title: 20 µg versus >20 µg estrogen combined oral contraceptives for contraception.
abstract: BACKGROUND
  Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns.
  
  
  OBJECTIVE
  To test the hypothesis that COCs containing ≤ 20 μg ethinyl estradiol (EE) perform similarly as those containing > 20 μg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects.
  
  
  METHODS
  In July 2013, we searched CENTRAL, MEDLINE, and POPLINE, and examined references of potentially eligible trials. We also searched for recent clinical trials using ClinicalTrials.gov and ICTRP. No new trials met the inclusion criteria. Previous searches included EMBASE. For the initial review, we wrote to oral contraceptive manufacturers to identify trials.
  
  
  METHODS
  English-language reports of randomized controlled trials were eligible that compare a COC containing ≤ 20 μg EE with a COC containing > 20 μg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non-contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding-related reasons or other side effects, or side effects to be included in the review.
  
  
  METHODS
  One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan.
  
  
  RESULTS
  No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 μg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting).
  
  
  CONCLUSIONS
  While COCs containing 20 μg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results.
authors.affiliation: Division of Epidemiology, The Ohio State University, Room 324 Cunz Hall, 1841 Neil Avenue, Columbus, Ohio, USA, 43210-1351.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gallo
authors.forename: Kavita
authors.initials: K
authors.lastname: Nanda
authors.forename: David A
authors.initials: DA
authors.lastname: Grimes
authors.forename: Laureen M
authors.initials: LM
authors.lastname: Lopez
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Schulz
mesh_terms: D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage* / Q000009:adverse effects; D003278:Contraceptives, Oral, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D017135:Desogestrel / Q000008:administration & dosage / Q000009:adverse effects; D004967:Estrogens / Q000008:administration & dosage* / Q000009:adverse effects; D004997:Ethinyl Estradiol / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008599:Menstruation Disturbances / Q000139:chemically induced; D016032:Randomized Controlled Trials as Topic
chemical_list: D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D004967:Estrogens; D004997:Ethinyl Estradiol; D017135:Desogestrel
references.citation: Am J Obstet Gynecol. 1998 Sep;179(3 Pt 1):577-82
references.pmid: 9757954
references.citation: Contraception. 1986 Sep;34(3):253-60
references.pmid: 3539509
references.citation: Eur J Contracept Reprod Health Care. 1999 Jun;4(2):75-83
references.pmid: 10427482
references.citation: Obstet Gynecol. 2009 Dec;114(6):1205-1212
references.pmid: 19935020
references.citation: Obstet Gynecol. 1992 Apr;79(4):529-33
references.pmid: 1553170
references.citation: Lancet. 1996 Jun 22;347(9017):1713-27
references.pmid: 8656904
references.citation: Contraception. 2003 Jan;67(1):25-32
references.pmid: 12521654
references.citation: Contraception. 1996 Feb;53(2):75-84
references.pmid: 8838483
references.citation: Br J Obstet Gynaecol. 1996 Mar;103(3):261-7
references.pmid: 8630312
references.citation: Contraception. 1996 Nov;54(5):291-7
references.pmid: 8934063
references.citation: Am J Obstet Gynecol. 1979 Jun 1;134(3):315-20
references.pmid: 377968
references.citation: BMJ. 2003 May 31;326(7400):1167-70
references.pmid: 12775614
references.citation: Contraception. 2005 Aug;72(2):98-104
references.pmid: 16022847
references.citation: Contraception. 1993 Sep;48(3):193-204
references.pmid: 8222650
references.citation: Obstet Gynecol. 2005 Jul;106(1):89-96
references.pmid: 15994622
references.citation: Br J Obstet Gynaecol. 1993 Sep;100(9):832-8
references.pmid: 8218004
references.citation: Contraception. 2006 Apr;73(4):336-43
references.pmid: 16531162
references.citation: Contraception. 2001 Jun;63(6):289-95
references.pmid: 11672549
references.citation: Gynecol Endocrinol. 1995 Dec;9(4):299-305
references.pmid: 8629458
references.citation: Contraception. 1997 Mar;55(3):131-7
references.pmid: 9115000
references.citation: J Reprod Med. 2007 Nov;52(11):1030-4
references.pmid: 18161401
references.citation: Contraception. 2000 Sep;62(3):131-5
references.pmid: 11124360
references.citation: Acta Obstet Gynecol Scand Suppl. 1997;164:63-5
references.pmid: 9225641
references.citation: Adv Contracept. 1994 Mar;10(1):1-4
references.pmid: 8030448
references.citation: Fertil Steril. 2001 Sep;76(3):461-8
references.pmid: 11532465
references.citation: Obstet Gynecol. 2001 Nov;98(5 Pt 1):771-8
references.pmid: 11704167
references.citation: Drug Ther Bull. 2000 Jan;38(1):1-5
references.pmid: 10820893
references.citation: Contraception. 2004 Sep;70(3):191-8
references.pmid: 15325887
references.citation: Lancet. 2002 Feb 16;359(9306):614-8
references.pmid: 11867132
references.citation: Contraception. 1996 Aug;54(2):71-7
references.pmid: 8842582
references.citation: Fertil Steril. 2009 Aug;92(2):434-40
references.pmid: 18930189
references.citation: Gynecol Endocrinol. 2000 Apr;14(2):90-8
references.pmid: 10836195
references.citation: Adv Contracept. 1992 Oct;8 Suppl 1:35-45
references.pmid: 1442248
references.citation: Contraception. 2005 Feb;71(2):111-7
references.pmid: 15707560
references.citation: Cochrane Database Syst Rev. 2004;(3):CD004861
references.pmid: 15266546
references.citation: Contraception. 2001 Oct;64(4):235-41
references.pmid: 11747873
references.citation: Contraception. 1996 Feb;53(2):85-90
references.pmid: 8838484
references.citation: Contraception. 1994 Jan;49(1):33-46
references.pmid: 8137624
references.citation: Contraception. 1982 Mar;25(3):231-41
references.pmid: 6804161
references.citation: Am J Epidemiol. 2000 Aug 1;152(3):233-41
references.pmid: 10933270
references.citation: Contraception. 2007 Jan;75(1):4-10
references.pmid: 17161116
references.citation: Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003989
references.pmid: 15846690
references.citation: Int J Fertil. 1989 Sep;34 Suppl:31-9
references.pmid: 2576255
references.citation: Eur J Obstet Gynecol Reprod Biol. 2012 May;162(1):91-5
references.pmid: 22391750
references.citation: Am J Public Health. 1991 Jan;81(1):90-6
references.pmid: 1983923
references.citation: Contraception. 2000 Feb;61(2):105-11
references.pmid: 10802275
references.citation: Contraception. 1991 May;43(5):435-46
references.pmid: 1833126
references.citation: Contraception. 2002 Dec;66(6):407-9
references.pmid: 12499032
references.citation: Contraception. 1987 Jun;35(6):523-32
references.pmid: 3311619
references.citation: Contraception. 1999 Dec;60(6):321-9
references.pmid: 10715366
references.citation: Br J Obstet Gynaecol. 1979 Apr;86(4):325-9
references.pmid: 373792
references.citation: Contraception. 2007 Jan;75(1):11-5
references.pmid: 17161117
references.citation: Am J Obstet Gynecol. 1999 Nov;181(5 Pt 2):45-52
references.pmid: 10561675