Browsing by Subject "PREGNANCY"

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  • Tammiste, Triin; Kask, Keiu; Padrik, Peeter; Idla, Kulli; Rosenstein, Karin; Jatsenko, Tatjana; Veerus, Piret; Salumets, Andres (2019)
    BackgroundOvarian insufficiency is a major concern for long-term cancer survivors. Although semen freezing is well established to preserve male fertility, the possibilities to secure post-cancer female fertility are mostly limited to oocyte or embryo freezing. These methods require time-consuming ovarian stimulation with or without in vitro fertilization (IVF) that evidently delays cancer therapy. Ovarian tissue cryopreservation and subsequent thawed tissue autotransplantation are considered the most promising alternative strategy for restoring the fertility of oncology patients, which has not yet received the full clinical acceptance. Therefore, all successful cases are needed to prove its reliability and safety.Case presentationHere we report a single case in Estonia, where a 28-year-old woman with malignant breast neoplasm had ovarian cortex cryopreserved before commencing gonadotoxic chemo- and radiotherapy. Two years after cancer therapy, the patient underwent heterotopic ovarian tissue transplantation into the lateral pelvic wall. The folliculogenesis was stimulated in the transplanted tissue by exogenous follicle-stimulating hormone and oocytes were collected under ultrasound guidance for IVF and embryo transfer. The healthy boy was born after full-term gestation in 2014, first in Eastern Europe.ConclusionDespite many countries have reported the first implementation of the ovarian tissue freezing and transplantation protocols, the data is still limited on the effectiveness of heterotopic ovarian transplant techniques. Thus, all case reports of heterotopic ovarian tissue transplantation and long-term follow-ups to describe the children's health are valuable source of clinical experience.
  • Toijonen, Anna E.; Heinonen, Seppo T.; Gissler, Mika V. M.; Macharey, Georg (2020)
    Purpose To determine if the common risks for breech presentation at term labor are also eligible in preterm labor. Methods A Finnish cross-sectional study included 737,788 singleton births (24-42 gestational weeks) during 2004-2014. A multivariable logistic regression analysis was used to calculate the risks of breech presentation. Results The incidence of breech presentation at delivery decreased from 23.5% in pregnancy weeks 24-27 to 2.5% in term pregnancies. In gestational weeks 24-27, preterm premature rupture of membranes was associated with breech presentation. In 28-31 gestational weeks, breech presentation was associated with maternal pre-eclampsia/hypertension, preterm premature rupture of membranes, and fetal birth weight below the tenth percentile. In gestational weeks 32-36, the risks were advanced maternal age, nulliparity, previous cesarean section, preterm premature rupture of membranes, oligohydramnios, birth weight below the tenth percentile, female sex, and congenital anomaly. In term pregnancies, breech presentation was associated with advanced maternal age, nulliparity, maternal hypothyroidism, pre-gestational diabetes, placenta praevia, premature rupture of membranes, oligohydramnios, congenital anomaly, female sex, and birth weight below the tenth percentile. Conclusion Breech presentation in preterm labor is associated with obstetric risk factors compared to cephalic presentation. These risks decrease linearly with the gestational age. In moderate to late preterm delivery, breech presentation is a high-risk state and some obstetric risk factors are yet visible in early preterm delivery. Breech presentation in extremely preterm deliveries has, with the exception of preterm premature rupture of membranes, similar clinical risk profiles as in cephalic presentation.
