Adenomyosis and Pregnancy Outcomes in Women Undergoing Assisted Reproductive Technology Treatment

NCT05418140 | Active Not Recruiting

• 1 other identifier: AdAPT-ART
• Study Type: observational
• Target: 828
• Locations: 1 country
• Sites: 9

Brief Summary

Rationale: A rising number of adenomyosis cases are being diagnosed in women in the age group of 30 to 40 years. This is due to a combination of better diagnostic imaging techniques and a higher number of women delaying the fulfilment of their fertility aspirations. The association between adenomyosis and pregnancy outcomes in women with subfertility has not been adequately explained by existing evidence due to lack of data on the association between the severity of adenomyosis, disease location, presence of symptoms and coexisting gynaecological conditions and pregnancy loss in women undergoing fertility treatment. There is a need to improve our understanding of prognostic features which would be beneficial in counselling women with adenomyosis undergoing fertility treatment and inform future management options. The investigators propose a research body of work aimed at improving our understanding of adenomyosis and its association with pregnancy loss. Objective: The aim of the study is to determine the association between adenomyosis and pregnancy loss in women undergoing assisted reproductive technology (ART) treatment. Study design: Prospective multicentre cohort study. The cohort will comprise of women with adenomyosis undergoing ART treatment and the control group will include women with normal uterus on baseline ultrasound scan undergoing ART treatment during the study duration. Settings: The study will be conducted at all main CARE fertility units, one of the largest providers of fertility treatment in the United Kingdom. Participant population with exposure and sample size: The cohort group will comprise of women diagnosed with adenomyosis on pre-treatment baseline ultrasound scan before ART treatment who satisfy the eligibility criteria and consent to participate in the study. The total sample size for this study will be 750 participants with 375 women in each arm. Recruitment will take place over the course of 18 months. Diagnostic tool for detection of exposure: The diagnosis of adenomyosis will be made using transvaginal ultrasound scan (TVS) (2D and 3D Ultrasound and applying Morphological Uterus Sonographic Assessment (MUSA) criteria. Schematic mapping system of adenomyosis severity proposed by Lazzeri and colleagues will be used to grade the severity of adenomyosis. Eligibility: Inclusion criteria: All women aged \>18 years and ≤42 years undergoing IVF/ICSI cycle. Exclusion criteria: Women with coexisting fibroid uterus, endometrioma confirmed on USS or known laparoscopic diagnosis of endometriosis (with histological confirmation), untreated hydrosalpinx, uterine malformation, previous myomectomy, previous surgery for adenomyosis or inconclusive USS. Recruitment: All women undergoing pre-treatment pelvic ultrasound scans before ART treatment will be screened for adenomyosis at the participating centres. Women who meet the eligibility criteria will be provided with an information leaflet about the study. They will be enrolled in the study after informed consent is obtained. The severity of adenomyosis will be subsequently evaluated using stored 2D and 3D ultrasound scan (USS) images. Several demographic, clinical and treatment characteristics will be recorded for each participant. Control: To ensure adequate comparability of the cohort, women with normal uterus on baseline ultrasound scan during the study duration will be used as control and will be matched for the following variables: age, embryo quality, type of ART cycle (donor or self and IVF or ICSI) and number of embryos transferred. The eligibility criteria will be applicable to the controls as well. Outcome measures: Primary outcome: Pregnancy loss up to 24 weeks out of all pregnancies achieved. The pregnancy loss will include biochemical pregnancy loss, miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy. This will be reported per embryo transfer and per woman. Secondary outcomes:1. Implantation rate per embryo transfer (number of gestational sacs divided by number of embryos transferred) and per woman; 2. Biochemical pregnancy rate per embryo transfer (positive pregnancy test following embryo transfer) and per woman; 3. Clinical pregnancy rate per embryo transfer (presence of at least one intrauterine gestational sac on ultrasound) and per woman; 4. Ongoing pregnancy rate per woman (defined as a live pregnancy at 12 weeks onwards); 5. Live birth rate after 34 weeks per woman. Subgroup analysis: We will carry out subgroup analysis according to specific patient characteristics. These analyses will include, but not necessarily be limited to women with the following characteristics:1. Varying severity of adenomyosis; 2. Presence /absence of symptoms of adenomyosis; 3. Frozen vs. Fresh embryo transfer; 4. Short vs. long vs. ultralong ovarian stimulation protocol; 5. Recurrent miscarriages; 6. Other associations that may become apparent in post-hoc analyses.

