A systematic review of outcome reporting and outcome measures in studies investigating uterine-sparing treatment for adenomyosis

Abstract

STUDY QUESTION

Which outcomes and outcome measures are reported in interventional trials evaluating the treatment of adenomyosis?

SUMMARY ANSWER

We identified 38 studies, reporting on 203 outcomes using 133 outcome measures.

WHAT IS KNOWN ALREADY

Heterogeneity in outcome evaluation and reporting has been demonstrated for several gynaecological conditions and in fertility studies. In adenomyosis, previous systematic reviews have failed to perform a quantitative analysis for central outcomes, due to variations in outcome reporting and measuring.

STUDY DESIGN, SIZE, DURATION

A systematic search of Embase, Medline and Cochrane Register of Controlled Trials (CENTRAL) was performed with a timeframe from 1950 until February 2021, following the preferred reporting items for systematic reviews and meta-analysis (PRISMA).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Studies reporting on any uterus-sparing intervention to treat adenomyosis, both prospective and retrospective, were eligible for inclusion. Inclusion criteria were a clear definition of diagnostic criteria for adenomyosis and the modality used to make the diagnosis, a clear description of the intervention, a follow-up time of ≥6 months, a study population of n ≥ 20, a follow-up rate of at least 80%, and English language. The population included premenopausal women with adenomyosis. Risk of bias was assessed using the Evidence Project risk of bias tool.

MAIN RESULTS AND THE ROLE OF CHANCE

We included 38 studies (6 randomized controlled trials and 32 cohort studies), including 5175 participants with adenomyosis. The studies described 10 interventions and reported on 203 outcomes, including 43 classified as harms, in 29 predefined domains. Dysmenorrhoea (reported in 82%), heavy menstrual bleeding (HMB) (in 79%) and uterine volume (in 71%) were the most common outcomes. Fourteen different outcome measures were used for dysmenorrhoea and 17 for HMB. Quality of life was reported in 9 (24%) studies, patient satisfaction with treatment in 1 (3%). A clear primary outcome was stated in only 18%.

LIMITATIONS, REASONS FOR CAUTION

This review includes studies with a high risk of bias.

WIDER IMPLICATIONS OF THE FINDINGS

Shortcomings in the definition and choice of outcomes and outcome measures limit the value of the conducted research. The development and implementation of a core outcome set (COS) for interventional studies in adenomyosis could improve research quality. This review suggests a lack of patient-centred research in adenomyosis and people with adenomyosis should be involved in the development and implementation of the COS.

STUDY FUNDING/COMPETING INTERESTS

No funds specifically for this work were received. T.T. receives fees from General Electrics for lectures on ultrasound independently of this project.

TRIAL REGISTRATION NUMBER

This review is registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42020177466) and the Core Outcome Measures in Effectiveness Trials (COMET) initiative (registration number 1649).

WHAT DOES THIS MEAN FOR PATIENTS?

A treatment for a disease is developed and tested in research studies, to find out how effective the treatment is and to make sure it is safe. Researchers do this by measuring how a treatment changes so-called ‘outcomes’. Examples for outcomes could be pain or bleeding. It is important that the measured outcomes are relevant to the patients that are treated, and that they are measured with tools that are reliable. Also, the outcomes and measuring tools should be the same in all studies on the same disease, so that studies can be compared with each other.

In our work, we investigated the nature of outcomes that were reported in trials on the treatment of adenomyosis, a common benign disease of the uterus.

We found that the reported outcomes are largely focused on menstrual symptoms and uterine size, with only a minority of studies reporting outcomes relating to fertility or quality of life. Furthermore, the outcomes were measured with different types of measuring instruments, which made it difficult to compare studies. This inconsistent outcome reporting and measuring prevents clinicians to determine which treatments are best and should be recommended to patients with adenomyosis.

We recommend the development of a set of outcomes that should be measured and reported in all future trials on adenomyosis. This work needs to include input from all relevant stakeholders, especially people with adenomyosis.

