PRE-Pregnancy Weight Loss And the Reducing Effect on CHILDhood Overweight - Copenhagen

Study Overview
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Brief Summary
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The study is a single site parallel randomized controlled study. The study will be assessing the effect of a 10% weight loss intervention vs a control group among healthy couples where the prospective mother is overweight or obese (BMI 27-45 kg/m^2) and between 18-38 years. The investigators will recruit a total of 240 healthy couples who will be randomized 1:1 to either intervention or control, stratified according to maternal pre-pregnancy BMI. The overall objective is to test whether a comprehensive pre-conceptional parental weight loss intervention effectively reduces the risk of offspring overweight and adiposity and its complications compared to a control group. The investigators hypothesize that parental weight loss intervention, initiated before conception, will facilitate lower parental insulin resistance, inflammation, body weight and adiposity, incretin responses compared to usual care. For the offspring the investigators hypothesize that the intervention will reduce adverse pregnancy outcomes with a reduction in offspring neonatal adiposity, reduced risk of being born large for gestational age (LGA) and with lower BMI z-score at 18 months.

Official Title
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PRE-Pregnancy Weight Loss And the Reducing Effect on CHILDhood Overweight - a Randomized Controlled Study in Copenhagen

Conditions
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Overweight and Obesity, Weight Loss, Pregnancy Related

Intervention / Treatment
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* Behavioral: Weight loss intervention


Participation Criteria
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Eligibility Criteria
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Maternal inclusion Criteria: Maternal pre-pregnancy BMI 27.0-44.9 kg/m^2 Maternal age range 18-38 years Connected to Hvidovre Hospital as place of birth Not pregnant or breastfeeding Paternal Inclusion Criteria: Paternal pre-pregnancy BMI 18.5-44.9 kg/m^2 Paternal age range 18-55 years Parental Inclusion Criteria: Couples (male and female) Planning pregnancy within 1 year Provided voluntary informed consent Danish or English speaking Intention to permit the planned offspring to participate in the follow-up study Able to store biological samples from the offspring at home in the freezer in a box given by the study personnel Parental Exclusion Criteria: Diabetes mellitus (Type 1 or 2) Previous or present eating disorder Allergy towards ingredients in the very low calorie diet products Severe heart, liver or kidney disease Conception by in vitro fertilization ≥4 consecutive spontaneous pregnancy loss (female) Having tried to conceive or prior time to pregnancy of more than 12 months Any medical condition or concomitant medication as judged by the medical responsible Adherence to vegan diets or other diets interfering with the dietary guidelines in the study Participation in other clinical trial Engagement in elite sports or similar strenuous exercise ≥5 h/week Blood donation or transfusion within the past month before baseline Blood donation during the study Inability or unwillingness to follow the study protocol and instructions given by the study personnel Pregnancy registered at baseline visit (urinary analysis with dipstick) A detailed description of the exclusion criteria is given below: Medical conditions as known by the participant: Diabetes mellitus (type 1 and 2) History or diagnosis of eating disorder (e.g. restrained eating, disinhibition, emotional eating) Any significant medical condition as assessed by the investigator (e.g. dysregulated thyroid disease or reproductive diseases) Any significant psychiatric disorder (i.e. schizophrenia, bipolar disease or depression) as assessed by the investigator Severe chronic heart, liver and kidney disease Polycystic ovary syndrome with irregular cycle Amenorrhea Severely reduced semen quality incl. azoospermia Medication: - Current use of medication or use within the previous three months with a potential to affect body weight or pregnancy as judged by the investigator (e.g. systemic corticoids) Personal/other: Having tried to conceive or prior time to pregnancy of more than 12 months Weight changes ± 5% three months prior to inclusion Severe food allergies, food intolerances or dislike expected to interfere with the study, including allergy towards ingredients in the VLCD products Engagement in elite sports or similar strenuous exercise ≥5 h/week Blood donation or transfusion within the past month before baseline Planned blood donation for other purpose than this study during participation Alcohol abuse, as judged by the investigator, within the previous 12 months Drug abuse, as judged by the investigator, within the previous 12 months Psychological or behavioral problems which, in the judgement of the investigator, would lead to difficulty in complying with the study protocol Participation in other clinical trials within the past three months or intention to do so during the study, which are judged by the investigator to affect the present study Unable to consume the interventional product for religious reasons, swallowing disorders, other physiological reasons or any other reasons for not being able to follow the recommended diet Inability or unwillingness to give written informed consent or communicate with study personnel Inability or unwillingness to follow the study protocol and instructions given by the study personnel Illiteracy or inadequate understanding of Danish or English language. Any other condition that judged by the investigator may interfere with the adherence to the study protocol

