Odds and Predictors of Monozygotic Twinning in a Multicentre Cohort of 25,794 IVF Cycles.

The rate of monozygotic twinning (MZT) has seen a gradual increase in recent years. Numerous parameters involved in ART procedures are blamed for this surge, even though the exact explanation is as yet unknown. Our study's objectives were to determine the risk variables for monozygotic twinning after ART and to estimate their prevalence. We examined 25,794 IVF cycles for the incidence of monozygotic twinning in this observational analysis. Our study, which was carried out across seven tertiary IVF centres over the course of four years, found an overall MZT rate of 0.37% per embryo transfer procedure and 0.88% of all pregnancies. Monozygotic twinning was more commonly seen in fresh single-embryo transfer (SET) and blastocyst transfer cycles. Larger multicentre studies are needed to explore the potential risk variables.

Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.

OBJECTIVE: How do numbers of oocytes retrieved per In vitro fertilisation (IVF) cycle impact on the live birth rate (LBR) and multiple gestation pregnancy (MGP) rates? DESIGN: Retrospective observational longitudinal study. SETTING: UK IVF clinics. POPULATION: Non-donor IVF patients. MAIN OUTCOME MEASURES: LBR per IVF cycle and MGP levels against number of oocytes retrieved into subgroups: 0, 1-5, 6-15, 16-25, 26-49 oocytes and 50+ oocytes. Relative risk (RR) and 95% CIs were calculated for each group against the intermediate responder with '6-15 oocytes collected'. RESULTS: From 172 341 attempted fresh oocyte retrieval cycles, the oocyte retrieved was: 0 in 10 148 (5.9%) cycles from 9439 patients; 1-5 oocytes in 42 574 cycles (24.7%); 6-15 oocytes in 91 797 cycles (53.3%); 16-25 oocytes in 23 794 cycles (13.8%); 26-49 oocytes in 3970 cycles (2.3%); ≥50 oocytes in 58 cycles (0.033%). The LBRs for the 1-5, 6-15, 16-25 and 26-49 subgroups of oocytes retrieved were 17.2%, 32.4%, 35.3% and 18.7%, respectively. The RR (95% CI) of live birth in comparison to the intermediate group (6-15) for 1-5, 16-25 and 26-49 groups was 0.53 (0.52 to 0.54), 1.09 (1.07 to 1.11) and 0.58 (0.54 to 0.62), respectively. The corresponding MGP rates and RR were 9.2%, 11.0%, 11.4% and 11.3%, respectively and 0.83 (0.77 to 0.90), 1.04 (0.97 to 1.11) and 1.03 (0.84 to 1.26), respectively. CONCLUSION: There was only limited benefit in LBR beyond the 6-15 oocyte group going to the 16-25 oocytes group, after which there was significant decline in LBR. The MGP risk was lower in 1-5 group.

The prevalence of hyperprolactinaemia in subfertile ovulatory women and its impact on fertility treatment outcome.

