Meryam Sugulle

• Hagen, Kristine Krüger; Eyjolfsdottir, Brynhildur; Dahl, Gunn Fallås; Wang, Yun; Lund, Kjersti Vassmo & Nordskar, Nina Jebens [Vis alle 13 forfattere av denne artikkelen] (2026). Early post-operative complications after fertility-sparing surgery for cervical carcinoma: a retrospective study of a centralized national cohort of 127 consecutive women. International Journal of Gynecological Cancer. ISSN 1048-891X. doi: 10.1016/j.ijgc.2026.104986. Fulltekst i vitenarkiv
• Sundet, Birgitte Kordt; Fiskå, Bendik Seth; Staff, Anne Cathrine; Jacobsen, Daniel Pitz; Bratseth, Vibeke & Palmero, Sheryl [Vis alle 13 forfattere av denne artikkelen] (2026). Circulating neutrophil extracellular traps and deoxyribonuclease in gestational diabetes mellitus. Journal of Reproductive Immunology. ISSN 0165-0378. 176. doi: 10.1016/j.jri.2026.104928.
• Klepp, Kristina; Moe, Kjartan; Jacobsen, Daniel Pitz; Sugulle, Meryam; Angel, Kristin & Lueder, Thomas Gero von [Vis alle 8 forfattere av denne artikkelen] (2026). Circulating Cardiovascular Biomarkers 1–3 Years Following Hypertensive Pregnancy Disorders: Associations With Postpartum Cardiovascular Structure and Function. Reproductive Sciences. ISSN 1933-7191. doi: 10.1007/s43032-026-02171-y. Fulltekst i vitenarkiv Vis sammendrag

  Hypertensive disorders of pregnancy (HDP) confer increased cardiovascular disease (CVD) risk postpartum. Screening methods targeting women with increased risk are lacking, limiting personalized follow-up. Circulating biomarkers may assist CVD risk stratification. We aimed to assess whether circulating biomarkers were associated with measures of cardiovascular structure and function following HDP and normotensive pregnancies (controls). We examined 275 women 1–3 years postpartum (176 following HDP and 99 parous controls). Circulating biomarkers (hs-CRP, non-HDL cholesterol, glucose, eGFR, cTnT, NT-proBNP, GDF-15, sHLA-G, SAA1) and cardiovascular function and structure measures were examined [pulse wave velocity (PWV), carotid intima-media thickness (CIMT) and echocardiography]. Group differences were tested by Mann-Whitney U test and chi-square. Associations were assessed by univariate regression analyses. A p-value < 0.05 was considered statistically significant. Women following HDP displayed significantly higher rates of hypertension (5% vs. 0%) and metabolic syndrome (7% vs. 1%) than controls. Circulating biomarker levels were similar between study groups. In univariate regression analyses for the prior HDP group, non-HDL cholesterol was significantly associated with PWV and CIMT. Additionally, glucose and hs-CRP were significantly associated with PWV. These associations were not reproduced for controls, except for non-HDL cholesterol which was significantly associated with CIMT. In conclusion, women following HDP and normotensive pregnancies had similar postpartum levels of circulating biomarkers, but circulating biomarkers were significantly associated with measures of arterial stiffness (PWV and CIMT) in women with prior HDP. Our findings support current guidelines recommending CVD follow-up after HDP. Non-HDL cholesterol, glucose and hs-CRP may possibly help refining personalized cardiovascular follow-up postpartum.

• Staff, Anne Cathrine; Sjaavik, Anja Dusik; Noll, Josef; Sugulle, Meryam; Fiskå, Bendik Seth & Klovning, Atle [Vis alle 11 forfattere av denne artikkelen] (2026). Co-creation of a mobile health program (MumCare) for preventing maternal cardiovascular disease after pregnancy complications. Frontiers in Global Women's Health. 7. doi: 10.3389/fgwh.2026.1717203. Fulltekst i vitenarkiv
• Fiskå, Bendik Seth; Turowski, Gitta Erika; Rocha, Maria Linda; Lekva, Tove; Ueland, Thor & Staff, Anne Cathrine [Vis alle 7 forfattere av denne artikkelen] (2026). Placenta tissue-based and circulating markers of cellular senescence in gestational diabetes mellitus. Placenta. ISSN 0143-4004. 177, s. 8–16. doi: 10.1016/j.placenta.2026.02.015. Fulltekst i vitenarkiv
• Bentsen, Ingerid; Waldum, Åsa; Sugulle, Meryam & Staff, Anne Cathrine (2026). Self-reported primary preventive follow-up of women’s cardiovascular health after hypertensive pregnancy complications and gestational diabetes. Pregnancy Hypertension. ISSN 2210-7789. 44. doi: 10.1016/j.preghy.2026.101474. Fulltekst i vitenarkiv
• Ziesler, Charlotte Philippa Øxnevad; Staff, Anne Cathrine; Klepp, Kristina; Sugulle, Meryam & Moe, Kjartan (2026). Physical activity and cardiovascular risk factors after hypertensive pregnancy complications. Pregnancy Hypertension. ISSN 2210-7789. 44. doi: 10.1016/j.preghy.2026.101466. Fulltekst i vitenarkiv
• Sugulle, Meryam; Laine, Hely Katariina; Tingleff, Tiril; Lahmami, Gulim & Räisänen, Sari (2025). Effects of fetal presentation on mode of delivery in 26 143 twin pregnancies: A nationwide, population-based observational study of 31-year real-world data. International Journal of Gynecology & Obstetrics. ISSN 0020-7292. 170(3), s. 1309–1316. doi: 10.1002/ijgo.70103. Fulltekst i vitenarkiv
• Klepp, Kristina; Moe, Kjartan; Angel, Kristin; Lueder, Thomas Gero von; Sugulle, Meryam & Ziesler, Charlotte Philippa Øxnevad [Vis alle 8 forfattere av denne artikkelen] (2025). Cardiovascular phenotype in women 1–3 years after hypertensive pregnancy disorders: Impact of sex-independent and pregnancy-specific risk factors. Pregnancy Hypertension. ISSN 2210-7789. 43. doi: 10.1016/j.preghy.2025.101404. Fulltekst i vitenarkiv
• Jacobsen, Daniel Pitz; Fjeldstad, Heidi; Olsen, Maria Belland; Sugulle, Meryam; Schjørlien, Therese & Skjelland, Mona Elisabeth [Vis alle 8 forfattere av denne artikkelen] (2025). Postpartum levels of circulating fetal microchimeric cells are lower after early-onset preeclampsia. Journal of Reproductive Immunology. ISSN 0165-0378. 172. doi: 10.1016/j.jri.2025.104646. Fulltekst i vitenarkiv Vis sammendrag

  Fetal cells may persist in the mother following pregnancy, termed fetal microchimerism. These cells have been attributed positive and negative effects. The number of fetal cells transferred during pregnancy appears to be higher in preeclampsia. Here, we investigate whether fetal cell presence and quantity in the maternal circulation 1–8 years postpartum is influenced by a previous preeclamptic pregnancy. We also relate fetal cells detected postpartum to fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics. A cohort of 139 women was included in the present study: 21 with previous early-onset preeclampsia, 31 with previous late-onset preeclampsia and 87 with a clinically uncomplicated index pregnancy. Circulating fetal microchimerism was detected in maternal buffy coat using qPCR, targeting alleles unique to the fetus. Pregnancy buffy coat samples were available for 129 of the 139 included women. Early-onset, but not late-onset, preeclampsia was associated with reduced quantity of fetal microchimeric cells in maternal circulation postpartum. Fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics were not predictive of microchimerism postpartum in our cohort. Our findings suggest that early-onset, but not late-onset preeclampsia, affects circulating microchimerism postpartum. Our observation that fetal microchimerism postpartum did not correlate with number of fetal cells detected during pregnancy nor time since index pregnancy supports the notion that fetal microchimerism is a dynamic phenomenon, with fetal cells moving in and out of maternal circulation and surrounding tissues, possibly affected by the current physiologic state of the mother.

• Hagen, Kristine Krüger; Lie, Agnes Kathrine; Dahl, Gunn Fallås; Eyjólfsdóttir, Brynhildur; Wang, Yun & Ranum, Petter Skauen [Vis alle 12 forfattere av denne artikkelen] (2025). The Silva pattern-based classification and oncological outcomes in women undergoing fertility-sparing surgery for early-stage cervical cancer. International Journal of Gynecological Cancer. ISSN 1048-891X. 35(9). doi: 10.1016/j.ijgc.2025.102012. Fulltekst i vitenarkiv Vis sammendrag

  Objective To explore the association between Silva pattern-based classification, lymphovascular invasion, and oncological outcomes in women undergoing fertility-sparing surgery for cervical cancer. Methods Retrospective nationwide cohort study of patients with human papillomavirus (HPV)-associated cervical adenocarcinomas <2 cm undergoing radical vaginal trachelectomy, simple vaginal trachelectomy, or conization with nodal assessment between 2000 and 2022. Clinical data were retrieved from electronic medical records and institutional databases. Histological specimens were retrospectively assigned the Silva pattern classification after review by an expert gynecologic oncology pathologist. The primary endpoint was recurrence-free survival categorized by the Silva pattern classification. Survival rates were compared between groups defined by the Silva pattern classification using Kaplan-Meier estimates. Results Of 61 women with cervical adenocarcinoma, 59 were HPV-associated, with HPV 16 and 18 being the most prevalent genotypes. Among HPV-associated adenocarcinomas, 20 (33.9%) were classified as pattern A, 26 (44.1%) as pattern B, and 13 (22.0%) as pattern C. HPV 18 was noted in 9 (69.2%) of tumors with pattern C, compared to 7 (35.5%) and 10 (38.5%) in patterns A and B, respectively. Most cases were International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB1 (N = 50 [84.8%]). Lymphovascular invasion was present in 6 (23.1%) of cases with pattern B and in 7 (53.9%) with pattern C. There was no difference in surgical radicality between groups. Five women abandoned fertility preservation due to nodal metastasis (N = 2), positive surgical margins (N = 2), or multifocal disease (N = 1). Of these, 3 tumors exhibited pattern C, 1 pattern B with lymphovascular invasion, and 1 pattern B without lymphovascular invasion. Median follow-up was 79 months (range; 14-248 months). Five-year recurrence-free survival was 100% for the Silva patterns A and B, compared to 75.5% for pattern C (95% CI 41.6% to 91.4%). Conclusions Recurrence occurred exclusively among patients with the Silva pattern C, highlighting the prognostic potential of this classification system. Silva classification should be considered when counseling women regarding fertility-sparing surgery.

• Sundet, Birgitte Kordt; Carlsen, Karin Cecilie Lødrup; Haugen, Guttorm Nils; Hedlin, Gunilla; Hilde, Katarina & Jonassen, Christine M [Vis alle 17 forfattere av denne artikkelen] (2025). Midpregnancy maternal circulating angiogenic biomarkers: Associations with placental dysfunction-related pregnancy complications and fetal sex. Placenta. ISSN 0143-4004. 171, s. 52–61. doi: 10.1016/j.placenta.2025.09.006. Fulltekst i vitenarkiv
• Jacobsen, Daniel Pitz; Olsen, Maria Belland; Fjeldstad, Heidi; Sugulle, Meryam & Staff, Anne Cathrine (2025). Human leukocyte antigens and fetal microchimerism: Relating fetal-origin cells in maternal circulation to maternal and fetal HLA genetics. Journal of Reproductive Immunology. ISSN 0165-0378. 173. doi: 10.1016/j.jri.2025.104826. Fulltekst i vitenarkiv Vis sammendrag

  Fetal microchimerism denotes the presence of small amounts of fetal cells within the mother, which may persist for decades after pregnancy. The mechanisms by which these semiallogeneic cells avoid alloreactivity and manage to persist for years within the host are unknown. Previous reports have linked microchimerism to human leukocyte antigen (HLA) variants, such as HLA-C groups based on killer cell Immunoglobulin-like receptor (KIR) reactivity, HLA-DQA1*05:01, and soluble HLA-G (sHLA-G). In the present study, we attempt to verify these associations during pregnancy and postpartum. We included 255 pregnant women and 188 women between one and eight years postpartum. Data on HLA-C and HLADQA genotypes, as well as maternal circulating sHLA-G were available for a varying number of women, with cohorts ranging from 167 to 252 during pregnancy and 79–118 postpartum. Maternal and fetal HLA-C groups did not correlate with microchimerism during pregnancy or postpartum. HLA-C group mismatch from the perspective of the mother, on the other hand, negatively correlated with presence and quantity of fetal microchimerism in maternal circulation in the postpartum cohort, but not during pregnancy. Neither HLA-DQA1*05:01 nor circulating levels of sHLA-G were associated with microchimerism measurements. We confirm a negative correlation between circulating fetal microchimerism postpartum and fetal-maternal HLA-C mismatch based on KIR reactivity. Considering that such an association was not found at an HLA-C allele level in a previous publication, our present observation indicates that the interaction between microchimeric cell HLA-C variants and host killer-cell immunoglobulin-like receptors may be relevant for the longevity of microchimerism.

