Intervention(s) Results primary outcome Results secondary and other outcomes

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1 Uitgangsvraag 1: evidence tables Wat is de sensitiviteit, specificiteit, positief voorspellende waarde, negatief voorspellende waarde en haalbaarheid van MRI naast mammografie in plaats van alleen mammografie bij vrouwen met een verhoogd risico op mammacarcinoom op grond van familiaire belasting? Systematic reviews Study other outcomes Critical appraisal of review Granad er, Academ ic Radiolo gy Warner, Ann Int Med Design: systematic review not stated Search date: August 2007 Searched databases: MEDLINE, EBM Reviews, ACP Journal Club, Cochrane Database MEDSEARCH, and SCOPUS Included study designs: diagnostic accuracy studies Number of included studies: 8 Design: systematic review Program in Evidencebased Care, of Care Ontario Search date: September 2007 Searched databases: Medline, Embase and Cochrane Central Included study designs: prospective diagnostic accuracy studies Number of included studies: 11 Asymptomatic women at increased risk of breast cancer: BRCA 1/2 mutation carriers or strong family histories : not clearly stated prospective studies, MRI + mammography, with or without ultrasonography and clinical breast examination, to screen women at very high risk for breast cancer : Women at high risk for breast cancer: known mutation in BRCA1, BRCA2, or another gene associated with Index test(s): MRI, mammography and MRI+mammography pathology Index test(s): MRI, mammography and MRI + mammography pathology although not defined in advance detection rate: MRI alone: ( ) Mammography alone: ( ) Combination of MRI and mammography: ( ) Sensitivity MRI alone: ( ) Mammography alone: ( ) Combination of MRI and mammography: ( ) False positive rate: MRI alone: ( ) Mammography alone: ( ) Combination of MRI and mammography: ( ) OR: o BIRADS 3: MRI: 18.3 ( ) Mammography: 14.7 ( ) MRI + mammography: 45.9 ( ) o BIRADS 4: MRI: 88.7 ( ) Mammography: 38.5 ( ) MRI + mammography: ( ) o BIRADS 3: MRI: 77 (70 84) Mammography: 39 (37 41) MRI + mammography: 94 (90 97) Individual studies: MRI: % Mammography: 23-50% MRI + mammography: % Specificity: MRI: 79-98% Mammography: % MRI + mammography: 72-96% PPV: MRI: 3-67% Mammography: 6-89% MRI + mammography: 3-43% Individual studies: MRI % Mammography 14-59% MRI + mammography % Specificity: MRI 75-98% Mammography % MRI + mammography 73-96% PPV: MRI 7-79% Mammography 8-100% MRI + mammography 7-79% Level of evidence: A2 Results critical appraisal : o Per lesion analyses o Only positive results were verified o Large heterogeneity between studies (I2 >90% in 5/12 analyses) Includes: o Leach MO, Lancet 2005 o Kuhl CK, J Clin Oncol 2005 o Kriege M, Breast Res Treat 2006 o Stoutjesdijk MJ, J Natl Inst 2001 o Lehman CD, 2005 o Lehman CD, Radiology 2007 o Warner E, J Clin Oncol 2001 o Warner E, JAMA 2004 Level of evidence: A2 Results critical appraisal ; English language only, verification unclear, probably only verification of positive screening tests, unit of analysis?, heterogeneity among studies Included studies; o Kuhl CK, J Clin Oncol o Kriege M, N Engl J Med o Leach Lancet o Warner, J Clin Oncol o Warner JAMA o Trecate Tumori o Hartman o Lehman o Sardanelli Radiology o Lehman Radiology 2007