Introduction

Adenomyosis is a common benign disease of the uterus that can be found in 20–70% of patients, depending on the characteristics of study populations (Upson and Missmer, 2020). Despite its reported negative impact on quality of life (QOL), fertility and obstetric outcomes (Harada et al., 2019; Horton et al., 2019; Upson and Missmer, 2020), data on the efficacy of treatments for adenomyosis are lacking. Systematic reviews evaluating interventions for adenomyosis have been unable to perform quantitative data-synthesis of commonly reported outcomes, such as abnormal uterine bleeding, due to the variation in outcome reporting (de Bruijn et al., 2017; Abbas et al., 2020). These reviews highlighted a significant variation in both the definition and measurement of outcomes, thereby preventing useful comparison of treatment outcomes. Variations in outcome reporting and measurements also contribute to the exaggeration of treatment effects and reporting bias by omitting unfavourable data (Duffy et al., 2017). For example, there is a controversy regarding the extent to which surgery could improve fertility outcomes in patients with adenomyosis. As reporting of fertility and obstetric outcomes is highly selective, the success of treatment is interpreted differently by the authors, with the risk of being overstated (Abbott, 2017; Dueholm, 2017).

Carefully selected outcomes and outcome measures can enhance research quality, increase the relevance of research results for the people treated for a condition, and reduce research waste. There is a growing consensus that the use of standardized or ‘core’ outcome sets in clinical trials would improve research into womens’ health. Such examples are published consensus on core outcomes in endometriosis research or fertility reporting (Duffy et al., 2020, 2021). There is currently no consensus amongst key stakeholders regarding which outcomes should be measured in trials assessing interventions for adenomyosis-related symptoms. A collection of 84 editors of women’s health journals, including the Cochrane Gynaecology and Fertility Group, have formed a consortium to support core outcome sets (COSs): the Core Outcomes in Women’s Health (CROWN) (Khan, 2016). The Core Outcome Set in Adenomyosis Research (COSAR) initiative aims to develop a COS for studies investigating therapeutic interventions for adenomyosis in conjunction with the CROWN-network.

As part of this work, the aim of the present review was to develop an inventory and systematically evaluate the outcomes and outcome measures reported in clinical trials investigating the treatment of adenomyosis.

Materials and methods

This review is registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020177466) and reports in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Liberati et al., 2009). COSAR is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative (registration number 1649). No approval from the institutional review board or ethics committee was sought owing to the nature of this work.

Literature search

The literature search was performed with support from a trained medical librarian. The electronic databases Medline, Embase and Cochrane Register of Controlled Trials were searched using the terms ‘adenomyosis’ and ‘treatment’, as well as a range of treatment-specific key words that were identified through a pilot search. The electronic search strategy is presented in Supplementary Data S1. The time range was from 1950 until February 2021. In addition, the reference lists of included articles and identified reviews on the topic were scanned, and manually searched for further studies.

Study selection

Studies reporting on any uterus-sparing intervention to treat adenomyosis, of any study design, both prospective and retrospective, were eligible for inclusion. Inclusion criteria were a study population comprising ≥20 women, a clear description of the modality and diagnostic criteria used to diagnose adenomyosis, a clear description of the intervention, follow-up time ≥6 months, loss to follow-up <20% and English language. Exclusion criteria included data presented in short communications, reviews, letters to the editors and congress abstracts. Studies with experimental design (e.g. performed on tissue samples or looking exclusively at molecular markers) or fundamental design flaws (unclear intervention) were also excluded. Two researchers (T.T. and M.O.) independently screened the retrieved titles and abstracts using the Rayyan application (Ouzzani et al., 2016). Potentially eligible studies were retrieved in full text for the assessment of their eligibility. Their methodological quality was independently assessed by two researchers (T.T. and M.O.) using the Evidence project risk of bias tool (Kennedy et al., 2019). The signalling questions were answered with ‘yes’, ‘no’, ‘not reported’ or ‘not applicable’. At each step, conflicting decisions were resolved through discussion.

The quality of outcome reporting was assessed by T.T. and M.O. using the Management of Otitis Media with Effusion in Cleft Palate (MOMENT) criteria (Harman et al., 2013), as described previously (Hirsch et al., 2016; Pergialiotis et al., 2018). One point was given for each of the following six domains: whether a primary outcome was clearly stated; whether the primary outcome was clearly defined for reproducible measures; whether the secondary outcomes were clearly stated; whether the secondary outcomes were clearly defined for reproducible measures; whether the authors explain the choice of outcome; whether the methods that were used were appropriate to enhance the quality of measures. We awarded a point for stating a primary outcome even if multiple primary outcomes were described. We did not award a point for a clear definition of the primary outcome if no primary outcome was stated. When most of the secondary outcomes were clearly defined for reproducible measures, we awarded a point even if not all secondary outcomes were clearly described. We did not award a point under the last domain if the study was retrospective and if it was not described how the outcomes were documented.

