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The Copenhagen Analgesic Study (COPANA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04369222
Recruitment Status : Recruiting
First Posted : April 30, 2020
Last Update Posted : June 5, 2020
Sponsor:
Information provided by (Responsible Party):
Anders Juul, Rigshospitalet, Denmark

Brief Summary:
Fundamental aspects of reproductive function are established in fetal life and there is a present increased awareness of the potential effects of fetal exposures on reproductive health of offspring. Experimental studies strongly suggest detrimental effects of prenatal exposure to mild analgesics such as acetaminophen (e.g. paracetamol) and non-steroidal anti-inflammatory drugs, NSAIDs (e.g. ibuprofen and acetylsalicylic acid) on male as well as female gonadal development. Declining fertility has become a growing problem in developing countries, potentially resulting in severe socioeconomic challenges, and fetal exposure of mild analgesics causes part of these alarming observations.This is the first prospective human study designed primarily to assess the effect of fetal exposure of mild analgesics on male and female reproductive function.

Condition or disease Intervention/treatment
Gonad Regulating Hormone Adverse Reaction Analgesic Adverse Reaction Other: Observational

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Study Type : Observational
Estimated Enrollment : 600 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Copenhagen Analgesic Study
Actual Study Start Date : March 1, 2020
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022

Group/Cohort Intervention/treatment
Controls
Children born from mothers with no consumption of mild analgesics 3 months before or during pregnancy
Exposed
Children born from mothers with consumption of mild analgesics 3 months before or during pregnancy
Other: Observational
Maternal consumption of mild analgesics
Other Names:
  • Acetaminophen
  • Non steroidal antiinflammatory drugs
  • Acetyl salicylic acid




Primary Outcome Measures :
  1. Ovarian volume (female infants) [ Time Frame: 2.5 months old ]
    Ovarian volumen, measured by abdominal ultrasound

  2. Ovarian follicle count (female infants) [ Time Frame: 2.5 months old ]
    Ovarian follicle count, measured by abdominal ultrasound

  3. Blood sample (female infants) [ Time Frame: 2.5 months old ]
    Serum metabolites Anti Müllarian Hormone (AMH)

  4. Testes volumen (male infants) [ Time Frame: 2.5 months old ]
    Testes volumen, measured by ultrasound

  5. Blood sample (male infants) [ Time Frame: 2.5 months old ]
    Serum metabolites testosterone, free testosterone.


Secondary Outcome Measures :
  1. Length (male and female infants) [ Time Frame: 2.5 months old ]
    Length in cm

  2. Weight (male and female infants) [ Time Frame: 2.5 months old ]
    Weight in kilograms

  3. Head circumference (male and female infants) [ Time Frame: 2.5 months old ]
    Head circumference measured with a measurement tape, mm.

  4. Abdominal circumference (male and female infants) [ Time Frame: 2.5 months old ]
    Abdonimal circumference measured with a measurement tape, mm.

  5. Height (fathers) [ Time Frame: Gestational week 12 ]
    Height in cm, by stadiometer (Holtain Ltd, Crymych, UK) with a precision of 0.1 cm

  6. Weight (fathers) [ Time Frame: Gestational week 12 ]
    Weight in kilograms, by digital scale with a precision of 0.1 kg (SECA delta, model 707)

  7. Biceps skinfold (father) [ Time Frame: Gestational week 12 ]
    Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  8. Triceps skinfold(father) [ Time Frame: Gestational week 12 ]
    Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  9. Flank skinfold (father) [ Time Frame: Gestational week 12 ]
    Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  10. Scapula skinfold (father) [ Time Frame: Gestational week 12 ]
    Skinfold measured below the scapula all on the left side, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  11. Biceps skinfold (male and female infants) [ Time Frame: 2.5 months old ]
    Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  12. Triceps skinfold (male and female infants) [ Time Frame: 2.5 months old ]
    Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  13. Flank skinfold (male and female infants) [ Time Frame: 2.5 months old ]
    Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  14. Scapula skinfold (male and female infants) [ Time Frame: 2.5 months old ]
    Skinfold measured below the scapula all on the left side, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)

  15. Asphyxia, adverse events (newborn) [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Asphyxia (yes/no)

  16. Meconium, adverse events (newborn) [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Meconium in amionic fluids (yes/no)

  17. Partus mode [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Partus mode (vaginal delivery, cesarean section, instrumental delivery) (yes/no)

  18. Birth weight (newborn) [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Birth weight, grams

  19. Birth length (newborn) [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Birth length, cm

  20. Gestational age (newborn) [ Time Frame: Retrieved from patient files postpartum within 1 year of study completion ]
    Gestational age at birth, weeks and days

  21. Drug intake (mother) [ Time Frame: Retrieved from patient questionnaire postpartum within one year ]
    Pre- and perinatal drug intake, filled in by mother during the whole prengancy every two weeks online

  22. Pregnancy outcome, preeclampsia (mother) [ Time Frame: Retrieved from patient files postpartum within one year ]
    Preeclampsia (yes/no)

