty to end plastic pollution.Norges forskningsrådpublishedVersio

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

Funder: Folkehelseinstituttet/Norwegian Institute of Public HealthFunder: Norwegian Ministry of Health and Care ServicesFunder: Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and ResearchFunder: Norwegian Ministry of Education and ResearchStudy questionWhat is the association between BMI and subfertility?Summary answerWe observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis.What is known alreadyHigh BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies.Study design, size, durationCohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008.Participants/materials, setting, methodsWomen (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months).Main results and the role of chanceOur findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI Limitations, reasons for cautionThe main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values Wider implications of the findingsOur results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values Study funding/competing interest(s)The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist.Trial registration numberN/A

Associations between insomnia and pregnancy and perinatal outcomes: Evidence from Mendelian randomization and multivariable regression analyses

BACKGROUND: Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW). METHODS AND FINDINGS: We used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age 4,500 grams). We used data from women of European descent (N = 356,069, mean ages at delivery 25.5 to 30.0 years) from UK Biobank (UKB), FinnGen, Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Norwegian Mother, Father and Child Cohort (MoBa). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N = 11,745). IVW showed evidence of an association of genetic susceptibility to insomnia with miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17, p = 0.002), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54, p = 0.004), and LBW (OR 3.17, 95% CI: 1.69, 5.96, p < 0.001). IVW results did not support associations of insomnia with stillbirth, GD, HDP, PTB, and HBW, with wide CIs including the null. Associations of genetic susceptibility to insomnia with miscarriage, perinatal depression, and LBW were not observed in weighted median or MR-Egger analyses. Results from these sensitivity analyses were directionally consistent with IVW results for all outcomes, with the exception of GD, perinatal depression, and PTB in MR-Egger. Multivariable regression showed associations of insomnia at 18 weeks of gestation with perinatal depression (OR 2.96, 95% CI: 2.42, 3.63, p < 0.001), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24, p = 0.60). Multivariable regression with miscarriage and stillbirth was not possible due to small numbers in index pregnancies. Key limitations are potential horizontal pleiotropy (particularly for perinatal depression) and low statistical power in MR, and residual confounding in multivariable regression. CONCLUSIONS: In this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts

STUDY QUESTION: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction? SUMMARY ANSWER: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation. WHAT IS KNOWN ALREADY: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes. STUDY DESIGN, SIZE, DURATION: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls). MAIN RESULTS AND THE ROLE OF CHANCE: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling. LIMITATIONS, REASONS FOR CAUTIONS: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction. WIDER IMPLICATIONS OF THE FINDINGS: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health. STUDY FUNDING/COMPETING INTERESTS(S): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A

Pregnancy and risk of COVID‐19: a Norwegian registry‐linkage study

Objective To compare the risk of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and contact with specialist healthcare services for coronavirus disease 2019 (COVID-19) between pregnant and non-pregnant women. Population or sample All women ages 15–45 living in Norway on 1 March 2020 (n = 1 033 699). Methods We linked information from the national birth, patient, communicable diseases and education databases using unique national identifiers. Main outcome measure We estimated hazard ratios (HR) among pregnant compared to non-pregnant women of having a positive test for SARS-CoV-2, a diagnosis of COVID-19 in specialist healthcare, or hospitalisation with COVID-19 using Cox regression. Multivariable analyses adjusted for age, marital status, education, income, country of birth and underlying medical conditions. Results Pregnant women were not more likely to be tested for or to a have a positive SARS-CoV-2 test (adjusted HR 0.99; 95% CI 0.92–1.07). Pregnant women had higher risk of hospitalisation with COVID-19 (HR 4.70, 95% CI 3.51–6.30) and any type of specialist care for COVID-19 (HR 3.46, 95% CI 2.89–4.14). Pregnant women born outside Scandinavia were less likely to be tested, and at higher risk of a positive test (HR 2.37, 95% CI 2.51–8.87). Compared with pregnant Scandinavian-born women, pregnant women with minority background had a higher risk of hospitalisation with COVID-19 (HR 4.72, 95% CI 2.51–8.87). Conclusion Pregnant women were not more likely to be infected with SARS-CoV-2. Still, pregnant women with COVID-19, especially those born outside of Scandinavia, were more likely to be hospitalised