Trond Melbye Michelsen

• Bains, Sukhjeet Kaur; Tellum, Tina; Abebe, Dawit Shawel; Michelsen, Trond Melbye & Sørbye, Ingvil Krarup (2026). Influence of migration status on hysterectomy surgical approach and indications for benign conditions—a nationwide cohort register study. European Journal of Public Health. ISSN 1101-1262. 36(5), s. 1–10. doi: 10.1093/eurpub/ckag176. Fulltekst i vitenarkiv
• Ueland, Thor; Michelsen, Annika Elisabet; Qvigstad, Elisabeth; Roland, Marie Cecilie; Westerberg, Ane Cecilie & Michelsen, Trond Melbye [Vis alle 9 forfattere av denne artikkelen] (2026). Secreted frizzled-related protein 3 is associated with metabolic disturbances in gestational diabetes. Frontiers in Endocrinology. 17. doi: 10.3389/fendo.2026.1905877. Fulltekst i vitenarkiv
• Rosland, Tina Ellinor; Johansen, Nora; Liavaag, Astrid Helene; Åsvold, Bjørn Olav; Pripp, Are Hugo & Michelsen, Trond Melbye (2026). All-cause mortality after self-reported vs. hospital-reported gynecological surgery: The HUNT study. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. s. 1–10. doi: 10.1111/aogs.70354. Fulltekst i vitenarkiv
• Zykova, Svetlana; Plaksienko, Anna; Solevåg, Anne Lee; Brigtsen, Anne Karin; Michelsen, Trond Melbye & Sørbye, Ingvil Krarup [Vis alle 12 forfattere av denne artikkelen] (2026). Neonatal reference intervals for salivary steroids: focus on prematurity, stressful events and perinatal betamethasone. Frontiers in Pediatrics. 14. doi: 10.3389/fped.2026.1808446. Fulltekst i vitenarkiv
• Henriksen, Tore & Michelsen, Trond Melbye (2026). Placental handling of glucose in the human – beyond the maternal-fetal glucose gradient. Placenta. ISSN 0143-4004. 179, s. 103–112. doi: 10.1016/j.placenta.2026.03.002. Fulltekst i vitenarkiv
• Sellevoll, Hilde Bastøe; Andresen, Ina Jungersen; Westerberg, Ane Cecilie; Degnes, Maren-Helene Langeland; Ueland, Thor & Zucknick, Manuela [Vis alle 7 forfattere av denne artikkelen] (2026). Placental Protein Release and Uptake From the Fetal Circulation in Healthy Term Pregnancies—A Human In Vivo Exploratory Study. The FASEB Journal. ISSN 0892-6638. 40(3). doi: 10.1096/fj.202503626R. Fulltekst i vitenarkiv
• Leeves, Lisa Tangnes; Michelsen, Trond Melbye; Jacobsen, Anne Flem; Solhoff, Aslak Vimme; Gunnes, Nina & Sørbye, Ingvil Krarup (2025). Is indication for induction of labor associated with mode of delivery in term first births? A Norwegian registry-based study. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 104(11), s. 2165–2177. doi: 10.1111/aogs.70060. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Few previous studies have examined the association between the indication for induction of labor (IOL) and the mode of delivery. To improve information for clinicians and women undergoing IOL, our study aimed to assess the association between the indication for IOL and the risk of cesarean and operative vaginal birth among nulliparous women with single cephalic term pregnancies. Furthermore, we examined whether associations varied by gestational length. Lastly, we evaluated reasons for cesarean and operative vaginal birth across indications for IOL. Material and Methods Data were extracted from the Medical Birth Registry of Norway from 2020 to 2021. We used the registered main indication for IOL. Multinomial logistic regression was applied to estimate relative risk ratios (RRRs) with associated 95% confidence intervals (CIs) of cesarean and operative vaginal birth versus spontaneous vaginal birth for the different IOL indications, using prelabor rupture of membranes (PROM) as the reference indication. Results Risk of cesarean versus spontaneous vaginal birth was four times higher for women induced due to large fetus compared to women induced due to PROM (adjusted RRR: 4.39; 95% CI: 3.21 to 5.99). Indications such as maternal request, post-term pregnancy, oligo−/polyhydramnios, preeclampsia/hypertension, and diabetes were associated with a 40%–91% increased relative risk of cesarean versus spontaneous vaginal birth compared to PROM. Relative risk of operative vaginal versus spontaneous vaginal birth was increased by 23%–29% for oligo−/polyhydramnios, diabetes, and post-term pregnancy compared to PROM. Indication large fetus had similar relative risk ratios at all gestational lengths. Rate of operative delivery for fetal distress was highest for IOL due to intrauterine growth restriction (IUGR). For secondary outcomes, IOL due to IUGR had the highest proportions of cesarean and operative vaginal birth for fetal distress. Indication post-term pregnancy had the highest proportion of cesarean birth for prolonged labor, while large fetus had the highest proportion of operative vaginal birth for prolonged labor. Conclusions Nulliparous women undergoing IOL for indications such as large fetus, post-term pregnancy, oligo-/polyhydramnios, preeclampsia/hypertension, and diabetes are at an elevated relative risk of cesarean versus spontaneous vaginal birth compared to IOL for PROM. In contrast, the relative risk of operative vaginal birth showed less variation by indication for IOL.

• Michelsen, Trond Melbye; Sajjad, Muhammad Umar; Haugen, Guttorm Nils; Moore, Lorna; Julian, Colleen G. & Sørbye, Ingvil Krarup [Vis alle 7 forfattere av denne artikkelen] (2025). Maternal body mass index is related to fetal uptake of glucose and oxygen via fetal insulin resistance rather than fetal glucose levels. Philosophical Transactions of the Royal Society of London. Biological Sciences. ISSN 0962-8436. 380(1933). doi: 10.1098/rstb.2024.0178. Fulltekst i vitenarkiv
• Sajjad, Muhammad Umar; Henriksen, Tore; Haugen, Guttorm Nils & Michelsen, Trond Melbye (2025). Placental hexokinase activity is related to fetal blood flow distribution in a cross-sectional study of healthy human pregnancies at term. Placenta. ISSN 0143-4004. 168, s. 1–8. doi: 10.1016/j.placenta.2025.05.015. Fulltekst i vitenarkiv
• Andresen, Ina Jungersen; Romero, Roberto; Westerberg, Ane C.; Than, Nándor Gábor; Gomez-Lopez, Nardhy & Bhatti, Gaurav [Vis alle 14 forfattere av denne artikkelen] (2025). Large-Scale Proteomics Reveals New Candidate Biomarkers for Late-Onset Preeclampsia. Hypertension. ISSN 0194-911X. 83(2). doi: 10.1161/hypertensionaha.125.25189. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Preeclampsia is classified as either a more severe early onset or a more prevalent late-onset form. Lower PlGF (placental growth factor) and increased sFlt-1 (fms-like tyrosine kinase-1) in maternal circulation are promising biomarkers, yet they lack specificity for preeclampsia. METHODS: We quantified ≈7000 proteins in 673 samples collected from 89 patients with late-onset preeclampsia and 91 controls at T1 (15–22), T2 (22–30), and T3 (30–42) weeks. Elastic net and random forest models were fitted and evaluated by cross-validation. Differential abundance analysis followed by functional profiling, was used to identify and interpret protein changes. RESULTS: An increase in protein differential abundance in late-onset preeclampsia was observed with advancing gestation, reaching 806 proteins at T3 related to angiogenesis, cell adhesion, and extracellular matrix remodeling. FAAH2 (fatty acid amide hydrolase 2), SIGLEC6 (sialic acid-binding Ig-like lectin-6), IL17RC (interleukin-17 receptor C), HTRA1 (serine protease), sFlt-1, and 47 other proteins dysregulated at T3 were validated in a reanalysis of a ≈5000 protein Norwegian data set. Random forest models with 20 proteins showed high accuracy at T3 (area under the curve [AUC], 0.83 [0.77–0.89], sensitivity 59%) even in cases not yet diagnosed at sampling (n=31, AUC, 0.80 [0.71–0.90], sensitivity 58%), outperforming sFlt-1 and PlGF. Moderate accuracy was obtained at T1 (AUC, 0.63 [0.54–0.72], sensitivity 33%) and T2 (AUC, 0.59 [0.50–0.68], sensitivity 17%). Combining maternal characteristics and obstetric history with proteomics data increased accuracy at T1 (AUC, 0.68 [0.59–0.77], sensitivity 28%), T2 (AUC, 0.68 [0.60–0.77], sensitivity 31%), and T3 (AUC, 0.87 [0.81–0.92], sensitivity 69%). CONCLUSIONS: The findings confirm the involvement of abnormal trophoblast invasion, angiogenesis, and extracellular matrix remodeling in late-onset preeclampsia, while highlighting new protein alterations consistent across diverse cohorts.

• Frisch, Ingrid Kverndalen; Michelsen, Trond Melbye; Lekva, Tove; Roland, Marie Cecilie & Westerberg, Ane Cecilie (2025). Adhesion molecules in the maternal–fetal interface in healthy pregnancies and preeclampsia. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 105(2), s. 209–388. doi: 10.1111/aogs.70111. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Adhesion molecules are markers of endothelial activation, and they are involved in placentation and inflammation. We compared levels of vascular cell adhesion molecule‐1 (VCAM1), intercellular adhesion molecule‐1 (ICAM1), and E‐selectin (SELE) in maternal and fetal vessels of preeclampsia and healthy pregnancies. Furthermore, we investigated if the placenta releases adhesion molecules. Material and Methods Blood was sampled from three maternal (antecubital vein, uterine vein, and radial artery as a proxy for the uterine artery) and two fetal vessels (umbilical vein and artery) in 75 healthy pregnancies and 37 cases of preeclampsia undergoing cesarean delivery. Samples were also collected among 70 healthy pregnancies and 35 preeclampsia cases at three visits (gestational weeks 14–16, 22–24, and 30–32) in a longitudinal cohort. Proteins were relatively quantified on SomaLogic's 5000‐multiplex platform. Venoarterial differences on both sides of the placenta were used to indicate placental release and uptake. Results Before the onset of preeclampsia, we observed elevated maternal antecubital vein levels of VCAM1 (visits 1 and 3) and ICAM1 (all three visits). At delivery, VCAM1 and SELE were elevated in maternal vessels in preeclampsia compared to healthy, except for VCAM1 in the uterine vein. On the fetal side of the placenta, adhesion molecules were lower in preeclampsia compared to healthy pregnancies. There were no venoarterial differences on the maternal side of the placenta that indicated placental protein release. On the fetal side of the placenta, healthy controls had a positive venoarterial difference of SELE, indicating placental release to the fetus. VCAM1 and SELE levels were higher in fetal circulation as compared to maternal circulation in healthy pregnancies, whereas in preeclampsia, this was only the case for VCAM1. ICAM1 was higher in maternal than fetal circulation in healthy controls and preeclampsia. Conclusions Alterations in maternal levels of adhesion molecules were seen before the onset of PE. In preeclampsia, adhesion molecules were elevated in the maternal and lower in the fetal circulation. There was no placental release of the adhesion molecules to the mother, indicating a general systemic endothelial dysfunction. The results highlight new insights into the pathophysiology of preeclampsia that warrant further exploration.

