Evidence synthesis is considered a corner stone of modern health care and clinical practice. Systematic reviews of randomised trials, when undertaken with meta-analysis provide summary estimates on the effectiveness of interventions. However, the findings of meta-analysis are often limited by the selective reporting of primary studies, and the variations in population, intervention and outcomes. Furthermore, difficulties in disentangling the study and individual level associations in meta-analysis make them susceptible to ecological fallacy, and may lead to incorrect conclusions. Meta-analysis using Individual Participant Data (IPD) has the potential to overcome many of the above limitations, by using raw trial data. Access to IPD minimises problems from incomplete or incorrect reporting of trial outcomes, by verifying reported results, and by standardising the definition of outcomes where possible. Importantly, this allows detecting any variation in the effects of interventions according to characteristics of the participants. Amalgamated individual datasets assembled to address the effectiveness question, can be further used to explore secondary objectives such as the relationship between surrogate and clinical outcomes. This maximises the use of available clinical data, and addresses the problem of research waste. In this thesis, I evaluated the effects of diet and physical activity based interventions in pregnancy on maternal and offspring outcomes using both study-level and IPD meta-analyses, and assessed the differential effects of interventions on outcomes according to mother's BMI pre or in early pregnancy. I reviewed the variation in outcomes reported in this field, and developed composite outcomes for IPD meta-analysis. I also evaluated the relationship between weight gain in pregnancy and clinical outcomes in pregnancy using the IPD meta-analysis methodology. Aims The aim of this thesis was to evaluate the effects of diet and physical activity based interventions in pregnancy on clinical outcomes using standard and advance methods of evidence synthesis; assess the variation in outcomes and their clinical importance in a trial with those interventions and examine the relationship between gestational weight gain and important clinical outcomes. Methods Delphi methodology, systematic reviews of literature, and meta-analyses using study-level and individual participant data of randomised controlled trials (RCTs). Results Composite outcomes Developed composite outcomes comprise of four maternal (gestational diabetes, hypertensive disorders in pregnancy, preterm birth, caesarean section) and four offspring outcomes (stillbirth, small for gestational age, large for gestational age, and admission to neonatal intensive care unit). The components to assess maternal composite outcome were available in two-thirds (66.7%, 24/36) and for offspring composite in half (50%, 18/36) of the studies in the IPD meta-analysis. The effect of interventions was not statistically significant neither on the maternal nor on the offspring composite - Odds Ratio (OR) 0.90 (95% CI 0.79, 1.03) and OR 0.94 (95% CI 0.83, 1.08), respectively. The direction of the pooled effect was consistent between the composite and its components for the maternal composite and variable for the offspring outcomes. 6 Effects of diet and physical activity based interventions The IPD meta-analysis of 36 RCTs (>12 500 women) showed a significant effect of diet and physical activity based interventions in pregnancy in reducing gestational weight gain (Mean Difference -0.70 kg, 95% CI -0.92, -0.48) and chance of caesarean section delivery (OR 0.91, 95% CI 0.83, 0.99) in comparison to routine antenatal care. There was no effect of the interventions on any of the offspring complications. Incorporation of outcome data unavailable on study-level returned more modest magnitude of the summary estimates in comparison to effects obtained using study-level data of trials that shared IPD. The addition of study-level data from non-IPD trials changed the magnitude and the statistical significance of the summary effects on GDM - from OR 0.89 with only IPD (95% CI 0.72, 1.10; 27 studies, 9 427 women) to OR 0.76 (95% CI 0.65, 0.89; 59 studies, 16 885 women). It has also changed the funnel plot structure in the meta-analysis for gestational weight gain (Egger's test p = 0.04 with only IPD to p= 0.61). The IPD meta-analysis shows that the effects of diet and physical activity based interventions on the maternal and the offspring outcomes did not differ by women's BMI status. While the study-level meta-regression indicated that the interventions might reduce gestational weight gain stronger for the obese women - coefficient -0.22 (95% CI -0.33, -0.11) for each 10% change in the proportion of women in the obese class. Outcomes in trials with diet and physical activity based interventions 66 primary publications from trials with diet and physical activity based interventions in pregnancy reported 142 outcomes. Half of those outcomes appeared in the publications once (72/142). 