The overall aim of the study is to develop a nutritional preventive fish oil supplementation strategy in pregnancy for early childhood asthma/persistent wheeze during the first three years of life as we hypothesize that both supplementations in higher doses than recommended could reduce the risk of disease development.
Randomization of 2000 pregnant women to fish oil of 2.4 g/day (55% EPA and 37% DHA) in triacylglycerol form vs placebo. Supplementation begins in gestational week 24 (22-26) until 1 week after delivery. Allocation to the trial will be determined based on the pre-interventional maternal blood levels of EPA+DHA with a dried blood screening test. Women with low levels (below 4.7% of total fatty acids) will be assigned to the fish oil RCT. Maternal blood will be used for genetic, metabolomic and proteomic profiling. A 3-year follow-up of the children with longitudinal registration of parent reported symptoms, diagnoses, medication use, and hospitalizations will be performed. The primary outcome is persistent wheeze or asthma until age 3 years, with predefined analyses of effect modification by maternal genotypes. Secondary outcomes are lower respiratory tract infections, gastrointestinal infections, croup, troublesome lung symptoms, eczema, allergy, bone fractures, developmental milestones, mental health, cognition, and growth until age 3 years. A follow-up on both primary and secondary outcomes is planned after unblinding, from age 3 to 6 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
2,000
Oral intake of 4 capsules per day from week 22-26 in pregnancy to 1 week after delivery
Oral intake of 4 capsules per day from week 22-26 in pregnancy to 1 week after delivery
Copenhagen University Hospital of Copenhagen
Gentofte Municipality, Denmark
RECRUITINGEarly childhood asthma/persistent wheeze age 0-3 years
Defined as either a) parental report of a minimum of 2 wheeze episodes with at least 1 after the child's second birthday and redemption of at least 2 prescriptions of asthma controller medication with at least 1 being after the child's second birthday or b) a minimum of 2 ED visits or hospitalizations due to asthmatic symptoms, and at least 1 of these being after the child's second birthday or c) parental report of physician-diagnosed asthma age 0-3 years Outcome analysis: risk (survival analysis) of persistent wheeze or asthma at age 0-3 years.
Time frame: 3 years
Atopic/non-atopic wheeze or asthma age 0-3 years
Parental reports of physician diagnosed asthma in combination with eczema and/or allergic rhinitis. Outcome analyses: asthma/persistent wheeze with/without eczema and/or allergic rhinitis (yes/no) by age 3 years. Each subtype is compared with children without asthma.
Time frame: 3 years
Troublesome lung symptoms age 0-3 years
Defined as cough, wheeze or dyspnea severely affecting the well-being of the child for at least 3 consecutive days based on parental reports. Outcome analyses: total no. of episodes with symptoms age 0-3 years.
Time frame: 3 years
Wheeze episodes age 0-3 years
Parental reports of wheezing. Outcome analyses: total no. of episodes with wheeze age 0-3 years.
Time frame: 3 years
Inhaled bronchodilator use from parental reports age 0-3 years
Outcome analyses: total no. of days with bronchodilator use age 0-3.
Time frame: 3 years
Inhaled bronchodilator prescriptions from medical record checks age 0-3 years
Outcome analyses: total no. of prescriptions age 0-3.
Time frame: 3 years
Asthma controller medication use from parental reports age 0-3 years
Outcome analyses: total no. of days with use of asthma controller medication age 0-3.
Time frame: 3 years
Asthma controller medication prescriptions from medical record checks age 0-3 years
Outcome analyses: total no. of prescriptions age 0-3.
Time frame: 3 years
Asthma hospitalizations or emergency department visits age 0-3 years
Outcome analyses: total no. of episodes age 0-3 years.
Time frame: 3 years
Eczema age 0-3 years
Parental reports of physician-diagnosed eczema and prescribed topical antiinflammatory medication on medical record checks. Outcome analyses: risk (survival analysis) of any eczema age 0-3 years and current eczema (yes/no) by age 3 years.
