Safety of Vaginal Estrogens: A Systematic Review Supplemental Tables Page # Supplemental Table 1. National Library of Medicine’s DAILYMED Repository 2 Search Results Supplemental Table 2. Contraindications to vaginal estrogens approved by the U.S. 3 Food and Drug Administration Supplemental Table 3. Excluded articles and reasons for exclusion 4 Supplemental Table 4. Study design characteristics of clinical trials of vaginal 30 estrogen in postmenopausal women Supplemental Table 5. Serum sex steroid, and/or gonadotropin assay methods (and 45 manufacturer if stated) in clinical trials of vaginal estrogen in postmenopausal women Supplemental Table 6. Endometrial biopsy results in clinical trials of vaginal estrogen 52 in postmenopausal women Supplemental Table 7a. Summary of Heterogeneity of Level 1 Studies with 55 Endometrial Biopsy Outcomes Supplemental Table 7b. Summary of Heterogeneity of Level 2 Studies with 55 Endometrial Biopsy Outcomes Supplemental Table 7c. Summary of Heterogeneity of Level 1 Studies with 56 Endometrial Thickness Outcomes Supplemental Table 7d. Summary of Heterogeneity of Level 2 Studies with 57 Endometrial Thickness Outcomes Bibliography 58 1 Supplemental Table 1. National Library of Medicine’s DAILYMED Repository Search Resultsa Retrieved result for non-injectable preparation of Vaginal route confirmed after estrogen alone (without other hormones) review of label Alora estradiol transdermal system patch No Climara estradiol patch No Divigel estradiol gel No Dotti estradiol patch extended release No Elestrin estradiol gel No Estra-50 estradiol pellet, implantable No Estrace estradiol cream 0.01% Yes Estrace estradiol tablet No Estraderm estradiol patch No Estradiol cream 0.01% Yes Estradiol film, extended release No Estradiol insert, 10mcg estradiol per insert Yes Estradiol patch No Estradiol tablet No Estradiol transdermal system estradiol patch No Estradiol vaginal cream 0.01% Yes Estradiol vaginal inserts estradiol tablet film-coated, 10mcg Yes estradiol Estring estradiol ring 2 mg releasing 7.5 mcg/d Yes Estrogel estradiol gel No Evamist estradiol spray No Femring estradiol acetate ring Yes Imvexxy estradiol insert 10mcg estradiol per insert Yes Menostar estradiol patch No Minivelle estradiol film No Premarin conjugated estrogens tablet No Premarin vaginal conjugated estrogens cream Yes Vagifem estradiol insert, film-coated, 10mcg or 25 mcg Yes estradiol per insert Vivelle dot estradiol patch No Yuvafem estradiol tablet 10mcg estradiol per tablet Yes a Note: To ensure that the list of estrogen preparations used as search terms was inclusive of all U.S. FDA-approved vaginal estrogen preparations, we performed a search of the U.S. National Library of Medicine’s DAILYMED webpage (https://dailymed.nlm.nih.gov/dailymed/index.cfm) “estrogen” drug class on 3/8/2019. The search revealed vaginal estrogens in the form of estradiol cream, estradiol insert (also known as estradiol vaginal tablet), estradiol ring, and conjugated equine estrogens cream. 