Conditions

Adenomyosis; Infertility; ART; Pregnancy Loss; Miscarriage

Keywords

Adenomyosis; Infertility; ART

Outcome Measures

Primary Outcomes (1)

• Number of participants with pregnancy loss at <24 weeks gestation

  Pregnancy loss up to 24 weeks out of all pregnancies achieved. The pregnancy loss will include biochemical pregnancy loss, miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy.1. Biochemical pregnancy: Spontaneous pregnancy demise based on a previous positive pregnancy test that then becomes negative without an ultrasound evaluation 2. Miscarriage: Intrauterine pregnancy demise confirmed by TVS or histology of pregnancy tissue. This would be before 24 completed weeks of gestational age. The gestational age limit is based on the legal viability limit in the United Kingdom. 3\. Pregnancy of unknown location (PUL): Temporary classification to describe when no pregnancy can be visualised inside or outside the uterus on TVS in a woman with a positive pregnancy test.

  up to 24 weeks gestation

Secondary Outcomes (5)

• Number of gestational sacs observed at vaginal ultrasound 3-5 weeks after transfer per embryo transfer

  3-5 weeks after transfer

• Number of participants with positive pregnancy test following embryo transfer

  14-16 days after embryo transfer

• Number of participants with clinical pregnancy per embryo transfer

  6-7 weeks gestation

• Number of participants with ongoing pregnancy

  12 weeks gestation

• Number of participants with live birth

  34 weeks gestation

Study Arms (2)

Women with diagnosis of adenomyosis on ultrasound scan

The cohort group (375 participants) will comprise of women diagnosed with adenomyosis on pre-treatment baseline ultrasound scan before ART treatment who satisfy the eligibility criteria and consent to participate in the study. September 2022: Amendments to the protocol: Some of the methodological aspects of the AdAPT-ART study have been revisited to ensure timely delivery of the study to a full sample size. These amendments have been approved by the local ethics committee. Amendment sample size: Sample size of 276 women with adenomyosis and 552 women with normal uterus with 2:1 control: cohort design. Power remains 80%

Other: Ultrasound diagnosis of adenomyosis

Control group: Women with normal uterus on baseline ultrasound scan

Women with normal uterus on baseline ultrasound scan during the study duration will be used as control (375 participants) and will be matched for the following variables: age, embryo quality, type of ART cycle (donor or self and IVF or ICSI) and number of embryos transferred. The eligibility criteria will be applicable to the controls as well. September 2022: Amendments to the protocol: Some of the methodological aspects of the AdAPT-ART study have been revisited to ensure timely delivery of the study to a full sample size. These amendments have been approved by the local ethics committee. Amendment sample size: Sample size of 276 women with adenomyosis and 552 women with normal uterus with 2:1 control: cohort design. Power remains 80%

Other: Ultrasound diagnosis of adenomyosis

Interventions

Ultrasound diagnosis of adenomyosis OTHER

The diagnosis of adenomyosis will be made using transvaginal ultrasound scan (TVS) (2D and 3D Ultrasound and applying Morphological Uterus Sonographic Assessment (MUSA) criteria (Van den Bosch et al, 2015).

Control group: Women with normal uterus on baseline ultrasound scan; Women with diagnosis of adenomyosis on ultrasound scan

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The study cohort will comprise of women diagnosed with adenomyosis on pre-treatment baseline ultrasound scan before ART treatment who satisfy the eligibility criteria and consent to participate in the study. The Morphological Uterus Sonographic Assessment (MUSA) criteria will be used to describe the ultrasound features of adenomyosis. The MUSA criteria outlines the ultrasound features of myometrium and myometrial lesions using standardised terms, definitions and measurements. A diagnosis of adenomyosis is made if any morphological features of adenomyosis are present.

You may qualify if:

• Age \>18 years and ≤42 years: Maternal age is an independent factor affecting the live birth rate in ART cycles. In 2019, a steep drop in the live birth rate has been reported in the United Kingdom in the latest Human Fertilisation and Embryology Authority (HFEA) data from the 32% per embryo transferred for patients under 35 years, compared to below 5% for patients aged 43+ when using their own eggs (HFEA, 2021). Hence, this is the age cut-off used in the study.
• Undergoing IVF/ICSI cycle.

You may not qualify if:

• Untreated hydrosalpinx
• Uterine malformation
• Previous myomectomy
• Previous surgery for adenomyosis
• Inconclusive USS
• September 2022: Amendments to the protocol: Some of the methodological aspects of the AdAPT-ART study have been revisited to ensure timely delivery of the study to a full sample size and to make the recruitment smooth. These amendments have been approved by the local ethics committee.
• Age: 18-45 years (Age will be adjusted for)
• Endometriosis: Subgroup analysis for isolated adenomyosis and those with coexisting endometriosis will be performed
• Rationale: Adenomyosis with coexisting endometriosis is common and is an important group to look at in terms of outcome of pregnancy loss.