Time frame: 3 years
Allergic rhinitis age 0-3 years
Based on parental reports of physician-diagnosed allergic rhinitis. Outcome analyses: allergic rhinitis (yes/no) by age 3 years.
Time frame: 3 years
Food allergy 0-3 years
Parental reports of physician-diagnosed food allergy. Outcome analyses: any food allergy (yes/no) by age 3 years.
Time frame: 3 years
Lower respiratory tract infections age 0-3 years
Parental reports of physician-diagnosed bronchiolitis or pneumonia. Outcome analysis: risk (survival analysis) of first lower respiratory tract infection and total no. of lower respiratory tract infections age 0-3 years.
Time frame: 3 years
Gastrointestinal infections age 0-3 years
Parental reports. Outcome analyses: risk (survival analysis) of any gastroenteritis episode and total no. of gastroenteritis episodes age 0-3 years.
Time frame: 3 years
Croup age 0-3 years
Parental reports of physician diagnosed croup. Outcome analysis: risk (survival analysis) of any croup episode and total no. of croup episodes age 0-3 years.
Time frame: 3 years
Fever episodes age 0-3 years
Based on parental reports. Outcome analyses: total no. of episodes with symptoms age 0-3 years.
Time frame: 3 years
Absences from daycare age 0-3 years
Due to illnesses based on parental reports. Outcome analyses: total no. of absence days age 0-3 years.
Time frame: 3 years
Bone fractures age 0-3 years
Assessed by medical record checks including all radiologically verified fractures of larger long bones (i.e. clavicle, radius, ulna, tibia, fibula, femur and humerus). Outcome analyses: total no. of fractures age 0-3 years.
Time frame: 3 years
Developmental milestones age 0-3 years
Monitored every 6 months until age 3 years by the parents using a registration form based on The Denver Development Index and WHO milestones registration. Outcome analyses: combined assessment of age at achievement across milestones by principal component analysis.
Time frame: 3 years
Strength and difficulties at age 3 years
From the Strengths and Difficulties Questionnaire (SDQ), which is a brief behavioral screening questionnaire. Outcome analyses: SDQ scores at age 3 years.
Time frame: 3 years
ADHD symptoms at age 3 years
From the ADHD rating scale-IV preschool, a dimensional questionnaire for ADHD symptoms in preschool children. Outcome analyses: ADHD symptom scores at age 3 years.
Time frame: 3 years
Social behavior assessment at age 3 years
From the Social Responsiveness Scale, Second Edition; a questionnaire for screening for autistic traits: Outcome analyses: Total problem scores at age 3 years.
Time frame: 3 years
Psychopathology screening at age 3 years
From the Child Behavior Check List 1,5-5 years; a questionnaire for general screening of preschool psychopathology. Outcome analyses: Total syndrome scales at age 3 years.
Time frame: 3 years
Cognitive assessment age 0-3 years
From Behavior Rating Inventory of Executive Function in preschool children; a measurement of executive functions. Outcome analyses: Index values at age 3 years.
Time frame: 3 years
BMI and waist circumference age 0-3 years
From parental reports every 6 months. Outcome analyses: development of BMI and waist circumference age 0-3 years and current BMI and waist circumference at age 3.
Time frame: 3 years
Persistent wheeze or asthma age 0-6 years
Defined similarly to the primary outcome Outcome analysis: risk (survival analysis) of persistent wheeze or asthma at age 0-6 years
Time frame: 6 years
Current asthma at age 6 years
Defined similarly to the primary outcome and with symptoms and/or asthma medication use in the last 12 months at age 6. Outcome analyses: Current wheeze or asthma (yes/no) by age 6 years.
Time frame: 6 years
Asthma or wheeze yearly prevalence 0-6 years
Defined as in the primary outcome and current disease defined from parental reports of wheeze and/or asthma medication use. Outcome analyses: Yearly prevalence of wheeze or asthma medication use (yes/no) 0-6 years.