Subtle hyperprolactinaemia is not an uncommon finding in ovulatory subfertile women. The objective of this study is to evaluate the prevalence of hyperprolactinaemia in subfertile ovulatory and oligo-anovulatory women, and to determine if hyperprolactinaemia influences fertility treatment outcome. All women (n = 1010) who attended the fertility clinic of a UK tertiary hospital during 2015-2019 were included. Out of 804 eligible women analysed, 575 women (71.5%) were ovulatory and 229 (28.5%) were oligo-anovulatory. Prevalence of hyperprolactinaemia was higher in the ovulatory group than in the oligo-anovulatory group (26.8% vs. 14.4%; OR: 2.2; 95% confidence interval (CI): 1.4-3.2). On sub-group analysis, the prevalence of mild, moderate and severe hyperprolactinaemia was 23.0%, 3.7% and 0.2% in ovulatory women and 11.8%, 1.7% and 0.9% in oligo-anovulatory women. Mild hyperprolactinaemia was found to be more prevalent in the ovulatory group (OR: 2.2; 95%CI: 1.4-3.5). Ongoing pregnancy/livebirth rates were similar between hyperprolactinaemic and normoprolactinaemic women (42.8% vs. 46.7%). Hyperprolactinaemia did not have an impact on ongoing pregnancy/livebirth rates in both ovulatory and oligo-anovulatory women (OR:0.8; 95%CI: 0.5-1.1; OR: 1.2; 95%CI: 0.6-2.5, respectively). Hyperprolactinaemia is prevalent among ovulatory women, although most had mildly raised clinically insignificant levels. Elevated prolactin levels in ovulatory women do not seem to impact on pregnancy outcome. Impact StatementWhat is already known on this subject? Prolactin has been linked to ovulation and fertility. Prolactin testing is not generally recommended for subfertile women with regular menstrual cycles, which is a surrogate marker of ovulation. However, some clinicians, particularly in the general practice, still perform prolactin test as part of baseline endocrine profile.What do the results of this study add? Prevalence of hyperprolactinaemia in subfertile ovulatory women was 26.8% (154/575), of which 86% (132/154) were mild. Further, the livebirth/ongoing pregnancy rates were similar between hyperprolactinaemic and normoprolactinaemic women. Prolactin being a sensitive hormone, responsive to even minimal stress and its high levels not influencing clinical pregnancy outcome, prolactin measurement is not needed in women having regular menstrual cycles.What are the implications of these findings for clinical practice and/or further research? Hyperprolactinaemia was not uncommon in ovulatory women, although most had mildly elevated levels. Hyperprolactinaemia did not have any impact on fertility treatment outcome. Serum prolactin should not be tested in ovulating women, as mild elevations are commonly present and have no clinical significance.

Diagnosis of Congenital Uterine Abnormalities: Practical Considerations.

As most congenital uterine abnormalities are asymptomatic, the majority of them are detected incidentally. While most women with uterine anomalies have a normal reproductive outcome, some may experience adverse reproductive outcomes. Accurate diagnosis and correct classification help in the appropriate counselling of women about their potential reproductive prognosis and risks and for planning any intervention. Evaluation of the internal and external contours of the uterus is the key in making a diagnosis and correctly classifying a uterine anomaly. Considering this, the gold standard test has been the combined laparoscopy and hysteroscopy historically, albeit invasive. However, 3D ultrasound has now become the diagnostic modality of choice for uterine anomalies due to its high degree of diagnostic accuracy, less invasive nature and it being comparatively less expensive. While 2D ultrasound and HSG are adequate for screening for uterine anomalies, MRI and combined laparoscopy and hysteroscopy are reserved for diagnosing complex Mullerian anomalies. Imaging for renal anomalies is recommended if a uterine anomaly is diagnosed.

Frozen Blastocyst Embryo Transfer: Comparison of Protocols and Factors Influencing Outcome.

BACKGROUND: Various factors, including treatment protocols, can influence the outcomes of frozen embryo transfers (FETs). The study objectives were to compare different endometrial preparation protocols of FET cycles and to evaluate the factors, including the endometrial thickness (ET), that affect outcomes. METHODS: This observational cohort study involved 5037 women undergoing FETs at eight tertiary clinics in the UK between January 2016 and March 2019. The endometrial preparation protocols used were natural cycle (NC-FETs), artificial hormone support cycle with oestradiol valerate but without pituitary downregulation (AC-FETs) and artificial hormone support cycle with agonist downregulation (ACDR-FETs). RESULTS: The mean (±SD) ages across NC-FET, AC-FET and ACDR-FET groups were 36.5 (±4.2), 35.9 (±5.0) and 36.4(±4.9) years, respectively. LBRs were comparable (40.7%, 175/430; 36.8%, 986/2658; and 36.7%, 716/1949, respectively) across the three groups. Clinical pregnancy, implantation, multiple pregnancies, miscarriage and ectopic pregnancy rates were also similar. In the regression analysis of variables including age, duration of infertility, number of embryos transferred, protocol type and endometrial thickness, age was the only significant predictor of LBRs, although its predictive ability was poor (AUC: 0.55). With the overall LBR of the study population being 37.1%, the post-test probability of a live birth at an ET of <5 mm was 0%, and at 5-5.9, 6-6.9, 7-7.9 and 8-8.9 mm, the probabilities were 16.7%, 33.8%, 36.7% and 37.7%, respectively. The LBR remained above 35% up to the 14-14.9 mm range and then declined gradually to 23% for the 17-25 mm range. CONCLUSIONS: The FET outcomes were similar for the three protocols used for endometrial preparation. The protocol type and endometrial thickness were not predictive of FET outcomes; age was the only predictive variable, despite its low predictive ability.

