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Combined oral contraceptives: venous thrombosis

  1. Marcos de Bastos1,
  2. Bernardine H. Stegeman2,
  3. Frits R. Rosendaal3,
  4. Astrid Van Hylckama Vlieg4,
  5. Frans M Helmerhorst5,
  6. Theo Stijnen6,
  7. Olaf M Dekkers4,*

Editorial Group: Cochrane Fertility Regulation Group

Published Online: 3 MAR 2014

Assessed as up-to-date: 30 DEC 2013

DOI: 10.1002/14651858.CD010813.pub2


How to Cite

de Bastos M, Stegeman BH, Rosendaal FR, Van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, Dekkers OM. Combined oral contraceptives: venous thrombosis. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD010813. DOI: 10.1002/14651858.CD010813.pub2.

Author Information

  1. 1

    Instituto Previdencia dos Servidores do Estado de Minas Gerais, Minas Gerais, Brazil

  2. 2

    University College London, Department of Epidemiology and Public Health, London, UK

  3. 3

    Leiden University Medical Center, Epidemiology, Leiden, Netherlands

  4. 4

    Leiden University Medical Center, Department of Clinical Epidemiology, Leiden, Netherlands

  5. 5

    Leiden University Medical Center, Department of Gynaecology, Division of Reproductive Medicine and Dept. of Clinical Epidemiology, Leiden, Netherlands

  6. 6

    Leiden University Medical Center, Department of Medical Statistics, Leiden, Netherlands

*Olaf M Dekkers, Department of Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300RC, Netherlands. o.m.dekkers@lumc.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 3 MAR 2014

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Characteristics of included studies [ordered by study ID]
Andersen 1998

MethodsCase control study


Participants67 cases / 134 controls (hospital discharge)

diagnosis: anticoagulation


Interventions3rd generation


OutcomesEvents during 3rd generation: 16 / 23. Non-use: 27 / 133.

Adjustment for confounding: yes (matched)


NotesDenmark

Bird 2013

Methodscohort study


Participants2001-2009

432,178 women / 263,902 women years (healthcare plan)

age: 18-46 y

diagnosis: anticoagulation


Interventions2nd generation and Drospirenone


OutcomesEvents during 2nd generation: 118 / 132,681. Drospirenone: 236 / 131,221.

Adjustment for confounding: yes


NotesUSA

Bloemenkamp 1995

Methodscase control study


Participants1988-1995

126 cases / 159 controls (community based)

age: 15-49 y

diagnosis: anticoagulation


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st genaration: 8 / 13; 2nd generation 20 / 38; 3rd generation 37 / 52. Non-use: 46 / 150 .

Adjustment for confounding: yes


NotesThe Netherlands

Bloemenkamp 1999

Methodscase control study


Participants1982-1995

185 cases / 591 controls (community based)

age: 15-49 y

diagnosis: anticoagulation


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st genaration: 18 / 46; 2nd generation 8 / 22; 3rd generation 33 / 67. Non-use: 83 / 511.

Adjustment for confounding: yes


NotesThe Netherlands

Farmer 1996

Methodscohort study


Participants30 cases / 697,000 women (general practioners database)

age 14-45 y

diagnosis: anticoagulation


Interventions2nd and 3rd generation


OutcomesEvents using during 2nd generation 14 / 76,600; 3rd generation 15 / 65,100.

Adjustment for confounding: yes


NotesUnited Kingdom

Farmer 1998

Methodscase control study


Participants1992-1995

42 cases / 168 controls (healthcare plan)

age: 18-49 y

diagnosis: anticoagulation


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 27 / 116; 3rd generation 15 / 79.

Adjustment for confounding: yes (matched)


NotesGermany

Farmer 2000

Methodscohort study


Participants1992-1997

287 cases / 783,876 women years (prescription database)

age: 15-49 y

diagnosis: ad hoc


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st generation: 12 / 39,421; 2nd generation 98 / 307,070; 3rd generation 161 / 374,129.

Adjustment for confounding: no


NotesUnited Kingdom ('General Practice Research Database', GRPD)

Gronich 2011

Methodscohort study


Participants2002-2008

329,995 women / 819,749 women years (healthcare plan)

age: 12-50 y

diagnosis: ad hoc


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 23 / 33,187; 3rd generation 384 / 651,455.

Adjustment for confounding: yes


NotesIsrael

Hedenmalm 2004

Methodscohort study


Participants1965-2001

172 cases / 10,016,194 treatment years (community based)

diagnosis: medical records


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st generation 36 / 1,898,899; 2nd generation 74 / 6,343,562; 3rd generation 83 / 1,739,393.

Adjustment for confounding: no


NotesSweden

Heinemann 2002

Methodscase control study


Participants1994-1999

606 cases / 2,942 controls (community based)

age: 15-49 y

diagnosis: clinical criteria


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st generation 45 / 190; 2nd generation 131 / 865; 3rd generation 28 / 195. Non-use 246 / 2,115.

