Healthy Lifestyle Before and During Pregnancy to Prevent Childhood Obesity - the PRE-STORK-trial

Study Overview
=================
Brief Summary
-----------------
Introduction: The prevalence of childhood overweight and obesity has risen from just 4% in 1975 to more than 18% in 2016. Little is known about adiposity of the infant, but it positively associates to the mother's BMI. Globally, the prevalence of overweight has tripled since 1975 and is now affecting one of three Danish women at the time of pregnancy. However, despite increasing awareness of obesity and accumulating evidence of its health consequences limited effect of intervention in childhood obesity exists. Maternal obesity before conception, an excessive increase in body weight during pregnancy and physical inactivity are some of the risk factors suspected of infant adiposity. Lifestyle interventions during pregnancy have shown limited or no effect in the offspring. Therefore, renewed effort to improve the prevention of childhood obesity is warranted. Methods and analysis: This is a randomized, parallel group, tailored, multifactorial lifestyle intervention trial in women (age 18 to 38 years) with overweight or obesity (BMI 27 to 42 kg/m2) seeking pregnancy. The women are randomized 1:1 to either the lifestyle or standard of care group. The lifestyle intervention is initiated prior to pregnancy. The lifestyle intervention is set off with a low-calorie diet for 8 weeks and throughout the intervention period (prior to and during pregnancy) participants follow an intervention containing exercise according to the World Health Organization guidelines, healthy diet and mentorship to maintain healthy weight before and during pregnancy.The primary outcome is the difference in neonatal adiposity measured at birth. Finally, a child and family cohort will be established to follow the children throughout childhood for healthy weight development. The study will provide evidence of effects from pre-conception-initiated intervention and have the potential to improve health and quality of life for children. Ethics and dissemination: The trial has been approved by the ethical committee of the Capital Region of Denmark (H-22011403) The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.

Official Title
-----------------
Healthy Lifestyle Before and During Pregnancy to Prevent Childhood Obesity. A Randomized, Parallel Group, Tailored Multifactorial Lifestyle Intervention Trial Among Women With Overweight or Obesity Seeking Pregnancy - the PRE-STORK Trial

Conditions
-----------------
Overweight and Obesity, Pregnancy Related

Intervention / Treatment
-----------------
* Behavioral: Diet
* Behavioral: Exercise
* Behavioral: Mentorship


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Having overweight or obesity (BMI 27-42 kg/m2) Age 18-34 years (no previous pregnancy) or 18-38 years (previous pregnant >16 weeks) Planning a pregnancy within the next year Willingness to lose at least 10% of initial body weight before pregnancy and be physically able to adhere to WHO physical activity recommendations when entering the study Willing to postpone pregnancy until at least 6 months after randomization Planning antenatal care and delivery at either Herlev Hospital or Odense University Hospital Danish or English speaking Exclusion Criteria: Diabetes (fasting plasma glucose (FPG) >7 mmol/l and HbA1c ≥48 mmol/mol) Previous gestational diabetes mellitus (GDM) treated with insulin during pregnancy Polycystic ovary syndrome (PCOS) treated with metformin Treatment with medication which significantly affect glucose metabolism, appetite, or energy balance The use of medications that cause clinically significant weight gain or loss Habitual abortion (more than 3 abortions in a row) Known infertility (defined as fertility treatment and/or no obtained conception with the same partner after trying >12 months) Previous bariatric surgery Significant psychiatric disorders Uncontrolled/severe medical issues including cardiovascular, pulmonary, rheumatologic, hematologic, oncologic, infectious, or endocrine disease Regular exercise training at high intensity (e.g., spinning) >3 hours per week Known eating disorder