Sponsors & Collaborators

• CARE Fertility UK: lead
• University of Birmingham: collaborator

Study Sites (9)

CARE Fertility, Birmingham

Birmingham, England, B15 3DP, United Kingdom

Location

CARE Fertility, Chester

Chester, England, CH2 1UL, United Kingdom

Location

CARE Fertility, Manchester

Manchester, England, M14 5QH, United Kingdom

Location

CARE Fertility, Nottingham

Nottingham, England, NG8 6PZ, United Kingdom

Location

CARE Fertility, Sheffield

Sheffield, England, S7 1RA, United Kingdom

Location

CARE Fertility, Tamworth

Tamworth, England, B78 3HL, United Kingdom

Location

CARE Fertility Bolton

Bolton, United Kingdom

Location

CARE Fertility, Leeds

Leeds, United Kingdom

Location

CARE Fertility, Northampton

Northampton, United Kingdom

Location

Related Publications (25)

• Andres MP, Borrelli GM, Ribeiro J, Baracat EC, Abrao MS, Kho RM. Transvaginal Ultrasound for the Diagnosis of Adenomyosis: Systematic Review and Meta-Analysis. J Minim Invasive Gynecol. 2018 Feb;25(2):257-264. doi: 10.1016/j.jmig.2017.08.653. Epub 2017 Aug 30.

  PMID: 28864044 BACKGROUND

• Chapron C, Vannuccini S, Santulli P, Abrao MS, Carmona F, Fraser IS, Gordts S, Guo SW, Just PA, Noel JC, Pistofidis G, Van den Bosch T, Petraglia F. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update. 2020 Apr 15;26(3):392-411. doi: 10.1093/humupd/dmz049.

  PMID: 32097456 BACKGROUND

• Chiang CH, Chang MY, Shiau CS, Hou HC, Hsieh TT, Soong YK. Effect of a sonographically diffusely enlarged uterus without distinct uterine masses on the outcome of in vitro fertilization-embryo transfer. J Assist Reprod Genet. 1999 Aug;16(7):369-72. doi: 10.1023/a:1020593930366.

  PMID: 10459520 BACKGROUND

• Dueholm M, Lundorf E, Hansen ES, Sorensen JS, Ledertoug S, Olesen F. Magnetic resonance imaging and transvaginal ultrasonography for the diagnosis of adenomyosis. Fertil Steril. 2001 Sep;76(3):588-94. doi: 10.1016/s0015-0282(01)01962-8.

  PMID: 11532486 BACKGROUND

• Exacoustos C, Brienza L, Di Giovanni A, Szabolcs B, Romanini ME, Zupi E, Arduini D. Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet Gynecol. 2011 Apr;37(4):471-9. doi: 10.1002/uog.8900.

  PMID: 21433167 BACKGROUND

• Exacoustos C, Morosetti G, Conway F, Camilli S, Martire FG, Lazzeri L, Piccione E, Zupi E. New Sonographic Classification of Adenomyosis: Do Type and Degree of Adenomyosis Correlate to Severity of Symptoms? J Minim Invasive Gynecol. 2020 Sep-Oct;27(6):1308-1315. doi: 10.1016/j.jmig.2019.09.788. Epub 2019 Oct 7.

  PMID: 31600574 BACKGROUND

• Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017 Dec 6;17(1):162. doi: 10.1186/s12874-017-0442-1.

  PMID: 29207961 BACKGROUND

• Human Fertilisation and Embryology Authority (HFEA). Fertility-treatment 2019: trends and figures. UK statistics for IVF and DI treatment, storage, and donation. May 2021. Available from: Fertility treatment 2019: trends and figures | Human Fertilisation and Embryology Authority (hfea.gov.uk) [Accessed 12th July 2021]

  BACKGROUND

• Huang Y, Zhao X, Chen Y, Wang J, Zheng W, Cao L. Miscarriage on Endometriosis and Adenomyosis in Women by Assisted Reproductive Technology or with Spontaneous Conception: A Systematic Review and Meta-Analysis. Biomed Res Int. 2020 Dec 8;2020:4381346. doi: 10.1155/2020/4381346. eCollection 2020.

  PMID: 33490243 BACKGROUND

• Lazzeri L, Morosetti G, Centini G, Monti G, Zupi E, Piccione E, Exacoustos C. A sonographic classification of adenomyosis: interobserver reproducibility in the evaluation of type and degree of the myometrial involvement. Fertil Steril. 2018 Nov;110(6):1154-1161.e3. doi: 10.1016/j.fertnstert.2018.06.031.

  PMID: 30396560 BACKGROUND

• Maheshwari A, Gurunath S, Fatima F, Bhattacharya S. Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes. Hum Reprod Update. 2012 Jul;18(4):374-92. doi: 10.1093/humupd/dms006. Epub 2012 Mar 22.

  PMID: 22442261 BACKGROUND

• Munro MG. Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity. Fertil Steril. 2019 Apr;111(4):629-640. doi: 10.1016/j.fertnstert.2019.02.008.