Adjustment for confounding: yes


NotesGermany

Heinemann 2010

Methodscase control study


Participants2002-2006

451 cases / 1,920 controls (community based)

age: 15-49 y

diagnosis: clinical criteria


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 61 / 245; 3rd generation 62 / 238; Non-use 70 / 1,215.

Adjustment for confounding: yes


NotesAustria

Herings 1999

Methodscohort study


Participants1986-1995

33 cases / 450,000 women (prescription database)

age: 15-49 y

diagnosis: ad hoc


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 29 / 121,411; 3rd generation 49 / 88,295.

Adjustment for confounding: yes


NotesThe Netherlands

Jick 2006

Methodsnested case control study


Participants2000-2005

281 cases / 1,055 controls (claims database)

age: 15-39 y

diagnosis: anticoagulation


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 70 / 386; 3rd generation 211 / 950.

Adjustment for confounding: yes (matched)


NotesUSA

Jick 2011

Methodsnested case control study


Participants2002-2008

186 cases / 681 controls (claims database)

age: 15-44 y

diagnosis: anticoagulation


Interventions2nd generation and Drospirenone


OutcomesEvents during 2nd generation: 65 / 433. Drospirenone: 121 / 434.

Adjustment for confounding: yes (matched)


NotesUSA

Lewis 1996

Methodscase control study


Participants1991-1995

505 cases / 1,877 controls (community based)

age: 16-45 y

diagnosis: clinical symptoms


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 96 / 419; 3rd generation 156 / 451.

Adjustment for confounding: yes (matched)


NotesUK and Germany ('Transnational study')

Lidegaard 2002

Methodscase control study


Participants1994-1998

987 cases / 4,054 controls (community based)

age: 15-44 y

diagnosis: discharges


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st generation 36 / 143; 2nd generation 98 / 296; 3rd generation 351 / 1,204. Non-use 458 / 3,196.

Adjustment for confounding: yes (matched)


NotesDenmark

Lidegaard 2011

MethodsCohort study


Participants2001-2009

1,436,310 women / 9,954,925 women years (community based)

age: 15-49 y

diagnosis: anticoagulation


Interventions1st, 2nd and 3rd generation, Cyproterone and Drospirenone


OutcomesEvents during 1st generation 21 / 34,203; 2nd generation 198 / 233,912; 3rd generation 1,747 / 2,049,368; Cyproterone 109 / 120,934; Drospirenone 289 / 309,914. Non-use 1,812 / 4,960,730.

Adjustment for confounding: yes


NotesDenmark

Martinelli 1999

Methodscase control study


Participants1995-1998

total number of women was unclear, however, numberss were available for contraceptive of interest (community based)

diagnosis: ad hoc


Interventions3rd generation


OutcomesEvents during 3rd generation 43 / 79. Non-use 41 / 179.

Adjustment for confounding: no


NotesItaly

Parkin 2000

Methodscase control study


Participants1990-1998

26 cases / 111 controls (general practioner database)

age: not postmenopausal

diagnosis: death certficate


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 3 / 11; 3rd generation 12 / 27. Non-use 9 / 95.

Adjustment for confounding: yes


NotesNew Zealand

Parkin 2011

Methodsnested case control study


Participants2002-2009

61 cases / 215 controls (general practioners database)

age: 15-44 y

diagnosis: anticoagulation


Interventions2nd generation and Drospirenone


OutcomesEvents during 2nd generation 44 / 233; Drospirenone 17 / 43.

Adjustment for confounding: yes (matched)


NotesUK

Samuelsson 2004

Methodscohort study


Participants1991-2000

88 cases / 243,723 women years (adverse events database)

age: 15-44 y

diagnosis: anticoagulation


Interventions3rd generation


OutcomesEvents during 3rd generation 17 / 14,819. Non-use 32 / 171,206.

Adjustment for confounding: no


NotesSweden

Todd 1999

Methodscohort study


Participants1992-1997

99 cases / 216,356 women years (healthcare plan)

age: 15-49 y

diagnosis: anticoagulation


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 32 / 76,993; 3rd generation 53 / 92,052.

Adjustment for confounding: no


NotesUK

van Hylckama Vlieg 2009

Methodscase control study


Participants1999-2004

1,525 cases / 1,760 controls (community based)

age: <50 y

diagnosis: anticoagulation


Interventions1st, 2nd and 3rd generation


OutcomesEvents during 1st generation 55 / 81; 2nd generation 382 / 672; 3rd generation 412 / 582. Non-use 421 / 1,523.

Adjustment for confounding: yes


NotesThe Netherlands

WHO 1995a

Methodscase control study


Participants1989-1993

WHO 1 in Europe: 433 cases / 1,044 controls

WHO 2 in developing countries: 710 cases / 1,954 controls

WHO 1 and 2: community based

age: 20-44 y

diagnosis: clinical criteria


Interventions1st, 2nd and 3rd generation


OutcomesWHO 1: Events during 1st generation 29 / 74; 2nd generation 156 / 392; 3rd generation 53 / 104. Non-use 168 / 855.