Effect of endometrial scratching on unassisted conception for unexplained infertility: a randomized controlled trial.

OBJECTIVE: To investigate whether endometrial scratching increases the chance of live birth in women with unexplained infertility attempting to conceive without assisted reproductive technology. DESIGN: Randomized, placebo-controlled, participant-blind, multicenter international trial. SETTING: Fertility clinics. PATIENT(S): Women with a diagnosis of unexplained infertility trying to conceive without assistance. INTERVENTION(S): Participants were randomly assigned to receive an endometrial biopsy or a placebo procedure (placement of a biopsy catheter in the posterior fornix, without inserting it into the external cervical os). Both groups performed regular unprotected intercourse with the intention of conceiving over three consecutive study cycles. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. RESULT(S): A total of 220 women underwent randomization. The live birth rate was 9% (10 of 113 women) in the endometrial-scratch group and 7% (7 of 107 women) in the control group (adjusted OR, 1.39; 95% CI, 0.50-4.03). There were no differences between the groups in the secondary outcomes of clinical pregnancy, viable pregnancy, ongoing pregnancy, and miscarriage. Endometrial scratching was associated with a higher pain score on a 10-point scale (adjusted mean difference, 3.07; 95% CI, 2.53-3.60). CONCLUSION(S): This trial did not find evidence that endometrial scratching improves the live birth rate in women with unexplained infertility trying to conceive without assistance. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12614000656639.

Global inequality in sub-fertility treatment needs safer, cost effective, evidence-based and economically viable choices for patients and stakeholders.

The global increase in subfertility diagnosis and treatments and the rise of private equity investors concentrating on high profits based on in vitro fertilisation (IVF) treatments raise profound societal and economic questions for stakeholders and patients. The question remains as to whose benefits will ultimately be greater when promoting high margins treatment options resulting from cross-border mergers and acquisitions of IVF clinics.This paper covers wide-ranging issues from the erroneously constructed UK National Institute for Health and Care Excellence's (NICE) guidelines on treatment choices, the cost-effectiveness of treatments, the promotion of IVF, and add-ons where evidence remains minimal, the commercial size of the fertility industry. Investment in improving intrauterine insemination (IUI) success rates has understandably been avoided for its short-term impact on the IVF industry. However, IUI efficiency would cut across many of the global subfertility treatment economic and access problems while allowing stakeholder, feepaying, and patients financial savings will likely allow for more funded IVF cycles in acutely deserving cases. The recommendations will help expand choices for globally economically challenged patients' and services while enhancing an ethical and moral dimension towards fertility treatment choices for patients and stakeholders.

A randomized trial of endometrial scratching in women with PCOS undergoing ovulation induction cycles.

RESEARCH QUESTION: Does endometrial scratching improve the chance of a live birth in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction and trying to conceive? DESIGN: An international, multicentre, randomized, sham-controlled trial across six fertility clinics in three countries (New Zealand, UK and Brazil). Women with a diagnosis of PCOS who were planning to commence ovulation induction cycles (at least three cycles) in order to conceive were randomly assigned to receive the pipelle (scratch) procedure or a sham (placebo) procedure in the first cycle of ovulation induction. Women kept a diary of ovulation induction and sexual intercourse timing over three consecutive cycles and pregnancies were followed up to live birth. Primary outcome was live birth and secondary outcomes were clinical pregnancy, ongoing pregnancy, multiple pregnancy, adverse pregnancy outcomes, neonatal outcomes, bleeding following procedure and pain score following procedure. RESULTS: A total of 117 women were randomized; 58 to the scratch group and 59 to the sham group. Live birth occurred in 11 (19%) women in the scratch group and 14 (24%) in the sham group (odds ratio 0.76, 95% confidence interval [CI] 0.30-1.92). Secondary outcomes were similar in each group. Significantly higher pain scores were reported in the scratch group (adjusted mean difference 3.2, 95% CI 2.5-3.9) when measured on a visual analogue scale. CONCLUSION: No difference was detected in live birth rate for women with PCOS who received an endometrial scratch when trying to conceive using ovulation induction; however, uncertainty remains due to the small sample size in this study.

