A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P &lt; 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.</p

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P &lt; 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.</p

The roles of maternal characteristics and early-pregnancy serum parameters in gestational diabetes:the Finnish Gestational Diabetes study

Abstract Gestational diabetes (GDM) is defined as hyperglycaemia with onset or first recognition in pregnancy, affecting one of fifth of pregnancies in Finland. Besides its adverse perinatal outcomes, it predisposes both mother and child to long-term morbidity, such as type 2 diabetes, metabolic syndrome and cardiovascular disease. The major clinical risk factors for GDM, such as pre-pregnancy overweight and obesity, an advanced age and a family history of diabetes, are well established. However, the roles of other maternal clinical characteristics, such as polycystic ovary syndrome (PCOS), in the risk of developing GDM are controversial. The effect of an adequate gestational weight gain (GWG) on the prevention of fetal overgrowth also remain unclear. In addition to clinical risk factors, early-pregnancy serum parameters involved in the underlying pathophysiological mechanisms of GDM could improve the early detection of women with a high risk of GDM. The aim of this study was to evaluate the roles of maternal characteristics, especially PCOS and GWG, and serum parameters measured in early pregnancy, such as sex hormone-binding globulin (SHBG) and androgen excess, as well as of traditional lipids and ceramides (Cer), with subsequent GDM. The study was based on the Finnish Gestational Diabetes study, which included 1,146 women with GDM and 1,066 non-diabetic controls. The prevalence of PCOS was higher among women with GDM than in controls (10.7% vs. 7.4%), but PCOS was not an independent risk factor for GDM after considering pre-pregnancy BMI and age. Moderate GWG was an important factor in protecting against fetal overgrowth, especially in women with GDM and obesity. Lower early-pregnancy SHBG levels were associated with early-onset GDM, fasting hyperglycaemia and the need for insulin therapy, whereas androgen excess was associated with slightly higher post-prandial glucose values. Thus, low SHBG levels might reflect chronic insulin resistance, while androgen excess might impair post-prandial insulin secretion. Of the lipids measured in early pregnancy, higher levels of triglycerides, LDL and Cer(d18:1/24:0) were independent predictors of GDM. Along with clinical risk factors and triglycerides, ceramides did not markedly improve the prediction of GDM. Adverse alterations in hormonal and lipid parameters highlight the clustering of metabolic risk factors involved in GDM.Tiivistelmä Raskausdiabetes on raskausaikana ensimmäistä kertaa todettava sokeriaineenvaihdunnan häiriö, joka esiintyy Suomessa joka viidennellä synnyttäjällä. Siihen liittyy lisääntynyt raskausongelmien riski sekä myöhempi äidin ja lapsen suurentunut pitkäaikaissairauksien, kuten tyypin 2 diabeteksen, metabolisen oireyhtymän sekä sydän- ja verisuonisairauksien riski. Raskausdiabeteksen riskitekijöitä ovat ylipaino ja lihavuus, korkea ikä sekä lähisukulaisen diabetes. Muiden kliinisten tekijöiden, kuten munasarjojen monirakkulaoireyhtymän (PCOS) merkityksestä raskausdiabeteksen itsenäisenä riskitekijänä on kiistelty. Myös maltillisen raskauden aikaisen painonnousun roolista sikiön liikakasvulta suojaavana tekijänä tarvitaan lisätietoa. Lisäksi olisi tärkeää tunnistaa suuressa sairastumisriskissä olevat naiset jo varhaisraskaudessa. Yksi mahdollisuus on määrittää äidin alkuraskauden verinäytteistä merkkiaineita, jotka voivat olla yhteydessä raskausdiabeteksen kehittymiseen. Väitöskirjatutkimuksessa arvioitiin Suomalaisen raskausdiabetestutkimuksen (FinnGeDi) 1146 raskausdiabeetikkoa ja 1066 verrokkia sisältävässä aineistossa äidin kliinisten tekijöiden, erityisesti PCOS:n ja raskauden aikaisen painonnousun sekä alkuraskauden seerumin merkkiaineiden yhteyksiä raskausdiabetekseen. Työssä tarkasteltiin sukupuolihormoneja sitovan globuliinin (SHBG) ja androgeeniylimäärän sekä perinteisten rasva-arvojen ja keramidien (Cer) pitoisuuksia. PCOS oli raskausdiabetekseen sairastuneilla verrokkeja yleisempi (10,7 % vs. 7,4 %), mutta se ei ollut raskausdiabeteksen itsenäinen riskitekijä, vaan ero välittyi korkeamman iän ja ylipainon kautta. Suositusten mukainen raskauden aikainen painonnousu vähensi sikiön liikakasvua huolimatta raskausdiabeteksesta ja lihavuudesta. Matalampi alkuraskauden SHBG-taso oli yhteydessä varhaiseen raskausdiabetekseen, korkeaan paastoverensokeriin ja insuliinihoidon tarpeeseen. Androgeeniylimäärä oli yhteydessä hieman korkeampiin aterianjälkeisiin glukoosiarvoihin. Suuremmat triglyseridien, LDL-kolesterolin ja Cer(d18:1/24:0) pitoisuudet ennustivat itsenäisesti raskausdiabetesta, mutta keramidit eivät käytännössä parantaneet raskausdiabeteksen ennusteen tarkkuutta kliinisten riskitekijöiden ja triglyseridien rinnalla. Todetut hormonaaliset ja rasva-aineenvaihdunnan poikkeavuudet korostavat metabolisten häiriöiden laajuutta raskausdiabeteksen taustalla

