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1.
Psychol Med ; : 1-13, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439060

RESUMO

BACKGROUND: Maternal depression during pregnancy increases the risk for adverse developmental outcomes in children. However, the underpinning biological mechanisms remain unknown. We tested whether depression was associated with levels of and change in the inflammatory state during pregnancy, if early pregnancy overweight/obesity or diabetes/hypertensive pregnancy disorders accounted for/mediated these effects, and if depression added to the inflammation that typically accompanies these conditions. METHODS: We analyzed plasma high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls at three consecutive stages during pregnancy, derived history of depression diagnoses before pregnancy from Care Register for Healthcare (HILMO) (N = 375) and self-reports (N = 347) and depressive symptoms during pregnancy using the Center for Epidemiological Studies Depression Scale completed concurrently to blood samplings (N = 295). Data on early pregnancy body mass index (BMI) and diabetes/hypertensive pregnancy disorders came from medical records. RESULTS: Higher overall hsCRP levels, but not change, during pregnancy were predicted by history of depression diagnosis before pregnancy [HILMO: mean difference (MD) = 0.69 standard deviation (s.d.) units; 95% confidence interval (CI) 0.26-1.11, self-report: MD = 0.56 s.d.; 95% CI 0.17-0.94] and higher depressive symptoms during pregnancy (0.06 s.d. per s.d. increase; 95% CI 0.00-0.13). History of depression diagnosis before pregnancy also predicted higher overall glycoprotein acetyls (HILMO: MD = 0.52 s.d.; 95% CI 0.12-0.93). These associations were not explained by diabetes/hypertensive disorders, but were accounted for and mediated by early pregnancy BMI. Furthermore, in obese women, overall hsCRP levels increased as depressive symptoms during pregnancy increased (p = 0.006 for interaction). CONCLUSIONS: Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity.

2.
Nat Commun ; 10(1): 2548, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186427

RESUMO

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.


Assuntos
Metilação de DNA/genética , DNA/sangue , Interação Gene-Ambiente , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Genótipo , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
3.
Sleep Med ; 56: 201-210, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30819657

RESUMO

OBJECTIVE: Maternal depressive symptoms during pregnancy have been associated with poor offspring sleep. Yet, it remains unknown whether depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain time periods in pregnancy, whether associations are specific to pregnancy stage, whether maternal symptomatology after pregnancy mediates or adds to the prenatal effects, and whether any effects are specific to some child sleep characteristics. METHODS: A total of 2321 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiological Studies Depression Scale biweekly between gestational weeks + days 12 + 0/13 + 6 and 38 + 0/39 + 6. At child's mean age of 3.5 (standard deviation = 0.7) years, mothers completed the Beck Depression Inventory-II and answered questions on child sleep quantity and quality using the Brief Infant Sleep Questionnaire (BISQ) and sleep disorders using the Sleep Disturbance Scale for Children. RESULTS: Maternal depressive symptoms showed high stability throughout pregnancy. Children of mothers with clinically significant symptomatology throughout pregnancy had shorter mother-rated sleep duration, longer sleep latency, higher odds for waking up two or more times during the night and for total and several specific sleep disorders. These associations were robust to covariates. However, maternal depressive symptoms at the child follow-up fully mediated the associations with sleep duration and awakenings, partially mediated those with sleep latency and disorders, and added to the effects on sleep disorders. CONCLUSION: Maternal depressive symptoms throughout pregnancy are associated with mother-rated child sleep quantity, quality, and disorders. Maternal depressive symptoms at child follow-up mediate and add to the prenatal adverse effects on child sleep characteristics.