WHO 2: Events during 1st generation 26 / 65; 2nd generation 153 / 337; 3rd generation 18 / 25. Non-use 505 / 2,220.

WHO 1 and 2: adjustment for confounding: yes


NotesWHO 1: Europe

WHO 2: developing countries

WHO 1995b

Methodscase control study


Participants1989-1993

829 cases / 1,979 controls (community based)

diagnosis: clinical criteria


Interventions2nd and 3rd generation


OutcomesEvents during 2nd generation 137 / 340; 3rd generation 71 / 127. Non-use 397 / 1,916.

Adjustment for confounding: yes (matched)


NotesBrazil, Chile, Colombia, Germany, Hong Kong, Hungary, Jamaica, Thailand, UK.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Amundsen 2000No data on progestagen type or ethinylestradiol dose

Austin 2009Other hormonal contraceptives, such as transdermal patch, vaginal ring, were included

Barsoum 2010No data on progestagen type or ethinylestradiol dose

BCDSP 1973No data on progestagen type or ethinylestradiol dose

Bergendal 2012No data on progestagen type or ethinylestradiol dose

Bernstein 1986No data on progestagen type or ethinylestradiol dose

Bonifacj 1997Included recurrent venous thrombosis

Bottiger 1980No data on ethinylestradiol dose

Burnhill 1999Included progestagen-only contraceptives and retinal vein thrombosis

Diddle 1978Less than 10 venous thrombosis cases

Dinger 2007Included recurrent venous thrombosis

Dinger 2010Included recurrent venous thrombosis

Eng 2008Compared drospirenone versus other oral contraceptive users

Farmer 1997Ecologic study

Fuertes 1971Unclear reference group

Gerstman 1991Incomplete data on contraceptive use

Girolami 2004Included not only venous thrombosis

Grodstein 1996No data on progestagen type or ethinylestradiol dose

Grounds 1974Included not only venous thrombosis

Hall 2012No data on venous thrombosis

Hedenmalm 2005Included recurrent venous thrombosis and cerebral vein thrombosis

Heinemann 2000Report on Transnational study, already included (Lewis 1996, Lewis 1999)

Helmrich 1987Incomplete data on contraceptive use

Herings 1999aData already included: Herings 1999

Heuser 2004No extractable number of exposed and non-exposed women

Hirvonen 1990No data on progestagen type or ethinylestradiol dose

Huerta 2007No data on progestagen type or ethinylestradiol dose

Inman 1968No data on progestagen type or ethinylestradiol dose

Inman 1970No data on progestagen type or ethinylestradiol dose

IPPF 1976Communication to the editor

Kieler 2003Included recurrent venous thrombosis

Lambrekht 1986No data on venous thrombosis

Lawrenson 2000Review

Legnani 2002Included recurrent venous thrombosis

Lewis 1997Report on Transnational study, already included (Lewis 1996)

Lewis 1999bReport on Transnational study, already included: Lewis 1996, Lewis 1999)

Lewis 1999cCommentary

Lidegaard 1998aUpdated study see Lidegaard 2002

Lidegaard 1998bReview

Lidegaard 2001Review

Lidegaard 2009Updated study of this 2009 study (Lidegaard 2011) is included

Lindqvist 2009No data on progestagen type or ethinylestradiol dose

Lis 1993Publication of study protocol

Ludwig 1970Unclear what is defined as high progestagen

Martinelli 2003No data on progestagen type or ethinylestradiol dose

Meade 1980Included not only venous thrombosis

Meinel 1988Included not only venous thrombosis and no data on progestagen type or ethinylestradiol dose

Meurer 2001Review

Nightingale 20002000 443

Duplicate report on GPRD (Farmer 2000) and Mediplus Databases (Todd 1999)

Overgaard 1986No data on progestagen type or ethinylestradiol dose

Pearce 2005No comparison was included

Petitti 1979No data on progestagen type or ethinylestradiol dose

Pini 1996Included not only venous thrombosis and included recurrent venous thrombosis

Porter 1982Less than 10 venous thrombosis events

Porter 1985Less than 10 venous thrombosis events

Poulter 1996Data already included (WHO 1995)

Primignani 2005Included not only venous thrombosis

Quinn 1992No data on progestagen type or ethinylestradiol dose

RCPG 1978Included not only venous thrombosis

Realini 1997Less than 10 venous thrombosis events

Reed 2012Compared with other contraceptives

Roach 2013No data on progestagen type or ethinylestradiol dose

Seaman 2004Included recurrent venous thrombosis

Seeger 2007Included recurrent venous thrombosis

Seigel 1969No data on progestagen type or ethinylestradiol dose

Sidney 2004Incomplete data on contraceptive use

Spitzer 1993Publication of study protocol

Stolley 1975Included not only venous thrombosis

Suissa 1997Duration of contraceptive use on Transnational study, already included (Lewis 1996, Lewis 1999)

