Gonad Regulating Hormone Adverse ReactionCOPANANCT04369222
The Copenhagen Analgesic Study
An observational study of Gonad Regulating Hormone Adverse Reaction and Analgesic Adverse Reaction, run by Copenhagen University Hospital, Rigshospitalet at 2 sites in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Gonad Regulating Hormone Adverse Reaction, Analgesic Adverse Reaction
- What is being tested?
- Observational
- How many people
- 685 participants
- Where
- 2 sitesDenmark
- Study dates
- 1 Mar 2020to 30 Nov 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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
Who may be able to join
- 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
Who cannot join
- Infants:
- Fetal malformations or chromosomal disorders
- Parents:
- Serious maternal illness, including pre-existing maternal diabetes or thyroid gland diseases
- Gestational diabetes
Trial locations and contacts
2 sites in 1 country.
Denmark2 sites
Department of Growth and Reproduction, Rigshospitalet
Copenhagen, 2100
Department of Obstetrics and Section of fetal medicine, Rigshospitalet
Copenhagen, 2100
About this 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.
Read the detailed description
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.
- Being tested
- Observational
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ObservationalOther
Also called Acetaminophen, Non steroidal antiinflammatory drugs, Acetyl salicylic acid
Maternal consumption of mild analgesics
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Other: Observational |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ovarian volume (female infants)
Ovarian volumen, measured by abdominal ultrasound
Measured: 2.5 months old
Ovarian follicle count (female infants)
Ovarian follicle count, measured by abdominal ultrasound
Measured: 2.5 months old
Blood sample (female infants)
Serum metabolites Anti Müllarian Hormone (AMH)
Measured: 2.5 months old
Testes volumen (male infants)
Testes volumen, measured by ultrasound
Measured: 2.5 months old
Blood sample (male infants)
Serum metabolites testosterone, free testosterone.
Measured: 2.5 months old
Secondary outcomes (43)
Length (male and female infants)
Length in cm
Measured: 2.5 months old
Weight (male and female infants)
Weight in kilograms
Measured: 2.5 months old
Head circumference (male and female infants)
Head circumference measured with a measurement tape, mm.
Measured: 2.5 months old
Abdominal circumference (male and female infants)
Abdonimal circumference measured with a measurement tape, mm.
Measured: 2.5 months old
Height (fathers)
Height in cm, by stadiometer (Holtain Ltd, Crymych, UK) with a precision of 0.1 cm
Measured: Gestational week 12
Weight (fathers)
Weight in kilograms, by digital scale with a precision of 0.1 kg (SECA delta, model 707)
Measured: Gestational week 12
Biceps skinfold (father)
Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: Gestational week 12
Triceps skinfold(father)
Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: Gestational week 12
Flank skinfold (father)
Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: Gestational week 12
Scapula skinfold (father)
Skinfold measured below the scapula all on the left side, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: Gestational week 12
Biceps skinfold (male and female infants)
Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: 2.5 months old
Triceps skinfold (male and female infants)
Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: 2.5 months old
Flank skinfold (male and female infants)
Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: 2.5 months old
Scapula skinfold (male and female infants)
Skinfold measured below the scapula all on the left side, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)
Measured: 2.5 months old
Asphyxia, adverse events (newborn)
Asphyxia (yes/no)
Measured: Retrieved from patient files postpartum within 1 year of study completion
Meconium, adverse events (newborn)
Meconium in amionic fluids (yes/no)
Measured: Retrieved from patient files postpartum within 1 year of study completion
Partus mode
Partus mode (vaginal delivery, cesarean section, instrumental delivery) (yes/no)
Measured: Retrieved from patient files postpartum within 1 year of study completion
Birth weight (newborn)
Birth weight, grams
Measured: Retrieved from patient files postpartum within 1 year of study completion
Birth length (newborn)
Birth length, cm
Measured: Retrieved from patient files postpartum within 1 year of study completion
Gestational age (newborn)
Gestational age at birth, weeks and days
Measured: Retrieved from patient files postpartum within 1 year of study completion
Drug intake (mother)
Pre- and perinatal drug intake, filled in by mother during the whole prengancy every two weeks online
Measured: Retrieved from patient questionnaire postpartum within one year
Pregnancy outcome, preeclampsia (mother)
Preeclampsia (yes/no)
Measured: Retrieved from patient files postpartum within one year
Pregnancy outcome, gestational hypertension (mother)
Gestational hypertension (yes/no)
Measured: Retrieved from patient files postpartum within one year
Pregnancy outcome, induction of labor (mother)
In duction of labor (yes/no)
Measured: Retrieved from patient files postpartum within one year
Medical history and exposure (parents)
General- and reproductive health, the pregnancy, own birth weight, lifestyle, drinking and smoking habits from questionnaire
Measured: Retrived from questionnaire within a half year
Pubertal history (parents)
Pubertal history including age at menarche, pubertal timing with regard to peers, age at menopause of the mother of the parents etc. from questionnaire
Measured: Retrived from questionnaire within a half year
Blood sample (mother)
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).