• Sundet, Birgitte Kordt; Sugulle, Meryam; Jacobsen, Daniel Pitz; Bratseth, Vibeke; Palmero, Sheryl & Kindberg, Kristine Lovise Mørk [Vis alle 13 forfattere av denne artikkelen] (2025). Predelivery maternal circulating neutrophil extracellular traps and deoxyribonuclease in placental dysfunction and preeclampsia. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. 234(2), s. 550–569. doi: 10.1016/j.ajog.2025.10.003. Fulltekst i vitenarkiv Vis sammendrag

  Background Neutrophil extracellular traps consist of DNA and protein and are secreted by neutrophils upon activation. They are stable structures but may be degraded by deoxyribonucleases. Neutrophil extracellular traps can induce endothelial dysfunction, an important feature of the preeclampsia pathophysiology. However, the levels of neutrophil extracellular traps biomarkers and deoxyribonuclease in the maternal circulation during preeclampsia, gestational hypertension, and fetal growth restriction, as well as potential associations to placental dysfunction, remain to be elucidated. Objective We aimed to investigate levels of circulating neutrophil extracellular traps biomarkers and deoxyribonuclease in women with early-onset and late-onset preeclampsia, gestational hypertension, and isolated fetal growth restriction compared to clinically healthy pregnancies. Additionally, we aimed to compare these biomarkers with circulating placental dysfunction biomarkers and maternal as well as fetal clinical proxies of placental dysfunction in women with preeclampsia. Study design Plasma and serum samples from women categorized as having early-onset preeclampsia (n=49), late-onset preeclampsia (n=202), gestational hypertension (n=105), isolated fetal growth restriction (n=50), and normotensive, euglycemic controls (n=1126) were analyzed by immunoassays for the circulating neutrophil extracellular traps biomarkers citrullinated histone H3 and myeloperoxidase-DNA and deoxyribonuclease and for the placental dysfunction biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor. The Kruskal-Wallis H test was used to compare biomarker levels across groups. Post hoc pairwise comparisons were conducted using Dunn's test, with Bonferroni correction applied to adjust for multiple comparisons. In women with early-onset and late-onset preeclampsia, the residuals were not normally distributed. Therefore, univariable and multivariable quantile (median) regression for estimating models for the conditional median function were used to study associations between our biomarkers of interest and proxies for placental dysfunction. A 2-sided P value of <.05 was considered statistically significant. Results Women with early-onset and late-onset preeclampsia, but not gestational hypertension or isolated fetal growth restriction, had lower median levels of circulating citrullinated histone H3 (both adjusted P<.001) and deoxyribonuclease (both adjusted P<.001) compared to controls. Women with late-onset preeclampsia had lower myeloperoxidase-DNA (adjusted P<.001) compared to controls. Univariable regression analyses within the preeclampsia group revealed positive associations between citrullinated histone H3 and placental growth factor (P=.004) and negative associations between citrullinated histone H3 and soluble fms-like tyrosine kinase-1 (P=.034) and between deoxyribonuclease and soluble fms-like tyrosine kinase-1 (P=.038). In multivariable regression analyses, citrullinated histone H3 and placental growth factor (P=.009) and deoxyribonuclease and gestational age at blood sampling (P=.001) were positively associated, whereas citrullinated histone H3 (P=.027) and deoxyribonuclease (P=.034) were negatively associated with systolic blood pressure. Finally, citrullinated histone H3 was associated with newborn weight ≤10th percentile, representing a fetal proxy for placental dysfunction (P=.036). Conclusion The lower levels of circulating neutrophil extracellular traps and deoxyribonuclease in women with preeclampsia, but not in gestational hypertension or isolated fetal growth restriction, as well as associations between citrullinated histone H3 and biomarkers of placental dysfunction may indicate that neutrophil extracellular traps play a role in the placental dysfunction that exclusively characterizes preeclampsia. Additionally, the association between low citrullinated histone H3, low deoxyribonuclease, and high maternal blood pressure may suggest that insufficient presence of circulating deoxyribonucleases contributes to the excessive vascular inflammation in women with preeclampsia.

• Bowe, Sophie; Mitlid-Mork, Birgitte; Staff, Annetine & Sugulle, Meryam (2025). PlGF and sFlt-1, reduced fetal movements and adverse delivery outcome of a likely placental cause: A real world prospective observational study. European Journal of Obstetrics, Gynecology, and Reproductive Biology. ISSN 0301-2115. 307, s. 34–42. doi: 10.1016/j.ejogrb.2025.01.029. Fulltekst i vitenarkiv
• Klepp, Kristina; Staff, Annetine; Sugulle, Meryam & Moe, Kjartan (2025). Body mass index is similar to alternative anthropometric indices in evaluating plasma lipids as proxy for cardiovascular disease in women with previous hypertensive disorders of pregnancy: A cross-sectional study. Women's Health. ISSN 1745-5057. 21. doi: 10.1177/17455057241310316. Fulltekst i vitenarkiv Vis sammendrag

  Background: Women with previous hypertensive disorders of pregnancy (HDP) have increased risk of cardiovascular disease (CVD). Overweight is a modifiable risk factor for both conditions. Anthropometric indices such as waist circumference, hip circumference, waist-to-hip ratio, estimated total body fat, a body shape index, waist-to-hip-to-height ratio, and index of central obesity improve estimation of cardiovascular death risk in the general population as compared to body mass index (BMI). Objectives: We aimed to assess whether alternative body mass composition indices associate more strongly with postpartum blood lipid levels, as a proxy for CVD risk, than BMI. We also aimed to investigate whether associations differ between women with previous normotensive or hypertensive index pregnancies. Design: In this cross-sectional study, we examined 296 women 1 or 3 years after an index pregnancy that was normotensive (n = 116) or complicated by a hypertensive pregnancy disorder, including preeclampsia (n = 133) or gestational hypertension (n = 47). Methods: Uni- and multivariable regression analyses, adjusted for age and smoking, were conducted to evaluate associations between postpartum body mass composition indices and blood lipids. p < 0.05 was considered statistically significant. Results: Median BMI and overweight rates were higher in women with previous HDP than in controls (23.9 kg/m2 versus 22.8 kg/m2 and 44.4% versus 30.2%, both p ⩽ 0.03). No body mass composition indices in any pregnancy complication group showed stronger associations with adverse lipid levels than BMI. However, women with previous HDP more often displayed significant associations between adverse body mass composition indices and adverse lipid levels, compared with controls. Conclusion: Alternative anthropometric measurements are not better suited to evaluate circulating lipids as proxy for CVD risk after HDP, compared to BMI. We hence recommend using BMI in CVD risk assessment after HDP due to its current widespread use and feasibility.

• Jacobsen, Daniel Pitz; Fjeldstad, Heidi Elisabeth Storebø; Olsen, Maria Belland; Sugulle, Meryam & Staff, Annetine (2025). Microchimerism and pregnancy complications with placental dysfunction. Seminars in Immunopathology. ISSN 1863-2297. 47(1). doi: 10.1007/s00281-025-01045-w. Fulltekst i vitenarkiv
• Staff, Anne Cathrine; Costa, Maria Laura; Dechend, Ralf; Jacobsen, Daniel Pitz & Sugulle, Meryam (2024). Hypertensive disorders of pregnancy and long-term maternal cardiovascular risk: Bridging epidemiological knowledge into personalized postpartum care and follow-up. Pregnancy Hypertension. ISSN 2210-7789. 36. doi: 10.1016/j.preghy.2024.101127. Fulltekst i vitenarkiv Vis sammendrag

  Cardiovascular disease (CVD) is globally the leading cause of death and disability. Sex-specific causes of female CVD are under-investigated. Pregnancy remains an underinvestigated sex-specific stress test for future CVD and a hitherto missed opportunity to initiate prevention of CVD at a young age. Population-based studies show a strong association between female CVD and hypertensive disorders of pregnancy. This association is also present after other pregnancy complications that are associated with placental dysfunction, including fetal growth restriction, preterm delivery and gestational diabetes mellitus. Few women are, however, offered systematic cardio-preventive follow-up after such pregnancy complications. These women typically seek help from the health system at first clinical symptom of CVD, which may be decades later. By this time, morbidity is established and years of preventive opportunities have been missed out. Early identification of modifiable risk factors starting postpartum followed by systematic preventive measures could improve maternal cardiovascular health trajectories, promoting healthier societies. In this non-systematic review we briefly summarize the epidemiological associations and pathophysiological hypotheses for the associations. We summarize current clinical follow-up strategies, including some proposed by international and national guidelines as well as user support groups. We address modifiable factors that may be underexploited in the postpartum period, including breastfeeding and blood pressure management. We suggest a way forward and discuss the remaining knowledge gaps and barriers for securing the best evidence-based follow-up, relative to available resources after a hypertensive pregnancy complication in order to prevent or delay onset of premature CVD.

• Staff, Anne Cathrine; Fjeldstad, Heidi; Olsen, Maria Belland; Øgaard, Jonas Daniel Sjøberg; Viken, Marte Kathrine & Kramer, Cynthia S. M. [Vis alle 12 forfattere av denne artikkelen] (2024). Foetal Microchimerism Correlates With Foetal-Maternal Histocompatibility Both During Pregnancy and Postpartum. HLA. ISSN 2059-2302. 104:e15717(4), s. 1–11. doi: 10.1111/tan.15717. Fulltekst i vitenarkiv Vis sammendrag

  Foetal cells are detectable in women decades postpartum, a state termed foetal microchimerism. The interplay between these semi-allogeneic foetal cells and the mother could be affected by genetic mismatches in the HLA loci. Here, we relate HLA allele and molecular mismatch values to the presence and quantity of foetal microchimerism in the maternal circulation during pregnancy and postpartum. A total of 76 pregnant women were included, of which 59 were followed up 1–8 years postpartum. Maternal and foetal DNA was genotyped for HLA class I and II loci. Foetal cells in maternal buffy coat were detected by qPCR, targeting inherited paternal alleles. Antibody-verified eplet mismatch and Predicted Indirectly Recognisable HLA Epitopes (PIRCHE) scores were calculated to quantify foetal-maternal histocompatibility from the mother's perspective. Circulating foetal cells were detected in 50.0% (38/76) of women during pregnancy, and 25.4% (15/59) postpartum. During pregnancy, HLA class II antibody-verified eplet mismatch load and PIRCHE scores correlated negatively with the presence and quantity of foetal cells in the maternal circulation. Postpartum, HLA class I allele mismatches correlated negatively with foetal microchimerism presence, while HLA class II allele mismatches, HLA class I and II antibody-verified eplet mismatch load, and PIRCHE-I and PIRCHE-II scores correlated negatively with both microchimerism presence and quantity. The correlation between mismatch parameters aimed at evaluating the risk of humoral and T cell-mediated allorecognition and foetal microchimerism was more evident postpartum than during pregnancy. The observed predictive effect of foetal-maternal histocompatibility on foetal microchimerism suggests that circulating foetal cells are subject to clearance by the maternal immune system. We propose that allorecognition of foetal cells in the maternal circulation and tissues influences any long-term effect that foetal microchimerism may have on maternal health.

• Sugulle, Meryam; Fiskå, Bendik Seth; Jacobsen, Daniel Pitz; Fjeldstad, Heidi Elisabeth Storebø & Staff, Anne Cathrine (2024). Placental Senescence and the Two-Stage Model of Preeclampsia. American journal of reproductive immunology. ISSN 1046-7408. 92(1). doi: 10.1111/aji.13904. Fulltekst i vitenarkiv
• Værnesbranden, Caren Magdalena Rydland; Staff, Anne Cathrine; Wiik, Johanna; Sjøborg, Katrine Dønvold; Rüegg, Corina Silvia & Sugulle, Meryam [Vis alle 21 forfattere av denne artikkelen] (2024). Placental human papillomavirus infections and adverse pregnancy outcomes. Placenta. ISSN 0143-4004. 152, s. 23–30. doi: 10.1016/j.placenta.2024.05.126. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Knowledge on prevalence and association of human papillomavirus (HPV) in third trimester placentae and adverse pregnancy outcomes is limited. We investigated the prevalence of placental HPV at delivery, explored urine HPV characteristics associated with placental HPV and whether placental HPV increased the risk adverse pregnancy outcomes. Methods Pregnant women were enrolled in the Scandinavian PreventADALL mother-child cohort study at midgestation. Human papillomavirus genotyping was performed on placental biopsies collected at delivery (n = 587) and first-void urine at midgestation and delivery (n = 556). Maternal characteristics were collected by questionnaires at gestational week 18 and 34. Adverse pregnancy outcomes were registered from chart data including hypertensive disorders of pregnancy, gestational diabetes mellitus and newborns small for gestational age. Uni- and multivariable regression models were used to investigate associations. Results Placental HPV was detected in 18/587 (3 %). Twenty-eight genotypes were identified among the 214/556 (38 %) with midgestational urine HPV. Seventeen of the 18 women with placental HPV were midgestational HPV positive with 89 % genotype concordance. Midgestational high-risk-(HR)-HPV and high viral loads of Any- or HR-HPV were associated with placental HPV. Persisting HPV infection from midgestation to delivery was not associated with placental HPV. Adverse pregnancy outcomes were seen in 2/556 (0.4 %) of women with placental HPV. Discussion In this general cohort of pregnant women, the prevalence of placental HPV was 3 %, and midgestational urinary HPV 38 %. High HPV viral load increased the risk for placental HPV infections. We observed no increased risk for adverse pregnancy outcomes in women with placental HPV.

