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Background: A negative association between obesity and pregnancy outcomes has been described, as well as between time sedentary and pregnancy outcomes. Most interventions based on physical activity involving obese pregnant women have failed in improving pregnancy outcomes. Exchanging time spent in sedentary activities with time spent in light-intensity activities, performed in a home-based setting, might help morbidly obese pregnant women. We aimed to assess the feasibility of an exercise intervention., Methods: An exercise intervention for morbidly obese pregnant women was designed involving morbidly obese pregnant women. Pregnant women with BMI ≥ 40 kg/m² with 20 or less weeks of gestation were invited to take part in the OPALS Feasibility Study. A home-based approach was employed. Participants were asked to perform the intervention for at least 12 weeks, and to register their performance in an activity diary. After the intervention, participants were asked to return the activity diary and answer a feasibility questionnaire., Results: In the intervention, 28 participants took part. Six women completed the intervention for 12 weeks or more. All declared they intended to keep on doing the intervention. All women reported that the exercises made them feel better., Conclusion: Empowering, and involving morbidly obese pregnant women in taking care of themselves and giving them realistic tasks to do on their own and around their environment helps to increase commitment, as does avoiding the effect of their own weight whilst exercising. A 20% of compliance was observed in this study, which might be explained by the difficulties that pregnancy and excess weight mean. Thus, for future studies, we suggest adding a supervision plan to increase that number.

Background: Maternal antenatal stress, including symptoms of depression, anxiety and perceived stress, is associated with mental and behavioral problems in children. Whether it is associated with child mental and behavioral disorders remains uncertain. We examined if maternal antenatal symptoms of depression, anxiety and perceived stress were associated with mental and behavioral disorders in their children, if the associations varied according to gestational week, stress type, fluctuating or consistently high symptoms, and if they were driven by maternal or paternal lifetime mood or anxiety disorders., Methods: 3365 mothers participating in the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiologic Studies Depression Scale, the State Anxiety Inventory and the Perceived Stress Scale up to 14 times throughout pregnancy. The Care Register for Health Care provided data on mental and behavioral (including neurodevelopmental) disorders for their children from birth (11/07/2006-07/24/2010) until 12/31/2016 and for parental lifetime mood and anxiety disorders until 12/31/2016., Results: The hazard of any childhood mental and behavioral disorder (HR=1.91, 95% CI: 1.39-2.51) was significantly higher for children whose mothers reported consistently high in comparison to consistently low levels of all types of stress throughout pregnancy. The associations remained significant when adjusted for maternal and paternal lifetime mood and anxiety disorders (and their comorbidity and timing and mood disorder type)., Conclusion: Maternal antenatal stress is associated with higher risk of childhood mental and behavioral disorders. Efforts to reduce maternal antenatal stress should be given a high priority to improve child mental health., (Copyright © 2020. Published by Elsevier B.V.)

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.

Vitamin B12 (B12) is a micronutrient essential for one-carbon (1C) metabolism. B12 deficiency disturbs the 1C cycle and alters DNA methylation which is vital for most metabolic processes. Studies show that B12 deficiency may be associated with obesity, insulin resistance and gestational diabetes; and with obesity in child-bearing women. We therefore hypothesised that the associations between B12 deficiency, BMI and the metabolic risk could be mediated through altered 1C metabolites in early pregnancy. We explored these associations in two different early pregnancy cohorts in the UK (cohort 1; n = 244 and cohort 2; n = 60) with anthropometric data at 10-12 weeks and plasma/serum sampling at 16-18 weeks. B12, folate, total homocysteine (tHcy), methionine, MMA, metabolites of 1C metabolism (SAM, SAH) and anthropometry were measured. B12 deficiency (< 150 pmol/l) in early pregnancy was 23% in cohort 1 and 18% in cohort 2. Regression analysis after adjusting for likely confounders showed that B12 was independently and negatively associated with BMI (Cohort 1: β = - 0.260, 95% CI (- 0.440, - 0.079), p = 0.005, Cohort 2: (β = - 0.220, 95% CI (- 0.424, - 0.016), p = 0.036) and positively with HDL cholesterol (HDL-C) (β = 0.442, 95% CI (0.011,0.873), p = 0.045). We found that methionine (β = - 0.656, 95% CI (- 0.900, - 0.412), p < 0.0001) and SAH (β = 0.371, 95% CI (0.071, 0.672), p = 0.017) were independently associated with triglycerides. Low B12 status and alteration in metabolites in 1C metabolism are common in UK women in early pregnancy and are independently associated with maternal obesity and dyslipidaemia. Therefore, we suggest B12 monitoring in women during peri-conceptional period and future studies on the pathophysiological relationship between changes in 1C metabolites and its association with maternal and fetal outcomes on larger cohorts. This in turn may offer potential to reduce the metabolic risk in pregnant women and their offspring.