  • Lindh, Lena; Lindeberg, H.; Banting, A; Banting, S.; Sainmaa, S.; Beasley, S.; Korhonen, H.; Peltoniemi, Olli (2020)
    The interest in non-surgical approaches to contraception and fertility control in female dogs has increased in recent years. In this study the effect of an aromatase inhibitor (finrozole) was evaluated in fur production animals, farmed blue fox vixens, as a model for contraception in bitches. A total of 80 vixens were divided into 4 groups, receiving orally placebo (A) or finrozole 0.5 mg/kg (B), 3.5 mg/kg (C) or 24.5 mg/kg (D) for 21 consecutive days beginning in the pre-ovulatory period of heat. Monitoring of the vixens included clinical signs of heat, measurement of vaginal electrical resistance (VER) as well as oestradiol and progesterone concentrations in plasma. The approximate relation of the start of treatment to ovulation varied from 11 days before to one day after ovulation provided that the LH peak occurred 0.5 e2 days before the VER peak and ovulation was then estimated to occur 2 days after the LH peak. Seventy vixens were artificially inseminated within 8 h after a 50 Udecline in vaginal electrical resistance was detected. Ten vixens were not inseminated. Pregnancy was confirmed by transabdominal ultrasound examination and birth of cubs was recorded. The pregnancy rates in the groups were 89.5% (A), 81.3% (B), 55.6% (C) and 52.9% (D). The average number of live born pups in the four groups was 9.4 (A), 7.0 (B), 5.8 (C), and 3.8 (D), respectively. No deleterious effects (for instance malformations) of finrozole on pups could be verified. The administration of finrozole did not have a significant effect on oestradiol pa- rameters and VER values in vixens. Progesterone values were significantly higher in treatment groups compared with the placebo group. The results indicate that pregnancy could be avoided by finrozole provided that doses of 3.5 mg/kg were used and the treatment was initiated at least four days before the day of artificial insemination. This corresponds with two to six days before ovulation provided that the LH peak occurred 0.5e2 days before the VER peak and that ovulation then occurred in average 2 days after the LH peak.
  • Karppanen, Tiina; Kaartokallio, Tea; Klemetti, Miira M.; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Staff, Anne Cathrine; Laivuori, Hannele (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/m(2), and <30 kg/m(2)) (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.
  • Jääskeläinen, Tiina; Heinonen, Seppo; Hämäläinen, Esa; Pulkki, Kari; Romppanen, Jarkko; Laivuori, Hannele (2018)
    Objectives: To study first and second/third trimester levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) in FINNPEC case-control cohort. The participants were further divided into subgroups based on parity and onset of the disease. Recommended cut-off values in aid of pre-eclampsia (PE) prediction and diagnosis were also tested. Methods: First trimester serum samples were available from 221 women who later developed PE and 239 women who did not develop PE. Second/third trimester serum samples were available from 175 PE and 55 non-PE women. sFl1-1 and PlGF were measured electro-chemiluminescence immunoassays and sEng by ELISA. Results: In all timepoints PlGF, endoglin and the sFlt-1/PlGF ratio were increased in the PE group compared to the non-PE group. The serum concentrations of sFlt-1 were increased only a second/third trimester in PE women. Higher concentrations of s-Flt1, endoglin and higher sFlt/PlGF ratio were found a the third trimester in primiparous women compared to multiparous women. Primiparous PE women also had lower concentrations of PlGF a the third trimester. The proportion of women exceeding all cut-offs of the sFlt-1/PlGF ratio (>= 33, >= 38, >= 85 and >= 110) was greater in the PE group, but there were also pre-eclamptic women who met rule-out cut-off or did no meet rule-in cut-off. Conclusions: Primiparous pregnancies have more anti-angiogenic profile during second/third trimester compared with multiparous pregnancies. Our findings also suggest that certain maternal characteristics, e.g. BMI, smoking and pre-existing diseases, should be taken into account when different sFlt-1/PlGF ratio cut-offs are utilized.
  • Neumann, Alexander; Walton, Esther; Alemany, Silvia; Cecil, Charlotte; Gonzalez, Juan Ramon; Jima, Dereje D.; Lahti, Jari; Tuominen, Samuli T.; Barker, Edward D.; Binder, Elisabeth; Caramaschi, Doretta; Carracedo, Angel; Czamara, Darina; Evandt, Jorunn; Felix, Janine F.; Fuemmeler, Bernard F.; Gutzkow, Kristine B.; Hoyo, Cathrine; Julvez, Jordi; Kajantie, Eero; Laivuori, Hannele; Maguire, Rachel; Maitre, Lea; Murphy, Susan K.; Murcia, Mario; Villa, Pia M.; Sharp, Gemma; Sunyer, Jordi; Räikkönen, Katri; Bakermans-Kranenburg, Marian; van Ijzendoorn, Marinus; Guxens, Monica; Relton, Caroline L.; Tiemeier, Henning (2020)
    Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p <0.05) in either of the EWAS were correlated between timepoints (rho = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p <1 x 10(-7)), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p <1 x 10(-7). In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.