'Critically important' outcomes are reported less often in comparison to 'non-critical' ones (15.5%, 22/142 vs 68.3%, 97/142). The overall quality of outcome reporting varied between trials with the least frequently provided information on the methods to improve the quality of outcome measures (33.3%, 22/66 publications). 7 Gestational weight gain and pregnancy outcomes IPD from 4 429 pregnant women randomised to the control arms of RCTs with diet and physical activity based interventions were available for the analysis. Women who most often exceeded the IOM recommendation belonged to the overweight (51.5%, 641/ 1 245 women) and the obese groups (44.5%, 695/ 1 562 women) while women with normal BMI most often gained below the recommended amounts (40%, 649/1 622 women). Each kilogram of gestational weight gain within the IOM ranges was not link with a change in the chances of preterm birth, caesarean section, or birth of LGA and SGA infant. Not achieving of the recommended weight was associated with the decreasing chance of giving birth to LGA infant with each kilogram below the lower limit among the obese women (OR 0.80, 95% CI 0.65, 0.99). Each kilogram of weight gain above the upper limit was associated with an increase in the chance of caesarean section (adjusted 1.04, 95% CI 1.01, 1.08) and delivering LGA infant (adjusted 1.08, 95% CI 1.05, 1.12) regardless on women's BMI status. Conclusions Diet and physical activity based interventions in pregnancy moderately reduced gestational weight gain and decrease the odds of caesarean delivery. Overall, IPD meta-analysis improved the robustness of the evidence synthesis of RCTs with diet and physical activity based interventions. However, more attention is needed for the data-related issues in IPD meta-analysis as the purported benefits of the method are not always practically realised. The use of the composite outcomes was hampered by the variable availability of important clinical outcomes. The introduction of minimal core outcome set would facilitate the comparison of the wide range of the evaluated interventions and improve implementation of the composite outcomes. Gestational weight gain was found to be associated with the odds of delivering LGA infant and caesarean section. Future research should aim to collect and report a minimal set of outcomes, and ensure better reporting of study conduct and its findings.

Inappropriate weight gain during pregnancy is a widespread problem associated with adverse maternal and newborn outcomes. This study’s objective was to examine the impact of gestational weight gain (GWG) above and below the Institute of Medicine (IOM) guidelines on pregnancy, delivery, and newborn outcomes in a rural population. Women were recruited at the first prenatal visit, and data was collected through research interviews and examination of prenatal and delivery medical records. Prepregnancy weight and weight at delivery were obtained, and the final sample (n=913) was restricted to women with singleton pregnancies. Participants were categorized by prepregnancy body mass index (BMI) and GWG above, within, or below IOM guidelines based on gestational length. After controlling for pregnancy smoking, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to identify significant outcomes associated with high or low weight gain, with normal GWG as the control. Of the 913 participants, 208 (22.8%) had inadequate GWG, 255 (27.9%) gained within the recommended range, and 450 (49.3%) gained more than recommended. Inadequate GWG was associated with delivery before 39 weeks, oxygen administration to the infant, admission to the neonatal intensive care unit (NICU), and a hospital stay longer than seven days. Excess GWG was associated with preeclampsia, pregnancy-induced hypertension (PIH), gestational diabetes mellitus, cesarean delivery, labor longer than 12 hours, macrosomia, and large-for-gestational-age (LGA) infants. GWG outside IOM guidelines was prevalent in the sample and associated with numerous adverse outcomes, suggesting a need for increased awareness and improved management of GWG in this population.