• Fjeldstad, Heidi; Jacobsen, Daniel Pitz; Johnsen, Guro Mørk; Sugulle, Meryam; Chae, Angel & Kanaan, Sami B. [Vis alle 8 forfattere av denne artikkelen] (2024). Fetal-origin cells in maternal circulation correlate with placental dysfunction, fetal sex, and severe hypertension during pregnancy. Journal of Reproductive Immunology. ISSN 0165-0378. 162. doi: 10.1016/j.jri.2024.104206. Fulltekst i vitenarkiv Vis sammendrag

  Fetal microchimerism (FMc) arises when fetal cells enter maternal circulation, potentially persisting for decades. Increased FMc is associated with fetal growth restriction, preeclampsia, and anti-angiogenic shift in placenta-associated proteins in diabetic and normotensive term pregnancies. The two-stage model of preeclampsia postulates that placental dysfunction causes such shift in placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLt-1), triggering maternal vascular inflammation and endothelial dysfunction. We investigated whether anti-angiogenic shift, fetal sex, fetal growth restriction, and severe maternal hypertension correlate with FMc in hypertensive disorders of pregnancy with new-onset features (n = 125). Maternal blood was drawn pre-delivery at > 25 weeks' gestation. FMc was detected by quantitative polymerase chain reaction targeting paternally inherited unique fetal alleles. PlGF and sFlt-1 were measured by immunoassay. We estimated odds ratios (ORs) by logistic regression and detection rate ratios (DRRs) by negative binomial regression. PlGF correlated negatively with FMc quantity (DRR = 0.2, p = 0.005) and female fetal sex correlated positively with FMc prevalence (OR = 5.0, p < 0.001) and quantity (DRR = 4.5, p < 0.001). Fetal growth restriction no longer correlated with increased FMc quantity after adjustment for correlates of placental dysfunction (DRR = 1.5, p = 0.272), whereas severe hypertension remained correlated with both FMc measures (OR = 5.5, p = 0.006; DRR = 6.3, p = 0.001). Our findings suggest that increased FMc is independently associated with both stages of the two-stage preeclampsia model. The association with female fetal sex has implications for microchimerism detection methodology. Future studies should target both male and female-origin FMc and focus on clarifying which placental mechanisms impact fetal cell transfer and how FMc impacts the maternal vasculature.

• Hoel, Sissel; Moe, Kjartan; Sugulle, Meryam; Petrovski, Goran; Veiby, Nina & Staff, Anne Cathrine (2024). Retinal oximetry and microvascular assessment after hypertensive pregnancy complications. Acta Ophthalmologica. ISSN 1755-375X. 102(6), s. 653–661. doi: 10.1111/aos.16651. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Women with hypertensive disorders of pregnancy (HDP) are at increased risk of developing premature cardiovascular disease (CVD). The mechanisms behind this are not fully understood, but microvascular alterations have been documented in retinal arterioles and venules. The aim of this study was to use non-invasive retinal imaging to investigate the structural and functional properties of arterioles, venules and capillaries in this patient group. Methods We examined 27 women with previous HDP and 23 controls at 3 years postpartum. The retinal microvasculature was assessed by vessel calibre measurements, retinal oximetry and optical coherence tomography angiography. Differences were analysed using non-parametric tests and multiple regression analyses, adjusted for age and body mass index. Results Median arteriolar oxygen saturation (SaO2; 94.2% vs. 93.0%), venular oxygen saturation (SvO2; 60.1% vs. 62.4%) and arteriovenous saturation difference (AV-difference; 32.8% vs. 32.3%) were similar across groups. Capillary vessel density (VD; 46.2% vs. 46.3%), skeletonised VD (VSD; 21.3 vs. 21.1 mm/mm2) and vessel diameter index (21.65 vs. 21.86) were also comparable. In the HDP group, mean arterial pressure (MAP) was positively correlated with AV-difference (R2 = 0.209) and negatively correlated with arteriolar diameter (CRAE; r2 = 0.382). Conclusions Structural microvascular alterations appear not to be key biomarkers for CVD risk after HDP as early as 3 years postpartum in otherwise healthy women. Further studies are needed to evaluate whether such changes occur later in life. MAP was associated with AV-difference only in the HDP group, suggesting specific mechanisms affecting functional microvascular properties in these women.

• Nonn, Olivia; Debnath, Olivia; Valdes, Daniela S.; Sallinger, Katja; Secener, Ali Kerim & Fischer, Cornelius [Vis alle 42 forfattere av denne artikkelen] (2024). Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia. Hypertension. ISSN 0194-911X. doi: 10.1161/HYPERTENSIONAHA.124.23362. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. METHODS: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. RESULTS: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. CONCLUSIONS: This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

• Værnesbranden, Caren Magdalena Rydland; Staff, Anne Cathrine; Wiik, Johanna; Sjøborg, Katrine Dønvold; Rueegg, Corina Silvia & Sugulle, Meryam [Vis alle 19 forfattere av denne artikkelen] (2024). Human papillomavirus infections during pregnancy and adverse pregnancy outcomes: a Scandinavian prospective mother-child cohort study. BMC Pregnancy and Childbirth. 24(1). doi: 10.1186/s12884-024-06958-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Human papillomaviruses are common in the urogenital tract amongst women of childbearing age. A few studies indicate a possible association between human papillomavirus infections in pregnancy and adverse pregnancy outcomes whilst other studies find no such association. We aimed to investigate the association between human papillomavirus infections during pregnancy and adverse pregnancy outcomes linked to placental dysfunction, including hypertensive disorders of pregnancy, gestational diabetes mellitus and newborns small for gestational age. Materials and methods Pregnant women from the general population in Norway and Sweden were enrolled at the time of routine mid-gestational ultrasound examination. Urine samples collected at mid-gestation in 950 and at delivery in 753 participants, were analyzed for 28 human papillomavirus genotypes, including 12 high-risk genotypes. Participants completed electronic questionnaires at enrollment and medical records were reviewed for background characteristics and for the following adverse pregnancy outcomes: hypertensive disorders of pregnancy including gestational hypertension, preeclampsia, superimposed preeclampsia, eclampsia and Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syndrome, gestational diabetes mellitus, and newborns small for gestational age. Associations between adverse pregnancy outcomes and (a) any human papillomavirus, high-risk human papillomavirus and human papillomavirus genotype 16 infection at mid-gestation, (b) multiple genotype infections at mid-gestation, and (c) persisting infections during pregnancy were assessed with univariable and multivariable logistic regression models. Missing covariates were imputed using multiple imputation. Results At mid-gestation, 40% (377/950) of women were positive for any of the 28 genotypes, 24% (231/950) for high-risk genotypes and human papillomavirus 16 was found in 6% (59/950) of the women. Hypertensive disorders of pregnancy was observed in 9% (83/950), gestational diabetes mellitus in 4% (40/950) and newborns small for gestational age in 7% (67/950). Human papillomavirus infection with any genotype, high-risk or human papillomavirus genotype 16 at mid-gestation was not associated with adverse pregnancy outcomes. No associations were found for multiple genotype infections at mid-gestation or persisting infections. Conclusion In a general population of pregnant women, we found no evidence of human papillomavirus infections during pregnancy being associated with hypertensive disorders of pregnancy, gestational diabetes mellitus, or newborns small for gestational age. Trial registration Trial registration The study is registered at ClincialTrials.gov; NCT02449850 on May 19th, 2015. Graphical Abstract

• Jacobsen, Daniel Pitz; Fjeldstad, Heidi Elisabeth Storebø; Sugulle, Meryam; Johnsen, Guro Mørk; Olsen, Maria Belland & Kanaan, Sami [Vis alle 7 forfattere av denne artikkelen] (2023). Fetal microchimerism and the two-stage model of preeclampsia. Journal of Reproductive Immunology. ISSN 0165-0378. 159. doi: 10.1016/j.jri.2023.104124. Fulltekst i vitenarkiv Vis sammendrag

  Fetal cells cross the placenta during pregnancy and some have the ability to persist in maternal organs and circulation long-term, a phenomenon termed fetal microchimerism. These cells often belong to stem cell or immune cell lineages. The long-term effects of fetal microchimerism are likely mixed, potentially depending on the amount of fetal cells transferred, fetal-maternal histocompatibility and fetal cell-specific properties. Both human and animal data indicate that fetal-origin cells partake in tissue repair and may benefit maternal health overall. On the other hand, these cells have been implicated in inflammatory diseases by studies showing increased fetal microchimerism in women with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. During pregnancy, preeclampsia is associated with increased cell-transfer between the mother and fetus, and an increase in immune cell subsets. In the current review, we discuss potential mechanisms of transplacental transfer, including passive leakage across the compromised diffusion barrier and active recruitment of cells residing in the placenta or fetal circulation. Within the conceptual framework of the two-stage model of preeclampsia, where syncytiotrophoblast stress is a common pathophysiological pathway to maternal and fetal clinical features of preeclampsia, we argue that microchimerism may represent a mechanistic link between stage 1 placental dysfunction and stage 2 maternal cardiovascular inflammation and endothelial dysfunction. Finally, we postulate that fetal microchimerism may contribute to the known association between placental syndromes and increased long-term maternal cardiovascular disease risk. Fetal microchimerism research represents an exciting opportunity for developing new disease biomarkers and targeted prophylaxis against maternal diseases.

• Fjeldstad, Heidi Elisabeth Storebø; Jacobsen, Daniel Pitz; Johnsen, Guro Mørk; Sugulle, Meryam; Chae, Angel & Kanaan, Sami B. [Vis alle 8 forfattere av denne artikkelen] (2023). Poor glucose control and markers of placental dysfunction correlate with increased circulating fetal microchimerism in diabetic pregnancies. Journal of Reproductive Immunology. ISSN 0165-0378. 159, s. 1–9. doi: 10.1016/j.jri.2023.104114. Fulltekst i vitenarkiv Vis sammendrag

  Fetal microchimerism (FMc) arises during pregnancy as fetal cells enter maternal circulation and remain decades postpartum. Circulating FMc is increased in preeclampsia, fetal growth restriction, and as we recently showed, is associated with biomarkers of placental dysfunction in normotensive term pregnancies. Diabetes mellitus (DM) also correlates with placental dysfunction. We hypothesize that poor glucose control and markers of placental dysfunction are associated with increased circulating FMc in diabetic pregnancies. We included 122 pregnancies preceding active labor (pregestational DM, n = 77, gestational DM (GDM), n = 45) between 2001 and 2017. Maternal and fetal samples were genotyped for various human leukocyte antigen (HLA) loci, and other polymorphisms to identify fetus-specific alleles. We used validated polymerase chain reaction (PCR) assays to quantify FMc in maternal peripheral blood buffy coat. Negative binomial regression with adjustment for confounders was used to assess FMc quantity. In pregestational DM, increased circulating FMc correlated with elevation of HbA1c (≥ 6.0 %) (detection rate ratio (DRR) = 4.9, p = 0.010) and a 1000 pg/mL rise in the anti-angiogenic biomarker soluble fms-like tyrosine kinase-1 (sFlt-1) (DRR = 1.1, p = 0.011). In GDM, increased FMc correlated with elevated 2-hour oral glucose tolerance test results (DRR = 2.3, p = 0.046) and birthweight < 10th or > 90th percentile (DRR = 4.2, p = 0.049). These findings support our novel hypothesis that FMc correlates with poor glucose control and various aspects of placental dysfunction in DM. Whether increased FMc in pregnancies with poor glucose control and placental dysfunction contributes to the risk of preeclampsia in diabetic pregnancies and to the increased risk of chronic cardiovascular disease later in life remains to be investigated.

