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20 µg versus >20 µg estrogen combined oral contraceptives for contraception

  1. Maria F Gallo1,*,
  2. Kavita Nanda2,
  3. David A Grimes3,
  4. Laureen M Lopez4,
  5. Kenneth F Schulz5

Editorial Group: Cochrane Fertility Regulation Group

Published Online: 1 AUG 2013

Assessed as up-to-date: 15 JUL 2013

DOI: 10.1002/14651858.CD003989.pub5


How to Cite

Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF. 20 µg versus >20 µg estrogen combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD003989. DOI: 10.1002/14651858.CD003989.pub5.

Author Information

  1. 1

    The Ohio State University, Division of Epidemiology, Columbus, Ohio, USA

  2. 2

    FHI, Clinical Sciences, Research Triangle Park, North Carolina, USA

  3. 3

    University of North Carolina, School of Medicine, Obstetrics and Gynecology, Chapel Hill, North Carolina, USA

  4. 4

    FHI 360, Clinical Sciences, Research Triangle Park, North Carolina, USA

  5. 5

    FHI 360 and UNC School of Medicine, Quantitative Sciences, Research Triangle Park, North Carolina, USA

*Maria F Gallo, Division of Epidemiology, The Ohio State University, Room 324 Cunz Hall, 1841 Neil Avenue, Columbus, Ohio, 43210-1351, USA. mgallo@cdc.gov. fjr4@cdc.gov.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 1 AUG 2013

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Characteristics of included studies [ordered by study ID]
Akerlund 1993

MethodsSix sites in Norway, two in Sweden and one in Denmark.
12 treatment cycles.
Double-blinded but did not specify who was blinded.


ParticipantsWomen aged 18 to 35 (Norway sites) or 18 to 40 (Sweden and Denmark sites) years.
Excluded heavy smoking among women 35 years of age; risk factors for or history of certain diseases; lactation; and certain antibiotics.


InterventionsEE 20 µg and desogestrel 150 µg (N=500) versus EE 30 µg and desogestrel 150 µg (N=500).


OutcomesContraceptive efficacy, cycle control, and side effects.
'Withdrawal' bleeding defined as bleeding that began within the pill-free period and did not exceed eight days. 'Irregular' bleeding defined as any other bleeding.


NotesAllocated with simple random table.
Excluded randomized women from the analysis.
67% (672/1000) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskAllocation concealment not reported.

Appel 1987

Methods30 sites in unreported location(s).
Four treatment cycles.
Observer blinded.
Tablets were supplied from manufacturer in standard, unmarked packs.


ParticipantsHealthy women aged 18 to 36 years with regular menses.
Excluded pregnancy; history of certain diseases; and certain drugs.


InterventionsEE 20 µg and norethindrone acetate 1.0 mg versus EE 30 µg and norethindrone acetate 1.5 µg versus EE 50 µg and norethindrone acetate 1.0 µg versus EE 20-30-50 µg and norethindrone acetate 1.0-1.5-1.0 mg.
564 women randomized; initial number assigned to each study group not reported.


OutcomesContraceptive efficacy, cycle control, side effects, blood pressure, body weight and hemoglobin.
'Breakthrough' bleeding or spotting defined as bleeding or spotting occurring during the pill-taking period.


NotesRandomization method not reported.
76% (426/564) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Basdevant 1993

MethodsNumber and location of sites not reported.
Six treatment cycles.
Blinding not described.


ParticipantsHealthy, non-obese women with regular menses.
Excluded lactation; recent birth or abortion; recent steroid treatment; venous or arterial disease; diabetes; hyperlipidemia; eating disorders; smokers; hypertension; gynecological tumors; cancer; and certain drugs.


InterventionsEE 20 µg and desogestrel 150 µg (N=33) versus EE 30 µg and desogestrel 150 µg (N=25).


OutcomesPlasma lipid levels, glucose tolerance, blood pressure, hemostatic values, and discontinuation.
Did not report bleeding outcomes.


NotesRandomization method not reported.
76% (426/564) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Bounds 1979

MethodsSeven initial sites in the U.K. planned but increased to 12 due to slow enrollment.
12 treatment cycles.
Participants and clinic doctors blinded.
Pre-coded, sealed envelopes with unmarked blister packs used for pills.


ParticipantsSexually active women aged 16 to 39 years at risk for pregnancy with regular menses.
Excluded contraindications to oral contraceptive use; lactation; and irregular bleeding and spotting.


InterventionsEE 20 µg and norethisterone acetate 1.0 mg versus EE 30 µg and levonorgestrel 150 µg.
143 women randomized; initial number assigned to each study group not reported.


OutcomesContraceptive efficacy, discontinuation, cycle control, and side effects.
'Menstrual' bleeding defined as any bleeding requiring sanitary protection regardless of timing in cycle.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
Number completing study was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Brill 1996

MethodsOne site in unreported location.
Three pill-free pretreatment and 13 treatment cycles.
Unblinded.


ParticipantsWomen aged 18 to 35 years with regular menses.
Excluded smokers over 30 years of age; pregnancy; certain diseases; certain drugs; intrauterine device use; overweight or dieting; and heavy alcohol use.


InterventionsEE 20 µg and gestodene 75 µg (N=32) versus EE 30 µg and gestodene 75 µg (N=32).


OutcomesLipid metabolism, cycle control, and adverse events.
Did not report bleeding outcomes.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
Number completing study was not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Bruni 2000

MethodsUnreported number of sites in 18 nations.
13 treatment cycles.
Unblinded.


ParticipantsWomen 'over the legal age of consent' and less than 42 years of age with regular menses.
Excluded estrogen or progestogen hypersensitivity; pregnancy; lactation; and certain disorders.