Data extraction and analysis

The data extraction was performed by T.T. and M.O. First author, year of publication, country of origin, study design, number of participants with adenomyosis and type of intervention were noted. We also recorded whether a sample size calculation was carried out. Outcomes were documented as primary or secondary outcomes, according to how they were classified in the Materials and method (M&M) section. Generic statements found in the title or abstract, such as ‘efficacy’ or ‘clinical effect’, that were not further specified in the manuscript, were not regarded as (primary) outcomes. Outcomes that were described in the result section or the discussion, but not defined in the M&M section as outcomes, were still included as secondary outcomes in the synthesis. As this was a recurring problem, the authors found that it would not reflect the reporting of outcomes if only the outcomes mentioned in the M&M section were included. The outcome measure and, if given, the definition was recorded, as well as the time points of outcome measuring and reporting. The outcomes were classified to core areas and domains according to a taxonomy recommended by COMET (Dodd et al., 2018). Composite outcomes, such as QOL, were reported with each item classified to the respective domain.

Results from this review are presented as percentages. Means and SD are calculated for normally distributed data. Distribution of data within the samples was assessed by analysing skewness and kurtosis. Associations between date of publication and quality of outcomes were analysed using linear regression. Probability values were rounded to two decimal places, with the exception of P < 0.001. Data analysis was performed using Microsoft Excel software (Version 2102, Microsoft Corporation, Redmont, USA).

Results

The literature search identified 1364 unique citations; eight additional studies were found through searching of reference lists (Fig. 1). In total, 38 studies were included in the final selection. The characteristics of the final 38 articles are listed in Table I.

Figure 1.

PRISMA flow diagram for a systematic review of outcome reporting and outcome measures in studies investigating uterine-sparing treatment for adenomyosis.

Table I.

Study characteristics and types of intervention of the included studies.