Measured: Gestational week 12 and 2.5 months postpartum
Urine sample (mother)
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).
Measured: Gestational week 12 and 2.5 months postpartum
Blood sample (father)
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).
Measured: Gestational week 12
Urine sample (father)
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).
Measured: Gestational week 12
Anogenital distance (AGD) (male and female infants)
Distance from anus to genital tubercle, measured in mm with a ruler
Measured: 2.5 months old
Anogenital distance (AGD) (male and female infants)
Distance from anus to genital tubercle, third trimester ultrasound
Measured: App. gestational age 30 weeks
Blood sample (female infants)
(estradiol and inhibin B, luteinizing hormone (LH)/follicular stimulating hormone (FSH) ratio)
Measured: 2.5 months old
Blood sample (male infants)
Serum metabolites of reproductive hormones (AMH, inhibin B levels, ratios of inhibin B/FSH and LH/FSH)
Measured: 2.5 months old
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.
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.
Measured: 2.5 months old
Pubertal staging (male and female infants)
Pubertal staging using Tanners classification (including testicular size in boys assessed by Prader's orchidometer)
Measured: 2.5 months old
Penile measurements (male infants)
Penile measurements with a ruler
Measured: 2.5 months old
Epigenetic profiling (male and female infants)
Epigenetic variation of loci regulating hormone signalling
Measured: Single determination, 2.5 months old
Urine sample (10 mL) (male and female infants)
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).
Measured: 2.5 months old
Medical report (mother)
Specific medical report on medicine consumption incl. analgesics
Measured: Every 2 weeks from enrollment in early pregnancy to birth
Genetic profiling (male and female infants)
Genotyping of different genetic loci (genetic variation of loci regulating) hormone signalling, e.g. FSHB, etc.
Measured: Single determination, 2.5 months old
Endometrial thickness (female infants)
Endometrial thickness, measured by abdominal ultrasound
Measured: 2.5 months old
Uterine volume (female infants)
Uterine volume, measured by abdominal ultrasound
Measured: 2.5 months old
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2020
- Study start1 Mar 2020
- Primary completion30 Nov 2022
- Study completion30 Nov 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for Gonad Regulating Hormone Adverse ReactionStudies of the same condition, open and under way.
- More trials run by Copenhagen University Hospital, RigshospitaletThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 685 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Anders Juul, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Anders Juul, Professor, Principal investigator, Department of Growth and Reproduction, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04369222
- Sponsor's protocol ID
- COPANA5064
- Acronym
- COPANA
- Status last verified
- Jul 2025
- First submitted
- 20 Apr 2020
- Last updated
- 10 Jul 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell H, Hurtado-Gonzalez P, Chambers TJ, Stevenson K, Wolfinger E, Hrabalkova L, Calarrao A, Bayne RA, Hagen CP, Mitchell RT, Anderson RA, Sharpe RM. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci Rep. 2016 Jan 27;6:19789. doi: 10.1038/srep19789.
PubMed 26813099Arendrup FS, Mazaud-Guittot S, Jegou B, Kristensen DM. EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development? Endocr Connect. 2018 Jan;7(1):149-158. doi: 10.1530/EC-17-0298. Epub 2018 Jan 5.