InterventionsEE 20 µg and desogestrel 150 µg (N=805) versus EE 30 µg and gestodene 75 µg (N=806) versus EE 30-40-30 µg and gestodene 50-70-100 µg (N=808).


OutcomesCycle control and effect on well-being.
Bleeding terms not defined.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
71% (1721/2419) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Chavez 1999

Methods11 sites in the USA
Four treatment cycles.
Unblinded.


ParticipantsHealthy women at risk for pregnancy with regular menses.
Excluded contraindications for oral contraceptive use; smokers aged 35 years or older; heavy smoking; recent oral injectable, implantable, or intrauterine contraceptive use; and drug or alcohol abuse.


InterventionsEE 20 µg and levonorgestrel 100 µg (N=169) versus EE 35 µg and norethindrone 500-750-1000 µg (N=173).


OutcomesCycle control.
'Withdrawal' bleeding or spotting defined as bleeding or spotting beginning in pill-free interval and stopping by fourth day of the next cycle. 'Intermenstrual' bleeding defined as all other bleeding.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
56% (191/342) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Endrikat 1997

Methods10 sites in Germany.
12 treatment cycles.
Double-blinded but did not specify who was blinded.


ParticipantsHealthy, sexually active women aged 18 to 39 years who wanted contraception for at least 12 months.
Excluded recent depot-contraceptives; certain diseases; and contraindications for oral contraceptive use.


InterventionsEE 20 µg and gestodene 75 µg (N=428) versus EE 30 µg and gestodene 75 µg (N=221).


OutcomesContraceptive efficacy, cycle control, and tolerance.
'Intermenstrual' bleeding was defined as either spotting or breakthrough bleeding. The definition for 'intermenstrual' bleeding did not specify cycle days.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
75% (488/649) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Endrikat 2001

MethodsTwo sites in The Netherlands.
Six treatment cycles.
Participants and investigators blinded.


ParticipantsHealthy women aged 18 to 35 years who wanted contraception for at least six months. Excluded contraindications to oral contraceptive use; recent depot contraceptive use; genital bleeding; and menses-related migraines.


InterventionsEE 20 µg and gestodene 75 µg (23 pill days; N=35) versus EE 30 µg and gestodene 75 µg (21 pill days; N=34).
70 women randomized; the group assignment for one woman was not specified.


OutcomesHemostatic values, lipids, carbohydrate metabolism, and tolerability.
'Intracyclic' bleeding defined as any bleeding during cycle days 4 to 21 for the 21-day regimen and cycle days 6 to 23 for the 23-day regimen.


NotesRandomization method not reported.
94% (66/70) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Hampton 2001

Methods100 sites in USA and 10 in Canada.
First 1/3 of participants were to have 13 treatment cycles and the remaining 2/3 were to have 6 treatment cycles.
Allocated in block sizes of 11; blinded.


ParticipantsSexually active, healthy women aged 18 to 45 years at risk for pregnancy with regular menses.
Excluded recent pregnancy; recent lactation; contraindications to oral contraceptives; certain diseases; smokers aged 35 or more years; certain drugs or devices; recent DMPA use; and recent alcohol or substance abuse.


InterventionsEE 20 µg and norethindrone acetate 1.0 mg with 75 mg ferrous fumarate on days 22-28 (N=853 for 6 cycles / 318 for 13 cycles) versus EE 25 µg and norgestimate 180-215-250 µg (N=1236 for 6 cycles / 487 for 13 cycles).


OutcomesContraceptive efficacy, cycle control, and safety.
'Breakthrough' bleeding or spotting defined as bleeding or spotting that occurred during active pill days unless contiguous with menses.
'Amenorrhea' defined as two consecutive cycles without any bleeding or spotting.
Secondary report (Burkman 2007) included weight change.
Secondary report (Hampton 2009) re-analyzed bleeding data with new criteria (Mishell 2007b); unscheduled bleeding data presented here.


NotesCyclophasic regimens discontinued early and not reported.
74% (2130/2894) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskAllocation concealment methods not reported.

Inauen 1991

MethodsNumber and location of sites not reported.
Cross-over trial with 3 treatment cycles on each oral contraceptive.
Blinding not described.


ParticipantsHealthy women aged 18 to 30 years without oral contraceptive use during prior four months.
Excluded blood coagulation disorders.


InterventionsEE 20 µg and desogestrel 150 µg (N=20) versus EE 50 µg and desogestrel 125 µg (N=20).


OutcomesBlood coagulation, thrombogenesis, and side effects.
Bleeding terms were not defined.


NotesRandomization method not reported.
100% completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Kaunitz 2009

MethodsRCT at 20 centers in the USA. Computer-generated randomization schedule; stratified by center and recent hormonal contraceptive use (new user or switcher).
3 treatment cycles. Open label.
Sample size based on prior studies for total bleeding days for cycles 1 to 3; 90% power to detect difference between groups.


Participants334 healthy women, nonpregnant, non-lactating, sexually active, aged 18 to 45 years.
Inclusion criteria: nonsmokers, regular menstrual cycles, negative Chlamydia test, normal Pap test in past 12 months.
Exclusion criteria: contraindication to hormonal therapy, untreated thyroid disorder, body mass index (BMI) > 40 kg/m2, previously discontinued one of the treatments due to breakthrough bleeding; received injectable contraceptive in past 6 months, implant in past 60 days, or hormonal IUD in past 3 months.


InterventionsEE 20 µg and drospirenone 3 mg (24/4-day regimen) (N=167) versus EE 25 µg and norgestimate 180-215-250 µg (21/7-day regimen) (N=167)


OutcomesBleeding data were recorded daily via a voice-response system. Bleeding and unscheduled bleeding (days) defined as per Mishell 2007b. Unscheduled bleeding episode was defined as per Belsey 1986.