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 38 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The trial is a randomised, parallel-group, intervention study comparing a tailored, intensive, multifactorial lifestyle intervention before and during pregnancy in women with overweight or obesity with standard of care.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lifestyle group<br>A tailored multifactorial lifestyle intervention consisting of diet, exercise and mentorship in women with overweight or obesity to obtain a healthy lifestyle before and during pregnancy. | Behavioral: Diet<br>* An initial 8 weeks of low-calorie diet including meal replacements (total of 800 kcal/day) will be initiated with the objective to lose at least 10% of initial body weight. From week 8 until week 12, an individual food-reintroduction plan will take place with partial meal product substitution. At week 12 and until pregnancy dieticians will ensure sustained compliance with diet aligned with the general recommendations for women seeking pregnancy (low-fat diet, rich in protein and carbohydrates and in some individuals slightly carbohydrate-reduced diet (prediabetes or family disposition to diabetes) with focus on carbohydrate quality (more fiber and whole grain). Consultations with a dietician for mapping diet and eating patterns and regular follow-up with a dietitian to maintain diet changes and modify diets if needed.<br>Behavioral: Exercise<br>* After an initial 8-week ramp-up phase (during the initial low-calorie diet), the women will be encouraged to attend supervised exercise sessions on the study location (combination of vigorous-intensity, interval-based indoor cycling, and circuit training) twice weekly and to perform additional moderate-to vigorous-intensity exercise to obtain at least 150 min per week of moderate-intensity or 75 min per week of vigorous-intensity physical activity or a combination. The plan will include individual exercise and/or group exercise. Exercise watches with heart-rate monitors will be worn at each exercise session to determine whether the requirement regarding weekly time spent at moderate or vigorous intensity will be met. Regular follow-up with the women to maintain exercise changes and modify the exercise plan if needed.<br>Behavioral: Mentorship<br>* Women are offered an individualized plan to successfully fulfil the multifactorial lifestyle intervention and the women will be offered both individual and/or group sessions with a mentor. After 8 weeks of the intervention, the women will be invited to another meeting where the choice of mentor will be evaluated, and the women will be offered to join a pre-parents-group. Group sessions will include conversational sessions, cooking classes and exercise classes with focus on changing lifestyle and maintaining a healthy lifestyle change. At the time of pregnancy groups will be reconsidered and the women will be offered participation in pregnancy-groups.<br>|
| No Intervention: Standard of care group<br>The standard of care group will receive no active intervention but are encouraged to seek any possible guidance from the general practitioner for management of pre-pregnancy obesity according to current guidelines. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal adiposity | Total fat mass (in gram) assessed by air displacement plethysmography (PEA POD). | Assessed at birth or up to 72 hours postpartum. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Foetal and infant body weight | During pregnancy foetal body weight is determined by ultrasonographic method and infant body weight is measured on a scale. | Assessed during pregnancy (week 18-21, 24-28 and 34), at birth and 4 months after birth. | 
| Foetal and infant abdominal circumference | During pregnancy abdominal circumference is determined by ultrasonographic method and infants are measured to the nearest 1.0 cm. | Assessed during pregnancy (week 18-21, 24-28 and 34), at birth and 4 months after birth. | 
| Foetal and infant femur length | During pregnancy femur length is determined by ultrasonographic method and infants are measured to the nearest 1.0 cm. | Assessed during pregnancy (week 18-21, 24-28 and 34), at birth and 4 months after birth. | 
| Foetal and infant head circumference | During pregnancy head circumference is calculated by biparietal diameter and occiput-frontal diameter by ultrasonographic method and infants are measured to the nearest 1.0 cm. | Assessed during pregnancy (week 18-21, 24-28 and 34), at birth and 4 months after birth. | 
| Placenta function (during pregnancy) | Measured by the represented amount of amniotic fluid, cerebral media and umbilical artery doppler flow of the foetus. | Assessed during pregnancy (week 34). | 
| Neonatal body mass index (BMI) z-score | Body mass index (BMI) is body weight relative to height (kg/m^2) and BMI z-score is called BMI standard deviation (s.d.) scores and is a measure of relative weight adjusted for child age and sex. | Assessed at birth. | 
| Neonatal body composition (fat percent) | Measured by air displacement plethysmography (PEA POD). | Assessed at birth. | 
| Neonatal body composition (fat free mass) | Measured by air displacement plethysmography (PEA POD) and lean mass is also based on this assessment. | Assessed at birth. | 