• Westerberg, Ane Cecilie; Degnes, Maren-Helene Langeland; Andresen, Ina Jungersen; Sellevoll, Hilde Bastøe; Lekva, Tove & Ueland, Thor [Vis alle 11 forfattere av denne artikkelen] (2025). Placenta-Derived Proteins in Preeclampsia: A Human In Vivo Study. Hypertension. ISSN 0194-911X. 82(12), s. 2125–2139. doi: 10.1161/hypertensionaha.125.24886. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Placental dysfunction, a key feature of preeclampsia, has been linked to altered placental release of proteins into the maternal circulation. However, the identity of placenta-derived proteins in preeclampsia is unclear due to the inaccessibility of the placenta during pregnancy. This study aimed to identify placenta-derived proteins in preeclampsia, characterize their associated biological processes, and assess their biomarker potential. METHODS: We used the 4-vessel sampling method to collect blood from the ingoing and outgoing vessels of the placenta during cesarean section to identify proteins secreted from the placenta. Prospectively collected samples from a separate pregnancy cohort were also included. Proteins were quantified on the SomaLogic 5000-plex platform. RESULTS: We identified 620 placenta-derived proteins, including 229 proteins released in both healthy pregnancies and in preeclampsia, 345 proteins released in preeclampsia only, and 46 proteins released in healthy controls only. Biological process gene ontologies linked to oxidative stress and cellular turnover were enriched among the placenta-derived proteins in preeclampsia, but not in healthy pregnancies. In the prospective cohort, 21 of the 620 placenta-derived proteins had altered levels in preeclampsia at least 3 weeks before, and on average >7 weeks before delivery. Among these, prediction performance for preeclampsia was promising for 11 biomarker candidates in single protein models (area under the curve >0.7) and 17 significantly improved prediction when combined with clinical variables as compared with a clinical model alone. CONCLUSIONS: Using a unique in vivo sampling method, we identified placenta-derived proteins in preeclampsia, several of which showed promising biomarker potential.

• Christensen, Jacob J; Holven, Kirsten Bjørklund; Bogsrud, Martin Prøven; Retterstøl, Kjetil; Lennep, Jeanine E Roeters van & Michelsen, Trond Melbye [Vis alle 8 forfattere av denne artikkelen] (2025). Statin use in pregnancy and risk of congenital malformations: a Norwegian nationwide study. European Heart Journal. ISSN 0195-668X. 47(3), s. 318–327. doi: 10.1093/eurheartj/ehaf592. Fulltekst i vitenarkiv Vis sammendrag

  Background and Aims Statins and other lipid-modifying agents (LMAs) have traditionally been contraindicated during pregnancy due to concerns about harmful fetal effects; however, the risks associated with exposure to statins and other LMAs in human pregnancies remain unclear. Therefore, this study aimed to examine the associations between statin and LMA exposure in pregnancy and congenital malformations in offspring, while updating a 2022 meta-analysis with the results from the present study. Methods National registry data were linked for all pregnant women in Norway in 2005–18. Associations between first-trimester statin prescription fills and congenital malformations were estimated with mixed-effects logistic regression, adjusting for age, parity, pre-pregnancy folate use, smoking in early pregnancy, comorbidity, and co-medication. Meta-analyses were performed with the generic inverse–variance method and random-effects model. Results Congenital malformations occurred among 34 755 out of 803 830 (4.3%) statin non-exposed pregnancies, 74 out of 1255 (5.9%) statin-discontinuer pregnancies, and 19 out of 283 (6.7%) statin-exposed pregnancies. Adjusted odds ratios (ORs) for exposed vs non-exposed pregnancies were 1.30 [95% confidence interval (CI) .81–2.09] for any, 1.15 (.61–2.19) for major, and 1.47 (.75–2.89) for minor malformations. In analyses of exposed vs discontinuer pregnancies, there were no associations between statin exposure and any (adjusted OR 1.01, 95% CI .59–1.72), major (1.08, .52–2.25), or minor malformations (.94, .44–2.00). Results were similar across sensitivity analyses. There was also no association between any LMA exposure and heart malformations (adjusted OR 1.22, 95% CI .50–3.01). The updated meta-analysis suggested no increased risk of major (adjusted OR 1.06, 95% CI .86–1.31) or heart malformations (1.24, 95% CI .94–1.64). Conclusions In this large, nationwide study and updated meta-analysis, no significant association was observed between first-trimester exposure to statins or other LMAs and congenital malformations. Although limited power may have prevented detection of weak but clinically relevant associations, the findings do not support a strong or independent association between statin exposure in pregnancy and congenital malformations.

• Boer, Eline de; Strandmoe, Anne-Lise; Sokolova, Marina; Michelsen, Trond Melbye; Quach, Huy Quang & Chaban, Viktoriia [Vis alle 12 forfattere av denne artikkelen] (2025). Extracellular mitochondrial DNA activates complement and is associated with complement activation in patients with out-of-hospital cardiac arrest. Scientific Reports. 15(1). doi: 10.1038/s41598-025-24705-1. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Synthetic analogues of mitochondrial DNA (mtDNA) have been reported as potent complement system activators. This study investigated the impact of endogenous mtDNA on complement activation. mtDNA and nuclear DNA (nDNA) were extracted from human placental tissue and complement activation was determined using ELISA. When incubated in lepirudin-anticoagulated human blood and plasma, increasing concentrations of mtDNA, but not nDNA, resulted in dose- and time-dependent increases in C3bc, C3bBbP and soluble C5b-9 (sC5b-9). In a clinical context, mtDNA, nDNA, and complement levels of 55 resuscitated out-of-hospital cardiac arrest (OHCA) patients were determined using qPCR and ELISA. C3bc and sC5b-9 correlated significantly with mtDNA and nDNA in OHCA patients. We conclude that mtDNA, but not nDNA, triggers in vitro complement activation, which holds significance in a clinical context in OHCA patients. This novel mode of human complement activation might explain pathophysiological mechanisms of sterile inflammation and could be relevant for innovative therapeutic strategies.

• Kopcil, Pavel; Ervik, Carolina W.; Reint, Ganna; Mamia, Katariina; Szymanska, Monika & Dahal-Koirala, Shiva [Vis alle 17 forfattere av denne artikkelen] (2025). Editing of ADA2 Point Mutation in Human Hematopoietic Stem Cells. bioRxiv (preprint article). doi: 10.1101/2025.08.14.670303. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background The homozygous ADA2 : c.506G>A (p.Arg169Gln; p.R169Q) variant accounts for majority of Deficiency in Adenosine Deaminase 2 (DADA2). This monogenic disorder may be amenable to ex vivo gene therapy by correcting the pathogenic mutation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Objective To apply CRISPR-Cas9 and homology-directed repair (HDR) as a surrogate strategy to model correction of the pathogenic ADA2 c.506G>A variant in healthy cord blood HSPCs. Methods HSPCs were electroporated with optimised CRISPR-Cas9 editing reagents, and editing outcomes, including HDR and on-target deletions, were quantified by ddPCR. Cell functionality was assessed through colony-forming unit (CFU) assays and by xenotransplantation into NOD SCID Gamma (NSG) mice. Two HDR enhancement strategies were tested: (1) genetic inhibitors of p53 and non-homologous end joining (NHEJ) pathways, and (2) pharmacological NHEJ inhibition. Results Small-molecule NHEJ inhibitors increased HDR efficiency approximately two-fold (from ∼40 % to ∼80 %). Edited HSPCs retained normal CFU capacity and successfully engrafted in NSG mice. However, up to 8 % of edited cells exhibited on-target chromosome loss, though this declined over time. Up to 40 % of T cells and fibroblasts demonstrated similar losses under NHEJ inhibitors treatment. In contrast, genetically encoded inhibitors did not improve HDR. Conclusion The ADA2 p. c.506G>A variant can be effectively edited employing surrogate strategy in HSPCs without impairing functionality. Although pharmacological inhibition of NHEJ enhances HDR efficiency, it also increases the risk of on-target chromosome aberrations, highlighting the need for careful consideration of the associated risks and benefits in therapeutic gene editing. Key messages 1) The ADA2 p.R169Q variant can be efficiently corrected via HDR, and the edited CD34+ HSPCs retain their engraftment capability in NSG mice. 2) Pharmacological inhibition of NHEJ using small-molecule inhibitors increases HDR efficiency but is associated with significant on-target deletions and chromosomal arm loss, particularly in differentiated cell types, and in a donor-dependent manner. Capsule summary The ADA2 p.R169Q variant is a viable target for precision gene editing in hematopoietic stem cells. Although inhibition of NHEJ improves HDR efficiency, it concomitantly increases the risk of large on-target deletions, particularly in differentiated cells.

• Mamia, Katariina Aino Inkeri; Kolbeinsdottir, Solrun; Labun, Kornel; Li, Zhuokun; Komisarczuk, Anna Zofia & Keskitalo, Salla [Vis alle 32 forfattere av denne artikkelen] (2025). Precision T cell correction platform for Inborn Errors of Immunity. Molecular Therapy. ISSN 1525-0016. 33(11), s. 5624–5643. doi: 10.1016/j.ymthe.2025.08.018. Fulltekst i vitenarkiv Vis sammendrag

  CRISPR/Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting Inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knock-in, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function (STAT1-GOF), Cartilage Hair Hypoplasia (CHH), Deficiency of ADA2 (DADA2), and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.

• Hansen, Bo Lars Thorvald Terning; Dahl, Jesper; Greve-Isdahl, Margrethe; Winje, Brita Askeland; Rydland, Kjersti Margrethe & Campbell, Suzanne [Vis alle 9 forfattere av denne artikkelen] (2025). Low and inequitable influenza and COVID-19 vaccination coverage among pregnant women in Norway: Nationwide population-based cohort study. Vaccine. ISSN 0264-410X. 61. doi: 10.1016/j.vaccine.2025.127386. Fulltekst i vitenarkiv
• Andresen, Ina Jungersen; Westerberg, Ane Cecilie; Roland, Marie Cecilie; Zucknick, Manuela & Michelsen, Trond Melbye (2025). Maternal Plasma Proteins Associated with Birth Weight: A Longitudinal, Large Scale Proteomic Study. Journal of Proteome Research. ISSN 1535-3893. 24, s. 3247–3260. doi: 10.1021/acs.jproteome.4c00940. Fulltekst i vitenarkiv Vis sammendrag

  Small infants for gestational age (SGA) and large infants for gestational age (LGA) have increased risk of complications during delivery and later in life. Prediction of the fetal weight is currently limited to biometric parameters obtained by ultrasound scans that can be imprecise. Biomarkers of fetal growth would be crucial for tailoring clinical management and optimizing outcomes for the mother and child. Seventy pregnant women participated in the current study, including 58, 7, and 5 giving birth to adequate for gestational age (AGA), SGA, and LGA infants, respectively. Maternal venous blood was drawn at gestational weeks 12–19, 21–27, and 28–34 and quantified for nearly 5000 proteins on the SomaLogic platform. We used machine learning algorithms with leave-one-out cross-validation to construct multiprotein models for prediction of birth weight groups. Random forest models using only 20 predefined proteins (selected by moderated t tests) were able to predict LGA with good discrimination (AUC > 0.8) at all three visits, while prediction of SGA was less successful. Protein differential abundance analysis revealed 148 proteins with higher abundance in LGA compared to AGA pregnancies, while only four proteins were differentially abundant between the SGA and AGA. The principal findings indicate that the maternal plasma proteome may hold potential biomarkers of LGA.