• Fiskå, Bendik Seth; Pay, Aase Serine Devold; Staff, Anne Cathrine & Sugulle, Meryam (2023). Gestational diabetes mellitus, follow-up of future maternal risk of cardiovascular disease and the use of eHealth technologies—a scoping review. Systematic Reviews. 12(1). doi: 10.1186/s13643-023-02343-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Globally, gestational diabetes mellitus complicates 1 in 6 pregnancies and increases future risk of type 2 diabetes and cardiovascular disease in the affected women. There is a lack of consensus on the optimal follow-up of these women. eHealth is emerging as a health care tool, but its practical utility and advantages over standard care in the follow-up after pregnancy complications remains to be determined. Our aim was to systematically review the existing literature on cardiovascular follow-up after gestational diabetes, the utility of eHealth technology for this purpose, and to identify research gaps. Methods WeperformedasystematicscopingreviewfollowingapublishedprotocolandtheJoannaBriggsmethodol- ogy for studies up until May 2022. Four databases were searched: Ovid MEDLINE, Embase, Maternity and Infant Care, and Cochrane Database of Systematic Reviews. Primary research articles and systematic reviews were included in the final analyses. Two reviewers independently screened abstracts and performed full text assessment. Data was extracted using a data charting form. In all stages of the process, if consensus was not reached, a third reviewer was consulted. The findings from the data charting process provided the basis for summarizing the findings from the included studies. Results The search of the databases generated 2772 hits. After removing duplicates and manually adding a total of 19 studies, reviews, and guidelines, a total of 2769 titles and abstracts were screened, and 97 papers underwent full-text review. In the final analyses, 15 articles and 12 systematic reviews were included, whereas guidelines are presented as supplementary material. No studies were identified that examined follow-up regarding long-term overall cardiovascular risk after gestational diabetes. Various lifestyle interventions were tested for individual cardiovascular risk factors, with diverging effects. eHealth technologies were found acceptable by participants but had no consistent, statistically significant effect on relevant health outcomes. Conclusions This scoping review of the existing literature revealed neither an established systematic cardiovascular follow-up strategy for women after gestational diabetes nor evidence that eHealth technologies are superior to con- ventional follow-up. Further research into the utility of eHealth in cardiovascular follow-up after complicated pregnan- cies should include longer-term follow-up and core cardiovascular outcomes.

• Fjeldstad, Heidi Elisabeth Storebø; Jacobsen, Daniel Pitz; Johnsen, Guro Mørk; Sugulle, Meryam; Chae, Angel & Kanaan, Sami B. [Vis alle 8 forfattere av denne artikkelen] (2023). Markers of placental function correlate with prevalence and quantity of nucleated fetal cells in maternal circulation in normotensive term pregnancies. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 102(6), s. 690–698. doi: 10.1111/aogs.14547. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Transplacental fetal cell transfer results in the engraftment of fetal‐origin cells in the pregnant woman's body, a phenomenon termed fetal microchimerism. Increased fetal microchimerism measured decades postpartum is implicated in maternal inflammatory disease. Understanding which factors cause increased fetal microchimerism is therefore important. During pregnancy, circulating fetal microchimerism and placental dysfunction increase with increasing gestational age, particularly towards term. Placental dysfunction is reflected by changes in circulating placenta‐associated markers, specifically placental growth factor (PlGF), decreased by several 100 pg/mL, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), increased by several 1000 pg/mL, and the sFlt‐1/PlGF ratio, increased by several 10 (pg/mL)/(pg/mL). We investigated whether such alterations in placenta‐associated markers correlate with an increase in circulating fetal‐origin cells. Material and methods We included 118 normotensive, clinically uncomplicated pregnancies (gestational age 37+1 up to 42+2 weeks‘ gestation) pre‐delivery. PlGF and sFlt‐1 (pg/mL) were measured by Elecsys® Immunoassays. We extracted DNA from maternal and fetal samples and genotyped four human leukocyte antigen loci and 17 other autosomal loci. Paternally inherited, unique fetal alleles served as polymerase chain reaction (PCR) targets for detecting fetal‐origin cells in maternal buffy coat. Fetal‐origin cell prevalence was assessed by logistic regression, and quantity by negative binomial regression. Statistical exposures included gestational age (weeks), PlGF (100 pg/mL), sFlt‐1 (1000 pg/mL) and the sFlt‐1/PlGF ratio (10 (pg/mL)/(pg/mL)). Regression models were adjusted for clinical confounders and PCR‐related competing exposures. Results Gestational age was positively correlated with fetal‐origin cell quantity (DRR = 2.2, P = 0.003) and PlGF was negatively correlated with fetal‐origin cell prevalence (odds ratio [OR] 100 = 0.6, P = 0.003) and quantity (DRR 100 = 0.7, P = 0.001). The sFlt‐1 and the sFlt‐1/PlGF ratios were positively correlated with fetal‐origin cell prevalence (OR 1000 = 1.3, P = 0.014 and OR 10 = 1.2, P = 0.038, respectively), but not quantity (DRR 1000 = 1.1, P = 0.600; DRR 10 = 1.1, P = 0.112, respectively). Conclusions Our results suggest that placental dysfunction as evidenced by placenta‐associated marker changes, may increase fetal cell transfer. The magnitudes of change tested were based on ranges in PlGF, sFlt‐1 and the sFlt‐1/PlGF ratio previously demonstrated in pregnancies near and post‐term, lending clinical significance to our findings. Our results were statistically significant after adjusting for confounders including gestational age, supporting our novel hypothesis that underlying placental dysfunction potentially is a driver of increased fetal microchimerism.

• Jacobsen, Daniel Pitz; Fjeldstad, Heidi Elisabeth Storebø; Sugulle, Meryam; Johnsen, Guro Mørk; Olsen, Maria Belland & Kanaan, Sami B. [Vis alle 7 forfattere av denne artikkelen] (2023). Fetal microchimerism and the two-stage model of preeclampsia. Journal of Reproductive Immunology. ISSN 0165-0378. 159. doi: 10.1016/j.jri.2023.104124. Fulltekst i vitenarkiv Vis sammendrag

  Fetal cells cross the placenta during pregnancy and some have the ability to persist in maternal organs and circulation long-term, a phenomenon termed fetal microchimerism. These cells often belong to stem cell or immune cell lineages. The long-term effects of fetal microchimerism are likely mixed, potentially depending on the amount of fetal cells transferred, fetal-maternal histocompatibility and fetal cell-specific properties. Both human and animal data indicate that fetal-origin cells partake in tissue repair and may benefit maternal health overall. On the other hand, these cells have been implicated in inflammatory diseases by studies showing increased fetal microchimerism in women with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. During pregnancy, preeclampsia is associated with increased cell-transfer between the mother and fetus, and an increase in immune cell subsets. In the current review, we discuss potential mechanisms of transplacental transfer, including passive leakage across the compromised diffusion barrier and active recruitment of cells residing in the placenta or fetal circulation. Within the conceptual framework of the two-stage model of preeclampsia, where syncytiotrophoblast stress is a common pathophysiological pathway to maternal and fetal clinical features of preeclampsia, we argue that microchimerism may represent a mechanistic link between stage 1 placental dysfunction and stage 2 maternal cardiovascular inflammation and endothelial dysfunction. Finally, we postulate that fetal microchimerism may contribute to the known association between placental syndromes and increased long-term maternal cardiovascular disease risk. Fetal microchimerism research represents an exciting opportunity for developing new disease biomarkers and targeted prophylaxis against maternal diseases.

• Tingleff, Tiril; Räisänen, Sari; Vikanes, Åse Vigdis; Sandvik, Leiv; Sugulle, Meryam & Lahmami, Gulim [Vis alle 7 forfattere av denne artikkelen] (2022). Different pathways for preterm birth between singleton and twin pregnancies: a population-based registry study of 481 176 nulliparous women. BJOG: An International Journal of Obstetrics and Gynaecology. ISSN 1470-0328. s. 1–9. doi: 10.1111/1471-0528.17344. Fulltekst i vitenarkiv Vis sammendrag

  Objective To explore the contribution of pregnancy-related complications on the prevalence of extremely, very and late preterm births in singleton and twin pregnancies. To study the risk of spontaneous preterm birth in twin pregnancies compared with singleton pregnancies. Design Population-based registry study. Setting Medical birth registry of Norway and Statistics Norway. Population Nulliparous women with singleton (n = 472 449) or twin (n = 8727) births during 1999–2018. Methods Prevalence rates of pregnancy-related complications for extremely, very and late preterm birth in twin and singleton pregnancies were calculated with 95% confidence intervals. Multivariable logistic regression was applied to assess odds ratios for preterm birth, adjusted for obstetric and socio-economic factors. Main outcome measures Extremely preterm (<28+0 weeks of gestation), very preterm (28+0–33+6 weeks of gestation) and late preterm (34+0–36+6 weeks of geatation) birth. Results Preterm birth was significantly more prevalent in twin pregnancies than in singleton pregnancies in all categories: all preterm (54.7% vs 6.1%), extremely preterm (3.6% vs 0.4%), very preterm (18.2% vs 1.4%) and late preterm (33.0% vs 4.3%) births. Stillbirth, congenital malformation and pre-eclampsia were more prevalent in twin pregnancies than in singleton pregnancies, but the prevalence of complications differed in the three categories of preterm birth. Pre-eclampsia was more prevalent in singleton than in twin pregnancies ending in extremely and very preterm birth. The adjusted odds of spontaneous preterm live birth were between 19- and 54-fold greater in twin pregnancies than in singleton pregnancies. Conclusions Singleton and twin pregnancies seem to have different pathways leading to extremely, very and late preterm birth.

• Fosheim, Ingrid Knutsdotter; Jacobsen, Daniel Pitz; Sugulle, Meryam; Alnæs-Katjavivi, Patji; Fjeldstad, Heidi & Ueland, Thor [Vis alle 8 forfattere av denne artikkelen] (2022). Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction. American Journal of Obstetrics & Gynecology MFM (AJOG MFM). 5(1). doi: 10.1016/j.ajogmf.2022.100794. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid—aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear.<p> <p>OBJECTIVE: We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. <p>STUDY DESIGN: Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the MannWhitney U, chi-squared, or Fisher exact test as appropriate. Spearman’s rho was calculated for assessing correlations. <p>RESULTS: In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 mg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 mg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 mg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fmslike tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. <p>CONCLUSION: Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

• Mitlid-Mork, Birgitte; Bowe, Sophie; Staff, Anne Cathrine & Sugulle, Meryam (2022). Alterations in maternal sFlt-1 and PlGF: Time to labor onset in term-/late-term pregnancies with and without placental dysfunction. Pregnancy Hypertension. ISSN 2210-7789. 30, s. 148–153. doi: 10.1016/j.preghy.2022.10.004. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To investigate the placenta-associated biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) longitudinally in late third trimester extending to late-term pregnancies, and their correlation with time to labor onset in pregnancies with and without placental syndromes (ie preeclampsia and/or fetal growth restriction). Also, to compare whether time to labor onset after induction differ between these groups. Study design Pregnant women (n = 338, of which 75 had a placental syndrome) with serial blood samples from gestational week ≥37 until labor onset were included. Maternal serum PlGF and sFlt-1 concentrations were analyzed by immunoassay postpartum. Main outcome measures Rate of alteration in sFlt-1, PlGF and the sFlt-1/PlGF ratio prior to labor onset. Secondary outcome was rates of delivery within 48 h of labor induction. Results In placental syndrome pregnancies, sFlt-1 and sFlt-1/PlGF ratio increased more rapidly between the two last samples prior to labor onset compared to uncomplicated pregnancies (both p < 0.01), but there was no difference in the PlGF decrease (p = 0.513). Time to labor onset was significantly shorter in pregnancies with placental syndromes compared to those without (p = 0.001). In the induced deliveries, there was no difference in delivery within 48 h between the two groups. Conclusions An increase in sFlt-1 and sFlt-1/PlGF ratio at term prior to labor onset is more rapid in pregnancies with placental syndromes. This more rapid antiangiogenic shift might indicate a pregnancy more prone to acute placental failure and more inflammatory prepared for labor onset. Effect of labor induction was not impacted by placental dysfunction.

