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A. General What are the post-natal effects of maternal (pre-)pregnancy obesity on the offspring? Evidence from animal studies. 1.

Title of the review


Effects of maternal obesity and offspring’s development and behaviour Effects of maternal obesity on offspring’s growth and physical health

Corresponding author: M. D. Menting, MSc, Dept. of Clinical Epidemiology, Biostatistics and Bioinformatics /Gynaecology & Obstetrics, Academical Medical Centre, Other authors not in order of contributions: C. van de Beek, PhD, Dept. of Obstetrics & Gynaecology, Academical Medical Centre S. Mintjens, MD, Dept. of Pediatrics, VU University Medical Center/ Dept. of Obstetrics & Gynaecology, Academical Medical Centre 2.

Authors (names, affiliations, contributions)

Prof. dr. T. J Roseboom, PhD, Dept. of Clinical Epidemiology, Biostatistics and Bioinformatics / Obstetrics & Gynaecology, Academical Medical Centre Dr. R.C. Painter, PhD, Dept. of Obstetrics & Gynaecology, Academical Medical Centre J. Limpens, PhD, Dept. of Research Support –Medical Library Prof. dr. S.E. Ozanne, PhD, Dept. of Clinical Biochemistry, University of Cambridge Dr. C.R. Hooijmans, PhD, Dept. of SYRCLE and Anesthesiology, Radboud University Medical Center

3. 4. 5.

Other contributors (names, affiliations, contributions) Contact person + e-mail address Funding sources/sponsors

N/A M.D. Menting, ZonMw financed this review; the Dutch Heart foundation paid

Check for approval

6. 7. 8.


Conflicts of interest Date and location of protocol registration Registration number (if applicable)

Stage of review at time of registration

the salary of M.D. Menting, S. Mintjens and C. van de Beek. N/A Updated version 3/1/2017 of protocol published 28/08/2015

Preliminary searches Piloting of the study selection process Formal screening of search results against eligibility criteria Data extraction Risk of bias (quality) assessment Data analysis

Started Yes Yes Yes Yes No No

Completed Yes Yes No No No No

B. Objectives Background The ‘developmental overnutrition hypothesis’ proposes that the increased fuel supply to the developing foetus in maternal obesity or overnutrition leads to permanent changes in offspring. Therefore, maternal obesity is recognized as a ‘programming’ factor [1]. The importance of exploring the effects of maternal obesity on the offspring, is emphasized by the high proportion of overweight (40% in 2014) and obesity (15% in 2014) among adult women worldwide [2].


Up to now, there is a large body of evidence to suggest that maternal obesity during pregnancy is associated with increased risks of physical and neurodevelopmental health in the offspring [1, 3]. However these studies were observational and most studies were not of high methodological quality [3]. For example, human studies are confounded by the influence of genetic and environmental variables [4]. Additionally it is impossible to What is already known about this separate the prenatal influences of maternal obesity from the disease/model/intervention? Why is it postnatal influences on offspring outcome in any human study important to do this review? [1]. Therefore associations in human observational studies do not permit any inferences of causation of intrauterine programming by maternal obesity [3]. Experimental animal studies are needed. Although valuable reviews of animal studies have been published in the last two years (e.g. [5] [6] [7] [8]), these reviews were not performed systematically and were often limited to a narrow range of outcomes. By systematically reviewing all the available evidence from animal experiments in various animal models, it will be possible to explore the causal effect of maternal obesity on the offspring. Additionally, it will be possible to differentiate this effect by the cause of obesity, like obesity induced by diet, chemicals or physical inactivity. Thus, to explore the causal effects of maternal obesity on developmental, behavioral and physical health outcomes in the offspring, a systematic review of performed animal

experiments is needed. Research question 11.

The effects of maternal obesity pre-pregnancy and during Specify the disease/health problem of pregnancy on the offspring interest


Specify the population/species studied Specify the intervention/exposure


Specify the control population


Specify the outcome measures




State your research question (based on items 11-15) C. Methods Search and study identification Identify literature databases to search (e.g. Pubmed, Embase, Web of science)

Offspring of female animals with obesity pre-pregnancy and during pregnancy. Maternal obesity pre-pregnancy and during pregnancy Offspring of female animals with normal weight pre-pregnancy and during pregnancy Offspring postnatal development, behavior, growth and health. What are the post natal effects of maternal (pre-)pregnancy obesity on the offspring? Evidence from animal studies

□MEDLINE via OVID □Web of Science □SCOPUS □EMBASE via OVID □Other, namely: □Specific journal(s), namely: We searched for the following concepts, using both controlled terms (i.e. MESH) and text words:


Define electronic search strategies (e.g. use the step by step search guide15 and animal search filters20, 21)

[animals] [maternal, intrauterine] [offspring] [obese] The initial search was performed in June 2015. The search will be updated in 2017. Contact the authors for more information on the search strategy.