Thorogood 1992Included recurrent venous thrombosis and no data on progestagen type or ethinylestradiol dose

Tosetto 2003No data on progestagen type or ethinylestradiol dose

Tsankova 2010aCompared ever users versus never users

Tsankova 2010bNo data on progestagen type or ethinylestradiol dose

Ulmer 1997No data on progestagen type or ethinylestradiol dose

Vallee 2001Review

Van der Meer 1997Review

Vessey 1969Included recurrent venous thrombosis

Vessey 1986Incomplete data on contraceptive use

WHO 1989No data on progestagen type or ethinylestradiol dose

Worralurt 2005Included recurrent venous thrombosis and no data on progestagen type or ethinylestradiol dose

Yang 2007Exposed consisted of hormone replacement therapy users and oral contraceptive users

 
Table 1. Abbreviations

Specific abbreviationsExplanation

APCActivated protein C

APTTActivated partial thromboplastin time

CCohort study

CCCase-control study

COCCombined oral contraceptive

CTComputed axial tomography

DVTDeep-vein thrombosis

MRIMagnetic resonance imaging

NANot applicable

NCCNested case-control study

PCSProspective cohort study

PTSPost-thrombotic syndrome

RCTRandomized controlled trial

V/QVentilation-perfusion

20LNG20 μg ethinylestradiol with levonorgestrel

30LNG30 μg ethinylestradiol with levonorgestrel

50LNG50 μg ethinylestradiol with levonorgestrel

20GSD20 μg ethinylestradiol with gestodene

30GSD30 μg ethinylestradiol with gestodene

20DSG20 μg ethinylestradiol with desogestrel

30DSG30 μg ethinylestradiol with desogestrel

35NRG35 μg ethinylestradiol with norgestimate

35CPA35 μg ethinylestradiol with cyproterone acetate

30DRSP30 μg ethinylestradiol with drospirenone

 
Table 2. List of study design features

Question and checklist RCTPCSRCSNCCCC

Was there a comparison:      

Between two or more groups of participants receiving different interventions?YYYYY

Within the same group of participants over time?PNNNN

Were participants allocated to groups by:      

Concealed randomization?YNNNN

Quasi-randomization?NNNNN

Other action of researchers?NNNNN

Time differences?NNNNN

Location differences?NPPNANA

Treatment decisions?NPPNN

Participants' preferences?NPPNN

On the basis of outcome?NNNYY

Some other process? (specify)     

Which parts of the study were prospective:      

Identification of participants?YYNYN

Assessment of baseline and allocation to intervention?YYNYN

Assessment of outcomes?YYPYN

Generation of hypotheses?YYYYP

On what variables was comparability between groups assessed:      

Potential confounders?PPPPP

Baseline assessment of outcome variables?PPPNN

 RCT = randomized clinical trial
PCS = prospective cohort study
RCS = retrospective cohort study
NCC = nested case-control study
CC = case-control study
Y = yes
N = no
P = possibly
NA = not applicable
 
Table 3. Checklist for data collection/study assessment

Note: Users need to be very clear about the way in which the terms 'group' and 'cluster' are used in these tables. The above table only refers to groups, which is used in its conventional sense to mean a number of individual participants. With the exception of allocation on the basis of outcome, 'group' can be interpreted synonymously with 'intervention group'. Although individuals are nested in clusters, a cluster does not necessarily represent a fixed collection of individuals. For instance, in cluster-allocated studies, clusters are often studied at two or more time points (periods) with different collections of individuals contributing to the data collected at each time point.

Was there a comparison?

Typically, researchers compare two or more groups that receive different interventions; the groups may be studied over the same time period, or over different time periods (see below). Sometimes researchers compare outcomes in just one group but at two time points. It is also possible that researchers may have done both, i.e., studying two or more groups and measuring outcomes at more than one time point.

How were participants/clusters allocated to groups?

These items aim to describe how groups were formed. None will apply if the study does not compare two or more groups of participants. The information is often not reported or is difficult to find in a paper. The items provided cover the main ways in which groups may be formed. More than one option may apply to a single study, although some options are mutually exclusive (i.e., a study is either randomized or not).

- Randomization: Allocation was carried out on the basis of truly random sequence. Check carefully whether allocation was adequately concealed until participants were definitively recruited.

- Quasi-randomization: Allocation was done on the basis of a pseudo-random sequence, e.g., odd/even hospital number or date of birth, alternation. Note: when such methods are used, the problem is that allocation is rarely concealed.

- By other action of researchers: this is a catch-all category and further details should be noted if the researchers report them. Allocation happened as the result of some decision or system applied by the researchers. For example, participants managed in particular 'units' of provision (e.g. wards, general practices) were 'chosen' to receive the intervention and participants managed in other units to receive the control intervention.