NotesOf 355 randomized, 21 were screen failures (10 EE 20 µg and 11 EE 25 µg). The remaining 334 women who received study drug were included in safety analysis.
Completed study: EE 20 µg group, (156/167) 93%; EE 25 µg group, 154/167 (92%)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNo information

Kirkman 1994

Methods66 sites in Denmark, Italy, New Zealand and the UK.
Six treatment cycles. Unblinded.


ParticipantsHealthy women over 30 years of age with regular menses.
Excluded smokers over 34 years of age, select drug use, and lactation.


InterventionsEE 20 µg and desogestrel 150 µg (N=501) versus EE 30 µg and gestodene 75 µg (N=505).


OutcomesCycle control, discontinuation, body weight, blood pressure, and adverse events.
'Withdrawal' bleeding episode was defined as a sequence of one or more days of bleeding or spotting that began during the pill-free period and was bounded by two consecutive days without bleeding. Results, though, were reported for 'irregular' bleeding (with and without withdrawal bleeding), which was never defined.


NotesAllocated with pre-distributed schedules.
Excluded randomized women from the analysis.
87% (874/1006) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Kluft 2006

MethodsOpen-label, randomized trial at one center in The Netherlands from 1992 to 1993.


Participants75 healthy women, 18 to 35 years. Inclusion criteria: desiring contraception for at least 6 cycles, new OC users or switchers with at least 2 OC-free cycles before study.
Exclusion criteria: contraindications to OC use, family history of coagulation disorders, use of parenteral depot contraceptive in past 6 months, concomitant diseases (not specified in report), diagnostically unclassified genital bleeding, history of migraine with menstruation.


InterventionsDrospirenone 3 mg + EE 30 µg or drospirenone 3 mg + EE 20 µg versus desogestrel + EE 30 µg (N=25 in each group); 6 treatment cycles.


OutcomesFor pregnancy and serious adverse events, the researchers reported none occurred.


NotesNo information on method of randomization.
No losses reported; N=75 in per protocol analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Reisman 1999

Methods11 sites in the USA
Four treatment cycles.
Unblinded.


ParticipantsHealthy women over aged 18 years at risk for pregnancy with regular menses.
Excluded smokers over age 35 years; contraindications for oral contraceptive use; and recent oral contraceptive, intrauterine device, injectable, or implantable estrogens, progestins, or androgens.


InterventionsEE 20 µg and levonorgestrel 100 µg (N=192) versus EE 35 µg and norethindrone 500-750-1000 µg (N=195).


OutcomesCycle control and safety.
'Withdrawal' bleeding or spotting was defined as bleeding or spotting beginning in pill-free interval and stopping by fourth day of the next cycle. 'Intermenstrual' bleeding was defined as all other bleeding.


NotesExcluded randomized women from the analysis.
57% (220/387) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskAllocated with sequentially numbered, sealed envelopes.

Rosenberg 1999

Methods15 sites in US.
Six-month wash-out period for injectable or implant contraceptive users. Six treatment cycles.
Unblinded.


ParticipantsSexually active, normal weight women aged 18 to 50 years with regular menses.
Excluded contraindications to oral contraceptive use; smokers over 35 years of age; heavy alcohol use; and lactation.


InterventionsEE 20 µg and levonorgestrel 100 µg (N=154) versus EE 20 µg and desogestrel 150 µg (N=154) versus EE 35 µg and norgestimate 180-215-250 µg (N=155).


OutcomesCycle control.
'Unscheduled' bleeding was defined as bleeding not continuous with withdrawal bleeding. 'Withdrawal bleeding' was not defined.


NotesAllocated with masked randomization lists at each site generated with block size of six.
86% (398/463) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Skouby 2005

MethodsOpen-label, randomized trial at one center in Denmark


Participants70 healthy women, 18 to 35 years. Inclusion criteria: desiring contraception for at least 13 cycles, new OC users or switchers with at least 2 OC-free cycles before study.
Exclusion criteria: contraindications to OC use, parenteral depot contraceptive in past 6 months, co-existing diseases (not specified in report), diagnostically unclassified genital bleeding, history of migraine with menstruation.


InterventionsLevonorgestrel 100 µg + EE 20 µg (N=35) versus levonorgestrel 150 µg + EE 30 µg (N=35); 13 treatment cycles.


OutcomesPregnancy and adverse events.


NotesNo information on method of randomization.
Losses: 1 took no study medication (excluded) and 7 discontinued early (8/70 = 11%); no information about which groups these women were assigned to. Full analysis reportedly had N=69; 49 in per protocol analysis (22 in EE 20 µg group and 27 in 30 µg).


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Taneepanichskul 2002

MethodsOne site in Thailand.
Three-month wash-out period for OC users. 12 treatment cycles.
Unblinded.


ParticipantsWomen aged 18 to 35 years, willing to use contraception for over 12 complete cycles with at least a three-month washout period.
Excluded contraindications to OC use; liver, vascular or metabolic diseases; tumor; pregnancy; unclassified and genital bleeding.


InterventionsEE 20 µg and gestodene 75 µg (N=76) versus EE 30 µg and gestodene 75 µg (N=74).


OutcomesContraceptive efficacy, cycle control, and side effects.
'Regular' cycle was defined as periodic withdrawal bleeding every 28±7days.
'Breakthrough bleeding' was defined as intermenstrual bleeding that did not require sanitary protection.


NotesRandomization method not reported.
76% (114/150) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Teichmann 1995

MethodsOne site in Poland.
Two pretreatment and 12 treatment cycles.
Blinding not described.


ParticipantsHealthy, normal-weight, sexually active women aged 19 to 40 years seeking oral contraception with regular menses.
Excluded recent hormonal medication and certain other drugs; smokers; and contraindications to oral contraception.


