Gestational diabetes is associated with the risk of offspring's congenital anomalies: a register-based cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy-related disorder and a well-known risk factor for adverse pregnancy outcomes. There are conflicting findings on the association of GDM with the risk of congenital anomalies (CAs) in offspring. In this study, we aimed to determine study whether maternal GDM is associated with an increased risk of major CAs in offspring. METHODS: This Finnish Gestational Diabetes (FinnGeDi) register-based study included 6,597 women with singleton pregnancies and a diagnosis of GDM and 51,981 singleton controls with no diabetes identified from the Finnish Medical Birth Register (MBR) in 2009. Data from MBR were combined in this study with the Register of Congenital Malformations, which includes the data of CAs. We used logistic regression to calculate odds ratios (OR) for CAs, together with their 95% confidence intervals (CIs), adjusting for maternal age, parity, pre-pregnancy body mass index (BMI), and maternal smoking status. RESULTS: The risk of major CAs was higher in the GDM-exposed (n = 336, 5.09%) than in the non-exposed group (n = 2,255, 4.33%) (OR: 1.18, 95% CI: 1.05-1.33, p = 0.005). The adjusted OR (aOR) was 1.14 (95% CI: 1.00-1.30, p = 0.047). There was a higher overall prevalence of CAs, particularly chromosomal abnormalities (0.52% vs. 0.21%), in the GDM-exposed group (OR: 2.49, 95% Cl: 1.69-3.66, p < 0.001). The aOR was 1.93 (95% Cl: 1.25-2.99, p = 0.003). CONCLUSIONS: Offspring exposed to GDM have a higher prevalence of major CAs. Of note, risk factors other than GDM, such as older maternal age and a higher pre-pregnancy BMI, diminished the between group differences in the prevalence of major CAs. Nevertheless, our findings suggest that offspring exposed to maternal GDM are more likely to be diagnosed with a chromosomal abnormality, independent of maternal age, parity, pre-pregnancy BMI, and smoking.

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy.

Importance: A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood. Objective: To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy. Design, Setting, and Participants: This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023. Exposures: The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes. Results: A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP). Conclusions and Relevance: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.

Increased Oral Care Needs and Third Molar Symptoms in Women with Gestational Diabetes Mellitus: A Finnish Gestational Diabetes Case-Control Study.

(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.

Increased Risk of Preeclampsia in Women With a Genetic Predisposition to Elevated Blood Pressure.

BACKGROUND: Preeclampsia causes significant maternal and perinatal morbidity. Genetic factors seem to affect the onset of the disease. We aimed to investigate whether the polygenic risk score for blood pressure (BP; BP-PRS) is associated with preeclampsia, its subtypes, and BP values during pregnancy. METHODS: The analyses were performed in the FINNPEC study (Finnish Genetics of Pre-Eclampsia Consortium) cohort of 1514 preeclamptic and 983 control women. In a case-control setting, the data were divided into percentiles to compare women with high BP-PRS (HBP-PRS; >95th percentile) or low BP-PRS (≤5th percentile) to others. Furthermore, to evaluate the effect of BP-PRS on BP, we studied 3 cohorts: women with preeclampsia, hypertensive controls, and normotensive controls. RESULTS: BP values were higher in women with HBP-PRS throughout the pregnancy. Preeclampsia was more common in women with HBP-PRS compared with others (71.8% and 60.1%, respectively; P=0.009), and women with low BP-PRS presented with preeclampsia less frequently than others (44.8% and 61.5%, respectively; P<0.001). HBP-PRS was associated with an increased risk for preeclampsia (odds ratio, 1.7 [95% CI, 1.1-2.5]). Furthermore, women with HBP-PRS presented with recurrent preeclampsia and preeclampsia with severe features more often. CONCLUSIONS: Our results suggest that HBP-PRS is associated with an increased risk of preeclampsia, recurrent preeclampsia, and preeclampsia with severe features. Furthermore, women with HBP-PRS present higher BP values during pregnancy. The results strengthen the evidence pointing toward the role of genetic variants associated with BP regulation in the etiology of preeclampsia, especially its more severe forms.

Characteristics of preeclampsia in donor cell gestations.

Pregnancies conceived through donor oocytes or sperm show increased risk for preeclampsia. We studied this issue in a preeclampsia case-control cohort (n = 2778), and found overrepresentation of donor cell gestations among women with preeclampsia (14/1627, 0.86%; OR 1.81; 95% CI: 1.07-3.08; P = 0.025) compared to the population data. Moreover, we observed excess of male births from donor cell pregnancies (male-to-female ratio 2.5 vs. 0.97; OR 2.57; 95% CI 1.02-6.36; P = 0.043). Maternal age (36.7 vs. 30.2; P < 0.0001) and preterm deliveries (64% vs. 38%; P = 0.046) distinguished donor cell gestations from other pregnancies with preeclampsia. These results support foreign fetal antigens as modulators of preeclampsia.