• Jacobsen, Daniel Pitz; Røysland, Ragnhild; Strand, Heidi; Moe, Kjartan; Sugulle, Meryam & Omland, Torbjørn [Vis alle 7 forfattere av denne artikkelen] (2022). Cardiovascular biomarkers in pregnancy with diabetes and associations to glucose control. Acta Diabetologica. ISSN 0940-5429. 59(9), s. 1229–1236. doi: 10.1007/s00592-022-01916-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Aim Cardiovascular disease (CVD) is a leading cause of death in both men and women. Type 1 and 2 diabetes mellitus (DM1 and DM2) are well-known risk factors for CVD. In addition, gestational diabetes mellitus (GDM) is a female sex-specific risk factor for CVD. Here, we measure circulating concentrations of cardiac troponin T (cTNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) during pregnancy—a window of time often referred to as a cardiovascular stress test for women. Methods This study utilized data from 384 pregnant women: 64 with DM1, 16 with DM2, 35 with GDM and 269 euglycemic controls. Blood was predominantly sampled within a week before delivery. Cardiovascular biomarker concentrations were measured in serum using electrochemiluminescence immunoassay. Result Circulating cTnT levels were higher in women with DM1, DM2 and GDM as compared to controls, whereas NT-proBNP and GDF-15 levels were only increased in women with DM1. Glucose dysregulation, assessed by third trimester HbA1c levels, positively correlated with all three CVD biomarker levels, whereas pregestational body mass index correlated negatively with GDF-15. Conclusions Our results support the presence of myocardial affection in women with diabetic disorders during pregnancy. Although pregestational DM1 in this study was associated with the most adverse CVD biomarker profile, women with GDM displayed an adverse cTnT profile similar to what we found in women with pregestational DM2. This supports that women with GDM should be offered long-term intensified cardiovascular follow-up and lifestyle advice following delivery, similarly to the well-established CV follow-up of women with pregestational DM.

• Linge, Lydia Lande; Sugulle, Meryam; Wallukat, Gerd; Dechend, Ralf & Staff, Anne Cathrine (2022). Circulating angiotensin II type I receptor – autoantibodies in diabetic pregnancies. Journal of Reproductive Immunology. ISSN 0165-0378. 155. doi: 10.1016/j.jri.2022.103777. Fulltekst i vitenarkiv Vis sammendrag

  Pregnant women with either pre-existing or gestational diabetes mellitus are at increased risk of preeclampsia as well as future cardiovascular disease. The renin-angiotensin system is dysregulated in both diabetes mellitus and preeclampsia. In preeclampsia, maternal levels of circulating agonistic autoantibodies against the angiotensin II Type I receptor (AT1-AAs) are increased. Circulating AT1-AAs are thought to contribute to both the pathophysiology of preeclampsia and the increased risk of future cardiovascular disease. Studies exploring AT1-AA in diabetes outside pregnancy suggest their potential for both metabolic and cardiovascular pathogenicity. No studies have investigated AT1-AAs in diabetic pregnancies. We hypothesized elevated maternal circulating AT1-AA levels in pregnancies complicated by any type of diabetes mellitus. Third-trimester maternal serum from 39 women (controls: n = 10; type 1 diabetes: n = 9; type 2 diabetes: n = 10; gestational diabetes=10) were analyzed for AT1-AA using an established bioassay method. Circulating AT1-AAs were present in 70% (7/10) of the controls and 83% (24/29) of the diabetes group (P = 0.399). Presence of AT1-AA was correlated to hsCRP levels (P = 0.036), but neither with maternal circulating angiogenic factors (soluble fms-like tyrosine kinase-1 and placental growth factor), nor with maternal or fetal characteristics indicative of metabolic disease or placental dysfunction. Our study is the first to demonstrate presence of circulating AT1-AAs in pregnant women with any type of diabetes. Our findings suggest AT1-AAs presence in pregnancy independently of placental dysfunction, nuancing the current view on their pathogenicity. Whether AT1-AAs per se contribute to increased risk of adverse pregnancy outcomes and future cardiovascular disease remains currently unanswered.

• Kedziora, Sarah M.; Obermayer, Benedikt; Sugulle, Meryam; Herse, Florian; Kräker, Kristin & Haase, Nadine [Vis alle 11 forfattere av denne artikkelen] (2022). Placental transcriptome profiling in subtypes of diabetic pregnancies Is strongly confounded by fetal sex. International Journal of Molecular Sciences. ISSN 1661-6596. 23:15388(23), s. 1–16. doi: 10.3390/ijms232315388. Fulltekst i vitenarkiv Vis sammendrag

  The placenta is a temporary organ with a unique structure and function to ensure healthy fetal development. Placental dysfunction is involved in pre-eclampsia (PE), fetal growth restriction, preterm birth, and gestational diabetes mellitus (GDM). A diabetic state affects maternal and fetal health and may lead to functional alterations of placental metabolism, inflammation, hypoxia, and weight, amplifying the fetal stress. The placental molecular adaptations to the diabetic environment and the adaptive spatio–temporal consequences to elevated glucose or insulin are largely unknown (2). We aimed to identify gene expression signatures related to the diabetic placental pathology of placentas from women with diabetes mellitus. Human placenta samples (n = 77) consisting of healthy controls, women with either gestational diabetes mellitus (GDM), type 1 or type 2 diabetes, and women with GDM, type 1 or type 2 diabetes and superimposed PE were collected. Interestingly, gene expression differences quantified by total RNA sequencing were mainly driven by fetal sex rather than clinical diagnosis. Association of the principal components with a full set of clinical patient data identified fetal sex as the single main explanatory variable. Accordingly, placentas complicated by type 1 and type 2 diabetes showed only few differentially expressed genes, while possible effects of GDM and diabetic pregnancy complicated by PE were not identifiable in this cohort. We conclude that fetal sex has a prominent effect on the placental transcriptome, dominating and confounding gene expression signatures resulting from diabetes mellitus in settings of well-controlled diabetic disease. Our results support the notion of placenta as a sexual dimorphic organ. Keywords: diabetes mellitus; human; placenta; pregnancy; RNA sequencing

• Sundet, Birgitte Kordt; Kreyberg, Ina; Staff, Anne Cathrine; Carlsen, Karin Cecilie Lødrup; Bains, Karen Eline Stensby & Berg, Jens Petter [Vis alle 20 forfattere av denne artikkelen] (2022). The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers. Biology of Sex Differences. 13(1). doi: 10.1186/s13293-022-00443-1. Fulltekst i vitenarkiv Vis sammendrag

  In utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as “placenta health markers”, known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex. Methods Midpregnancy (16–22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex. Results Median sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [β − 0.12, (95% CI − 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [β − 0.05 (95% CI − 0.09 to (− 0.02)) and β − 0.07 (95% CI − 0.12 to (− 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels. Conclusions Midpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as “safe” by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

• Jacobsen, Daniel Pitz; Røysland, Ragnhild; Strand, Heidi; Moe, Kjartan; Sugulle, Meryam & Omland, Torbjørn [Vis alle 7 forfattere av denne artikkelen] (2022). Circulating cardiovascular biomarkers during and after preeclampsia: Crosstalk with placental function? Pregnancy Hypertension. ISSN 2210-7789. 30, s. 103–109. doi: 10.1016/j.preghy.2022.09.003. Fulltekst i vitenarkiv Vis sammendrag

  Cardiovascular disease (CVD) is the leading cause of death in women, yet sex-specific risk factors remain understudied. Preeclampsia and other adverse pregnancy outcomes imply an increased maternal cardiovascular risk. We hypothesized that cardiac troponin T (cTnT), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) are increased in such pregnancies and correlate with markers of placental dysfunction. We also investigated these cardiovascular biomarkers 1 or 3 years postpartum. Prior to delivery, we included serum from 417 pregnant women: 55 early-onset preeclampsia (EO-PE), 63 late-onset preeclampsia (LO-PE), 30 gestational hypertension (GH) and 269 healthy controls. Postpartum, we included 341 women 1 or 3 years after delivery: 26 EO-PE, 107 LO-PE, 61 GH, and 147 healthy pregnancies. Prior to delivery, median cTnT and NT-proBNP concentrations were higher in women with EO-PE, LO-PE, or GH than in controls. Median GDF-15 was higher in EO-PE and LO-PE compared to controls. Postpartum, GDF-15 was elevated in women with previous EO-PE. Markers of placental dysfunction correlated with CVD biomarkers in pregnancy, but not postpartum. Our findings underscore the cardiovascular burden of hypertensive disorders of pregnancy and the crosstalk with placental function. The upregulation of circulating GDF-15 following early-onset preeclampsia is in line with the epidemiological excessive risk of premature CVD in this group of women. GDF-15 may be explored for targeting postpartum women with most to gain from intensified preventive follow-up for CVD.

• Bowe, Sophie; Mitlid-Mork, Birgitte; Gran, Jon Michael; Distante, Sonia; Redman, Christopher W.G. & Staff, Anne Cathrine [Vis alle 8 forfattere av denne artikkelen] (2022). Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns. AJOG Global Reports. 3(1). doi: 10.1016/j.xagr.2022.100149. Fulltekst i vitenarkiv Vis sammendrag

  Background Increasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low “proangiogenic” placental growth factor concentrations and increased “antiangiogenic” soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome. Objective This study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low “proangiogenic” placental growth factor levels, increased “antiangiogenic” soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1–placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome. Study Design This was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37+0), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups—the “complicated” group (n=32) and the “uncomplicated” group (n=924)—according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results. Results Mean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P=.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start (rs=−0.068; 95% confidence interval, −0.131 to −0.004; P=.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end (rs=−0.068; 95% confidence interval, −0.131 to −0.005; P=.036), and high soluble fms-like tyrosine kinase-1–placental growth factor ratio and low short-term variation end (rs=−0.071; 95% confidence interval, −0.134 to −0.008; P=.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the “complicated” compared with the “uncomplicated” group (0% to 17% vs 4% to 8%). Conclusion More automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile...

• Jacobsen, Daniel Pitz; Fjeldstad, Heidi Elisabeth Storebø; Johnsen, Guro Mørk; Fosheim, Ingrid Knutsdotter; Moe, Kjartan & Alnæs-Katjavivi, Patji [Vis alle 9 forfattere av denne artikkelen] (2021). Acute Atherosis Lesions at the Fetal-Maternal Border: Current Knowledge and Implications for Maternal Cardiovascular Health. Frontiers in Immunology. 12, s. 1–16. doi: 10.3389/fimmu.2021.791606. Fulltekst i vitenarkiv Vis sammendrag

  Decidua basalis, the endometrium of pregnancy, is an important interface between maternal and fetal tissues, made up of both maternal and fetal cells. Acute atherosis is a uteroplacental spiral artery lesion. These patchy arterial wall lesions containing foam cells are predominantly found in the decidua basalis, at the tips of the maternal arteries, where they feed into the placental intervillous space. Acute atherosis is prevalent in preeclampsia and other obstetric syndromes such as fetal growth restriction. Causal factors and effects of acute atherosis remain uncertain. This is in part because decidua basalis is challenging to sample systematically and in large amounts following delivery. We summarize our decidua basalis vacuum suction method, which facilitates tissue-based studies of acute atherosis. We also describe our evidence-based research definition of acute atherosis. Here, we comprehensively review the existing literature on acute atherosis, its underlying mechanisms and possible short- and long-term effects. We propose that multiple pathways leading to decidual vascular inflammation may promote acute atherosis formation, with or without poor spiral artery remodeling and/or preeclampsia. These include maternal alloreactivity, ischemia-reperfusion injury, preexisting systemic inflammation, and microbial infection. The concept of acute atherosis as an inflammatory lesion is not novel. The lesions themselves have an inflammatory phenotype and resemble other arterial lesions of more extensively studied etiology. We discuss findings of concurrently dysregulated proteins involved in immune regulation and cardiovascular function in women with acute atherosis. We also propose a novel hypothesis linking cellular fetal microchimerism, which is prevalent in women with preeclampsia, with acute atherosis in pregnancy and future cardiovascular and neurovascular disease. Finally, women with a history of preeclampsia have an increased risk of premature cardiovascular disease. We review whether presence of acute atherosis may identify women at especially high risk for premature cardiovascular disease.