4.
Psychol Med ; : 1-11, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688183

RESUMO

BACKGROUND: Synthetic glucocorticoids, to enhance fetal maturation, are a standard treatment when preterm birth before 34 gestational weeks is imminent. While morbidity- and mortality-related benefits may outweigh potential neurodevelopmental harms in children born preterm (<37 gestational weeks), this may not hold true when pregnancy continues to term (⩾37 gestational weeks). We studied the association of antenatal betamethasone exposure on child mental health in preterm and term children. METHODS: We included 4708 women and their children, born 2006-2010, from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction Study with information on both antenatal betamethasone treatment and child mental and behavioral disorders from the Finnish Hospital Discharge Register from the child's birth to 31 December 2016. Additional follow-up data on mother-reported psychiatric problems and developmental milestones were available for 2640 children at 3.5 (s.d. = 0.07) years-of-age. RESULTS: Of the children, 187 were born preterm (61 betamethasone-exposed) and 4521 at term (56 betamethasone-exposed). The prevalence of any mental and behavioral, psychological development, emotional and behavioral, and comorbid disorders was higher in the betamethasone-exposed, compared to non-exposed children [odds ratio 2.76 (95% confidence interval 1.76-4.32), 3.61 (2.19-5.95), 3.29 (1.86-5.82), and 6.04 (3.25-11.27), respectively]. Levels of psychiatric problems and prevalence of failure to meet the age-appropriate development in personal-social skills were also higher in mother-reports of betamethasone-exposed children. These associations did not vary significantly between preterm and term children. CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30392118

RESUMO

Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days (SD 3.2, range 1-30), the Infant Behavior Questionnaire-Revised on temperament at 6.5 months (SD 0.9, range 4.2-12.4), and the Ages and Stages Questionnaire-3 on developmental milestones and the Child Behavior Checklist on behavioral problems at 3.5 years (SD 0.7, range 1.9-6.0). Maternal depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (infancy follow-ups) and Beck Depression Inventory-II (childhood follow-up). Father-rated infant temperament and paternal depressive symptoms were also available (n = 1474). Higher levels of infant regulatory behavior problems predicted higher levels of mother- and father-rated negative affectivity temperament (0.13 SD units per SD unit, 95% confidence interval 0.09-0.17; and 0.09, 0.04-0.14, respectively), lower levels of mother-rated orienting/regulation temperament (- 0.09, - 0.13 to - 0.05) and problem-solving skills (- 0.12, - 0.21 to - 0.04), and higher levels of Externalizing (0.07, 0.03-0.11) and Total behavioral problems (0.07, 0.03-0.11). Regulatory behaviors partially mediated the effect of maternal depressive symptoms. Regulatory behavior problems already during the first month of life predict neurobehavioral outcomes, and partially mediate the effect of maternal depressive symptoms. Our study may inform design of interventions aimed at timely prevention in children at risk.

6.
Pediatr Res ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305694

RESUMO

INTRODUCTION: Maternal overweight/obesity and comorbid hypertensive disorders and gestational diabetes associate with neurodevelopmental delay in the offspring in childhood. We hypothesize that these maternal conditions associate also with the offspring regulatory behavior problems and impact on neurodevelopment via the offspring regulatory behavior. METHODS: A number of 3117 women of the PREDO Study filled in a questionnaire on regulatory behavior problems at the child's mean age of 16.9 days and 2116 of them a questionnaire on developmental milestones at the child's mean age of 42.2 months. Data on maternal BMI and comorbid disorders come from the Finnish Medical Birth Register. RESULTS: Offspring of overweight/obese mothers in comparison to normal weight mothers had higher levels of regulatory behavior problems and 22% (95% confidence interval 5-42%) higher odds of having problems on multiple domains of behavioral regulation at the mean age of 16.9 days. Offspring regulatory behavior problems partially mediated the association between maternal overweight/obesity and developmental milestones comprising communication, gross motor, fine motor, problem solving, and personal/social domains of development. Comorbid disorders did not associate with offspring regulatory behavior problems. CONCLUSION: Regulatory behavior problems of the offspring have prenatal origins and partially mediate the effects of maternal overweight/obesity on offspring neurodevelopment.

7.
BMC Pregnancy Childbirth ; 18(1): 279, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970026

RESUMO

BACKGROUND: The proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGß, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. METHODS: We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. RESULTS: We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGß higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.

8.
J Am Acad Child Adolesc Psychiatry ; 57(5): 321-328.e2, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29706161

RESUMO

OBJECTIVE: Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. METHOD: A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. RESULTS: Maternal history of depression diagnosed before pregnancy (mean difference = -0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per 1-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. CONCLUSION: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.

