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Effectiveness and efficacy rates of progestin-only pills: A comprehensive literature review

Open AccessPublished:December 16, 2022DOI:https://doi.org/10.1016/j.contraception.2022.109925

      Abstract

      Objectives

      To synthesize published literature on POP effectiveness and efficacy.

      Study design

      We searched PubMed Central, PubMed, and the Cochrane library through March 07, 2022. We included articles written in English reporting a Pearl Index or life table rate for pregnancy. We excluded articles only assessing formulations that: were never marketed globally, are only sold in combination with estrogen, are currently sold only for noncontraceptive purposes, or were not given to participants continuously. Four researchers independently extracted data and two analyzed data using Excel and R.

      Results

      We included 54 studies. Among studies at low or moderate risk of bias, the median Pearl Index rate (the failure rate during typical use) was 1.63 (range 0.00–14.20, IQR 4.03) and the median method failure Pearl Index rate (the failure rate during perfect use) was 0.97 (range 0.40–6.50, IQR 0.68). Excluding the newer formulations, Desogestrel and Drospirenone, which are closer to combined oral contraceptives in that they prevent pregnancy by inhibiting ovulation, the median Pearl Index rate is 2.00 (range 0.00–14.12, IQR 2.5) and the median method failure Pearl Index rate is 1.05 (range 0.00–10.90, IQR 1.38).

      Conclusions

      Among studies at low or moderate risk of bias, the median Pearl Index rate during typical POP use was much lower than currently estimated (7.00), while the median perfect use rate was similar to current estimates.

      Implications

      Future research should investigate the possibility that POPs may be much more effective during typical use than currently believed.

      Keywords

      1. Introduction

      Moving oral contraceptive pills—combined oral contraceptives (COCs) or progestin-only pills (POPs) —to over-the-counter (OTC) status in the United States (US) could increase accessibility for individuals encountering barriers to getting a prescription [
      • Grindlay K
      • Grossman D.
      Prescription birth control access among U.S. women at risk of unintended pregnancy.
      ,
      • Dennis A
      • Grossman D.
      Barriers to contraception and interest in over-the-counter access among low-income women: a qualitative study.
      ]. At the time of writing, the United States Food and Drug Administration (FDA) is currently reviewing the first-ever application for an OTC POP product which contains .075 mg Norgestrel [

      HRA Pharma. Perrigo's HRA Pharma submits application to FDA for first-ever OTC birth control pill. n.d. https://www.hra-pharma.com/articles/perrigos-hra-pharma-submits-application-to-fda-for-first-ever-otc-birth-control-pill-66 (accessed October 7, 2022).

      ]. A large coalition of prominent clinicians, researchers, and reproductive health, rights, and justice organizations has long focused on making POPs available OTC in the US because POPs have few contraindications and would therefore be appropriate for a wide range of people [

      OCs OTC Working Group. Statement of purpose. n.d. https://ocsotc.org/statement-of-purpose/ (accessed March 1, 2022).