abstract: No studies have evaluated the impact of tracking resting energy expenditure (REE) and modifiable health behaviors on gestational weight gain (GWG). In this controlled trial, pregnant women aged >18 years (X=29.8±4.9 years) with a gestational age (GA) <17 weeks were randomized to Breezing™ (N=16) or control (N=12) for 13 weeks. The Breezing™ group used a real-time metabolism tracker to obtain REE. Anthropometrics, diet, and sleep data were collected every 2 weeks. Rate of GWG was calculated as weight gain divided by total duration. Early (GA weeks 14-21), late (GA weeks 21-28), and overall (GA week 14-28) changes in macronutrients, sleep, and GWG were calculated. Mediation models were constructed using SPSS PROCESS macro using a bootstrap estimation approach with 10,000 samples. The majority of women were non-Hispanic Caucasian (78.6%). A total of 35.7% (n=10), 35.7% (n=10), and 28.6% (n=8) were normal weight, overweight, and obese, respectively, with 83.3% (n=10) and 87.5% (n=14) of the Control and Breezing™ groups gaining above IOM GWG recommendations. At baseline, macronutrient consumption did not differ. Overall (Breezing™ vs. Control; M diff=-349.08±150.77, 95% CI: -660.26 to -37.90, p=0.029) and late (M diff=-379.90±143.89, 95% CI:-676.87 to -82.93, p=0.014) changes in energy consumption significantly differed between the groups. Overall (M diff=-22.45±11.03, 95% CI: -45.20 to 0.31, p=0.053), late (M diff=-23.16±11.23, 95% CI: -46.33 to 0.01, p=0.05), and early (M diff=20.3±10.19, 95% CI: -0.74 to 41.34, p=0.058) changes in protein differed by group. Nocturnal total sleep time differed by study group (Breezing vs. Control; M diff=-32.75, 95% CI: -68.34 to 2.84, p=0.069). There was a 11.5% increase in total REE throughout the study. Early changes in REE (72±211 kcals) were relatively small while late changes (128±294 kcals) nearly doubled. Interestingly, early changes in REE demonstrated a moderate, positive correlation with rates of GWG later in pregnancy (r=0.528, p=0.052), suggesting that REE assessment early in pregnancy may help predict changes in GWG. Changes in macronutrients did not mediate the relationship between the intervention and GWG, nor did sleep mediate relationships between dietary intake and GWG. Future research evaluating REE and dietary composition throughout pregnancy may provide insight for appropriate GWG recommendations. / Dissertation/Thesis / Doctoral Dissertation Nutrition 2019

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Background: Numerous maternal factors, such as body mass index (BMI), gestational weight gain (GWG), diet and physical activity (PA) have been shown to impact infant birth weight. In the UK, antenatal care tends to be based on pre-pregnancy BMI and women are not weighed routinely during pregnancy nor are there guidelines for GWG. However, it is widely acknowledged that maternal obesity and GWG in excess of the American Institute of Medicine guidelines are associated with increased risk of foetal macrosomia and recent studies have suggested a role of the timing and composition of GWG beyond that of BMI. The purpose of this study is to examine the effects of timing and composition of GWG on neonatal anthropometric outcomes in a prospective cohort study amongst women with a BMI≥30 kg/m2 in Plymouth, UK. Methods: Women (n=75) were recruited at 12 weeks gestation. Maternal height, weight and body composition assessed using skinfolds at biceps, triceps and subscapular were collected at baseline and repeated at 28 and 36 weeks gestation. Four-day food diaries and four days of accelerometry were collected in the days following each of the three study visits. Following delivery, infant weight and gestational age were obtained, and neonatal anthropometric measurements were recorded within 72 hours of delivery. Results: Maternal energy intake was positively associated with GWG and rate of fat mass (FM) accrual, in the second (r = 0.435 and r = 0.395, respectively, p < 0.05) and third trimesters (r = 0.333 and r = 0.317, respectively, p < 0.05), with no associations observed between maternal energy intake and rate of fat free mass (FFM) accrual in either trimester. Maternal rate of FFM accrual (in both trimester 2 and over total pregnancy), not FM nor rate of GWG, was positively associated with infant birth weight z scores (r = 0.360 and r = 468, respectively, p < 0.05) and upper arm area muscle estimate (UME) (r = 0.291 and r = 0.357, respectively, p < 0.05). Second trimester intake of sugar was positively associated with infant UME (r = 0.419, p < 0.05), while third trimester intake of sugar was positively associated with both infant UME and infant birth weight z score (r = 0.376 and r = 0.308, respectively, p < 0.05). Conclusion: The present study suggests that maternal accrual of FFM and intake of sugar during pregnancy may be associated with increased infant birth weight and lean mass. Further research is required to determine whether interventions should focus on changes in maternal body composition alongside diet and lifestyle during pregnancy, or if they should continue to focus on limiting total GWG.