Normal Gestational Weight Gain Protects From Large-for-Gestational-Age Birth Among Women With Obesity and Gestational Diabetes.

Background: Pre-pregnancy obesity, excess gestational weight gain (GWG), and gestational diabetes (GDM) increase fetal growth. Our aim was to assess whether normal GWG is associated with lower risk for a large-for-gestational-age (LGA; over the 90th percentile of birth weight for sex and gestational age) infant and lower birth weight standard deviation (SD) score in the presence of GDM and maternal obesity. Methods: This multicenter case-control study is part of the Finnish Gestational Diabetes (FinnGeDi) Study and includes singleton pregnancies of 1,055 women with GDM and 1,032 non-diabetic controls. Women were divided into 12 subgroups according to their GDM status, pre-pregnancy body mass index (BMI; kg/m2), and GWG. Non-diabetic women with normal BMI and normal GWG (according to Institute of Medicine recommendations) served as a reference group. Results: The prevalence of LGA birth was 12.2% among women with GDM and 6.2% among non-diabetic women (p < 0.001). Among all women, normal GWG was associated with lower odds of LGA [odds ratio (OR) 0.57, 95% CI: 0.41-0.78]. Among women with both obesity and GDM, the odds for giving birth to a LGA infant was 2.25-fold (95% CI: 1.04-4.85) among those with normal GWG and 7.63-fold (95% CI: 4.25-13.7) among those with excess GWG compared with the reference group. Compared with excess GWG, normal GWG was associated with 0.71 SD (95% CI: 0.47-0.97) lower birth weight SD score among women with GDM and obesity. Newborns of normal weight women with GDM and normal GWG had 0.28 SD (95% CI: 0.05-0.51) lower birth weight SD scores compared with their counterparts with excess GWG. In addition, in the group of normal weight non-diabetic women, normal GWG was associated with 0.46 SD (95% CI: 0.30-0.61) lower birth weight SD scores compared with excess GWG. Conclusion: GDM, obesity, and excess GWG are associated with higher risk for LGA infants. Interventions aiming at normal GWG have the potential to lower LGA rate and birth weight SD scores even when GDM and obesity are present.

Pregnancy outcomes according to the definition of gestational diabetes.

OBJECTIVE: To assess the frequency and perinatal outcomes of gestational diabetes mellitus (GDM) defined by the criteria according to the International Association of Diabetes in Pregnancy Study Group (IADPSG) and the National Institute for Health and Care Excellence (NICE) diagnostic criteria for GDM. DESIGN: A retrospective cohort study. SETTING: Six secondary and tertiary delivery hospitals in Finland in 2009. POPULATION: Pregnant women (N = 4,033) and their offspring. METHODS: We used data on comprehensive screening of pregnant women with a 2-h 75-g oral glucose tolerance test (OGTT), performed between gestational weeks 24 and 40. OGTT glucose concentrations were used to identify women who fulfilled IADPSG and NICE criteria. While cut-offs according to Finnish national criteria partly overlapped with both criteria, a subgroup of IADPSG- or NICE-positive GDM women remained undiagnosed by Finnish criteria and hence non-treated. They were analysed as subgroups and compared to controls who were negative with all cut-offs. MAIN OUTCOME MEASURES: GDM prevalence, birth weight SD score (BWSDS), large for gestational age (LGA) and caesarean section (CS) rates. RESULTS: Among the 4,033 women screened for GDM, 1,249 (31.0%) and 529 (13.1%) had GDM according to the IADPSG and NICE criteria, respectively. The LGA rate was similar in both groups. Regardless of the diagnostic criteria, women with GDM had a higher risk of induced delivery and CSs than controls. In IADPSG-positive non-treated women, offspring's BWSDS and CS rate were higher than in controls. CONCLUSIONS: GDM prevalence was 2.4-fold higher according to the IADPSG compared with the NICE criteria but the LGA rate did not differ. BWSDS and CS rate were increased already with mild untreated hyperglycaemia.

Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia.

Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GTn) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia, whether the length of fetal and maternal repeats affect HO-1 levels in placenta and maternal serum, and whether HO-1 levels are altered in preeclampsia. We genotyped the repeat in the cord blood of 609 preeclamptic and 745 nonpreeclamptic neonates. HO-1 levels were measured in 36 placental samples, and in the first (222 cases/243 controls) and third (176 cases/53 controls) pregnancy trimester serum samples using enzyme-linked immunosorbent assay. The long fetal GTn repeat was associated with preeclampsia and its severe and early-onset subtypes. Interaction analysis suggested the maternal and fetal effects to be independent. Placental or serum HO-1 levels were not altered in preeclamptics, possibly reflecting heterogeneity of preeclampsia. Carriers of the long fetal and maternal repeats had lower placental and serum HO-1 levels, respectively, providing functional evidence for the association. We conclude that the long fetal GTn repeat may increase mother's risk for especially severe and early-onset preeclampsia. The fetal and maternal risk alleles likely predispose to different disease subtypes.

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia.

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.

Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population.

Preeclampsia is a common pregnancy-specific vascular disorder characterized by new-onset hypertension and proteinuria during the second half of pregnancy. Predisposition to preeclampsia is in part heritable. It is associated with an increased risk of cardiovascular disease later in life. We have sequenced 124 candidate genes implicated in preeclampsia to pinpoint genetic variants contributing to predisposition to or protection from preeclampsia. First, targeted exomic sequencing was performed in 500 preeclamptic women and 190 controls from the FINNPEC cohort (Finnish Genetics of Preeclampsia Consortium). Then 122 women with a history of preeclampsia and 1905 parous women with no such history from the National FINRISK Study (a large Finnish population survey on risk factors of chronic, noncommunicable diseases) were included in the analyses. We tested 146 rare and low-frequency variants and found an excess (observed 13 versus expected 7.3) nominally associated with preeclampsia (P<0.05). The most significantly associated sequence variants were protective variants rs35832528 (E982A; P=2.49E-4; odds ratio=0.387) and rs141440705 (R54S; P=0.003; odds ratio=0.442) in Fms related tyrosine kinase 1. These variants are enriched in the Finnish population with minor allele frequencies 0.026 and 0.017, respectively. They may also be associated with a lower risk of heart failure in 11 257 FINRISK women. This study provides the first evidence of maternal protective genetic variants in preeclampsia.

Prenatal determinants of physical activity and cardiorespiratory fitness in adolescence - Northern Finland Birth Cohort 1986 study.

BACKGROUND: Lower levels of physical activity and cardiorespiratory fitness are key risk factors of chronic adult diseases. Physical activity and cardiorespiratory fitness are predicted by birth weight, but the underlying parental and pregnancy-related factors remain largely unknown. We examined how prenatal determinants are associated with physical activity and cardiorespiratory fitness in adolescence. METHODS: Of the 16-year-old members of the population-based Northern Finland Birth Cohort 1986 (NFBC 1986), 6682 singletons with no major physical disability reported their amount of physical activity outside school hours, and 4706 completed a submaximal cycle ergometer test assessing cardiorespiratory fitness. Physical activity was expressed as metabolic equivalent hours per week (METh/week) and cardiorespiratory fitness as peak oxygen uptake (ml·kg-1·min-1). Prenatal determinants included birth weight, length of gestation, mother's and father's body mass index (BMI), maternal gestational diabetes mellitus (GDM), and maternal hypertension and smoking during pregnancy. Data were analyzed by multiple linear regression. RESULTS: A higher birth weight and longer length of gestation predicted lower levels of physical activity and cardiorespiratory fitness at 16 years, although the association between length of gestation and physical activity was inverse U-shaped. Mother's or father's overweight or obesity before pregnancy were associated with lower levels of their offspring's physical activity and fitness in adolescence. Adjusting for maternal pregnancy disorders and the adolescent's own BMI attenuated the associations with the mother's but not the father's overweight/obesity. Furthermore, maternal GDM predicted lower cardiorespiratory fitness. CONCLUSIONS: A high birth weight and parental overweight/obesity are associated with lower levels of both physical activity and cardiorespiratory fitness in adolescence, while maternal GDM and longer length of gestation are associated with lower cardiorespiratory fitness. Both long and short lengths of gestation predict low physical activity.

Towards national comprehensive gestational diabetes screening - consequences for neonatal outcome and care.