20. 21.

Identify other sources for study identification

□Reference lists/citing articles of included studies of Science) □Books □Reference lists of relevant reviews □Conference proceedings, namely: □Contacting authors/ organisations, namely: □Other, namely:

Define search strategy for these other N/A sources Study selection Define screening phases (e.g. pre1. Pre-screening based on title/abstract.

(via Web

screening based on title/abstract, full text screening, both)





Specify (a) the number of reviewers per screening phase and (b) how discrepancies will be resolved

2. Full text screening 3. Check references of included studies

Two reviewers, discrepancies resolved by discussion and a third reviewer if needed.

Define all inclusion and exclusion criteria based on: Animal experiments: - Controlled intervention animal studies Type of study (design) - Primary studies (no review/conference article etc) Type of animals/population (e.g. age, gender, disease model)

Type of intervention (e.g. dosage, timing, frequency)

No restrictions. Only study must be free of additional disease factors or disease models. Maternal obesity pre-pregnancy and during pregnancy. In this review, obesity is defined as a significant higher weight/fat mass than the control group. Pre-pregnancy obesity is defined as obesity present at the time of conception. No restrictions on the cause of overweight/obesity. The cause of obesity does not have to be reported in the paper. If drugs or chemicals are used, the purpose of the use of these drugs/chemicals must be to induce obesity or closely related (for example affect the saturation level). The intention of the study must be to examine the effects of maternal (over)weight or obesity and the experimental dams must have a significantly higher body weight or higher fat mass than control dams pre-pregnancy and during pregnancy. If body weight is not reported and there is no data of increased fat mass, we exclude the article.

This is an explorative study, therefore no initial restriction will be made in terms of outcome measures. In the first analysis we will only extract study characteristics and name what type of outcome is measured.


Outcome measures

In the second analysis, meta-analyses will be performed if possible, on one or two reported measures per outcome category (see below) (with an exception on the category ‘behavior’ with a maximum of three meta-analysis). Outcome measures will be decided based on biological and clinical relevance and discussed with experts. We split the results into two papers, with one paper focusing on development and behavior and the other paper focusing on growth and physical health of the offspring.

Outcome categories could include, but are (not restricted to) the mentioned categories below.  -

Development and behavior Behavior Physical activity Executive functioning Brain structure Food preference and eating behavior

 -

Growth and physical health Growth Cardiovascular health Metabolic health Reproductive health Other physical health outcomes

See attachment A for a specification of the outcome categories. The aim of this review is to create an overview of outcomes and the mentioned outcomes in attachment A are examples.


Language restrictions


Publication date restrictions




Sort and prioritize your exclusion criteria per selection phase

Exclusion: Fetal outcomes No language restrictions. No publication date restriction Duplicated reports, conference articles, symposium abstracts will be excluded. Selection phase screening title/abstract: Exclusion criteria 1 Not a primary article (conference article, symposium, abstract, review) 2 Not an animal trial 3 No prenatal effects studied 4 No postnatal outcomes studied (thus not fetal) 5 No relevant outcomes studied (see overview attachment for details) 6 No pre-pregnancy or pregnancy obesity of the studied animals

Selection phase full-text screening: 1 Not a primary article (i.e. conference article, symposium, abstract, review) 2 Not an animal trial 3 No significant higher weight or higher fat mass of the intervention group than the females in the control group at time of conception and during pregnancy Help: - If unknown  exclude the article. - If described that weight has been measured pre-



pregnancy, but data is not reported in the article, then contact the authors. If there is referred to another article for the weight of the animals, look at the referred article. No intention of the study to examine the effects of maternal (over)weight or obesity or the effects of diet No effect of maternal weight/fat mass per se can be studied