2 other outcomes Critical appraisal of review Lord Eur J Design: systematic review Department of Health and Ageing, Commonwealth of Australia Search date: March 2007 Searched databases: Medline, Pre-Medline, Embase, Cochrane, HTA websites Included study designs: diagnostic accuracy studies or comparative studies Number of included studies: 5 hereditary breast cancer; untested first-degree relative of a person with such a gene mutation; or having a family history consistent with a hereditary breast cancer syndrome, atypical or lobular carcinoma in situ on previous biopsy, or radiation therapy to chest (before age 30 years and at least 8 years previously) studies evaluating the addition of MRI to mammography with or without ultrasound and : asymptomatic high-risk women Index test(s): MRI vs mammography with or without US and histology for positive index tests and consensus of all tests for negative index tests o BIRADS 4: MRI: 75 (62 88) Mammography: 32 (23 41) MRI + mammography: 84 (70 97) Specificity: o BIRADS 3: MRI: 86.3 ( ) Mammography: 94.7 ( ) MRI + mammography: 77.2 ( ) o BIRADS 4: MRI: 96.1 ( ) Mammography: 98.5 ( ) MRI + mammography: 95.2 ( ) Sensitivity MRI + mammography: 94% (95%CI 86 98%) Incremental sensitivity o MRI added to mammography: 58% (47 70%) o MRI added to mammography + ultrasound: 44% (27 61%) o MRI added to mammography, ultrasound + 44% (31 33%) Specificity: too heterogeneous - no meta-analysis MRI + conventional tests: % Mammography: 25 59% Mammography + US/: 49 67% Specificity: MRI + conventional testing: 77 96% Additional cancer yield: additional cancers detected by MRI per 1000 screening rounds Recall risk for false-positive results: RR = additional false positive recalls per 1000 screening rounds Benign percutaneous biopsy: RR = 7 46 additional benign biopsies per 1000 screening rounds o Hagen Breast Level of evidence: A2 Results critical appraisal : per patient analysis, statistical heterogeneity taken into account (no pooled specificity) Included studies: o Kuhl CK, J Clin Oncol 2005 o MARIBS study group. Lancet 2005 o Lehman CD, 2005 o Sardanelli F, Radiology o Warner E, JAMA 2004 Benign surgical biopsy: RR 2.0 ( ) = 2 additional benign surgical biopsies per 1000 screening rounds

3 other outcomes Critical appraisal of review Irwig Br J Bermejo -Perez Br J Radiolo gy Design: systematic review Agency for Healthcare Research And Quality Search date: October 2004 Searched databases: Medline, Cochrane and snowballing strategy Included study designs: diagnostic accuracy studies Number of included studies: 4 on MRI Design: systematic review not reported Search date: 2005 inclusive Searched databases: MEDLINE, EMBASE, Cochrane, ClinicalTrials.gov, the National Research Register of the National Health Service, CRD and websites related to the study topic. Included study designs: diagnostic accuracy studies of imaging techniques and surveillance programmes Number of included studies: 12 evaluated new tests in asymptomatic women, including populations considered at higher risk for breast cancer because of genetic predisposition or those in whom mammography may be less accurate because they are younger or have radiologically dense breast tissue. : high risk women studies evaluating the diagnostic performance of any imaging technique performed in the context of a surveillance programme or any programme intended to provide early diagnosis of breast or ovarian cancer : women carrying BRCA1/2 mutations Index test(s): MRI +conventional testing vs conventional testing alone not stated Index test(s): MRI vs mammo or US pathology for technique evaluation, pathology + follow-up for programme evaluation o MRI 100% o Mammography 33-46% False positive rate requiring biopsy: o MRI 5-9% o Mammography 1-7% Diagnostic techniques: o Sensitivity MRI % Mammography 20-50% US < 50% o Specificity MRI % Mammography >96% US> 91% o PPV MRI % Diagnostic surveillance o Sensitivity Programmes including MRI: 83-95% Programmes using MRI only in particular cases: 40-56% Level of evidence: A2 Results critical appraisal : per lesion analysis Included studies: o Kuhl Radiology 2000 o Tilanus-Linthorst Eur J 2000 o Stoutjesdijk J Natl Inst 2001 o Warner J Clin Oncol 2001 Level of evidence: A2 Results critical appraisal : comprehensive literature search and assessment of bias in original studies Included studies: o Warner E, JAMA 2004 o Meijers-Heijboer H, N Engl J Med o Leach MO, Lancet o Kuhl CK, J Clin Oncol o Robson M, Proc Am Soc Clin Oncol 2003 o Stoutjesdijk MJ, J Natl Inst 2001 o Podo F, J Exp Clin Res 2002 o Hartman AR, o Kriege M, N Engl J Med 2004 o Brekelmans CT, J Clin Oncol 2001 o Komenaka IK, 2004 o Scheuer L, J Clin Oncol 2002