Author, year	Country	Inclusion period	Study design	n, total (n per arm)	Diagnostic tool	Intervention group 1
						Intervention group 2
						Intervention group 3
Kwack et al., 2021	Korea	May 2011–May 2019	Cohort, retrospective	22	MRI	Adenomyomectomy, antenatal follow-up with strict protocol
Sun et al., 2021	China	January 2015–July 2018	Cohort, not reported if prospective or retrospective	52	MRI	Laparoscopic adenomyomectomy + insertion of LNG IUS
Sun et al., 2020	China	June 2012–August 2014	Cohort, not reported if prospective or retrospective	90	TVUS + MRI + Ca125	‘Major uterine wall resection and reconstruction of the uterus’ (MURU) + LNG-IUS
Lin et al., 2020	China	October 2015–October 2017	Prospective randomized parallel controlled trial	133 (68/65)	Ultrasound + MRI	Transcutaneous microwave ablation
						Percutaneous radiofrequency ablation
Li et al., 2020	China	January 2012–January 2017	Retrospective open, non-randomized, controlled trial	193 (57/83/53)	TVUS	Open adenomyomectomy
						Open adenomyomectomy + 6 months GnRH-a
						Open adenomyomectomy + 6 months GnRH-a + LNG IUS
Huang et al., 2020	China	January 2012–January 2017	Retrospective non-randomized controlled trial	93 (50/43)	TVUS	HIFU + GnRH-a for 4–6 months
						Adenomyomectomy + GnRH-a for 4–6 months
Yang et al., 2019	China	August 2015–November 2017	Cohort prospective	466	MRI + TVUS	HIFU + GnRH-a for 3 months + LNG IUS
Lee et al., 2019	Korea	February 2010–October 2017	Cohort retrospective	889	MRI + TVUS	HIFU
Jun-Min et al., 2018	China	January 2012–December 2014	Cohort, retrospective	198	MRI + TVUS	U-shaped myometrial excavation and modified suture approach
Li et al., 2018	China	February 2015–February 2016	Prospective, nonrandomized, parallel-controlled study	200 (40/40/40/40/20/20)	TVUS	Group 1: 3.75 mg GnRH-a	Group 2: 1.88 mg GnRH-a	Group 3: LNG IUS
						Group 4: 3.75 mg GnRH-a + LNG IUS	Group 5: 1.88 mg GnRH-a + LNG IUS	Group 6: San-Jie-Zhen-Tong capsules
Guo et al., 2018	China	January 2013–January 2015	Cohort retrospective	78 (45/15/18)	MRI + TVUS	HIFU only
						HIFU + LNG IUS
						HIFU + GnRH-a
Alizzi, 2018	Iraq	January 2016–January 2018	Cohort prospective	32	TVUS + clinical symptoms	GnRH-a every 28 days until uterine volume <150 cm, then LNG IUS.
Yang et al., 2017	China	January 2019–December 2013	Cohort prospective	112 (56/56)	TVUS and/or MRI	Laparoscopic uterine artery occlusion and partial adenomyomectomy + laparoscopic uterine pelvic plexus ablation
						Laparoscopic uterine artery occlusion and partial adenomyomectomy only
Osuga et al., 2017	Japan	August 2014–June 2015	Randomized, double-blind, multicentre, placebo-controlled phase III study	68 (35/33)	TVUS + MRI	Dienogest twice daily for 16 weeks, starting between the second and fifth day of the menstrual cycle, analgetic if needed
						Placebo twice daily for 16 weeks, starting between the second and fifth day of the menstrual cycle, analgetic if needed
Liu et al., 2017	China	January 2012–December 2016	Cohort retrospective	368 (66/302)	TVUS or MRI	HIFU
						Abdominal hysterectomy
Huang et al., 2017	China	January 2011–August 2015	Cohort retrospective	102	MRI	MR-HIFU alone
						MR HIFU + exercise
Hai et al., 2017	China	January 2013–October 2015	Cohort retrospective	87	MRI + TVUS + biopsy in some	Ultrasound-guided transcervical radiofrequency ablation
Park et al., 2016	Korea	February 2010–December 2014	Cohort retrospective	192	TVUS	HIFU
Liu et al., 2016	China	January 2007–December 2013	Cohort retrospective	230	MRI	HIFU
Chong et al., 2016	Korea	August 2008–May 2011	Cohort prospective	33	TVUS + MRI	Laparoscopic or robotic adenomyomectomy with uterine artery ligation
						N = 18 (random) GnRH-a additionally
Long et al. 2015	China	January 2012–December 2012	Cohort prospective	51	MRI	HIFU
Lee et al., 2015	Korea	February 2010–October 2013	Cohort retrospective	346	TVUS + MRI	HIFU
Huang et al., 2015	China	March 2011–February 2014	Cohort prospective (patient chose group)	94 (48/46)	MRI + TVUS	Adenomyomectomy, conventional + 6 months GnRH-a
						Adenomyomectomy double flap + 6 months GnRH-a
Zhang et al., 2014	China	November 2010–June 2012	RCT	86 (43/43)	MRI	HIFU + oxytocin injection during HIFU ablation procedure
						HIFU + 0.9% saline injection
Liu et al., 2014	China	July 2003–July 2009	Retrospective cohort	182	TVUS	Bilateral laparoscopic uterine artery occlusion + adenomyomectomy
Ekin et al., 2013	Turkey	January 2012–December 2012	Cohort prospective	70	TVUS	LNG IUS
Kelekci et al., 2012	Turkey	March 2006–May 2009	Prospective, open, nonrandomized	74 (23/25/26)	TVUS	LNG IUS (patients with adenomyosis)
						LNG IUS (patients without adenomyosis)
						Copper intrauterine device (patients without adenomyosis)
Zhou et al., 2011	China	March 2007–September 2008	Cohort prospective	78	MRI	HIFU
Ozdegirmenci et al., 2011	Turkey	April 2007–February 2009	RCT	75 (43/32)	TVUS + MRI	LNG IUS
						Abdominal hysterectomy
Kang et al., 2010	China	January 2005–June 2007	Randomized prospective observational	70	MRI or TVUS	‘4-dose regimen’ (triptorelin 3.75 mg by intramuscular injection every 6 weeks for a total of 4 doses)
						Conventional regimen (1 injection every 4 weeks for a total of 6 doses).
Sheng et al., 2009	China	NR	Prospective cohort	94	TVUS	LNG IUS
Kang et al., 2009	China	July 2003–October 2005	Retrospective cohort study	37	TVUS + clinical symptoms	Laparoscopic adenomyosis resection + uterine artery occlusion
Cho et al., 2008	Korea	July 2003–March 2007	Cohort prospective	47	TVUS	LNG IUS
Kim et al., 2007	Korea	1998–2000	Cohort prospective	54	MRI	Uterine artery embolization
Bragheto et al., 2007	Brazil	NR	Cohort prospective	29	MRI	LNG IUS
Hadisaputra and Anggraeni, 2006	Indonesia	June 2003–June 2004	Randomized controlled trial	20 (10/10)	TVUS	Laparoscopic resection + GnRH-a for 3 months
						Laparoscopic myolysis + GnRH-a for 3 months
Maia et al., 2003	Brazil	NR	Cohort retrospective	95 (53/42)	TVUS	Transcervical endometrial resection + LNG IUS
						Transcervical endometrial resection
Fedele et al., 1997	Italy	NR	Cohort prospective	25	TVUS or MRI	LNG IUS

