Socioeconomic status, maternal risk factors, and gestational diabetes mellitus across reproductive years: a Finnish register-based study.

INTRODUCTION: To evaluate the degree to which socioeconomic differences in gestational diabetes mellitus (GDM) are accounted for by differences in maternal risk factors, to assess whether age-related risks of GDM differ across socioeconomic groups, and to identify priority populations for future interventions. RESEARCH DESIGN AND METHODS: We performed a register-based study using data from the Finnish Medical Birth Register and Statistics Finland on the 474 166 women who gave birth in Finland from 2008 to 2015. We collected information on GDM based on the International Classification of Diseases 10th Revision codes O24.4 and O24.9. We used multivariable models to examine the association between socioeconomic status, maternal risk factors, and GDM. We further tested interaction on multiplicative and additive scales. RESULTS: The incidence of GDM was 8.7% in 2008-2011 and 12.5% in 2012-2015. Lower socioeconomic levels than upper level employees were associated with an increased risk of GDM. Up to 64.0% of socioeconomic differences in GDM were attributed to body mass index and 5.5% to smoking. There was evidence for effect modification. Relative to women in the upper level category who were aged less than 19 years, GDM adjusted ORs (95% CIs) for women 35 years or older in upper level versus long-term unemployed groups were 3.28 (2.08-5.18) and 5.29 (3.35-8.35), respectively. CONCLUSIONS: There is a paradox that socioeconomic advantage increases the incidence of GDM at the population level while reducing the incidence of GDM within the population. Nevertheless, socioeconomic differences in GDM persist and widen with increasing maternal age, even after accounting for maternal risk factors.

High estradiol levels during a long agonist IVF protocol are associated with decreased food intake, higher leptin concentrations, and lower levels of high-sensitivity C-reactive protein.

PURPOSE: To study whether different hormonal phases affect appetite regulation, food intake, and concentrations of leptin, glucagon-like peptide-1 (GLP-1), and high-sensitivity C-reactive protein (hs-CRP) during a long agonist in vitro fertilization (IVF) protocol. METHODS: Fifty-four infertile women were encountered thrice, the first of which was at the beginning of their period (low estradiol). The other two visits were during a gonadotrophin-releasing hormone (GnRH) analog downregulation (low estradiol) and at the end of a follicle-stimulating hormone (FSH) stimulation (high estradiol). The first visit was the reference; the women served as their controls. The concentrations of leptin, GLP-1, and hs-CRP were assessed from plasma. Dietary intake was assessed using food records (FRs). In addition, weight, height, body mass index (BMI), and plasma levels of estradiol, glucose, HbA1c, insulin, and lipids were monitored. Twenty-six of the subjects also had a postprandial test. RESULTS: During the stimulation protocol, leptin concentrations elevated (P < 0.001), and energy intake decreased (P = 0.03), while estradiol levels increased (P < 0.001). GLP-1 levels unchanged (P = 0.75) and hs-CRP (P = 0.03) concentrations diminished, while estradiol levels increased. CONCLUSION: No increased food intake or weight gain occurred during the stimulation protocol; thus, leptin may protect from overeating during high estradiol levels, and leptin resistance may not occur during a short follow-up. Also, a favorable anti-inflammatory effect was detected. During this study, we observed no harmful metabolic effects, which might affect negatively maternal health.

Endothelial function and concentrations of high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha during a long agonist IVF protocol.

We examined possible changes in endothelial function during a long agonist in vitro fertilization (IVF) protocol. We measured flow-mediated dilatation (FMD) and FMD percent (FMD%) from the brachial artery and plasma levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-〈). We studied longitudinally three time points in 27 women undergoing a long agonist IVF treatment at Kuopio University Hospital. The first visit was at the beginning of their period (low estradiol). The other two visits were during gonadotrophin-releasing hormone (GnRH) analog downregulation (low estradiol) and at the end of follicle-stimulating hormone (FSH) stimulation (high estradiol). The first visit was used as the reference, and the women served as their own controls. During the stimulation protocol, FMD and FMD% remained. Toward the end of stimulation, hsCRP (P = 0.003), IL-6 (P = 0.04), and TNF-〈 (P = 0.008) concentrations all decreased, while estradiol levels increased (P < 0.001). Correlations between estradiol and proinflammatory factors or FMD were, however, non-significant. The only significant correlation appeared between FMD% and hsCRP at Visit 2 (r = 0.485, P = 0.01). In conclusion, IVF stimulation promoted no change in endothelial function, whereas hsCRP, IL-6, and TNF-〈 decreased. These findings indicate that estrogen may improve the cytokine profile among healthy women undergoing IVF, but this is not reflected in endothelial function.

