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Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures. 1-3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

The process of ovarian aging is influenced by a complex and poorly understood interplay of endocrine, metabolic, and environmental factors. The purpose of this study was to explore the feasibility of using latent class analysis to identify subgroups based on cardiometabolic, psychological, and reproductive parameters of health and to describe patterns of anti-Müllerian hormone levels, a biomarker of the ovarian reserve, within these subgroups. Sixty-nine lean (body mass index [BMI] ⩽ 25 kg/m 2 ) and severely obese (BMI ⩾ 40 kg/m 2 ) postpartum women in Edinburgh, Scotland, were included in this exploratory study. The best fitting model included three classes: Class 1, n = 23 (33.5%); Class 2, n = 30 (42.2%); Class 3, n = 16 (24.3%). Postpartum women with lower ovarian reserve had less favorable cardiometabolic and psychological profiles. Examining the ovarian reserve within distinct subgroups based on parameters of health that affect ovarian aging may facilitate risk stratification in the context of ovarian aging.

Objective: To model breastfed infant growth and body composition patterns over the first 4 months with multiple bioactive components of human milk (HM) and clinical factors (including maternal BMI status), which are related to growth., Methods: Longitudinal observation of infant growth and body composition from 0 to 4 months among 41 predominantly breastfed infants (25 mothers of Normal-weight and 16 mothers with overweight/obesity). Fasted morning HM samples were collected at 5 time-points. Macronutrients, leptin, adiponectin, ghrelin, insulin, cytokines and n-6:n-3 esterified fatty acid ratio were measured. Infant weight-for-length Z-score (WLZ) trajectory, fat-free mass (FFM) gain, fat mass gain and %fat gain were modelled controlling for clinical covariates., Results: HM insulin negatively associated with WLZ trajectory among infants of NW mothers (P = 0.028), but not associated with WLZ trajectory among infants of OW/Ob mothers. HM glucose (P < 0.001) was associated with slower rates of infant FFM gain. Infants of mothers with OW/Ob exhibited slower rates of FFM gain. HM protein, adiponectin and insulin concentrations, and n-6:n-3 ratio were all significant predictors in the model of infant fat mass gain (P < 0.03). Any amount of formula supplementation was associated with faster fat gain (P = 0.002). The model of %fat gain was similar to that of fat mass gain, excepting HM adiponectin was not a significant covariate, and a trend for maternal OW/Ob to correlate with faster %fat gain (P = 0.056)., Conclusions: Bioactive components in HM may contribute to regulation of partitioning of body composition, and these contributions may differ between mothers of normal-weight vs. with OW/Ob., (© 2018 World Obesity Federation.)

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: 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.)

Epidemiologic and clinical research has provided a large body of evidence supporting the developmental origins of health and disease (DOHaD), but there has been a relative dearth of mechanistic studies in humans due to the complexity of working with large, longitudinal cohorts. Nonetheless, animal models of undernutrition have provided substantial evidence for the potential epigenetic, metabolic, and endocrine mechanisms behind DOHaD. Furthermore, recent research has explored the interaction between the environment and the gastrointestinal system by investigating how the gut microbial ecology may impact the capacity for nutrient processing and absorption in a manner that may limit growth. This review presents a summary of current research that supports the concept of DOHaD, as well as potential mechanisms and interactions that explain how nutrition in utero and during early childhood influences lifelong health., (© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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.

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.)

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.)

Background: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress., Method: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively., Results: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression., Conclusions: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.

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.