5 Help: -



6 Help: -

In case of additional interventions: investigate if the effect of maternal weight/fat mass per se can be studied by including the right groups. Exclude when additional interventions were performed that would interfere the study of maternal obesity and offspring effects. Also exclude when an animal model with additional ‘disease factors’ was used such as Alzheimer disease or severe diabetes. Diabetes induced by streptozotocin or an obese diabetic animal model is considered as severe diabetes and you should exclude; mild glucose intolerance is not considered as severe diabetes and you should include No control group with normal weight or fat mass at time of conception and during pregnancy i.e. in case of dietary induced obesity: was a standard control (chow) diet used in the control group? A standard (chow) diet will normally have about 4% Fat (w/w) (about 11% by calories)


No control group similar to the intervention group on important baseline characteristics (i.e. genetically similar, same age, same breed; etc)?


No postnatal outcomes studied or the postnatal outcomes are not relevant for this study?

Help: -

see overview attachment for details

There is an hierarchy of the exclusion criteria.

31. 32.

Study characteristics to be extracted (for assessment of external validity, reporting quality) Study ID (e.g. authors, year) First author, year Among others: Study design characteristics (e.g. Number of groups experimental groups, number of Number of animals in group animals)




Among others: Animal species, animal strain Maternal body weight, if applicable: fat mass. Animal model characteristics (e.g. Timing of measurement maternal body weight/fat mass. species, gender, disease induction) by If mentioned: father body weight or fat mass. group? % Male

Intervention characteristics (e.g. intervention, timing, duration)

Among others: Method of inducing obesity, Timing of inducing obesity

Outcome measures

In a first descriptive analysis, we will name what type of outcome measures are used in the studies and how it is measured; not the values of the outcome measures. For example: Outcome - spatial learning and memory, Measured by - Morris water navigation task In the second analysis we will select outcomes to perform a further (meta-)analysis for the most relevant outcomes based on biological/clinical relevance.








Other (e.g. drop-outs) N/A Assessment risk of bias (internal validity) or study quality Specify (a) the number of reviewers Two reviewers, discrepancies resolved by discussion and a assessing the risk of bias/study quality third reviewer if needed. in each study and (b) how discrepancies will be resolved Define criteria to assess (a) the internal validity of included studies (e.g. selection, performance, detection and attrition bias) and/or (b) other study quality measures (e.g. reporting quality, power) Collection of outcome data For each outcome measure, define the type of data to be extracted (e.g. continuous/dichotomous, unit of measurement) Methods for data extraction/retrieval (e.g. first extraction from graphs using a digital screen ruler, then contacting authors) Specify (a) the number of reviewers extracting data and (b) how discrepancies will be resolved Data analysis/synthesis Specify (per outcome measure) how

 By use of SYRCLE's Risk of Bias tool4 □By use of SYRCLE’s Risk of Bias tool, adapted as follows: □By use of CAMARADES' study quality checklist, e.g 22 □By use of CAMARADES' study quality checklist, adapted as follows: □Other criteria, namely:

To be determined, see question 26.

Data from graphs will extracted using a screen ruler. If not possible, the author will be contacted. One reviewer will extract the data and the second reviewer will check this. Discrepancies will be resolved by discussion and a third reviewer if needed. See question 26.

you are planning to combine/compare the data (e.g. descriptive summary, If possible, subanalyses will be done separately for: meta-analysis) - Gender - Age (roughly divided in directly post-natal, childhood or adulthood) - Animal species


44. 45. 46.


A minimum of 2 articles per outcome measure is required Specify (per outcome measure) how it No restrictions in terms of heterogeneity will be applied, will be decided whether a metainstead, sources of heterogeneity will be investigated analysis will be performed through sensitivity and subgroup analysis. If a meta-analysis seems feasible/sensible, specify (for each outcome measure): The effect measure to be used (e.g. Continuous outcomes: SMD mean difference, standardized mean Dichotomous: RR difference, risk ratio, odds ratio) The statistical model of analysis (e.g. Random effects model random or fixed effects model) The statistical methods to assess I2 heterogeneity (e.g. I2, Q) - Gender - Age (roughly divided in directly post-natal, Which study characteristics will be childhood or adulthood) examined as potential source of - Animal species heterogeneity (subgroup analysis) Subgroup analyses are only performed when a minimum of 3 studies or 5 independent comparisons are available


Any sensitivity analyses you propose to perform


Other details meta-analysis (e.g. correction for multiple testing, correction for multiple use of control group)