  • Fan, Yuxin; Wang, Leishen; Liu, Huikun; Zhang, Shuang; Tian, Huiguang; Shen, Yun; Tuomilehto, Jaakko; Yu, Zhijie; Yang, Xilin; Hu, Gang; Liu, Ming (2020)
    Introduction To evaluate the single association of postpartum beta-cell dysfunction and insulin resistance (IR), as well as different combinations of postpartum beta-cell dysfunction, IR, obesity, and a history of gestational diabetes mellitus (GDM) with postpartum type 2 diabetes risk. Research design and methods The study included 1263 women with prior GDM and 705 women without GDM. Homeostatic model assessment was used to estimate homeostatic model assessment of beta-cell secretory function (HOMA-%beta) and homeostatic model assessment of insulin resistance (HOMA-IR). Results Multivariable-adjusted ORs of diabetes across quartiles of HOMA-%beta and HOMA-IR were 1.00, 1.46, 2.15, and 6.25 (p(trend) Conclusions beta-cell dysfunction or IR was significantly associated with postpartum diabetes. IR and beta-cell dysfunction, together with obesity and a history of GDM, had the highest ORs of postpartum diabetes risk.
  • Macharey, Georg; Gissler, Mika; Rahkonen, Leena; Ulander, Veli-Matti; Vaisanen-Tommiska, Mervi; Nuutila, Mika; Heinonen, Seppo (2017)
    Purpose The aim of this study was to estimate whether breech presentation at term was associated with known individual obstetric risk factors for adverse fetal outcome. Methods This was a retrospective, nationwide Finnish population-based cohort study. Obstetric risks in all breech and vertex singleton deliveries at term were compared between the years 2005 and 2014. A multivariable logistic regression model was used to determine significant risk factors. Results The breech presentation rate at term for singleton pregnancies was 2.4%. The stillbirth rate in term breech presentation was significantly higher compared to cephalic presentation (0.2 vs 0.1%). The odds ratios (95% CIs) for fetal growth restriction, oligohydramnios, gestational diabetes, a history of cesarean section and congenital fetal abnormalities were 1.19 CI (1.07-1.32), 1.42 CI (1.27-1.57), 1.06 CI (1.00-1.13), 2.13 (1.98-2.29) and 2.01 CI (1.92-2.11). Conclusions The study showed that breech presentation at term on its own was significantly associated with antenatal stillbirth and a number of individual obstetric risk factors for adverse perinatal outcomes. The risk factors included oligohydramnios, fetal growth restriction, gestational diabetes, history of caesarean section and congenital anomalies.
  • Lynch, Robert; Lummaa, Virpi; Briga, Michael; Chapman, Simon; Loehr, John (2020)
    Understanding how conditions experienced during development affect reproductive timing is of considerable cross-disciplinary interest. Life-history theory predicts that organisms will accelerate reproduction when future survival is unsure. In humans, this can be triggered by early exposure to mortality. Previous studies, however, have been inconclusive due to several confounds that are also likely to affect reproduction. Here we take advantage of a natural experiment in which a population is temporarily divided by war to analyze how exposure to mortality affects reproduction. Using records of Finnish women in World War II, we find that young girls serving in a paramilitary organization wait less time to reproduce, have shorter inter-birth intervals, and have more children than their non-serving peers or sisters. These results support the hypothesis that exposure to elevated mortality rates during development can result in accelerated reproductive schedules and adds to our understanding of how participation in warfare affects women.