• Nonn, Olivia; Fischer, Cornelius; Geisberger, Sabrina; El-Heliebi, Amin; Kroneis, Thomas & Forstner, Désirée [Vis alle 20 forfattere av denne artikkelen] (2021). Maternal Angiotensin Increases Placental Leptin in Early Gestation via an Alternative Renin-Angiotensin System Pathway: Suggesting a Link to Preeclampsia. Hypertension. ISSN 0194-911X. 77(5), s. 1723–1736. doi: 10.1161/HYPERTENSIONAHA.120.16425. Fulltekst i vitenarkiv
• Mitlid-Mork, Birgitte; Turowski, Gitta Erika; Bowe, Sophie; Staff, Anne Cathrine & Sugulle, Meryam (2021). Circulating angiogenic profiles and histo-morphological placental characteristics of uncomplicated post-date pregnancies. Placenta. ISSN 0143-4004. 109, s. 55–63. doi: 10.1016/j.placenta.2021.04.017. Fulltekst i vitenarkiv Vis sammendrag

  Introduction The objectives of this study were to describe the histo-morphology of post-date placentas in clinically uncomplicated pregnancies without adverse delivery outcomes and the association with maternal circulating pre-delivery Placental Growth Factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), as well as the sFlt-1/PlGF ratio. Methods Post-date placentas (gestational week ≥40+2, n = 87) were macroscopically and histo-morphologically assessed according to the international, standardized Amsterdam Workshop Consensus Group criteria. Inter-rater agreement was evaluated by percentage of agreement. PlGF and sFlt-1 concentrations were available from maternal serum sampled close to delivery, and were compared by Mann-Whitney U test. Linear regression analyses were adjusted for predefined potential confounders. Results The majority of the post-date placentas showed morphological signs of delayed maturation. About half of the placentas showed increased syncytial knotting and fibrin. In placentas with increased presence of intervillous fibrin, median maternal PlGF level was significantly lower (p = 0.004), median sFlt-1 level higher and sFlt-1/PlGF ratio significantly higher (p = 0.002) compared to those with normal fibrin amounts. Increased placental syncytial knotting was associated with lower levels of PlGF, higher sFlt-1 and higher sFlt-1/PlGF ratio compared to those with normal knotting. Discussion Our standardized morphological study of post-date placentas in clinically healthy women with uncomplicated pregnancies and delivery outcomes revealed delayed maturation in the majority of placentas. Increased pre-delivery circulating anti-angiogenic profile was associated with increased intervillous fibrin and syncytial knotting. We propose that circulating maternal angiogenic biomarkers may be of future use in clinical post-date pregnancy assessment, as they reflect important aspects of placental health and function.

• Sugulle, Meryam; Halldórsdóttir, Erna; Kvile, Janne; Berntzen, Line Dahlgaard & Jacobsen, Anne Flem (2021). Prospective assessment of vacuum deliveries from midpelvic station in a tertiary care university hospital: Frequency, failure rates, labor characteristics and maternal and neonatal complications. PLOS ONE. 16(11), s. 1–12. doi: 10.1371/journal.pone.0259926. Fulltekst i vitenarkiv Vis sammendrag

  Background Midpelvic vacuum extractions are controversial due to reports of increased risk of maternal and perinatal morbidity and high failure rates. Prospective studies of attempted midpelvic vacuum outcomes are scarce. Our main aims were to assess frequency, failure rates, labor characteristics, maternal and neonatal complications of attempted midpelvic vacuum deliveries, and to compare labor characteristics and complications between successful and failed midpelvic vacuum deliveries. Study design Clinical data were obtained prospectively from all attempted vacuum deliveries (n = 891) over a one-year period with a total of 6903 births (overall cesarean section rate 18.2% (n = 1258). Student’s t-test, Mann-Whitney U-test or Chi-square test for group differences were used as appropriate. Odds ratios and 95% confidence intervals are given as indicated. The uni- and multivariable analysis were conducted both as a complete case analysis and with a multiple imputation approach. A p-value of <0.05 was considered statistically significant. Results Attempted vacuum extractions from midpelvic station constituted 36.7% (n = 319) of all attempted vacuum extractions (12.9% (n = 891) of all births). Of these 319 midpelvic vacuum extractions, 11.3% (n = 36) failed and final delivery mode was cesarean section in 86.1% (n = 31) and forceps in the remaining 13.9% (n = 5). Successful completion of midpelvic vacuum by 3 pulls or fewer was achieved in 67.1%. There were 3.9% third-degree and no fourth-degree perineal tears. Cup detachments were associated with a significantly increased failure rate (adjusted OR 6.13, 95% CI 2.41–15.56, p< 0.001). Conclusion In our study, attempted midpelvic vacuum deliveries had relatively low failure rate, the majority was successfully completed within three pulls and they proved safe to perform as reflected by a low rate of third-degree perineal tears. We provide data for nuanced counseling of women on vacuum extraction as a second stage delivery option in comparable obstetric management settings with relatively high vacuum delivery rates and low cesarean section rates.

• Bowe, Sophie; Mitlid-Mork, Birgitte; Georgieva, Antoniya; Gran, Jon M.; Redman, Christopher W.G. & Staff, Anne Cathrine [Vis alle 7 forfattere av denne artikkelen] (2021). The association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in healthy post-date pregnancies. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 100(10), s. 1893–1901. doi: 10.1111/aogs.14223. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Post-date pregnancies have an increased risk of adverse delivery outcome. Our aim was to explore the association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in clinically healthy post-date pregnancies. Material and methods Women with healthy singleton post-date pregnancies between 40+2 and 42+2 weeks of gestation were recruited to this prospective, observational study conducted at Oslo University Hospital, Norway (NCT03100084). Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the maternal serum samples closest to delivery. The composite adverse delivery outcome included fetal acidemia, low Apgar score (<4 at 1 min or <7 at 5 min), asphyxia, fetal death, assisted ventilation for more than 6 h, meconium aspiration, hypoxic–ischemic encephalopathy, therapeutic hypothermia, operative delivery due to fetal distress, or pathological placental histology findings. Two study-independent senior consultant obstetricians blinded to biomarker results concluded, based on clinical expert opinion, whether the adverse delivery outcomes were most likely associated with placental dysfunction (“likely placental cause”) or not. Means were compared using one-way analysis of variance and Bonferroni corrected pairwise comparisons between groups. Receiver operating characteristic (ROC) curves assessed the predictive ability of PlGF, sFlt-1/PlGF ratio, and PlGF <10th centile after adjustment for gestational age at blood sampling. Results Of 501 pregnancies reviewed for predefined adverse delivery outcomes and for a likely placental cause, 468 were healthy pregnancies and subsequently assigned to either the “uncomplicated” (no adverse outcome, n = 359), “intermediate” (non-placental cause/undetermined, n = 90), or “complicated” (likely placental cause, n = 19) group. There was a significant difference in mean PlGF and sFlt-1/PlGF ratio between the “complicated”, “intermediate”, and “uncomplicated” groups (108, 185, and 179 pg/mL, p = 0.001; and 48.3, 23.4, and 24.6, p = 0.002, respectively). There was a higher proportion of PlGF concentration <10th centile in the “complicated” group compared with the “intermediate” and “uncomplicated” groups (42.1% vs. 11.1% and 9.5%, p = 0.001). The largest area under the ROC curve for predicting “complicated” outcome was achieved by PlGF concentration and gestational age at blood sampling (0.76; 95% CI 0.65–0.86). Conclusions In clinically healthy post-date pregnancies, an antiangiogenic pre-delivery profile (lower PlGF level and higher sFlt-1/PlGF ratio) was associated with composite adverse delivery outcome of a likely placental cause.

• Kedziora, Sarah M.; Kräker, Kristin; Markó, Lajos; Binder, Julia; Sugulle, Meryam & Gauster, Martin [Vis alle 10 forfattere av denne artikkelen] (2021). Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model. International Journal of Molecular Sciences. ISSN 1661-6596. 22(7), s. 1–13. doi: 10.3390/ijms22073762. Fulltekst i vitenarkiv
• Ziesler, Charlotte Philippa Øxnevad; Staff, Anne Cathrine; Sugulle, Meryam & Moe, Kjartan (2021). Low physical activity levels 1 year after pregnancy complications. Pregnancy Hypertension. ISSN 2210-7789. 25, s. 136–142. doi: 10.1016/j.preghy.2021.05.022. Fulltekst i vitenarkiv
• Lekva, Tove; Jacobsen, Daniel Pitz; Sugulle, Meryam; Moe, Kjartan; Fjeldstad, Heidi E. & Dechend, Ralf [Vis alle 7 forfattere av denne artikkelen] (2021). Circulating HLA-G and its association with cardiovascular markers in pregnancy. Journal of Reproductive Immunology. ISSN 0165-0378. 146. doi: 10.1016/j.jri.2021.103331. Fulltekst i vitenarkiv
• Fosheim, Ingrid Knutsdotter; Johnsen, G.M.; Alnaes-Katjavivi, P.; Turowski, Gitta Erika; Sugulle, M. & Staff, A.C. (2021). Decidua basalis and acute atherosis: Expression of atherosclerotic foam cell associated proteins. Placenta. ISSN 0143-4004. 107, s. 1–7. doi: 10.1016/j.placenta.2021.03.001. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Uteroplacental acute atherosis is frequently observed in preeclampsia, and shares features with early atherosclerotic lesions, including artery wall foam cells. The lipid-associated proteins FABP4 (fatty acid binding protein 4), perilipin-2, and LOX-1 (lectin-like oxidized LDL-receptor 1) are involved in atherosclerotic foam cell formation. Increased levels of these proteins have been associated with preeclampsia systemically and in placental tissue. Their role in acute atherosis is yet unidentified. Our aim was to describe the presence of these proteins in acute atherosis, and compare our findings to what is known in early atherosclerotic lesions. Methods Serial sections of decidua basalis tissue from 12 normotensive (4 with acute atherosis) and 23 preeclamptic pregnancies (16 with acute atherosis) were stained with HE and immunostained for CK7, CD68, FABP4, perilipin-2, and LOX-1. Artery wall and perivascular protein expression was assessed in 190 spiral artery sections; 55 with acute atherosis. Results Acute atherosis foam cells were commonly positive for perilipin-2 (55%), less often for FABP4 (13%), and never for LOX-1. LOX-1 was frequently observed in intramural trophoblasts of normal spiral arteries. Perivascularly, LOX-1 positivity of decidual stromal cells surrounding arteries with acute atherosis was significantly increased as compared to arteries lacking acute atherosis (38% vs. 15%, p < 0.001). Discussion We found that perilipin-2 and FABP4 are expressed by acute atherosis foam cells, similar to atherosclerosis, supporting possible shared pathways for foam cell generation. Unlike atherosclerosis, LOX-1 is not present in acute atherosis, possibly explained by pregnancy-specific routes to decidua basalis foam cell generation.

• Moe, Kjartan; Sugulle, Meryam; Dechend, Ralf; Angel, Kristin & Staff, Anne Cathrine (2020). Functional and structural vascular biomarkers in women 1 year after a hypertensive disorder of pregnancy. Pregnancy Hypertension. ISSN 2210-7789. 21, s. 23–29. doi: 10.1016/j.preghy.2020.04.008. Fulltekst i vitenarkiv
• Jacobsen, Daniel Pitz; Lekva, Tove; Moe, Kjartan; Fjeldstad, Heidi Elisabeth; Johnsen, Guro Mørk & Sugulle, Meryam [Vis alle 7 forfattere av denne artikkelen] (2020). Pregnancy and postpartum levels of circulating maternal sHLA-G in preeclampsia. Journal of Reproductive Immunology. ISSN 0165-0378. 143. doi: 10.1016/j.jri.2020.103249. Fulltekst i vitenarkiv Vis sammendrag

  Preeclampsia is a leading cause of maternal and offspring mortality and morbidity, and predicts increased future cardiovascular disease risk. Placental dysfunction and immune system dysregulation are likely key pathophysiological factors. Soluble human leukocyte antigen G (sHLA-G) may dampen the specific immune response towards placental trophoblasts. Previous studies have shown low sHLA-G levels in preeclampsia, but postpartum, levels are unknown. Furthermore, the relationship between sHLA-G and sFlt-1 and PlGF, placental function markers, is unknown. We hypothesized that low maternal sHLA-G during pregnancy would be associated with placental dysfunction, including preeclampsia, gestational hypertension, and dysregulated sFlt-1 and PlGF, and that sHLA-G would remain decreased following preeclampsia. We included 316 pregnant women: 58 with early-onset preeclampsia (<34 weeks’ gestation), 81 with late-onset preeclampsia (≥34 weeks’ gestation), 25 with gestational hypertension, and 152 normotensive controls. Postpartum (1 or 3 years), we included 321 women: 29 with early-onset preeclampsia, 98 with late-onset preeclampsia, 57 with gestational hypertension, and 137 who were normotensive during their index pregnancies. In pregnancy, plasma sHLA-G was significantly lower both in the early- and late-onset preeclampsia groups compared to controls. In women with preeclampsia or gestational hypertension, sHLA-G was inversely correlated with serum sFlt-1. Postpartum, plasma sHLA-G levels were significantly higher in women who had had early-onset preeclampsia compared to controls. Our results support that sHLA-G may be important for placental function. Unexpectedly, sHLA-G was elevated up to 3 years after early-onset preeclampsia, suggesting an excessively activated immune system following this severe preeclampsia form, potentially contributing to future cardiovascular disease risk.