4 Observationele studies Study Chereau Clinical Breast Design: comparative non-randomised study none reported Setting: genetic clinic Sample size: 123 Duration: between All new breast cancers among proven BRCA1/2 deleterious mutation carriers A priori patient : BRCA1/2 carriers Group comparability: women in intensively screened group significantly younger, significantly more prior breast cancer and with significantly longer followup; >95% of patients in control group were unaware of BRCA status Intervention(s): intensive screening programme: annual digital mammography, biannual ultrasound and, and annual MRI Comparator(s): annual digital mammography, a biannual ultrasound Median size of the invasive tumour: 6 mm vs. 22 mm (P < ) o pt1: 81% vs. 40% (P = 0.001) o pt2: 0% vs. 39% (P = 0.001) Axillary lymphadenectomy: 43% vs. 68% (P = 0.03) Adjuvant chemotherapy: 43%vs. 86% (P < ) Radiation therapy : 62% vs. 81% (P = 0.05) Hormonal therapy 43% vs. 38% (P = 0.42) 3-year disease-free survival rate 93% vs. 74% (P = 0.1) Level of evidence: A1 Dropouts: not applicable outcome=survival and not mortality, cases included retrospectively, two groups not comparable, confounders were not taken into account Metastasis-free survival rate: 93% vs. 80% (P = 0.2) Schmutzler Eur J Prevention Design: comparative cohort study German Aid Setting: 2 academic centres Sample size: 413 women of whom 49 were BRCA1/2 carriers Duration: 7 years personal history or a history of a relative with breast cancer diagnosed 35 years; a personal history or a history of a relative with ovarian cancer diagnosed 40 years; a personal history or a history of a relative with bilateral breast cancer; a personal history or a history of a relative with both breast and ovarian cancers; a history of at least 2 relatives with breast and/or ovarian cancer, one of whom received a diagnosis 50 years; or a man with a personal history of breast cancer or a history of a male relative with breast cancer. Intervention(s): halfyearly +US and annual mammography + MRI Comparator(s): breast carcinomas in local cancer registry and breast cancers in family members Survival: 100% vs. 84% (P=0.2) detection rates in surveillance programme: o carrier group: 107.2/1000 WY o high-risk group: 45.8/1000 WY o moderate-risk group: 23.9/ 1000 WY o BRCA1 carriers: 127/1000 WY o BRCA2 carriers: 73/1000 WY (P=0.37) o BRCA1/2 carriers vs. moderate risk (P=0.01) o BRCA1/2 carriers vs. high risk (P=0.06) o Compared to general population: standardised detection rate BRCA1/2 carriers 155.3, high-risk 65.0, medium risk 39.9 Tumour (41 screen-detected tumours were compared to 297 tumours detected in family members outside the programme and to 7844 women from the local Registry) Pre-invasive or < 2 cm: o Screen-detected 85.4% o Family members 44% (P<0.0001) o registry: 47.6 (P< ) Node negative: o Screen-detected 82.8% o Family members 48% (P=0.0005) o registry 55.7% (P=0.004) Dropouts: none reported groups not comparable, possible confounders not taken into account, high potential for biased results

5 A priori patient : not reported Group comparability: not comparable at all Bigenwald Epidemiol Biomarker s Prev Design: crosssectional diagnostic Canadian Breast Research Alliance, Terry Fox Foundation, International Breast MRI Consortium, the (Canadian) National Breast Fund, and the Papoff Family. MRI contrast agent supplied by GE Healthcare. Setting: familial cancer centers Sample size: 507 Duration: >9 years women with or without a past history of breast cancer who (a) were known BRCA mutation carriers, (b) were untested firstdegree relatives of a BRCA mutation carrier, or (c) had three relatives on the same side of the family with breast cancer diagnosed before age 50 or epithelial ovarian cancer. : reported only for women diagnosed with cancer (n=45) 9.5% Index test(s):, mammography, ultrasound, and MRI Pathology + followup Sensitivity: BIRADS 1: o MRI 100%(31-100) o Mammography 33%(2-87) BIRADS 2: o MRI 93%(66-100) o Mammography 33% (13-61) BIRADS 3: o MRI 88%(68-97) o Mammography 16% (5-37) BIRADS 4 o MRI 66% (13-98) o Mammography 33% (2-87) Quantitative o 10% dense MRI : 92% (62-100) o Mammography 31% (10-61) Dropouts: none reported unclear whether consecutive inclusion, no CI provided o 11-25% dense MRI: 87% (58-98) o Mammography 27% (9-55) o 26-50% dense MRI: 100% (66-100) o Mammography 20% (4-56) o >50% dense MRI: 75% (36-96) o Mammography 12.5% (1-53)