Background: Excessive gestational weight gain (GWG) is common in developed countries and is associated with an increased risk of maternal and offspring morbidity. Evidence regarding efficacy and safety of antenatal lifestyle intervention is limited in terms of both systematic reviews and original trials. This thesis is based on the need to further explore this research area. Objectives: To assess and grade current evidence and evaluate short and long-term effects of an antenatal lifestyle intervention on women and their offspring Materials: Controlled trials of intervention publishedbefore August 2009 were systematically searched and reviewed. A randomized controlled trial (RCT) including 445 healthy women aged &gt;18 years with a body mass index (BMI) ≥19 and ≤16 weeks pregnant and their offspring was performed during 2007-2015 in Örebro Region, Sweden. Methods: The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used for review. Our RCT (called the VIGA trial) compared standard care with a composite intervention consisting of education, application of a personalized weight graph, prescription of exercise and more frequent monitoring of weight. Standardized measures of weight and height in offspring waere analysed based on World Health Organization (WHO) Child Growth Standards. Results: Quality of evidence across the studies published pre-August 2009 was concluded to be very low. Our intervention significantly reduced mean GWG (kg) but the proportion of women with excessive GWG, according to recommendations, was not significantly reduced. Short- term postpartum weight retention (PPWR) was significantly lower after the intervention but no significant difference remained 1 year after delivery. Offspring mean BMI z-scores or proportion of obesity did not differ between study groups at either birth or age 5. Conclusions: The antenatal lifestyle intervention reduced mean GWG and short-term PPWR but no long-term effects on maternal weight retention or offspring obesity were seen. Alternative modes and timing of intervention should be considered in future research. Reducing the prevalence of pre-conception obesity must still be considered the primary means to improve maternal and fetal outcome.

Gestational weight gain outside the recommended ranges puts women at risk for pregnancy complications and adverse birth outcomes. Food insecurity and environmental factors including neighborhood deprivation may influence gestational weight gain. This research 1) examines the impact of neighborhood deprivation on gestational weight gain, 2) identifies if the association varies by selected maternal characteristics, 3) examines the relationship between food insecurity and gestational weight gain, 4) determines if stress mediates the relationship between food insecurity and gestational weight gain, and 5) examines whether selected maternal characteristics mediate this relationship. The research was conducted through the analysis of the Pregnancy Risk Assessment Monitoring System, the American Community Survey and Florida Vital Statistics. Bivariate analyses, logistic regression and multilevel logistic regression were conducted to examine the associations. Results indicate that neighborhood deprivation and food insecurity are important risk factors for gestational weight gain that vary by stress and maternal characteristics.

