Browsing by Subject "preeclampsia"

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  • Karppanen, Tiina; Kaartokallio, Tea; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Staff, Anne Cathrine; Laivuori, Hannele; Klemetti, Miira M. (Helsingfors universitet, 2016)
    Background Preeclampsia is a common and heterogeneous vascular syndrome of pregnancy. Its genetic risk profile is yet unknown and may vary between individuals and populations. The rs4606 3' UTR polymorphism of the Regulator of G-protein signaling 2 gene (RGS2) in the mother has been implicated in preeclampsia as well as in the development of chronic hypertension after preeclampsia. The RGS2 protein acts as an inhibitor of physiological vasoconstrictive pathways, and a low RGS2 level is associated with hypertension and obesity, two conditions that predispose to preeclampsia. We genotyped the rs4606 polymorphism in 1339 preeclamptic patients and in 697 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort to study the association of the variant with preeclampsia. Results No association between rs4606 and preeclampsia was detected in the analysis including all women. However, the polymorphism was associated with preeclampsia in a subgroup of overweight women (body mass index ≥ 25 kg/m2, and < 30 kg/m2) (dominant model; odds ratio, 1.64; 95% confidence interval, 1.10-2.42). Conclusions Our results suggest that RGS2 might be involved in the pathogenesis of preeclampsia particularly in overweight women and contribute to their increased risk for hypertension and other types of cardiovascular disease later in life.
  • Lokki, A. Inkeri; Kaartokallio, Tea; Holmberg, Ville; Onkamo, Paivi; Koskinen, Lotta L. E.; Saavalainen, Paivi; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Villa, Pia M.; Hiltunen, Leena; Laivuori, Hannele; Meri, Seppo (2017)
    Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.
  • Lokki, A. Inkeri; Haapio, Mikko; Heikkinen-Eloranta, Jenni (2020)
    Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women.
  • Rahnasto, Johanna (Helsingin yliopisto, 2019)
    Preeclampsia is a vascular pregnancy disorder characterized by new-onset hypertension and proteinuria and/or new-onset preeclampsia associated symptoms during the second half of pregnancy. The pathophysiology of the disorder is not fully understood, but incomplete placentation and maternal tolerance towards fetal tissue are known to play a part in the disease pathogenesis. Predisposing factors include nulliparity, obesity, diabetes, chronic hypertension and autoimmune diseases. Furthermore, women who have experienced preeclampsia are more susceptible to cardiovascular disease later in life. One established biomarker for preeclampsia is the increased concentration of the soluble Fms-like tyrosine kinase 1 (sFlt1) in the maternal serum. sFlt1 is frequently overexpressed in preeclampsia and it is linked with angiogenic imbalance and endothelial dysfunction, although its role in the disorder is not completely clear. Preeclampsia has a genetic background. There are protective and predisposing variants in and near the Fms related tyrosine kinase 1 gene (FLT1; coding for sFlt1) that have been associated with preeclampsia either in the mother or in the fetus. In this study, five genetic polymorphisms over a 2.3 kb region in the 3’ untranslated region of FLT1 were genotyped by Sanger sequencing and fragment analysis in altogether 1200 individuals consisting of case and control mother–child pairs of the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort. These polymorphisms were tested for association with various preeclampsia-related phenotypes by Fisher’s exact test. In the maternal genome, the minor alleles of rs17086497 and rs57760154 were associated with extreme hypertension (systolic blood pressure >180 mmHg) (p=0.004, OR=1.77) and obesity (p=0.023, OR=1.63). Homozygosity for these minor alleles was associated with pregnancy complications in general (p=0.026, OR=2.53) and the early-onset form of preeclampsia (p=0.004, OR=3.34). Additionally, the minor alleles of rs9554314, rs3138582 and rs149279513 were associated with extreme hypertension (p=0.045, OR=1.63) and obesity (p=0.023, OR=1.78). Moreover, a suggestive association to severe proteinuria (> 5 g/24h) was found in the maternal genome. In the fetal genome, significant negative associations were reached for rs17086497 and rs57760154 in terms of the serum concentration of sFlt1 in the preeclampsia group (p=0.008, OR=0.23). Overall, the results seem to link the studied region in the maternal genome to preeclampsia with severe features. This supports the idea of preeclampsia as a heterogeneous disorder with varying etiology and mechanisms and thus highlights the importance of differentiating between the various sub-phenotypes. For example, the association of the same allele in the fetal genome with lower maternal sFlt1 levels and in the maternal genome with severe symptoms of preeclampsia suggests that the sFlt1 level might not be a good measure in all patients. Additionally, the observed associations with extreme hypertension and obesity point to the possibility that this region might be relevant for the endothelial damage that is thought to be a central factor in creating the later-in-life disease susceptibility.