GnRH-a, gonadotropin-releasing hormone analogue; HIFU, high-intensity focused ultrasound; LNG IUS, levonorgestrel-releasing intrauterine system; TVUS, transvaginal ultrasound.

Study characteristics

We included 38 trials, reporting on data from 5175 women (Table I) (Fedele et al., 1997; Maia et al., 2003; Hadisaputra and Anggraeni, 2006; Bragheto et al., 2007; Kim et al., 2007; Cho et al., 2008; Kang et al., 2009; Sheng et al., 2009; Kang et al., 2010; Ozdegirmenci et al., 2011; Zhou et al., 2011; Kelekci et al., 2012; Ekin et al., 2013; Liu et al., 2014; Zhang et al., 2014; Huang et al., 2015; Lee et al., 2015, 2019; Long et al., 2015; Chong et al., 2016; Liu et al., 2016; Park et al., 2016; Hai et al., 2017; Huang et al., 2017; Liu et al., 2017; Osuga et al., 2017; Yang et al., 2017, 2019; Alizzi, 2018; Guo et al., 2018; Jun-Min et al., 2018; Li et al., 2018, 2020; Huang et al., 2020; Lin et al., 2020; Sun et al., 2020; Kwack et al., 2021; Sun et al., 2021). There were six (16%) randomized controlled trials (RCTs) (Hadisaputra and Anggraeni, 2006; Kang et al., 2010; Ozdegirmenci et al., 2011; Zhang et al., 2014; Osuga et al., 2017; Lin et al., 2020); 13 studies (34%) were prospective, non-randomized trials, of which nine had cohorts with a single arm (Fedele et al., 1997; Bragheto et al., 2007; Kim et al., 2007; Cho et al., 2008; Sheng et al., 2009; Zhou et al., 2011; Ekin et al., 2013; Alizzi, 2018; Yang et al., 2019) and four studies had two or more arms (Kelekci et al., 2012; Huang et al., 2015; Yang et al., 2017; Li et al., 2018). There were 17 (45%) retrospective cohort studies, 12 with a single arm (Kang et al., 2009; Liu et al., 2014, 2016; Lee et al., 2015, 2019; Long et al., 2015; Chong et al., 2016; Park et al., 2016; Hai et al., 2017; Huang et al., 2017; Jun-Min et al., 2018; Kwack et al., 2021) and five with two or more arms (Maia et al., 2003; Liu et al., 2017; Guo et al., 2018; Huang et al., 2020; Li et al., 2020). Two studies with a single cohort did not specify if the cohort was retrospective or prospective (Sun et al., 2020, 2021).

Only five studies had a low risk of bias (Ozdegirmenci et al., 2011; Zhang et al., 2014; Osuga et al., 2017; Yang et al., 2017; Lin et al., 2020) with all the other studies having an unclear or high risk of bias in at least one domain (Supplementary Data S2). Common concerns in terms of risk of bias were the retrospective nature of the studies, unclear representativeness of participants, the lack of control groups, and lack of randomization.

The majority of the 38 studies (84%) were conducted in Asia, of which 22 (58%) were from China (Fig. 2).

Figure 2.

World map with an overview over the countries of origin for the included studies.

Ten different interventions, alone or in combination, were described in at least one arm (Table I).

Outcomes

We identified 203 outcomes in 29 domains, including 41 complications or adverse outcomes (Table II and Supplementary Data S3). Table III shows which studies measured the most frequent outcomes.

Table II.

Number of outcomes reported, classified by core area and outcome domain.