      ].
      Although there is interest among US women in an OTC POP product [
      • Grindlay K
      • Grossman D.
      Interest in over-the-counter access to a progestin-only pill among women in the United States.
      ], POP users constitute only 4% of contraceptive pill users [
      • Liang S-Y
      • Grossman D
      • Phillips KA.
      User characteristics and out-of-pocket expenditures for progestin-only versus combined oral contraceptives.
      ], and this low user rate may be due to clinicians’ hesitation to prescribe POPs based on their views of the pill's effectiveness. One study assessing how evidenced-based information influences clinicians’ thoughts about an OTC oral contraceptive found that before receiving information, 69% of clinicians did not support an OTC POP, with 17% citing “less effective pill formulation” as a reason [
      • Wollum A
      • Zuniga C
      • Lezama N
      • Grossman D
      • Grindlay K.
      A randomized study evaluating the effect of evidence-based information on clinician attitudes about moving oral contraceptives over the counter.
      ]. However, a 2013 systematic literature review of randomized controlled trials of progestin-only pills concluded there was insufficient evidence to compare POPs to COCs [
      • Grimes DA
      • Lopez LM
      • O'Brien PA
      • Raymond EG.
      Progestin-only pills for contraception.
      ].
      Efficacy rates refer to failure rates only when the pill is taken as directed (perfect use), whereas effectiveness refers to failure rates during typical use (which includes perfect use as well as incorrect and inconsistent use) [
      • Trussell J.
      • Aiken A.
      Efficacy, safety, and personal considerations.
      ]. Although pill effectiveness rates vary based on the population using the method [
      • Moreau C
      • Trussell J
      • Rodriguez G
      • Bajos N
      • Bouyer J
      Contraceptive failure rates in France: results from a population-based survey.
      ], it is estimated that in the US 7% of individuals using oral contraceptives will have an unintended pregnancy during their first year of typical use [
      • Trussell J.
      • Aiken A.
      Efficacy, safety, and personal considerations.
      ]. However, this estimation does not distinguish between COCs and POPs and may be a better reflection of the failure rate of COCs because they are more commonly used in the US [
      • Trussell J.
      • Aiken A.
      Efficacy, safety, and personal considerations.
      ]. It is thought that this failure rate may be slightly higher for POPs because a common belief is that POPs lose effectiveness when not taken within a rigid timeframe of 24 hours after the previous pill with a strict 3-hour window [
      • Trussel J
      • Aiken A
      ,
      • Freeman S
      • Shulman LP.
      Considerations for the use of progestin-only contraceptives.
      ], although little clinical data exist to support this belief [
      • Grimes DA
      • Lopez LM
      • O'Brien PA
      • Raymond EG.
      Progestin-only pills for contraception.
      ,
      • Han L
      • Taub R
      • Jensen JT.
      Cervical mucus and contraception: what we know and what we don't.
      ].
      In addition to a lack of evidence for the 3-hour window, there are many different POP formulations, including two newer formulations—Desogestrel and Drospirenone—that have been shown to inhibit ovulation even after long delays in pill intake (12-hour delays for Desogestrel and 24-hour delays for Drospirenone) [
      • Korver T
      • Klipping C
      • Heger-Mahn D
      • Duijkers I
      • Van Osta G
      • Dieben T.
      Maintenance of ovulation inhibition with the 75-microg desogestrel-only contraceptive pill (Cerazette) after scheduled 12-h delays in tablet intake.
      ,
      • Duijkers IJM
      • Heger-Mahn D
      • Drouin D
      • Colli E
      • Skouby S.
      Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake.
      ] so the 3-hour window recommendation is likely not applicable to them. One study has also found that a 6-hour delay or a single missed POP containing Norgestrel 0.075 mg appears to not negatively impact contraceptive efficacy [
      • Glasier A
      • Edelman A
      • Creinin MD
      • Brache V
      • Westhoff CL
      • Han L
      • et al.
      The effect of deliberate non-adherence to a norgestrel progestin-only pill: a randomized, crossover study.
      ] Current estimates of the pregnancy rate for the first year of use among perfect users is based on the lowest reported pregnancy rate as well as pregnancy rates reported in recent studies—for COCs, the rate of pregnancy among perfect users is estimated to be 0.30% and although this rate is cited as the rate for all oral contraceptives, the pregnancy rate among perfect users of POPs is unknown [
      • Trussel J
      • Aiken A
      ]. As of 2018, the lowest reported pregnancy rate for POP use was 1.1% [
      • Trussel J
      • Aiken A
      ].
      Contraceptive effectiveness and efficacy rates can both be measured by the Pearl Index and the life table. The Pearl Index calculates an effectiveness rate by dividing the number of total pregnancies (contraceptive failures) by 100 person-years of exposure to the contraceptive method [
      • Burkman RT.
      Clinical pearls: factors affecting reported contraceptive efficacy rates in clinical studies.
      ]. A Pearl Index that measures efficacy (often referred to as a method failure Pearl Index) only includes pregnancies resulting from a method failure among perfect users. Due to its ease of calculation, the Pearl Index has been reported more frequently in the literature than life table rates, but a significant limitation is that estimates can vary with study length. For longer durations of pill use, the Pearl Index tends to underestimate failure rates since pregnancies are more common at the beginning of pill use and study participants more likely to conceive become pregnant early and withdraw from the study, leaving a group of participants less likely to conceive [
      • Trussell J.
      Understanding contraceptive failure.
      ]. This limitation is eliminated by a life table analysis, which estimates monthly probabilities of failure and cumulative probabilities over time.
      Previous reviews of the effectiveness and efficacy of POPs have focused on few formulations [
      • Glasier A
      • Sober S
      • Gasloli R
      • Goyal A
      • Laurora I.
      A review of the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day.
      ,
      • Graham S
      • Fraser IS.
      The progestogen-only mini-pill.
      ] and there is insufficient information among randomized trials to make comparisons between different POPs [
      • Grimes DA
      • Lopez LM
      • O'Brien PA
      • Raymond EG.
      Progestin-only pills for contraception.
      ]. This review aims to expand upon previous reviews by including a range of study types reporting effectiveness and efficacy rates of various POP formulations, while recognizing the limitations of nonrandomized trials. Our findings can help ensure that policymakers, reproductive health advocates, and the general public have the necessary information, backed by clinical evidence, to make decisions about an OTC POP product.

