The study is a single site parallel randomized controlled study. The study will be assessing the effect of approximately 10% weight loss intervention vs a control group among healthy females/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 females/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 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
240
Subjects will receive very low-calorie diet for 8-10 weeks to introduce a rapid weight loss of approximately 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 approximately 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.
University of Copenhagen
Frederiksberg, DK, Denmark
Neonatal fat mass
Offspring's neonatal fat mass (grams) assessed by air displacement plethysmography (Pea POD)
Time frame: Assessed at birth (strived <24 hours, but allow <48 hours)
Obstetrics outcome - length of gestational age
Length of gestational age.
Time frame: Assessed at birth of offspring.
Obstetric - medication use
Medication use during labor
Time frame: 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).
Time frame: 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).
Time frame: Collected at registration of pregnancy, in gestational age (GA) 8, GA13, GA20, GA28, GA36 and GA39).
Obstetric - Neonatal unit admissions
Neonatal unit admissions.
Time frame: 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).
Time frame: Collected at birth of offspring
Obstetrics - birth defects/abnormalities
Birth defects/abnormalities
Time frame: 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.
Time frame: 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.
Time frame: Collected in gestational age (GA)11-13, GA19-21 and GA28, at birth and 3, 6 and 12 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.
Time frame: Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6 and 12 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
Time frame: Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6 and 12 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
Time frame: Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6 and 12 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.
Time frame: Collected in gestational age (GA) 11-13, GA19-21 and GA28, at birth and 3, 6 and 12 months after birth.
Fetal growth - fractional limb volume
Fractional limb volume will be measured with ultrasound during pregnancy.
Time frame: Collected in gestational age 28.
Offspring growth - BMI z-score
Offspring body mass index (BMI) z-score (BMI adjusted for age and sex).
Time frame: Collected at birth and 3, 6 and 12 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.
Time frame: Collected at birth and 3, 6 and 12 months after birth of offspring.
Offspring growth - large for gestational age
Large for gestational age. Prevalence of infants being LGA.
Time frame: Collected at birth and 3, 6 and 12 months after birth of offspring.
Offspring growth - small for gestational age
Small for gestational age. Prevalence of offspring being small for gestational age (SGA).
Time frame: Collected at birth and 3, 6 and 12 months after birth of offspring.
Offspring growth - apgar score
Apgar score (0-10). The higher the score, the better health condition of the offspring)
Time frame: 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
Time frame: Collected at birth and 3, 6 and 12 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)
Time frame: Collected at birth (strived <24 hours, but allow <48 hours) and 3 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.
Time frame: Collected 12 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.
Time frame: Collected 12 months after birth of offspring
Offspring growth - self-reported body weight
Self-reported body weight
Time frame: 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
Time frame: 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
Time frame: The intervention: each visit(V) throughout the study (baseline to 12mo. after birth). The control: before pregnancy (baseline, V11 and V14), all visits during pregnancy, at birth, at V27≤6days after birth and 3, 6 and 12 mo. 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.
Time frame: 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.
Time frame: Collected at baseline (V0).
Adult BMI
Calculated ad weight (kg)/height(m)\^2
Time frame: 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 and 12 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.
Time frame: 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 and 12 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Use of medication will be collected at all visits.
Offspring medication use
Use of medication will be collected throughout the study.
Time frame: Birth, after 3, 6 and 12 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.
Time frame: Registration of pregnancy
Adult reproduction - Success rate
Success rate of pregnancy defined as number of achieved pregnancies.
Time frame: Registration of pregnancy
Reproduction (male) - Sperm motility
Sperm motility (%).
Time frame: 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).
Time frame: Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group.
Reproduction (male) - Sperm morphology
Morphology (%).
Time frame: Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group.
Reproduction (male) - Sperm acrosomal status
Acrosomal status (%).
Time frame: Collected baseline and at visit (V) 11. Additionally, at V8 (prior to pregnancy) for the intervention group.
Reproduction (male) - Sperm DNA fragmentation
DNA fragmentation (%)
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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 12-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
Time frame: Collected at 12 months after birth
Offspring lipid profile
Total amount of venous blood will be drawn at 12-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.
Time frame: Collected at 12 months after birth
Offspring inflammation markers
Total amount of venous blood will be drawn at 12-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.
Time frame: Collected at 12 months after birth
Offspring growth factors and hormones
Total amount of venous blood will be drawn at 12-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).
Time frame: Collected at 12 months after birth
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