InterventionsEE 20 µg and desogestrel 150 µg versus EE 30 µg and gestodene 75 µg.
500 women randomized; initial number assigned to each study group not reported.


OutcomesContraceptive efficacy, discontinuation, adverse events, and follicle growth.
Bleeding terms not defined.


NotesAllocated according to a randomization list in chronological order.
Excluded randomized women from the analysis.
63% (314/500) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

WHO 1982

Methods10 sites in unreported location(s).
24 treatment cycles.
Clinic staff and participants blinded.
Pills were repackaged in packets and identified only by random number.


ParticipantsHealthy women aged 18 to 38 with regular menses.
Excluded contraindications for oral contraceptive use; postpartum; lactation; and recent oral or injectable contraception.


InterventionsEE 20 µg and norethisterone acetate 1.0 mg (N=448) versus EE 35 µg and norethisterone acetate 400 µg (N=434) versus EE 50 µg and levonorgestrel 150 µg (N=435) versus EE 30 µg and levonorgestrel 150 µg (N=430) versus mestranol 50 µg and norethisterone 1.0 mg (N=436) versus EE 50 µg and norethisterone acetate 1.0 mg (N=431).


OutcomesContraceptive efficacy, discontinuation, and cycle control.
'Segments' were defined as the start of one menstrual-like bleeding episode to the start of the next. 'Infrequent' bleeding defined as when the longest menstrual segment was greater than 35 days and not over 60 days. 'Frequent' bleeding defined as when the shortest complete menstrual segment was less than 24 days. 'Irregular' bleeding defined as when the shortest complete segment was less than 24 days and the longest segment was greater than 35 days. 'Prolonged' bleeding defined as when bleeding or spotting episode was longer than 7 days.


NotesRandomization method not reported.
Excluded randomized women from the analysis.
46% (1196/2614) completed study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

Winkler 1996

MethodsOne site in unreported location.
Duration: 2 pretreatment cycles, 6 treatment cycles, and 1 post-treatment cycle.
Unblinded.


ParticipantsHealthy women aged 18 to 30 with regular menses.
Excluded contraindications to oral contraceptive use; smoking; and certain drugs.


InterventionsEE 20 µg and gestodene 75 µg (N=20) versus EE 30 µg and gestodene 75 µg (N=20).


OutcomesHemostatic values.
Did not report bleeding outcomes.


NotesRandomization method not reported.
Number completing study not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot reported

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bassol 2000The sum of the percentages of women completing the study and withdrawing appears to be greater than 100%.

Lawson 1979Initiated as randomized controlled trial but some participants were re-assigned treatments in a nonrandom manner during the trial.

Marr 2012Not an RCT; analysis involved pooling data from two uncontrolled trials.

Rosenberg 1996Reported bleeding and spotting outcomes by percentages without providing absolute numbers.

Westhoff 2005Ring released EE < 20 mcg; OC contained EE 25 mcg

Wiegratz 2003Reported relevant outcomes by percentages without providing absolute numbers.

 
Comparison 1. EE 20 µg and desogestrel 150 µg versus EE 30 µg and desogestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1982Peto Odds Ratio (Peto, Fixed, 95% CI)0.69 [0.12, 3.97]

 2 Discontinuation - overall11000Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.92, 1.56]

 3 Discontinuation - mood changes11000Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.68, 3.33]

 4 Discontinuation - irregular bleeding11000Peto Odds Ratio (Peto, Fixed, 95% CI)2.59 [1.35, 5.00]

 5 Discontinuation - nausea158Peto Odds Ratio (Peto, Fixed, 95% CI)0.75 [0.04, 12.64]

 6 Amenorrhea - cycle 31778Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.75, 2.97]

 7 Amenorrhea - cycle 61721Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.65, 3.12]

 8 Irregular bleeding - cycle 31778Peto Odds Ratio (Peto, Fixed, 95% CI)1.56 [1.10, 2.20]

 9 Duration of irregular bleeding in days - cycle 31778Mean Difference (IV, Fixed, 95% CI)0.70 [0.30, 1.10]

 10 Duration of irregular bleeding in days - cycle 61721Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.46, 0.26]

 11 Dizziness1982Peto Odds Ratio (Peto, Fixed, 95% CI)7.65 [1.54, 38.08]

 12 Dysmenorrhea1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.46 [0.70, 3.06]

 13 Headache1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.71 [0.94, 3.11]

 14 Increased weight1982Peto Odds Ratio (Peto, Fixed, 95% CI)2.46 [1.04, 5.84]

 15 Irregular bleeding1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.69 [1.07, 2.69]

 16 Mood change1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.93 [1.05, 3.56]

 17 Nausea, diarrhea, vomiting1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.42 [0.74, 2.72]

 18 Prolonged withdrawal bleeding1982Peto Odds Ratio (Peto, Fixed, 95% CI)1.98 [1.03, 3.78]

 
Comparison 2. EE 20 µg and desogestrel 150 µg versus EE 50 µg and desogestrel 125 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Breakthough bleeding - cycles 1 to 3140Peto Odds Ratio (Peto, Fixed, 95% CI)8.23 [0.81, 84.07]

 2 Breakthrough spotting - cycles 1 to 3140Peto Odds Ratio (Peto, Fixed, 95% CI)7.79 [0.47, 129.11]

 3 Acne140Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 2.13]

 4 Breast tenderness140Peto Odds Ratio (Peto, Fixed, 95% CI)1.0 [0.13, 7.69]

 5 Headache140Peto Odds Ratio (Peto, Fixed, 95% CI)0.14 [0.00, 6.82]

 6 Weight gain140Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 2.13]

 
Comparison 3. EE 20 µg and desogestrel 150 µg versus EE 30 µg and gestodene 75 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman22027Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.20, 4.96]