  • Keikkala, Elina; Mustaniemi, Sanna; Koivunen, Sanna; Kinnunen, Jenni; Viljakainen, Matti; Männistö, Tuija; Ijäs, Hilkka; Pouta, Anneli; Kaaja, Risto; Eriksson, Johan G.; Laivuori, Hannele; Gissler, Mika; Erkinheimo, Tiina-Liisa; Keravuo, Ritva; Huttunen, Merja; Metsälä, Jenni; Stach‑Lempinen, Beata; Klemetti, Miira M.; Tikkanen, Minna; Kajantie, Eero; Vääräsmäki, Marja (2020)
  • Loo, Evelyn Xiu Ling; Zhang, Yuqing; Yap, Qai Ven; Yu, Guoqi; Soh, Shu E.; Loy, See Ling; Lau, Hui Xing; Chan, Shiao-Yng; Shek, Lynette Pei-Chi; Luo, Zhong-Cheng; Yap, Fabian Kok Peng; Tan, Kok Hian; Chong, Yap Seng; Zhang, Jun; Eriksson, Johan Gunnar (2021)
    Background Gestational diabetes mellitus (GDM) has been associated with adverse health outcomes for mothers and offspring. Prevalence of GDM differs by country/region due to ethnicity, lifestyle and diagnostic criteria. We compared GDM rates and risk factors in two Asian cohorts using the 1999 WHO and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Methods The Shanghai Birth Cohort (SBC) and the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort are prospective birth cohorts. Information on sociodemographic characteristics and medical history were collected from interviewer-administered questionnaires. Participants underwent a 2-h 75-g oral glucose tolerance test at 24-28 weeks gestation. Logistic regressions were performed. Results Using the 1999 WHO criteria, the prevalence of GDM was higher in GUSTO (20.8%) compared to SBC (16.6%) (p = 0.046). Family history of hypertension and alcohol consumption were associated with higher odds of GDM in SBC than in GUSTO cohort while obesity was associated with higher odds of GDM in GUSTO. Using the IADPSG criteria, the prevalence of GDM was 14.3% in SBC versus 12.0% in GUSTO. A history of GDM was associated with higher odds of GDM in GUSTO than in SBC, while being overweight, alcohol consumption and family history of diabetes were associated with higher odds of GDM in SBC. Conclusions We observed several differential risk factors of GDM among ethnic Chinese women living in Shanghai and Singapore. These findings might be due to heterogeneity of GDM reflected in diagnostic criteria as well as in unmeasured genetic, lifestyle and environmental factors.
  • Nissinen, Niina-Maria; Gissler, Mika; Sarkola, Taisto; Kahila, Hanna; Autti-Rämö, Ilona; Koponen, Anne M. (2021)
    Introduction: The dual impact of prenatal substance exposure (i.e. alcohol/drugs) and adverse postnatal caregiving environment on offspring secondary education completion is an understudied research area. The aim was to investigate the influence of childhood adversities, out-of home care, and offspring's mental and/or behavioural disorders on secondary education completion among prenatally exposed offspring in comparison to matched unexposed offspring. Methods: This is a longitudinal register-based matched cohort study in Finland including offspring with a history of prenatal substance exposure and a matched unexposed cohort. The study sample included 283 exposed and 820 unexposed offspring aged 18-23 years. Results: The results showed a time lag in secondary education completion and lower educational attainment overall among exposed compared with unexposed (37.8% vs. 51.0%, respectively). The results from the multivariate logistic regression models showed that the differences in the secondary education completion between exposed and unexposed were diminished in the presence of covariates. A cumulative childhood adversity score and out-of-home care were not associated with secondary education completion in the multivariate models, whereas the different domains of offspring's mental and/or behavioural disorders including psychiatric disorders (AOR 0.65, 95% CI 0.45-0.96), neuropsychological disorders (AOR 0.35, 95% CI 0.23-0.54) and dual psychiatric and neuropsychological disorder (AOR 0.29, 95% CI 0.18-0.48) showed an independent negative effect on secondary education completion. Conclusions: Inferior educational outcomes may not be directly linked with prenatal substance exposure but may rather reflect the extent of evolving offspring's mental and/or behavioural disorders over time influenced by childhood adversities.
  • Yeung, Edwina H.; Guan, Weihua; Zeng, Xuehuo; Salas, Lucas A.; Mumford, Sunni L.; de Prado Bert, Paula; van Meel, Evelien R.; Malmberg, Anni; Sunyer, Jordi; Duijts, Liesbeth; Felix, Janine F.; Czamara, Darina; Hämäläinen, Esa; Binder, Elisabeth B.; Räikkönen, Katri; Lahti, Jari; London, Stephanie J.; Silver, Robert M.; Schisterman, Enrique F. (2020)
    Background Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Results Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (<18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p <0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Conclusions Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.