- Time differences: Recruitment to groups did not occur contemporaneously. For example, in a historically controlled study participants in the control group are typically recruited earlier in time than participants in the intervention group; the intervention is then introduced and participants receiving the intervention are recruited. Both groups are usually recruited in the same setting. If the design was under the control of the researchers, both this option and 'other action of researchers' must be ticked for a single study. If the design 'came about' by the introduction of a new intervention, both this option and 'treatment decisions' must be ticked for a single study.

- Location differences: Two or more groups in different geographic areas were compared, and the choice of which area(s) received the intervention and control interventions was not made randomly. So, both this option and 'other action of researchers' could be ticked for a single study.

- Treatment decisions: Intervention and control groups were formed by naturally occurring variation in treatment decisions. This option is intended to reflect treatment decisions taken mainly by the clinicians responsible; the following option is intended to reflect treatment decisions made mainly on the basis of participants' preferences. If treatment preferences are uniform for particular provider 'units', or switch over time, both this option and 'location' or 'time' differences should be ticked.

- Patient preferences: Intervention and control groups were formed by naturally occurring variation in patients' preferences. This option is intended to reflect treatment decisions made mainly on the basis of patients' preferences; the previous option is intended to reflect treatment decisions taken mainly by the clinicians responsible.

- On the basis of outcome: A group of people who experienced a particular outcome of interest were compared with a group of people who did not, i.e., a case-control study. Note: this option should be ticked for papers that report analyses of multiple risk factors for a particular outcome in a large series of participants, i.e. in which the total study population is divided into those who experienced the outcome and those who did not. These studies are much closer to nested case-control studies than cohort studies, even when longitudinal data are collected prospectively for consecutive patients.

Which parts of the study were prospective?

These items aim to describe which parts of the study were conducted prospectively. In a randomized controlled trial, all four of these items would be prospective. For non-randomized trials (NRS) it is also possible that all four are prospective, although inadequate detail may be presented to discern this, particularly for generation of hypotheses. In some cohort studies, participants may be identified, and have been allocated to treatment retrospectively, but outcomes are ascertained prospectively.

On what variables was comparability of groups assessed?

These questions should identify 'before-and-after' studies. Baseline assessment of outcome variables is particularly useful when outcomes are measured on continuous scales, e.g., health status or quality of life.

Response options

Try to use only 'Yes', 'No', and 'Can't tell' response options. 'NA' should be used if a study does not report a comparison between groups.

 
Table 4. Included publications with data on generation of progestogens and reference group non-use

DesignStudyStudy designNon-use1st2nd3rd

n event / n totaln event / n totaln event / n totaln event / n total

1Bloemenkamp 1995case control46 / 1508 / 1320 / 3837 / 52

Bloemenkamp 1999case control83 / 51118 / 468 / 2233 / 67

Heinemann 2002case control246 / 2,11545 / 190131 / 86528 /195

Lidegaard 2011cohort1,812 / 4,960,73021 / 34,203198 / 233,9121,747 / 2,049,368

van Hylckama Vlieg 2009case control421 / 1,52355 / 81382 / 672412 / 582

WHO 1995a WHO 1case control168 / 85529 / 74156 / 39253 / 104

WHO 1995a WHO 2case control505 / 2,22026 / 65153 / 33718 / 25

2Heinemann 2010case control70 / 1,215-61 / 24562 / 238

Lidegaard 2002case control458 / 3,196-98 / 296351 / 1,204

Parkin 2000case control9 / 95-3 / 1112 / 27

WHO 1995bcase control397 / 1,916-137 / 34071 / 127

3Andersen 1998case control27 / 133--16 / 23

Martinelli 1999case control41 / 179--43 / 79

Samuelsson 2004cohort32 / 171,206--17 / 14,819

4Farmer 2000cohort-12 / 39,42198 / 307,070161 / 374,129

Hedenmalm 2004cohort-36 / 1,898,89974 / 6,343,56283 / 1,739,393

5Farmer 1996cohort--14 / 76,60015 / 65,100

Farmer 1998case control--27 / 11615 / 79

Gronich 2011cohort--23 / 33,187384 / 651,455

Herings 1999cohort--29 / 121,41149 / 88,295

Jick 2006nested case control--70 / 386211 / 950

Lewis 1996case control--96 / 419156 / 451

Todd 1999cohort--32 / 76,99353 / 92,052

Total can be total number of women in the group, or the total follow-up time.

Design refers to the type and number of direct comparisons provided in a single study.