 2 Discontinuation - overall33033Peto Odds Ratio (Peto, Fixed, 95% CI)1.03 [0.85, 1.26]

 3 Discontinuation - abdominal pain1416Peto Odds Ratio (Peto, Fixed, 95% CI)1.49 [0.43, 5.22]

 4 Discontinuation - adverse event33033Peto Odds Ratio (Peto, Fixed, 95% CI)1.28 [0.98, 1.68]

 5 Discontinuation - breast tension1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.51 [0.05, 4.90]

 6 Discontinuation - colpitis1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.06, 15.89]

 7 Discontinuation - depressive mood1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.51 [0.05, 4.90]

 8 Discontinuation - dizziness1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.43 [1.04, 53.09]

 9 Discontinuation - headache1416Peto Odds Ratio (Peto, Fixed, 95% CI)1.24 [0.33, 4.65]

 10 Discontinuation - hypertension1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.32 [0.15, 368.86]

 11 Discontinuation - hypomenorrhea11006Peto Odds Ratio (Peto, Fixed, 95% CI)7.46 [0.47, 119.49]

 12 Discontinuation - intermenstrual bleeding1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.74 [0.17, 3.30]

 13 Discontinuation - menorrhagia11006Peto Odds Ratio (Peto, Fixed, 95% CI)1.01 [0.14, 7.18]

 14 Discontinuation - menstrual disorder11006Peto Odds Ratio (Peto, Fixed, 95% CI)0.52 [0.05, 4.98]

 15 Discontinuation - metrorrhagia22617Peto Odds Ratio (Peto, Fixed, 95% CI)2.35 [1.16, 4.77]

 16 Discontinuation - nausea1416Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.24, 4.01]

 17 Discontinuation - nervousness1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.39 [0.76, 71.43]

 18 Discontinuation - pruritus1416Peto Odds Ratio (Peto, Fixed, 95% CI)7.32 [0.15, 368.86]

 19 Discontinuation - vomiting1416Peto Odds Ratio (Peto, Fixed, 95% CI)3.82 [0.76, 19.10]

 20 Irregular bleeding - cycle 31910Peto Odds Ratio (Peto, Fixed, 95% CI)2.51 [1.77, 3.56]

 21 Irregular bleeding - cycle 61823Peto Odds Ratio (Peto, Fixed, 95% CI)1.72 [1.15, 2.55]

 22 Amenorrhea - cycle 31910Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [0.83, 6.82]

 23 Amenorrhea - cycle 61823Peto Odds Ratio (Peto, Fixed, 95% CI)0.37 [0.09, 1.47]

 24 Abdominal pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.19 [0.71, 2.01]

 25 Acne11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.46, 1.91]

 26 Breast pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.85 [0.56, 1.30]

 27 Decreased libido11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.64 [0.25, 1.62]

 28 Depression11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.76 [0.40, 1.46]

 29 Dizziness11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.60 [0.23, 1.62]

 30 Dysmenorrhea11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.48, 1.85]

 31 Emotional lability11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.72 [0.38, 1.38]

 32 Flatulence11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.59 [0.24, 1.45]

 33 Headache11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.08 [0.81, 1.42]

 34 Menstrual disorder11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.41, 2.42]

 35 Metrorrhagia11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.67 [1.05, 2.66]

 36 Migraine11611Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [0.83, 6.80]

 37 Nausea11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.68, 1.95]

 38 Pain11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.37 [0.63, 2.97]

 39 Vaginal moniliasis11611Peto Odds Ratio (Peto, Fixed, 95% CI)1.45 [0.62, 3.36]

 40 Vomiting11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.48 [0.19, 1.17]

 41 Weight gain11611Peto Odds Ratio (Peto, Fixed, 95% CI)0.68 [0.34, 1.38]

 42 Weight gain in kg1805Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.40, -0.00]

 
Comparison 4. EE 20 µg and desogestrel 150 µg versus EE 30-40-30 µg and gestodene 50-70-100 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.14, 7.14]

 2 Discontinuation - overall11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.07 [0.82, 1.40]

 3 Discontinuation - adverse reaction11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.35 [0.91, 1.99]

 4 Discontinuation - metrorrhagia11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.97 [1.00, 8.85]

 5 Abdominal pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.71, 2.01]

 6 Acne11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.75 [0.38, 1.46]

 7 Breast pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.70 [0.47, 1.05]

 8 Decreased libido11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.00 [0.35, 2.87]

 9 Depression11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.07 [0.53, 2.18]

 10 Dizziness11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.40 [0.17, 0.93]

 11 Dysmenorrhea11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.22 [0.60, 2.49]

 12 Emotional lability11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.89 [0.45, 1.76]

 13 Flatulence11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.17 [0.39, 3.49]

 14 Headache11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.04 [0.78, 1.37]

 15 Menstrual disorder11613Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.55, 3.73]

 16 Metrorrhagia11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.28 [1.39, 3.73]

 17 Migraine11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.83 [0.36, 1.94]

 18 Nausea11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.73 [0.46, 1.17]

 19 Pain11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.10 [0.90, 4.86]

 20 Vaginal moniliasis11613Peto Odds Ratio (Peto, Fixed, 95% CI)2.11 [0.86, 5.22]

 21 Vomiting11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.29, 2.56]

 22 Weight gain11613Peto Odds Ratio (Peto, Fixed, 95% CI)0.62 [0.31, 1.22]

 
Comparison 5. EE 20 µg and desogestrel 150 µg versus EE 35 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1309Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 1.30]

 
Comparison 6. EE 20 µg and gestodene 75 µg versus EE 30 µg and gestodene 75 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman2799Peto Odds Ratio (Peto, Fixed, 95% CI)0.23 [0.02, 2.55]