Risk factors for adverse outcomes in vaginal preterm breech labor.

PURPOSE: To assess the risk factors for adverse outcomes in attempted vaginal preterm breech deliveries. METHODS: A retrospective case-control study, including 2312 preterm breech deliveries (24 + 0 to 36 + 6 gestational weeks) from 2004 to 2018 in Finland. The preterm breech fetuses with adverse outcomes born vaginally or by emergency cesarean section were compared with the fetuses without adverse outcomes with the same gestational age. A multivariable logistic regression analysis was used to calculate the risk factors for adverse outcomes (umbilical arterial pH below 7, 5-min Apgar score below 4, intrapartum stillbirth and neonatal death < 28 days of age). RESULTS: Adverse outcome in vaginal preterm breech delivery was associated with maternal obesity (aOR 32.19, CI 2.97-348.65), smoking (aOR 2.29, CI 1.12-4.72), congenital anomalies (aOR 4.50, 1.56-12.96), preterm premature rupture of membranes (aOR 1.87, CI 1.00-3.49), oligohydramnios (28-32 weeks of gestation: aOR 6.50, CI 2.00-21.11, 33-36 weeks of gestation: aOR 19.06, CI 7.15-50.85), epidural anesthesia in vaginal birth (aOR 2.44, CI 1.19-5.01), and fetal growth below the second standard deviation (28-32 weeks of gestation: aOR 5.89, CI 1.00-34.74, 33-36 weeks of gestation: aOR 12.27, CI 2.81-53.66). CONCLUSION: The study shows that for each subcategory of preterm birth, there are different risk factors for adverse neonatal outcomes in planned vaginal breech delivery. Due to the extraordinary increased risk of adverse outcomes, we would recommend a planned cesarean section in very preterm breech presentation (28 + 0 to 32 + 6 weeks) with severe maternal obesity, oligohydramnios, or fetal growth restriction and in moderate to late preterm breech presentation (33 + 0 to 36 + 6 weeks) with oligohydramnios or fetal growth restriction.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

The effect of maternal alcohol and drug abuse on first trimester screening analytes: a retrospective cohort study.

BACKGROUND: The purpose of this study was to determine whether first trimester trisomy screening (FTS) parameters are affected by alcohol and drug use. METHODS: A routine combined FTS including measurements of maternal serum levels of free ß-human chorionic gonadotropin subunit (free ß-hCG) and pregnancy-associated plasma protein A (PAPP-A) were measured at 9-11 weeks of gestation, and fetal nuchal translucency thickness (NTT) at 11-13 weeks of gestation. In total 544 women with singleton pregnancies [71 alcohol and drug abusers, 88 smokers, 168 non-smokers delivering a small for gestational age (SGA) child, and 217 unexposed control women] were assessed. RESULTS: Free ß-hCG levels were higher in alcohol and drug abusing than in unexposed pregnant women [mean 1.5 vs. 1.2 multiples of medians (MoM); P = 0.013]. However, stepwise multiple linear regression analyses suggested that smoking could explain increased free ß-hCG. Additionally, we observed lower PAPP-A levels in the smoking mothers (0.9 vs. 1.2 MoM; P = 0.045) and in those giving birth to an SGA child compared to the controls (1.1 vs.. 1.2 MoM; P < 0.001). Fetal NTT did not differ significantly between any of the groups. CONCLUSIONS: The present study shows increased free ß-hCG levels in alcohol and drug abusers, but maternal smoking may explain the result. Maternal serum PAPP-A levels were lower in smoking than non-smoking mothers, and in mothers delivering an SGA child. However, FTS parameters (PAPP-A, free ß-hCG and NTT) seem not to be applicable for the use as alcohol biomarkers because of their clear overlap between alcohol abusers and healthy controls.

Associations between maternal age and socioeconomic status with smoking during the second and third trimesters of pregnancy: a register-based study of 932 671 women in Finland from 2000 to 2015.