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Rapid moderate weight loss (at least 10% of body weight at baseline over 8-10 weeks or BMI 23 kg/m^2 is achieved) by very low-calorie diet (VLCD), reintroduction (4 weeks), weight loss maintenance until pregnancy (up to 12 months), and a high protein, high fiber diet during pregnancy (n=120 couples). | Behavioral: Weight loss intervention<br>* Subjects will receive very low-calorie diet for 8-10 weeks to introduce a rapid weight loss of at least 10%. Once target weight is achieved, participants will be reintroduced to foods to introduce weight stability. The male will follow the maternal randomization, i.e. weight loss if BMI ≥25 until a BMI of 23 or a weight loss of at least 10% is obtained. During weight loss maintenance, subjects will receive dietary counseling to follow a diet high in protein (corresponding to 22-25E%), high fiber and wholegrain while fulfilling the requirements for essential fatty acids, micronutrients and trace elements in accordance with Nordic Nutrition Recommendations (NNR) 2012. Throughout the study period participants will be encouraged to follow the official recommendations for physical activity as recommended by the Danish health authorities 2022.<br>|
| No Intervention: Standard of care<br>The control group will not receive any dietary advice prior to pregnancy. During pregnancy control subjects will receive dietary advice similar to the intervention group, i.e. a high protein, high fiber diet (n=120 couples). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal fat mass | Offspring's neonatal fat mass (grams) assessed by air displacement plethysmography (Pea POD) | Assessed at birth (strived <24 hours, but allow <48 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Obstetrics outcome - length of gestational age | Length of gestational age. | Assessed at birth of offspring. | 
| Obstetric - medication use | Medication use during labor | Collected from initiation of labor until completed birth of offspring. | 
| Obstetric - delivery mode | Delivery mode (rupture of membranes or premature contractions, vaginal, cesarean section, instrumental delivery, miscarriage and stillbirth). | Collected at birth of offspring. | 
| Obstetric - pregnancy complications | Pregnancy complications e.g. miscarriage, abortion (induced and indication for abortion), hydramnios, gestational hypertension, preeclampsia, need for maternal corticosteroid treatment for fetal lung maturation, urinary tract infection). | Collected at registration of pregnancy, in gestational age (GA) 8, GA13, GA20, GA28, GA36 and GA39). | 
| Obstetric - Neonatal unit admissions | Neonatal unit admissions. | Collected at birth and until 6 months after birth of offspring. | 
| Obstetric - obstetrics complications | Obstetrics complications (e.g. preterm prelabour rupture of the membranes, shoulder dystocia, birth trauma (perinatal rupture), postpartum hemorrhage, maternal infections, maternal hospitalization). | Collected at birth of offspring | 
| Obstetrics - birth defects/abnormalities | Birth defects/abnormalities | Collected at birth of offspring | 
| Neonatal morbidities | Neonatal morbidity (e.g. major congenital malformations (ICD10 Q00-Q99 or requiring medical or surgical treatment), birth injury, respiratory distress, transient tachypnoea, neonatal hypoglycemia, systemic infections, admission to neonatal intensive care unit, number of admission days, hyperbilirubinemia), deaths. | Collected at birth of offspring | 
| Fetal and offspring growth - body weight | Fetal body weight will be measured with ultrasound during pregnancy and offspring body weight will be measured using an electronic scale. | Collected in gestational age (GA)11-13, GA19-21 and GA28, at birth and 3, 6, 12 and 18 months after birth. | 
| Fetal and offspring growth - length | Fetal length will be measured with ultrasound during pregnancy and offspring length will be measured using using an infantometer as appropriate for measuring infant, baby and toddler length. | Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6, 12 and 18 months after birth. | 
| Fetal and offspring growth - abdominal circumference | Abdominal circumference will be measured with ultrasound during pregnancy and offspring abdominal circumference will be measured three times to the nearest 0.1 cm using a stretch-resistant measuring tape | Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6, 12 and 18 months after birth. | 
| Fetal and offspring growth - crown circumference | Crown circumference will be measured with ultrasound during pregnancy and offspring crown circumference will be measured three times to the nearest 0.1 cm using a stretch-resistant measuring tape | Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6, 12 and 18 months after birth. | 
| Fetal and offspring growth - femur length | Femur length will be measured with ultrasound during pregnancy and offspring thigh will be measured three times to the nearest 0.1 cm using a stretch-resistant measuring tape. | Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6, 12 and 18 months after birth. | 
| Fetal growth - fractional limb volume | Fractional limb volume will be measured with ultrasound during pregnancy. | Collected in gestational age 28. | 