      2. Material and methods

      2.1 Literature search and study selection

      We searched PubMed Central, PubMed, and the Cochrane library for articles and reports written in English on the effectiveness or efficacy of POPs through March 07, 2022. The search did not include limits by study publication type, date, or study design. We did not include overall findings from literature reviews but searched the references of reviews and included articles with original or primary research. Four researchers screened the titles and abstracts of articles for eligibility. We included randomized and nonrandomized studies (with or without a control group) with data on pregnancy rates among users of at least one POP formulation currently or previously sold in any country. We excluded articles assessing formulations that: were never marketed globally, are only sold in combination with estrogen, are currently sold only for noncontraceptive purposes, or were not given to participants continuously (except for the newer Drospirenone-only pills which is the only POP product sold with placebo pills in a pack). We also excluded articles if they did not report information on the duration of person-time used for estimations of effectiveness. See Appendix A for details of our search process and Appendix B for search terms.

      2.2 Data extraction and calculations

      We extracted the following data from each study: first author, title, year of publication, study location, participant characteristics, study design features (n, duration, randomization), POP formulation and dosage, loss-to-follow-up, number of total pregnancies, number of pregnancies attributed to user error and method failure, Pearl Index, method failure Pearl Index, Pearl Index rates adjusted for patient characteristics or behaviors, and life table data. We converted dosage units to milligrams and summed up dosages taken more than once a day as a single daily dosage. We also calculated Pearl Index rates if sufficient data were available and compared them to reported rates. In our analyses, we used Pearl Index rates reported by studies and only used calculated rates if no single Pearl Index rate was reported. We included aggregated Pearl Index rates that combined rates from multiple formulations or studies.
      As failure rates tend to be high at the start of studies and decrease over time [
      • Trussell J.
      Understanding contraceptive failure.
      ], we also extracted data on study duration to analyze effectiveness and efficacy rates by study length. Studies reported study duration in different units (cycles, months, years), which we converted into months. (since 12 months is equivalent to 13 cycles, we calculated that there are .92 months in a cycle). If study length was not reported, we estimated study duration based on the longest reported cycle or month of treatment completed. If we could not estimate study length, we used average length of participation in the study, if available. In our analysis of study duration and Pearl Index rates, we excluded one Pearl Index rate that was pooled from two studies of different durations [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ].
      Since person-time depends on both duration of use and number of participants, we also looked at Pearl Index rates by study size. We recorded the number of participants who started treatment in each study arm. For retrospective studies, we extracted the number of participants included in the analysis, if available.
      Four researchers independently extracted data and placed data in an Excel spreadsheet.. Two researchers used Excel and R for data analysis and visualizations [

      R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/. 

      ].

      2.3 Assessing risk of bias

      We assessed risk of bias for included studies using the Cochrane risk-of-bias tool for randomized trials (RoB 2) [
      • Sterne J
      • Savović J
      • Page M
      • Elbers R
      • Blencowe N
      • Boutron I
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ], the Cochrane Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool [
      • Sterne JA
      • Hernán MA
      • Reeves BC
      • Savović J
      • Berkman ND
      • Viswanathan M
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ] for nonrandomized studies with a comparator, and a newly developed tool for assessing bias in estimation of contraceptive failure rates in studies lacking a comparator. We included data from a single arm of a study when a POP was compared with a non-POP method or compared with a POP formulation not given continuously to participants. We only extracted pooled data when studies compared the impact of the same formulation on different groups of participants (as opposed to comparing two or more different formulations). To assess risk of bias for these single arm estimates of contraceptive failure, we created a tool adapted from existing Cochrane tools that included domains for assessing bias relevant to valid estimation of contraceptive failure rates [
      • Trussell J.
      Methodological pitfalls in the analysis of contraceptive failure.
      ]. We assessed all studies using the appropriate risk of bias tool by two researchers, who judged all studies to be in one of three categories: low risk, moderate risk, or high risk of bias. Across all tools, we judged studies based on the most severely rated domain. If we assessed three or more domains to be at moderate risk of bias, then we judged the study's overall risk of bias to be high. If a domain did not have enough information for us to make an assessment, we assessed the domain as moderate. If more than one domain did not have sufficient information to make an assessment, we excluded the study from our analysis. See Appendix C for our tool to assess risk of bias in noncomparative studies and Appendix D for tables summarizing our risk of bias judgments for all studies.