One in 5 pregnant women is obese but the impact on later health is unknown. We aimed to determine whether maternal obesity during pregnancy associates with increased premature mortality and later life major cardiovascular events. Maternity records of women who gave birth to their first child between 1950 and 1976 (n=18 873) from the Aberdeen Maternity and Neonatal databank were linked to the National Register of Deaths, Scotland and Scottish Morbidity Record. The effect of maternal obesity at first antenatal visit on death and hospital admissions for cardiovascular events was tested using time-to-event analysis with Cox proportional hazard regression to compare outcomes of mothers in underweight, overweight, or obese body mass index (BMI) categories compared with normal BMI. Median follow-up was at 73 years. All-cause mortality was increased in women who were obese during pregnancy (BMI>30 kg/m(2)) versus normal BMI after adjustment for socioeconomic status, smoking, gestation at BMI measurement, preeclampsia, and low birth weight (hazard ratio, 1.35; 95% confidence interval, 1.02-1.77). In adjusted models, overweight and obese mothers had increased risk of hospital admission for a cardiovascular event (1.16; 1.06-1.27 and 1.26; 1.01-1.57) compared with normal BMI mothers. Adjustment for parity largely unchanged the hazard ratios (mortality: 1.43, 1.09-1.88; cardiovascular events overweight: 1.17, 1.07-1.29; and obese: 1.30, 1.04-1.62). In conclusion, maternal obesity is associated with increased risk of premature death and cardiovascular disease. Pregnancy and early postpartum could represent an opportunity for interventions to identify obesity and reduce its adverse consequences., (© 2015 American Heart Association, Inc.)

Aims: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies., Methods: We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case-control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy (n = 10/group)., Results: Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04)., Conclusions/interpretation: Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy.

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.)

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.

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.

Objective: FFQ are popular instruments for assessing dietary intakes in epidemiological studies but have not been validated for use in severely obese pregnancy. The aim of the present study was to compare nutrient intakes assessed by an FFQ with those obtained from a food diary among severely obese pregnant women., Design: Comparison of an FFQ containing 170 food items and a food diary for 4 d (three weekdays and one weekend day); absolute agreement was assessed using the paired t test and relative agreement by Pearson/Spearman correlation, crossclassification into tertiles and weighted kappa values., Setting: Antenatal metabolic clinic for severely obese women., Subjects: Thirty-one severely obese (BMI at booking ≥ 40.0 kg/m2) and thirty-two lean control (BMI520.0–24.9 kg/m2) pregnant women., Results: The findings showed that nutrient intakes estimated by the FFQ were significantly higher than those from the food diary; average correlation was 0.32 in obese and 0.43 in lean women. A mean of 48.5% of obese and 47.3% of lean women were correctly classified, while 12.9% (obese) and 10.0% (lean) were grossly misclassified. Weighted k values ranged from 20.04 to 0.79 in obese women and from 0.16 to 0.78 in lean women., Conclusions: Overall, the relative agreement between the FFQ and food diary was lower in the obese group than in the lean group, but was comparable with earlier studies conducted in pregnant women. The validity assessments suggest that the FFQ is a useful tool for ranking severely obese pregnant women according to the levels of their dietary intake.

The prevalence of maternal obesity has risen dramatically in recent years, with approximately one in five pregnant women in the UK now classed as obese (body mass index ≥ 30 kg/m(2) ) at antenatal booking. Obesity during pregnancy has been hypothesized to exert long-term health effects on the developing child through 'early life programming'. While this phenomenon has been well studied in a maternal undernutrition paradigm, the processes by which the programming effects of maternal obesity are mediated are less well understood. In humans, maternal obesity has been associated with a number of long-term adverse health outcomes in the offspring, including lifelong risk of obesity and metabolic dysregulation with increased insulin resistance, hypertension and dyslipidaemia, as well as behavioural problems and risk of asthma. The complex relationships between the maternal metabolic milieu and the developing foetus, as well as the potential influence of postnatal lifestyle and environment, have complicated efforts to study the programming effects of maternal overnutrition in humans. This review will examine the emerging evidence from human studies linking maternal obesity to adverse offspring outcomes., (© 2012 Blackwell Publishing Ltd.)

Objectives: Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-eclampsia., Design: Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic., Patients: Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women., Measurements: A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight., Results: Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-eclampsia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-eclampsia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001)., Conclusions: Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers., (© 2011 Blackwell Publishing Ltd.)

