The Copenhagen Analgesic Study (COPANA)

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.

Study Overview

• Status: Unknown
• Conditions: Analgesic Adverse Reaction; Gonad Regulating Hormone Adverse Reaction
• Intervention / Treatment: Other: Observational

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.

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

• Study Contact: Name: Margit B. Fischer, M.D.; Phone Number: 0045 28790715; Email: mfis0039@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Growth and Reproduction, Rigshospitalet
    • Contact: Anders Juul, M.D., DMSc; Phone Number: 0045 35455064; Email: anders.juul@rh.regionh.dk
    • Contact: Margit B. Fischer, M.D., PhD.-student; Phone Number: 0045 28790715; Email: mfis0039@regionh.dk
    • Principal Investigator: Anders Juul, M.D., DMSc
    • Sub-Investigator: Margit B. Fischer, M.D., PhD.-student
    • Sub-Investigator: Casper Hagen, M.D.
    • Sub-Investigator: Kristian Almstrup, MSc, PhD.
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Obstetrics and Section of fetal medicine, Rigshospitalet
    • Contact: Peter Damm, M.D., DMSc, PhD.; Phone Number: 0045 35451334; Email: peter.damm@regionh.dk
    • Principal Investigator: Peter Damm, M.D., DMSc, PhD.
    • Sub-Investigator: Karin Sundberg, M.D., DMSc, PhD.
    • Sub-Investigator: Hanne K. Heegaard, Associated professor, PhD.
    • Sub-Investigator: Rikke N. Møller, Head midwife
    • Sub-Investigator: Ane L. Rom, Midwife, PhD.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• 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

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Controls; Children born from mothers with no consumption of mild analgesics 3 months before or during pregnancy
Exposed; Children born from mothers with consumption of mild analgesics 3 months before or during pregnancy	Other: Observational; Maternal consumption of mild analgesics; Other Names: Acetaminophen; Acetyl salicylic acid; Non steroidal antiinflammatory drugs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ovarian volume (female infants)	Ovarian volumen, measured by abdominal ultrasound	2.5 months old
Ovarian follicle count (female infants)	Ovarian follicle count, measured by abdominal ultrasound	2.5 months old
Blood sample (female infants)	Serum metabolites Anti Müllarian Hormone (AMH)	2.5 months old
Testes volumen (male infants)	Testes volumen, measured by ultrasound	2.5 months old
Blood sample (male infants)	Serum metabolites testosterone, free testosterone.	2.5 months old

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length (male and female infants)	Length in cm	2.5 months old
Weight (male and female infants)	Weight in kilograms	2.5 months old
Head circumference (male and female infants)	Head circumference measured with a measurement tape, mm.	2.5 months old
Abdominal circumference (male and female infants)	Abdonimal circumference measured with a measurement tape, mm.	2.5 months old
Height (fathers)	Height in cm, by stadiometer (Holtain Ltd, Crymych, UK) with a precision of 0.1 cm	Gestational week 12
Weight (fathers)	Weight in kilograms, by digital scale with a precision of 0.1 kg (SECA delta, model 707)	Gestational week 12
Biceps skinfold (father)	Skinfold measured above the biceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Triceps skinfold(father)	Skinfold measured above the triceps, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
Flank skinfold (father)	Skinfold measured at the flank, measured in mm (Harpenden skinfold Caliper, British Indicators Ltd, London, UK)	Gestational week 12
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
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
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
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
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
Asphyxia, adverse events (newborn)	Asphyxia (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Meconium, adverse events (newborn)	Meconium in amionic fluids (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Partus mode	Partus mode (vaginal delivery, cesarean section, instrumental delivery) (yes/no)	Retrieved from patient files postpartum within 1 year of study completion
Birth weight (newborn)	Birth weight, grams	Retrieved from patient files postpartum within 1 year of study completion
Birth length (newborn)	Birth length, cm	Retrieved from patient files postpartum within 1 year of study completion
Gestational age (newborn)	Gestational age at birth, weeks and days	Retrieved from patient files postpartum within 1 year of study completion
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
Pregnancy outcome, preeclampsia (mother)	Preeclampsia (yes/no)	Retrieved from patient files postpartum within one year
Pregnancy outcome, gestational hypertension (mother)	Gestational hypertension (yes/no)	Retrieved from patient files postpartum within one year
Pregnancy outcome, induction of labor (mother)	In duction of labor (yes/no)	Retrieved from patient files postpartum within one year
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
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
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
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
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
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
Anogenital distance (AGD) (male and female infants)	Distance from anus to genital tubercle, measured in mm with a ruler	2.5 months old
Anogenital distance (AGD) (male and female infants)	Distance from anus to genital tubercle, third trimester ultrasound	App. gestational age 30 weeks
Blood sample (female infants)	(estradiol and inhibin B, luteinizing hormone (LH)/follicular stimulating hormone (FSH) ratio)	2.5 months old
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
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
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
Penile measurements (male infants)	Penile measurements with a ruler	2.5 months old
Epigenetic profiling (male and female infants)	Epigenetic variation of loci regulating hormone signalling	Single determination, 2.5 months old
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
Medical report (mother)	Specific medical report on medicine consumption incl. analgesics	Every 2 weeks from enrollment in early pregnancy to birth
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
Endometrial thickness (female infants)	Endometrial thickness, measured by abdominal ultrasound	2.5 months old
Uterine volume (female infants)	Uterine volume, measured by abdominal ultrasound	2.5 months old

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Anders Juul, Professor, Department of Growth and Reproduction, Rigshospitalet

Publications and helpful links

General Publications

• 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.
• 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.
• Arendrup FS, Mazaud-Guittot S, Jegou 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.
• Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesne L, Serrano T, Main KM, Jegou 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.
• Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jegou 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.
• Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou 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.
• 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. doi: 10.1098/rspb.1963.0055. No abstract available.
• 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. doi: 10.1016/0272-0590(92)90051-i.
• 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.
• Ersboll 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.
• Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebaek 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. doi: 10.1093/humrep/dew285. Epub 2016 Nov 16.
• Rebordosa C, Zelop CM, Kogevinas M, Sorensen 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.
• 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.
• Myrskyla M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature. 2009 Aug 6;460(7256):741-3. doi: 10.1038/nature08230.
• 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.
• 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. doi: 10.1016/s0890-6238(99)00036-2.
• Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek 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.
• 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.
• Leverrier-Penna S, Mitchell RT, Becker E, Lecante L, Ben Maamar M, Homer N, Lavoue V, Kristensen DM, Dejucq-Rainsford N, Jegou 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.
• 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.
• 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.
• Mendiola J, Stahlhut RW, Jorgensen 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.
• Kuiri-Hanninen 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): April 1, 2022

Study Registration Dates

• First Submitted: April 20, 2020
• First Submitted That Met QC Criteria: April 27, 2020
• First Posted (Actual): April 30, 2020

Study Record Updates

• Last Update Posted (Actual): June 5, 2020
• Last Update Submitted That Met QC Criteria: June 3, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Dermatologic Agents; Antifungal Agents; Keratolytic Agents; Aspirin; Anti-Inflammatory Agents; Acetaminophen; Salicylic Acid; Anti-Inflammatory Agents, Non-Steroidal; Salicylates
• Other Study ID Numbers: COPANA5064

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No