Clinical trial NCT04369222: The Copenhagen Analgesic Study
Official title: The Copenhagen Analgesic Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Gonad Regulating Hormone Adverse Reaction
Analgesic Adverse Reaction
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2020-04-30
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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

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.

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

Primary outcomes:
measure: Ovarian volume (female infants)
timeFrame: 2.5 months old
measure: Ovarian follicle count (female infants)
timeFrame: 2.5 months old
measure: Blood sample (female infants)
timeFrame: 2.5 months old
measure: Testes volumen (male infants)
timeFrame: 2.5 months old
measure: Blood sample (male infants)
timeFrame: 2.5 months old
Secondary outcomes:
measure: Length (male and female infants)
timeFrame: 2.5 months old
measure: Weight (male and female infants)
timeFrame: 2.5 months old
measure: Head circumference (male and female infants)
timeFrame: 2.5 months old
measure: Abdominal circumference (male and female infants)
timeFrame: 2.5 months old
measure: Height (fathers)
timeFrame: Gestational week 12
measure: Weight (fathers)
timeFrame: Gestational week 12
measure: Biceps skinfold (father)
timeFrame: Gestational week 12
measure: Triceps skinfold(father)
timeFrame: Gestational week 12
measure: Flank skinfold (father)
timeFrame: Gestational week 12
measure: Scapula skinfold (father)
timeFrame: Gestational week 12
measure: Biceps skinfold (male and female infants)
timeFrame: 2.5 months old
measure: Triceps skinfold (male and female infants)
timeFrame: 2.5 months old
measure: Flank skinfold (male and female infants)
timeFrame: 2.5 months old
measure: Scapula skinfold (male and female infants)
timeFrame: 2.5 months old
measure: Asphyxia, adverse events (newborn)
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Meconium, adverse events (newborn)
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Partus mode
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Birth weight (newborn)
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Birth length (newborn)
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Gestational age (newborn)
timeFrame: Retrieved from patient files postpartum within 1 year of study completion
measure: Drug intake (mother)
timeFrame: Retrieved from patient questionnaire postpartum within one year
measure: Pregnancy outcome, preeclampsia (mother)
timeFrame: Retrieved from patient files postpartum within one year
measure: Pregnancy outcome, gestational hypertension (mother)
timeFrame: Retrieved from patient files postpartum within one year
measure: Pregnancy outcome, induction of labor (mother)
timeFrame: Retrieved from patient files postpartum within one year
measure: Medical history and exposure (parents)
timeFrame: Retrived from questionnaire within a half year
measure: Pubertal history (parents)
timeFrame: Retrived from questionnaire within a half year
measure: Blood sample (mother)
timeFrame: Gestational week 12 and 2.5 months postpartum
measure: Urine sample (mother)
timeFrame: Gestational week 12 and 2.5 months postpartum
measure: Blood sample (father)
timeFrame: Gestational week 12
measure: Urine sample (father)
timeFrame: Gestational week 12
measure: Anogenital distance (AGD) (male and female infants)
timeFrame: 2.5 months old
measure: Anogenital distance (AGD) (male and female infants)
timeFrame: App. gestational age 30 weeks
measure: Blood sample (female infants)
timeFrame: 2.5 months old
measure: Blood sample (male infants)
timeFrame: 2.5 months old
measure: 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.
timeFrame: 2.5 months old
measure: Pubertal staging (male and female infants)
timeFrame: 2.5 months old
measure: Penile measurements (male infants)
timeFrame: 2.5 months old
measure: Epigenetic profiling (male and female infants)
timeFrame: Single determination, 2.5 months old
measure: Urine sample (10 mL) (male and female infants)
timeFrame: 2.5 months old
measure: Medical report (mother)
timeFrame: Every 2 weeks from enrollment in early pregnancy to birth
measure: Genetic profiling (male and female infants)
timeFrame: Single determination, 2.5 months old
measure: Endometrial thickness (female infants)
timeFrame: 2.5 months old
measure: Uterine volume (female infants)
timeFrame: 2.5 months old
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Growth and Reproduction, Rigshospitalet
city: Copenhagen
country: Denmark
facility: Department of Obstetrics and Section of fetal medicine, Rigshospitalet
Study officials:
affiliation: Department of Growth and Reproduction, Rigshospitalet
name: Anders Juul, Professor
role: PRINCIPAL_INVESTIGATOR
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