OBJECTIVES: This study aimed to explore the association between maternal age and smoking during the second and third trimesters of pregnancy across socioeconomic groups and to evaluate the interacting effect of maternal age and socioeconomic status on smoking with a view to informing public health interventions. DESIGN: This is a register-based study. SETTINGS: Data from the Finnish Medical Birth Register were cross-linked with background data from Statistics Finland. PARTICIPANTS: The information of 932 671 pregnant women who gave birth in Finland from 2000 to 2015. MAIN OUTCOME MEASURES: Maternal smoking during the second and third trimesters of pregnancy by occupation and maternal age. RESULTS: The proportion of women who smoked during the second and third trimesters of pregnancy was 10.5%. Using women 30-34 years as the reference group, adjusted ORs (aOR) and 95% CIs for smoking were 6.02 (5.81 to 6.24) in women below 20 years and 2.77 (2.71 to 2.84) in women 20 to 24 years. The prevalence of smoking across socioeconomic groups compared with upper-level employees increased, peaking for women in manual occupations (aOR 3.39, 95% CI 3.25 to 3.52) and unemployed women (aOR 4.49, 95% CI 4.30 to 4.68). Significant interactions on the additive scale with the relative excess risk due to interaction >2 were found for unemployed women aged 25-29 years and for teenage mothers and mothers aged 20-24 years across all socioeconomic groups, but not for self-employed women. CONCLUSIONS: Smoking during the second and third trimesters of pregnancy was most common among teenage mothers across all socioeconomic groups. The association between maternal age and smoking differed by socioeconomic status for young mothers. Interventions should address a wider range of maternal risk factors among young mothers with low socioeconomic status and simultaneously target a broader number of women who smoke during the pregnancy.

The effect of different estradiol levels on carotid artery distensibility during a long agonist IVF protocol.

BACKGROUND: This study was made to figure out, does low and high estradiol levels during in vitro fertilization (IVF) cycles have a different effect on carotid artery distensibility (Cdis), carotid artery diameter (Cdia), blood pressure and metabolic factors? Can the stimulation protocol be considered safe to women's vasculature? METHODS: We studied 28 women having a long agonist protocol IVF-treatment in Kuopio University Hospital during the years 2011-2016. Patients were examined at three time points: in the beginning of their own period (low estradiol), during the gonadotrophin releasing hormone (GnRH) analogue downregulation (low estradiol) and during the follicle stimulating hormone (FSH) stimulation (high estradiol). Women served as their own controls and their menstrual phase (2- to 5-day period after the beginning of menstruation with low estrogen) was used as the reference. Cdis and Cdia were assessed using ultrasound. Blood pressure, weight, estradiol levels and lipids were monitored. RESULTS: Cdis, Cdia, systolic and diastolic blood pressures peaked during the GnRH-analogue treatment with the lowest estradiol levels. Cdis, Cdia and systolic blood pressures declined by 11% (P = 0.002), 3,8% (P < 0.001) and 2,5% (P = 0.026) during the FSH-stimulation when the estradiol levels were high. Cdis correlated significantly (P < 0.05) with systolic blood pressure, diastolic blood pressure and triglycerides in high estrogenic environment and with diastolic blood pressure (P < 0.05) when estrogen profiles were low. CONCLUSIONS: Carotid artery stiffens during the high estradiol levels compared to low levels and this was not explained by the higher diameter of the carotid artery, hyperlipidemia or blood pressure profiles. All the changes in Cdis and Cdia are variations of normal, and if there is no history of cardiovascular problems, it can be considered, that the stimulation protocol is not hazardous to vasculature.

Smoking during pregnancy reduces vitamin D levels in a Finnish birth register cohort.

OBJECTIVE: Maternal vitamin D level in pregnancy may have implications for both the mother and fetus. Deficiency of vitamin D has been linked to several pregnancy complications and fetal skeletal health. Smoking has been associated with reduced serum level of the vitamin D metabolite, 25-hydroxyvitamin D (25(OH)D). DESIGN: A nested case-control study within the Finnish Maternity Cohort, a population-based cohort which includes first-trimester sera from 98 % of pregnancies in Finland since 1987. The selection consisted of women with uncomplicated pregnancies. We studied serum concentration of 25(OH)D in 313 non-smoking and forty-six self-reported smoking pregnant women. SETTING: We hypothesize that pregnant smokers may have an increased risk of low 25(OH)D levels especially during winter months. PARTICIPANTS: A control group from an unpublished pregnancy complication study consisting of 359 uncomplicated pregnancies. Individuals who reported that they do not smoke were considered 'non-smokers' (n 313) and those who reported continued smoking after the first trimester of pregnancy were considered 'smokers' (n 46). RESULTS: Smokers had significantly lower levels of 25(OH)D irrespective of sampling time (P<0·0001). Furthermore, during the low sun-exposure season, only 14 % of smokers met the guideline level of 40 nmol/l for serum 25(OH)D in comparison with 31 % of non-smokers. CONCLUSIONS: Expectant mothers who smoke have an increased risk of vitamin D deficiency during low sun-exposure months in northern regions. Further studies are needed to assess the associated risks for maternal and fetal health as well as possible long-term implications for the infant.