Objective: Depression in Type 2 diabetes is associated with obesity, cardiovascular disease, and mortality. Leptin is a plausible mediating factor because it has been related to obesity, depression, and cardiovascular disease in nondiabetic populations. We sought to assess whether leptin is related to depressive symptoms in people with Type 2 diabetes., Methods: One thousand fifty-seven subjects (48.5% women, mean [standard deviation] age = 67.9 [4.2] years) with Type 2 diabetes were assessed for depressive symptoms using the Hospital Anxiety and Depression Scale and other clinical variables by interview and physical examination. Plasma leptin was determined by radioimmunoassay. Multiple linear regression was performed to assess the relationship between depressive symptoms and ln leptin while adjusting for other covariates. A mediation analysis was performed to test whether depressive symptoms mediated the relationship between obesity and leptin., Results: In univariate analyses, symptoms of depression were related to leptin in men (r = 0.214, p < .001) and women (r = 0.146, p = .007). When adjusting for other covariates including body mass index, ischemic heart disease, glycated hemoglobin, duration of diabetes, and treatment with antidepressants, insulin, or glucocorticoids, using a hierarchical multiple linear regression, depressive symptoms (ln Hospital Anxiety and Depression Scale-depression score) were significant only in men (B = 0.083, standard error = 0.037, p = .03). In the mediation analysis, depressive symptoms partially mediated the effect of obesity (body mass index) on leptin in men but not in women., Conclusions: There is a sex difference in the relationship between depressive symptoms and leptin in people with Type 2 diabetes, with a positive association in men but not in women. Adipocyte-derived factors are associated with depressive symptoms in Type 2 diabetes.

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.)

Context: The prevalence of obesity among women of childbearing age is increasing. Emerging evidence suggests that this has long-term adverse influences on offspring health., Objective: The aim was to examine whether maternal body composition and gestational weight gain have persisting effects on offspring adiposity in early adulthood., Design and Setting: The Motherwell birth cohort study was conducted in a general community in Scotland, United Kingdom., Participants: We studied 276 men and women whose mothers' nutritional status had been characterized in pregnancy. Four-site skinfold thicknesses, waist circumference, and body mass index (BMI), were measured at age 30 yr; sex-adjusted percentage body fat and fat mass index were calculated., Main Outcome Measure: Indices of offspring adiposity at age 30 yr were measured., Results: Percentage body fat was greater in offspring of mothers with a higher BMI at the first antenatal visit (rising by 0.35%/kg/m2; P<0.001) and in offspring whose mothers were primiparous (difference, 1.5% in primiparous vs. multiparous; P=0.03). Higher offspring percentage body fat was also independently associated with higher pregnancy weight gain (7.4%/kg/wk; P=0.002). There were similar significant associations of increased maternal BMI, greater pregnancy weight gain, and parity with greater offspring waist circumference, BMI, and fat mass index., Conclusions: Adiposity in early adulthood is influenced by prenatal influences independently of current lifestyle factors. Maternal adiposity, greater gestational weight, and parity all impact on offspring adiposity. Strategies to reduce the impact of maternal obesity and greater pregnancy weight gain on offspring future health are required.

Epidemiological studies have shown that low birthweight is associated with increased risk of development of diabetes and obesity in later life. Over-exposure of the developing fetus to glucocorticoids is one of the major hypotheses that has been proposed to explain this association. In animal models, a range of manipulations that increase fetal glucocorticoid load, 'programme' permanent changes in glucose and insulin metabolism and adiposity. This may be mediated by alterations in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In humans, low birthweight is associated with increased circulating glucocorticoid levels, and an increased cortisol response to physiological and psychosocial stressors, in child- and adulthood. This activation of the HPA axis is also associated with increased risk of development of diabetes and obesity in later life., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations.

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.

Context: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline, and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR)., Objective: The objective of the study was to use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity., Design: This was a double-blind, placebo-controlled, randomized, crossover study., Setting: The study was conducted at a clinical research facility., Participants: Participants included 15 lean (body mass index 22.0 +/- 1.6 kg/m(2)) and 16 overweight/obese (body mass index 30.1 +/- 3.5 kg/m(2)) men., Intervention: Subjects attended on four occasions for blood and saliva sampling every 30 min between 1800 and 2200 h. At 1100 and 1600 h before visits, subjects took 200 mg spironolactone, 400 mg RU38486, 200 mg spironolactone + 400 mg RU38486, or placebo orally., Main Outcome Measures: Serum cortisol levels after drug or placebo were measured., Results: Cortisol levels did not differ between lean and obese after placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by less than 50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, more so in lean than obese men [2.9- (0.3) vs. 2.2 (0.3)-fold elevation, P = 0.002]., Conclusions: Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.

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.