Core area Outcome domain	Number of outcomes in this domain/of those harms
Physiological/clinical
Blood and lymphatic system outcomes	5/0
Cardiac outcomes	2/2
Endocrine outcomes	7/4
Gastrointestinal outcomes	4/4
General outcomes	12/3
Infection and infestation outcomes	2/2
Injury and poisoning outcomes	1/1
Musculoskeletal and connective tissue outcomes	2/2
Outcomes relating to neoplasms: benign, malignant and unspecified (including cysts and polyps)	1/1
Nervous system outcomes	4/4
Pregnancy, puerperium and perinatal outcomes	17/0
Renal and urinary outcomes	12/4
Reproductive system and breast outcomes	28/2
Psychiatric outcomes	4/2
Skin and subcutaneous tissue outcomes	2/2
Vascular outcomes	3/2
Life impact
Physical functioning	24/0
Social functioning	5/0
Role functioning	6/0
Emotional functioning/wellbeing	32/0
Cognitive functioning	2/0
Global quality of life	1/0
Perceived health status	5/0
Delivery of care	15/2
Personal circumstances	4/0
Resource use
Economic	2/1
Hospital	1/0
Need for further intervention	2/2
Adverse events
Adverse events/effects	1/1
Total *	203/41

^*Outcomes could be classified in several domains but are counted once in the total. All individual outcomes are reported in Supplementary Data S3.

Table III.

Outcome reporting and outcome quality scores in adenomyosis trials.

First author, year of publication	Dysmenor rhoea	Menstrual blood volume	Uterine volume	Lesion volume	Quality of life	Sexual (dys) function	Urinary symptoms	Pelvic pain	Adverse outcomes with classification	Adverse outcomes, unstructured	Pregnancy outcomes	Outcome quality score
Kwack et al., 2021										x	x	3
Sun et al., 2021	x	x	x							x		4
Sun et al., 2020	x	x	x							x		3
Lin et al., 2020	x		x	x			x		x			4
Li et al., 2020	x		x							x	x	5
Huang et al., 2020	x	x	x		x	x	x			x	x	4
Yang et al., 2019	x	x	x									4
Lee et al., 2019		x	x		x	x	x			x		3
Jun-Min et al., 2018	x	x	x							x	x	2
Li et al., 2018	x	x	x						x			2
Guo et al., 2018	x	x	x	x						x	x	2
Alizzi, 2018	x	x	x							x		2
Yang et al., 2017	x	x	x				x			x		4
Osuga et al., 2017			x		x	x		x	x			6
Liu et al., 2017	x	x	x	x	x					x		0
Huang et al., 2017	x		x									2
Hai et al., 2017	x	x	x	x			x		x			2
Park et al., 2016			x	x								1
Liu et al., 2016	x								x			2
Chong et al., 2016	x	x	x							x		3
Long et al. 2015	x	x		x		x	x			x		3
Lee et al., 2015		x	x		x	x	x			x	x	3
Huang et al., 2015	x	x	x							x	x	3
Zhang et al., 2014	x	x		x	x	x	x		x			3
Liu et al., 2014	x	x	x		x	x				x		5
Ekin et al., 2013	x	x			x		x					4
Kelekci et al., 2012	x	x								x		6
Zhou et al., 2011	x	x							x			6
Ozdegirmenci et al., 2011		x			x	x				x		6
Kang et al., 2010	x		x							x		4
Sheng et al., 2009	x	x	x							x		6
Kang et al., 2009	x	x	x							x		2
Cho et al., 2008	x	x	x							x		4
Kim et al., 2007	x	x	x								x	5
Bragheto et al., 2007	x	x		x					x			5
Hadisaputra and Anggraeni, 2006	x	x		x				x				3
Maia et al., 2003	x									x		1
Fedele et al., 1997		x	x							x		6
Reported by, n (%)	31 (82)	30 (79)	27 (71)	9 (24)	9 (24)	8 (21)	9 (24)	2 (5)	8 (21)	24 (63)	7 (18)

The mean quality score for the outcomes was 3.5 ± 0.51, with scores of 2, 3 and 4 being equally frequent and accounting for 66% of the studies (Table III). The association between the age of the publication and its quality score was not statistically significantly (P = 0.08).

Only seven (18%) studies had a clearly defined primary outcome (Fedele et al., 1997; Maia et al., 2003; Sheng et al., 2009; Chong et al., 2016; Liu et al., 2017; Osuga et al., 2017; Sun et al., 2021) and 11 (29%) studies stated multiple or all reported outcomes to be the primary (Hadisaputra and Anggraeni, 2006; Bragheto et al., 2007; Kang et al., 2010; Ozdegirmenci et al., 2011; Zhou et al., 2011; Kelekci et al., 2012; Ekin et al., 2013; Liu et al., 2014; Long et al., 2015; Li et al., 2018; Huang et al., 2020). Twenty studies (53%) did not define a primary outcome at all (Kim et al., 2007; Cho et al., 2008; Kang et al., 2009, 2010; Zhang et al., 2014; Huang et al., 2015; Lee et al., 2015, 2019; Liu et al., 2016; Park et al., 2016; Hai et al., 2017; Huang et al., 2017; Yang et al., 2017, 2019; Alizzi, 2018; Guo et al., 2018; Jun-Min et al., 2018; Li et al., 2018; Lin et al., 2020; Sun et al., 2020; Kwack et al., 2021). Most of these studies described the aims in non-specific terms, such as ‘clinical efficiency’, but without defining the terms ‘clinical’ or ‘efficiency’. Most studies did not provide a justification for the chosen outcomes.