Impact of obesity on angiogenic and inflammatory markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort.

BACKGROUND: While several studies have demonstrated that obesity increases the risk of pre-eclampsia (PE), the mechanisms have yet to be elucidated. We assessed the association between maternal/paternal obesity and PE and hypothesized that maternal body mass index (BMI) would be associated with an adverse inflammatory and angiogenic profile. High-sensitivity C-reactive protein (hs-CRP) and following serum angiogenic markers were determined: soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). METHODS: Data on BMI were available from 1450 pregnant women with PE and 1065 without PE. Serum concentrations of hs-CRP and angiogenic markers were available from a subset at first and third trimesters. RESULTS: Prepregnancy BMI was higher in the PE group than in controls (mean ± SD) 25.3 ± 5.2 vs. 24.1 ± 4,4, p < 0.001, adjusted for parity, mother's age, and smoking status before pregnancy. Increased hs-CRP concentrations were observed in both PE and non-PE women similarly according to BMI category. In women with PE, a higher BMI was associated with lower sFlt-1 and sEng concentrations throughout the pregnancy (p = 0.004, p = 0.008, respectively). There were no differences in PlGF in PE women according to BMI. CONCLUSIONS: We confirmed increased pre-pregnancy BMI in women with PE. Enhanced inflammatory state was confirmed in all women with overweight/obesity. Partly paradoxically we observed that PE women with obesity had less disturbed levels of angiogenic markers than normal weight women with PE. This should be taken into account when angiogenic markers are used in PE prediction.

Kuopio birth cohort - design of a Finnish joint research effort for identification of environmental and lifestyle risk factors for the wellbeing of the mother and the newborn child.

BACKGROUND: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. METHODS: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omics; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. DISCUSSION: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.

The association between gestational diabetes mellitus and postpartum depressive symptomatology: A prospective cohort study.

BACKGROUND: The literature suggests an association between type 2 diabetes mellitus and depression, but data on the association between gestational diabetes mellitus (GDM) and postpartum depressive symptomatology (PPDS) are scarce. METHODS: Altogether, 1066 women with no previous mental health issues enrolled in the Kuopio Birth Cohort (KuBiCo, www.kubico.fi) were selected for this study. GDM was diagnosed according to the Finnish Current Care Guidelines. Depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS) during the third trimester of pregnancy and eight weeks after delivery. Additionally, a subgroup of women (n = 505) also completed the EPDS during the first trimester of pregnancy. RESULTS: The prevalence rates of GDM and PPDS in the whole study population were 14.1% and 10.3%, respectively. GDM was associated with an increased likelihood of belonging to the PPDS group (OR 2.23, 95% CI 1.23-4.05; adjusted for maternal age at delivery, BMI in the first trimester, smoking before pregnancy, relationship status, nulliparity, delivery by caesarean section, gestational age at delivery, neonatal intensive care unit admission and third-trimester EPDS scores). A significant association between GDM and PPDS was found in the subgroup of women with available data on first-trimester depression (n = 505). LIMITATIONS: The participation rate of the KuBiCo study was relatively low (37%). CONCLUSIONS: Women with GDM may be at increased risk of PPDS. Future studies should investigate whether these women would benefit from a closer follow-up and possible supportive interventions during pregnancy and the postpartum period to avoid PPDS.

Manual handling of burdens as a predictor of birth outcome-a Finnish Birth Register Study.

Background: Negative effects of manual handling of burdens on pregnancy outcomes are not elucidated in Finland. This study examines the association between perinatal outcomes and occupational exposure to manual handling of burdens. Methods: The study cohort was identified from the Finnish Medical Birth Register (MBR, 1997-2014) and information on exposure from the Finnish job-exposure matrix (FINJEM) 1997-2009. The cohort included all singleton births of mothers who were classified as 'service and care workers' representing the exposure group (n=74 286) and 'clerks' as the reference (n=13 873). Study outcomes were preterm birth (PTB) (<37 weeks), low birthweight (LBW) (<2500 g), small for gestational age (<2.5th percentile), perinatal death (stillbirth or early neonatal death within first seven days) and eclampsia. We used logistic regression analysis to calculate odds ratio (OR) and adjusted for maternal age, marital status, BMI, parity and smoking during pregnancy. Results: The risks of PTB [OR 1.16, 95% confidence interval (CI) 1.06-1.27], LBW (OR 1.12, 95% CI 1.01-1.25) and perinatal death (OR 1.51, 95% CI 1.09-2.09) were significantly higher among the high exposure group than in the reference group. All adverse outcomes were statistically insignificant among primiparous women except perinatal death (OR=1.95, 95% CI 1.13-3.39). Conclusions: The study indicates that the risk of adverse pregnancy outcomes might be more common among women that are highly exposed to occupational manual handling of burdens. The results should be interpreted with caution due to the use of occupational level exposure. Further studies with information on individual level exposure and start of maternity leave are recommended.