      2.4 Data synthesis and analysis approach

      Our main outcome was median effectiveness and efficacy rates reported by studies assessed to be at low or moderate risk of bias, although we also conducted a sensitivity analysis by calculating the median effectiveness and efficacy rates across all studies. We also analyzed effectiveness and efficacy rates by study duration, size, and formulation. We conducted additional sensitivity analysis by removing rates for Desogestrel and Drospirenone, as these newer formulations are different from other POP because they reliably inhibit ovulation after delayed pill intake [
      • Korver T
      • Klipping C
      • Heger-Mahn D
      • Duijkers I
      • Van Osta G
      • Dieben T.
      Maintenance of ovulation inhibition with the 75-microg desogestrel-only contraceptive pill (Cerazette) after scheduled 12-h delays in tablet intake.
      ,
      • Duijkers IJM
      • Heger-Mahn D
      • Drouin D
      • Colli E
      • Skouby S.
      Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake.
      ]. In addition, given the FDA's current review of an application for an OTC product containing Norgestrel 0.075 mg, we also looked at Pearl Index rates reported by studies analyzing that particular dosage and formulation. As most Pearl Index rates were not accompanied by confidence intervals, we report ranges and interquartile ranges to provide information on the spread of data. If a study was aiming to compare different groups of participants (e.g., lactating versus nonlactating) and reported separate Pearl Index rates, these rates are included in our main findings. However, if studies reported rates that took into account participant behaviors or characteristics (e.g., taking into account that their sample included some lactating participants and reporting analyses with this group excluded from calculations) in addition to overall Pearl Index rates, we did not include these adjusted or stratified rates in our overall calculations but report these separately.

      3. Results

      3.1 Included studies

      Fifty-four studies met our eligibility criteria [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Christie G.
      Chlormadinone acetate 0-5 mg. A report on its effectiveness in continuous use as an oral contraceptive.
      ,
      • Cox H.
      Progestogen-only oral contraceptives.
      ,
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      ,
      • Howard G
      • Elstein M
      • Blair M
      • Morris N.
      Low-dose continuous chlormadinone acetate as an oral contraceptive.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      ,
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      ,
      • Lakha F
      • Ho P
      • Van der Spuy Z
      • Dada K
      • Elton R
      • Glasier A
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Cortes-Gallegos V
      • Aznar R
      • Rojas B
      • Guitterez-Najar A
      • et al.
      Daily progestogen for contraception: a clinical study.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      ,
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      ,
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      ,
      • Moggia A
      • Mischler T
      • Beauquis A
      • Zarate J
      • Torrado M
      • Ferrari F
      • et al.
      Evaluation of the contraceptive efficacy of Quingestanol acetate in daily microdose and post coitum.
      ,
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      ,
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      ,
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,

      Scharff H. Clinical experience with d-norgestrel as a continuous microdose. Presented at the Seventh World Congress on Fertility and Sterility, Tokyo, October 1971.

      ,
      • Sheth A
      • Jain U
      • Sharma S
      • Adatia A
      • Patankar S
      • Andolsek L
      • et al.
      A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.
      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Tyler ET.
      Studies of “mini-micro” contraceptive doses of a new progestrogen.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ,
      • Vessey M
      • Lawless M
      • Yeates D
      • McPherson K.
      Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      ,
      • Bisset A
      • Dingwall-Fordyce I
      • Hamilton M.
      The efficacy of the progestogen-only pill as a contraceptive method.
      ,
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ,
      • Broome M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ]. Table 1 displays descriptive information for each article. Included studies were published between 1966 and 2019, with almost half published in the 1970s [
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      ,
      • Moggia A
      • Mischler T
      • Beauquis A
      • Zarate J
      • Torrado M
      • Ferrari F
      • et al.
      Evaluation of the contraceptive efficacy of Quingestanol acetate in daily microdose and post coitum.
      ,
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      ,
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      ,
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,

      Scharff H. Clinical experience with d-norgestrel as a continuous microdose. Presented at the Seventh World Congress on Fertility and Sterility, Tokyo, October 1971.