2 Supplemental Table 2. Contraindications to vaginal estrogens approved by the U.S. Food and Drug Administration Preparation Contraindications Vaginal conjugated estrogens • Undiagnosed abnormal genital bleeding, cream, estradiol cream, vaginal • known, suspected, or history of breast cancer estradiol insert (tablet) • known or suspected estrogen-dependent neoplasia • active deep vein thrombosis, pulmonary embolism, or a history of these conditions • active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions • known liver dysfunction or disease • known protein C, protein S, or antithrombin deficiency or other known thrombophilic a disorders b • known or suspected pregnancy a known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders is not listed as a contraindication of the estradiol vaginal ring (Estring) b Known or suspected pregnancy is not listed as a contraindication of Imvexxy vaginal estradiol insert. 3 Supplemental Table 3. Excluded Articles and Reasons for Exclusion Ref. Author, year Reason for Reason for exclusion after full-text # exclusion after search title/abstract search 1 1972 Eur J Cancer Not VE 2 1989 Contraception Special pop 3 1991 Fertil Steril Not VE 4 1993 Int J Fertil Menopausal Not VE Stud 5 Abate 1999 Clin Exp Obstet Not VE Gynecol 6 Abdalla 1992 Contraception Special pop 7 Abdel-Aleem 2005 Not VE Contraception 8 Abdelbary 2015 Urology Excluded after full- No AE text search 9 Abdullah 2005 J Coll Not VE Physicians Surg Pak 10 Abraham 2014 Maturitas Not VE 11 Achiron 1995 Fertil Steril Not VE 12 Adler 2005 Gynecol Obstet Not VE Invest 13 Affinito 1998 Ultrasound Not VE Obstet Gynecol 14 Agarwal 2016 J Obstet Special pop Gynaecol 15 Aguirre 2010 Gynecol Not VE Endocrinol 16 Ahlstrom 1990 Gynecol Obstet Not FDA app prep Invest 17 AinMelk 1996 Fertil Steril Not VE 18 Akrivis 2003 Clin Exp Obstet I Gynecol 19 Al-Azzawi 2003 Climacteric Hi dose VE 20 Al-Azzawi 2005 Menopause Excluded after full- Not VE Alone text search 21 Albert 2002 Obstet Gynecol Not VE 22 Albertazzi 1999 Obstet Gynecol Not VE 23 Algorta 2017 Eur J Contracept Special pop Reprod Health Care 24 Al-Saqi 2015 Post Reprod Not VE Health 25 Alvarez 1996 Contraception Not VE 26 Alvarez-Sanchez 1992 Special pop Contraception 27 Anderson 2003 JAMA Not VE 28 Andersson 2000 Maturitas Not VE 4 29 Andreen 2003 Eur J Endocrinol Not VE 30 Andreen 2005 Not VE Psychoneuroendocrinology 31 Apperloo 2006 J Sex Med Not VE 32 Apter 1990 Contraception Special 33 Apter 2016 Contraception Not VE 34 Archer 2017 Menopause I 35 Archer 2001 Fertil Steril Not VE 36 Archer 2007 J Clin Not VE Endocrinol Metab 37 Archer 2018 J Womens Excluded after full- Not FDA app prep Health (Larchmt) text search 38 Archer 2012 Menopause Not VE 39 Archer 2014 Menopause Not VE 40 Archer 2016 Contraception Special 41 Artini 1995 J Endocrinol Special Invest 42 Artymuk 2010 Int J Gynaecol Special Obstet 43 Ata 2010 J Reprod Med Special 44 Atmaca 2005 Tohoku J Exp Med Not VE Alone 45 Aylward 1974 Curr Med Res Not VE Opin 46 Aylward 1978 Postgrad Med J Not VE 47 Ayton 1996 Br J Obstet I Gynaecol 48 Bachmann 2010 Climacteric Not VE 49 Bachmann 2009 Menopause I 50 Bachmann 2011 Menopause Not VE 51 Bachmann 2008 Obstet Gynecol I 52 Bachmann 2010 Menopause Not VE 53 Bachmann 2009 Menopause Not VE 54 Back 1987 Contraception