Angiogenic profile in the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort.

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. sFlt-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 at second/third trimester in PE women. Higher concentrations of s-Flt1, endoglin and higher sFlt/PlGF ratio were found at the third trimester in primiparous women compared to multiparous women. Primiparous PE women also had lower concentrations of PlGF at 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 not 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.

Alcohol and substance use are associated with altered metabolome in the first trimester serum samples of pregnant mothers.

BACKGROUND: Although the effects of alcohol on metabolic processes in the body have been studied widely, there do not appear to be any previous reports clarifying how substance abuse changes metabolic profiles of pregnant women during the first trimester of pregnancy. OBJECTIVE: Our aim was to evaluate the effect of substance abuse, especially alcohol use, on the metabolic profile of pregnant women during the first trimester. STUDY DESIGN: We applied mass spectrometry based non-targeted metabolite profiling of serum collected during routine visit to the hospital between gestational weeks 9 + 0 to 11 + 6 from controls (n = 55), alcohol users (n = 19), drug users (n = 24) and tobacco smokers (n = 40). RESULTS: We observed statistically significantly differences among the study groups in serum levels of glutamate, glutamine, and serotonin (p-values ≤ 0.0001). The serum levels of glutamate were increased in alcohol and drug using mothers when compared to the controls, whereas levels of glutamine were decreased in alcohol and drug using mothers. In addition, serum levels of serotonin were decreased in alcohol using mothers when compared to the controls. CONCLUSION: The present study shows that alcohol and drug use were associated with increased glutamate, and decreased glutamine levels, and alcohol use is associated with decreased serotonin levels. This study serves as a proof-of-concept that the metabolite profile of human first trimester serum samples could be used to detect alcohol exposure during pregnancy.

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.

Angiogenic profile and smoking in the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort.

OBJECTIVES: The biological mechanism by which smoking reduces the risk of pre-eclampsia (PE) is unresolved. We studied serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and their ratio, in addition to soluble endoglin (sEng) in early and late pregnancy to ascertain whether these factors are altered in women who smoke. SUBJECTS AND METHODS: First trimester serum samples were available from 217 women who later developed PE and 238 women who did not develop PE. Second/third trimester serum samples were available from 174 PE and 54 non-PE women. RESULTS: PE women who smoked during pregnancy had elevated first trimester concentrations of serum PlGF [geometric mean (95% CI): 39.8 (32.6-48.5) pg/ml, p = .001] and reduced sEng concentration [5.0 (4.6-5.6) ng/ml, p = .047] compared to PE non-smokers [30.0 (28.1-32.1) pg/ml and 6.1 (5.9-6.4) ng/ml, respectively]. Non-smoking women in the PE group had the highest sFlt-1/PlGF ratio in early and late pregnancy. CONCLUSIONS: The protective effect of smoking in reducing the risk of PE may be due to the early pregnancy change towards pro-angiogenic marker profile. Also, in late pregnancy, smoking exerted effect in sFlt-1/PlGF ratio in PE pregnancies, and may complicate its use as a prognostic and diagnostic marker. Key messages Smoking appears to have angiogenic effects in early pregnancy with reduced sEng concentrations and elevated PlGF concentrations in both normal and PE pregnancies. Throughout pregnancy, smoking exerted effect in PlGF concentration and sFlt-1/PlGF ratio in PE pregnancies, and thus may complicate its use as a prognostic and diagnostic marker.

Women's choices for invasive or non-invasive testing: influence of gestational age and service delivery.