9.
Int J Obes (Lond) ; 42(5): 995-1007, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29686379

RESUMO

BACKGROUND/OBJECTIVES: Previous studies have linked maternal pre-pregnancy obesity (BMI ≥30 kg/m2) with suboptimal neurodevelopment in her offspring; however, the literature is not entirely consistent. Whether these effects are muddled by maternal self-reports of pre-pregnancy weight and height, or are driven or amplified by the well often comorbid hypertensive and diabetic pregnancy and pre-pregnancy disorders, remains unclear. We examined whether maternal early pregnancy obesity is associated with developmental delay in her offspring, and if the associations are driven or amplified by diabetic and hypertensive pregnancy and pre-pregnancy disorders. SUBJECTS/METHODS: A total of 2504 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Data on maternal early pregnancy obesity, pre-pregnancy, and gestational hypertension, pre-eclampsia, type 1 and gestational diabetes were derived from the Finnish Medical Birth Register. At the child's mean age of 42.1 (SD = 8.2) months the mothers completed the Ages and Stages Questionnaire (ASQ) Third edition for developmental milestones. RESULTS: Children of obese mothers had 1.81-2.74 (p-values <0.02) higher odds of failing to meet the development that is typical for a child's age (developmental domain score ≤-2SD below the child's age) on the communication, fine and gross motor, problem solving and personal/social skills and children of overweight mothers had 2.14 (p = 0.002) higher odds of failing to meet the development that is typical for the child's age on communication skills. Odds of developmental delay were also higher for children of mothers with pre-eclampsia and gestational diabetes. The associations were robust to covariates and confounders, the effects of overweight/obesity and pre-eclampsia were not driven by the other disorders, and overweight/obesity and hypertensive and diabetic disorders did not show additive effects. CONCLUSIONS: Maternal early pregnancy overweight, obesity, and pre-eclampsia are independently associated with neurodevelopmental delay in her offspring. Further studies unraveling the underlying mechanisms are warranted.

10.
Depress Anxiety ; 35(8): 732-741, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29667739

RESUMO

BACKGROUND: Maternal depressive symptoms during and after pregnancy predict poorer child neurodevelopment. The effects of timing, symptom severity, and additive influences remain unclear. METHODS: A total of 2,231 mothers of the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiological Studies Depression Scale biweekly up to 14 times during pregnancy and twice up to 12 months after pregnancy. At child's age 1.9-5.7 years, the mothers completed the Beck Depression Inventory-II on their concurrent depressive symptoms and Ages and Stages Questionnaire on child developmental milestones. RESULTS: Higher mean maternal depressive symptoms, each biweekly score, and consistently clinically relevant symptomatology during pregnancy predicted lower total developmental milestones, fine and gross motor, communication, problem solving, and personal/social skills scores in children. Although maternal depressive symptoms up to 12 months after pregnancy and in early childhood also predicted lower developmental milestones scores, developmental milestones scores were the lowest in children whose mothers' depressive symptoms were above the clinical cutoff either only during pregnancy, both during and up to 12 months after pregnancy, or at each three time-points. CONCLUSION: Maternal depressive symptoms during pregnancy, in the first year postpartum and in early childhood are associated with poorer child neurodevelopment. Our findings further suggest that antenatal and postpregnancy depression have additive effects on neurodevelopment. Children of mothers with the most chronic and severe depressive symptoms during pregnancy had the most neurodevelopmental disadvantages. Our findings emphasize the adverse effects of maternal depression during and after pregnancy and in early childhood on child neurodevelopment.