The method for assessment of publication bias

Final approval by (names, affiliations):

Correction of p-value for the number of subgroup analyses by Bonferroni-Holmes correction. Correction for multiple comparisons with the same control group by dividing the number of control animals by the number of comparisons with the control group. Funnel plots, performing Duval and Tweedie's trim and fill analysis


Attachment A – Outcomes specified 

Part A Behavior and development, outcomes specified

Executive function: for example memory, attention, learning, visuo-spatial learning, cognitive function

Behavior: for example stress, stress response, behavioral disturbance, behavioral disorder, social behavior, emotional behavior, communication, avoidance, emotions, conditioning, conditioned fear, anxiety, depression, fighting, aggressive, mood, impulsivity, addiction, risk taking Physical activity: for example spontaneous movements, exploratory behavior, motor activity, sensori-motor (reflex response), locomotion, hyperactivity Brain structure: for example brain development, brain weight, brain composition, hippocampus, functional imaging

Food preference and eating behavior: for example food choice, food intake

EXCLUDED Gene/neuron specific parameters like: Neuronal activity, gene expression, neurogenesis, proliferation, differentiation, migration, integration phase , synaptogenesis, synapse, neuro-transmitters

Part B Growth and physical health, outcomes specified

Growth Growth: for example length, body growth, growth pattern, weight, BMI, birth weight, SGA/LGA, bone growth Body composition: for example fat percentage, fat distribution, muscle fat

Cardiovascular Cardiac structure and function: for example ventricle mass, hypertrophy, atherosclerosis, coronary artery function, response to ischemia/reperfusion Vessel structure and function: arterial wall structure and compliance Blood pressure: for example systolic and diastolic Automatic Nervous System in blood pressure regulation: for example heart rate variability Electrocardiogram variances Ultrasound measured parameters: for example cardiac echo, carotid Intima Media Thickness, Aortic Pulse Wave Velocity Kidney (functioning): for example weight, glomerular filtration rate

Metabolic Insulin/glucose (metabolism): for example insulin sensitivity (fasting, not fasting), glucosetolerance Pancreas deficit: for example structure, amount beta-cell , islet size Lipid profile: for example LDL, HDL, TG, Apolipoprotein A, Apolipoprotein B Adipokines: for example adiponectin, leptin, resistin, Ghrelin Endothelial/inflammation markers: for example VCAM-1, ICAM-1, HS-CRP, TNFa, IL-1 and 6, Plasmine activator inhibitor 1 (PAI-1), MCP1 Liver: steatosis, weight Epigenetic change: DNA methylation, histone modification, micro RNA. Endocrine function: Thyroid, HPA, HPG, cortisol response, leptin response, weight/feed gain, ‘metabolic efficiency’ Other: for example Homocysteine, Vitamine D, Thrombin, Fibrinogen, D-Dimer.

Reproductive health and other health outcomes Fertility/reproductive health (gonadal axis, gonad weight, function); Endometrium function

Other health outcomes Tumor genesis; Immune system; lung function, HPA-function

EXCLUDED Gene/neuron specific parameters like specific gene expression, gene activation

Literature 1. O'Reilly, J.R. and R.M. Reynolds, The risk of maternal obesity to the long-term health of the offspring. Clin Endocrinol (Oxf), 2013. 78(1): p. 9-16. 2. WHO, Obesity and overweight. 2015. Retrieved at July, 20th 2015. 3. Van Lieshout, R.J., Role of maternal adiposity prior to and during pregnancy in cognitive and psychiatric problems in offspring. Nutr Rev, 2013. 71 Suppl 1: p. S95-101. 4. Alfaradhi, M.Z. and S.E. Ozanne, Developmental programming in response to maternal overnutrition. Front Genet, 2011. 2: p. 27. 5. Penfold, N.C. and S.E. Ozanne, Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions. Horm Behav, 2015. 6. Zambrano, E. and P.W. Nathanielsz, Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. Nutr Rev, 2013. 71 Suppl 1: p. S42-54. 7. Sullivan, E.L., E.K. Nousen, and K.A. Chamlou, Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav, 2014. 123: p. 236-42. 8. Rivera, H.M., K.J. Christiansen, and E.L. Sullivan, The role of maternal obesity in the risk of neuropsychiatric disorders. Front Neurosci, 2015. 9: p. 194.

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