 2 Discontinuation - overall2799Peto Odds Ratio (Peto, Fixed, 95% CI)1.14 [0.80, 1.63]

 3 Discontinuation - adverse event3753Peto Odds Ratio (Peto, Fixed, 95% CI)1.46 [0.86, 2.46]

 4 Discontinuation - intermenstrual bleeding164Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Discontinuation - metrorrhagia140Peto Odds Ratio (Peto, Fixed, 95% CI)0.14 [0.00, 6.82]

 6 Breakthrough bleeding - cycle 31114Peto Odds Ratio (Peto, Fixed, 95% CI)6.90 [0.14, 348.82]

 7 Breakthrough bleeding - cycle 61114Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.00, 6.36]

 8 Spotting - cycle 31114Peto Odds Ratio (Peto, Fixed, 95% CI)0.61 [0.10, 3.66]

 9 Spotting - cycle 61114Peto Odds Ratio (Peto, Fixed, 95% CI)0.93 [0.06, 15.10]

 10 Acne2707Peto Odds Ratio (Peto, Fixed, 95% CI)1.35 [0.60, 3.08]

 11 Breast tension or tenderness3821Peto Odds Ratio (Peto, Fixed, 95% CI)1.18 [0.68, 2.05]

 12 Change in libido1649Peto Odds Ratio (Peto, Fixed, 95% CI)1.72 [0.64, 4.61]

 13 Chloasma1114Peto Odds Ratio (Peto, Fixed, 95% CI)0.93 [0.13, 6.79]

 14 Depressive moods2707Peto Odds Ratio (Peto, Fixed, 95% CI)2.12 [0.80, 5.66]

 15 Diarrhea1114Peto Odds Ratio (Peto, Fixed, 95% CI)0.33 [0.05, 2.43]

 16 Dizziness2763Peto Odds Ratio (Peto, Fixed, 95% CI)1.52 [0.57, 4.02]

 17 Edema1649Peto Odds Ratio (Peto, Fixed, 95% CI)0.49 [0.09, 2.66]

 18 Headache2707Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.60, 1.59]

 19 Nausea2707Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.66, 2.45]

 20 Nausea and vomiting1114Peto Odds Ratio (Peto, Fixed, 95% CI)1.84 [0.19, 18.04]

 21 Nervousness1649Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.59, 3.87]

 22 Varicose conditions1649Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.20, 3.72]

 23 Vomiting2707Peto Odds Ratio (Peto, Fixed, 95% CI)0.68 [0.20, 2.25]

 24 Weight gain >2 kg1452Peto Odds Ratio (Peto, Fixed, 95% CI)1.06 [0.63, 1.81]

 25 Weight gain in kg1114Mean Difference (IV, Fixed, 95% CI)-1.5 [-4.23, 1.23]

 
Comparison 7. EE 20 µg and gestodene 75 µg (23-day) versus EE 30 µg and gestodene 75 µg (21-day)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman169Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.00, 6.63]

 2 Intracyclic bleeding - cycle 1 and at least once during cycles 2 to 6166Peto Odds Ratio (Peto, Fixed, 95% CI)0.11 [0.02, 0.46]

 
Comparison 8. EE 20 µg and levonorgestrel 100 µg versus EE 35 µg and norethindrone 500-750-1000 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman2729Peto Odds Ratio (Peto, Fixed, 95% CI)0.52 [0.10, 2.60]

 2 Discontinuation - overall2729Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.78, 1.73]

 3 Discontinuation - adverse events2729Peto Odds Ratio (Peto, Fixed, 95% CI)1.44 [0.86, 2.41]

 4 Discontinuation - breakthrough bleeding1387Peto Odds Ratio (Peto, Fixed, 95% CI)2.78 [0.39, 19.91]

 5 Discontinuation - headache1387Peto Odds Ratio (Peto, Fixed, 95% CI)3.42 [0.59, 19.90]

 6 Discontinuation - nausea or vomiting1387Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.34, 4.77]

 7 Intermenstrual bleeding - cycle 32420Peto Odds Ratio (Peto, Fixed, 95% CI)0.85 [0.57, 1.26]

 8 Amenorrhea - cycle 32420Peto Odds Ratio (Peto, Fixed, 95% CI)1.43 [0.32, 6.34]

 9 Breast pain1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.22, 0.93]

 10 Dysmenorrhea1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.82 [0.49, 1.36]

 11 Headache1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.94 [0.57, 1.56]

 12 Nausea1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.74 [0.40, 1.36]

 13 Vomiting1289Peto Odds Ratio (Peto, Fixed, 95% CI)0.33 [0.11, 0.96]

 
Comparison 9. EE 20 µg and levonorgestrel 100 µg versus EE 35 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1309Peto Odds Ratio (Peto, Fixed, 95% CI)0.37 [0.05, 2.63]

 
Comparison 10. EE 20 µg and norethindrone acetate 1 mg versus EE 30 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman1110Peto Odds Ratio (Peto, Fixed, 95% CI)2.80 [0.38, 20.41]

 2 Discontinuation - bleeding1110Peto Odds Ratio (Peto, Fixed, 95% CI)5.38 [1.82, 15.91]

 3 Frequent bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)2.92 [2.08, 4.09]

 4 Infrequent bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)2.84 [1.80, 4.46]

 5 Irregular bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)4.01 [2.12, 7.61]

 6 Prolonged bleeding - cycles 1 to 31629Peto Odds Ratio (Peto, Fixed, 95% CI)1.51 [0.94, 2.43]

 
Comparison 11. EE 20 µg and norethindrone acetate 1 mg versus EE 50 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)4.59 [3.24, 6.51]