In the US, 8.4% of children are diagnosed with asthma by age 18, making asthma one of the most common chronic conditions among children. Additionally, 25% of children experience persistent wheezing by age 6, an indicator of childhood asthma. Both childhood asthma and persistent wheezing may be linked to inflammatory and immune mechanisms, which are associated with inadequate and excessive gestational weight gain. Studies investigating the relationship between gestational weight gain and offspring asthma and wheeze phenotypes are limited by self-reported gestational weight gain, early age at asthma and wheeze assessments, limited adjustment for potential confounders and no trimester-specific evaluations. Therefore, we investigated the association between total and trimester-specific gestational weight gain, offspring asthma and wheeze phenotypes among 2128 mother-child pairs in Project Viva, a prospective cohort study in eastern Massachusetts. Gestational weight gain was abstracted from medical records and self-reported prepregnancy weight, and defined both continuously and using Institute of Medicine guidelines. Offspring asthma was obtained via maternal report at approximately 7 years, while wheeze trajectories were derived via latent class mixed models based on presence of wheeze between 1 and 9 years, inclusively, via maternal report. We investigated the relationship between gestational weight gain, offspring asthma and wheeze phenotypes using multivariable regressions and predicted probabilities, adjusting for important covariates. Most women had excessive gestational weight gain (56%), while 31% had adequate gestational weight gain and 13% had inadequate gestational weight gain. Approximately 18% of children had current mid-childhood asthma, 13% had early transient wheeze and 13% had persistent wheeze. We found a non-linear association between total gestational weight gain and offspring current mid-childhood asthma. Additionally, there was a 36% decreased odds of early transient wheeze among children of mothers with excessive third trimester gestational weight gain (aOR= 0.64; 95% CI: 0.42-0.98). This study adds to the body of literature by incorporating adequate inclusion of confounders and risk factors for adjustment, as well as being the first study to evaluate the association between trimester-specific gestational weight gain, offspring asthma and wheeze phenotypes.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23377号 / 医博第4746号 / 新制||医||1051(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 近藤 尚己, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Orientador: Cristina Maria Garcia de Lima Parada / Resumo: Introdução: As alterações do sono durante a gestação são frequentes, em decorrência das modificações anatômicas e fisiológicas típicas dessa fase da vida e associam-se a diversos problemas de saúde para o binômio materno-fetal, especialmente déficit de desenvolvimento placentário, ocasionando pré-eclâmpsia e restrição de crescimento intrauterino; parto prematuro e alterações no sono do lactente. A presença de sobrepeso e/ou obesidade tem sido associada a distúrbios do sono em adultos e existe base para a hipótese de que o padrão nutricional pré- gestacional possa influir na qualidade do sono da mulher na gestação e que a má qualidade do sono, independente do estado nutricional pré-gestacional, é fator de risco para ganho de peso inadequado na gestação. Objetivo: estudar as associações entre estado nutricional pré-gestacional, ganho de peso na gravidez e qualidade do sono; construir tecnologia para autocontrole do ganho de peso na gravidez. Método: Trata-se de estudo transversal aninhado a um estudo de coorte que analisou aspectos da saúde mental de gestantes, sono e desfechos nutricionais. A coleta de dados foi realizada no período de maio de 2018 a junho de 2019 mediante entrevistas presenciais, telefônicas e consulta aos prontuários das gestantes. Utilizou-se a escala de sono Mini-sleep Questionnaire, adotando-se como ponto de corte o escore 30 para definição de distúrbio severo do sono. Calculou-se o Índice de Massa Corpórea pré-gestacional, classificando as participantes ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Sleep changes during pregnancy are frequent, due to anatomical and physiological typical changes of this stage of life and are associated with several health problems for the maternal-fetal binomial, especially deficit in placental development, causing preeclampsia and fetal growth restriction; prematurity and changes in the infant's sleep. The presence of overweight and/or obesity has been associated with sleep disorders in adults and there is a basis for the hypothesis that the pre-gestational nutritional pattern may influence the quality of sleep during pregnancy and that poor sleep quality, regardless of the pre-gestational nutritional status, is a risk factor for inadequate weight gain during pregnancy. Methods: This is a nested cohort cross-sectional study. The collection was carried out from May to December 2018 and included 210 pregnant women who participated in face-to-face and telephone interviews. The Mini-sleep Questionnaire sleep scale was used, adopting a score of 30 as the cutoff point for the definition of severe sleep disorder. The pre-gestational Body Mass Index was also calculated, classifying participants as eutrophic, underweight, overweight and obese. Bivariate analysis of the data was performed and variables associated with the level of p <0.20 were included in multivariate analysis, with a 95% confidence interval and adopting a critical p <0.05. Results: Regarding the investigated associations, there was no relationship between pre-gestat... (Complete abstract click electronic access below) / Mestre