The associations of maternal hypertensive pregnancy disorders with offspring mental disorders remain unclear. We examined whether maternal hypertensive disorders and maximum blood pressure during pregnancy predict offspring childhood mental disorders, whether the associations are independent of maternal and paternal mental disorders and paternal hypertensive disorders, independent of or additive with maternal early pregnancy overweight/obesity and diabetes mellitus disorders, and mediated or moderated by preterm birth, small-for-gestational-age birth and neonatal intensive care unit admission. Our prospective study comprised 4743 mother-child dyads of Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. Women were recruited to the study in early pregnancy at Finnish maternity hospitals. Children were born 2006 to 2010 and followed-up until December 31, 2016, to ages 6.4 to 10.8 years. Hypertensive pregnancy disorders were identified from medical records, Medical Birth Register, and Care Register for Health Care. Systolic and diastolic blood pressure were measured at antenatal clinics and hospital visits. Mental disorder diagnoses were identified from Care Register for Health Care. Maternal gestational and chronic hypertension, preeclampsia and its severity increased offspring hazard of any childhood mental disorder. The associations of preeclampsia (hazard ratio=1.66 [95% CI, 1.14-2.42]) and severe preeclampsia (hazard ratio=2.01 [95% CI, 1.08-3.73]) were independent of all covariates. Maternal hypertensive and diabetes mellitus disorders and overweight/obesity also additively increased offspring hazard of mental disorders. Preterm and small-for-gestational-age births and neonatal intensive care unit admission partially mediated the effects of any and severe preeclampsia on offspring mental disorders. To conclude, maternal hypertensive pregnancy disorders carry adverse consequences for offspring mental health.

Sleep disordered breathing (SDB) is a common obesity-related co-morbidity with strong associations to cardiometabolic disease. The risk of SDB is increased during pregnancy, particularly among obese pregnant women. Accumulating evidence suggests that an association exists between maternal SDB and the development of adverse pregnancy outcomes, particularly gestational diabetes and hypertensive disorders of pregnancy. Intermittent hypoxia, a central characteristic of SDB, has been shown in animal and clinical studies to dysregulate several biological pathways. This includes the promotion of oxidative stress, increased inflammation, activation of the hypothalamic-pituitary-adrenal axis, increased sympathetic activity and impaired glucose and insulin metabolism. This review considers how, during pregnancy, these pathophysiological processes are plausible mechanisms through which SDB may contribute to an increased risk of adverse outcomes, for the mother and perhaps also the offspring. However, a lack of robust evidence specific to the pregnant population, including limited evaluation of the placental function in affected pregnancies, limits our ability to draw definite conclusions on mechanisms contributing to adverse pregnancy outcomes and, indeed, the strength of association between SDB and certain pregnancy complications., (© 2020 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Prenatal exposure to environmental adversities, including maternal overweight/obesity, diabetes/hypertensive disorders, or mood/anxiety disorders, increases the risk for adverse neurodevelopmental outcomes in children. However, the underlying biological mechanisms remain elusive. We tested whether maternal antenatal inflammation was associated with the number of neurodevelopmental delay areas in children and whether it mediated the association between exposure to any prenatal environmental adversity and child neurodevelopmental delay., Methods: Mother-child dyads (N = 418) from the PREDO (Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction) study were followed up to 10.8 years. We analyzed maternal plasma high-sensitivity C-reactive protein and glycoprotein acetyls at 3 consecutive antenatal time points, measured maternal body mass index in early pregnancy, extracted data on diabetes/hypertensive disorders in pregnancy from medical records, and extracted data on mood/anxiety disorders until childbirth from the Care Register for Health Care. To estimate the number of neurodevelopmental delay areas in children across cognitive, motor, and social functioning, we pooled data from the Care Register for Health Care on psychological development disorders with mother-reported Ages and Stages Questionnaire data on developmental milestones., Results: Higher levels of maternal high-sensitivity C-reactive protein and glycoprotein acetyls at and across all 3 antenatal time points were associated with 1.30- to 2.36-fold (p values < .02) increased relative risk for higher number of areas of child neurodevelopmental delay. Higher maternal inflammation across the 3 time points also mediated the effect of any prenatal environmental adversity on child neurodevelopmental delay., Conclusions: Higher levels of maternal inflammation, especially when persisting throughout pregnancy, increase a child's risk of neurodevelopmental delay and mediate the effect of prenatal environmental adversity on child neurodevelopmental delay., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aim: Gestational diabetes (GDM) and mental disorder are common perinatal morbidities and are associated with adverse maternal and child outcomes. While there is a relationship between type 2 diabetes and mental disorder, the relationship between GDM and mental disorder has been less studied. We conducted a systematic review and meta-analysis of the prevalence of mental disorders in women with GDM and their risk for mental disorders compared with women without GDM., Methods: Published, peer-reviewed literature measuring prevalence and/or odds of GDM and perinatal mental disorders was reviewed systematically. Risk of bias was assessed using a checklist. Two independent reviewers were involved. Analyses were grouped by stage of peripartum, i.e. antepartum at the time of GDM diagnosis and after diagnosis, and in the postpartum., Results: Sixty-two studies were included. There was an increased risk of depressive symptoms in the antenatal period around the time of diagnosis of GDM [odds ratio (OR) 2.08; 95% confidence interval (CI) 1.42, 3.05] and in the postnatal period (OR 1.59; 95% CI 1.26, 2.00)., Conclusions: Given the potential relationship between GDM and perinatal mental disorders, integration of physical and mental healthcare in women experiencing GDM and mental disorders could improve short- and long-term outcomes for women and their children., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims/hypothesis: Maternal obesity in pregnancy is associated with cardiovascular disease and mortality rate in the offspring. We aimed to determine whether maternal obesity is also associated with increased incidence of type 2 and type 1 diabetes in the offspring, independently of maternal diabetes as a candidate mechanistic pathway., Methods: Birth records of 118,201 children from 1950 to 2011 in the Aberdeen Maternity and Neonatal Databank were linked to Scottish Care Information-Diabetes, the national register for diagnosed diabetes in Scotland, to identify incident and prevalent type 1 and type 2 diabetes up to 1 January 2012. Maternal BMI was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on offspring outcomes was tested using time-to-event analysis with Cox proportional hazards regression to compare outcomes in offspring of mothers in underweight, overweight or obese categories of BMI, compared with offspring of women with normal BMI., Results: Offspring of obese (BMI ≥30 kg/m 2 ) and overweight (BMI 25-29.9 kg/m 2 ) mothers had an increased hazard of type 2 diabetes compared with mothers with normal BMI, after adjustment for gestation when weight was measured, maternal history of diabetes before pregnancy, maternal history of hypertension, age at delivery, parity, socioeconomic status, and sex of the offspring: HR 3.48 (95% CI 2.33, 5.06) and HR 1.39 (1.06, 1.83), respectively., Conclusions/interpretation: Maternal obesity is associated with increased incidence of type 2 diabetes in the offspring. Evidence-based strategies that reduce obesity among women of reproductive age and that might reduce the incidence of diabetes in their offspring are urgently required.