Studies with the same design provide direct comparisons of exactly the same generations or same individual oral contraceptives

 
Table 5. Study specific adjusted risk estimates: generations of contraceptives

StudyComparison in RR (95% CI)


1st vs non-use2nd vs non-use3nd vs non-use1st vs 2nd3nd vs 2nd1st vs 3nd

Andersen 1998--48.6 (5.6-423)---

Bloemenkamp 1995------

Bloemenkamp 1999------

Farmer 1996------

Farmer 1998------

Farmer 2000------

Gronich 2011------

Hedenmalm 2004------

Heinemann 20028.1 (5.3-12.5)4.9 (3.5-6.9)4.3 (2.6-7.2)-0.9 (0.6-1.4)-

Heinemann 2010-6.9 (4.3-10.9)8.1 (5.0-13.1)---

Herings 1999----3.5 (1.4-8.8)-

Jick 2006------

Lewis 19966.2 (3.8-10.23.4 (2.4-4.6)5.4 (3.9-7.3)-1.6 (1.2-2.2)-

Lidegaard 20024.1 (2.4-7.1)2.9 (2.2-3.8)4.0 (3.2-4.9)1.5 (0.9-2.7)1.3 (1.0-1.8)-

Lidegaard 2011------

Martinelli 1999------

Parkin 2000------

Samuelsson 2004------

Todd 1999------

van Hylckama Vlieg 2009------

WHO 1995a WHO 1------

WHO 1995a WHO 2------

WHO 1995b------

 
Table 6. Network meta-analysis, by generation of progestogen used in combined oral contraceptives

Reference group




Non-use1st2nd3rd

Non-use1---

1st3.2 (2.0-5.1)1--

2nd2.8 (2.0-4.1)0.9 (0.6-1.4)1-

3rd3.8 (2.7-5.4)1.2 (0.8-1.9)1.3 (1.0-1.8)1

Data are in relative risk (95% CI) of venous thrombosis

 
Table 7. Included publications with data on the 3 / 10 selected contraceptives and reference group non-use (see also Table 8)

DesignStudyStudy designNon-use20 LNG30 LNG50 LNG

n event / n total




1van Hylckama Vlieg 2009Case-control421 / 1,5238 / 14485 / 85860 / 80

2Lidegaard 2011Cohort1,812 / 4,960,730-78 / 104,25131 / 23,691

3Parkin 2000Case-control9 / 95-2 / 60 / 2

4Lidegaard 2002Case-control458 / 2,738--12 / 28

5Bloemenkamp 1999Case-control83 / 511-18 / 46-

6Bloemenkamp 1995Case-control46 / 150-20 / 38-

7Farmer 2000Cohort--64 / 190,191-

8Todd 1999Cohort--22 / 49,484-

9Farmer 1996Cohort--5 / 35,800-

10Jick 2006Nested cae-control--70 / 386-

11Bird 2013Cohort-30 / 28,78256 / 58,356-

Jick 2011Nested case-control-20 / 15145 / 282-

12Parkin 2011Nested case-control--44 / 233-

13Lewis 1996Case-control----

Design refers to the type and number of direct comparisons provided in a single study.


Studies with the same design provide direct comparisons of exactly the same generations or same individual oral contraceptives.

 
Table 8. Included publications with data on the 7 / 10 selected contraceptives and reference group non-use (continuation of Table 7)

DesignStudyStudy designNon-use20 GSD30 GSD20 DSG30 DSG35 NRG35 CPA30 DRSP

n event / n total




1van Hylckama Vlieg 2009Case-control421 / 1,52314 / 32119 / 18658 / 85289 / 3979 / 13125 / 18719 / 33

2Lidegaard 2011Cohort1,812 / 4,960,730321 / 472,118738 / 668,355322 / 470,982201 / 170,249165 / 267,664109 / 120,934266 / 286,859

3Parkin 2000Case-control9 / 95-5 / 104 / 93 / 8-2 / 3-

4Lidegaard 2002Case-control458 / 2,7386 / 36206 / 69258 / 18763 / 15318 / 118--

5Bloemenkamp 1999Case-control83 / 511-5 / 96 / 722 / 51---

6Bloemenkamp 1995Case-control46 / 150---37 / 52---

7Farmer 2000Cohort--63 / 143,58118 / 37,58465 / 152,52415 / 40,44016 / 25,709-

8Todd 1999Cohort--21 / 41,9479 / 10,42623 / 39,679---

9Farmer 1996Cohort--5 / 30,500-10 / 34,600---

10Jick 2006Nested case-control----87 / 315124/635--

11Bird 2013Cohort-------151/96217

Jick 2011Nested case-control-------121/434

12Parkin 2011Nested case-control-------17/43

13Lewis 1996Case-control---15 / 5164 / 17419 / 50--

Design refers to the type and number of direct comparisons provided in a single study.

Studies with the same design provide direct comparisons of exactly the same generations or same individual oral contraceptives.