• Lekva, Tove; Sugulle, Meryam; Moe, Kjartan; Redman, Christopher W.G.; Dechend, Ralf & Staff, Anne Cathrine (2020). Multiplex Analysis of Circulating Maternal Cardiovascular Biomarkers Comparing Preeclampsia Subtypes. Hypertension. ISSN 0194-911X. 75(6), s. 1513–1522. doi: 10.1161/HYPERTENSIONAHA.119.14580. Fulltekst i vitenarkiv Vis sammendrag

  Preeclampsia, a hypertensive pregnancy disorder, links to increased long-term maternal cardiovascular disease (CVD). The risk is further increased with early-onset preeclampsia (EPE) and delivery of a growth-restricted child. We hypothesized that circulating biomarkers associated with CVD risk differed between preeclampsia subtypes and controls. We compared EPE; n=37, delivery &lt;week 34, late-onset preeclampsia (LPE); n=29, delivery ≥week 34, and normotensive controls (n=49) using Olink Proseek multiplex CVD I assay (targeting 92 biomarkers). We stratified analysis to uteroplacental spiral artery acute atherosis presence in preeclampsia patients, sharing morphological similarities with atherosclerosis. We found 47 CVD-related biomarkers differing between the groups, 42 markers between normotensive controls and EPE, 28 markers between normotensive controls and LPE, and 9 markers between EPE and LPE. Among these 9 markers, ST2 (ST2 protein), MMP (matrix metalloproteinase) 1, MMP3, and fractalkine (CX3CL1) were uniquely dysregulated in EPE. Principal component (PC) analysis of the differing markers identified 4 clusters (named PC1–PC4) that largely separated the preeclampsia and control groups as well as pregnancies with low and high circulating PlGF (placental growth factor). The combination of the single markers PlGF, ST2, MMP1, MMP3, and CX3CL1 had a high discriminatory property to differentiate between EPE and LPE. Preeclampsia with acute atherosis or with fetal growth restriction could be differentiated by Olink biomarkers as compared with preeclampsia without these features. We identified specific CVD-related biomarkers in pregnancy depending on preeclampsia subtypes and uteroplacental acute atherosis. Assessment of these pregnancy measured biomarkers’ relation to long-term cardiovascular dysfunction and hard end points is warranted.

• Mitlid-Mork, Birgitte; Bowe, Sophie; Gran, Jon Michael; Bolstad, Nils; Berg, Jens Petter & Redman, Christopher W.G. [Vis alle 8 forfattere av denne artikkelen] (2020). Maternal placental growth factor and soluble fms-like tyrosine kinase-1 reference ranges in post-term pregnancies: A prospective observational study. PLOS ONE. 15:e0240473(10), s. 1–14. doi: 10.1371/journal.pone.0240473. Fulltekst i vitenarkiv Vis sammendrag

  Background Post-term pregnancies have increased risks for adverse fetal and maternal outcomes. Maternal concentrations of the placenta-associated proteins placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have been identified as predictors for preeclampsia and fetal growth restriction, both syndromes of placental dysfunction. We have proposed that low maternal circulating PlGF and increased sFlt-1 are general markers for syncytiotrophoblast stress, which increases at and beyond term, even in apparently uncomplicated pregnancies. Our aim was to establish circulating PlGF, sFlt-1, and sFlt-1/PlGF reference ranges in healthy post-term pregnancies (gestational week ≥40+2), comparing with healthy term pregnancies and evaluating associations between time to delivery and biomarker percentiles. Methods Of 501 healthy, singleton post-term pregnancies prospectively recruited between September 2016 and December 2017 at our tertiary obstetric department, 426 with an uncomplicated delivery outcome contributed PlGF and sFlt-1 serum concentrations for reference range construction. A retrospective, cross-sectional, term group with an uncomplicated delivery outcome (n = 146) served as comparison. Differences in percentile values between groups and confidence intervals were calculated by quantile regression. Results In post-term pregnancies the 5th, 50th, and 95th percentiles for PlGF were: 70, 172, and 496 pg/mL; for sFlt-1: 2074, 4268, and 9141 pg/mL; and for sFlt-1/PlGF 5.3, 25.5, and 85.2. Quantile regression analyses comparing the post-term to the term group showed for PlGF a trend towards higher 10th through 30th percentiles, for sFlt-1 significantly higher 10th through 80th percentiles, and for sFlt-1/PlGF ratio significantly higher 30th percentile and significantly lower 95th percentile. PlGF below the 5th percentile and sFlt-1/PlGF ratio above the 95th percentile was associated with shorter time to delivery (p = 0.031 and p = 0.025, respectively). Conclusions Our findings support the concept of increasing syncytiotrophoblast stress post-term in clinically healthy pregnancies. Whether post-term dysregulated angiogenic markers reflect a biological placental clock merits further investigation.

• Staff, Anne Cathrine; Fjeldstad, Heidi Elisabeth; Fosheim, Ingrid Knutsdotter; Moe, Kjartan; Turowski, Gitta Erika & Johnsen, Guro Mørk [Vis alle 8 forfattere av denne artikkelen] (2020). Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. American Journal of Obstetrics and Gynecology. ISSN 0002-9378. s. 1–12. doi: 10.1016/j.ajog.2020.09.026. Fulltekst i vitenarkiv
• Thorsteinsdottir, Hjørdis; Salvador, Cathrin Lytomt; Mjøen, Geir; Lie, Anine; Sugulle, Meryam & Tøndel, Camilla [Vis alle 9 forfattere av denne artikkelen] (2020). Growth Differentiation Factor 15 in Children with Chronic Kidney Disease and after Renal Transplantation. Disease Markers. ISSN 0278-0240. 2020:6162892, s. 1–8. doi: 10.1155/2020/6162892. Fulltekst i vitenarkiv Vis sammendrag

  Growth differentiation factor 15 (GDF-15) is strongly associated with cardiovascular disease (CVD). The aim of our study was to evaluate plasma and urinary levels of GDF-15 after pediatric renal transplantation (Rtx) and in children with chronic kidney disease (CKD) and its associations to cardiovascular risk factors. In this cross-sectional study, GDF-15 was measured in plasma and urine from 53 children with a renal transplant and 83 children with CKD and related to cardiovascular risk factors (hypertension, obesity, and cholesterol) and kidney function. Forty healthy children served as a control group. Plasma levels of GDF-15 (median and range) for a Tx (transplantation) cohort, CKD cohort, and healthy controls were, respectively, 865 ng/L (463-3039 ng/L), 508 ng/L (183-3279 ng/L), and 390 ng/L (306-657 ng/L). The CKD and Tx cohorts both had significantly higher GDF-15 levels than the control group (p < 0:001). Univariate associations between GDF-15 and hyperuricemia (p < 0:001), elevated triglycerides (p = 0:028), low HDL (p = 0:038), and obesity (p = 0:028) were found. However, mGFR (p < 0:001) and hemoglobin (p < 0:001) were the only significant predictors of GDF-15 in an adjusted analysis. Urinary GDF15/creatinine ratios were 448 ng/mmol (74–5013 ng/mmol) and 540 ng/mmol (5–14960 ng/mmol) in the Tx cohort and CKD cohort, respectively. In the CKD cohort, it was weakly correlated to mGFR (r = −0:343, p = 0:002). Plasma levels of GDF-15 are elevated in children with CKD and after Rtx. The levels were not associated with traditional cardiovascular risk factors but strongly associated with renal function.

• Moe, Kjartan; Sugulle, Meryam; Dechend, Ralf & Staff, Anne Cathrine (2019). Risk prediction of maternal cardiovascular disease one year after hypertensive pregnancy complications or gestational diabetes mellitus. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. s. 1–11. doi: 10.1177/2047487319879791. Fulltekst i vitenarkiv
• Moe, Kjartan; Alnæs-Katjavivi, Patji; Størvold, Gro Leite; Sugulle, Meryam; Johnsen, Guro Mørk & Redman, Christopher W.G. [Vis alle 8 forfattere av denne artikkelen] (2018). Classical cardiovascular risk markers in pregnancy and associations to uteroplacental acute atherosis. Hypertension. ISSN 0194-911X. 72(3), s. 695–702. doi: 10.1161/HYPERTENSIONAHA.118.10964. Fulltekst i vitenarkiv Vis sammendrag

  Uteroplacental acute atherosis (AA) is a pregnancy-specific arterial lesion resembling early stages of atherosclerosis. AA is frequent in preeclamptic pregnancies, which associate with increased long-term maternal risk of atherosclerotic cardiovascular disease. We hypothesized that AA in pregnant women associates with classical risk factors for cardiovascular disease, including hypertension, hyperlipidemia, glucose intolerance, elevated C-reactive protein, age, and body mass index. We included 237 women delivered by cesarean section (healthy pregnancies, n=94; preeclampsia, n=87; pregestational and gestational diabetes mellitus, n=39; diabetes mellitus with preeclampsia, n=17). They provided blood before delivery for biomarker analyses. AA was diagnosed by immunohistochemistry in uteroplacental (decidual) tissue collected after placental removal. Statistical analyses were performed with Mann-Whitney test. Levels of traditional cardiovascular markers were not associated with decidual AA within the groups of women with normotensive pregnancies, preeclampsia, diabetes mellitus, or diabetes mellitus superimposed with preeclampsia. However, the oldest patient age quartile (36–43 years old) with AA had significantly higher levels of LDL (low-density lipoprotein) and apolipoprotein B (both P<0.01) than women of the same age without AA. AA was associated with elevated median prepregnancy/early pregnancy systolic blood pressure (P=0.01) in the total cohort, but as preeclampsia was strongly associated with this finding (P<0.01), this was likely caused by a large proportion of preeclamptic pregnancies in the AA group (62.7%). Our findings demonstrate that dyslipidemia associated with cardiovascular risk is a feature of uteroplacental AA in older women, not of AA in pregnancy in general.

• Rieber-Mohn, Amalie; Sugulle, Meryam; Wallukat, Gerd; Alnæs-Katjavivi, Patji; Størvold, Gro Leite & Bolstad, Nils [Vis alle 9 forfattere av denne artikkelen] (2018). Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum. Journal of Reproductive Immunology. ISSN 0165-0378. 128, s. 23–29. doi: 10.1016/j.jri.2018.05.008. Fulltekst i vitenarkiv Vis sammendrag

  Background Uteroplacental acute atherosis is a pregnancy-specific lesion resembling early stages of atherosclerosis found frequently in preeclampsia. Preeclampsia is associated with an increased risk for future maternal atherosclerotic cardiovascular disease. The renin-angiotensin-system plays a role both in atherosclerosis and in preeclampsia. Circulating agonistic autoantibodies at the angiotensin-II type 1 receptor (AT1-AA) are increased in preeclampsia. We hypothesized an association between AT1-AA at delivery and postpartum with acute atherosis in pregnancy. Material and Methods Maternal serum and decidua basalis tissue was collected at elective cesarean section (n = 41; 24 preeclampsia, 17 normotensive controls). Circulating AT1-AA were detected by a bioassay using spontaneously beating rat cardiomyocytes at delivery (n = 41) and 5–8 years postpartum in a subgroup (n = 10). Decidual acute atherosis was assessed by immunohistochemistry. Results Significantly less normotensive controls (18%; 3/17) than women with preeclampsia (58%; 14/24) were AT1-AA positive at delivery, p<0.01. Uteroplacental acute atherosis and circulating AT1-AA at delivery were not significantly correlated. Postpartum, 2 prior preeclamptic women had circulating AT1-AA, both without acute atherosis in pregnancy. Conclusions Our results confirm that circulating AT1-AA are present significantly more often in preeclampsia than in normotensive pregnancy, however without association to acute atherosis. Whether circulating maternal AT1-AA or acute atherosis target young women at increased long-term cardiovascular risk warrants further investigations.