Background Maternal early pregnancy overweight (body mass index [BMI] 25.0-29.9 kg/m 2 ) and obesity (BMI ≥ 30 kg/m 2 ) are associated with mental and physical health adversities in the offspring. Prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been put forward as one of the mechanisms that may play pathophysiological role. However, evidence linking maternal overweight and obesity with offspring HPA-axis activity is scarce. We studied if maternal early pregnancy BMI is associated with diurnal salivary cortisol, a marker of HPA-axis activity, in young adult offspring. Methods At a mean age of 25.3 (standard deviation [SD) = 0.6) years, 653 Arvo Ylppö Longitudinal Study participants collected saliva samples for cortisol analyses, at awakening, 15 and 30 min thereafter, 10:30AM, 12:00PM, 5:30PM and at bedtime. Maternal BMI was calculated from weight and height verified by a measurement in the first antenatal clinic visit before 12 weeks of gestation derived from healthcare records. Results Per each one kg/m 2 higher maternal early pregnancy BMI offspring diurnal average salivary cortisol was -1.4% (95% CI:-2.6, -0.2, p FDR  = 0.033) lower, at awakening it was -2.4% (95% CI:-4.0, -0.7, p FDR  = 0.025) lower and the morning average salivary cortisol was -2.0% (95% CI:-3.4, -0.5, p FDR =0.017) lower. These associations were independent of the offspring's own young adulthood BMI, and other important covariates. Conclusion Our findings show that young adult offspring born to mothers with higher early pregnancy BMI show lower average levels of diurnal cortisol, especially in the morning. Whether these findings reflect prenatal programming of the offspring HPA-axis activity warrants further investigation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Maternal depression complicates a large proportion of pregnancies. Current evidence shows numerous harmful effects on the offspring. Reviews, which include depression, concluded that stress has harmful effects on the offspring's outcomes neuro-cognitive development, temperament traits, and mental disorders., Objective: This mini review of recent studies, sought to narrow the scope of exposure and identify studies specifically assessing prenatal depression and offspring neuropsychiatric outcomes., Study Eligibility Criteria: The review included longitudinal, cohort, cross-sectional, clinical, quasi-experimental, epidemiological, or intervention study designs published in English from 2014 to 2018., Participants: Study populations included mother-child dyads, mother-father-child triads, mother-alternative caregiver-child triads, and family studies utilizing sibling comparisons., Methods: We searched PubMED and Web of Science. Study inclusion and data extraction were based on standardized templates. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS)., Results: Thirteen studies examining neuropsychiatric outcomes were included. We judged the evidence to be moderate to high quality., Conclusions: Our review supports that maternal prenatal depression is associated with neuropsychiatric adversities in children., Implications: Future investigations should unravel the biological underpinnings and target timely interventions as early in pregnancy as possible to prevent offspring neuropsychiatric harms.

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.

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.

Aims: Evidence suggests that screening for gestational diabetes (GDM) occurs too late in pregnancy, when changes in glucose metabolism and fetal growth rates can already be detected. In August 2016 NHS Lothian began screening women with risk factors for GDM during early pregnancy (11-13 weeks). We hypothesised that an earlier identification and treatment of dysglycaemia would improve pregnancy outcomes compared to previous standard care., Methods: We compared management and outcomes for singleton pregnancies with GDM delivering at Royal Infirmary Edinburgh, UK, diagnosed through routine or early screening from 01/01/2015-31/10/2017 (routine screening n = 335, early screening n = 241)., Results: Early screening increased the proportion of women diagnosed before 24 weeks' gestation (n = 59/335, 17.6% vs n = 103/241, 42.7%, p < 0.001) but did not change the average monthly rate of diagnosis. Early screening increased the median duration of GDM during pregnancy (71 vs 93 days of gestation, p < 0.001) with no significant changes in the pharmacological management. Early screening improved the primary composite outcome (emergency caesarean section, neonatal hypoglycaemia and macrosomia; n = 138/335, 41.2% vs n = 73/241, 30.3%, adjusted Odds Ratio [95% confidence interval] 0.62 [0.43-0.91]., Conclusions: There is a role for early screening and management of GDM however it is unclear whether this represents a cost-effective intervention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (© 2018 Wiley Periodicals, Inc.)