PubMed 29305399Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesne L, Serrano T, Main KM, Jegou B. Analgesic use - prevalence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol. 2016 Jul;12(7):381-93. doi: 10.1038/nrendo.2016.55. Epub 2016 May 6.
PubMed 27150289Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jegou B, Leffers H. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod. 2011 Jan;26(1):235-44. doi: 10.1093/humrep/deq323. Epub 2010 Nov 8.
PubMed 21059752Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou B, Kristiansen K, Kristensen DM. Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicol Sci. 2016 Mar;150(1):178-89. doi: 10.1093/toxsci/kfv332. Epub 2016 Jan 5.
PubMed 26732887BAKER TG. A QUANTITATIVE AND CYTOLOGICAL STUDY OF GERM CELLS IN HUMAN OVARIES. Proc R Soc Lond B Biol Sci. 1963 Oct 22;158:417-33. doi: 10.1098/rspb.1963.0055. No abstract available.
PubMed 14070052Reel JR, Lawton AD, Lamb JC 4th. Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol. Fundam Appl Toxicol. 1992 Feb;18(2):233-9. doi: 10.1016/0272-0590(92)90051-i.
PubMed 1601223Johansson HK, Jacobsen PR, Hass U, Svingen T, Vinggaard AM, Isling LK, Axelstad M, Christiansen S, Boberg J. Perinatal exposure to mixtures of endocrine disrupting chemicals reduces female rat follicle reserves and accelerates reproductive aging. Reprod Toxicol. 2016 Jun;61:186-94. doi: 10.1016/j.reprotox.2016.03.045. Epub 2016 Apr 2.
PubMed 27049580Ersboll AS, Hedegaard M, Damm P, Johansen M, Tabor A, Hegaard HK. Changes in the pattern of paracetamol use in the periconception period in a Danish cohort. Acta Obstet Gynecol Scand. 2015 Aug;94(8):898-903. doi: 10.1111/aogs.12667. Epub 2015 May 29.
PubMed 25939806Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebaek NE, Jensen TK. Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs. Hum Reprod. 2017 Jan;32(1):223-231. doi: 10.1093/humrep/dew285. Epub 2016 Nov 16.
PubMed 27852690Rebordosa C, Zelop CM, Kogevinas M, Sorensen HT, Olsen J. Use of acetaminophen during pregnancy and risk of preeclampsia, hypertensive and vascular disorders: a birth cohort study. J Matern Fetal Neonatal Med. 2010 May;23(5):371-8. doi: 10.3109/14767050903334877.
PubMed 19929241Nitsche JF, Patil AS, Langman LJ, Penn HJ, Derleth D, Watson WJ, Brost BC. Transplacental Passage of Acetaminophen in Term Pregnancy. Am J Perinatol. 2017 May;34(6):541-543. doi: 10.1055/s-0036-1593845. Epub 2016 Nov 2.
PubMed 27806383Myrskyla M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature. 2009 Aug 6;460(7256):741-3. doi: 10.1038/nature08230.
PubMed 19661915Tromp M, Ravelli AC, Reitsma JB, Bonsel GJ, Mol BW. Increasing maternal age at first pregnancy planning: health outcomes and associated costs. J Epidemiol Community Health. 2011 Dec;65(12):1083-90. doi: 10.1136/jech.2009.095422. Epub 2010 Aug 13.
PubMed 20709858Gallavan RH Jr, Holson JF, Stump DG, Knapp JF, Reynolds VL. Interpreting the toxicologic significance of alterations in anogenital distance: potential for confounding effects of progeny body weights. Reprod Toxicol. 1999 Sep-Oct;13(5):383-90. doi: 10.1016/s0890-6238(99)00036-2.