INTRODUCTION: The change from risk-factor-based to nearly comprehensive screening of gestational diabetes (GDM) identifies more but milder cases of the disease. The main aim of this study was to evaluate the effect of this screening policy change on neonatal outcomes and care. MATERIAL AND METHODS: A population-based register study in Finland. GDM cases during risk-factor-based (year 2006, n = 5179) and comprehensive (2010, n = 6679) screenings were identified through the Medical Birth Register. All singletons without maternal GDM or prepregnancy diabetes served as controls (n = 51 746 and n = 52 386, respectively). The main outcomes were macrosomia, neonatal hypoglycemia and the need for care in a neonatal ward. RESULTS: In the GDM group, the mean birthweight decreased between the study years from 3660 g to 3595 g and the prevalence of macrosomia from 5.6 to 4.1% even after adjustment for maternal age, parity and prepregnancy body mass index. The adjusted mean difference in birthweight between GDM and control newborns decreased from 70 to 22 g between the study years. The prevalence of neonatal hypoglycemia increased from 18.0 to 22.1% in the GDM group. However, neonatal hypoglycemia was more often treated without care in a neonatal ward. The proportion of infants treated on a neonatal ward decreased in both the GDM and control groups between the study years. CONCLUSIONS: In newborns, comprehensive GDM screening led to decreased mean birthweight and macrosomia rates, but the prevalence of neonatal hypoglycemia increased. This places substantial demands for delivery hospitals and healthcare resources.

Metabolic signatures of birthweight in 18 288 adolescents and adults.

BACKGROUND: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults. METHODS: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15-75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI). RESULTS: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood. CONCLUSIONS: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.

The diagnosis of pre-eclampsia using two revised classifications in the Finnish Pre-eclampsia Consortium (FINNPEC) cohort.

BACKGROUND: The Finnish Pre-eclampsia Consortium (FINNPEC) case-control cohort consisting of 1447 pre-eclamptic and 1068 non-pre-eclamptic women was recruited during 2008-2011 to study genetic background of pre-eclampsia and foetal growth. Pre-eclampsia was defined by hypertension and proteinuria according to the American College of Obstetricians and Gynecologists (ACOG) 2002 classification. The ACOG Task Force Report on Hypertension in Pregnancy (2013) and The International Society for the Study of Hypertension in Pregnancy (ISSHP) (2014) have published new classifications, in which proteinuria is not necessary for diagnosis when specific symptoms are present. For diagnoses based on proteinuria, the ISSHP 2014 criteria raised its threshold to 2+ on dipstick. We studied how the new classifications would affect pre-eclampsia diagnoses in the FINNPEC cohort. METHODS: We re-evaluated pre-eclampsia diagnosis using the ACOG 2013 and the ISSHP 2014 classifications in pre-eclamptic women whose proteinuria did not exceed 1+ on dipstick (n = 68), in women with gestational hypertension (n = 138) and in women with chronic hypertension (n = 66). RESULTS: The number of women with pre-eclampsia increased 0.8 % (1459/1447) according to the ACOG 2013 criteria and 0.6 % (1455/1447) according to the ISSHP 2014 criteria. All 68 women with the amount of proteinuria not exceeding 1+ on dipstick diagnosed originally pre-eclamptic met the ACOG 2013 criteria but only 20 women (29.4 %) met the ISSHP 2014 criteria. Seven (5.1 %) and 35 (25.4 %) women with gestational hypertension were diagnosed with pre-eclampsia according to the ACOG 2013 and the ISSHP 2014 criteria, respectively. Correspondingly five (7.6 %) and 21 (31.8 %) women with chronic hypertension were diagnosed with pre-eclampsia according to the ACOG 2 013 and the ISSHP 2014 criteria. CONCLUSIONS: Only minor changes were observed in the total number of pre-eclamptic women in the FINNPEC cohort when comparing the ACOC 2002 classification with the ACOG 2013 and ISSHP 2014 classifications.

An RGS2 3'UTR polymorphism is associated with preeclampsia in overweight women.

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.

Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants.

Pre-eclampsia is a common pregnancy disorder that is a major cause for maternal and perinatal mortality and morbidity. Variants predisposing to pre-eclampsia might be under negative evolutionary selection that is likely to keep their population frequencies low. We exome sequenced samples from a hundred Finnish pre-eclamptic women in pools of ten to screen for low-frequency, large-effect risk variants for pre-eclampsia. After filtering and additional genotyping steps, we selected 28 low-frequency missense, nonsense and splice site variants that were enriched in the pre-eclampsia pools compared to reference data, and genotyped the variants in 1353 pre-eclamptic and 699 non-pre-eclamptic women to test the association of them with pre-eclampsia and quantitative traits relevant for the disease. Genotypes from the SISu project (n = 6118 exome sequenced Finnish samples) were included in the binary trait association analysis as a population reference to increase statistical power. In these analyses, none of the variants tested reached genome-wide significance. In conclusion, the genetic risk for pre-eclampsia is likely complex even in a population isolate like Finland, and larger sample sizes will be necessary to detect risk variants.

Cohort profile: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC).

PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study was established to set up a nationwide clinical and DNA database on women with and without pre-eclampsia (PE), including their partners and infants, in order to identify genetic risk factors for PE. PARTICIPANTS: FINNPEC is a cross-sectional case-control cohort collected from 5 university hospitals in Finland during 2008-2011. A total of 1450 patients with PE and 1065 pregnant control women without PE (aged 18-47 years) were recruited. Altogether, there were 1377 full triads (625 PE and 752 control triads). FINDINGS TO DATE: The established cohort holds both clinical and genetic information of mother-infant-father triads representing a valuable resource for studying the pathogenesis of the disease. Furthermore, maternal biological samples (first and third trimester serum and placenta) will provide additional information for PE research. Until now, research has encompassed studies on candidate genes, Sanger and next-generation sequencing, and various studies on the placenta. FINNPEC has also participated in the InterPregGen study, which is the largest investigation on maternal and fetal genetic factors underlying PE until now. FUTURE PLANS: Ongoing studies focus on elucidating the role of immunogenetic and metabolic factors in PE. Data on morbidity and mortality will be collected from mothers and fathers through links to the nationwide health registers.

The changing face of gestational diabetes: the effect of the shift from risk factor-based to comprehensive screening.

OBJECTIVE: To evaluate the effect of the change in the gestational diabetes (GDM) screening policy from risk-factor based to comprehensive screening on the prevalence and type of GDM and characteristics of GDM pregnancies. DESIGN: Population-based register study in Finland. Subjects were GDM women who gave birth before (2006, n=5185) and after (2010, n=6683) the policy change. All the other women in those years without pre-pregnancy diabetes acted as controls (51 759 and 52 398 respectively). METHODS: GDM women with singleton pregnancy were identified through The Finnish Medical Birth Register by abnormal oral glucose tolerance test or initiation of insulin. Main outcome measures were prevalence of GDM (total and insulin/diet-treated), and caesarean section rate. RESULTS: The proportion of screened mothers increased from 27.5 to 51.3% and the total prevalence of GDM from 9.1 to 11.3%. This increase consisted mainly of diet-treated mothers, while the number and proportion of insulin-treated mothers decreased (21.8% vs13.3%, P<0.001). The proportion of primiparous women increased (34.5-39.4%, P<0.0001) and mean pre-pregnancy BMI decreased (28.6-28.2, P<0.001). The overall caesarean section rate remained the same but increased among women with GDM (20.8-22.1%) adjusted odds ratios being 1.22 (95% CI 1.14, 1.31) during comprehensive and 1.10 (95% CI 1.02, 1.19) during risk factor-based screening. CONCLUSIONS: The shift to comprehensive screening led to a significant increase in women with GDM, who were more often primiparous and had a lower BMI. Comprehensive screening did not perform better in diagnosing women needing insulin treatment.

Cardiometabolic risk factors in young adults who were born preterm.

Adults who were born preterm with a very low birth weight have higher blood pressure and impaired glucose regulation later in life compared with those born at term. We investigated cardiometabolic risk factors in young adults who were born at any degree of prematurity in the Preterm Birth and Early Life Programming of Adult Health and Disease (ESTER) Study, a population-based cohort study of individuals born in 1985-1989 in Northern Finland. In 2009-2011, 3 groups underwent clinical examination: 134 participants born at less than 34 gestational weeks (early preterm), 242 born at 34-36 weeks (late preterm), and 344 born at 37 weeks or later (controls). Compared with controls, adults who were born preterm had higher body fat percentages (after adjustment for sex, age, and cohort (1985-1986 or 1987-1989), for those born early preterm, difference = 6.2%, 95% confidence interval (CI): 0.4, 13.2; for those born late preterm, difference = 8.0%, 95% CI: 2.4, 13.8), waist circumferences, blood pressure (for those born early preterm, difference = 3.0 mm Hg, 95% CI: 0.9, 5.1; for those born late preterm, difference = 1.7, 95% CI: -0.1, 3.4), plasma uric acid levels (for those born early preterm, difference = 20.1%, 95% CI: 7.9, 32.3; for those born late preterm, difference = 20.2%, 95% CI: 10.7, 30.5), alanine aminotransferase levels, and aspartate transaminase levels. They were also more likely to have metabolic syndrome (for those born early preterm, odds ratio = 3.7, 95% CI: 1.6, 8.2; for those born late preterm, odds ratio = 2.5, 95% CI: 1.2, 5.3). Elevated levels of conventional and emerging risk factors suggest a higher risk of cardiometabolic disease later in life. These risk factors are also present in the large group of adults born late preterm.