      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ]. Forty-four studies were conducted primarily in either Europe or North America [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Christie G.
      Chlormadinone acetate 0-5 mg. A report on its effectiveness in continuous use as an oral contraceptive.
      ,
      • Cox H.
      Progestogen-only oral contraceptives.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      ,
      • Howard G
      • Elstein M
      • Blair M
      • Morris N.
      Low-dose continuous chlormadinone acetate as an oral contraceptive.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      ,
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Cortes-Gallegos V
      • Aznar R
      • Rojas B
      • Guitterez-Najar A
      • et al.
      Daily progestogen for contraception: a clinical study.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      ,
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      ,
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,

      Scharff H. Clinical experience with d-norgestrel as a continuous microdose. Presented at the Seventh World Congress on Fertility and Sterility, Tokyo, October 1971.

      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Vessey M
      • Lawless M
      • Yeates D
      • McPherson K.
      Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Bisset A
      • Dingwall-Fordyce I
      • Hamilton M.
      The efficacy of the progestogen-only pill as a contraceptive method.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ,
      • Broome M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ], and all were prospective studies with the exception of three that were retrospective [
      • Bisset A
      • Dingwall-Fordyce I
      • Hamilton M.
      The efficacy of the progestogen-only pill as a contraceptive method.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ,
      • Broom M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      ]. Seven were randomized trials [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      ,
      • Lakha F
      • Ho P
      • Van der Spuy Z
      • Dada K
      • Elton R
      • Glasier A
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      ,
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      ,
      • Sheth A
      • Jain U
      • Sharma S
      • Adatia A
      • Patankar S
      • Andolsek L
      • et al.
      A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ], 15 were nonrandomized comparative studies [
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Cortes-Gallegos V
      • Aznar R
      • Rojas B
      • Guitterez-Najar A
      • et al.
      Daily progestogen for contraception: a clinical study.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      ,
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Tyler ET.
      Studies of “mini-micro” contraceptive doses of a new progestrogen.
      ,
      • Vessey M
      • Lawless M
      • Yeates D
      • McPherson K.
      Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness.
      ,
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      ,
      • Bisset A
      • Dingwall-Fordyce I
      • Hamilton M.
      The efficacy of the progestogen-only pill as a contraceptive method.
      ,
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ], and 32 were noncomparative studies [
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Christie G.
      Chlormadinone acetate 0-5 mg. A report on its effectiveness in continuous use as an oral contraceptive.
      ,
      • Cox H.
      Progestogen-only oral contraceptives.
      ,
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      ,
      • Howard G
      • Elstein M
      • Blair M
      • Morris N.
      Low-dose continuous chlormadinone acetate as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      ,
      • Moggia A
      • Mischler T
      • Beauquis A
      • Zarate J
      • Torrado M
      • Ferrari F
      • et al.
      Evaluation of the contraceptive efficacy of Quingestanol acetate in daily microdose and post coitum.
      ,
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      ,
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,

      Scharff H. Clinical experience with d-norgestrel as a continuous microdose. Presented at the Seventh World Congress on Fertility and Sterility, Tokyo, October 1971.

      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ,
      • Broome M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ]. All studies were peer-reviewed except two—one was described in a letter published in the correspondence section of a peer-reviewed journal [
      • Cox H.
      Progestogen-only oral contraceptives.
      ] and one was an abstract published in a conference proceeding [
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ].
      Table 1Description of studies reporting effectiveness and/or efficacy rates of progestin-only pills
      First authorYear publishedStudy location (country)Progestin(s)Study design**Risk of bias assessmentParticipant characteristics
      Apelo
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      1973The PhilippinesLevonorgestrelNoncomparative studyHighAge

      Range: 17–37 years

      Mean: 26 years

      Fertility

      All participants had at least one pregnancy

      Mean 3.5

      Mean interval between last delivery and start of medication was 8 months with a range of 1–55 months