Only three (8%) of the studies provided a sample size calculation based on an outcome (Liu et al., 2014; Osuga et al., 2017; Ozdegirmenci et al., 2011), and none of the other 35 studies provided a posthoc estimation of statistical power.

Outcome reporting and outcome measures

The majority of the studies provided an outcome measure for the main outcomes. The most common time points for measuring outcomes were at 3, 6 and 12 months after the intervention, as described in 14 studies (Fedele et al., 1997; Kang et al., 2009; Sheng et al., 2009; Huang et al., 2015; Lee et al., 2015, 2019; Long et al., 2015; Liu et al., 2016; Li et al., 2018; Yang et al., 2019; Lin et al., 2020; Sun et al., 2020). However, only 19 studies reported on all their outcomes at all the predetermined time points according to the described methods. Several studies provided only a visual or summarized outcome reporting for at least one of the outcomes, without values, SD or 95% CI (Maia et al., 2003; Bragheto et al., 2007; Ozdegirmenci et al., 2011; Ekin et al., 2013; Alizzi, 2018).

The various outcome measures and interpretation of the most common outcomes, namely dysmenorrhoea, menstrual volume/menorrhagia and QOL, are presented in Supplementary Data S4. There were 14 different measuring tools and interpretations for dysmenorrhoea, and 17 for menstrual blood loss (Supplementary Data S4). Only a minority of the studies reported how outcome measurement was performed, for example if the patients were instructed to use the Pictorial Blood Loss Assessment Chart (PBLAC), or if questionnaires were filled out by the patient or by the doctor, for example by telephone interview.

Uterine volume was reported as an outcome in 27 (71%) studies (Table III). In most cases, the volume was measured using transvaginal ultrasound. Only three studies reported if the measurement included the cervix and how uterine length was measured. None of the papers provided a clinical justification for this outcome.

Eight (21%) studies followed a classification when registering and reporting adverse events (Zhou et al., 2011; Liu et al., 2016; Hai et al., 2017; Li et al., 2018; Lin et al., 2020), while the others did not report how complications or side effects were registered or reported.

Discussion

In this review, we identified substantial heterogeneity in outcome reporting in studies evaluating interventions for the treatment of adenomyosis-associated symptoms. Only six studies that met the inclusion criteria were RCTs. A small proportion of studies provided a clear primary outcome, or a sample size/power calculation and incomplete outcome reporting was common.

The most frequently reported outcome was dysmenorrhoea, which was reported in 31 (82%) of studies. There were 14 different outcome measures used to assess dysmenorrhoea, with different visual analogue scales being the most frequently used. Most researchers attempted to use validated measuring tools for the main outcomes.

Interpretation

Outcomes identified through this systematic review of published studies reflect outcomes that healthcare professionals or researchers have chosen to select, collect and report. These outcomes are largely focused on menstrual symptoms and uterine volume with only a minority of studies reporting outcomes relating to fertility or QOL.

Dyspareunia, chronic pelvic pain and other pain-related outcomes were measured in very few studies. A review of outcome reporting in endometriosis, a condition which has significant overlap of both patient population and associated symptoms with adenomyosis, reported eight different pain-related outcomes (Hirsch et al., 2016). This difference may be explained by the wider variation in pain symptoms that women with endometriosis may experience.

Patient-centredness is defined by ‘health care which takes into account the preferences and aspirations of individual service users’ and is one of the dimensions of quality of care (World Health Organization, 2006). Focus on outcomes such as satisfaction with the treatment or health-related QOL in clinical studies reflect patient-centredness. These outcomes are important for patients to make informed decisions about different treatment options. However, those type of outcomes were reported infrequently.

