The Copenhagen Analgesic Study
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.
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.
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