• Bjørnerem, Åshild Marit; Kolstad, Caroline Renland; Helmersen, Tonje Agnete Gravvold; Michelsen, Trond Melbye & Sørbye, Ingvil Krarup (2025). Fødselsmåte etter igangsatt fødsel ved pregravid overvekt og fedme. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(7). doi: 10.4045/tidsskr.24.0643. Fulltekst i vitenarkiv
• Henriksen, Tore; Sajjad, Muhammad Umar; Haugen, Guttorm Nils & Michelsen, Trond Melbye (2024). Placental energy metabolism: Evidence for a placental-maternal lactate-ketone trade in the human. Placenta. ISSN 0143-4004. 148, s. 31–37. doi: 10.1016/j.placenta.2024.01.020. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Glucose from placenta is the predominant energy source for the fetus. Individual placentas exhibit a range of glucose handling from apparent net production to high consumption, presumably reflecting an ability of placenta to secure both own and fetal energy needs. A dependency of placenta on glucose as the main energy source could impede fetal supply. Placenta seems to release lactate to maternal side implying loss of energy. Whether placenta takes up ketones is unclear. Our main hypothesis was that the human placenta can release lactate to the maternal side but take up maternal ketones. Methods An in vivo study of term uncomplicated pregnancies including 56 women delivered by cesarean section. We measured uterine and umbilical blood flow by Doppler ultrasonography, combined with blood sampling from maternal radial artery, uterine vein, umbilical artery and vein. Lactate and ketones were determined by quantitative nuclear magnetic resonance. Results Placenta released lactate to the maternal side (median −36.65 μmol/min. Q1, Q3: 78.53, 13.29), p < 0.001), but not to the fetal side. A net uptake of maternal ketones was found (median (Q1, Q3): 59.12 (30.64, 131.46) μmol acetate equivalents/min, p < 0.001) which largely was metabolized by the uteroplacenta. The uptake of ketones was comparable in energy to the loss of lactate. Discussion Placenta may release lactate to the maternal side. The energy lost by lactate may be compensated by uptake of maternal ketones. This lactate-ketone trade could benefit both placenta and the fetus by providing lactate for maternal gluconeogenesis and ketones for uteroplacental oxidative energy production.

• Michelsen, Trond Melbye; Skytte, Hege Nyhus; Gunnes, Nina; Holven, Kirsten Bjørklund; Christensen, Jacob J. & Roland, Marie Cecilie (2024). Metabolic profiles in early pregnancy associated with metabolic pregnancy complications in women with obesity. Journal of Reproductive Immunology. ISSN 0165-0378. 166. doi: 10.1016/j.jri.2024.104397. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Higher maternal body mass index (BMI) is associated with metabolic disturbances and pregnancy complications. We aimed to examine whether metabolic profiles in early pregnancy were associated with metabolic pregnancy complications in women with obesity (BMI ≥ 30 kg/m2). Material and methods Nested cohort study from a prospective longitudinal cohort (n = 1031) of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002–2008. The sample comprised 81 women with obesity. Metabolic pregnancy complications included gestational diabetes mellitus, gestational hypertension and preeclampsia. In plasma samples from gestational weeks 14–16, 91 metabolites were analyzed by nuclear magnetic resonance spectroscopy. We performed a principal component analysis to reduce the metabolic dimensions. Logistic regression models were fitted to estimate crude and adjusted odds ratios (ORs) of metabolic pregnancy complications. Results Twenty-four out of 81 women developed metabolic pregnancy complications (gestational hypertension, preeclampsia, and/or gestational diabetes). Two of five principal components (80 % explained variance) were significantly associated with metabolic pregnancy complications. The ratio of monounsaturated to total fatty acids increased the risk of metabolic pregnancy complications (OR 2.09, 95 % confidence interval [CI] 1.25–3.75), while the ratio of polyunsaturated to monounsaturated fatty acids decreased the risk (OR 0.54, 95 % CI 0.30–0.89). The ratio of omega-3 to total fatty acids (OR 0.59, 95 % CI 0.34–0.98) and the ratio of docosahexaenoic acid to total fatty acids (OR 0.57, 95 % CI 0.31–0.97) also decreased the risk of metabolic pregnancy complications. Conclusion Metabolic profile in early pregnancy was associated with risk of metabolic pregnancy complications in women with obesity. We observed the strongest associations between fatty acid composition and metabolic pregnancy complications.

• Sletner, Line; Yajnik, Chittaranjan S.; Turowski, Gitta Erika; Michelsen, Trond Melbye; Sommer, Christine & Birkeland, Kåre Inge [Vis alle 8 forfattere av denne artikkelen] (2024). Placental weight, surface area, shape and thickness - Relations with maternal ethnicity and cardio-metabolic factors during pregnancy. Placenta. ISSN 0143-4004. 148, s. 69–76. doi: 10.1016/j.placenta.2024.02.002. Fulltekst i vitenarkiv Vis sammendrag

  Introduction A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. Methods A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks’ gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. Results Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (−51 g (95% CI: 75, −27) and −55 g (−95, −14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. Discussion Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness.

• Andresen, Ina Jungersen; Zucknick, Manuela; Degnes, Maren-Helene Langeland; Angst, Martin S.; Aghaeepour, Nima & Romero, Roberto [Vis alle 10 forfattere av denne artikkelen] (2024). Prediction of late-onset preeclampsia using plasma proteomics: a longitudinal multi-cohort study. Scientific Reports. 14(1). doi: 10.1038/s41598-024-81277-2. Fulltekst i vitenarkiv Vis sammendrag

  Preeclampsia is a pregnancy disorder with substantial perinatal and maternal morbidity and mortality. Pregnant women at risk of preeclampsia would benefit from early detection for follow-up, timely interventions and delivery. Several attempts have been made to identify protein biomarkers of preeclampsia, but findings vary with demographics, clinical characteristics, and time of sampling. In the current study, we combined three independent longitudinal pregnancy cohorts (Detroit, Stanford and Oslo) resulting in 124 late-onset preeclampsia (LOPE) cases and 178 gestational age matched controls, and analyzed > 1000 proteins in maternal plasma sampled between 12 and 34 weeks of gestation. Differential abundance analysis of combined protein data revealed increased deviation in protein abundance trajectories throughout gestation in women destined to develop LOPE compared to controls. There were no differentially abundant proteins at time interval T1 (12–19 weeks), yet 31 differentially abundant proteins were found at time interval T2 (19–27 weeks), and 48 proteins at time interval T3 (27- 34 weeks). Multi-protein random forest models assessed via cross-validation predicted LOPE with an area under the ROC curve of 0.72 (0.65–0.78), 0.76 (0.71–0.81) and 0.80 (0.75–0.85) at time interval T1, T2 and T3, respectively. The results at T3 were confirmed using a leave-one-cohort-out analysis suggesting cross-cohort consistency, and at T1 and T2 when the largest two cohorts were used as training sets.

• Rosland, Tina Ellinor; Johansen, Nora; Åsvold, Bjørn Olav; Pripp, Are Hugo; Liavaag, Astrid Helene & Michelsen, Trond Melbye (2024). Validity of self-reported hysterectomy and oophorectomy in a population-based cohort: The HUNT study. BJOG: An International Journal of Obstetrics and Gynaecology. ISSN 1470-0328. 131(11), s. 1555–1562. doi: 10.1111/1471-0528.17859. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To validate self-reported hysterectomy and bilateral oophorectomy. Design: Validation study. Setting: Large population-based cohort study in Norway: The Trøndelag Health Study (HUNT). Population: The Trøndelag Health Study 2 and 3 (HUNT2 and HUNT3) included questions on gynaecological history. Women who answered questions regarding hysterectomy and/or oophorectomy were included. In total, 30 263 women were included from HUNT2 (1995–1997) and 23 138 from HUNT3 (2006–2008), of which 16 261 attended both HUNT2 and HUNT3. Methods: We compared self-reported hysterectomy and bilateral oophorectomy with electronic hospital procedure codes. Main outcome measures: Sensitivity, specificity, positive predictive value and negative predictive value of self-reported hysterectomy and bilateral oophorectomy, by comparing with hospital procedure codes. Results: Self-reported hysterectomy and bilateral oophorectomy in HUNT2 and/or HUNT3 both had specificity and negative predictive value above 99%. Self-reported hysterectomy had a sensitivity of 95.9%, and for bilateral oophorectomy sensitivity was 91.2%. Positive predictive value of self-reported hysterectomy was 85.8%, but for self-reported bilateral oophorectomy it was 65.4%. Conclusions: Self-reported hysterectomy corresponded quite well with hospital data and can be used in epidemiological studies. Self-reported bilateral oophorectomy, on the other hand, had low positive predictive value, and results based on such data should be interpreted with caution. Women who report no previous hysterectomy or bilateral oophorectomy can safely be classified as unexposed to these surgeries.

• Degnes, Maren-Helene Langeland; Westerberg, Ane Cecilie; Andresen, Ina Jungersen; Henriksen, Tore; Roland, Marie Cecilie & Zucknick, Manuela [Vis alle 7 forfattere av denne artikkelen] (2024). Protein biomarker signatures of preeclampsia - a longitudinal 5000-multiplex proteomics study. Scientific Reports. 14(1). doi: 10.1038/s41598-024-73796-9. Fulltekst i vitenarkiv Vis sammendrag

  We aimed to explore novel biomarker candidates and biomarker signatures of late-onset preeclampsia (LOPE) by profiling samples collected in a longitudinal discovery cohort with a high-throughput proteomics platform. Using the Somalogic 5000-plex platform, we analyzed proteins in plasma samples collected at three visits (gestational weeks (GW) 12–19, 20–26 and 28–34 in 35 women with LOPE (birth ≥ 34 GW) and 70 healthy pregnant women). To identify biomarker signatures, we combined Elastic Net with Stability Selection for stable variable selection and validated their predictive performance in a validation cohort. The biomarker signature with the highest predictive performance (AUC 0.88 (95% CI 0.85–0.97)) was identified in the last trimester of pregnancy (GW 28–34) and included the Fatty acid amid hydrolase 2 (FAAH2), HtrA serine peptidase 1 (HTRA1) and Interleukin-17 receptor C (IL17RC) together with sFLT1 and maternal age, BMI and nulliparity. Our biomarker signature showed increased or similar predictive performance to the sFLT1/PGF-ratio within our data set, and we were able to validate the biomarker signature in a validation cohort (AUC ≥ 0.90). Further validation of these candidates should be performed using another protein quantification platform in an independent cohort where the negative and positive predictive values can be validly calculated.

• Gaudernack, Lise Christine; Einarsen, Angeline Elisabeth Styve; Sørbye, Ingvil Krarup; Lukasse, Mirjam; Gunnes, Nina & Michelsen, Trond Melbye (2024). The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial. PLoS Medicine. ISSN 1549-1277. 21(3), s. 1–24. doi: 10.1371/journal.pmed.1004352. Fulltekst i vitenarkiv Vis sammendrag

  Background: Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor. Methods and findings In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated.Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eli- gible women with signed informed consent receiving either of the 2 treatments. The follow- up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson’s chi-square test: p = 0.002). More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have repre- sented a selected group of women reducing the external validity of the study. Conclusions One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to pla- cebo in preventing slow labor progress in a population of first-time mothers at risk of pro- longed labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor.

• Westerberg, Ane Cecilie; Degnes, Maren-Helene Langeland; Andresen, Ina Jungersen; Roland, Marie Cecilie & Michelsen, Trond Melbye (2024). Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. 231(5), s. 550.e1–550.e22. doi: 10.1016/j.ajog.2024.03.012. Fulltekst i vitenarkiv Vis sammendrag

  Background Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels. Objective We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1–3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations. Study Design Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins. Results The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower. Conclusion An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins’ involvement in the pathophysiology and as treatment targets is warranted.