| Gestational age | The gestational age is registered when giving birth. | Assessed at birth. | 
| Weight for gestational age | Measured as percent of normal weight related to gestational age. | Assessed at birth. | 
| Large for gestational age (LGA) | Assessed as the proportions of infants being born LGA | Assessed at birth. | 
| Small for gestational age (SGA) | Assessed as the proportions of infants being born SGA. | Assessed at birth. | 
| Apgar score | Assessed as the proportions of infants born with Apgar score <7. | Assessed at birth. | 
| Placenta function (birth) | Assessed by the weight of the placenta (in gram). | Assessed at birth. | 
| Faeces (infant) | Changes in faecal microbiota composition. | Assessed at birth and 4 months after birth. | 
| Infant body composition (fat mass, fat free mass) PEA POD | Body composition (fat mass (g), and fat free mass (g)) is assessed by air displacement plethysmography (PEA POD). | Assessed 4 months after birth | 
| Infant body composition (fat percent) PEA POD | Body composition (fat percent (%) ) is assessed by air displacement plethysmography (PEA POD). | Assessed 4 months after birth | 
| Infant body composition (fat mass, fat free mass) dual energy x-ray absorptiometry. | Body composition (fat mass (g) and fat free mass (g)) is assessed by dual energy x-ray absorptiometry scans. | Assessed 4 months after birth. | 
| Infant body composition (fat percent) dual energy x-ray absorptiometry. | Body composition (fat percent (%)) is assessed by dual energy x-ray absorptiometry scans. | Assessed 4 months after birth. | 
| Infant BMI z-score | Body mass index (BMI) is body weight relative to height (kg/m^2) and BMI z-score is called BMI standard deviation (s.d.) scores and is a measure of relative weight adjusted for child age and sex. | Assessed 4 months after birth. | 
| Weight loss (women) | Assessed as the proportion of women who achieve a weight loss of ≥10% at time of pregnancy (or two years after randomisation without achieving pregnancy) | Assessed up to 2 years. | 
| Pregnancy (women) | Assessed as the proportion of women without obtaining pregnancy or live-born offspring within a period of two years. | Assessed up to 2 years. | 
| Glucose tolerance (OGTT) | Maximum observed glucose concentration, time to maximum observed glucose concentration and baseline-subtracted area under the plasma glucose concentration time curve (0-120 min) are assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28) | 
| Insulin resistance (fasting insulin) | Fasting insulin concentration is assessed prior to a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Insulin resistance (OGTT) | Area under the insulin concentration time curve (0-60 min), area under the insulin concentration time curve (0-120 min), maximum observed insulin concentration, time to maximum observed insulin concentration, baseline-subtracted area under the insulin concentration time curve (0-60 min) and baseline-subtracted area under the insulin concentration time curve (0-120 min), Matsuda index and homeostasis model assessment-insulin resistance (HOMA-IR) are assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Hormonal response - glucagon (OGTT) | Glucagon assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Hormonal response - GLP-1 (OGTT) | Glucagon-like peptide-1 (GLP-1) assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Hormonal response - PYY (OGTT) | Peptide tyrosine tyrosine (PYY) assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Hormonal response - GIP (OGTT) | Gastric inhibitory peptide (GIP) assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Hormonal response - ghrelin (OGTT) | Ghrelin assessed during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| Glycaemic variability (CGM and OGTT) | Measured by 10-day coefficient of variance (CV) of glucose levels measured by continous glucose monitoring (CGM) and during a 75 gram oral glucose tolerance test. | Assessed during pregnancy (week 24-28). | 
| BMI (women) | Calculated as weight (kg) divided by height(m)^2. | Assessed prior to pregnancy (baseline, 6 months, 12 months), during pregnancy (week 11-14, 18-21, 24-28 and 34) and four months after giving birth. | 
| Body weight (women) | Measured by scale to nearest 0.1 kg | Assessed prior to pregnancy (baseline, 6 months, 12 months), during pregnancy (week 11-14, 18-21, 24-28 and 34) and four months after giving birth. | 
| Height (women) | Measured to the nearest 0.5 cm. | Assessed prior to pregnancy (baseline). | 
| Body composition (fat percent and muscle mass percent) (women) | Body composition measured by Dual-energy X-ray absorptiometry scans prior to and after pregnancy. During pregnancy measured by bioelectrical impedance analysis. | Assessed prior to pregnancy (baseline, 6 months, 12 months), during pregnancy (week 11-14, 18-21, 24-28 and 34) and four months after giving birth. | 