 
Table 9. Study specific adjusted risk estimates: per combined oral contraceptive in RR (95% CI) part I

ComparisonsStudy


van Hylckama Vlieg 2009Lidegaard 2011Parkin 2000Lidegaard 2002Bloemenkamp 1999Bloemenkamp 1995

20LNG vs non-use------

30LNG vs non-use3.6 (2.9-4.6)2.2 (1.7-2.8)--3.7 (1.9-7.2)3.8 (1.7-8.4)

50LNG vs non-use-3.5 (2.5-5.1)-5.3 (2.3-12.3)--

20GSD vs non-use-3.5 (3.1-4.0)-2.0 (0.7-5.7)--

30GSD vs non-use5.6 (3.7-8.4)4.2 (3.9-4.6)-3.5 (2.8-4.5)5.2 (1.3-20.6)-

20DSG vs non-use-3.3 (2.9-3.7)-4.8 (3.2-7.1)24.7 (2.8-213.5)-

30DSG vs non-use7.3 (5.3-10.0)4.2 (3.6-4.9)-5.4 (3.6-8.0)4.9 (2.5-9.4)8.7 (3.9-19.3)

35NRG vs non-use5.9 (1.7-21.0)2.6 (2.2-3.0)-1.7 (1.0-3.1)--

35CPA vs non-use6.8 (4.7-10.0)4.1 (3.4-5.0)17.6 (2.7-113.0)3.3 (1.4-7.6)--

30DRSP vs non-use6.3 (2.9-13.7)4.5 (3.9-5.1)----

30LNG vs 20LNG0.9 (0.3-2.5)-----

50LNG vs 20LNG------

20GSD vs 20LNG------

30GSD vs 20LNG------

20DSG vs 20LNG------

30DSG vs 20LNG------

35NRG vs 20LNG------

35CPA vs 20LNG------

30DRSP vs 20LNG------

50LNG vs 30LNG2.2 (1.3-3.7)-----

20GSD vs 30LNG------

30GSD vs 30LNG------

20DSG vs 30LNG------

30DSG vs 30LNG------

35NRG vs 30LNG------

35CPA vs 30LNG------

30DRSP vs 30LNG------

20GSD vs 50LNG------

30GSD vs 50LNG------

20DSG vs 50LNG------

30DSG vs 50LNG------

35NRG vs 50LNG------

35CPA vs 50LNG------

30DRSP vs 50LNG------

30GSD vs 20GSD3.3 (1.4-7.1)-----

20DSG vs 20GSD------

30DSG vs 20GSD------

35NRG vs 20GSD------

35CPA vs 20GSD------

30DRSP vs 20GSD------

20DSG vs 30GSD------

30DSG vs 30GSD------

35NRG vs 30GSD------

35CPA vs 30GSD------

30DRSP vs 30GSD------

30DSG vs 20DSG1.4 (0.8-2.5)-----

35NRG vs 20DSG------

35CPA vs 20DSG------

30DRSP vs 20DSG------

35NRG vs 30DSG------

35CPA vs 30DSG------

30DRSP vs 30DSG------

35CPA vs 35NRG------

30DRSP vs 35NRG------

30DRSP vs 35CPA------

 
Table 10. Study specific adjusted risk estimates: per combined oral contraceptive in RR (95% CI) part II

ComparisonsStudy


Farmer 2000*Todd 1999Farmer 1996Jick 2006Bird 2013Jick 2011Parkin 2011Lewis 1996

20LNG vs non-use--------

30LNG vs non-use--------

50LNG vs non-use--------

20GSD vs non-use--------

30GSD vs non-use--------

20DSG vs non-use--------

30DSG vs non-use--------

35NRG vs non-use--------

35CPA vs non-use--------

30DRSP vs non-use--------

30LNG vs 20LNG--------

50LNG vs 20LNG--------

20GSD vs 20LNG--------

30GSD vs 20LNG--------

20DSG vs 20LNG--------

30DSG vs 20LNG--------

35NRG vs 20LNG--------

35CPA vs 20LNG--------

30DRSP vs 20LNG-----3.2 (1.8-5.5)--

50LNG vs 30LNG--------

20GSD vs 30LNG--------

30GSD vs 30LNG1.3 (0.9-1.9)-------

20DSG vs 30LNG1.4 (0.8-2.4)-------

30DSG vs 30LNG1.3 (0.9-1.8)-1.5 (0.3-8.3)1.7 (1.2-2.4)----

35NRG vs 30LNG1.1 (0.6-2.0)--1.1 (0.8-1.5)----

35CPA vs 30LNG1.8 (0.9-3.2)-------

30DRSP vs 30LNG----1.8 (1.3-2.5)2.2 (1.5-3.4)3.3 (1.4-7.6)-

20GSD vs 50LNG--------

30GSD vs 50LNG--------

20DSG vs 50LNG--------

30DSG vs 50LNG--------

35NRG vs 50LNG--------

35CPA vs 50LNG--------

30DRSP vs 50LNG--------

30GSD vs 20GSD--------

20DSG vs 20GSD--------

30DSG vs 20GSD--------

35NRG vs 20GSD--------

35CPA vs 20GSD--------

30DRSP vs 20GSD--------

20DSG vs 30GSD--------

30DSG vs 30GSD--1.2 (0.3-4.0)-----

35NRG vs 30GSD--------

35CPA vs 30GSD--------

30DRSP vs 30GSD--------

30DSG vs 20DSG--------

35NRG vs 20DSG--------

35CPA vs 20DSG--------

30DRSP vs 20DSG--------

35NRG vs 30DSG--------

35CPA vs 30DSG--------

30DRSP vs 30DSG--------

35CPA vs 35NRG--------

30DRSP vs 35NRG--------

30DRSP vs 35CPA--------

 
Table 11. Results of the network meta-analysis per combined oral contraceptive pill