  23. Pregnancy outcome, gestational hypertension (mother) [ Time Frame: Retrieved from patient files postpartum within one year ]
    Gestational hypertension (yes/no)

  24. Pregnancy outcome, induction of labor (mother) [ Time Frame: Retrieved from patient files postpartum within one year ]
    In duction of labor (yes/no)

  25. Medical history and exposure (parents) [ Time Frame: Retrived from questionnaire within a half year ]
    General- and reproductive health, the pregnancy, own birth weight, lifestyle, drinking and smoking habits from questionnaire

  26. Pubertal history (parents) [ Time Frame: Retrived from questionnaire within a half year ]
    Pubertal history including age at menarche, pubertal timing with regard to peers, age at menopause of the mother of the parents etc. from questionnaire

  27. Blood sample (mother) [ Time Frame: Gestational week 12 and 2.5 months postpartum ]

    Blood samples will be drawn from an antecubital vein and will be measured for steroid hormone metabolites and metabolites of reproductive hormones.

    Testosterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), Estradiol, Estrone, Progesterone, 17-hydroxyprogesterone: in-house mass-spectrometry; Turboflow (LC-MS/MS).

    Luteinizing hormone (LH), follicle stimulating hormone (FSH), Sex hormone Binding Globulin (SHBG): Time-resolved immuno- flouroimmunoassay; Delfia, Turko, Finland.

    Inhibin B: Specific enzyme-linked immunosorbent assay; Beckman Coulter GenII. Anti- Müllerian hormone (AMH): Specific enzyme immuno-metric assay; Immunotech Beckman Coulter.

    INSL3: Time-resolved immuno- flouroimmunoassay. IGF-I and IGFBP-3 will be analyzed using an immunoassay (iSYS, iDS).


  28. Urine sample (mother) [ Time Frame: Gestational week 12 and 2.5 months postpartum ]

    The urine sample will be collected in a cup and analyzed for:

    Steroid hormone metabolites using in-house mass-spectrometry; Turboflow (LC-MS/MS).

    Glycoprotein hormones, specifically FSH and LH, using immunoassays.

    Endocrine disrupting chemicals, specifically phthalates, phenols, perfluorinated compounds and parabens also using in-house mass-spectrometry; Turboflow (LC-MS/MS).


  29. Blood sample (father) [ Time Frame: Gestational week 12 ]

    Blood samples will be drawn from an antecubital vein and will be measured for steroid hormone metabolites and metabolites of reproductive hormones:

    Testosterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), Estradiol, Estrone, Progesterone, 17-hydroxyprogesterone: in-house mass-spectrometry; Turboflow (LC-MS/MS).

    Luteinizing hormone (LH), follicle stimulating hormone (FSH), Sex hormone Binding Globulin (SHBG): Time-resolved immuno- flouroimmunoassay; Delfia, Turko, Finland.

    Inhibin B: Specific enzyme-linked immunosorbent assay; Beckman Coulter GenII. Anti- Müllerian hormone (AMH): Specific enzyme immuno-metric assay; Immunotech Beckman Coulter.

    INSL3: Time-resolved immuno- flouroimmunoassay. IGF-I and IGFBP-3 will be analyzed using an immunoassay (iSYS, iDS).


  30. Urine sample (father) [ Time Frame: Gestational week 12 ]

    The urine sample will be collected in a cup and analyzed for:

    Steroid hormone metabolites using in-house mass-spectrometry; Turboflow (LC-MS/MS).

    Glycoprotein hormones, specifically FSH and LH, using immunoassays.

    Endocrine disrupting chemicals, specifically phthalates, phenols, perfluorinated compounds and parabens also using in-house mass-spectrometry; Turboflow (LC-MS/MS).


  31. Anogenital distance (AGD) (male and female infants) [ Time Frame: 2.5 months old ]
    Distance from anus to genital tubercle, measured in mm with a ruler

  32. Anogenital distance (AGD) (male and female infants) [ Time Frame: App. gestational age 30 weeks ]
    Distance from anus to genital tubercle, third trimester ultrasound

  33. Blood sample (female infants) [ Time Frame: 2.5 months old ]
    (estradiol and inhibin B, luteinizing hormone (LH)/follicular stimulating hormone (FSH) ratio)

  34. Blood sample (male infants) [ Time Frame: 2.5 months old ]
    Serum metabolites of reproductive hormones (AMH, inhibin B levels, ratios of inhibin B/FSH and LH/FSH)

  35. Classification of external genitalia with an external masculinization score (EMS) (male and female infants). EMS provides an objective aggregate score of the extent of masculinization of the external genitalia. [ Time Frame: 2.5 months old ]

    It is an individual score with a maximum of 12 points. The following is assessed:

    Classification of genital tubercle, measured length with a ruler (mm) >30mm = 3 points, 21-30mm = 2 points, 11-20mm = 1 point,< 10mm = 0 points) Location of gonads, (objectively assessed): labioscrotal = 1,5 points, inguino-scrotal = 1, inguinal = 0,5 points, impalpable = 0 points Site of the urinary meatus (objectively assessed): typical male = 3 points, coronal/glandular = 2,5 points, penile = 2 points, peno-scrotal = 1,5 points, perineal = 0,5 points, typical female = 0 points.