PubMed 10560587
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Copenhagen Analgesic Study
- ClinicalTrials.gov ID
- NCT04369222
- Acronym / sponsor ID
- COPANA / COPANA5064
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 685 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Study start
- 1 Mar 2020 (actual)
- Primary completion
- 30 Nov 2022 (actual)
- Study completion
- 30 Nov 2022 (actual)
- First posted
- 30 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Controls | – | –Children born from mothers with no consumption of mild analgesics 3 months before or during pregnancy |
| Exposed | – | Other: ObservationalChildren born from mothers with consumption of mild analgesics 3 months before or during pregnancy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (6 listed)
- Singleton pregnancies
- Term pregnancy (week 37+0 to 42+0)
- Maternal and paternal Caucasian origin
- Maternal pre-pregnancy BMI between 18 and 35 kg/m2
Key exclusion criteria (5 listed)
- Fetal malformations or chromosomal disorders
- Serious maternal illness, including pre-existing maternal diabetes or thyroid gland diseases
- Gestational diabetes
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ObservationalAlso: Acetaminophen, Non steroidal antiinflammatory drugs, Acetyl salicylic acidMaternal consumption of mild analgesics | Other | Exposed |
Primary outcome
Ovarian volume (female infants)
Time frame: 2.5 months old
Ovarian volumen, measured by abdominal ultrasound
Ovarian follicle count (female infants)
Time frame: 2.5 months old
Ovarian follicle count, measured by abdominal ultrasound
Blood sample (female infants)
Time frame: 2.5 months old
Serum metabolites Anti Müllarian Hormone (AMH)
Testes volumen (male infants)
Time frame: 2.5 months old
Testes volumen, measured by ultrasound
Blood sample (male infants)
Time frame: 2.5 months old
Serum metabolites testosterone, free testosterone.
43 secondary outcomes
Length (male and female infants)
Time frame: 2.5 months old
Weight (male and female infants)
Time frame: 2.5 months old
Head circumference (male and female infants)
Time frame: 2.5 months old
Abdominal circumference (male and female infants)
Time frame: 2.5 months old
Height (fathers)
Time frame: Gestational week 12
Weight (fathers)
Time frame: Gestational week 12
Biceps skinfold (father)
Time frame: Gestational week 12
Triceps skinfold(father)
Time frame: Gestational week 12
Flank skinfold (father)
Time frame: Gestational week 12
Scapula skinfold (father)
Time frame: Gestational week 12
Biceps skinfold (male and female infants)
Time frame: 2.5 months old
Triceps skinfold (male and female infants)
Time frame: 2.5 months old
Flank skinfold (male and female infants)
Time frame: 2.5 months old
Scapula skinfold (male and female infants)
Time frame: 2.5 months old
Asphyxia, adverse events (newborn)
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Meconium, adverse events (newborn)
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Partus mode
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Birth weight (newborn)
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Birth length (newborn)
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Gestational age (newborn)
Time frame: Retrieved from patient files postpartum within 1 year of study completion
Drug intake (mother)
Time frame: Retrieved from patient questionnaire postpartum within one year
Pregnancy outcome, preeclampsia (mother)
Time frame: Retrieved from patient files postpartum within one year
Pregnancy outcome, gestational hypertension (mother)
Time frame: Retrieved from patient files postpartum within one year
Pregnancy outcome, induction of labor (mother)
Time frame: Retrieved from patient files postpartum within one year
Medical history and exposure (parents)
Time frame: Retrived from questionnaire within a half year
Pubertal history (parents)
Time frame: Retrived from questionnaire within a half year
Blood sample (mother)
Time frame: Gestational week 12 and 2.5 months postpartum
Urine sample (mother)
Time frame: Gestational week 12 and 2.5 months postpartum
Blood sample (father)
Time frame: Gestational week 12
Urine sample (father)
Time frame: Gestational week 12
Anogenital distance (AGD) (male and female infants)
Time frame: 2.5 months old
Anogenital distance (AGD) (male and female infants)
Time frame: App. gestational age 30 weeks
Blood sample (female infants)
Time frame: 2.5 months old
Blood sample (male infants)
Time frame: 2.5 months old
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
Pubertal staging (male and female infants)
Time frame: 2.5 months old
Penile measurements (male infants)
Time frame: 2.5 months old
Epigenetic profiling (male and female infants)
Time frame: Single determination, 2.5 months old
Urine sample (10 mL) (male and female infants)
Time frame: 2.5 months old
Medical report (mother)
Time frame: Every 2 weeks from enrollment in early pregnancy to birth
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2025.