Alkuraskauden verenvuoto säikäyttää:milloin on kiire?

Tiivistelmä Alkuraskauden verenvuoto on tavallisin gynekologisen päivystyskäynnin syy. Vuodon etiologia voi olla esimerkiksi uhkaava keskenmeno, keskenmeno tai ektooppinen (kohdunulkoinen) raskaus. Jatkohoidon tarpeen ja kiireellisyyden suunnittelussa keskeisiä ovat vuotomäärän, kivun ja hemodynamiikan arviointi sekä kaikukuvaus, jonka käyttö ja tulkinta vaativat kuitenkin harjoittelua. Ektooppisen raskauden mahdollisuus tulee pitää mielessä, jos alkuraskauteen liittyy poikkeavaa vuotoa tai kipua. Tällöin lähete erikoissairaanhoitoon on tarpeellinen. Kivulias tai runsaasti vuotava potilas lähetetään päivystyksenä. Tilanteen ollessa rauhallinen arvio voidaan tehdä seuraavana arkipäivänä. Kaikukuvauksen ohella seerumin istukkagonadotropiinin määritys on hyödyllinen ektooppisen raskauden diagnostiikassa. Anti-D-immunoglobuliinia suositellaan kahdeksannen raskausviikon jälkeen Rh-negatiivisille naisille.Abstract Bleeding in early pregnancy can frighten : when should on hurry? Vaginal bleeding in early pregnancy is the most common reason for gynecological on-call visits. The etiology can be for instance impending miscarriage, miscarriage or an ectopic pregnancy. Treatment strategy and urgency are based on the amount of bleeding, pain, hemodynamics, and transvaginal ultrasound scan (if available), which however requires some training and experience. In cases with abnormal bleeding and/or pain in early pregnancy and no visible intrauterine pregnancy, the possibility of ectopic pregnancy should be kept in mind. Patients with suspected ectopic pregnancy should be referred to a gynecological unit. Immediate evaluation by gynecologist is needed in cases with extensive pain, heavy bleeding and/or unstable hemodynamic status. Stable cases can be evaluated the next working day. Serum human chorionic gonadotropin measurement is useful in the diagnostics of ectopic pregnancy. Anti-D immunoglobulin is recommended for Rh-negative patients with vaginal bleeding after 8 weeks of pregnancy

Polycystic ovary syndrome and risk factors forngestational diabetes

Abstract Objective: To study the roles of self-reported symptoms and/or prior diagnosis of polycystic ovary syndrome (PCOS) and other potential risk factors for gestational diabetes mellitus (GDM) and to clarify whether the screening of GDM in early pregnancy is beneficial for all women with PCOS. Design: The FinnGeDi multicentre case-control study including 1146 women with singleton pregnancies diagnosed with GDM and 1066 non-diabetic pregnant women. There were 174 women with PCOS (symptoms and/or diagnosis self-reported by a questionnaire) and 1767 women without PCOS (data missing for 271). Methods: The study population (N = 1941) was divided into four subgroups: GDM + PCOS (N = 105), GDM + non-PCOS (N = 909), non-GDM + PCOS (N = 69), and controls (N = 858). The participants’ characteristics and their parents’ medical histories were compared. Results: The prevalence of PCOS was 10.4% among GDM women and 7.4% among nondiabetics (odds ratios (OR) 1.44, 95% CI: 1.05–1.97), but PCOS was not an independent risk for GDM after adjustments for participants’ age and pre-pregnancy BMI (OR 1.07, 95% CI: 0.74–1.54). In a multivariate logistic regression analysis, the most significant parameters associated with GDM were overweight, obesity, age ≥35 years, participant’s mother’s history of GDM, either parent’s history of type 2 diabetes (T2D) and participant’s own preterm birth. Conclusions: The increased risk of GDM in women with PCOS was related to obesity and increased maternal age rather than to PCOS itself, suggesting that routine early screening of GDM in PCOS women without other risk factors should be reconsidered. Instead, family history of GDM/T2D and own preterm birth were independent risk factors for GDM