• Øyri, Linn K. L.; Christensen, Jacob J.; Sebert, Sylvain; Thoresen, Magne; Michelsen, Trond M. & Ulven, Stine M. [Vis alle 12 forfattere av denne artikkelen] (2023). Maternal prenatal cholesterol levels predict offspring weight trajectories during childhood in the Norwegian Mother, Father and Child Cohort Study. BMC Medicine. 21. doi: 10.1186/s12916-023-02742-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Numerous intrauterine factors may affect the offspring’s growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. Methods This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). Results Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99). Conclusions Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

• Skytte, Hege; Roland, Marie Cecilie; Christensen, Jacob J.; Holven, Kirsten Bjørklund; Lekva, Tove & Gunnes, Nina [Vis alle 7 forfattere av denne artikkelen] (2023). Maternal metabolic profiling across body mass index groups: An exploratory longitudinal study. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 103(3), s. 540–550. doi: 10.1111/aogs.14750. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Increased BMI has been identified as a risk factor for most pregnancy complications, but the underlying metabolic factors mediating the detrimental effects of BMI are largely unknown. We aimed to compare metabolic profiles in overweight/obese women (body mass index [BMI] ≥ 25 kg/m 2 ) and normal weight/underweight women (BMI &lt; 25 kg/m 2 ) across gestation. We also explored how gestational weight gain (GWG) affected maternal metabolic profiles. Material and methods Exploratory nested case–control study based on a prospective longitudinal cohort of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002 to 2008. The sample consisted of 48 women who were overweight/obese and 59 normal‐weight/underweight women. Plasma samples from four time points in pregnancy (weeks 14–16, 22–24, 30–32 and 36–38) were analyzed by nuclear magnetic resonance spectroscopy and 91 metabolites were measured. Linear regression models were fitted for each of the metabolites at each time point. Results Overweight or obese women had higher levels of lipids in very‐low‐density lipoprotein (VLDL), total triglycerides, triglycerides in VLDL, total fatty acids, monounsaturated fatty acids, saturated fatty acids, leucine, valine, and total branched‐chain amino acids in pregnancy weeks 14–16 compared to underweight and normal‐weight women. Docosahexaenoic acid and degree of unsaturation were significantly lower in overweight/obese women in pregnancy weeks 36–38. In addition, overweight or obese women had higher particle concentration of XXL‐VLDL and glycoprotein acetyls (GlycA) at weeks 14–16 and 30–32. GWG did not seem to affect the metabolic profile, regardless of BMI group when BMI was treated as a dichotomous variable, ≥25 kg/m 2 (yes/no). Conclusions Overweight or obese women had smaller pregnancy‐related metabolic alterations than normal‐weight/underweight women. There was a trend toward higher triglyceride and VLDL particle concentration in overweight/obese women. As this was a hypothesis‐generating study, the similarities with late‐onset pre‐eclampsia warrant further investigation. The unfavorable development of fatty acid composition in overweight/obese women, with possible implication for the offspring, should also be studied further in the future.

• Michelsen, Trond Melbye; Rosland, Tina Ellinor; Åsvold, Bjørn Olav; Pripp, Are Hugo; Liavaag, Astrid Helene & Johansen, Nora (2023). All-cause and cardiovascular mortality after hysterectomy and oophorectomy in a large cohort (HUNT2). Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 102(4), s. 465–472. doi: 10.1111/aogs.14531. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Hysterectomy and bilateral oophorectomy are common major surgical procedures that have been associated with increased mortality risk. We aimed to assess the association of hysterectomy and/or bilateral oophorectomy with all-cause and cardiovascular mortality in a Norwegian population. Material and methods Cohort study with data from The Trøndelag Health Study (HUNT2) linked to the Norwegian Cause of Death Registry, with follow-up from 1996 until 2014 or death. The unexposed group (n = 18 673) included women with both their ovaries and uterus intact, while the two exposed groups included women with hysterectomy alone (n = 1199), or bilateral oophorectomy with or without hysterectomy (n = 907). We compared mortality in exposed vs unexposed groups and adjusted for relevant covariates by Cox regression. Further, we performed analyses stratified by age at surgery (≤39, 40–52, ≥53 years) and subgroup analyses among women ≤52 years of age at inclusion. Results Among the 47 312 women in HUNT2 (1995–1997), 20 779 provided complete information regarding gynecological surgery and previous health. The hysterectomy group had increased all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06–1.58) and cardiovascular mortality (HR 1.47, 95% CI 1.09–1.97). We found no significant association between bilateral oophorectomy and all-cause or cardiovascular mortality in the total population. However, among women ≤52 years at inclusion, cardiovascular mortality was increased in the hysterectomy group (HR 2.71, 95% CI 1.19–6.17) with a similar, but less precise estimate in the bilateral oophorectomy group (HR 2.42, 95% CI 0.84–6.93). Conclusions Hysterectomy was associated with increased all-cause and cardiovascular mortality, whereas bilateral salpingo-oophorectomy was not. Among women ≤52 years at inclusion, both hysterectomy and bilateral oophorectomy were associated with a twofold increased risk of cardiovascular mortality, but the results were imprecise. Women after hysterectomy and/or bilateral salpingo-oophorectomy constitute a group with increased cardiovascular mortality that may need closer attention to cardiovascular disease risk from the healthcare system to ensure timely and effective preventive interventions.

• Skytte, Hege; Christensen, Jacob J.; Gunnes, Nina; Holven, Kirsten Bjørklund; Lekva, Tove & Henriksen, Tore [Vis alle 8 forfattere av denne artikkelen] (2023). Metabolic profiling of pregnancies complicated by preeclampsia: A longitudinal study. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 102(3), s. 334–343. doi: 10.1111/aogs.14505. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Preeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures. Material and methods We measured 91 metabolites by high‐throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14–16, 22–24, 30–32 and 36–38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia ( n  = 38) and healthy controls ( n  = 70). Results Among women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid‐related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very‐low‐density lipoprotein particles, the smallest high‐density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4. Conclusions In early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre‐pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia‐specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very‐low‐density lipoprotein, triglycerides, and total fatty acids.

• Sajjad, Muhammad Umar; Henriksen, Tore; Roland, Marie Cecilie; Haugen, Guttorm Nils & Michelsen, Trond Melbye (2023). Maternal body mass index, birthweight, and placental glucose metabolism: evidence for a role of placental hexokinase. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. s. 1–10. doi: 10.1016/j.ajog.2023.10.043. Fulltekst i vitenarkiv Vis sammendrag

  Background The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta’s glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose-6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown. Objective This study aimed to test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birthweight. Study Design Overall, 67 healthy pregnant participants at term were included in this study at Oslo University Hospital, Oslo, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arteriovenous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptakes. The Spearman rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (milliunit per milligram of protein) with prepregnancy body mass index, maternal glucose and insulin, birthweight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (micromole per minute). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight. Results Hexokinase activity was detectable in all placental tissue samples. The mean activity was 19.6 (standard deviation, 4.64) mU/mg protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman rho=0.33; P=.006). On controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=.01) and insulin (r=0.28; P=.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (Spearman rho=0.31; P=.01) and consumption (Spearman rho=0.28; P=.02). Hexokinase activity did not correlate with fetal glucose uptake. On controlling for placental weight, hexokinase activity showed a positive correlation with birthweight (r=0.31; P=.01). Conclusion Our findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for disposition, is related to both maternal body mass index and birthweight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.

• Henriksen, Tore; Roland, Marie Cecilie; Sajjad, Muhammad Umar; Haugen, Guttorm Nils & Michelsen, Trond Melbye (2022). Uteroplacental versus fetal use of glucose in healthy pregnancies at term. A human in vivo study. Placenta. ISSN 0143-4004. 128, s. 116–122. doi: 10.1016/j.placenta.2022.09.001. Fulltekst i vitenarkiv
• Kristiansen, Oddrun; Roland, Marie Cecilie; Zucknick, Manuela; Reine, Trine M.; Kolset, Svein Olav & Henriksen, Tore [Vis alle 8 forfattere av denne artikkelen] (2022). Maternal body mass index and placental weight: a role for fetal insulin, maternal insulin and leptin. Journal of Endocrinological Investigation. ISSN 0391-4097. 45, s. 2105–2121. doi: 10.1007/s40618-022-01842-2. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Placental weight (PW) has been found to mediate the main effect of maternal BMI on fetal size. Still, the BMI–PW association is poorly understood. Therefore, we aimed to explore potential explanatory variables, including gestational weight gain (GWG), early- and late-pregnancy circulating levels of maternal glucose, insulin, leptin, adiponectin, triglycerides, LDL-C, and HDL-C, and fetal insulin. Methods We included two studies of pregnant women from Oslo University Hospital, Norway: the prospective STORK (n = 263) and the cross-sectional 4-vessel method study (4-vessel; n = 165). We used multiple linear regression for data analyses. A non-linear BMI-PW association was observed, which leveled off from BMI25. Therefore, BMI <25 and ≥25 were analyzed separately (n = 170/122 and 93/43 for STORK/4-vessel). Confounding variables included maternal age, parity, and gestational age. Results PW increased significantly per kg m−2 only among BMI <25 (univariate model’s std.β[p] = 0.233 [0.002] vs. 0.074[0.48]/0.296[0.001] vs. −0.030[0.85] for BMI <25 vs. ≥25 in STORK/4-vessel). Maternal early- but not late-pregnancy insulin and term fetal insulin were associated with PW. The estimated effect of early pregnancy insulin was similar between the BMI groups but statistically significant only among BMI <25 (std.β[p] = 0.182[0.016] vs. 0.203[0.07] for BMI <25 vs. ≥25). Late pregnancy leptin was inversely associated with PW with a 1.3/1.7-fold greater effect among BMI ≥25 than BMI <25 in the STORK/4-vessel. Conclusions The BMI–PW association was non-linear: an association was observed for BMI <25 but not for BMI ≥25. Leptin may be involved in the non-linear association through a placental–adipose tissue interplay. Maternal early pregnancy insulin and fetal insulin at term were associated with PW.

• Zahid, Saba Muneer; Opheim, Gun Lisbeth; Henriksen, Tore; Michelsen, Trond Melbye & Haugen, Guttorm Nils (2022). Effect of a standardized maternal meal on fetal middle cerebral artery Doppler indices: A single-blinded crossover study. PLOS ONE. 17(8), s. 1–12. doi: 10.1371/journal.pone.0272062. Fulltekst i vitenarkiv Vis sammendrag

  Objective Measures of Doppler blood flow velocity profiles are an integral part of monitoring fetal well-being during pregnancy. These examinations are performed at different times of the day and at different maternal meal states. In uncomplicated pregnancies, we assessed the effect of a standardized maternal meal on middle cerebral artery (MCA) and umbilical artery (UA) Doppler blood flow velocity pulsatility indices (PIs) and MCA peak systolic velocity (PSV). Methods In this prospective single-blinded crossover study 25 healthy women were examined at 36 weeks of pregnancy. The first examination was performed in the morning following overnight fast, and repeated after extended fast (state A), and after a standard breakfast meal (state B). Results Irrespective of maternal prandial status, the MCA-PI values were lower in the 2nd compared to the 1st examination (-0.187; p = 0.071, and -0.113; p = 0.099, state A and B, respectively). Compared to the values in the 1st examination, the UA-PI values, were higher after extended fast (0.014; p = 0.436), and lower post-prandially (-0.036; p = 0.070). The difference (state B minus state A) between the meal states were not significant (0.074; p = 0.487 and -0.050; p = 0.058, for MCA-PI and UA-PI, respectively). Adjusting for the possible influence of fetal heart rate on MCA-PI and UA-PI, the differences between meal states remained non-significant (p = 0.179, p = 0.064, respectively). The MCA-PSV values increased after the meal (6.812; p = 0.035), whereas no increase was observed following extended fast (0.140; p = 0.951). The difference in MCA-PSV values between the two meal states was not significant (6.672; p = 0.055). Conclusion Our results demonstrate possible diurnal variations in MCA-PI and UA-PI, with and without adjustment for fetal heart rate, that seem to be unaffected by maternal meal intake in healthy pregnancies.