  • Huilaja, Laura; Makikallio, Kaarin; Hannula-Jouppi, Katariina; Vakeva, Liisa; Hook-Nikanne, Johanna; Tasanen, Kaisa (2015)
    Gestational pemphigoid, a rare autoimmune skin disease typically occurring during pregnancy, is caused by autoantibodies against collagen XVII. Clinically it is characterised by severe itching followed by erythematous and bullous lesions of the skin. Topical or oral glucocorticoids usually relieve symptoms, but in more severe cases systemic immunosuppressive treatments are needed. Data on immunosuppressive medication controlling gestational pemphigoid are sparse. We report 3 intractable cases of gestational pemphigoid treated with cyclosporine.
  • Bazelier, Marloes T.; Eriksson, Irene; de Vries, Frank; Schmidt, Marjanka K.; Raitanen, Jani; Haukka, Jari; Starup-Linde, Jakob; De Bruin, Marie L.; Andersen, Morten (2015)
    PurposeTo identify pharmacoepidemiological multi-database studies and to describe data management and data analysis techniques used for combining data. MethodsSystematic literature searches were conducted in PubMed and Embase complemented by a manual literature search. We included pharmacoepidemiological multi-database studies published from 2007 onwards that combined data for a pre-planned common analysis or quantitative synthesis. Information was retrieved about study characteristics, methods used for individual-level analyses and meta-analyses, data management and motivations for performing the study. ResultsWe found 3083 articles by the systematic searches and an additional 176 by the manual search. After full-text screening of 75 articles, 22 were selected for final inclusion. The number of databases used per study ranged from 2 to 17 (median=4.0). Most studies used a cohort design (82%) instead of a case-control design (18%). Logistic regression was most often used for individual-level analyses (41%), followed by Cox regression (23%) and Poisson regression (14%). As meta-analysis method, a majority of the studies combined individual patient data (73%). Six studies performed an aggregate meta-analysis (27%), while a semi-aggregate approach was applied in three studies (14%). Information on central programming or heterogeneity assessment was missing in approximately half of the publications. Most studies were motivated by improving power (86%). ConclusionsPharmacoepidemiological multi-database studies are a well-powered strategy to address safety issues and have increased in popularity. To be able to correctly interpret the results of these studies, it is important to systematically report on database management and analysis techniques, including central programming and heterogeneity testing. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
  • Vijayan, Madhavi; Lee, Cheuk-Lun; Wong, Vera H. H.; Wang, Xia; Bai, Kungfeng; Wu, Jian; Koistinen, Hannu; Seppälä, Markku; Lee, Kai-Fai; Yeung, William S. B.; Ng, Ernest H. Y.; Chiu, Philip C. N. (2020)
    Decidual macrophages constitute 20-30% of the total leukocytes in the uterus of pregnant women, regulating the maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages (dMs) are associated with fetal loss and pregnancy complications, such as preeclampsia. Monocytes differentiate into dMs in a decidua-specific microenvironment. Despite their important roles in pregnancy, the exact factors that regulate the differentiation into dMs remain unclear. Glycodelin-A (PAEP, hereafter referred to as GdA) is a glycoprotein that is abundantly present in the decidua, and plays an important role in fetomaternal defense and placental development. It modulates the differentiation and activity of several immune cell types residing in the decidua. In this study, we demonstrated that GdA induces the differentiation of human monocytes into dM-like phenotypes in terms of transcriptome, cell surface marker expression, secretome, and regulation of trophoblast and endothelial cell functions. We found that Sialic acid-binding Ig-like lectin 7 (Siglec-7) mediates the binding and biological actions of GdA in a sialic acid-dependent manner. We, therefore, suggest that GdA, induces the polarization of monocytes into dMs to regulate fetomatemal tolerance and placental development.