Assuntos
Desenvolvimento Infantil/fisiologia , Filho de Pais Incapacitados/psicologia , Transtorno Depressivo/psicologia , Mães/psicologia , Complicações na Gravidez/psicologia , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Gravidez
11.
Sci Rep ; 8(1): 791, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335435

RESUMO

Maternal depressive symptoms during pregnancy predict increased psychiatric problems in children. The underlying biological mechanisms remain unclear. Hence, we examined whether alterations in the morphology of 88 term placentas were associated with maternal depressive symptoms during pregnancy and psychiatric problems in 1.9-3.1-years old (Mean = 2.1 years) toddlers. Maternal depressive symptoms were rated biweekly during pregnancy with the Center of Epidemiological Studies Depression Scale (n = 86). Toddler psychiatric problems were mother-rated with the Child Behavior Checklist (n = 60). We found that higher maternal depressive symptoms throughout pregnancy [B = -0.24 Standard Deviation (SD) units: 95% Confidence Interval (CI) = -0.46; -0.03: P = 0.03; Mean difference = -0.66 SDs; 95% CI = -0.08; -1.23: P = 0.03; between those with and without clinically relevant depressive symptoms] were associated with lower variability in the placental villous barrier thickness of γ-smooth muscle actin-negative villi. This placental morphological change predicted higher total (B = -0.34 SDs: 95% CI = -0.60; -0.07: P = 0.01) and internalizing (B = -0.32 SDs: 95% CI = -0.56; -0.08: P = 0.01) psychiatric problems in toddlers. To conclude, our findings suggest that both maternal depressive symptoms during pregnancy and toddler psychiatric problems may be associated with lower variability in the villous membrane thickness of peripheral villi in term placentas. This lower heterogeneity may compromise materno-fetal exchange, suggesting a possible role for altered placental morphology in the fetal programming of mental disorders.


Assuntos
Depressão/patologia , Transtornos Mentais/diagnóstico , Mães/psicologia , Placenta/patologia , Actinas/metabolismo , Adulto , Pré-Escolar , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Lactente , Masculino , Relações Mãe-Filho , Pré-Eclâmpsia/diagnóstico , Gravidez , Complicações na Gravidez , Escalas de Graduação Psiquiátrica
12.
Psychol Med ; 48(14): 2353-2363, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29338797

RESUMO

BACKGROUND: Previous studies have linked maternal obesity with depressive symptoms during and after pregnancy. It remains unknown whether obesity associates with consistently elevated depressive symptoms throughout pregnancy, predicts symptoms postpartum when accounting for antenatal symptoms, and if co-morbid hypertensive and diabetic disorders add to these associations. We addressed these questions in a sample of Finnish women whom we followed during and after pregnancy. METHODS: Early pregnancy body mass index, derived from the Finnish Medical Birth Register and hospital records in 3234 PREDO study participants, was categorized into underweight (<18.5 kg/m2), normal weight (18.5-24.99 kg/m2), overweight (25-29.99 kg/m2), and obese (⩾30 kg/m2) groups. The women completed the Center for Epidemiological Studies Depression Scale biweekly during pregnancy, and at 2.4 (s.d. = 1.2) and/or 28.2 (s.d. = 4.2) weeks after pregnancy. RESULTS: In comparison to normal weight women, overweight, and obese women reported higher levels of depressive symptoms and had higher odds of clinically significant depressive symptoms during (23% and 43%, respectively) and after pregnancy (22% and 36%, respectively). Underweight women had 68% higher odds of clinically significant depressive symptoms after pregnancy. Overweight and obesity also predicted higher depressive symptoms after pregnancy in women not reporting clinically relevant symptomatology during pregnancy. Hypertensive and diabetic disorders did not explain or add to these associations. CONCLUSIONS: Maternal early pregnancy overweight and obesity and depressive symptoms during and after pregnancy are associated. Mental health promotion should be included as an integral part of lifestyle interventions in early pregnancy obesity and extended to benefit also overweight and underweight women.

