The Copenhagen Analgesic Study

NCT ID: NCT04369222

Last Updated: 2025-07-10

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 685 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-03-01
• Study Completion Date: 2022-11-30

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.

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.

Conditions

Gonad Regulating Hormone Adverse Reaction; Analgesic Adverse Reaction

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Controls

Children born from mothers with no consumption of mild analgesics 3 months before or during pregnancy

No interventions assigned to this group

Exposed

Children born from mothers with consumption of mild analgesics 3 months before or during pregnancy

Observational

Intervention Type: OTHER

Maternal consumption of mild analgesics

Interventions

Observational

Maternal consumption of mild analgesics

Intervention Type: OTHER

Other Intervention Names

Acetaminophen; Non steroidal antiinflammatory drugs; Acetyl salicylic acid

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Anders Juul

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anders Juul, Professor

Role: PRINCIPAL_INVESTIGATOR

Department of Growth and Reproduction, Rigshospitalet

Locations

Department of Growth and Reproduction, Rigshospitalet

Copenhagen, , Denmark

Department of Obstetrics and Section of fetal medicine, Rigshospitalet

Copenhagen, , Denmark

Countries

Denmark

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Other Identifiers

COPANA5064

Identifier Type: -

Identifier Source: org_study_id