The Copenhagen Analgesic Study

Analgesic Adverse Reaction Clinical Trial

— COPANA  

Official title:

The Copenhagen Analgesic Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04369222
• Other study ID #: COPANA5064
• Status: Recruiting
• Start date: March 1, 2020
• Est. completion date: April 2022

Study information

• Verified date: June 2020
• Source: Rigshospitalet, Denmark
• Contact: Margit B. Fischer, M.D.
• Phone: 0045 28790715
• Email: mfis0039[@]regionh.dk
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: April 2022
• Est. primary completion date: April 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Analgesic Adverse Reaction
• Gonad Regulating Hormone Adverse Reaction

Intervention

Other:
• Observational
Maternal consumption of mild analgesics

Locations

Country	Name	City	State
Denmark	Department of Growth and Reproduction, Rigshospitalet	Copenhagen
Denmark	Department of Obstetrics and Section of fetal medicine, Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (23)

Arendrup FS, Mazaud-Guittot S, Jégou 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. — View Citation

BAKER 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. — View Citation

Dean A, Sharpe RM. Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013 Jun;98(6):2230-8. doi: 10.1210/jc.2012-4057. Epub 2013 Apr 8. Review. — View Citation

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. — View Citation

Ersbøll 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. — View Citation

Gallavan 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. — View Citation

Gilboa Y, Perlman S, Kivilevitch Z, Messing B, Achiron R. Prenatal Anogenital Distance Is Shorter in Fetuses With Hypospadias. J Ultrasound Med. 2017 Jan;36(1):175-182. doi: 10.7863/ultra.16.01006. Epub 2016 Nov 28. — View Citation

Holm JB, Mazaud-Guittot S, Danneskiold-Samsøe NB, Chalmey C, Jensen B, Nørregård MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jégou 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. — View Citation

Johansson 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. — View Citation

Juul A, Almstrup K, Andersson AM, Jensen TK, Jørgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebæk NE. Possible fetal determinants of male infertility. Nat Rev Endocrinol. 2014 Sep;10(9):553-62. doi: 10.1038/nrendo.2014.97. Epub 2014 Jun 17. Review. — View Citation

Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jégou 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. — View Citation

Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesné L, Serrano T, Main KM, Jégou 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. Review. — View Citation

Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr. 2014;82(2):73-80. doi: 10.1159/000362414. Epub 2014 Jul 5. Review. — View Citation

Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne). 2018 Jul 23;9:410. doi: 10.3389/fendo.2018.00410. eCollection 2018. Review. — View Citation

Leverrier-Penna S, Mitchell RT, Becker E, Lecante L, Ben Maamar M, Homer N, Lavoué V, Kristensen DM, Dejucq-Rainsford N, Jégou B, Mazaud-Guittot S. Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo. Hum Reprod. 2018 Mar 1;33(3):482-493. doi: 10.1093/humrep/dex383. — View Citation

Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebæk 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. Epub 2016 Nov 16. — View Citation

Mendiola J, Stahlhut RW, Jørgensen N, Liu F, Swan SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect. 2011 Jul;119(7):958-63. doi: 10.1289/ehp.1103421. Epub 2011 Mar 4. — View Citation

Myrskylä M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature. 2009 Aug 6;460(7256):741-3. doi: 10.1038/nature08230. — View Citation

Nitsche 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. — View Citation

Rebordosa C, Zelop CM, Kogevinas M, Sørensen 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. — View Citation

Reel 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. — View Citation

Snijder CA, Kortenkamp A, Steegers EA, Jaddoe VW, Hofman A, Hass U, Burdorf A. Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum Reprod. 2012 Apr;27(4):1191-201. doi: 10.1093/humrep/der474. Epub 2012 Feb 2. — View Citation