• Sugulle, Meryam; Heidecke, Harald; Maschke, Ulrike; Herse, Florian; Danser, A.H. Jan & Mueller, Dominik [Vis alle 8 forfattere av denne artikkelen] (2017). Soluble (pro)renin receptor in preeclampsia and diabetic pregnancies. Journal of the American Society of Hypertension : JASH. ISSN 1933-1711. 11(10), s. 644–652. doi: 10.1016/j.jash.2017.08.001. Fulltekst i vitenarkiv
• Weedon-Fekjær, Mina Susanne; Sheng, Ying; Sugulle, Meryam; Johnsen, Guro Mørk; Herse, F & Redman, Christopher W.G. [Vis alle 9 forfattere av denne artikkelen] (2014). Placental miR-1301 is dysregulated in early-onset preeclampsia and inversely correlated with maternal circulating leptin. Placenta. ISSN 0143-4004. 35(9), s. 709–717. doi: 10.1016/j.placenta.2014.07.002. Fulltekst i vitenarkiv
• Goldman-Wohl, D.; Cesla, T.; Smith, Y; Greenfield, C.; Dechend, R. & Staff, Anne Cathrine [Vis alle 11 forfattere av denne artikkelen] (2013). Expression profiling of autophagy associated genes in placentas of preeclampsia. Placenta. ISSN 0143-4004. 34(10), s. 959–962. doi: 10.1016/j.placenta.2013.07.069. Fulltekst i vitenarkiv
• Herse, Florian; LaMarca, Babbette; Hubel, Carl A; Kaartokallio, Tea; Lokki, A Inkeri & Ekholm, Eeva [Vis alle 24 forfattere av denne artikkelen] (2012). Cytochrome P450 Subfamily 2J Polypeptide 2 Expression and Circulating Epoxyeicosatrienoic Metabolites in Preeclampsia. Circulation. ISSN 0009-7322. 126(25), s. 2990–2999. doi: 10.1161/CIRCULATIONAHA.112.127340. Fulltekst i vitenarkiv
• Sugulle, Meryam; Herse, Florian; Hering, Lydia; Möckel, Martin; Dechend, Ralf & Staff, Anne Cathrine (2012). Cardiovascular Biomarker Midregional Proatrial Natriuretic Peptide During and After Preeclamptic Pregnancies. Hypertension. ISSN 0194-911X. 59(2), s. 395–401. doi: 10.1161/HYPERTENSIONAHA.111.185264. Fulltekst i vitenarkiv
• Weedon-Fekjær, Mina Susanne; Johnsen, Guro Mørk; Anthonisen, Elin Holter; Sugulle, Meryam; Nebb, Hilde Irene & Duttaroy, Asim K. [Vis alle 7 forfattere av denne artikkelen] (2010). Expression of Liver X Receptors in Pregnancies Complicated by Preeclampsia. Placenta. ISSN 0143-4004. 31(9), s. 818–824. doi: 10.1016/j.placenta.2010.06.015. Fulltekst i vitenarkiv Vis sammendrag

  Preeclampsia is a pregnancy-specific disorder associated with hyperlipidemia. Liver X receptor (LXR) alpha and LXRbeta are key regulators of lipid homeostasis. In the current study, we investigated expression of LXRalpha, LXRbeta and their target genes in human term placenta, decidua and subcutaneous adipose tissue from pregnancies complicated by preeclampsia. Furthermore, we analyzed the protein levels of LXRalpha and LXRbeta in placenta. We also analyzed lipid concentrations in term placental tissue. Gene expression of LXRalpha, LXRbeta and fatty acid transporter CD36 was significantly decreased in placental tissues, while increased expression was observed for LXRalpha in adipose tissue, from pregnancies complicated by preeclampsia. The placental protein level of LXRbeta was reduced, and there was a positive correlation between placental LXRbeta mRNA expression and placental free fatty acids in preeclampsia. Our results suggest a possible role for LXRbeta as a transcriptional regulator in preeclampsia.

• Sugulle, Meryam; Dechend, R; Herse, F; Weedon, Mina Susanne; Johnsen, Guro Mørk & Broshnihan, KB [Vis alle 9 forfattere av denne artikkelen] (2009). Circulating and Placental Growth-Differentiation Factor 15 in Preeclampsia and in Pregnancy Complicated by Diabetes Mellitus. Hypertension. ISSN 0194-911X. 54(1), s. 106–112. doi: 10.1161/HYPERTENSIONAHA.109.130583. Fulltekst i vitenarkiv

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• Waldum, Åsa; Pay, Aase Serine Devold; Aasbø, Gunvor; Mishra, Vinod Kumar; Sugulle, Meryam & Staff, Anne Cathrine (2025). The HOME (home monitoring of high-risk pregnancies) study: a study protocol for an observational study of a telemedicine-assisted follow-up at home vs. hospitalization. doi: 10.3389/fgwh.2025.1599153. Fulltekst i vitenarkiv
• Staff, Annetine; Fjeldstad, Heidi Elisabeth Storebø; Jacobsen, Daniel Pitz & Sugulle, Meryam (2024). Placental dysfunction, fetal microchimerism, and long-term maternal cardiovascular risk. Fulltekst i vitenarkiv
• Sugulle, Meryam (2024). Preeclampsia, the placenta, ethnicity, and social determinants of health. Acta Obstetricia et Gynecologica Scandinavica. ISSN 0001-6349. 103(9), s. 1686–1688. doi: 10.1111/aogs.14939. Fulltekst i vitenarkiv
• Palmrich, P.; Haase, N.; Sugulle, Meryam; Kalafat, E.; Haberl, C. & Schirwani-Hartl, N. [Vis alle 8 forfattere av denne artikkelen] (2024). Abstracts of the 34th World Congress on Ultrasound in Obstetrics and Gynecology, 15-18 September 2024, Budapest, Hungary. Ultrasound in Obstetrics and Gynecology. ISSN 0960-7692. 64, s. 44–44. doi: 10.1002/uog.27837. Fulltekst i vitenarkiv
• Fiskå, Bendik Seth; Pay, Aase Serine Devold; Staff, Anne Cathrine & Sugulle, Meryam (2023). Correction: Gestational diabetes mellitus, follow-up of future maternal risk of cardiovascular disease and the use of eHealth technologies – a scoping review (Systematic Reviews, (2023), 12, 1, (178), 10.1186/s13643-023-02343-w). Systematic Reviews. 12(1). doi: 10.1186/s13643-023-02383-2. Fulltekst i vitenarkiv
• Ziesler, Charlotte P.Ø.; Staff, Anne Cathrine; Sugulle, Meryam & Moe, Kjartan (2023). Corrigendum to “Low physical activity levels 1 year after pregnancy complications” [Pregnancy Hyperten. 25 (2021) 136–142, (S221077892100060X), (10.1016/j.preghy.2021.05.022)]. Pregnancy Hypertension. ISSN 2210-7789. 33, s. 30–31. doi: 10.1016/j.preghy.2023.06.003. Fulltekst i vitenarkiv
• Yakub, Sheraz; Bjørk, Ida; Sugulle, Meryam & Folseraas, Trine (2023). Biopsy helpful in diagnosing a liver mass in pregnancy: focal nodular hyperplasia. The Lancet. ISSN 0140-6736. doi: 10.1016/S0140-6736(23)01606-9. Fulltekst i vitenarkiv
• Palmrich, Pilar; Haase, Nadine; Sugulle, Meryam; Kalafat, Erkan; Khalil, Asma & Binder, Julia (2023). Maternal haemodynamics in Hypertensive Disorders of Pregnancy under antihypertensive therapy (HyperDiP): study protocol for a prospective observational case-control study. BMJ Open. 13(6), s. e065444–e065444. doi: 10.1136/bmjopen-2022-065444. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Hypertensive disorders of pregnancy (HDP) are associated with a high incidence of maternal and perinatal morbidity and mortality. HDP, in particular pre-eclampsia, have been determined as risk factors for future cardiovascular disease. Recently, the common hypothesis of pre-eclampsia being a placental disorder was challenged as numerous studies show evidence for short-term and long-term cardiovascular changes in pregnancies affected by HDP, suggesting a cardiovascular origin of the disease. Despite new insights into the pathophysiology of HDP, concepts of therapy remain unchanged and evidence for improved maternal and neonatal outcome by using antihypertensive agents is lacking. Methods and analysis A prospective observational case–control study, including 100 women with HDP and 100 healthy controls, which will assess maternal haemodynamics using the USCOM 1A Monitor and Arteriograph along with cardiovascular markers (soluble fms-like kinase 1/placental-like growth factor, N-terminal pro-B type natriuretic peptide) in women with HDP under antihypertensive therapy, including a follow-up at 3 months and 1 year post partum, will be conducted over a 50-month period in Vienna. A prospective, longitudinal study of cardiovascular surrogate markers conducted in Oslo will serve as a comparative cohort for the Vienna cohort of haemodynamic parameters in pregnancy including a longer follow-up period of up to 3 years post partum. Each site will provide a dataset of a patient group and a control group and will be assessed for the outcome categories USCOM 1A measurements, Arteriograph measurements and Angiogenic marker measurements. To estimate the effect of antihypertensive therapy on outcome parameters, ORs with 95% CIs will be computed. Longitudinal changes of outcome parameters will be compared between normotensive and hypertensive pregnancies using mixed-effects models. Ethics and dissemination Ethical approval has been granted to all participating centres. Results will be published in international peer-reviewed journals and will be presented at national and international conferences.

• Fjeldstad, Heidi Elisabeth Storebø; Johnsen, Guro Mørk; Sugulle, Meryam & Staff, Annetine (2022). Føtale celler i mors sirkulasjon ved normotensive svangerskap til termin: korrelasjon med biomarkører for placentadysfunksjon. Fulltekst i vitenarkiv
• Fjeldstad, Heidi Elisabeth Storebø; Jacobsen, Daniel Pitz; Johnsen, Guro Mørk; Sugulle, Meryam & Staff, Annetine (2022). Fetal microchimerism and dysregulation of PlGF in pregnancy. Fulltekst i vitenarkiv
• Fosheim, Ingrid; Johnsen, Guro Mørk; Alnæs-Katjavivi, Patji Haakon; Turowski, Gitta Erika; Sugulle, Meryam & Staff, Anne Cathrine (2021). Corrigendum to "Decidua basalis and acute atherosis: Expression of atherosclerotic foam cell associated proteins" [Placenta 107 (2021) 1-7]. Placenta. ISSN 0143-4004. doi: 10.1016/j.placenta.2021.10.014. Fulltekst i vitenarkiv
• Weedon-Fekjær, Mina Susanne; Sheng, Ying; Herse, Florian; Lyle, Robert; Sugulle, Meryam & Dechend, Ralf [Vis alle 7 forfattere av denne artikkelen] (2012). DIFFERENTIAL EXPRESSION OF MIRNAS IN PLACENTA FROM EARLY AND LATE ONSET PREECLAMPSIA VERSES CONTROLS. Placenta. ISSN 0143-4004. 33(9), s. A78–A78. Fulltekst i vitenarkiv
• Sugulle, Meryam; Herse, Florian; Kvehaugen, Anne Stine; Mueller, Dominik; Dechend, Ralf & Staff, Anne Cathrine (2011). Atrial Natriuretic Peptide Reflects The Cardiovascular Alterations in Preeclampsia. Hypertension. ISSN 0194-911X. 58(5), s. E172–E173. Fulltekst i vitenarkiv
• Johnsen, GM; Weedon-Fekjaer, MS; Sugulle, Meryam; Kliman, HJ & Staff, Anne Cathrine (2010). ADRP IS ASSOCIATED WITH FOAM CELLS AND ACUTE ATHEROSIS IN DECIDUAL TISSUE. Placenta. ISSN 0143-4004. 31(9), s. A124–A124. Fulltekst i vitenarkiv
• Herse, F; Hering, L; Verlohren, S; Sugulle, Meryam; Luft, F & Müller, Daniel [Vis alle 8 forfattere av denne artikkelen] (2008). Adipocytes Produce their Own Endogenous Inhibitor for Angiogenesis (Sflt): Implications for Preeclampsia and Fat Cell Proliferation. Hypertension in Pregnancy. ISSN 1064-1955. 27(4), s. 461–461. Fulltekst i vitenarkiv
• Weedon-Fekjaer, MS; Johnsen, Guro Mørk; Sugulle, Meryam; Duttaroy, Asim K.; Nebb, Hilde Irene & Staff, Anne Cathrine (2008). Regulation of liver X receptor and target genes in primary trophoblasts, placenta, dfcidua and fat tissue. Placenta. ISSN 0143-4004. 29, s. A44–A44. Fulltekst i vitenarkiv
• Klepp, Kristina; Staff, Annetine; Moe, Kjartan & Sugulle, Meryam (2026). Cardiometabolic indices following pregnancy complications: Impact of sex-independent and pregnancy-specific risk factors. Universitetet i Oslo. ISSN 9788234808722. Fulltekst i vitenarkiv Vis sammendrag

  Hypertensive disorders of pregnancy are associated with adverse cardiovascular changes and increased risk of future maternal cardiovascular disease. Pregnancy may be considered a cardiovascular stress test, as it puts extra strain on the heart and blood vessels. A cardiovascular follow-up is therefore recommended after such hypertensive pregnancy complications. However, optimal screening strategies for personalized cardiovascular disease risk evaluation and prevention remain unclear. This thesis aimed to explore both pregnancy-specific and sex-independent cardiovascular risk factors and their associations with a broad range of clinical, biochemical and imaging cardiovascular biomarkers. To this end, 319 women from the clinical Health after Pregnancy Complications (HAPPY) study were examined 1-3 years after a normotensive or a hypertensive pregnancy. We found that women with a recent history of a hypertensive pregnancy disorder had more unfavorable cardiometabolic profiles than women with prior normotensive pregnancy. Our findings support previous reports of adverse cardiovascular risk profiles after such hypertensive pregnancy complications, also after adjustment for other known sex-independent risk factors. This thesis supports the need for intensified and personalized cardiovascular follow-up already from the first years after hypertensive disorders of pregnancy. Cardiovascular follow-up should include assessments of classical, modifiable risk factors (e.g., hypertension, overweight, hyperglycemia and dyslipidemia) to enable early personalized prevention of cardiovascular disease in women.

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