The Use of Androgen Priming in Women with Reduced Ovarian Reserve Undergoing Assisted Reproductive Technology.

Androgen priming with either dehydroepiandrosterone (DHEA) or testosterone has been suggested as an adjunct to improve in vitro fertilization (IVF) outcomes in women with diminished ovarian reserve (DOR). Numerous studies have investigated the effects of both DHEA and testosterone on IVF outcome. The results were inconsistent, and the quality of most studies is substandard. Meta-analyses have consistently reported that DHEA does appear to significantly improve IVF outcome in women with predicted or proven poor ovarian response (POR), but these have included some normal responders and/or nonrandomized studies. Our meta-analyses including randomized controlled trials (RCTs) incorporating only women with DOR or POR suggest that DHEA confers no benefit. While meta-analyses of RCTs on the use of testosterone in women with DOR or POR showed an improved IVF outcome, most studies included are of low quality with high risk of bias. When analysis of data from studies of only low-risk bias was performed, such a benefit with testosterone was not observed. Although recruitment may well be a challenge, a large, well-designed RCT is, however, still warranted to investigate whether or not androgen priming with either DHEA or testosterone should be recommended as an adjuvant treatment for women with DOR or POR undergoing IVF.

Evaluating the influence of progesterone concentration and time of exposure on in vitro endometrial decidualisation.

This study aimed to evaluate the influence of progesterone (concentration and time of exposure) on endometrial decidualisation using an in vitro model cell line: Human Endometrial Stromal Cells (HESCs). HESCs exposed to progesterone (1 and 10 µM) had higher percentages of decidualised cells and higher expression of the decidual marker (Insulin Like Growth Factor Binding Protein 1 (IGFBP1)) compared with those exposed to (0.1 µM). Among those HESCs cultured with 1 µM progesterone for 11 days, the highest rate of morphological differentiation (40-50%) occurred between days 7-9 and IGFBP1 peaked on day 7. The cell-cycle pathway was significantly down-regulated in HESCs exposed to at least 1 µM progesterone regardless of the incubation period. We conclude that exposure to high progesterone concentration for 7-9 days is essential to maximise the process of decidualisation.

Suboptimal mid-luteal progesterone concentrations are associated with aberrant endometrial gene expression, potentially resulting in implantation failure.

RESEARCH QUESTION: What is the difference in endometrial transcriptomics between women with normal and with low mid-luteal progesterone during the implantation window? DESIGN: An endometrial biopsy and serum progesterone concentration were taken from participants during the mid-luteal phase (LH+7 to LH+9). A total of 12 participants were recruited and categorized into two groups based on their progesterone concentrations: normal progesterone (>15 ng/ml, n = 6) and low progesterone (<15 ng/ml, n = 6). Global endometrial gene expression between the two groups was compared by microarray techniques. Principal component analysis was used to display the gene's expression pattern. Pathway and gene ontology enrichment analysis were performed to determine the biological mechanism of progesterone on the endometrium. RESULTS: Several key genes related to endometrial receptivity were found to be regulated by progesterone. With regard to gene ontology and pathway analysis, progesterone was shown to be mainly involved in structure morphogenesis predominantly during a process of decidualization, extracellular matrix-receptor interaction and cell adhesion. Distinct differences were observed in the transcriptomic profiles between the two groups, indicating potential impairment of endometrial receptivity in women with suboptimal progesterone concentrations. There was a relatively similar pattern of gene expression between endometrial samples with progesterone concentrations approximately 10 ng/ml and >15 ng/ml. Thus, a progesterone concentration of between 10 and 15 ng/ml appears to be sufficient to induce endometrial receptivity. CONCLUSIONS: Abnormally low progesterone below the threshold of 10-15 ng/ml during the implantation window results in aberrant endometrial gene expression that may affect implantation potential.

A comparative evaluation of subendometrial and intrauterine platelet-rich plasma treatment for women with recurrent implantation failure.