13.
PLoS One ; 12(12): e0190248, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29267405

RESUMO

Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Mothers filled in the Center of Epidemiological Studies Depression Scale biweekly from 12+0-13+6 to 38+0-39+6 weeks+days of gestation or delivery, and the Beck Depression Inventory-II and the Conners' Hyperactivity Index at the child's age of 3 to 6 years (mean 3.8 years, standard deviation [SD] 0.5). Maternal depressive symptoms were highly stable throughout pregnancy, and children of mothers with consistently high depressive symptoms showed higher average levels (mean difference = 0.46 SD units, 95% Confidence Interval [CI] 0.36, 0.56, p < 0.001 compared to the low group), and proportion (32.1% vs. 14.7%) and odds (odds ratio = 2.80, 95% CI 2.20, 3.57, p < 0.001) of clinically significant ADHD symptoms. These associations were not explained by the effects of maternal depressive symptoms after pregnancy, which both added to and partially mediated the prenatal effects. Maternal depressive symptoms throughout pregnancy are associated with increased ADHD symptomatology in young children. Maternal depressive symptoms after pregnancy add to, but only partially mediate, the prenatal effects. Preventive interventions suited for the pregnancy period may benefit both maternal and offspring mental health.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Adulto , Criança , Pré-Escolar , Depressão/fisiopatologia , Feminino , Humanos , Gravidez
14.
Front Immunol ; 8: 589, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28611769

RESUMO

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.

15.
Clin Epigenetics ; 9: 49, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28503212

RESUMO

BACKGROUND: A recent study has shown that it is possible to accurately estimate gestational age (GA) at birth from the DNA methylation (DNAm) of fetal umbilical cord blood/newborn blood spots. This DNAm GA predictor may provide additional information relevant to developmental stage. In 814 mother-neonate pairs, we evaluated the associations between DNAm GA and a number of maternal and offspring characteristics. These characteristics reflect prenatal environmental adversity and are expected to influence newborn developmental stage. RESULTS: DNAm GA acceleration (GAA; i.e., older DNAm GA than chronological GA) of the offspring at birth was associated with maternal age of over 40 years at delivery, pre-eclampsia and fetal demise in a previous pregnancy, maternal pre-eclampsia and treatment with antenatal betamethasone in the index pregnancy, lower neonatal birth size, lower 1-min Apgar score, and female sex. DNAm GA deceleration (GAD; i.e., younger DNAm GA than chronological GA) of the offspring at birth was associated with insulin-treated gestational diabetes mellitus (GDM) in a previous pregnancy and Sjögren's syndrome. These findings were more accentuated when the DNAm GA calculation was based on the raw difference between DNAm GA and GA than on the residual from the linear regression of DNAm GA on GA. CONCLUSIONS: Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity.


Assuntos
Peso ao Nascer/genética , Metilação de DNA , Idade Gestacional , Adulto , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de Risco
16.
PLoS One ; 12(3): e0174399, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28350823

RESUMO

OBJECTIVES: Preeclampsia is divided into early-onset (delivery before 34 weeks of gestation) and late-onset (delivery at or after 34 weeks) subtypes, which may rise from different etiopathogenic backgrounds. Early-onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function. Our aim was to use cluster analysis to investigate clinical factors predicting the onset and severity of preeclampsia in a cohort of women with known clinical risk factors. METHODS: We recruited 903 pregnant women with risk factors for preeclampsia at gestational weeks 12+0-13+6. Each individual outcome diagnosis was independently verified from medical records. We applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, we computed the risk ratio of each disease outcome, relative to the risk in the general population. RESULTS: The risk of preeclampsia increased exponentially with respect to the number of risk factors. Our analysis revealed 25 number of clusters. Preeclampsia in a previous pregnancy (n = 138) increased the risk of preeclampsia 8.1 fold (95% confidence interval (CI) 5.7-11.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset preeclampsia 17.5 fold (95%CI 2.1-60.5). Cluster of those two risk factors together (n = 21) increased the risk of severe preeclampsia to 23.8-fold (95%CI 5.1-60.6), intermediate onset (delivery between 34+0-36+6 weeks of gestation) to 25.1-fold (95%CI 3.1-79.9) and preterm preeclampsia (delivery before 37+0 weeks of gestation) to 16.4-fold (95%CI 2.0-52.4). Body mass index over 30 kg/m2 (n = 228) as a sole risk factor increased the risk of preeclampsia to 2.1-fold (95%CI 1.1-3.6). Together with preeclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.5-20.9). Chronic hypertension (n = 60) increased the risk of preeclampsia 5.3-fold (95%CI 2.4-9.8), of severe preeclampsia 22.2-fold (95%CI 9.9-41.0), and risk of early-onset preeclampsia 16.7-fold (95%CI 2.0-57.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier preeclampsia, the risk of term preeclampsia increased 4.8-fold (95%CI 0.1-21.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of preeclampsia. CONCLUSION: The risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia.