Patient-centredness is also reflected in outcomes being important to women, and we assume that dysmenorrhoea and heavy menstrual bleeding are amongst those. These were frequently reported. A challenge is, however, that many of those outcomes are by nature patient-reported and can be difficult to measure and replicate (Magnay et al., 2020). In addition, there is no disease-specific QOL measurement for adenomyosis, which makes the QOL results reported by other tools less reliable for this group of women.

In contrast, imaging outcomes, such as the uterine size, were reported in the majority of the studies. It remains unclear whether this surrogate marker of disease severity is associated with clinical symptoms in women with adenomyosis. This suggests that uterine volume may be an outcome of convenience rather than clinical significance. Similarly, serum levels of CA-125 were commonly reported without a clear clinical justification. The use of these outcomes suggests a lack of patient involvement and input in adenomyosis research.

Reporting fertility and pregnancy outcomes is highly relevant for adenomyosis trials, as many women with adenomyosis find it difficult to fall pregnant. Unfortunately, those outcomes are only reported sporadically. Seemingly random reporting on pregnancies or live birth, as well as leaving it unclear how many women in a study sample tried to get pregnant, possibly augments the effect of certain interventions on fertility outcomes.

The lack of well-designed randomized trials in adenomyosis exacerbates the difficulty in determining which treatments are more effective and better to use.

Outcome reporting variation seen in this study prohibits the combination, comparison, and synthesis of research data into meta-analysis. This limits the ability of research to inform clinical care guidelines and progress the specialty. This variation in outcome reporting may reflect selective outcome reporting and outcome reporting bias. This has been identified to be a major limitation in Cochrane systematic reviews. Following adjustment for outcome reporting bias, 19% of all their reviews would no longer have statistically significant treatment effects while 26% of their reviews would have over-estimated the treatment effects by 20% (Chalmers and Glasziou, 2009). This represents a large area of potentially avoidable research waste. Three key areas of avoidable research waste are related to outcome reporting. These include: important outcomes are not assessed; research studies fail to consider outcomes in the context of previously published research; and over half of all outcomes collected are never reported in the final publication (Chalmers and Glasziou, 2009).

Strengths and limitations

The strengths of this study include its originality, and the robust search strategy and design. The review process was performed by two independent researchers, to prevent bias. This is the first systematic review to describe outcome reporting variation in adenomyosis studies.

This review is not without limitations. We included studies written in English only. Four studies published in Chinese had to be left out, but no further papers were excluded for language reasons. We included studies of differing methodological design, limiting the ability to compare and contrast the study quality.

Most studies were retrospective and had a high risk of bias, which could have influenced the quality and type of reported outcomes. We considered limiting the inclusion criteria to high quality RCTs or prospective observational studies, however this would have limited the number of outcomes and not accurately reflected current outcome reporting.

Recommendations

This review highlights the importance of the recent initiatives to enhance research methodology including the CONSORT statement, the AllTrials initiative and the CROWN initiative. These initiatives aim to ensure that all prospectively registered RCTs are published regardless of their findings, eliminating publication bias from studies that are withheld where there is negative or no effect demonstrated (Song et al., 2010). The development and use of a collection of widely agreed and well-defined outcomes, termed a COS, would help to address selective outcome reporting bias and facilitate the production of comparable data for improved evidence-based patient care. This progressive approach to standardize research methodology is supported by national and international stakeholders. The World Health Organization, the National Institutes of Health and the Cochrane Collaboration are committed to supporting, developing and implementing COSs.

There is a clear and evident need for the development of a COS together with recommendations for uniform outcome measures in adenomyosis research and it is important that people with adenomyosis participate in this process.

This systematic review is the first step in the development of a minimum data set to be selected, collected, and reported in all future clinical trials on adenomyosis. It will be developed by the COSAR initiative with reference to methods described by the COMET initiative (Williamson et al., 2017). The development of a COS for therapeutic interventional studies in adenomyosis research will enhance the quality of adenomyosis research facilitating a more patient-centred approach to care.

Data availability

The data underlying this article are available in the article and in its online supplementary material.

Authors’ roles

Conception of work, study design: T.T., M.O., J.N., M.H., D.J.; Literature search, quality assessment, data extraction: T.T., M.O.; Interpretation of results, drafting of manuscript and approval of final version: T.T., M.O., J.N., M.H., D.J.

Funding

T.T. receives a grant (2020083) from the South Eastern Norwegian Health Authority, which had no influence on study design, data extraction, analysis or interpretation.

Conflict of interest

T.T. receives fees from General Electrics for lectures on ultrasound independently of this project.