6 Hoogerbru gge Ann Oncol Design: diagnostic none reported Setting: genetics department Sample size: 196 Duration : 6 year BRCA1 or BRCA2 mutation : 127 women with BRCA1, 69 women with BRCA2 mutation Median age at start 40 years (range y) 8.7% (including occult cancers detected at prophylactic mastectomy) Index test(s): MRI + mammography + histology and followup o MRI 60% o Mammography 41% o MRI + mammography 71% Specificity: o MRI 90% o Mammography 93% o MRI + mammography 90% Number of woman-years needed to detect one tumour: 50 Positive surveillance MRI scans : 12% o first surveillance : 18% o during follow-up: 9% Impact of false positive MRI + mammography on choice for prophylactic mastectomy: Prior preference for mastectomy: P=0.06 Prior preference for surveillance: P=0.47 Dropouts selection procedure unclear, unclear how follow-up was used in calculation of sens/spec, no CI given, analysis on impact of false positive result on preference for mastectomy/surveillance: univariate and with limited sample size Kriege Breast Res Treatment Kriege Design: diagnostic (MRISC study) Dutch Health Insurance Council and ZonMw Setting: 6 academic and/or cancer centres Sample size: 1909 Duration : 4 years Design: diagnostic (MRISC study) Dutch Health Insurance Council and ZonMw Setting: 6 academic and/or cancer centres Sample size: 1909 Duration : 4 years cumulative lifetime risk of breast cancer from 15% because of a genetic or familial predisposition according to the modified tables of Claus, age at entry years, and no evident symptoms suspicious for breast cancer or previous breast cancer. : mean age at entry: 40 years (range 19-72), 358 proven gene mutation carriers: 276 BRCA1, 77 BRCA2, 1 BRCA1 + BRCA2, 2 PTEN n, 2 TP % cumulative lifetime risk of breast cancer from 15% because of a genetic or familial predisposition according to the modified tables of Claus, age at entry years, and no evident symptoms suspicious for breast cancer or previous breast cancer. Index test(s): MRI + mammography + histology and followup Index test(s): MRI + mammography + histology and followup False positive rate MRI: 83% s detected by MRI only: 20/45 s detected by mammography only: 6/45 detected by only: 1/45 Tumour : No significant difference between MRI only detected tumours and other detected tumours for: o Size o Grade o Oestrogen receptor, progesterone receptor and tumour type Node positivity: MRI-only detected tumours 6% vs. 44% in all other screen-detected tumours (P = 0.02) All breast cancers, positive tests (%): : P = 0.25 o 1st round 3.0 o 2 nd round 3.1 o 3 rd round 3.1 o 4 th round 2.0 o 5 th next rounds 2.8 Mammography: P = 0.16 o 1st round 6.7 o 2 nd round 4.8 o 3 rd round 5.5 Sensitivity MRI vs. Mammo MRI significantly more sensitive for tumours 1cm, N0, not ductal tumours and ER+/ER- Invasive cancers Positive Tests (%): Mammography: P = 0.09 mammography: 7.6 mammography: 5.6 o Subsequent rounds: 4.8 MRI: P <0.001 mammography: 8.3 Dropouts: 5 cancers excluded consecutive inclusion?, verification neg index test results Dropouts Results critical appraisal : consecutive inclusion?, verification neg index test results