Assuntos
Retardo do Crescimento Fetal/epidemiologia , Pré-Eclâmpsia/epidemiologia , Adulto , Teorema de Bayes , Análise por Conglomerados , Feminino , Retardo do Crescimento Fetal/prevenção & controle , Idade Gestacional , Humanos , Razão de Chances , Pré-Eclâmpsia/prevenção & controle , Gravidez , Fatores de Risco
18.
J Am Acad Child Adolesc Psychiatry ; 56(1): 30-39.e7, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27993226

RESUMO

OBJECTIVE: Maternal depressive symptoms during pregnancy are associated with increased risk of psychiatric problems in children. A more precise understanding of the timing of the symptoms during pregnancy and their independence of other prenatal and postnatal factors in predicting child psychopathology risk is needed. We examined whether maternal depressive symptoms during pregnancy predict child psychiatric problems, whether these associations are trimester- or gestational-week-specific and/or independent of pregnancy disorders, and whether maternal depressive symptoms after pregnancy mediate or add to the prenatal effects. METHOD: The study sample comprised 2,296 women and their children born in Finland between 2006-2010, participating in the prospective pregnancy cohort study Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) and followed up from 1.9 to 5.9 years of age. The women completed the Center for Epidemiologic Studies Depression Scale biweekly between gestational weeks+days 12+0/13+6 and 38+0/39+6 or delivery. In the follow-up, they completed the Beck Depression Inventory-II and Child Behavior Checklist 1½-5. RESULTS: Maternal depressive symptoms during pregnancy predicted significantly higher internalizing (0.28 SD unit per SD unit increase [95% CI = 0.24-0.32]), externalizing (0.26 [0.23-0.30]), and total problems (0.31 [0.27-0.35]) in children. These associations were nonspecific to gestational week and hence pregnancy trimester, independent of pregnancy disorders, and independent of, although partially mediated by, maternal depressive symptoms after pregnancy. Psychiatric problems were greatest in children whose mothers reported clinically significant depressive symptoms across pregnancy trimesters and during and after pregnancy. CONCLUSION: Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health.


Assuntos
Comportamento Infantil , Filho de Pais Incapacitados/estatística & dados numéricos , Depressão/epidemiologia , Transtornos Mentais/epidemiologia , Complicações na Gravidez/epidemiologia , Adulto , Criança , Pré-Escolar , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Transtornos Mentais/etiologia , Gravidez , Estudos Prospectivos
19.
Genome Biol ; 17(1): 206, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27717399

RESUMO

BACKGROUND: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. RESULTS: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. CONCLUSIONS: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.


Assuntos
Envelhecimento/genética , Biomarcadores/sangue , Metilação de DNA/genética , Idade Gestacional , Adulto , Peso ao Nascer , Ilhas de CpG/genética , Epigênese Genética , Feminino , Desenvolvimento Fetal/genética , Humanos , Recém-Nascido , Masculino , Gravidez
20.
Pregnancy Hypertens ; 6(1): 53-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26955773

RESUMO

BACKGROUND: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. METHODS: Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. RESULTS: Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves. CONCLUSIONS: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes.


Assuntos
Algoritmos , Análise Química do Sangue/normas , Biologia Computacional/métodos , Hipertensão Induzida pela Gravidez/sangue , Fator de Crescimento Placentário/sangue , Biomarcadores/sangue , Calibragem , Estudos de Casos e Controles , Bases de Dados Factuais , Estudos de Viabilidade , Feminino , Idade Gestacional , Humanos , Hipertensão Induzida pela Gravidez/diagnóstico , Variações Dependentes do Observador , Valor Preditivo dos Testes , Gravidez , Valores de Referência , Reprodutibilidade dos Testes
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