OBJECTIVE: To investigate the factors influencing women's post-counseling choices between non-invasive prenatal testing (NIPT) and invasive prenatal diagnosis in pregnancies with elevated a priori risk of fetal chromosomal abnormalities or after the initial screening. METHODS: Data were collected from test choice database at Fetomaternal Medical Center (FMC) at Helsinki University Hospital, Finland. We focused on the women with gestational age less than 15 weeks and who were offered NIPT or invasive procedure (CVS or amniocentesis) after pre-test counseling. The Chi-square test, ANOVA test and multinomial logistic regressions were used to explore significant factors affecting women's choice. RESULTS: In 2015, 333 women in our study group participated in prenatal testing, 260 (78.1%) initially chose NIPT, 62 (18.6%) chose CVS and 11 (3.3%) chose amniocentesis. There was a statistically significant difference among these three test groups with regard to gestational age (p = 0.025), counseling day (p < 0.001), certain medical indications and serum screening risk score (p = 0.028). However, multinomial logistic regressions only confirmed the predictive value of gestational age and counseling day on women's choice. CONCLUSIONS: Maternal age was not a strong factor affecting women's choice for prenatal further tests. Medical indications and risk scores have less influence than previously thought. Gestational age and service availability were strong factors. © 2016 John Wiley & Sons, Ltd.

Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators.

CONTEXT AND OBJECTIVES: The study represents the first comprehensive analysis of Stanniocalcin-1 (STC1) hormone in human pregnancy, assessing clinical, lifestyle, and genetic determinants of circulating STC1 at term. DESIGN, SETTING, AND PARTICIPANTS: Participants included women with (n = 50) and without (n = 316) preeclampsia (PE) at delivery, recruited in the REPROgrammed fetal and/or maternal METAbolism (REPROMETA) study (2006-2011, Estonia). Genetic association analysis combined PE cases (n = 597) and controls (n = 623) from the REPROMETA and Finnish Genetics of Preeclampsia Consortium (2008-2011) studies. MAIN OUTCOME MEASURE(S): Maternal postpartum plasma STC1 was measured by ELISA (n = 366) and placental STC1 gene expression by TaqMan quantitative RT-PCR (n = 120). Genotyping was performed using Sequenom MassArray. RESULTS: Significantly higher STC1 plasma level was measured for the PE (median, 1952 pg/mL; 1030-4284 pg/mL) compared with non-PE group (median, 1562 pg/mL; 423-3781 pg/mL; P = 3.7 × 10-4, Mann-Whitney U test). Statistical significance was enhanced after adjustment for cofactors (linear regression, P = 1.8 × 10-6). STC1 measurements were negatively correlated with maternal smoking. Prepregnancy body mass index had a positive correlation with STC1 only among PE patients (r = 0.45; P = .001). The strongest genetic association with hormone concentrations was detected for STC1 single nucleotide polymorphisms rs3758089 (C allele: minor allele frequency, 5%; linear regression: ß = 249.2 pg/mL; P = .014) and rs12678447 (G allele: minor allele frequency, 7%; ß = 147.0 pg/mL; P = .082). rs12678447 placental genotypes were significantly associated with STC1 gene expression (P = .014). The REPROMETA/Finnish Genetics of Preeclampsia Consortium meta-analysis suggested an increased risk to develop late-onset PE for the rs12678447 G allele carriers (P = .05; odds ratio = 1.38 [0.98-1.93]). CONCLUSIONS: Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone levels.

Parental smoking and cessation during pregnancy and the risk of childhood asthma.

BACKGROUND: To evaluate the association between maternal and paternal smoking during pregnancy, and asthma among offspring. METHODS: We conducted a hospital-based birth retrospective observational birth cohort study in a University-based Obstetrics and Gynecology Department, Kuopio University Hospital, Finland. 39 306 women, delivering between 1989 and 2006, were linked to the national register for asthma reimbursement for their offspring (2641 asthmatics). Pregnancy factors were recorded during pregnancy. RESULTS: The risk of asthma was significantly elevated if both parents smoked (aOR 3.7; 95 % Cl 3.2-4.4) and it remained high in only paternal smoking families (aOR 2.9; 95 % Cl 2.5-3.3) as well as only maternal smoking families (aOR 1.7; 95 % Cl 1.2-2.2). Paternal cessation of smoking during pregnancy seemed to reduce the risk of asthma regardless of maternal smoking (aOR 0.3-0.4). CONCLUSIONS: Parental smoking, and especially paternal smoking, was significantly associated with the risk of asthma in offspring and paternal cessation of smoking during pregnancy was associated with a decreased risk of childhood asthma regardless of maternal smoking. The results indicate that both parents should be encouraged to quit smoking during pregnancy, since it is a relatively easy and cheap way to reduce the risk of asthma in offspring. TRIAL REGISTRATION: The study is registered in Kuopio University Hospital register (TUTKI): ID5302448.