 2 Infrequent bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)3.08 [1.95, 4.86]

 3 Irregular bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)5.33 [2.74, 10.34]

 4 Prolonged bleeding - cycles 1 to 31631Peto Odds Ratio (Peto, Fixed, 95% CI)3.11 [1.83, 5.27]

 
Comparison 12. EE 20 µg and norethindrone acetate 1 mg versus EE 30 µg and norethindrone acetate 1.5 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of breakthrough bleeding or spotting in days - cycle 31228Mean Difference (IV, Fixed, 95% CI)1.1 [0.37, 1.83]

 2 Amenorrhea - cycle 31228Peto Odds Ratio (Peto, Fixed, 95% CI)2.17 [0.68, 6.93]

 
Comparison 13. EE 20 µg and norethindrone acetate 1 mg versus EE 50 µg and norethindrone acetate 1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of breakthrough bleeding or spotting in days - cycle 31214Mean Difference (IV, Fixed, 95% CI)1.20 [0.43, 1.97]

 2 Amenorrhea - cycle 31215Peto Odds Ratio (Peto, Fixed, 95% CI)3.34 [0.94, 11.84]

 3 Frequent bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.97 [1.42, 2.73]

 4 Infrequent bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.95 [1.27, 3.00]

 5 Irregular bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)2.38 [1.31, 4.31]

 6 Prolonged bleeding - cycles 1 to 31626Peto Odds Ratio (Peto, Fixed, 95% CI)1.27 [0.80, 2.02]

 
Comparison 14. EE 20 µg and norethindrone acetate 1 mg versus EE 20-30-50 µg and norethindrone acetate 1-1.5-1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of bleeding or spotting in days - cycle 31219Mean Difference (IV, Fixed, 95% CI)1.6 [0.94, 2.26]

 2 Amenorrhea - cycle 31221Peto Odds Ratio (Peto, Fixed, 95% CI)2.04 [0.64, 6.50]

 
Comparison 15. EE 20 µg and norethindrone acetate 1 mg versus EE 35 µg and norethindrone acetate 400 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)0.87 [0.64, 1.20]

 2 Infrequent bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)1.88 [1.22, 2.90]

 3 Irregular bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)1.92 [1.08, 3.43]

 4 Prolonged bleeding - cycles 1 to 31616Peto Odds Ratio (Peto, Fixed, 95% CI)0.91 [0.59, 1.41]

 
Comparison 16. EE 20 µg and norethindrone acetate 1 mg versus mestranol 50 µg and norethindrone 1 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Frequent bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.82 [2.00, 3.97]

 2 Infrequent bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.49 [1.58, 3.91]

 3 Irregular bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)4.85 [2.49, 9.43]

 4 Prolonged bleeding - cycles 1 to 31602Peto Odds Ratio (Peto, Fixed, 95% CI)2.67 [1.58, 4.52]

 
Comparison 17. EE 20 µg and norethindrone acetate 1 mg versus EE 25 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman12814Peto Odds Ratio (Peto, Fixed, 95% CI)1.41 [0.74, 2.68]

 2 Discontinuation - overall12894Peto Odds Ratio (Peto, Fixed, 95% CI)0.98 [0.81, 1.18]

 3 Discontinuation - adverse events12894Peto Odds Ratio (Peto, Fixed, 95% CI)0.79 [0.54, 1.16]

 4 Breakthrough bleeding - cycle 312330Peto Odds Ratio (Peto, Fixed, 95% CI)2.79 [2.09, 3.74]

 5 Breakthrough bleeding - cycle 612118Peto Odds Ratio (Peto, Fixed, 95% CI)2.40 [1.78, 3.24]

 6 Breakthrough bleeding or spotting - cycle 312330Peto Odds Ratio (Peto, Fixed, 95% CI)2.32 [1.85, 2.90]

 7 Breakthrough bleeding or spotting - cycle 612118Peto Odds Ratio (Peto, Fixed, 95% CI)2.51 [1.97, 3.20]

 8 Unscheduled bleeding - cycle 312478Peto Odds Ratio (Peto, Fixed, 95% CI)1.92 [1.61, 2.29]

 9 Unscheduled bleeding - cycle 612222Peto Odds Ratio (Peto, Fixed, 95% CI)1.91 [1.58, 2.32]

 10 Weight loss, maintenance, or gain <5% - cycle 612157Peto Odds Ratio (Peto, Fixed, 95% CI)1.16 [0.92, 1.46]

 
Comparison 18. EE 20 µg and drospirenone 3 mg versus EE 30 µg and drospirenone 3 mg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman150Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 19. EE 20 µg and drospirenone 3 mg versus EE 25 µg and norgestimate 180-215-250 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Unscheduled bleeding days - cycle 31332Mean Difference (IV, Fixed, 95% CI)1.0 [0.44, 1.56]

 
Comparison 20. EE 20 µg and levonorgestrel 100 µg versus EE 30 µg and levonorgestrel 150 µg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy per woman170Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Adverse events170Peto Odds Ratio (Peto, Fixed, 95% CI)1.57 [0.62, 3.98]

 
Table 1. Twenty µg estrogen combination oral contraceptive

FormulationBrand nameManufacturer

150 µg desogestrel and 20 µg EECiclidon 20Lafi S.A.

Cycleane-20G D Searle & Co

DalOsteolab

Desmin 20Grunenthal GmbH

Desoren 20Beta-Grunenthal

FemilonOrganon International NV

Lovelle

Marvelon 20

Mercilon

Mircette

Myralon

Securgin

Segurin

Suavuret

FeminaAche Laboratorios Farmaceuticos S/A

Gedarel 20/150Consilient Health Ltd

Gynostat-20Pharmatrade S.A.

Lovina 20Hexal

Midalet 20Silesia

Neolette

NovynetteGedeon Richter

75 µg gestodene and 20 µg EECiclomex 20Pharmafina S.A.