      Weight

      Range: 75–149 lbs

      Mean 101.6 lbs
      Archer
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      2015Czech Republic, Germany, Hungary, Poland, and RomaniaDrospirenoneNoncomparative studyModerateAge

      Range: 18–46 years

      Mean: 28.7 years

      Age group: 79.8% were 35 years old or younger

      Fertility

      42.8% had a previous delivery

      Previous Contraceptive Use

      63.8% had "prior treatment with sex hormones and modulators of the genital system"

      Race

      99.6% Caucasian

      Weight

      BMI range: 16–38

      Mean BMI: 23
      Aznar-Ramos
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      1971MexicoChlormadinone acetateNonrandomized comparative study (comparing two different divided dosages)ModerateAge

      Range: 19–35 years
      Bernstein
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      1972United StatesChlormadinone acetateNoncomparative studyHighAge

      Maximum: All participants were under 40 years
      Bisset
      • Bisset A
      • Dingwall-Fordyce I
      • Hamilton M.
      The efficacy of the progestogen-only pill as a contraceptive method.
      1990United KingdomEthynodiol diacetate

      Levonorgestrel

      Norethisterone

      Norgestrel
      Nonrandomized comparative restrospective studyHighLactating or postpartum

      6% of participants on ethynoldiol diacetate lactating

      26% of participants on levonorgestrel lactating

      2% of participants on norethisterone lactating

      23% of participants on norgestrel lactating
      Board
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      1971United StatesNorethindroneNoncomparative studyHighFertilitiy

      Each participant of proved fertility

      Marital Status

      All participants were living with their husbands

      Previous Contraceptive Use

      All had taken either combination or sequential oral contraceptives

      31.8% of participants had not been using OCs for at least 2 months prior to the study

      Most participants started norethindrone immediately after discontinuing their previous oral contraceptive
      Board
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      1976United StatesNorethindroneNoncomparative studyHighFertility

      Each participant of proved fertility

      Marital Status

      All participants were living with their husbands

      Previous Contraceptive Use

      Most had taken either combination or sequential oral contraceptives

      29% of participants did not take an oral contraceptive for 2 months prior to beginning the study
      Broome
      • Broome M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      1990United KingdomEthynodial diacetate



      Norethisterone



      Levonorgestrel
      Noncomparative restrospective studyHighAge

      Majority: 59% of 358 women were 31–40 years old

      Lactating or postpartum

      Excluded from analysis (not included in the 358)
      Butler
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      1969United Kingdom
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateNoncomparative studyModerateAge

      Maximum: 34 years

      Fertility

      Each participant had at least one living child

      Marital Status

      All participants were married

      Previous Contraceptive Use

      No OCs used in the 2 months before the study
      Canto
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      1989MexicoNorgestrelNoncomparative studyHighAge

      Minimum: 18 years

      Majority: 56% were 20–29 years

      Mean: 26.1 years

      Fertility

      All participants had given at least one live birth

      Mean: 3.5 births

      Lactating or postpartum

      All were breast feeding on admission

      43.5% were <6 weeks postpartum

      56.5% were 6–26 weeks postpartum

      83% were still breastfeeding at end of study

      Previous Contraceptive Use (month before the study)

      38.5% participants were not using any method

      26.5% used oral contraceptives

      17% used injectables

      11.5% used an IUD

      5% used withdrawal/rhythm

      1.5% used a condom
      Cerais
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      1991SudanNorgestrelNoncomparative studyHighAge

      Mean: 26.3 years

      Fertility

      All participants had at least one live birth

      Mean: 2.3 live births

      Lactating or postpartum

      All were breastfeeding on admission

      177 women were between 42 day and 26 weeks postpartum

      23 women were less than 42 days postpartum

      Previous Contraceptive Use (month before the study)

      61% of participants not using any contraception immediately prior to admission or conception

      32% of those using a method were using an oral contraceptive

      34.5% reported ever having used an oral contraceptive prior to the study
      Christie
      • Christie G.
      Chlormadinone acetate 0-5 mg. A report on its effectiveness in continuous use as an oral contraceptive.
      1969Jamaica

      Mexico

      United Kingdom

      United States
      Chlormadinone acetateNoncomparative studyHigh
      Cox
      • Cox H.
      Progestogen-only oral contraceptives.
      1969United Kingdom
      Study location was not reported in the article so the country where researchers were based are listed instead.
      NorgestrelNoncomparative studyHighFertility