| Bone density (T-score) (women) | Bone density is measured by Dual-energy X-ray absorptiometry scans prior to and after pregnancy. During pregnancy measured by bioelectrical impedance analysis. | Assessed prior to pregnancy (baseline, 6 months, 12 months) and four months after giving birth. | 
| Blood pressure (women) | After resting for a minimum of 10 minutes systolic and diastolic blood pressure is measured 3 times with 2 min in between each measurement. | Assessed prior to pregnancy (baseline, 6 months, 12 months), during pregnancy (week 11-14, 18-21, 24-28 and 34) and four months after giving birth. | 
| Resting heart rate (women) | After resting for a minimum of 10 minutes heart rate measured 3 times with 2 min in between each measurement. | Assessed prior to pregnancy (baseline, 6 months, 12 months), during pregnancy (week 11-14, 18-21, 24-28 and 34) and four months after giving birth. | 
| Fasting plasma glucose (women) | Fasting plasma glucose is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| HbA1c (women) | HbA1c is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - cholesterol (women) | Cholesterol is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - HDL (women) | High-density lipoprotein (HDL) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - LDL (women) | Low-density lipoprotein (LDL) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - VLDL (women) | Very-low-density lipoprotein (VLDL) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - TG (women) | Triglycerides is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Lipid profile - ApoA/ApoB ratio (women) | Apolipoprotein B/apolipoprotein A1 ratio assessed by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Liver function - liver fat (women) | Liver function by Fibro-Scan (a proxy for liver fibrosis) measured by Fibro-Scan (UL-based elastography) and liver fat is measured by the controlled attenuation parameter score in decibel per meter. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Liver function - liver stiffness (women) | Liver function by Fibro-Scan (a proxy for liver fibrosis) is measured by Fibro-Scan (UL-based elastography) and liver stiffness is measured by shear wave velocity in kilopascal. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Food preference (women) | Food preference is measured using the Steno Biometric Food Preference Task after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Bone homeostasis - CTX (women) | Pharmacodynamic endpoints for bone homeostasis derived from bone turnover markers carboxy-terminal collagen crosslinks (CTX) as a marker for bone resorption after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Bone homeostasis - P1NP (women) | Pharmacodynamic endpoints for bone homeostasis derived from bone turnover markers type 1 amino-terminal pro-peptide (P1NP) as a marker for bone formation after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Bone homeostasis - OC (women) | Pharmacodynamic endpoints for bone homeostasis derived from bone turnover markers osteocalcin (OC) as a marker of bone formation after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Inflammatory markers - hs-CRP (women) | High-sensitivity C-reactive protein (hs-CRP) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Inflammatory markers - TNFa (women) | Tumour necrosis factor-α (TNF-α) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Inflammatory markers - IL-6 (women) | Interleukin-6 (IL-6) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Inflammatory markers - LBP (women) | Lipopolysaccharide-binding protein (LBP) is measured by blood sampling after an overnight of fasting. | Assessed prior to pregnancy (baseline and 6 months) during pregnancy (week 24-28) and 4 months after giving birth. | 
| Waist and hip circumference (women) | Waist and hip circumference is measured to the nearest 0.1 cm. | Assessed prior to pregnancy (baseline, 8 weeks, 6 months, 12 months and 18 months) and 4 months after giving birth. | 
| Resting energy expenditure (women) | Resting energy expenditure is meaured using indirect calorimetry. | Assessed prior to pregnancy (baseline and 6 months) | 
| Exercise capacity (women) | Exercise capacity is measured by maximal exercise test with direct measurement of maximal oxygen consumption. | Assessed prior to pregnancy (baseline and 6 months) | 
| Prediabetes (women) | Assessed as the proportion of women with prediabetes. | Assessed prior to pregnancy (6 months from baseline) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diet, Exercise, Mentors