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NCT Number: NCT04369222

The Copenhagen Analgesic Study

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.

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Key information

Conditions

Gonad Regulating Hormone Adverse Reaction Analgesic Adverse Reaction

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark

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About this study

Fetal gonadal development is essential for adult reproductive health. Experimental studies strongly suggest that maternal use of mild analgesics (e.g. paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs)) during pregnancy affect fetal gonadal development with possible severe reproductive repercussions.

In rodents, paracetamol and NSAIDs administered in therapeutic doses in early and mid-pregnancy are endocrine disruptive in the fetus causing reduced prostaglandin synthesis and delayed transition from germ cell mitosis to meiosis resulting in fetal germ cell apoptosis in both female and male gonads. Female offspring were born with reduced ovarian weight and concerning reduction (40-50%) in number of ovarian follicles. Females are born with a defined number of follicles that depletes throughout their reproductive lifespan, inevitably leading to menopause. Establishment of the primordial follicle pool during fetal life is therefore essential for female reproductive health and disruption of this process has important and lasting consequences. Although spermatogenesis is not restricted to fetal life, essential aspects of male gonadal development are tightly regulated in utero and in rodents exposure to mild analgesics causes decreased testosterone production and decreased fertility in male offspring.

In adulthood, exposed animals exhibited longer time to conceive and gave birth to fewer pubs per litter compared with controls. Furthermore, studies of rodents suggest that in both males and females, adverse reproductive effects are passed on to the next generation indicating altered genetic programming, i.e. epigenetic changes.

Analgesics are sold over the counter and up to 56% of pregnant women use mild analgesics during pregnancy. The bioavailability of acetaminophen is high (app. 90%), and the reactive metabolite passes freely over the placenta to the fetus.

Declining fertility has become a growing problem in developing countries, potentially resulting in severe socioeconomic challenges.

The anogenital distance (AGD) is defined as the distance from the anus to genital tubercle and is strongly affected by androgens in fetal life resulting in a longer AGD in males than in females.

The AGD has shown to be a sensitive marker of androgen exposure in fetal life, and remains the most sensitive parameter when evaluating prenatal exposure to endocrine disruptive environmental agents. Therefore, AGD has been identified as an endpoint in the US Environmental Protection Agency guidelines for reproductive toxicity studies.

In humans, use of mild analgesic during the first and second trimester was associated with reduced male AGD, congenital cryptorchidism and hypospadias suggestive of insufficient androgenic action. In male infants born with hypospadias, the reduction in AGD can be seen as early as in the third trimester where fetal AGD is below the fifth percentile compared to normative fetal AGD data. Thus, fetal AGD may assist in early detection of insufficient androgenic action and genital abnormalities.

In adult life, consequences can be impaired testosterone production, sub- and infertility as well as testis cancer.

Assessment of reproductive function in early life - minipuberty Minipuberty is a term used to describe the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during infancy in both boys and girls and is a window of opportunity for diagnosis of endocrine disorders as well as future reproductive function. Reproductive hormones exert effects on target tissue resulting in follicle maturation, growth of breast tissue and thickening of uterine endometrium (females) as well as testicular- and penile growth (males). The minipuberty is followed by a quiescent period during mid childhood until pubertal reactivation of the HPG axis at pubertal onset.

To date, no prospective human studies have assessed the effect of analgesic exposure on reproductive function. The few retrospective studies that are published are hampered by recall bias and/or lack of thorough reproductive evaluation, and no studies have in detail assessed human female reproductive function after the use of mild analgesics during pregnancy.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Observational

Other

Maternal consumption of mild analgesics

Other names: Acetaminophen, Non steroidal antiinflammatory drugs, Acetyl salicylic acid

Primary outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Rigshospitalet, Denmark

Other

Registry information

Acronym: COPANA

Important dates

Study start
2020
Primary completion
2022
Study completion
2022
First posted
Apr 30, 2020
Registry last updated
Jul 10, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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