OBJECTIVE: To compare the effectiveness of treatment with autologous activated platelet-rich plasma (PRP), administered to either the subendometrium (SE-PRP) or endometrial surface (intrauterine; IU-PRP), against controls. DESIGN: Prospective observational cohort study. SETTING: Tertiary fertility unit. PATIENTS: Women aged <40 years with a history of recurrent implantation failure undergoing frozen embryo transfer (FET) (n = 318). INTERVENTIONS: In SE-PRP, PRP was injected into the subendometrial space transvaginally in the luteal phase of the previous cycle of embryo transfer under ultrasound guidance (n = 55). In IU-PRP, PRP was administered during the index FET cycle when the endometrium was approximately 7 mm (n = 109). Both SE-PRP and IU-PRP groups were administered 300 µg of granulocyte colony-stimulating factor (G-CSF) subcutaneously once a day for 3 days to boost white blood cells (WBC) and growth factor production in the PRP sample. The control group consisted of women who did not choose PRP treatment and underwent standard FET with no intervention (n = 154). MAIN OUTCOME MEASURES: Ongoing pregnancy rate or live birth rate (OPR/LBR) per transfer cycle, clinical pregnancy rate (CPR) per transfer cycle, and miscarriage rate. RESULTS: As a result, OPR/LBR was higher in the SE-PRP (22/55, 40%) and IU-PRP (45/109, 41.3%) groups than that in the control group (34/154, 22.1%). It was similar between the SE-PRP and IU-PRP groups. Moreover, CPR showed a similar trend with a higher rate in the SE-PRP (28/55, 51%) and IU-PRP (57/109, 52.3%) groups than that in the controls (52/154, 33.8%). No statistical difference in the CPR was noted between the SE-PRP and IU-PRP groups. The miscarriage rate was similar in all three groups (14/55, 25.45%; 25/109, 22.23%; and 34/154, 22.07%, respectively). CONCLUSION: In women with a history of recurrent implantation failure, PRP treatment appears to improve FET outcome with an increase in OPR/LBR. However, SE-PRP treatment does not offer any advantage over lesser invasive IU-PRP treatment.

Observational retrospective study of UK national success, risks and costs for 319,105 IVF/ICSI and 30,669 IUI treatment cycles.

OBJECTIVE: To compare success rates, associated risks and cost-effectiveness between intrauterine insemination (IUI) and in vitro fertilisation (IVF). DESIGN: Retrospective observational study. SETTING: The UK from 2012 to 2016. PARTICIPANTS: Data from Human Fertilisation and Embryology Authority's freedom of information request for 2012-2016 for IVF/ICSI (intracytoplasmic sperm injection)and IUI as practiced in 319 105 IVF/ICSI and 30 669 IUI cycles. Direct-cost calculations for maternal and neonatal expenditure per live birth (LB) was constructed using the cost of multiple birth model, with inflation-adjusted Bank of England index-linked data. A second direct-cost analysis evaluating the incremental cost-effective ratio (ICER) was modelled using the 2016 national mean (baseline) IVF and IUI success rates. OUTCOME MEASURES: LB, risks from IVF and IUI, and costs to gain 1 LB. RESULTS: This largest comprehensive analysis integrating success, risks and costs at a national level shows IUI is safer and more cost-effective than IVF treatment.IVF LB/cycle success was significantly better than IUI at 26.96% versus 11.49% (p<0.001) but the IUI success is much closer to IVF at 2.35:1, than previously considered. IVF remains a significant source of multiple gestation pregnancy (MGP) compared with IUI (RR (Relative Risk): 1.45 (1.31 to 1.60), p<0.001) as was the rate of twins (RR: 1.58, p<0.001).In 2016, IVF maternal and neonatal cost was £115 082 017 compared with £2 940 196 for IUI and this MGP-related perinatal cost is absorbed by the National Health Services. At baseline tariffs and success rates IUI was £42 558 cheaper than IVF to deliver 1LB with enhanced benefits with small improvements in IUI. Reliable levels of IVF-related MGP, OHSS (ovarian hyperstimulation syndrome), fetal reductions and terminations are revealed. CONCLUSION: IUI success rates are much closer to IVF than previously reported, more cost-effective in delivering 1 LB, and associated with lower risk of complications for maternal and neonatal complications. It is prudent to offer IUI before IVF nationally.

The strength of evidence supporting luteal phase progestogen after assisted reproduction: A systematic review with reference to trial registration and pre-specified endpoints.