Background/objectives: Previous studies have linked maternal pre-pregnancy obesity (BMI ≥30 kg/m 2 ) 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.

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., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy., Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI <25 kg/m 2 ) and 7 obese (BMI > 35 kg/m 2 ) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours., Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean., Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy., (© 2018 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Glucocorticoids are vital for lung maturation. We previously showed that cortisol is lower in obese pregnancy. Whether this is maintained at delivery is unknown but is clinically relevant as maternal and cord blood cortisol levels are correlated and offspring of obese are more likely to need neonatal respiratory support. We hypothesized that glucocorticoids are lower in maternal and cord blood at delivery in obese pregnancies. Glucocorticoids (cortisol and corticosterone) and their inactive versions (cortisone and 11-dehydrocorticosterone) were measured by LC-MS/MS in maternal and cord plasma from 259 Caucasian women at delivery (BMI 18-55 kg/m 2 ). Analyses adjusted for labour status, delivery mode, offspring gender, birthweight and gestational age. Cortisol and corticosterone were significantly higher in maternal than cord blood. Inactive versions were significantly higher in cord than maternal blood. Increased maternal BMI associated with lower maternal cortisol, corticosterone and 11-dehydrocorticosterone. Despite significant positive correlations between maternal and cord blood glucocorticoid levels, increased maternal BMI was not associated with lower cord blood glucocorticoid levels. Conditions at delivery may overcome any potential negative effects of low maternal glucocorticoids on the fetus in the short-term. This may not preclude the longer-term effects of fetal exposure to lower glucocorticoid levels during obese pregnancy.

BackgroundPrenatal maternal obesity has been associated with an increased risk of neurocognitive problems in childhood, but there are fewer studies on executive functioning.MethodsTests and questionnaires to assess neurodevelopment, executive functioning, and the ability to delay gratification were conducted in 113 children (mean (SD)=4.24 (0.63) years of age) born to mothers with very severe obesity (SO, body mass index (BMI)⩾40 kg/m 2 , n=51) or to lean mothers (BMI⩽25 kg/m 2 , n=62).ResultsPrenatal maternal SO predicted poorer neurodevelopment (unstandardized regression coefficient (B)=-0.42, 95% confidence interval (CI) (-0.82; -0.02)), worse problem-solving (odd ratio (OR)=0.60, 95% CI (1.13; 0.07)), and fine motor skills (OR=4.91, 95% CI (1.27; 19.04)), poorer executive functioning in areas of attention, inhibitory control, and working memory (standardized B=3.75, 95% CI (1.01; 13.93)) but not in self-gratification delay. The effects were independent of maternal concurrent psychological well-being and child's BMI, but not independent of maternal education.ConclusionFuture studies should investigate whether perinatal management of maternal obesity could prevent adverse outcomes in child neurodevelopment.

Objectives: To determine whether attendance at a specialised multidisciplinary antenatal clinic for women with class III obesity (BMI >40 kg/m 2 ) is associated with improved clinical outcomes compared with standard antenatal care., Design: Retrospective cohort study using routinely collected data from electronic patient record., Setting: Community and hospital based antenatal care., Participants: Women with a singleton pregnancy with class III obesity booked for antenatal care and delivered in one of two hospitals in NHS Lothian, Scotland, UK between 2008 and 2014. Maternal and offspring outcomes were compared in women who attended a specialised obesity clinic (n=511) compared with standard antenatal care (n=502)., Main Outcome Measures: Included stillbirth, low birth weight, gestational diabetes, induction of labour and caesarean section., Results: Compared with standard care, women receiving specialist care were less likely to have a stillbirth (OR 0.12, 95% CI 0.06 to 0.97) and a low birthweight baby (OR 0.57, 95% CI 0.33 to 0.99) and more likely to be screened for (100% vs 73.6%; p<0.001) and diagnosed with (26.0% vs 12.5%; p<0.001) gestational diabetes, to require induction of labour (38.4% vs 29.9%; p=0.009), an elective (20.3% vs 17.7%; p<0.001) and emergency (23.9% vs 20.3%; p<0.001) caesarean section and attend antenatal triage one or more times during pregnancy (77.7% vs 53.1%; p<0.001). Women attending the specialist clinic had a higher BMI (44.5 kg/m 2 (4.3) vs 43.2 kg/m 2 (3.1); p<0.001) and were more likely to be nulliparous (46.0% vs 24.9%; p<0.001). There were no other differences in maternal demographic or maternal and offspring outcomes between groups., Conclusions: Attendance at a specialised antenatal clinic for obesity is associated with reduced rates of stillbirth and low birth weight and improved detection of gestational diabetes. The improvement in clinical outcomes is associated with an increase in healthcare attendance to obstetric triage and clinical interventions including induction of labour and caesarean section., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Purpose: Offspring exposed to maternal diabetes are at increased risk of neurocognitive impairment, but its origins are unknown. With MR imaging, we investigated the feasibility of comprehensive assessment of brain metabolism ( 1 H-MRS), microstructure (DWI), and macrostructure (structural MRI) in third-trimester fetuses in women with diabetes and determined normal ranges for the MR imaging parameters measured., Materials and Methods: Women with singleton pregnancies with diabetes ( n = 26) and healthy controls ( n = 26) were recruited prospectively for MR imaging studies between 34 and 38 weeks' gestation., Results: Data suitable for postprocessing were obtained from 79%, 71%, and 46% of women for 1 H-MRS, DWI, and structural MRI, respectively. There was no difference in the NAA/Cho and NAA/Cr ratios (mean [SD]) in the fetal brain in women with diabetes compared with controls (1.74 [0.79] versus 1.79 [0.64], P = .81; and 0.78 [0.28] versus 0.94 [0.36], P = .12, respectively), but the Cho/Cr ratio was marginally lower (0.46 [0.11] versus 0.53 [0.10], P = .04). There was no difference in mean [SD] anterior white, posterior white, and deep gray matter ADC between patients and controls (1.16 [0.12] versus 1.16 [0.08], P = .96; 1.54 [0.16] versus 1.59 [0.20], P = .56; and 1.49 [0.23] versus 1.52 [0.23], P = .89, respectively) or volume of the cerebrum (243.0 mL [22.7 mL] versus 253.8 mL [31.6 mL], P = .38)., Conclusions: Acquiring multimodal MR imaging of the fetal brain at 3T from pregnant women with diabetes is feasible. Further study of fetal brain metabolism in maternal diabetes is warranted., (© 2017 by American Journal of Neuroradiology.)

