The Copenhagen Analgesic Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 685
- 试验地点
- 2
- 主要终点
- Testes volumen (male infants)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Testes volumen (male infants)
时间窗: 2.5 months old
Testes volumen, measured by ultrasound
Ovarian volume (female infants)
时间窗: 2.5 months old
Ovarian volumen, measured by abdominal ultrasound
Ovarian follicle count (female infants)
时间窗: 2.5 months old
Ovarian follicle count, measured by abdominal ultrasound
Blood sample (female infants)
时间窗: 2.5 months old
Serum metabolites Anti Müllarian Hormone (AMH)
Blood sample (male infants)
时间窗: 2.5 months old
Serum metabolites testosterone, free testosterone.
次要结局
- Weight (fathers)(Gestational week 12)
- Triceps skinfold (male and female infants)(2.5 months old)
- Asphyxia, adverse events (newborn)(Retrieved from patient files postpartum within 1 year of study completion)
- Birth weight (newborn)(Retrieved from patient files postpartum within 1 year of study completion)
- Pregnancy outcome, preeclampsia (mother)(Retrieved from patient files postpartum within one year)
- Blood sample (mother)(Gestational week 12 and 2.5 months postpartum)
- Urine sample (mother)(Gestational week 12 and 2.5 months postpartum)
- Length (male and female infants)(2.5 months old)
- Scapula skinfold (male and female infants)(2.5 months old)
- Drug intake (mother)(Retrieved from patient questionnaire postpartum within one year)
- Pubertal history (parents)(Retrived from questionnaire within a half year)
- Penile measurements (male infants)(2.5 months old)
- Epigenetic profiling (male and female infants)(Single determination, 2.5 months old)
- Genetic profiling (male and female infants)(Single determination, 2.5 months old)
- Weight (male and female infants)(2.5 months old)
- Triceps skinfold(father)(Gestational week 12)
- Scapula skinfold (father)(Gestational week 12)
- Birth length (newborn)(Retrieved from patient files postpartum within 1 year of study completion)
- Biceps skinfold (father)(Gestational week 12)
- Flank skinfold (father)(Gestational week 12)
- Flank skinfold (male and female infants)(2.5 months old)
- Partus mode(Retrieved from patient files postpartum within 1 year of study completion)
- Gestational age (newborn)(Retrieved from patient files postpartum within 1 year of study completion)
- Pubertal staging (male and female infants)(2.5 months old)
- Head circumference (male and female infants)(2.5 months old)
- Abdominal circumference (male and female infants)(2.5 months old)
- Height (fathers)(Gestational week 12)
- Biceps skinfold (male and female infants)(2.5 months old)
- Meconium, adverse events (newborn)(Retrieved from patient files postpartum within 1 year of study completion)
- Pregnancy outcome, gestational hypertension (mother)(Retrieved from patient files postpartum within one year)
- Medical history and exposure (parents)(Retrived from questionnaire within a half year)
- Blood sample (father)(Gestational week 12)
- Anogenital distance (AGD) (male and female infants)(App. gestational age 30 weeks)
- Blood sample (female infants)(2.5 months old)
- Pregnancy outcome, induction of labor (mother)(Retrieved from patient files postpartum within one year)
- Urine sample (father)(Gestational week 12)
- 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.(2.5 months old)
- Uterine volume (female infants)(2.5 months old)
- Blood sample (male infants)(2.5 months old)
- Urine sample (10 mL) (male and female infants)(2.5 months old)
- Endometrial thickness (female infants)(2.5 months old)
- Medical report (mother)(Every 2 weeks from enrollment in early pregnancy to birth)
研究者
Anders Juul
Professor
Rigshospitalet, Denmark