| Offspring growth - BMI z-score | Offspring body mass index (BMI) z-score (BMI adjusted for age and sex). | Collected at birth and 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - weight for gestational age | Weight for gestational age. Measured as percent of normal weight related to gestational age. | Collected at birth and 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - large for gestational age | Large for gestational age. Prevalence of infants being LGA. | Collected at birth and 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - small for gestational age | Small for gestational age. Prevalence of offspring being small for gestational age (SGA). | Collected at birth and 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - apgar score | Apgar score (0-10). The higher the score, the better health condition of the offspring) | Collected at birth of offspring | 
| Offspring growth | Offspring circumference (upper arm and hip) and 5 points skinfold (bi- and triceps, subscapularis, belly and waist). Circumferences will be measured to the nearest 0.1 cm using a stretch-resistant measuring tape and skinfolds are measured to the nearest 0.02 cm using a caliper to lightly pinch the skin and the underlying fat | Collected at birth and 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - body composition by the POD system | Offspring fat free mass (g) and fat mass (g) will be assessed by air displacement plethysmography using the POD system (either the Pea POD or the Bod POD system depending on the most appropriate for age) | Collected at birth (strived <24 hours, but allow <48 hours), 3, 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - body composition by DEXA scan | Offspring fat free mass (g) and fat mass (g) will be assessed by a Dual-energy X-ray absorptiometry-scan (DEXA). | Collected at 6, 12 and 18 months after birth of offspring. | 
| Offspring growth - bone markers by DEXA scan | Offspring bone area (cm^2), bone mineral density (g/cm^2) and bone mineral content (g) will be assessed by a Dual-energy X-ray absorptiometry-scan (DEXA). | Collected at 6, 12 and 18 months after birth of offspring. | 
| Offspring blood pressure | Offspring blood pressure (diastolic and systolic blood pressure) will be measured three times after 5-10 minutes rest using an automated device placed on the arm and in direct contact with the skin. | Collected 6, 12 and 18-months after birth of offspring | 
| Offspring heart rate | Offspring heart rate will be measured three times after 5-10 minutes rest using an automated device placed on the arm and in direct contact with the skin. | Collected 6, 12 and 18-months after birth of offspring | 
| Offspring growth - self-reported body weight | Self-reported body weight | 18 months after birth the study staff will make an annual follow-up phone call to the parents to collect information about the offspring's self-reported body weight until the offspring is 14 of age. | 
| Offspring growth - self-reported height | Self-reported height | 18 months after birth the study staff will make an annual follow-up phone call to the parents to collect information about the offspring's self-reported body weight until the offspring is 14 of age. | 
| Adult weight | Adult body weight is measured to the nearest 0.1 kg using a calibrated scale | The intervention: each visit(V) throughout the study (baseline to 18mo. after birth). The control: before pregnancy (baseline, V11 and V14), all visits during pregnancy, at birth, at V27≤6days after birth and 3,6,12 and 18mo. after birth | 
| Adult self-reported body weight (control group) | The control group will be instructed to self-report their body weight in a fasting state (no food or drink besides a maximum of 500 mL of water from 10 pm the night before) by using their own personal weight scale at home after having emptied their bladder at time point 9 and approximately monthly from time point 9 until registration of pregnancy. | From baseline to registration of pregnancy (4, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 52 weeks after baseline) | 
| Adult Height | Adult height will be measured to the nearest 0.5 cm using a wall-mounted stadiometer. | Collected at baseline (V0). | 
| Adult BMI | Calculated ad weight (kg)/height(m)^2 | Collected baseline, visit (V)1-19, registration of pregnancy, in gestational age (GA)8, GA13, GA20, GA28, GA36, GA39, when giving birth and at 3, 6, 12 and 18 months after birth. | 
| Adult anthropometric | Waist- and hip circumference will be measured to the nearest 0.5 cm. During pregnancy and at birth the waist of the female will not be measured. | Collected prior to pregnancy (at baseline, visit(V)5, V6, V7, V8, V12, and V16 (V5-V16 only the intervention)), during pregnancy (at registration of pregnancy, in gestational age(GA)13 and GA36), and at 3, 6, 12, and 18 months after birth of offspring. | 