  PMID: 30929720 BACKGROUND

• Naftalin J, Hoo W, Nunes N, Mavrelos D, Nicks H, Jurkovic D. Inter- and intraobserver variability in three-dimensional ultrasound assessment of the endometrial-myometrial junction and factors affecting its visualization. Ultrasound Obstet Gynecol. 2012 May;39(5):587-91. doi: 10.1002/uog.10133.

  PMID: 22045594 BACKGROUND

• Neal S, Morin S, Werner M, Gueye NA, Pirtea P, Patounakis G, Scott R Jr, Goodman L. Three-dimensional ultrasound diagnosis of adenomyosis is not associated with adverse pregnancy outcome following single thawed euploid blastocyst transfer: prospective cohort study. Ultrasound Obstet Gynecol. 2020 Oct;56(4):611-617. doi: 10.1002/uog.22065.

  PMID: 32349167 BACKGROUND

• Pinzauti S, Lazzeri L, Tosti C, Centini G, Orlandini C, Luisi S, Zupi E, Exacoustos C, Petraglia F. Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms. Ultrasound Obstet Gynecol. 2015 Dec;46(6):730-6. doi: 10.1002/uog.14834.

  PMID: 25728241 BACKGROUND

• Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J, Brosens JJ, Brewin J, Ramhorst R, Lucas ES, McCoy RC, Anderson R, Daher S, Regan L, Al-Memar M, Bourne T, MacIntyre DA, Rai R, Christiansen OB, Sugiura-Ogasawara M, Odendaal J, Devall AJ, Bennett PR, Petrou S, Coomarasamy A. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021 May 1;397(10285):1658-1667. doi: 10.1016/S0140-6736(21)00682-6. Epub 2021 Apr 27.

  PMID: 33915094 BACKGROUND

• Rasmussen CK, Hansen ES, Dueholm M. Inter-rater agreement in the diagnosis of adenomyosis by 2- and 3-dimensional transvaginal ultrasonography. J Ultrasound Med. 2019 Mar;38(3):657-666. doi: 10.1002/jum.14735. Epub 2018 Sep 4.

  PMID: 30182497 BACKGROUND

• ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B, Quenby S, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018 Apr 6;2018(2):hoy004. doi: 10.1093/hropen/hoy004. eCollection 2018.

  PMID: 31486805 BACKGROUND

• Sun YL, Wang CB, Lee CY, Wun TH, Lin P, Lin YH, Tseng CC, Chen CH, Tseng CJ. Transvaginal sonographic criteria for the diagnosis of adenomyosis based on histopathologic correlation. Taiwan J Obstet Gynecol. 2010 Mar;49(1):40-4. doi: 10.1016/S1028-4559(10)60007-1.

  PMID: 20466291 BACKGROUND

• Tummers P, De Sutter P, Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod. 2003 Aug;18(8):1720-3. doi: 10.1093/humrep/deg308.

  PMID: 12871890 BACKGROUND

• Van den Bosch T, de Bruijn AM, de Leeuw RA, Dueholm M, Exacoustos C, Valentin L, Bourne T, Timmerman D, Huirne JAF. Sonographic classification and reporting system for diagnosing adenomyosis. Ultrasound Obstet Gynecol. 2019 May;53(5):576-582. doi: 10.1002/uog.19096. No abstract available.

  PMID: 29790217 BACKGROUND

• Van den Bosch T, Dueholm M, Leone FP, Valentin L, Rasmussen CK, Votino A, Van Schoubroeck D, Landolfo C, Installe AJ, Guerriero S, Exacoustos C, Gordts S, Benacerraf B, D'Hooghe T, De Moor B, Brolmann H, Goldstein S, Epstein E, Bourne T, Timmerman D. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015 Sep;46(3):284-98. doi: 10.1002/uog.14806. Epub 2015 Aug 10.

  PMID: 25652685 BACKGROUND

• Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014 May;29(5):964-77. doi: 10.1093/humrep/deu041. Epub 2014 Mar 12.

  PMID: 24622619 BACKGROUND

• Younes G, Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta-analysis. Fertil Steril. 2017 Sep;108(3):483-490.e3. doi: 10.1016/j.fertnstert.2017.06.025.

  PMID: 28865548 BACKGROUND

• Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod. 2017 Sep 1;32(9):1786-1801. doi: 10.1093/humrep/dex234.

  PMID: 29117321 BACKGROUND

MeSH Terms

Conditions

Adenomyosis; Infertility; Abortion, Spontaneous

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Pregnancy Complications

Study Officials

• Arri Coomarasamy

  University of Birmingham

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2022
• First Posted: June 14, 2022
• Study Start: June 14, 2022
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: March 12, 2025

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (9)