      Mean parity: over 2
      Dunson
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      199322 medical facilities in Africa, Latin America and the CaribbeanNorgestrelNoncomparative studyHighAge

      Mean: 25.7 (±4.9)

      Fertility

      Mean number of live births: 2.5 (±1.7)

      Lactating or postpartum

      74% entered the study when they were between 1 and 2 months postpartum

      56.6% breastfeeding at admission with no supplementation:

      43.4% breastfeeding at admission with supplementation

      Previous Contraceptive Use

      62% of participants had not used any contraception in the month before the study began

      Of women who had used a method, oral contraception was the most common (23.5%)
      Eckstein
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      1972United KingdomNorgestrelNoncomparative studyHighAge

      Maximum: All participants were under 40 years

      Majority: 24–35 years

      Fertility

      All participants had at least one living child of the present marriage
      Foss
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      1975United KingdomNorgestrelNoncomparative studyModerateAge

      Range: 19–41 years

      Fertility

      All participants had more than one child

      Previous Contraceptive Use

      This study included participants who wished to continue using Norgestrel from Foss study, so all had previously used this pill.
      Foss
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      1968United KingdomNorgestrelNoncomparative studyHighAge:

      Age group: 92% of participants were between 17 and 40 years old;

      8% were between 41 and 18 years old

      Fertility

      88% of participants were of proven fertility

      Range of number of children: 0–9
      Hawkins
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      1977United KingdomChlormadinone acetate

      Norethisterone
      Nonrandomized comparative studyModerateAge

      Mean age for chlormadinone acetate: 26.1 (±6.1)

      Mean age for norethisterone: 24.7 (±5.1)

      Fertility

      95% of participants parous

      Average parity: 1.9 (±1.5)

      Lactating or postpartum

      71% of patients were within 3 months postpartum at start of study and a higher proportion of patients given norethisterone were more than 6 months postpartum on admission

      Race

      76% White

      16% Black

      8% Asian, Latin American, mixed race
      Heinen
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      1970Germany
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateNoncomparative studyHighAge

      Average: 30 years

      Majority: 60% of study participants were 26 –35 years old
      Hernandez-Torres
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      1970Puerto RicoNorgestrelNoncomparative studyModerateAge

      Maximum: No one was older than 36 years

      Fertility

      All had one or more previous pregnancies or abortions

      Lactating or postpartum

      All were nonlactating

      Previous Contraceptive Use

      No participants received oral contraceptive treatment for 90 days prior to the study
      Howard
      • Howard G
      • Elstein M
      • Blair M
      • Morris N.
      Low-dose continuous chlormadinone acetate as an oral contraceptive.
      1969United KingdomChlormadinone acetateNoncomparative studyHighFertility

      Participants not necessarily of proven fertility

      Lactating or postpartum

      26% of patients were lactating and amenorrhoeic at the start of the study
      Jeppsson
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      1970SwedenChlormadinone acetateNonrandomized comparative studyHighAge

      Majority: 83.5% were between the ages of 20–39 years

      Fertility

      32% had never been pregnant

      Previous Contraceptive Use

      The sample included both women who had and hadn't use oral contraceptives before

      Other

      48% of patients were upper-middle class and sought contraceptive advice at an outpatient department for private patients; 52% sought free advice on contraceptives at a public family planning facility

      Jick
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      2009United KingdomLevonorgestrel

      Norethisterone

      Desogestrel
      Nonrandomized comparative retrospective studyModerateAge

      Range: Minimum 13 years

      Fertility

      71% had no prior deliveries

      Lactating or postpartum

      Evaluated the recency of delivery in users of the progestin-only pills compared to the COCs (to evaluate whether POP users were more likely to be breastfeeding)

      Weight

      BMI: (<20, 20–23, 24–27, 28+, Unknown)
      Jubhari
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      1974United StatesQuingestanol acetateNoncomparative studyHighAge

      Mean: 23.1 years

      Fertility

      Most had never had a child

      Marital Status

      Most were single

      Race

      Most were White
      Kesserü
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      1972PeruLevonorgestrelNoncomparative studyHighAge

      Range: 16–43 years

      Mean: 26.5 years

      Fertility

      Range number of pregnancies: 1–19

      Mean number of pregnancies: 4.9
      Korba
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      1974Puerto Rico