• Degnes, Maren-Helene Langeland; Westerberg, Ane Cecilie; Zucknick, Manuela; Powell, Theresa L.; Jansson, Thomas & Henriksen, Tore [Vis alle 8 forfattere av denne artikkelen] (2022). Placenta-derived proteins across gestation in healthy pregnancies—a novel approach to assess placental function? BMC Medicine. 20. doi: 10.1186/s12916-022-02415-z. Fulltekst i vitenarkiv Vis sammendrag

  ackground Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function. Methods We analyzed proteins in plasma samples collected in two cohorts using the Somalogic 5000-plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14–16, 22–24, and 30–32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function. Results Among the nearly 5000 measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a “placental proteomic clock.”

• Waage, Christin; Mdala, Ibrahimu; Stigum, Hein; Jenum, Anne Karen; Birkeland, Kåre Inge & Shakeel, Nilam [Vis alle 9 forfattere av denne artikkelen] (2022). Lipid and lipoprotein concentrations during pregnancy and associations with ethnicity. BMC Pregnancy and Childbirth. 22(1). doi: 10.1186/s12884-022-04524-2. Fulltekst i vitenarkiv Vis sammendrag

  Background To describe ethnic differences in concentrations of lipids and lipoproteins, and their changes, during pregnancy to postpartum. Methods This was a population-based cohort study conducted in primary antenatal care in Norway. The participants (n = 806) were healthy, pregnant women, 59% were ethnic minorities. Outcomes were triglycerides, total cholesterol, HDL- and LDL-cholesterol, analysed from fasting blood samples drawn at gestational age (weeks) 15, 28 and 14 weeks postpartum. We performed linear regression models and linear mixed models to explore the total effect of ethnicity on the outcomes, adjusting for gestational age /week postpartum, maternal age and education. The analyses are corrected for multiple testing using the Bonferroni correction. Results At gestational age 15, triglyceride concentrations were lower in women of African origin (1.03 mmol/mol (95% CI: 0.90, 1.16)) and higher in women of South Asian (primarily Pakistan and Sri Lanka) origin (1.42 mmol/mol (1.35, 1.49)) and East Asian (primarily Vietnam, Philippines and Thailand) origin (1.58 mmol/mol (1.43, 1.73)) compared with Western Europeans (1.26 mmol/mol (1.20, 1.32)). Women of Asian and African origin had a smaller increase in triglycerides, LDL- and total cholesterol from gestational age 15 to 28. At gestational age 28, LDL-cholesterol levels were lowest among East Asians (3.03 mmol/mol (2.72, 3.34)) compared with Western Europeans (3.62 mmol/mol (3.50, 3.74)). Triglycerides and HDL-cholesterol were lower postpartum than at gestational age 15 in all groups, but the concentration of LDL-cholesterol was higher, except in Africans. South and East Asian women had lower HDL-cholesterol and higher triglycerides postpartum, while African women had lower triglycerides than Western Europeans. Conclusion We found significant differences in the concentrations of lipids and lipoproteins and their changes during pregnancy and the early postpartum period related to ethnic origin.

• Aye, Irving L. M. H; Rosario, Fredrick J; Kramer, Anita; Kristiansen, Oddrun; Michelsen, Trond Melbye & Powell, Theresa L [Vis alle 7 forfattere av denne artikkelen] (2022). Insulin Increases Adipose Adiponectin in Pregnancy by Inhibiting Ubiquitination and Degradation: Impact of Obesity. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 107(1), s. 53–66. doi: 10.1210/clinem/dgab680. Fulltekst i vitenarkiv
• Kristiansen, Oddrun; Zucknick, Manuela; Reine, Trine M.; Kolset, Svein Olav; Jansson, Thomas & Powell, Theresa L. [Vis alle 9 forfattere av denne artikkelen] (2021). Mediators linking maternal weight to birthweight and neonatal fat mass in healthy pregnancies. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 106(7), s. 1977–1993. doi: 10.1210/clinem/dgab166. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Context Lifestyle interventions have not efficaciously reduced complications caused by maternal weight on fetal growth, requiring insight into explanatory mediators. Objective We hypothesized that maternal mediators, including adiponectin, leptin, insulin, and glucose, mediate effects of pregestational BMI (pBMI) and gestational weight gain (GWG) on birthweight and neonatal fat mass percentage (FM%) through placental weight and fetal mediators, including insulin levels (Ifv) and venous-arterial glucose difference (ΔGfva). Hypothesized confounders were maternal age, gestational age, and parity. Methods A cross-sectional study of healthy mother-offspring-pairs (n = 165) applying the 4-vessel in vivo sampling method at Oslo University Hospital, Norway. We obtained pBMI, GWG, birthweight, and placental weight. FM% was available and calculated for a subcohort (n = 84). We measured circulating levels of adiponectin, leptin, glucose, and insulin and performed path analysis and traditional mediation analyses based on linear regression models. Results The total effect of pBMI and GWG on newborn size was estimated to be 30 g (range, 16-45 g) birthweight and 0.17 FM% (range, 0.04-0.29 FM%) per kg∙m–2 pBMI and 31 g (range, 18-44 g) and 0.24 FM% (range, 0.10-0.37 FM%) per kg GWG. The placental weight was the main mediator, mediating 25-g birthweight and 0.11 FM% per kg∙m–2 pBMI and 25-g birthweight and 0.13 FM% per kg GWG. The maternal mediators mediated a smaller part of the effect of pBMI (3.8-g birthweight and 0.023 FM% per kg∙m–2 pBMI) but not GWG. Conclusion Placental weight was the main mediator linking pBMI and GWG to birthweight and FM%. The effect of pBMI, but not GWG, on birthweight and FM%, was also mediated via the maternal and fetal mediators.

• Øyri, Linn Kristin Lie; Bogsrud, Martin Prøven; Christensen, Jacob J.; Ulven, Stine Marie; Brantsæter, Anne Lise & Retterstøl, Kjetil [Vis alle 13 forfattere av denne artikkelen] (2021). Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study. BMC Medicine. 19(19). doi: 10.1186/s12916-021-01959-w. Fulltekst i vitenarkiv Vis sammendrag

  Background:More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal andpaternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. Methods:This study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and ChildCohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in thisstudy consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure wasused to correct for multiple testing. Results:Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoproteincholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine,creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated(0.001≤q≤0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine,tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoproteinwere significantly positively associated (0.02≤q≤0.08). Among fathers with hypercholesterolemia, paternal andnewborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q= 0.04). Amongfathers without hypercholesterolemia, no significant associations were found between paternal and newbornmetabolites. Sex differences were found for many cord blood lipids. Conclusions:Maternal and paternal metabolites and newborn sex were associated with several cord bloodmetabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.Keywords:MoBa, the Norwegian Mother, Father and Child Cohort Study, MBRN, Medical Birth Registry of Norway,Cholesterol, Metabolic profiling, Cord blood, Sex differences

• Rosario, Fredrick J.; Pardo, Sammy; Michelsen, Trond Melbye; Erickson, Kathryn; Moore, Lorna & Powell, Theresa L. [Vis alle 8 forfattere av denne artikkelen] (2021). Characterization of the Primary Human Trophoblast Cell Secretome Using Stable Isotope Labeling With Amino Acids in Cell Culture. Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.704781. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Tronstad, Christian & Rosseland, Leiv Arne (2021). Blood pressure and cardiac output during caesarean delivery under spinal anaesthesia: A prospective cohort study. BMJ Open. 11(6), s. 1–9. doi: 10.1136/bmjopen-2020-046102. Fulltekst i vitenarkiv Vis sammendrag

  Objectives We have previously established a method to measure transfer of nutrients between mother, placenta and fetus in vivo. The method includes measurements of maternal and fetal blood flow by Doppler ultrasound prior to spinal anaesthesia. Spinal anaesthesia affects maternal blood pressure and cardiac output. We aimed to determine the effect of spinal anaesthesia in mothers undergoing an elective caesarean section on blood pressure, heart rate and cardiac output, and whether cardiac output levels were comparable before induction of spinal anaesthesia and before delivery. Design Prospective cohort study. Setting Tertiary hospital in Norway. Participants 76 healthy women with uneventful pregnancies undergoing an elective caesarean section. Interventions We induced spinal anaesthesia with a standard prevention of hypotension including intravenous fluid coloading and phenylephrine infusion. Primary and secondary outcome measures Primary outcome measure was maternal cardiac output, and secondary outcome measures were invasive systolic blood pressure and heart rate. We measured heart rate and blood pressure by continuous invasive monitoring with a cannula in the radial artery. Cardiac output was estimated based on continuous arterial waveform. We compared maternal parameters 30 s before induction of spinal anaesthesia to 30 s before delivery. Results Median age at delivery was 34.5 (range 21–43) years and 17 of 76 women were nulliparous. The most prevalent indications were previous caesarean section and maternal request. Among 76 included women, 71 had sufficient data for analysis of endpoints. Median cardiac output was 6.51 (IQR (5.56–7.54) L/min before spinal anaesthesia and 6.40 (5.83–7.56) L/min before delivery (p=0.40)). Median invasive systolic blood pressure increased from 128.5 (120.1–142.7) mm Hg to 134.1 (124.0–146.6) mm Hg (p=0.014), and mean heart rate decreased from 86.0 (SD 13.9) to 75.2 (14.2) (p<0.001). Conclusions Maternal cardiac output at the time of caesarean delivery is comparable to levels before induction of spinal anaesthesia.

• Johansen, Nora; Tonstad, Serena; Liavaag, Astrid Helene; Selmer, Randi Marie; Tanbo, Tom Gunnar & Michelsen, Trond Melbye (2020). Risk of cardiovascular disease after preventive salpingo-oophorectomy. International Journal of Gynecological Cancer. ISSN 1048-891X. 30(5), s. 575–582. doi: 10.1136/ijgc-2019-000856. Fulltekst i vitenarkiv
• Opheim, Gun Lisbeth; Holme, Ane Moe; Holm, Maia Blomhoff; Michelsen, Trond Melbye; Zahid, Saba Muneer & Roland, Marie Cecilie [Vis alle 8 forfattere av denne artikkelen] (2020). The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies. The FASEB Journal. ISSN 0892-6638. 34(9), s. 12481–12491. doi: 10.1096/fj.202000766R. Fulltekst i vitenarkiv Vis sammendrag

  Glucose is a major energy substrate for the fetus, including liver, heart, and brain metabolism. The umbilical vein (UV) blood flow supplies the fetal liver directly from the placenta, whereas a fraction is shunted via ductus venosus (DV) to the fetal systemic circulation bypassing the fetal liver. We hypothesized UV glucose concentration to be a major regulator of the distribution of glucose supply between the fetal liver and DV, and explored the influence of maternal metabolic status on this distribution. We included 124 healthy women with normal singleton pregnancies, scheduled for elective cesarean section. UV and DV blood flow measurements were performed by Doppler ultrasound immediately before, and blood samples were obtained during surgery. UV blood flow was significantly correlated with DV blood flow, liver blood flow, and the DV shunting fraction, while UV glucose concentration was not. For normal‐weight mothers, the maternal‐fetal glucose gradient was positively correlated with DV shunting fraction, and negatively with liver blood flow. For the fetuses of the overweight mothers no such correlation was found. This indicates that within the normal physiological range the human fetus makes adaptations of blood flow to ensure individual needs related to the offered maternal energy supply.