In addition to immediate implications for pregnancy complications, increasing evidence implicates maternal obesity as a major determinant of offspring health during childhood and later adult life. Observational studies provide evidence for effects of maternal obesity on her offspring's risks of obesity, coronary heart disease, stroke, type 2 diabetes, and asthma. Maternal obesity could also lead to poorer cognitive performance and increased risk of neurodevelopmental disorders, including cerebral palsy. Preliminary evidence suggests potential implications for immune and infectious-disease-related outcomes. Insights from experimental studies support causal effects of maternal obesity on offspring outcomes, which are mediated at least partly through changes in epigenetic processes, such as alterations in DNA methylation, and perhaps through alterations in the gut microbiome. Although the offspring of obese women who lose weight before pregnancy have a reduced risk of obesity, few controlled intervention studies have been done in which maternal obesity is reversed and the consequences for offspring have been examined. Because the long-term effects of maternal obesity could have profound public health implications, there is an urgent need for studies on causality, underlying mechanisms, and effective interventions to reverse the epidemic of obesity in women of childbearing age and to mitigate consequences for offspring., Competing Interests: statement KMG reports other from Nestle Nutrition Institute, grants from Abbott Nutrition & Nestec, outside the submitted work; in addition, KMG has a patent Phenotype prediction pending, a patent Predictive use of CpG methylation pending, and a patent Maternal Nutrition Composition pending. SLP reports other from Danone Scientific Advisory Board, other from Nestle Nutrition Institute Scientific Advisory Board, other from ALK Abello, outside the submitted work. The other authors have nothing to disclose., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

In a Perspective, Jane Norman and Rebecca Reynolds discuss two randomized controlled trials aimed at testing behavioral interventions for women at risk of gestational diabetes.

Background: Perinatal depression is strikingly common with a prevalence of 10-15%. The adverse effects of perinatal depression on maternal and child health are profound with considerable costs. Despite this, few women seek medical attention. E-health, providing healthcare via the Internet is an accessible and effective solution for the treatment of depression in the general population. We aimed to conduct a systematic review of web-based interventions for the prevention and treatment of mood disorders in the perinatal period, defined as the start of pregnancy to 1 year post-partum., Methods: Six databases were searched until 26(th) March 2015. Two researchers independently screened articles for eligibility. Of the 547 screened articles, four met the inclusion criteria. These included three randomised-controlled trials and one feasibility trial, with total data from 1274 participants. MOOSE and PRISMA guidelines were adhered to for the conduct and reporting of the systematic review., Results: All studies were conducted in the post-partum period. All reported an improvement in maternal mood following intervention. A significant improvement in depressive symptoms was measured using validated rating scales, such as the Edinburgh Postnatal Depression Scale (EPDS), either at post-treatment or follow-up which ranged from 3 to 12 months post study completion. For the two RCTs utilising the EPDS, the EPDS score reductions were (mean ± SEM) 8.52 ± 0.22 (Range 19.46 to10.94) and 9.19 ± 0.63 (Range, 20.24 to 11.05) for treatment groups and 5.16 ± 0.25 (Range 19.44 to 14.28) and 6.81 ± 0.71 (Range 21.07 to 14.26) for comparator groups. However attrition within studies ranged from 13 to 61%. One study was rated as 'good' quality., Conclusions: Preliminary data suggests web-based therapies for perinatal depression delivered in the post-partum period may play a role in improving maternalmood but more studies are needed, particularly with interventions delivered antenatally. Further research is needed to address the limitations of the existing evidence base.