  • Kajantie, Eero; Osmond, Clive; Eriksson, Johan G. (2017)
    BACKGROUND: Women with hypertensive disorders in pregnancy are at an increased risk of cardiovascular disease and type 2 diabetes later in life. Offspring born from these hypertensive pregnancies have increased levels of cardiovascular risk factors; whether they are at an increased risk of type 2 diabetes is not known. OBJECTIVE: The objective of the investigation was to study the risk of type 2 diabetes in the adult offspring exposed to maternal preeclampsia or gestational hypertension in utero. STUDY DESIGN: We studied 5335 members of the Helsinki Birth Cohort Study, who were born between 1934 and 1944 and who lived in Finland in 1995 when the National Medication Purchase Register was initiated. We ascertained gestational hypertension and preeclampsia according to modern criteria by using maternal and birth records. We defined type 2 diabetes through purchases of antidiabetic medication recorded in the comprehensive National Medication Purchase Register, excluding the 31 subjects who had purchased only insulin. We used Cox regression to assess hazard ratios for type 2 diabetes. RESULTS: A total of 590 men (21.6%) and 433 women (16.9%) had purchased medication for diabetes. The hazard ratio for type 2 diabetes for offspring exposed to any maternal hypertension in pregnancy was 1.13 (95% confidence interval, 1.00-1.29; n = 1780). For maternal gestational hypertension, it was 1.15 (95% confidence interval, 1.00-1.33; n = 1336) and for preeclampsia 0.98 (95% confidence interval, 0.71-1.34; n = 231). For type 2 diabetes with first medication purchase before 62 years, the corresponding hazard ratios were 1.25 (95% confidence interval, 1.04-1.51); 1.28 (95% confidence interval, 1.05-1.58), and 1.18 (95% confidence interval, 0.75-1.84). The hazard ratios were similar when adjusted for birthweight SD score for gestation, length of gestation, maternal body mass index in late pregnancy, height, age, and parity and for childhood or adult socioeconomic position. An increased risk of type 2 diabetes was also associated with low birthweight SD score, independent of the association with gestational hypertension. CONCLUSION: Offspring exposed to maternal gestational hypertension in utero have an increased risk of type 2 diabetes in late adult life. This finding underlines the role of the whole spectrum of hypertensive disorders of pregnancy as risk factors of offspring disease throughout life. It also reinforces previous suggestions that adult health care providers should incorporate birth histories when evaluating an individual's risk to develop type 2 diabetes.
  • Kazmi, Nabila; Sharp, Gemma C.; Reese, Sarah E.; Vehmeijer, Florianne O.; Lahti, Jari; Page, Christian M.; Zhang, Weiming; Rifas-Shiman, Sheryl L.; Rezwan, Faisal I.; Simpkin, Andrew J.; Burrows, Kimberley; Richardson, Tom G.; Ferreira, Diana L. Santos; Fraser, Abigail; Harmon, Quaker E.; Zhao, Shanshan; Jaddoe, Vincent W. V.; Czamara, Darina; Binder, Elisabeth B.; Magnus, Maria C.; Haberg, Siri E.; Nystad, Wenche; Nohr, Ellen A.; Starling, Anne P.; Kechris, Katerina J.; Yang, Ivana V.; DeMeo, Dawn L.; Litonjua, Augusto A.; Baccarelli, Andrea; Oken, Emily; Holloway, John W.; Karmaus, Wilfried; Arshad, Syed H.; Dabelea, Dana; Sorensen, Thorkild I. A.; Laivuori, Hannele; Räikkönen, Katri; Felix, Janine F.; London, Stephanie J.; Hivert, Marie-France; Gaunt, Tom R.; Lawlor, Debbie A.; Relton, Caroline L. (2019)
    Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R-2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.