Increased oral care needs and third molar symptoms in women with gestational diabetes mellitus:a finnish gestational diabetes case–control study

Abstract (1) Hyperglycemia and oral pathology accelerate each other in diabetes. We evaluated whether gestational diabetes mellitus (GDM) is associated with self-reported increased oral health care needs and oral symptoms, including third molar symptoms, during pregnancy. (2) Pregnant women with (n = 1030) and without GDM (n = 935) were recruited in this multicenter Finnish Gestational Diabetes study in 2009–2012. Of the women with GDM, 196 (19.0%) receiving pharmacological treatment, 797 (77.0%) receiving diet treatment and 233 (23.0%) with recurrent GDM were analyzed separately. Oral health was assessed using structured questionnaires and analyzed by multivariable logistic regression adjusted for background risk factors. (3) Women with GDM were more likely to report a higher need for oral care than controls (31.1% vs. 24.5%; odds ratio (OR) 1.39; 95% confidence interval (CI) 1.14–1.69), particularly women with recurrent GDM (38.1% vs. 24.5%; OR 1.90; 95% CI 1.40–2.58). Women with pharmacologically treated GDM (46.9%) more often had third molar symptoms than controls (36.1%; OR 1.57; 95% CI 1.15–2.15) than women with diet-treated GDM (38.0%; OR 1.47; 95% CI 1.07–2.02). (4) GDM is associated with perceived oral care needs. Third molar symptoms were associated with pharmacologically treated GDM

Epigenome-wide association study reveals methylation loci associated with offspring gestational diabetes mellitus exposure and maternal methylome

Abstract Objective: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. Research Design and Methods: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. Results: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10⁻²) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. Conclusions: Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM exposure, but also other factors indicated by maternal epigenetic status, such as maternal metabolic history

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity

Abstract Aims: We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. Materias and Methods: This nationwide case–control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2 h glucose concentrations during the oral glucose tolerance test), early-onset GDM (&lt;20 gestational weeks) and the need for anti-diabetic medication. Results: After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%–7.3%) lower SHBG levels, 3.1% (95% CI 0.1%–6.2%) higher T levels, and 4.6% (95% CI 1.9%–7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%–12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%–14.8%) lower SHBG levels than other women with GDM. Conclusions: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion

Serum ceramides in early pregnancy as predictors of gestational diabetes

Abstract Ceramides contribute to the development of type 2 diabetes but it is uncertain whether they predict gestational diabetes (GDM). In this multicentre case–control study including 1040 women with GDM and 958 non-diabetic controls, early pregnancy (mean 10.7 gestational weeks) concentrations of four ceramides—Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)—were determined by a validated mass-spectrometric method from biobanked serum samples. Traditional lipids including total cholesterol, LDL, HDL and triglycerides were measured. Logistic and linear regression and the LASSO logistic regression were used to analyse lipids and clinical risk factors in the prediction of GDM. The concentrations of four targeted ceramides and total cholesterol, LDL and triglycerides were higher and HDL was lower among women with subsequent GDM than among controls. After adjustments, Cer(d18:1/24:0), triglycerides and LDL were independent predictors of GDM, women in their highest quartile had 1.44-fold (95% CI 1.07–1.95), 2.17-fold (95% CI 1.57–3.00) and 1.63-fold (95% CI 1.19–2.24) odds for GDM when compared to their lowest quartiles, respectively. In the LASSO regression modelling ceramides did not appear to markedly improve the predictive performance for GDM alongside with clinical risk factors and triglycerides. However, their adverse alterations highlight the extent of metabolic disturbances involved in GDM