• Gaudernack, Lise Christine; Michelsen, Trond Melbye; Egeland, Thore; Voldner, Nanna & Lukasse, Mirjam (2020). Does prolonged labor affect the birth experience and subsequent wish for cesarean section among first-time mothers? A quantitative and qualitative analysis of a survey from Norway. BMC Pregnancy and Childbirth. 20:605, s. 1–13. doi: 10.1186/s12884-020-03196-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Prolonged labor might contribute to a negative birth experience and influence first-time mothers’ attitudes towards future pregnancies. Previous studies have not adjusted for possible confounding factors, such as operative delivery, induction and postpartum hemorrhage. We aimed to determine the impact of prolonged labor on birth experience and a wish for cesarean section in subsequent pregnancies. Methods A survey including the validated “Childbirth Experience Questionnaire”. First-time mothers giving birth between 2012 and 2014 at a Norwegian university hospital participated. Data from deliveries were collected. Regression analysis and thematic content analysis were performed. Results 459 (71%) women responded. Women with labor duration > 12 h had significantly lower scores on two out of four sub-items of the questionnaire: own capacity (p = 0.040) and perceived safety (p = 0.023). Other factors contributing to a negative experience were: Cesarean section vs vaginal birth: own capacity (p = 0.001) and perceived safety (p = 0.007). Operative vaginal vs spontaneous birth: own capacity (p = 0.001), perceived safety (p < 0.001) and participation (p = 0.047). Induced vs spontaneous start: own capacity (p = 0.039) and participation (p = 0.050). Postpartum hemorrhage ≥500 ml vs < 500 ml: perceived safety (p = 0.002) and participation (p = 0.031). In the unadjusted analysis, prolonged labor more than doubled the risk (odds ratio (OR) 2.66, 95%CI 1.42–4.99) of a subsequent wish for cesarean delivery. However, when adjustments were made for mode of delivery and induction, emergency cesarean section (OR 8.86,95%CI 3.85–20.41) and operative vaginal delivery (OR 3.05, 95%CI 1.46–6.38) remained the only factors significantly increasing the probability of wanting a cesarean section in subsequent pregnancies. The written comments on prolonged labor (n = 46) indicated four main themes: Difficulties gaining access to the labor ward. Being left alone during the unexpectedly long, painful early stage of labor. Stressful operative deliveries and worse pain than imagined. Lack of support and too little or contradictory information from the staff. Conclusions Women with prolonged labors are at risk of a negative birth experience. Prolonged labor per se did not predict a wish for a cesarean section in a subsequent pregnancy. However, women with long labors more often experience operative delivery, which is a risk factor of a later wish for a cesarean section.

• Michelsen, Trond Melbye; Holme, Ane Moe; Holm, Maia Blomhoff; Roland, Marie Cecilie; Haugen, Guttorm & Powell, Theresa L. [Vis alle 8 forfattere av denne artikkelen] (2019). Uteroplacental glucose uptake and fetal glucose consumption: A quantitative study in human pregnancies. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 104(3), s. 873–882. doi: 10.1210/jc.2018-01154. Fulltekst i vitenarkiv Vis sammendrag

  Context Maternal glucose levels and body mass index (BMI) are determinants of fetal overgrowth, but their relation to fetal glucose consumption is not well characterized in human pregnancy. Objectives To quantify uteroplacental glucose uptake and the allocation of glucose between the placenta and fetus and to identify factors that affect fetal glucose consumption. Design Human in vivo study in term pregnancies. Setting Oslo University Hospital, Norway. Participants One hundred seventy-nine healthy women with elective cesarean section. Interventions Uterine and umbilical blood flow was determined using Doppler ultrasonography. Glucose and insulin were measured in the maternal radial artery and uterine vein and the umbilical artery and vein. In a subcohort (n = 33), GLUT1 expression was determined in isolated syncytiotrophoblast basal and microvillous plasma membranes. Main Outcome Measures Uteroplacental glucose uptake and placental and fetal glucose consumption quantified by the Fick principle. Results Median (Q1, Q3) uteroplacental glucose uptake was 117.1 (59.1, 224.9) μmol⋅min−1, and fetal and placental glucose consumptions were 28.9 (15.4, 41.8) µmol⋅min−1⋅kg fetus−1 and 51.4 (−65.8, 185.4) µmol⋅min−1⋅kg placenta−1, respectively. Fetal glucose consumption correlated with birth weight (ρ: 0.34; P < 0.001) and maternal–fetal glucose gradient (ρ: 0.60; P < 0.001), but not with maternal BMI or uteroplacental glucose uptake. Uteroplacental glucose uptake was correlated to placental glucose consumption (ρ: 0.77; P < 0.001). Fetal and placental glucose consumptions were inversely correlated (ρ: −0.47; P < 0.001), but neither was correlated with placental GLUT1 expression. Conclusion These findings suggest that fetal glucose consumption is balanced against the placental needs for glucose and that placental glucose consumption is a key modulator of maternal–fetal glucose transfer in women.

• Horne, Hildegunn; Holme, Ane Moe; Roland, Marie Cecilie; Holm, Maia Blomhoff; Haugen, Guttorm & Henriksen, Tore [Vis alle 7 forfattere av denne artikkelen] (2019). Maternal-fetal cholesterol transfer in human term pregnancies. Placenta. ISSN 0143-4004. 87, s. 23–29. doi: 10.1016/j.placenta.2019.09.001. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Henriksen, Tore; Reinhold, Dominik; Powell, Theresa L & Jansson, Thomas (2019). The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling. The FASEB Journal. ISSN 0892-6638. 33(2), s. 2944–2956. doi: 10.1096/fj.201801193R. Fulltekst i vitenarkiv
• Gaudernack, Lise Christine; Frøslie, Kathrine Frey; Michelsen, Trond Melbye; Voldner, Nanna & Lukasse, Mirjam (2018). De-medicalization of birth by reducing the use of oxytocin for augmentation among first-time mothers - A prospective intervention study. BMC Pregnancy and Childbirth. 18:76(Article number: 76), s. 1–9. doi: 10.1186/s12884-018-1706-4. Fulltekst i vitenarkiv Vis sammendrag

  Background: The use of synthetic oxytocin for augmentation of labor is rapidly increasing worldwide. Hyper-stimulation is the most significant side effect, which may cause fetal distress and operative delivery. We performed an intervention consisting of an educational program and modified guidelines to achieve a more appropriate use of oxytocin. Methods: This prospective intervention study included 431 first-time mothers at term with spontaneous onset of labor before (October 2012 to May 2013), and 664 after the intervention (April 2014 to April 2015). Our outcomes were prevalence and duration of oxytocin treatment, mode of delivery, indication for operative delivery, episiotomy, anal sphincter tears, bleeding, labor duration, pain relief and the effect of oxytocin on mode of delivery. Results: After the intervention, 52.9% were diagnosed with dystocia, compared with 68.9% before (p<0.001). Oxytocin was not always used in accordance with the guidelines, but a significant reduction in oxytocin rates from 63.3% to 54.1% (p<0.001) was obtained. More women without dystocia according to the existing guidelines were augmented after the intervention (18.9% vs 8.4%, p<0.001). Assessing all labors, the median duration of oxytocin treatment was reduced by 72% (from 90 to 25 min) without increasing the median duration of labor (385 min in both groups). There was a moderate reduction in operative vaginal deliveries from 26.9 to 21.5% (p=0.04), and dystocia as an indication for these deliveries increased (p=0.01). There was a moderate increase in caesarean sections from 6.7 to 10.2% (p=0.05), but no increase in dystocia as an indication for these deliveries. Women receiving oxytocin were more likely to have an operative vaginal birth, even after adjusting for birth weight, epidural analgesia and labor duration, OR: 2.1 (CI 1.1-4.0) before and OR 2.7 (CI 1.6-4.5) after the intervention. Conclusions: Our intervention led to a significant reduction in the use of oxytocin. However, more than half of the women remained diagnosed with dystocia. Operative vaginal births seem to be associated with oxytocin treatment. Therefore, augmentation with oxytocin should be used with caution and only when medically indicated. Even more modified guidelines for augmentation than the ones applied in this study might be appropriate.

• Holm, Maia Blomhoff; Kristiansen, Oddrun; Holme, Ane Moe; Bastani, Nasser Ezzatkhah; Horne, Hildegunn & Blomhoff, Rune [Vis alle 9 forfattere av denne artikkelen] (2018). Placental release of taurine to both the maternal and fetal circulations in human term pregnancies. Amino Acids. ISSN 0939-4451. 50(9), s. 1205–1214. doi: 10.1007/s00726-018-2576-9. Fulltekst i vitenarkiv Vis sammendrag

  Taurine is regarded as an essential amino acid in utero, and fetal taurine supply is believed to rely solely on placental transfer from maternal plasma. Despite its potential role in intrauterine growth restriction and other developmental disturbances, human in vivo studies of taurine transfer between the maternal, placental, and fetal compartments are scarce. We studied placental transfer of taurine in uncomplicated human term pregnancies in vivo in a cross-sectional study of 179 mother-fetus pairs. During cesarean section, we obtained placental tissue and plasma from incoming and outgoing vessels on the maternal and fetal sides of the placenta. Taurine was measured by liquid chromatography–tandem mass spectrometry. We calculated paired arteriovenous differences, and measured placental expression of the taurine biosynthetic enzyme cysteine sulfinic acid decarboxylase (CSAD) with quantitative real-time polymerase chain reaction and western blot. We observed a fetal uptake (p < 0.001), an uteroplacental release (p < 0.001), and a negative placental consumption of taurine (p = 0.001), demonstrating a bilateral placental release to the maternal and fetal compartments. Increasing umbilical vein concentrations and fetal uptake was associated with the uteroplacental release to the maternal circulation (rs = − 0.19, p = 0.01/rs = − 0.24, p = 0.003), but not with taurine concentrations in placental tissue. CSAD-mRNA was expressed in placental tissue, suggesting a potential for placental taurine synthesis. Our observations show that the placenta has the capacity to a bilateral taurine release, indicating a fundamental role of taurine in the human placental homeostasis beyond the supply to the fetus.