- Background: PubMed 26813099Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell H, Hurtado-Gonzalez P, Chambers TJ, Stevenson K, Wolfinger E, Hrabalkova L, Calarrao A, Bayne RA, Hagen CP, Mitchell RT, Anderson RA, Sharpe RM. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci Rep. 2016 Jan 27;6:19789. doi: 10.1038/srep19789.
- Background: PubMed 29305399Arendrup FS, Mazaud-Guittot S, Jegou B, Kristensen DM. EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development? Endocr Connect. 2018 Jan;7(1):149-158. doi: 10.1530/EC-17-0298. Epub 2018 Jan 5.
- Background: PubMed 27150289Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesne L, Serrano T, Main KM, Jegou B. Analgesic use - prevalence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol. 2016 Jul;12(7):381-93. doi: 10.1038/nrendo.2016.55. Epub 2016 May 6.
- Background: PubMed 21059752Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jegou B, Leffers H. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod. 2011 Jan;26(1):235-44. doi: 10.1093/humrep/deq323. Epub 2010 Nov 8.
- Background: PubMed 26732887Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou B, Kristiansen K, Kristensen DM. Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicol Sci. 2016 Mar;150(1):178-89. doi: 10.1093/toxsci/kfv332. Epub 2016 Jan 5.
- Background: PubMed 14070052BAKER TG. A QUANTITATIVE AND CYTOLOGICAL STUDY OF GERM CELLS IN HUMAN OVARIES. Proc R Soc Lond B Biol Sci. 1963 Oct 22;158:417-33. doi: 10.1098/rspb.1963.0055. No abstract available.
- Background: PubMed 1601223Reel JR, Lawton AD, Lamb JC 4th. Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol. Fundam Appl Toxicol. 1992 Feb;18(2):233-9. doi: 10.1016/0272-0590(92)90051-i.
- Background: PubMed 27049580Johansson HK, Jacobsen PR, Hass U, Svingen T, Vinggaard AM, Isling LK, Axelstad M, Christiansen S, Boberg J. Perinatal exposure to mixtures of endocrine disrupting chemicals reduces female rat follicle reserves and accelerates reproductive aging. Reprod Toxicol. 2016 Jun;61:186-94. doi: 10.1016/j.reprotox.2016.03.045. Epub 2016 Apr 2.
- Background: PubMed 25939806Ersboll AS, Hedegaard M, Damm P, Johansen M, Tabor A, Hegaard HK. Changes in the pattern of paracetamol use in the periconception period in a Danish cohort. Acta Obstet Gynecol Scand. 2015 Aug;94(8):898-903. doi: 10.1111/aogs.12667. Epub 2015 May 29.
- Background: PubMed 27852690Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebaek NE, Jensen TK. Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs. Hum Reprod. 2017 Jan;32(1):223-231. doi: 10.1093/humrep/dew285. Epub 2016 Nov 16.
- Background: PubMed 19929241Rebordosa C, Zelop CM, Kogevinas M, Sorensen HT, Olsen J. Use of acetaminophen during pregnancy and risk of preeclampsia, hypertensive and vascular disorders: a birth cohort study. J Matern Fetal Neonatal Med. 2010 May;23(5):371-8. doi: 10.3109/14767050903334877.
- Background: PubMed 27806383Nitsche JF, Patil AS, Langman LJ, Penn HJ, Derleth D, Watson WJ, Brost BC. Transplacental Passage of Acetaminophen in Term Pregnancy. Am J Perinatol. 2017 May;34(6):541-543. doi: 10.1055/s-0036-1593845. Epub 2016 Nov 2.
- Individual participant dataSharing planned: No
Related trials for Gonad Regulating Hormone Adverse Reaction
Enrolling by invitationObservational study
Neurobehavioral Development in Toddlers and Preschoolers in Relation to Prenatal Exposure of Mild Analgesics (NeuroToP - a COPANA Follow up)
Gonad Regulating Hormone Adverse Reaction, Analgesic Adverse Reaction
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anders Juul, Professor principal investigator
Department of Growth and Reproduction, Rigshospitalet
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gonad Regulating Hormone Adverse Reaction and Analgesic Adverse Reaction, run by Copenhagen University Hospital, Rigshospitalet at 2 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ovarian volume (female infants) (time frame: 2.5 months old). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04369222, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2025.