| Adult body composition by DEXA scan | Lean mass (g), fat mass (g), abdominal fat (g), visceral fat (g) assessed by a Dual-energy X-ray absorptiometry-scan. | Collected at baseline (visit (V)0), at registration of pregnancy (only male) and after birth (≤6 days after birth of offspring). Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult bone markers by DEXA scan | Bone area (cm^2), bone mineral density (g/cm^2) and bone mineral content (g) assessed by a Dual-energy X-ray absorptiometry-scan. | Collected at baseline (visit (V)0), at registration of pregnancy (only male) and after birth (≤6 days after birth of offspring). Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult blood pressure | Blood pressure (diastolic and systolic blood pressure) will be measured three times with two minutes apart after 5-10 minutes rest using a validated automatic device. | Collected at baseline (visit (V)0) and in gestational age (GA)36. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult heart rate | Heart rate will be measured three times with two minutes apart after 5-10 minutes rest using a validated automatic device. | Collected at baseline (visit (V)0) and in gestational age (GA)36. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult resting metabolic rate | Resting metabolic rate (calories/24-h) and respiratory quotient will be measured by indirect calorimetry using a ventilated hood system. Participants will lie in the supine position and rest for at least 5 min before measurements commence. The measurement will be performed twice and last for 25 min with 5 min between measurements. | Collected at baseline visit (V)0. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult resting respiratory quotient | Resting respiratory quotient will be measured by indirect calorimetry using a ventilated hood system. Participants will lie in the supine position and rest for at least 5 min before measurements commence. The measurement will be performed twice and last for 25 min with 5 min between measurements. | Collected at baseline visit (V)0. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult medication use | Use of medication will be collected throughout the study. | Use of medication will be collected at all visits. | 
| Offspring medication use | Use of medication will be collected throughout the study. | Birth, after 3, 6, 12, and 18 months after birth of offspring. | 
| Adult reproduction - Time to pregnancy | Duration of time to conception defined from time point allowed to conceive to registration of pregnancy. | Registration of pregnancy | 
| Adult reproduction - Success rate | Success rate of pregnancy defined as number of achieved pregnancies. | Registration of pregnancy | 
| Reproduction (male) - Sperm motility | Sperm motility (%). | Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Reproduction (male) - Sperm concentration | Concentration (in million sperm cells/ml). | Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Reproduction (male) - Sperm morphology | Morphology (%). | Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Reproduction (male) - Sperm acrosomal status | Acrosomal status (%). | Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Reproduction (male) - Sperm DNA fragmentation | DNA fragmentation (%) | Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult glucose metabolism (OGTT, only female) | 2-h oral glucose tolerance test (OGTT) will be performed at gestational age 20 and  28 or only  28. | Collected at gestational age (GA)20 and 28 or only 28 (only female) | 
| Adult glucose metabolism (CGM, only female) | A continuous glucose monitoring system will be attached to the designated area on the upper body as stated by the manufacture. | Collected at gestational age (GA)28+GA29 | 
| Adult glucose metabolism | All blood samples will be collected by venous puncture in the antecubital vein after an overnight fast from at least 10 pm the night before. Samples will be analysed for fasting glucose, insulin, C-peptide and HbA1c | Collected at baseline (visit(V)0) and during pregnancy in gestational age (GA)36 (only female). Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult lipid profile | All blood samples will be collected by venous puncture in the antecubital vein after an overnight fast from at least 10 pm the night before. Samples will be analysed for triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low-density lipoprotein VLDL and total cholesterol | Collected at baseline (visit(V)0) and during pregnancy in gestational age (GA)36 (only female). Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Adult inflammation markers | All blood samples will be collected by venous puncture in the antecubital vein after an overnight fast from at least 10 pm the night before. Samples will be analysed for hsCRP, Tumor necrosis factor alpha (TNF-α) and interleukin (IL6). | Collected at baseline (visit(V)0) and during pregnancy in gestational age (GA)36 (only female). Additionally, at V8 (prior to pregnancy) for the intervention group. | 
| Offspring glucose metabolism | Total amount of venous blood will be drawn at 6-, 12- and 18-months follow-up visit. Parents will be instructed that the offspring should not have eaten two hours prior to the assessment. Samples will be analysed for glucose, insulin, C-peptide and HbA1c | Collected at 6, 12 and 18 months after birth | 
| Offspring lipid profile | Total amount of venous blood will be drawn at 6-, 12- and 18-months follow-up visit. Parents will be instructed that the offspring should not have eaten two hours prior to the assessment. Samples will be analysed for triglycerides, LDL, HDL, VLDL and total cholesterol. | Collected at 6, 12 and 18 months after birth | 
| Offspring inflammation markers | Total amount of venous blood will be drawn at 6-, 12- and 18-months follow-up visit. Parents will be instructed that the offspring should not have eaten two hours prior to the assessment. Samples will be analysed for hsCRP, TNF-α and IL6. | Collected at 6, 12 and 18 months after birth | 
| Offspring growth factors and hormones | Total amount of venous blood will be drawn at 6-, 12- and 18-months follow-up visit. Parents will be instructed that the offspring should not have eaten two hours prior to the assessment. Samples will be analysed for Insulin-like Growth Factor 1 (IGF-1) and growth hormone (GH). | Collected at 6, 12 and 18 months after birth |