• Johansen, Nora; Liavaag, Astrid Helene; Mørkrid, Lars & Michelsen, Trond Melbye (2018). Hormone Levels and Sexual Functioning After Risk-Reducing Salpingo-Oophorectomy. Sexual Medicine - Open Access. 6(2), s. 143–153. doi: 10.1016/j.esxm.2018.02.002. Fulltekst i vitenarkiv
• Majak, Guri Bårdstu; Reisæter, Anna Varberg; Weedon-Fekjær, Harald; Henriksen, Tore & Michelsen, Trond Melbye (2018). The effect of pregnancy on the long-term risk of graft loss, cardiovascular disease, and death in kidney transplanted women in Norway: A retrospective cohort study. Transplantation. ISSN 0041-1337. 102(9), s. e391–e396. doi: 10.1097/TP.0000000000002167. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Holme, Ane Moe & Henriksen, Tore (2017). Transplacental nutrient transfer in the human in vivo determined by 4 vessel sampling. Placenta. ISSN 0143-4004. 59, s. S26–S31. doi: 10.1016/j.placenta.2017.03.014. Fulltekst i vitenarkiv
• Holme, Ane Moe; Holm, Maia Blomhoff; Roland, Marie Cecilie; Horne, Hildegunn; Michelsen, Trond Melbye & Haugen, Guttorm [Vis alle 7 forfattere av denne artikkelen] (2017). The 4-vessel sampling approach to integrative studies of human placental physiology in vivo. Journal of Visualized Experiments. 2017(126). doi: 10.3791/55847. Fulltekst i vitenarkiv Vis sammendrag

  The human placenta is highly inaccessible for research while still in utero. The current understanding of human placental physiology in vivo is therefore largely based on animal studies, despite the high diversity among species in placental anatomy, hemodynamics and duration of the pregnancy. The vast majority of human placenta studies are ex vivo perfusion studies or in vitro trophoblast studies. Although in vitro studies and animal models are essential, extrapolation of the results from such studies to the human placenta in vivo is uncertain. We aimed to study human placenta physiology in vivo at term, and present a detailed protocol of the method. Exploiting the intraabdominal access to the uterine vein just before the uterine incision during planned cesarean section, we collect blood samples from the incoming and outgoing vessels on the maternal and fetal sides of the placenta. When combining concentration measurements from blood samples with volume blood flow measurements, we are able to quantify placental and fetal uptake and release of any compound. Furthermore, placental tissue samples from the same mother-fetus pairs can provide measurements of transporter density and activity and other aspects of placental functions in vivo. Through this integrative use of the 4-vessel sampling method we are able to test some of the current concepts of placental nutrient transfer and metabolism in vivo, both in normal and pathological pregnancies. Furthermore, this method enables the identification of substances secreted by the placenta to the maternal circulation, which could be an important contribution to the search for biomarkers of placenta dysfunction.

• Johansen, Nora; Liavaag, Astrid Helene; Iversen, Ole-Erik; Dørum, Anne; Braaten, Tonje & Michelsen, Trond Melbye (2017). Use of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 96(5), s. 547–555. doi: 10.1111/aogs.13120. Fulltekst i vitenarkiv
• Holm, Maia Blomhoff; Bastani, Nasser Ezzatkhah; Holme, Ane Moe; Zucknick, Manuela; Jansson, Thomas & Refsum, Helga [Vis alle 10 forfattere av denne artikkelen] (2017). Uptake and release of amino acids in the fetal-placental unit in human pregnancies. PLOS ONE. 12(10). doi: 10.1371/journal.pone.0185760. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: The current concepts of human fetal-placental amino acid exchange and metabolism are mainly based on animal-, in vitro- and ex vivo models. We aimed to determine and assess the paired relationships between concentrations and arteriovenous differences of 19 amino acids on the maternal and fetal sides of the human placenta in a large study sample. Methods: This cross-sectional in vivo study included 179 healthy women with uncomplicated term pregnancies. During planned cesarean section, we sampled blood from incoming and outgoing vessels on the maternal (radial artery and uterine vein) and fetal (umbilical vein and artery) sides of the placenta. Amino acid concentrations were measured by liquid chromatography—tandem mass spectrometry. We calculated paired arteriovenous differences and performed Wilcoxon signed-rank tests and Spearman’s correlations. Results: In the umbilical circulation, we observed a positive venoarterial difference (fetal uptake) for 14 amino acids and a negative venoarterial difference (fetal release) for glutamic acid (p<0.001). In the maternal circulation, we observed a positive arteriovenous difference (uteroplacental uptake) for leucine (p = 0.005), isoleucine (p = 0.01), glutamic acid (p<0.001) and arginine (p = 0.04) and a negative arteriovenous difference (uteroplacental release) for tyrosine (p = 0.002), glycine (p = 0.01) and glutamine (p = 0.02). The concentrations in the maternal artery and umbilical vein were correlated for all amino acids except tryptophan, but we observed no correlations between the uteroplacental uptake and the fetal uptake or the umbilical vein concentration. Two amino acids showed a correlation between the maternal artery concentration and the fetal uptake. Conclusions: Our human in vivo study expands the current insight into fetal-placental amino acid exchange, and discloses some differences from what has been previously described in animals. Our findings are consistent with the concept that the fetal supply of amino acids in the human is the result of a dynamic interplay between fetal and placental amino acid metabolism and interconversions.

• Majak, Guri Bårdstu; Reisæter, Anna Varberg; Zucknick, Manuela; Lorentzen, Bjørg; Vangen, Siri & Henriksen, Tore [Vis alle 7 forfattere av denne artikkelen] (2017). Preeclampsia in kidney transplanted women; Outcomes and a simple prognostic risk score system. PLOS ONE. 12:e0173420(3), s. 1–11. doi: 10.1371/journal.pone.0173420. Fulltekst i vitenarkiv
• Waage, Christin; Mdala, Ibrahimu; Jenum, Anne Karen; Michelsen, Trond Melbye; Birkeland, Kåre I. & Sletner, Line (2016). Ethnic differences in blood pressure from early pregnancy to postpartum: A Norwegian cohort study. Journal of Hypertension. ISSN 0263-6352. 34(6), s. 1151–1159. doi: 10.1097/HJH.0000000000000918. Fulltekst i vitenarkiv
• Majak, Guri Bårdstu; Sandven, Irene; Lorentzen, Bjørg; Vangen, Siri; Reisæter, Anna Varberg & Henriksen, Tore [Vis alle 7 forfattere av denne artikkelen] (2016). Pregnancy outcomes following maternal kidney transplantation: a national cohort study. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 95(10), s. 1153–1161. doi: 10.1111/aogs.12937. Fulltekst i vitenarkiv
• Holme, Ane Moe; Paasche, Marie Cecilie; Henriksen, Tore & Michelsen, Trond Melbye (2016). In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. 215(6), s. 782.e1–782.e9. doi: 10.1016/j.ajog.2016.07.056. Fulltekst i vitenarkiv
• Johansen, Nora; Liavaag, Astrid Helene; Tanbo, Tom Gunnar; Dahl, Alv A; Pripp, Are Hugo & Michelsen, Trond Melbye (2016). Sexual activity and functioning after risk-reducing salpingo-oophorectomy: Impact of hormone replacement therapy. Gynecologic Oncology. ISSN 0090-8258. 140(1), s. 101–106. doi: 10.1016/j.ygyno.2015.11.016. Fulltekst i vitenarkiv
• Holme, Ane Moe; Paasche, Cecilie; Lorentzen, Bjørg; Michelsen, Trond Melbye & Henriksen, Tore (2015). Placental glucose transfer: A human in vivo study. PLOS ONE. 10(2). doi: 10.1371/journal.pone.0117084. Fulltekst i vitenarkiv Vis sammendrag

  Objectives The placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption). Methods Cross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery). Results There were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = −0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values. Conclusions We did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.

• Michelsen, Trond Melbye; Dørum, Anne; Småstuen, Milada C; Liavaag, Astrid Helene & Dahl, Alv A (2013). Association between Hysterectomy with Ovarian Preservation and Cardiovascular Disease in a Norwegian Population-Based Sample. Gynecologic and Obstetric Investigation. ISSN 0378-7346. 75(1), s. 61–67. doi: 10.1159/000345072. Fulltekst i vitenarkiv
• Gultekin, Murat; Dursun, Polat; Vranes, Boris; Laky, Rene; Bossart, Michaela & Grabowski, Jacep P. [Vis alle 40 forfattere av denne artikkelen] (2011). Gynecologic Oncology Training Systems in Europe A Report From the European Network of Young Gynaecological Oncologists. International Journal of Gynecological Cancer. ISSN 1048-891X. 21(8), s. 1500–1506. doi: 10.1097/IGC.0b013e3182202d17. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye & Iversen, Ole-Erik (2011). Masseundersøkelser mot gynekologisk kreft - status og fremtid. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 131(16), s. 1550–1553. doi: 10.4045/tidsskr.11.0026. Fulltekst i vitenarkiv
• Erichsen, Eva Martina Moter; Husebye, Eystein Sverre; Michelsen, Trond Melbye; Dahl, Alv A & Løvås, Kristian (2010). Sexuality and Fertility in Women with Addison's Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 95(9), s. 4354–4360. doi: 10.1210/jc.2010-0445. Fulltekst i vitenarkiv Vis sammendrag

  Martina M Erichsen har oppgitt Department of Medicine , Haukeland University Hospital, og Institute of Medicine, University of Bergen, N-5007 Bergen, Norway; i artikkelen/aa

• Michelsen, Trond Melbye; Tonstad, Serena; Pripp, Are Hugo; Tropé, Claes Gøran & Dørum, Anne (2010). Coronary Heart Disease Risk Profile in Women Who Underwent Salpingo-Oophorectomy to Prevent Hereditary Breast Ovarian Cancer. International Journal of Gynecological Cancer. ISSN 1048-891X. 20(2), s. 233–239. doi: 10.1111/IGC.0b013e3181ca5ff4. Fulltekst i vitenarkiv Vis sammendrag

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• Michelsen, Trond Melbye; Dorum, Anne; Tropé, Claes Gøran; Fosså, Sophie Dorothea & Dahl, Alv A (2009). Fatigue and Quality of Life After Risk-Reducing Salpingo-Oophorectomy in Women at Increased Risk for Hereditary Breast-Ovarian Cancer. International Journal of Gynecological Cancer. ISSN 1048-891X. 19(6), s. 1029–1036. doi: 10.1111/IGC.0b013e3181a83cd5. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Dørum, Anne & Dahl, Alv A (2009). A controlled study of mental distress and somatic complaints after risk-reducing salpingo-oophorectomy in women at risk for hereditary breast ovarian cancer. Gynecologic Oncology. ISSN 0090-8258. 113(1), s. 128–133. doi: 10.1016/j.ygyno.2008.12.024. Fulltekst i vitenarkiv

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• Karabulut, Hatice; Ervik, Carolina Wieczorek; Flister, Renate Sæther; Kopcil, Pavel; Szymanska, Monika & Hedhili, Dalila [Vis alle 12 forfattere av denne artikkelen] (2026). Chasing Better Models: Human HSPC Engraftment in Mouse Models (PRIMA). Fulltekst i vitenarkiv
• Karabulut, Hatice; Ervik, Carolina Wieczorek; Flister, Renate Sæther; Kopcil, Pavel; Szymanska, Monika & Hedhili, Dalila [Vis alle 12 forfattere av denne artikkelen] (2026). Chasing Better Models: Human HSPC Engraftment in Mouse Models. Fulltekst i vitenarkiv
• Ervik, Carolina Wieczorek; Kopcil, Pavel; Szymanska, Monika; Kristiansen, Oddrun; Mamia, Katariina Aino Inkeri & Dahal-Koirala, Shiva [Vis alle 11 forfattere av denne artikkelen] (2025). ENHANCING CRISPR GENE CORRECTION IN HEMATOPOIETIC STEM/PROGENITOR CELLS. Fulltekst i vitenarkiv Vis sammendrag

  CRISPR/Cas9 is a powerful tool for precise gene correction of monogenic blood diseases, such as deficiency of adenosine deaminase 2 (DADA2), a rare disorder that causes recurrent inflammation and vascular damage. However, the efficiency of homology-directed repair (HDR) in CD34+ hematopoietic stem/progenitor cells (HSPCs) is low and limits the therapeutic potential of this approach. In this study, we used a Finnish founder mutation (R169Q) in ADA2 as a model locus for gene correction. We introduced four silent single nucleotide polymorphisms (SNPs) by electroporation using RNPs (ribonucleoproteins) and single-stranded oligodeoxynucleotide (ssODN) repair template in wild-type CD34+ cells isolated from umbilical cord blood. We evaluated the effect of IDT HDR Enhancer v2, and two PKc inhibitors (KU0060684 and AZD7648) on enhancing HDR in CD34+ cells. We measured the colony forming unit (CFU) output of edited cells was compared: a solid assay based on morphology and pigment of cells, and a liquid assay based on cell surface markers (CD14, CD15, CD235), enabling a higher-throughput setup. Using droplet digital PCR as a method to quantify edited cells, we found that PKc inhibitors increased HDR up to 80% in CD34+ cells. Our results suggest that PKc inhibitors is a promising HDR modulator for gene correction in HSPCs. Viability and proliferation were affected in IDT and KU0060684, but in AZD7648 function as well as mock and control. In conclusion, our preliminary results indicates that AZD7648 could lead to the development of more effective gene therapies for monogenic blood diseases in the future. Furthermore, we are optimizing the in vitro culturing of the long-term repopulating hematopoietic stem cells to keep stemness and potentially expanding this population. While initial in vivo testing has been performed, we will also create a novel human xenograft model for modelling diseases e.g. monogenetic disease and leukemia that are irradiation free.