  • Clayton-Smith, Jill; Bromley, Rebecca; Dean, John; Journel, Hubert; Odent, Sylvie; Wood, Amanda; Williams, Janet; Cuthbert, Verna; Hackett, Latha; Aslam, Neelo; Malm, Heli; James, Gregory; Westbom, Lena; Day, Ruth; Ladusans, Edmund; Jackson, Adam; Bruce, Iain; Walker, Robert; Sidhu, Sangeet; Dyer, Catrina; Ashworth, Jane; Hindley, Daniel; Diaz, Gemma Arca; Rawson, Myfanwy; Turnpenny, Peter (2019)
    Background: A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. Methods: An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Results: Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. Conclusion: The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.
  • Chen, Jing; Bacelis, Jonas; Sole-Navais, Pol; Srivastava, Amit; Juodakis, Julius; Rouse, Amy; Hallman, Mikko; Teramo, Kari; Melbye, Mads; Feenstra, Bjarke; Freathy, Rachel M.; Smith, George Davey; Lawlor, Deborah A.; Murray, Jeffrey C.; Williams, Scott M.; Jacobsson, Bo; Muglia, Louis J.; Zhang, Ge (2020)
    Author summaryWhy was this study done? Maternal height, BMI, blood glucose, and blood pressure are associated with gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects underlying these observed associations are not clear. What did the researchers do and find? We dissected the relative contributions of maternal and fetal genetic effects using haplotype genetic score analysis in 10,734 mother-infant pairs of European ancestry. Genetically elevated maternal height is associated with longer gestational duration and larger birth size. In the fetus, alleles associated with adult height are positively associated with birth size. Alleles elevating blood pressure are associated with shorter gestational duration through a maternal effect and are associated with reduced fetal growth through a fetal genetic effect. Alleles that increase blood glucose in the mother are associated with increased birth weight, whereas risk alleles for type 2 diabetes in the fetus are associated with reduced birth weight. Alleles raising birth weight in fetus are associated with shorter gestational duration and higher maternal blood pressure during pregnancy. What do these findings mean? Maternal size and fetal growth are important factors in shaping the duration of gestation. Fetal growth is influenced by both maternal and fetal effects. Higher maternal BMI and glucose levels positively associate with birth weight through maternal effects. In the fetus, alleles associated with higher metabolic risks are negatively associated with birth weight. More rapid fetal growth is associated with shorter gestational duration and higher maternal blood pressure. These maternal and fetal genetic effects can largely explain the observed associations between maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes. Background Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved. Methods and findings Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p= 2.2 x 10(-4)). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p<1 x 10(-17)). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p= 1.6 x 10(-4)). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p= 9.4 x 10(-3)), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p= 3.3 x 10(-2)andp= 4.5 x 10(-3), respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p= 4.7 x 10(-6)); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p= 2.2 x 10(-3)). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p= 6.4 x 10(-3)) and a stronger fetal effect (p= 1.3 x 10(-5)). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p= 1.8 x 10(-4)) and increased maternal systolic BP during pregnancy (p= 2.2 x 10(-2)). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits. Conclusions We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.
  • Lindblom, Jallu; Peltola, Mikko J.; Vanska, Mervi; Hietanen, Jari K.; Laakso, Anu; Tiitinen, Aila; Tulppala, Maija; Punamaki, Raija-Leena (2017)
    The family environment shapes children's social information processing and emotion regulation. Yet, the long-term effects of early family systems have rarely been studied. This study investigated how family system types predict children's attentional biases toward facial expressions at the age of 10 years. The participants were 79 children from Cohesive, Disengaged, Enmeshed, and Authoritarian family types based on marital and parental relationship trajectories from pregnancy to the age of 12 months. A dot-probe task was used to assess children's emotional attention biases toward threatening (angry) and affiliative (happy) faces at the early (500 ms) and late (1250 ms) stages of processing. Situational priming was applied to activate children's sense of danger or safety. Results showed that children from Cohesive families had an early-stage attentional bias toward threat, whereas children from Enmeshed families had a late-stage bias toward threat. Children from Disengaged families had an early-stage attentional bias toward threat, but showed in addition a late-stage bias away from emotional faces (i.e., both angry and happy). Children from Authoritarian families, in turn, showed a late-stage attentional bias toward emotional faces. Situational priming did not moderate the effects of family system types on children's attentional biases. The findings confirm the influence of early family systems on the attentional biases, suggesting differences in the emotion regulation strategies children have developed to adapt to their family environments.