Background: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation., Method: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects., Results: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation)., Conclusion: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To explore the barriers and facilitators to physical activity and lifestyle interventions in pregnant women with Class III obesity (body mass index >40 kg/m(2))., Design: Qualitative study using in-depth, semi-structure interviews framed by the Theory of Planned Behaviour. Semi-structured, in-depth interviews were conducted using a topic guide. Data analysis was undertaken using a Framework Approach and was informed by the theory of planned behaviour. Recruitment and analysis continued until data saturation was reached., Setting: Participants were recruited from an antenatal clinic for women with Class III obesity., Participants: Pregnant women (n=13) with Class III obesity., Measurements and Outcomes: Three major themes emerged from the data analysis: having a healthy lifestyle awareness, complex barriers to lifestyle changes and having personalised solutions to promote healthy lifestyle. Women were aware of the benefits of physical activity during pregnancy but had complex barriers to engaging with activity., Conclusions and Implications for Practice: future lifestyle interventions for women with Class III in pregnancy should take into account individual, societal and support barriers towards weight management and lifestyle choices in pregnancy. Programs that provide personalised support which are sensitive to the specific physical and psychological needs of women with Class III obesity which focus on the benefits and safety of physical activity for both mother and baby may be more likely to be successful. Further research is needed to explore the feasibility and acceptability of tailored programs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Both maternal obesity and disordered mood have adverse effects on pregnancy outcome. We hypothesized that maternal very severe obesity (SO) is associated with increased anxiety and depression (A&D) symptoms during pregnancy, with adverse effects on gestational weight gain (GWG), postpartum mood and postpartum weight retention (PPWR) and explored any mediation by circulating glucocorticoids., Method: We measured A&D symptoms with validated questionnaires at weeks 17 and 28 of pregnancy and 3 months postpartum in 135 lean [body mass index (BMI) ⩽25 kg/m2] and 222 SO (BMI ⩾40 kg/m2) pregnant women. Fasting serum cortisol was measured by radioimmunoassay; GWG and PPWR were recorded., Results: A&D symptoms were higher in the SO group during pregnancy and postpartum despite adjusting for multiple confounders including previous mental health diagnosis (p < 0.05), and were non-linearly correlated with total GWG (anxiety R 2 = 0.06, p = 0.037; depression R 2 = 0.09, p = 0.001). In the SO group only, increased maternal anxiety (β = 0.33, p = 0.03) and depression (β = 0.19, p = 0.04) symptoms at week 17 of pregnancy were associated with increased PPWR, independent of total GWG and breastfeeding. Anxiety symptoms at week 28 of pregnancy, but not depression, were non-linearly correlated with serum cortisol level at week 36 of pregnancy (R 2 = 0.06, p = 0.02). Cortisol did not mediate the link between A&D symptoms and GWG., Conclusions: Maternal SO was associated with increased A&D symptoms, and with adverse effects on GWG and PPWR independent of circulating glucocorticoids. Strategies to optimize GWG and postpartum weight management in SO women should include assessment and management of maternal mood in early pregnancy.

Background: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors., Method: Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days., Results: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05)., Conclusions: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

The health behaviours of pregnant women with very severe obesity are not known, though these women are at high risk of pregnancy complications. We carried out a prospective case-control study including 148 very severely obese (BMI >40 kg/m²) and 93 lean (BMI <25 kg/m²) pregnant women. Diet, physical activity, smoking, alcohol and folic acid consumption were assessed by questionnaire in early and late (16 and 28 weeks gestation) pregnancy. Circulating levels of iron, vitamin B12 and folate and other essential trace elements and minerals were measured in a subset at each time point. The findings biochemically confirmed that very severely obese women consumed diets that were energy-rich but poor in essential micronutrients. A third of all women met physical activity recommendations for pregnancy. A third of very severely obese women and two thirds of lean women took folic acid supplements prior to pregnancy. Very severely obese women were more likely to smoke but less likely to drink alcohol than lean women (all p < 0.05). Women with very severe obesity have low self-reported intakes and circulating levels of essential micronutrients in pregnancy and few follow current recommendations for pregnancy nutrition and lifestyle. These high-risk women represent a group to target for education about health behaviours prior to and during pregnancy.

Background: Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes., Methods: We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs ≥40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843., Findings: Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0·029, 95% CI -0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74-17·50; p=0·11)., Interpretation: Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes., Funding: The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership., (Copyright © 2015 Chiswick et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Maternal prenatal depression predicts post-partum depression and increases risk of prematurity and low birth weight. These effects may be mediated by altered placental function. We hypothesized that placental function would be influenced by the gestational week of experiencing depressive symptoms and aimed to examine associations between maternal depressive symptoms during pregnancy and placental expression of genes involved in glucocorticoid and serotonin transfer between mother and fetus., Method: We studied women participating in a prospective pregnancy cohort: the Prediction and Prevention of Preeclampsia (PREDO) Study, Helsinki, Finland. Maternal depressive symptoms were assessed at 2-week intervals throughout pregnancy in 56 healthy women with singleton, term pregnancies. Messenger ribonucleic acid (mRNA) levels of glucocorticoid (GR) and mineralocorticoid (MR) receptors and serotonin transporter (SLC6A4), 11β-hydroxysteroid dehydrogenase type 1 (HSD1) and 2 (HSD2) were quantified in placental biopsies., Results: In adjusted analyses women who reported higher depressive symptoms across the whole pregnancy had higher mRNA levels of GR [effect size 0.31 s.d. units, 95% confidence interval (CI) 0.01-0.60, p = 0.042] and MR (effect size 0.34 s.d. units, 95% CI 0.01-0.68, p = 0.047). These effects were significant for symptoms experienced in the third trimester of pregnancy for GR; findings for MR were also significant for symptoms experienced in the second trimester. GR and MR mRNA levels increased linearly by having the trimester-specific depressive symptoms scores 0, 1 or 2-3 times above the clinical cut-off for depression (p = 0.003, p = 0.049, respectively, and p = 0.004, p = 0.15 in adjusted analyses)., Conclusions: Our findings offer potential gestational-age-specific mechanisms linking maternal depressive symptoms during pregnancy via placental biology. Future studies will test whether these also link with adverse offspring outcomes.