DiminutLibbs

Estinette 20Effik Group

FedraSchering AG

Femiane

Femodette

Gynera 75/20

Gynovin 20

Logest

Meliane

Meloden

Melodene

Minigeste

Femadiol-Mepha 20Mepha Pharma AG

Feminol-20Pharmatrade S.A.

Gyselle 20Spirig Pharma Ltd

HarmonetWyeth-Ayerst International Inc

Lerogin 20Recalcine

Lindynette 20Gedeon Richter, Ltd

MicrogenSilesia

MillinetteConsilient Health Ltd

MinifemUrufarma

SunyaStratgen Pharma SA

100 µg levonorgestrel and 20 µg EEAlesseWyeth-Ayerst International Inc

Leois

Loette

Loette 21

Lovette

Anulette 20Silesia

AprllGador

Elyfem 20Berlis

FemexinUrufarma

LevliteBerlex Inc - subsidiary of Schering AG

Microgynon 20Schering AG

Microgynon 20 ED

Microgynon Suave

Microlite

Miranova

MicrolevlenBayer HealthCare

Minisiston

NorvetalRecalcine

500 µg norethisterone and 20 µg EEEveGrunenthal

1000 µg norethisterone acetate and 20 µg EELoestrinPfizer Inc

Loestrin 1/20

Loestrin 20

Loestrin 21 1/20

Loestrin Fe 1/20+

Minestril-20

Minestrin 1/20

3 mg drospirenone and 20 µg EEAlianeBayer HealthCare

Beyaz

Dschess

Dzhess

Eloine

Jasminelle

Jasminellecontinu

Liofora

Yasmin 24/4

Yasminelle

Yasminique

YAZ

DivaUrufarma

 
Table 2. Fifteen µg estrogen combination oral contraceptive

FormulationBrand nameManufacturer

60 µg gestodene and 15 µg EEAriannaBayer HealthCare

CarezaSilesia

Meliane LightSchering AG

Melodene 15

Melodia

Mirelle

MinesseWyeth-Ayerst International Inc

Secret 28Urufarma

 
Table 3. Pregnancy

Study IDEffect measureOCRate95% CIP value log rank test

Akerlund 1993Pearl index (12 cycle)EE 20 µg and desogestrel 150 µg0.4(0.0 to 1.5)

EE 30 µg and desogestrel 150 µg0.6(0.1 to 1.6)

Hampton 2001Kaplan-Meier (13 cycle)EE 20 µg and norethindrone acetate 1 mg2.6(1.1 to 4.2)

EE 25 µg and norgestimate 180-215-250 µg1.9(0.8 to 2.9)

WHO 1982Life-table (676 days)EE 20 µg and norethindrone acetate 1 mg5.00.07

EE 30 µg and levonorgestrel 150 µg5.1

EE 50 µg and levonorgestrel 150 µg4.2

Mestranol 50 µg and norethistrone 1 mg1.0

EE 35 µg and norethindrone acetate 400 µg6.0

EE 50 µg and norethindrone acetate 1 mg4.2

 
Table 4. Lifetable discontinuation at 676 days per 100 women (WHO 1982)

Effect estimateOCRateP value log rank test

OverallEE 20 µg and norethisterone acetate 1 mg68.80.04

EE 30 µg and levonorgestrel 150 µg62.0

EE 50 µg and levonorgestrel 150 µg60.6

Mestranol 50 µg and norethistrone 1 mg60.4

EE 35 µg and norethisterone acetate 400 µg63.5

EE 50 µg and norethindrone acetate 1 mg64.9

Due to medical reasonsEE 20 µg and norethisterone acetate 1 mg46.40.00

EE 30 µg and levonorgestrel 150 µg35.0

EE 50 µg and levonorgestrel 150 µg33.8

Mestranol 50 µg and norethistrone 1 mg30.9

EE 35 µg and norethisterone acetate 400 µg39.4

EE 50 µg and norethindrone acetate 1 mg40.3

Due to amenorrheaEE 20 µg and norethisterone acetate 1 mg13.70.00

EE 30 µg and levonorgestrel 150 µg1.5

EE 50 µg and levonorgestrel 150 µg0.5

Mestranol 50 µg and norethistrone 1 mg3.3

EE 35 µg and norethisterone acetate 400 µg2.6

EE 50 µg and norethindrone acetate 1 mg3.3

Due to irregular bleedingEE 20 µg and norethisterone acetate 1 mg4.20.00

EE 30 µg and levonorgestrel 150 µg2.8

EE 50 µg and levonorgestrel 150 µg2.6

Mestranol 50 µg and norethistrone 1 mg2.8

EE 35 µg and norethisterone acetate 400 µg8.5

EE 50 µg and norethindrone acetate 1 mg6.2

Due to prolonged bleedingEE 20 µg and norethisterone acetate 1 mg1.80.26

EE 30 µg and levonorgestrel 150 µg0.3

EE 50 µg and levonorgestrel 150 µg0.7

Mestranol 50 µg and norethistrone 1 mg0.3

EE 35 µg and norethisterone acetate 400 µg1.5

EE 50 µg and norethindrone acetate 1 mg1.2

Due to light bleedingEE 20 µg and norethisterone acetate 1 mg2.40.13

EE 30 µg and levonorgestrel 150 µg0.0

EE 50 µg and levonorgestrel 150 µg1.2

Mestranol 50 µg and norethistrone 1 mg2.2

EE 35 µg and norethisterone acetate 400 µg1.6

EE 50 µg and norethindrone acetate 1 mg2.0

Due to spottingEE 20 µg and norethisterone acetate 1 mg5.30.00

EE 30 µg and levonorgestrel 150 µg2.8

EE 50 µg and levonorgestrel 150 µg2.9

Mestranol 50 µg and norethistrone 1 mg2.8

EE 35 µg and norethisterone acetate 400 µg9.0

EE 50 mcg and norethindrone acetate 1 mg6.8