    Labia/scrotal fusion (objectively assessed): fused = 3 points, posterior fusion = 1,5 points, unfused = 0 points.


  36. Pubertal staging (male and female infants) [ Time Frame: 2.5 months old ]
    Pubertal staging using Tanners classification (including testicular size in boys assessed by Prader's orchidometer)

  37. Penile measurements (male infants) [ Time Frame: 2.5 months old ]
    Penile measurements with a ruler

  38. Epigenetic profiling (male and female infants) [ Time Frame: Single determination, 2.5 months old ]
    Epigenetic variation of loci regulating hormone signalling

  39. Urine sample (10 mL) (male and female infants) [ Time Frame: 2.5 months old ]

    Steroid hormone metabolites using in-house mass-spectrometry; Turboflow (LC-MS/MS).

    Glycoprotein hormones, specifically FSH and LH, using immunoassays.

    Endocrine disrupting chemicals, specifically phthalates, phenols, perfluorinated compounds and parabens also using in-house mass-spectrometry; Turboflow (LC-MS/MS).


  40. Medical report (mother) [ Time Frame: Every 2 weeks from enrollment in early pregnancy to birth ]
    Specific medical report on medicine consumption incl. analgesics

  41. Genetic profiling (male and female infants) [ Time Frame: Single determination, 2.5 months old ]
    Genotyping of different genetic loci (genetic variation of loci regulating) hormone signalling, e.g. FSHB, etc.

  42. Endometrial thickness (female infants) [ Time Frame: 2.5 months old ]
    Endometrial thickness, measured by abdominal ultrasound

  43. Uterine volume (female infants) [ Time Frame: 2.5 months old ]
    Uterine volume, measured by abdominal ultrasound


Biospecimen Retention:   Samples With DNA
DNA EDTA-Blood Serum


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

This study is a population based prospective cohort study of 600 families (healthy pregnant mothers, biological fathers and their healthy male/female offspring.

Pregnant women, meeting the inclusion criteria, and the fathers-to-be followed at the Department of Obstetrics, Rigshospitalet will be invited to participate.

There are two groups of participants in this study:

  1. Healthy infants recruited specifically for this study
  2. The parents, i.e. the mother and father, of the healthy infants

The two groups will include the following numbers (approximately) of participants:

  1. 600 healthy infants (based on expected son to daughter ratio of 105 to 100 in Denmark, we expect approximately equal distribution of boys and girl).
  2. 600 mothers and 600 fathers of healthy infants
Criteria

Inclusion criteria:

Infants:

  • Singleton pregnancies
  • Term pregnancy (week 37+0 to 42+0)

Parents:

  • Maternal and paternal Caucasian origin
  • Maternal pre-pregnancy BMI between 18 and 35 kg/m2

Exclusion criteria:

Infants:

• Fetal malformations or chromosomal disorders

Parents:

  • Serious maternal illness, including pre-existing maternal diabetes or thyroid gland diseases
  • Gestational diabetes

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04369222


Contacts
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Contact: Margit B. Fischer, M.D. 0045 28790715 mfis0039@regionh.dk

Locations
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Denmark
Department of Growth and Reproduction, Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Anders Juul, M.D., DMSc    0045 35455064    anders.juul@rh.regionh.dk   
Contact: Margit B. Fischer, M.D., PhD.-student    0045 28790715    mfis0039@regionh.dk   
Principal Investigator: Anders Juul, M.D., DMSc         
Sub-Investigator: Margit B. Fischer, M.D., PhD.-student         
Sub-Investigator: Casper Hagen, M.D.         
Sub-Investigator: Kristian Almstrup, MSc, PhD.         
Department of Obstetrics and Section of fetal medicine, Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Peter Damm, M.D., DMSc, PhD.    0045 35451334    peter.damm@regionh.dk   
Principal Investigator: Peter Damm, M.D., DMSc, PhD.         
Sub-Investigator: Karin Sundberg, M.D., DMSc, PhD.         
Sub-Investigator: Hanne K. Heegaard, Associated professor, PhD.         
Sub-Investigator: Rikke N. Møller, Head midwife         
Sub-Investigator: Ane L. Rom, Midwife, PhD.         
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
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Principal Investigator: Anders Juul, Professor Department of Growth and Reproduction, Rigshospitalet
Additional Information:
Publications:

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Responsible Party: Anders Juul, Professor, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04369222    
Other Study ID Numbers: COPANA5064
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: June 5, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Acetaminophen
Aspirin
Salicylic Acid
Salicylates
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Infective Agents
Antifungal Agents
Keratolytic Agents
Dermatologic Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Fibrinolytic Agents
Fibrin Modulating Agents
Platelet Aggregation Inhibitors