Introduction: Increasing evidence suggests obesity has its origins prior to birth. There is clear correlation between maternal obesity, high birthweight and offspring risk of obesity in later life. It is also clear that women who are obese during pregnancy are at greater risk of adverse outcomes, including gestational diabetes and stillbirth. The mechanism(s) by which obesity causes these problems is unknown, although hyperglycaemia and insulin resistance are strongly implicated. We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications., Methods and Analysis: The Efficacy of Metformin in Pregnant Obese Women, a Randomised controlled (EMPOWaR) trial is a double-masked randomised placebo-controlled trial to determine whether metformin given to obese (body mass index >30 kg/m(2)) pregnant women from 16 weeks' gestation until delivery reduces the incidence of high birthweight babies. A secondary aim is to test the mechanism(s) of any effect. Obese women with a singleton pregnancy and normal glucose tolerance will be recruited prior to 16 weeks' gestation and prescribed study medication, metformin or placebo, to be taken until delivery. Further study visits will occur at 28 and 36 weeks' gestation for glucose tolerance testing and to record anthropometric measurements. Birth weight and other measurements will be recorded at time of delivery. Anthropometry of mother and baby will be performed at 3 months postdelivery. As of January 2014, 449 women had been randomised across the UK., Ethics and Dissemination: The study will be conducted in accordance with the principles of Good Clinical Practice. A favourable ethical opinion was obtained from Scotland A Research Ethics Committee, reference number 10/MRE00/12. Results will be disseminated at conferences and published in peer-reviewed journals., Trial Registration Number: ISRCTN51279843., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Rates of obesity are increasing in women of child bearing age with negative impacts on maternal and offspring health. Emerging evidence suggests in utero origins of respiratory health in offspring of obese mothers but mechanisms are unknown. Changes in maternal cortisol levels are one potential factor as cortisol levels are altered in obesity and cortisol is separately implicated in development of offspring wheeze. We aimed to assess whether increased pre-pregnancy maternal body mass index (BMI) was associated with offspring early life wheezing, and whether this was mediated by altered cortisol levels in the mother. In a prospective community-based cohort (Amsterdam Born Children and their Development cohort), women completed questionnaires during pregnancy and at 3-5 months post-delivery regarding self-history of asthma and atopy, and of wheezing of their offspring (n=4860). Pre-pregnancy BMI was recorded and serum total cortisol levels were measured in a subset of women (n=2227) at their first antenatal visit. A total of 20.2% (n=984) women were overweight or obese and 10.3% reported wheezing in their offspring. Maternal BMI was associated with offspring wheezing (1 unit (kg/m2) increase, OR: 1.03; 95% CI: 1.00-1.05), after correction for confounders. Although maternal cortisol levels were lower in overweight mothers and those with a history of asthma, maternal cortisol levels did not mediate the increased offspring wheezing. Pre-pregnancy BMI impacts on baby wheezing, which is not mediated by lower cortisol levels. As the prevalence of obesity in women of child-bearing age is increasing, further studies are needed to investigate modifiable maternal factors to avoid risk of wheezing in young children.

The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus 'programming' the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring., Design: Record linkage cohort analysis., Setting: Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems., Population: 37 709 people with birth records from 1950 to present day., Main Outcome Measures: Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI., Results: All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes., Conclusions: Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required.

Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of venepuncture, and increased cortisol responses to psychosocial stress. We have developed new dynamic tests to dissect the mechanisms regulating HPA axis central negative feedback sensitivity in humans, and demonstrated that this may be altered in obesity, one component of the metabolic syndrome. There are now studies in humans demonstrating that high circulating levels of maternal cortisol during pregnancy correlate negatively with birthweight, suggesting that excess glucocorticoids can by-pass the placental barrier. Deficiencies in the barrier enzyme, potentially increasing fetal glucocorticoid exposure, can also arise in association with maternal stress, malnutrition and disease, and can be inhibited by consumption of liquorice, which contains glycyrrhizin, an HSD inhibitor. Importantly, studies in humans have now demonstrated that high maternal cortisol in pregnancy and/or inhibition of HSD2 are associated with programmed outcomes in childhood including higher blood pressure, behavioural disorders as well as altered brain structure. We are investigating this further, using novel magnetic resonance imaging techniques to study the developing fetal brain in utero. The translational studies in support of the glucocorticoid hypothesis, and demonstrating that glucocorticoids are both mediators and targets of programming, are exciting and raise the question of whether this information can be used to identify those individuals most at risk of later life disease. In a recent study we showed that alterations in DNA methylation at genes important in regulating cortisol levels, tissue glucocorticoid action, blood pressure and fetal growth, are present in adulthood in association with both early life parameters and cardiometabolic risk factors. These preliminary data add to the limited literature in humans indicating a persisting epigenetic link between early life events and subsequent disease risk. Such findings open novel avenues for further exploration of the contribution of glucocorticoids to later life disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The prevalence of obesity in pregnancy is rising exponentially; about 15-20% of pregnant women now enter pregnancy with a BMI which would define them as obese. This paper provides a review of the strong links between obesity and adverse pregnancy outcome which operate across a range of pregnancy complications. For example, obesity is associated with an increased risk of maternal mortality, gestational diabetes mellitus, thromboembolism, pre-eclampsia and postpartum haemorrhage. Obesity also complicates operative delivery; it makes operative delivery more difficult, increases complications and paradoxically increases the need for operative delivery. The risk of the majority of these complications is amplified by excess weight gain in pregnancy and increases in proportion to the degree of obesity, for example, women with extreme obesity have OR of 7·89 for gestational diabetes and 3·84 for postpartum haemorrhage compared to their lean counterparts. The consequences of maternal obesity do not stop once the baby is born. Maternal obesity programmes a variety of long-term adverse outcomes, including obesity in the offspring at adulthood. Such an effect is mediated at least in part via high birthweight; a recent study has suggested that the odds of adult obesity are two-fold greater in babies weighing more than 4 kg at birth. The mechanism by which obesity causes adverse pregnancy outcome is uncertain. This paper reviews the emerging evidence that hyperglycaemia and insulin resistance may both play a role: the links between hyperglycaemia in pregnancy and both increased birthweight and insulin resistance have been demonstrated in two large studies. Lastly, we discuss the nature and rationale for possible intervention strategies in obese pregnant women.

Background: Pre-gravid obesity is associated with increased morbidity and mortality for both mother and offspring. Recent studies have demonstrated a heightened inflammatory response both systemically and locally within the adipose and placental tissue in women with pre-gravid obesity, which may play a role in mediating the adverse pregnancy outcomes. The aim of this study was to characterise the maternal and placental inflammatory status and investigate associated changes in placental structure in obese women., Methods: The pro-inflammatory status of a cohort of 47 non-obese (BMI 20-25 kg/m(2)) and 33 obese (≥30 kg/m(2)) women was characterised by measuring maternal circulating levels and placental gene expression of pro-inflammatory cytokines, and quantifying immune cell populations within the placenta. The effect of pre-gravid obesity on placental structure was investigated by examining placental maturity, vessel density, the formation of syncytial knots and sprouts, and the degree of fibrin deposition, chorangiosis and muscularisation of vessel walls., Results: Maternal obesity was associated with significantly greater IL-1β (p < 0.05), IL-8 (p < 0.05), MCP-1 (p < 0.001) and CXCR2 (p < 0.05) mRNA expression within the placenta and higher circulating maternal levels of IL-6 (3.30 ± 0.38 vs. 1.77 ± 0.15 pg/ml) (p < 0.001) compared with non-obese women. There were no differences in the number of CD14(+), CD68(+) cells or neutrophils within the placental villi of non-obese and obese women. However there were significantly higher numbers of neutrophils within the interstitial space (p < 0.05). Greater muscularity of placental vessel walls was associated with maternal obesity (p = 0.03), however no other associated structural changes were observed., Conclusions: Our findings show that although pre-gravid obesity was associated with greater expression of placental pro-inflammatory cytokines and higher circulating IL-6 in pregnancy, there were no major differences in immune cell populations within the placental villi and only a greater degree of muscularity in the vessel walls., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To investigate the effect of maternal body mass index (BMI) on minor complications, associated additional medication use during pregnancy and the consequent cost implications., Design: Retrospective analysis of case notes., Setting: Labour wards, tertiary referral hospital, Royal Infirmary Edinburgh, UK. Population Six hundred and fifty-one women with a singleton pregnancy over four separate time periods in 2007 and 2008., Methods: Descriptive statistics, univariate and multivariate logistic regression analysis and cost analysis using standard techniques and inflation indices., Main Outcome Measures: Minor complications, use of medications during pregnancy and consequent incremental costs from the perspective of the National Health Service (NHS)., Results: 42.4% of women were overweight or obese (BMI > or = 25 kg/m(2)). Higher BMI during the first trimester (BMI > or = 30 kg/m(2) compared with BMI < 25 kg/m(2)) was associated with an increased risk of minor complications including symphysis pubis dysfunction (OR 3.97; 95% CI 2.19-7.18), heartburn (OR 2.65; 95% CI 1.42-4.94) and chest infection (OR 8.71; 95% 2.20-34.44) and with drugs used to treat these complications including Gaviscon (OR 3.52; 95% CI 1.78-6.96). The mean incremental (additional) NHS costs per woman for treating minor complications increased with maternal BMI were 15.45 pounds/woman, 17.64 pounds/woman and 48.66 pounds/woman for BMI < 25 kg/m(2), BMI > or = 25 to <30 kg/m(2) and BMI > or = 30 kg/m(2) respectively., Conclusions: Increased maternal BMI is associated with increased risk of developing minor complications during pregnancy; use of medications associated with treating these conditions and has significant NHS costs.

The article discusses the guidelines on the care of pregnant women with obesity. Topics include the information on the risks of obesity during pregnancy and childbirth, the nutritional supplements to be recommended, the measurement of weight, height and body mass index and the factors to be considered in screening, diagnosing and managing maternal disease in obese pregnant women.