• Kristiansen, Hege & Michelsen, Trond Melbye (2025). Uassistert hjemmefødsel – trygghet på egne premisser eller undervurdert risiko? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.25.0646. Fulltekst i vitenarkiv
• Ervik, Carolina Wieczorek; Kopcil, Pavel; Szymanska, Monika; Mamia, Katariina Aino Inkeri; Dahal-Koirala, Shiva & Komisarczuk, Anna Zofia [Vis alle 10 forfattere av denne artikkelen] (2025). Enhancing CRISPR gene correction in hematopoetic stem/progenitor cells. doi: https:/iuis2025.org/. Fulltekst i vitenarkiv Vis sammendrag

  CRISPR/Cas9 is a powerful tool for precise gene correction of monogenic blood diseases, such as deficiency of adenosine deaminase 2 (DADA2), a rare disorder that causes recurrent inflammation and vascular damage. However, the efficiency of homology-directed repair (HDR) in CD34+ hematopoietic stem/progenitor cells (HSPCs) is low and limits the therapeutic potential of this approach. In this study, we used a Finnish founder mutation (R169Q) in ADA2 as a model locus for gene correction. We introduced four silent single nucleotide polymorphisms (SNPs) by electroporation using RNPs (ribonucleoproteins) and single-stranded oligodeoxynucleotide (ssODN) repair template in wild-type CD34+ cells isolated from umbilical cord blood. We evaluated the effect of IDT HDR Enhancer v2, and two PKc inhibitors (KU0060684 and AZD7648) on enhancing HDR in CD34+ cells. We measured the colony forming unit (CFU) output of edited cells was compared: a solid assay based on morphology and pigment of cells, and a liquid assay based on cell surface markers (CD14, CD15, CD235), enabling a higher-throughput setup. Using droplet digital PCR as a method to quantify edited cells, we found that PKc inhibitors increased HDR up to 80% in CD34+ cells. Our results suggest that PKc inhibitors is a promising HDR modulator for gene correction in HSPCs. Viability and proliferation were affected in IDT and KU0060684, but in AZD7648 function as well as mock and control. In conclusion, our preliminary results indicates that AZD7648 could lead to the development of more effective gene therapies for monogenic blood diseases in the future. Furthermore, we are optimizing the in vitro culturing of the long-term repopulating hematopoietic stem cells to keep stemness and potentially expanding this population. While initial in vivo testing has been performed, we will also create a novel human xenograft model for modelling diseases e.g. monogenetic disease and leukemia that are irradiation free.

• Sørbye, Ingvil Krarup; Gunnes, Nina; Solhoff, Aslak Vimme; Haavaldsen, Camilla; Kessler, Jørg & Kjøllesdal, Anne M [Vis alle 14 forfattere av denne artikkelen] (2025). Multicentre double-blind randomised placebo-controlled four-arm trial to assess the effect of oral sodium bicarbonate and intravenous hyoscine butylbromide on spontaneous delivery after induction of labour in nulliparous women: Protocol for the Safe Induction of Labour Trial (SAINT). doi: 10.1136/bmjopen-2024-093992. Fulltekst i vitenarkiv
• Bekkenes, Maria Egeland; Stubhaug, Audun; Reme, Silje Endresen; Fagerland, Morten Wang; Michelsen, Trond Melbye & Rosseland, Leiv Arne (2022). Effects of 2.5 IU oxytocin or 100 μg carbetocin on pain intensity and opioid consumption after planned cesarean delivery; a randomized controlled trial. Fulltekst i vitenarkiv
• Kessler, Jørg; Eggebø, Torbjørn Moe; Jacobsen, Anne Flem; Michelsen, Trond Melbye; Rasmussen, Svein & Yli, Branislava Markovic (2022). Can a population study assess the impact of fetal monitoring technology? Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. doi: 10.1111/aogs.14426. Fulltekst i vitenarkiv
• Degnes, Maren-Helene Langeland; Westerberg, AC; Andresen, Ina Jungersen; Zucknick, Manuela; Powell, Theresa L & Jansson, Thomas [Vis alle 9 forfattere av denne artikkelen] (2022). Six placenta-derived proteins as markers of placental function. Fulltekst i vitenarkiv
• Andresen, Ina Jungersen; Degnes, Maren-Helene Langeland; Zucknick, Manuela; Powell, Theresa L; Jansson, Thomas & Henriksen, Tore [Vis alle 8 forfattere av denne artikkelen] (2022). Protein biomarkers of late-onset preeclampsia. Fulltekst i vitenarkiv
• Sørbye, Ingvil; Gaudernack, Lise Christine; Einarsen, Angeline Elisabeth Styve; Rosseland, Leiv Arne; Lukasse, Mirjam & Gunnes, Nina [Vis alle 7 forfattere av denne artikkelen] (2022). Study protocol for the BUSCopan in LABor (BUSCLAB) study: A randomized placebocontrolled trial investigating the effect of butylscopolamine bromide to prevent prolonged labor. PLOS ONE. 17(11). doi: 10.1371/journal.pone.0276613. Fulltekst i vitenarkiv Vis sammendrag

  Background First-time mothers are prone to prolonged labor, defined as the crossing of partograph alert or action lines. Prolonged labor may occur among as many as one out of five women, and is associated with a range of adverse birth outcomes. Oxytocin is the standard treatment for prolonged labor, but has a narrow therapeutic window, several adverse effects and limited efficacy. Despite poor evidence, labor wards often use antispasmodic agents to treat prolonged labor. The antispasmodic drug butylscopolamine bromide (Buscopan®) may shorten duration of labor, but studies on prevention of prolonged labor are lacking. In this randomized double-blind placebo-controlled clinical trial, we aim to evaluate the effect of butylscopolamine bromide on duration of labor in first-time mothers showing first signs of slow labor progress by crossing the World Health Organization partograph alert line. Methods and analysis The study is a single center study at Oslo University Hospital, Oslo, Norway. We will recruit 250 primiparous women with spontaneous labor start at term. Women are included in the first stage of labor if they show signs of slow labor progress, defined as the crossing of the partograph alert line with a cervical dilation between 3–9 cm. Participants are randomized 1:1 to either 20 mg intravenous butylscopolamine bromide or intravenous placebo (1 mL sodium chlorine 9 mg/mL). We considered a mean difference of 60 minutes in labor duration clinically relevant. The primary outcome is duration of labor from the provision of the investigational medicinal product to vaginal delivery. The secondary outcomes include change in labor pain, use of oxytocin augmentation, delivery mode, and maternal birth experience. The primary data for the statistical analysis will be the full analysis set and will occur on completion of the study as per the prespecified statistical analysis plan. The primary outcome will be analyzed using Weibull regression, and we will treat cesarean delivery as a censoring event.

• Westerberg, AC; Degnes, Maren-Helene Langeland; Andresen, Ina Jungersen; Zucknick, Manuela; Powell, Theresa L & Jansson, Thomas [Vis alle 9 forfattere av denne artikkelen] (2022). Pleiotrophin and Fatty-acid Amide Hydrolase 2 – Placenta-derived Biomarkers of Preeclampsia? Fulltekst i vitenarkiv
• Øyri, Linn Kristin Lie; Bogsrud, Martin Prøven; Christensen, Jacob J.; Ulven, Stine Marie; Brantsæter, Anne Lise & Retterstøl, Kjetil [Vis alle 12 forfattere av denne artikkelen] (2019). Novel and comprehensive metabolite profiling in cord blood reveal sex differences: A sub-study from the Norwegian Mother, Father and Child Cohort study. Fulltekst i vitenarkiv
• Gaudernack, Lise Christine; Frøslie, Katrine Frey; Michelsen, Trond Melbye; Voldner, Nanna & Lukasse, Mirjam (2019). De-medicalization of birth by reducing the use of oxytocin for augmentation among first-time mothers - a prospective intervention study. Fulltekst i vitenarkiv
• Staff, Anne Cathrine; Andersgaard, Alice Beathe; Henriksen, Tore; Langesæter, Eldrid; Magnussen, Elisabeth & Michelsen, Trond Melbye [Vis alle 8 forfattere av denne artikkelen] (2016). Chapter 28 Hypertensive disorders of pregnancy and eclampsia. European Journal of Obstetrics, Gynecology, and Reproductive Biology. ISSN 0301-2115. 201, s. 171–178. doi: 10.1016/j.ejogrb.2016.04.001. Fulltekst i vitenarkiv
• Staff, Anne Cathrine; Henriksen, Tore; Langesæter, Eldrid; Magnussen, Elisabeth Balstad; Michelsen, Trond Melbye & Thomsen, Liv Cecilie Vestrheim [Vis alle 7 forfattere av denne artikkelen] (2014). Hypertensive svangerskapskomplikasjoner og eklampsi. I Øian, Pål; Jacobsen, Anne Flem & Kessler, Jørg (Red.), Veileder i fødselshjelp 2014. Den norske legeforening. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Vangen, Siri & Henriksen, Tore (2014). Cesarean sections and fetal death rates. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 93(3), s. 312–313. doi: 10.1111/aogs.12310. Fulltekst i vitenarkiv
• Roland, Marie Cecilie Paasche; Holme, Ane Moe; Lorentzen, Bjørg; Michelsen, Trond Melbye & Henriksen, Tore (2013). IN VIVO STUDIES OF GLUCOSE TRANSPORT OVER THE HUMAN PLACENTA. Pediatric Research. ISSN 0031-3998. 74(4), s. 483–483. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Dørum, Anne; Tropé, Claes Gøran; Liavaag, Astrid Helene; Fosså, Sophie Dorothea & Fiane, Bent [Vis alle 7 forfattere av denne artikkelen] (2007). Factors associated with fatigue in women who had prophylactic bilateral salpingo-oophorectomy for hereditary breast ovarian cancer. Fulltekst i vitenarkiv
• Michelsen, Trond Melbye; Dørum, Anne & Tropé, Claes Gøran (2010). Long term somatic and psychosocial morbidity after risk-reducing salpingo-oophorectomy in women at risk for hereditary breast ovarian cancer. Universitetet i Oslo. Fulltekst i vitenarkiv
• Liavaag, Astrid Helene; Dørum, Anne; Dahl, Alv A; Tropé, Claes Gøran; Fosså, Sophie Dorothea & Michelsen, Trond Melbye (2009). Epithelial ovarian cancer survivors: somatic and mental health, sexuality and quality of life studies. Universitetet i Oslo. ISSN 9788280723345. Fulltekst i vitenarkiv

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