7 : mean age at entry: 40 years (range 19-72), 358 proven gene mutation carriers: 276 BRCA1, 77 BRCA2, 1 BRCA1 + BRCA2, 2 PTEN n, 2 TP % o 4 th round 3.7 o 5 th next rounds 5.5 MRI: P<0.001 o 1st round 12.9 o 2 nd round 11.3 o 3 rd round 12.7 o 4 th round 9.3 o 5 th next rounds 6.9 Detected breast cancers (1000 tests): : P = 0.87 o 1st round 0.5 o 2 nd round 2.3 o 3 rd round 2.0 o 4 th round 0.8 o 5 th next rounds 1.0 Mammography: P = 0.15 o 1st round 6.1 o 2 nd round 3.5 o 3 rd round 5.3 o 4 th round 3.2 o 5 th next rounds 1.9 MRI: P = o 1st round 9.6 o 2 nd round 12.1 o 3 rd round 6.7 o 4 th round 3.4 o 5 th next rounds 4.1 PPV (%): : P = 0.94 o 1st round 1.8 o 2 nd round 7.4 o 3 rd round 6.4 o 4 th round 3.8 o 5 th next rounds 3.6 Mammography: P = 0.29 o 1st round 9.1 o 2 nd round 7.3 o 3 rd round 9.6 o 4 th round 8.7 o 5 th next rounds 3.4 MRI: P=0.30 o 1st round 7.5 o 2 nd round 10.8 o 3 rd round 5.3 mammography: 14.9 o Subsequent rounds: 8.7 Detection Rate (per 1000 Tests): Mammography: P= mammography:16.5 mammography: 2.1 o Subsequent rounds: 2.1 MRI: P = 0.05 mammography: 13.2 mammography: 19.9 o Subsequent rounds: 5.3 PPV (%):P= Mammography: mammography: 21.7 mammography: 3.8 o Subsequent rounds: 4.3 MRI: P = 0.18 mammography: 16.0 mammography: 6.6 o Subsequent rounds: 6.1 Sensitivity (%): Mammography: P = 0.05 mammography: 71.4 mammography: 20.0 o Subsequent rounds: 29.4 MRI: P = 0.14 mammography: 57.1 mammography: 93.3 o Subsequent rounds: 76.5 False Positive Rate (100- Specificity, %):

8 o 4 th round 3.7 o 5 th next rounds 6.1 Mammography: P= 0.33 mammography: 6.1 mammography: 5.5 o Subsequent rounds: 4.6 Kuhl J Clin Oncol Design: diagnostic German Aid Society Setting: 4 academic breast centres Sample size: 687 of whom 370 underwent half-yearly screening and 317 annual screening (half-yearly screening significantly younger, P < and significantly higher lifetime risk, P <0.0001) Duration: 5 years personal history or a history of a relative with breast cancer diagnosed 35 years; a personal history or a history of a relative with ovarian cancer diagnosed 40 years; a personal history or a history of a relative with bilateral breast cancer; a personal history or a history of a relative with both breast and ovarian cancers; a history of at least 2 relatives with breast and/or ovarian cancer, one of whom received a diagnosis 50 years; or a man with a personal history of breast: cancer or a history of a male relative with breast cancer. In addition, 6 patients with symptoms were recruited. : Mean age at breast cancer diagnosis 43.1 years (SD 0.9 years; median, 43 years; range, years). 3.9% Index test(s):, mammography, ultrasound, and MRI histology and followup s identified during half-yearly screening with and ultrasound: 0 Sensitivity: Mammography alone: 33% ( ) US alone: 37% ( ) Mammography + US: 48% ( ) MRI alone: 93% ( ) MRI + US: 93% ( ) MRI + Mammography: 100% ( ) MRI + Mammography + US:100% ( ) Specificity: Mammography alone: 99.1% ( ) US alone: 98.0% ( ) Mammography + US: 98.3% ( ) MRI alone: 98.4% ( ) MRI + US: 98.5% ( ) MRI + Mammography: 97.6% ( ) MRI + Mammography + US: 97.6% ( ) PPV: Mammography alone: 39.1% ( ) US alone: 35.7% ( ) Mammography +US: 32.5% ( ) MRI alone: 48.0% ( ) MRI + US: 50.0% ( ) MRI + Mammography: 40.2% ( ) MRI: P <0.001 mammography: 7.1 mammography: 14.0 o Subsequent rounds: 8.2 Dropouts: none reported unclear whether consecutive inclusion, follow-up too short