Special 55 Baerug 1998 Climacteric Not VE 56 Bahamondes 1995 Hum Reprod Not VE 57 Bahamondes 2000 Not VE Contraception 58 Bai 2007 Maturitas Not VE 59 Baird 1995 J Clin Endocrinol Not VE Metab 60 Baird 1996 J Clin Epidemiol Not VE 61 Baker 1995 J Assist Reprod Not VE Genet 62 Baker 1998 J Clin Endocrinol Not VE Metab 63 Balasch 1982 Fertil Steril Not VE 5 64 Balk 2002 J Soc Gynecol Not VE Investig 65 Ballagh 1994 Contraception Special 66 Ballagh 1994 Contraception Special 67 Baracat 2001 Clin Exp Obstet Not VE Gynecol 68 Barbosa 2009 Gynecol Not VE Endocrinol 69 Barentsen 1997 Eur J Obstet I Gynecol Reprod Biol 70 Barnabei 2005 Obstet Gynecol Not VE 71 Barnabei 2002 Obstet Gynecol Not VE 72 Barton 2018 Support Care Not VE Cance 73 Barton 2018 Support Care Not VE Cance 74 Bassol 2005 Maturitas Not VE 75 Basson 2003 BJOG Not VE 76 Bateson 2009 Menopause Excluded after full- No AE text search 77 Battaglia 2009 J Sex Med Not VE 78 Baysoy 2006 Reprod Biomed Not VE Online 79 Beardsworth 1999 Br J Obstet Not VE Gynaecol 80 Beaton 1967 Br J Clin Pract Not VE 81 Behilovic 1987 Contraception Not VE 82 Behre 2001 J Int Med Res Not VE 83 Bellantoni 1991 J Gerontol Not VE 84 Bellina 1983 Lasers Surg Med Not VE 85 Belsey 1988 Contraception Special 86 Ben-Chetrit 1996 Fertil Steril Not VE 87 Ben-Chetrit 2005 Isr Med Assoc Not FDA app prep J 88 Benjamin 1971 J Reprod Med Not VE 89 Benson 1996 Am J Obstet Not VE Gynecol 90 Berger 1979 Contraception Not VE 91 Berning 2000 Maturitas Not VE 92 Bhamra 2011 Menopause Not FDA app prep 93 Bishop 1992 Cancer Chemother Not VE Pharmacol 94 Bishun 1977 J Surg Oncol Not VE 95 Bjarnadottir 2002 Am J Obstet Special Gynecol 96 Blakely 2004 Clin Cancer Res Not VE 97 Bolaji 1996 Gynecol Endocrinol Not VE 6 98 Bolognese 2009 J Clin Not VE Endocrinol Metab 99 Bonneterre 2001 Cancer Not VE 100 Bonneterre 2000 J Clin Oncol Not VE 101 Boon 2003 Maturitas Not VE 102 Botsis 1997 Maturitas I 103 Bottiglione 1995 Maturitas Not FDA app prep 104 Bouchard 2015 Climacteric Not VE 105 Bouchard 2016 Horm Mol Biol Not VE Clin Investig 106 Brache 2007 Contraception Not VE 107 Brache 2000 Contraception Not VE 108 Brache 2001 Contraception Not VE 109 Breast International Group 2005 Not VE N Engl J Med 110 Brenner 1988 Obstet Gynecol Not Original 111 Brezina 2012 Reprod Biol Special Endocrinol 112 Brinsmead 1989 J In Vitro Fert Special Embryo Transf 113 Bronstein 1967 Int J Fertil Not VE 114 Brown 2001 Obstet Gynecol Not VE 115 Bruce 2004 Climacteric Not VE 116 Bruhat 2001 Maturitas Not VE 117 Bruni 2008 Eur J Obstet Not VE Gynecol Reprod Biol 118 Brunner 2010 Menopause Not VE 119 Bruyniks 2016 Climacteric Not VE 120 Brys 2009 Sao Paulo Med J Not FDA app prep 121 Brzyski 1992 Am J Obstet Not VE Gynecol 122 Buckler 2003 BJOG Hi Dose VE 123 Burch 1995 Br J Obstet Not VE Gynaecol 124 Buzdar 2001 J Clin Oncol Not VE 125 Bygdeman 1996 Maturitas Not FDA app prep 126 Cagnacci 1992 Life Sci Not VE 127 Cagnacci 1999 Maturitas Not FDA app prep 128 Campbell 1977 Clin Obstet Not VE Gynaecol 129 Cano 2012 Menopause Not FDA app prep 130 Cano 1999 Fertil Steril Not VE 131 Carmignani 2010 Maturitas Not VE 132 Carmignani 2015 Menopause