OBJECTIVE: To measure the potential for outcome switching and selective reporting, in trials of luteal phase progestogen in assisted reproduction. STUDY DESIGN: Trials identified through Medline and Embase in August 2017 using the MeSH term "assisted reproductive technology, luteal phase support" and associated text words. Randomised controlled trials (RCTs) comparing progestogen of any type, dose, and route of administration, with placebo or no treatment as luteal phase support in subfertile women undergoing in vitro fertilization (IVF) or intrauterine insemination (IUI). Eight trials after IVF and eleven after IUI, involving 1040 and 2764 participants respectively, were included. RESULTS: None of the eight trials of progestogen therapy after IVF had been registered. Only 5/11 trials of progestogen after IUI had been registered, and only two of these prospectively. One of these had a registered primary outcome of "pregnancy sac plus heartbeat", but reported "pregnancy sac alone"; we judged this as an altered primary outcome. Three other trial had a registered primary outcome of "clinical pregnancy undefined" and reported "intra or extra-uterine pregnancy with a heartbeat"; we judged this alteration as minimal. That trial was negative. Overall, 26 different outcomes had been reported by the various trials. The three outcomes reported most often were pregnancy undefined (9/19), miscarriage (11/19) and clinical pregnancy (9/19). This suggests considerable potential for selective outcome reporting or outcome switching. CONCLUSION: Apart from one negative trial, none of the evidence on luteal phase progestogen after assisted reproduction comes from prospectively registered trials: a slender reed indeed.

Ultrasound guidance in reproductive surgery.

Ultrasound plays a key role in diagnosis and guidance in reproductive medicine and surgery. In the field of reproductive surgery, some of the interventions, especially intrauterine procedures, are regularly conducted without imaging guidance but instead performed based on clinical skills and experience alone. Operative real-time US provides concurrent visualisation of the structures, contents and planes and operating instruments and, therefore, has the potential to improve efficacy and safety of the operative interventions. Ultrasound should be used in our operating theatres more often to guide various intrauterine procedures to reduce the intra-operative risks and complications including uterine perforations and visceral injury. The use of ultrasound necessitates an additional assistant experienced in ultrasound in the theatre, but regular use of ultrasound improves the training opportunities of the trainees and clinicians.

Aetiology of recurrent miscarriage and the role of adjuvant treatment in its management: a retrospective cohort review.

We conducted a retrospective review into the role of commonly prescribed conventional adjuvant treatments in improving live birth rates after recurrent miscarriage (RM). Data from 301 couples attending the RM clinic in two Tertiary teaching hospitals were analysed with their live birth rate following a further pregnancy and a prevalence of conditions investigated in RM being the main outcomes measured. We found that 26% of women had explained RM and 74% had unexplained RM. Adjuvant versus conservative management did not improve the live birth rates in those with unexplained RM (68.4% vs. 76.6%, respectively; p = .28). The prevalence of anti-phospholipid syndrome, inherited thrombophilia, thyroid disease, parental karyotype abnormalities and structural uterine abnormalities were 7.4%, 4.5%, 6.6%, 2.9% and 6.6%, respectively. In conclusion, empirical adjuvant treatment for the management of women with unexplained RM does not appear to offer any benefit as they have a good prognosis with early pregnancy support alone. Impact statement What is already known on this subject? Does the adjuvant treatment in the management of unexplained recurrent miscarriage (RM) improve successful pregnancy outcomes? High-quality data regarding the management and outcomes of RM is very limited, with many clinicians prescribing adjuvant treatments for unexplained RM with very little good quality evidence of their benefit or risk. What do the results of this study add? We carried out a retrospective cohort study of all patients attending a recurrent miscarriage clinic over a two-year period at specialist clinics in two tertiary referral centres to evaluate the prevalence of associated diseases, the treatments given and the outcomes in subsequent pregnancies. This study will help clinicians counsel their patients about management options in RM and help them reassure their patients that the prognosis with conservative management alone is good. This will help to avoid any unnecessary use of adjuvant treatment and its associated risks and cost. What are the implications of these findings for clinical practice and/or further research? This study demonstrates that adjuvant treatments in unexplained RM have no significant benefit on future live birth rates. Despite this finding, high quality, prospective, randomised controlled trials looking at both adverse outcomes and benefits of adjuvant treatment in RM are needed.