Time frame: 6 years
Atopic/non-atopic asthma at age 6 years
Parental reports of physician diagnosed asthma in combination with eczema and/or allergic rhinitis. Outcome analyses: Current asthma with/without eczema and/or allergic rhinitis (yes/no) by age 6 years. Each subtype is compared with children without asthma.
Time frame: 6 years
Asthma controller medication 0-6 years
From redeemed medication prescriptions (inhaled corticosteroids and leukotriene modifiers) based on medical record checks: Outcome analyses: total no. of prescriptions age 0-6 years.
Time frame: 6 years
Inhaled bronchodilators age 0-6 years
From redeemed inhaled bronchodilators based on medical record checks. Outcome analyses: total no. of prescriptions age 0-6 years.
Time frame: 6 years
Asthma hospitalizations or emergency department visits age 0-6 years
Based on medical record checks. Outcome analyses: total no. of episodes age 0-6 years.
Time frame: 6 years
Eczema age 0-6 years
Based on parental reports of physician diagnosed eczema. Outcome analyses: risk (survival analysis) of any eczema age 0-6 years and current eczema (yes/no) by age 6 years.
Time frame: 6 years
Allergic rhinitis age 0-6 years
Based on parental reports of physician-diagnosed allergic rhinitis and on medical record checks. Outcome analyses: allergic rhinitis (yes/no) by age 6 years.
Time frame: 6 years
Food allergy age 0-6 years
Based on parental reports of physician-diagnosed food allergy. Outcome analyses: any food allergy (yes/no) by age 6 years.
Time frame: 6 years
Lower respiratory tract infections age 0-6 years
Based on parental reports of physician-diagnosed bronchiolitis or pneumonia. Outcome analysis: risk (survival analysis) of first lower respiratory tract infection and total no. of lower respiratory tract infections age 0-6 years.
Time frame: 6 years
Gastrointestinal infections age 0-6 years
Based on parental reports. Outcome analyses: risk (survival analysis) of any gastroenteritis episode and total no. of gastroenteritis episodes age 0-6 years.
Time frame: 6 years
Croup age 0-6 years
Based on parental reports of physician diagnosed croup. Outcome analysis: risk (survival analysis) of any croup episode and total no. of croup episodes age 0-6 years.
Time frame: 6 years
Bone fractures age 0-6 years
Assessed by medical record checks including all radiologically verified fractures of larger long bones (i.e. clavicle, radius, ulna, tibia, fibula, femur and humerus). Outcome analyses: total no. of fractures age 0-6 years.
Time frame: 6 years
Strength and difficulties at age 6 years
From the Strengths and Difficulties Questionnaire (SDQ), which is a brief behavioral screening questionnaire. Outcome analyses: SDQ scores at age 6 years.
Time frame: 6 years
ADHD symptoms at age 6 years
From the ADHD rating scale-IV preschool, a dimensional questionnaire for ADHD symptoms in preschool children. Outcome analyses: ADHD symptom scores at age 6 years.
Time frame: 6 years
Social behavior assessment at age 6 years
From the Social Responsiveness Scale, Second Edition; a questionnaire for screening for autistic traits. Outcome analyses: Total problem scores at age 6 years.
Time frame: 6 years
Psychopathology screening at age 6 years
From the Child Behavior Check List; a questionnaire for general screening of preschool psychopathology. Outcome analyses: Total syndrome scales at age 6 years.
Time frame: 6 years
Cognitive assessment age 0-6 years
From Behavior Rating Inventory of Executive Function in preschool children; a measurement of executive functions. Outcome analyses: Index values at age 6 years.
Time frame: 6 years
BMI and waist circumference age 0-6 years
From parental reports every 6 months. Outcome analyses: development of BMI and waist circumference age 0-6 years and current BMI and waist circumference at age 6.
Time frame: 6 years
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