Tromp 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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ovarian volume (female infants)	Ovarian volumen, measured by abdominal ultrasound	2.5 months old
Primary	Ovarian follicle count (female infants)	Ovarian follicle count, measured by abdominal ultrasound	2.5 months old
Primary	Blood sample (female infants)	Serum metabolites Anti Müllarian Hormone (AMH)	2.5 months old
Primary	Testes volumen (male infants)	Testes volumen, measured by ultrasound	2.5 months old
Primary	Blood sample (male infants)	Serum metabolites testosterone, free testosterone.	2.5 months old
Secondary	Length (male and female infants)	Length in cm	2.5 months old
Secondary	Weight (male and female infants)	Weight in kilograms	2.5 months old
Secondary	Head circumference (male and female infants)	Head circumference measured with a measurement tape, mm.	2.5 months old
Secondary	Abdominal circumference (male and female infants)	Abdonimal circumference measured with a measurement tape, mm.	2.5 months old
Secondary	Height (fathers)	Height in cm, by stadiometer (Holtain Ltd, Crymych, UK) with a precision of 0.1 cm	Gestational week 12
Secondary	Weight (fathers)	Weight in kilograms, by digital scale with a precision of 0.1 kg (SECA delta, model 707)	Gestational week 12
Secondary	Biceps skinfold (father)	Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Secondary	Triceps skinfold(father)	Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Secondary	Flank skinfold (father)	Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Secondary	Scapula skinfold (father)	Skinfold measured below the scapula all on the left side, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Secondary	Biceps skinfold (male and female infants)	Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	2.5 months old
Secondary	Triceps skinfold (male and female infants)	Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	2.5 months old
Secondary	Flank skinfold (male and female infants)	Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	2.5 months old
Secondary	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)	2.5 months old
Secondary	Asphyxia, adverse events (newborn)	Asphyxia (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Meconium, adverse events (newborn)	Meconium in amionic fluids (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Partus mode	Partus mode (vaginal delivery, cesarean section, instrumental delivery) (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Birth weight (newborn)	Birth weight, grams	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Birth length (newborn)	Birth length, cm	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Gestational age (newborn)	Gestational age at birth, weeks and days	Retrieved from patient files postpartum within 1 year of study completion
Secondary	Drug intake (mother)	Pre- and perinatal drug intake, filled in by mother during the whole prengancy every two weeks online	Retrieved from patient questionnaire postpartum within one year
Secondary	Pregnancy outcome, preeclampsia (mother)	Preeclampsia (yes/no)	Retrieved from patient files postpartum within one year
Secondary	Pregnancy outcome, gestational hypertension (mother)	Gestational hypertension (yes/no)	Retrieved from patient files postpartum within one year
Secondary	Pregnancy outcome, induction of labor (mother)	In duction of labor (yes/no)	Retrieved from patient files postpartum within one year
Secondary	Medical history and exposure (parents)	General- and reproductive health, the pregnancy, own birth weight, lifestyle, drinking and smoking habits from questionnaire	Retrived from questionnaire within a half year
Secondary	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	Retrived from questionnaire within a half year
Secondary	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).	Gestational week 12 and 2.5 months postpartum
Secondary	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).	Gestational week 12 and 2.5 months postpartum
Secondary	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).	Gestational week 12
Secondary	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).	Gestational week 12
Secondary	Anogenital distance (AGD) (male and female infants)	Distance from anus to genital tubercle, measured in mm with a ruler	2.5 months old
Secondary	Anogenital distance (AGD) (male and female infants)	Distance from anus to genital tubercle, third trimester ultrasound	App. gestational age 30 weeks
Secondary	Blood sample (female infants)	(estradiol and inhibin B, luteinizing hormone (LH)/follicular stimulating hormone (FSH) ratio)	2.5 months old
Secondary	Blood sample (male infants)	Serum metabolites of reproductive hormones (AMH, inhibin B levels, ratios of inhibin B/FSH and LH/FSH)	2.5 months old
Secondary	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.	2.5 months old
Secondary	Pubertal staging (male and female infants)	Pubertal staging using Tanners classification (including testicular size in boys assessed by Prader's orchidometer)	2.5 months old
Secondary	Penile measurements (male infants)	Penile measurements with a ruler	2.5 months old
Secondary	Epigenetic profiling (male and female infants)	Epigenetic variation of loci regulating hormone signalling	Single determination, 2.5 months old
Secondary	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).	2.5 months old
Secondary	Medical report (mother)	Specific medical report on medicine consumption incl. analgesics	Every 2 weeks from enrollment in early pregnancy to birth
Secondary	Genetic profiling (male and female infants)	Genotyping of different genetic loci (genetic variation of loci regulating) hormone signalling, e.g. FSHB, etc.	Single determination, 2.5 months old
Secondary	Endometrial thickness (female infants)	Endometrial thickness, measured by abdominal ultrasound	2.5 months old
Secondary	Uterine volume (female infants)	Uterine volume, measured by abdominal ultrasound	2.5 months old

External Links

•   United States Environmental Protection Agency.