  • Kalapotharakos, Grigorios; Murtoniemi, Katja; Åkerström, Bo; Hämäläinen, Esa; Kajantie, Eero; Räikkönen, Katri; Villa, Pia; Laivuori, Hannele; Hansson, Stefan R. (2019)
    Women with established preeclampsia (PE) have increased plasma concentration of free fetal hemoglobin. We measured two hemoglobin scavenger system proteins, hemopexin (Hpx) and alpha-1 -microglobulin (A1M) in maternal plasma using enzyme-linked immunosorbent assay during the late second trimester of pregnancy in women with high and low risk of developing PE. In total 142 women were included in nested case-control study: 42 women diagnosed with PE and 100 controls (49 randomly selected high-risk and 51 low-risk controls). The concentration of plasma A1M in high-risk controls was higher compared to low-risk controls. Women with severe PE had higher plasma A1M levels compared to women with non-severe PE. In conclusion, the concentration of plasma A1M is increased in the late second trimester in high-risk controls, suggesting activation of endogenous protective system against oxidative stress.
  • Lokki, A. Inkeri; Heikkinen-Eloranta, Jenni K.; Laivuori, Hannele (2018)
    Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia.
  • Petersen., Sindre H.; Bergh, Christina; Gissler, Mika; Åsvold, Bjørn O.; Romundstad, Liv B.; Tiitinen, Aila; Spangmose, Anne L.; Pinborg, Anja; Wennerholm, Ulla-Britt; Henningsen, Anna-Karina A.; Opdahl, Signe (2020)
    Background The use of assisted reproductive technology (ART) is increasing worldwide and conception after assisted reproduction currently comprises 3-6% of birth cohorts in the Nordic countries. The risk of placenta-mediated pregnancy complications is higher after ART compared to spontaneously conceived pregnancies. Whether the excess risk of placenta-mediated pregnancy complications in pregnancies following assisted reproduction has changed over time, is unknown. Objectives To investigate whether time trends in risk of pregnancy complications (hypertensive disorders in pregnancy, placental abruption and placenta previa) differ for pregnancies after ART compared to spontaneously conceived pregnancies during three decades of assisted reproduction treatment in the Nordic countries. Study Design In a population-based cohort study, with data from national health registries in Denmark (1994-2014), Finland (1990-2014), Norway (1988-2015) and Sweden (1988-2015), we included 6,830,578 pregnancies resulting in delivery. Among these, 146,998 (2.2%) were pregnancies after assisted reproduction (125,708 singleton pregnancies, 20,668 twin pregnancies and 622 of higher order plurality) and 6,683,132 (97.8%) pregnancies were conceived spontaneously (6,595,185 singleton pregnancies, 87,106 twin pregnancies and 1,289 of higher order plurality). We used logistic regression with post-estimation to estimate absolute risks and risk differences for each complication. We repeated analyses for singleton and twin pregnancies, separately. In sub-samples with available information, we also adjusted for maternal body mass index, smoking during pregnancy, previous cesarean section, culture duration and cryopreservation. Results The risk of each placental complication was consistently higher in pregnancies following ART compared to spontaneously conceived pregnancies across the study period, except for hypertensive disorders in twin pregnancies, where risks were similar. Risk of hypertensive disorders increased over time in twin pregnancies for both conception methods, but more strongly for pregnancies following ART (risk difference 1.73 percentage points per 5 years, 95% confidence interval 1.35 to 2.11) than for spontaneously conceived twins (risk difference 0.75 percentage points, 95% confidence interval 0.61 to 0.89). No clear time trends were found for hypertensive disorders in singleton pregnancies. Risk of placental abruption decreased over time in all groups (risk difference -0.16 percentage points, 95% confidence interval -0.19 to -0.12 and -0.06 percentage points, 95% confidence interval -0.06 to -0.05 for pregnancies after assisted reproduction and spontaneously conceived pregnancies, respectively, for singletons and multiple pregnancies combined). Over time, the risk of placenta previa increased in pregnancies after assisted reproduction among both singletons (risk difference 0.21 percentage points, 95% confidence interval 0.14 to 0.27) and twins (risk difference 0.30 percentage points, 95% confidence interval 0.16 to 0.43), but remained stable in spontaneously conceived pregnancies. When adjusting for culture duration, the temporal increase in placenta previa became weaker in all groups of ART pregnancies, whereas adjustment for cryopreservation moderately attenuated trends in ART twin pregnancies. Conclusions The risk of placenta-mediated pregnancy complications following ART remains higher compared to spontaneously conceived pregnancies, despite declining rates of multiple pregnancies. For hypertensive disorders in pregnancy and placental abruption, pregnancies after assisted reproduction follow the same time trends as the background population, whereas for placenta previa, risk has increased over time in pregnancies after ART.