Non-use











(reference20 LNG30 LNG50 LNG20 GSD30 GSD20 DSG30 DSG35 NRG35 CPA30 DRSP

group)

Non-use1

20 LNG2.2 (1.3-3.6)10.9 (0.6-1.4)0.4 (0.2-0.8)1.0 (0.6 (1.8)0.6 (0.4-1.0)0.7 (0.4-1.1)0.5 (0.3-0.8)0.9 (0.5-1.5)0.6 (0.3-1.0)0.6 (0.4-0.9)

30 LNG2.4 (1.8-3.2)1.1 (0.7-1.7)10.5 (0.3-0.7)1.1 (0.8-1.7)0.7 (0.5-0.9)0.7 (0.5-1.0)0.6 (0.4-0.7)1.0 (0.7-1.4)0.6 (0.4-0.9)0.6 (0.5-0.8)

50 LNG5.2 (3.4-7.9)2.3 (1.3-4.2)2.1 (1.4-3.2)12.4 (1.5-4.0)1.4 (0.9-2.1)1.5 (1.0-2.4)1.2 (0.8-1.8)2.2 (1.4-3.3)1.3 (0.8-2.1)1.3 (0.8-2.1)

20 GSD2.2 (1.4-3.2)1.0 (0.5-1.7)0.9 (0.6-1.3)0.4 (0.3-0.7)10.6 (0.4-0.9)0.6 (0.4-1.0)0.5 (0.3-0.7)0.9 (0.6-1.4)0.6 (0.4-0.8)0.6 (0.4-0.9)

30 GSD3.7 (2.8-4.9)1.7 (1.0-2.7)1.5 (1.2-2.0)0.7 (0.5-1.1)1.7 (1.1-2.6)11.1 (0.8-1.5)0.9 (0.7-1.1)1.5 (1.1-2.1)1.0 (0.7-1.4)1.0 (0.7-1.3)

20 DSG3.4 (2.5-4.6)1.5 (0.9-2.6)1.4 (1.0-1.9)0.7 (0.4-1.0)1.6 (1.0-2.4)0.9 (0.7-1.2)10.8 (0.6-1.1)1.4 (1.0-2.0)0.9 (0.6-1.3)0.9 (0.6-1.3)

30 DSG4.3 (3.3-5.6)1.9 (1.2-3.1)1.8 (1.4-2.2)0.8 (0.5-1.2)2.0 (1.3-2.9)1.2 (0.9-1.5)1.3 (0.9-1.7)11.8 (1.3-2.4)1.1 (0.8-1.6)1.1 (0.8-1.5)

35 NRG2.4 (1.7-3.3)1.1 (0.7-1.8)1.0 (0.7-1.3)0.5 (0.3-0.7)1.1 (0.7-1.7)0.7 (0.5-0.9)0.7 (0.5-1.0)0.6 (0.4-0.8)10.6 (0.4-0.9)0.6 (0.4-0.9)

35 CPA3.9 (2.7-5.5)1.7 (1.0-3.0)1.6 (1.1-2.2)0.7 (0.5-1.2)1.8 (1.1-2.8)1.0 (0.7-1.5)1.1 (0.8-1.6)0.9 (0.6-1.3)1.6 (1.1-2.3)11.0 (0.7-1.5)

30 DRSP3.9 (2.7-5.5)1.7 (1.1-2.7)1.6 (1.2-2.1)0.7 (0.5-1.2)1.8 (1.2-2.8)1.1 (0.7-1.5)1.1 (0.8-1.6)0.9 (0.7-1.3)1.6 (1.1-2.3)1.0 (0.7-1.5)1

 
Table 12. Results of sensitivity analyses

Source of bias and No of studies


Generation of
progestogen
Industry (n=8)Non-industry (n=9)Cohort study (n=8)Case-control (n=15)Objectively confirmed
venous thrombosis (n=5)
Subjectively confirmed
venous thrombosis (n=11)

Non-use111111

1st2.6 (0.9-7.4)3.3 (2.4-4.6)2.0 (0.4-10.5)3.3 (2.3-4.7)4.5 (3.2-6.5)2.6 (1.3-5.3)

2nd2.1 (1.0-4.8)3.1 (2.5-3.8)1.7 (0.4-8.0)2.9 (2.3-3.7)3.3 (2.8-4.0)2.5 (1.4-4.5)

3rd1.9 (0.8-4.2)5.2 (4.2-6.5)2.0 (0.5-8.6)4.2 (3.3-5.3)6.2 (5.2-7.4)3.0 (1.7-5.4)

Data are relative risk (95% confidence interval) of venous thrombosis