9 MRI + Mammography + US: 40.2% ( ) Rijnsburge r Br J Design: of life measurement as part of a diagnostic (MRISC study) Dutch Health Insurance Council and ZonMw Setting: 6 academic and/or cancer centres, this study was performed in 1 centre Sample size: 329 Duration: not reported cumulative lifetime risk of breast cancer from 15% because of a genetic or familial predisposition according to the modified tables of Claus, age at entry years, and no evident symptoms suspicious for breast cancer or previous breast cancer. : mean age at entry 40.9 years; 72% low to intermediate level of education. not reported Index test(s): MRI + mammography + histology and followup NPV: Mammography alone: 98.9% ( ) US alone: 98.9% ( ) Mammography + US: 99.1% ( ) MRI alone: 99.9% ( ) MRI + US: 99.9% ( ) MRI + Mammography: 100.0% ( ) MRI + Mammography + US: 100.0% ( ) Change over time VAS scale changed significantly between T0 (81.9)-T1 (79.0)-T2 (80.7) SF-36 scores High-risk women higher scores (P 0.01/ P 0.05) than the age- and sex adjusted Dutch and USA general population EQ-5D utilities and SOM scale more favourable scores (P 0.01) compared to the age- and sex-adjusted Swedish general population and sex-adjusted Dutch general population Observed VAS scores significantly lower (P<0.01) compared to the ageand sex-adjusted reference scores from the Swedish general population Risk category (=model A) includes age, number of years adhering to regular surveillance, frequency of selfexamination, mother and/or sister(s) affected with breast cancer. No significant interaction between risk category and time No significant effect of risk category Pain intensity: Mammography: o Quite 21.1% o Very 9.0% MRI: o Quite 0.9% o Very 0% Discomfort: Mammography: o Quite 15.8% o Very 6.0% MRI: o Quite 4.6% o Very 4.6% Anxiety Mammography: o Quite 4.5 o Very 0.7 MRI: o Quite 7.4 o Very 2.8 Dropouts consecutive inclusion?, verification neg index test results Screening modality (=Model B) includes age, educational level, number of years adhering to regular surveillance, mother and/or sister(s) affected with breast cancer. No significant interaction effects between screening modality and time No significant main effect of screening modality

10 Weinstein J Clin Oncol Design: diagnostic National Institute of Health (NIH) Setting: not reported Sample size: 609 Duration: 5 years Women years, high risk for breast cancer based on any of the following: BRCA1 or BRCA2 mutation, 25% lifetime risk based on the Claus or Gail models, previous diagnosis of lobular carcinoma in situ or atypical hyperplasia, history of chest wall radiation before puberty, recent diagnosis of breast cancer in the contralateral breast. In addition, all women had a non-actionable mammogram within 180 days of enrollment as well as no suspicious findings on (non-actionable mammogram BIRADS 1 or 2, a resolved BIRADS 0 or 3, or a BIRADS 4 associated with a biopsy negative for cancer) : median age at study entry 49 years ( range years); BRCA1/2 mutation 7.2%, prior breast cancer 10.2% 2.96% (unit of analysis=patients) Index test(s): digital mammography, whole breast US, MRI pathology and follow-up for a minimum of 2 years Additional diagnostic evaluation (=Model C) includes age. For the VAS, there was a significant (P 0.01) interaction between additional diagnostic evaluation and time No significant main effect of additional diagnostic evaluation (P ) for any of the outcome scales Each modality independent of each other Sensitivity (%) Film mammography: 33 Digital mammography:39 MRI 71 US 17 Specificity (%) Film mammography: 94 Digital mammography:91 MRI 79 US 88 Biopsy yield (no. of cancers/no. of biopsies, %): Film mammography: 29 Digital mammography:35 MRI 25 US 15 yield (no. of cancers/no. of participants, %): Film mammography: 1.0 Digital mammography: 1.2 MRI 2.1 US 0.5 Actionable findings, blind to other modalities: Film mammography: 55 Digital mammography:72 MRI 129 US 79 Actionable findings, unblinded to other modalities: Film mammography: 31 Digital mammography:42 MRI 102 US 39 No. of biopsies Film mammography: 21 Digital mammography:20 MRI 48 US 20 No. of cancers Film mammography: 6 Digital mammography:7 MRI 12 US 3 Dropouts: 3 patients withdrew before imaging all patients had a non-actionable film mammography before study entry (thus estimating the incremental value of the other modalities), unclear whether inclusion consecutive, follow-up of 2 years for neg index tests Abbreviations: 95%CI: 95 percent confidence intervals; BRCA : breast cancer; BIRADS : Breast Imaging-Reporting and Data System; : clinical breast examination; MRI : magnetic resonance imaging ; NPV: negative predictive value; OR: odds ratio; PPV: positive predictive value; RR: risk ratio; SD: standard deviation; US : ultrasonography; VAS: visual analogue scale; WY: women years

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