      Unites States
      NorgestrelNoncomparative studyHigh
      Korver
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      Korver T is listed as the corresponding author. The study was written by a collaborative study group.
      1998Finland

      Germany

      The Netherlands

      Norway

      Sweden

      United Kingdom
      Desogestrel

      Levonorgestrel
      Randomized control trialLowAge

      Range: 18–45 years

      Mean age: 29.6

      Fertility

      Mean number of pregnancies: 1.6

      Lactating or postpartum

      Desogestrel users: 30.7% breastfeeding

      Levonorgestrel users: 30.9% breastfeeding

      Previous Contraceptive Use in Previous 2 months

      Desogestrel users: 36.5% switched directly from another pill

      Levonorgestrel users: 37.9% switched directly from another pill

      Weight

      Range: All were between 80% and 130% of the ideal body weight

      Mean BMI: 22.8 kg/m2
      Lakha
      • Lakha F
      • Ho P
      • Van der Spuy Z
      • Dada K
      • Elton R
      • Glasier A
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      2007China

      Nigeria

      South Africa

      United Kingdom
      LevonorgestrelRandomized control trialModerateAge

      Mean age: 30.4 years

      Previous Contraceptive Use

      The majority 21 (of 23) did not use contraceptives in the previous few months

      Weight

      Mean: 58.4 kg

      Mean BMI: 22.4 kg/m2
      Laurie
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      1972Puerto Rico

      Unites States
      NorgestrelNoncomparative studyHighAge

      Mean: 23 years

      Fertility

      87.4% of participants multigravidae

      Race

      52.7% White
      Lawson
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      1972Jamaica

      New Zealand

      United Kingdom
      NorethisteroneNoncomparative studyHighAge

      Range: 16–54 years

      Median: 27 years

      Fertility

      78% of participants had a previous pregnancy

      Lactating or postpartum

      9% of participants were breastfeeding

      Previous Contraceptive Use

      53% of participants switched directly from another oral contraceptive
      Maqueo
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      1972MexicoQuingestanol acetateNoncomparative studyHighAge

      Mean: 29 years

      Fertility

      Mean number of previous pregnancies: 4.5

      Previous Contraceptive Use

      36% of participants had previously received varying doses of quingestanol acetate for other studies

      61% patients had no previous oral contraceptive therapy
      Martinez-Manatou
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      1967Mexico
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateRandomized comparative study (comparing different doses)HighFertility

      Women of proven fertility with no more than two children



      Lactating or postpartum

      No participants were lactating
      Martinez-Manatou
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Cortes-Gallegos V
      • Aznar R
      • Rojas B
      • Guitterez-Najar A
      • et al.
      Daily progestogen for contraception: a clinical study.
      1967Mexico
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateNonrandomized comparative study (comparing lactating to nonlactating group)HighAge

      Maximum: Less than 36 (at least among the nonlactating group)

      Lactating or postpartum

      In one group, all women (100) were lactating and were between 1 and 15 months postpartum; the other group consisted of nonlactating participants
      Martinez-Manatou
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      1966Mexico
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateNonrandomized comparative study (comparing cyclical to continuous pill taking regimen)HighAge

      Maximum: Less than 36

      Fertility

      All participants of proven fertility

      Lactating or postpartum

      No participants were lactating
      McQuarrie
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      1972United States
      Study location was not reported in the article so the country where researchers were based are listed instead.
      NorethindroneNonrandomized comparative studyHighAge

      Range: 16–42 years

      Mean: 26.4 years

      Fertility

      Parity range: 1–9

      Mean: 2.5 children delivered
      Mears
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      1969YugoslaviaChlormadinone

      Norethisterone acetate

      Norgestrel
      Nonrandomized comparative studyModerateAge

      Range: 18–40 years

      Fertility

      All participants of proven fertility

      Previous Contraceptive Use

      All participants took no hormones or oral contraceptives during the previous 2 months
      Moggia
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      1991ArgentinaNorgestrelNonrandomized comparative studyModerateAge

      Range: 18–35 years

      Fertility

      All participants had given birth 2–6 times

      Lactating or postpartum

      All participants were lactating at beginning of study
      Moggia
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      1972ArgentinaQuingestanol acetateNoncomparative studyHighAge

      Range: 15–44 years

      Mean: 26.1 (±0.2)

      Fertility

      Mean number of prior pregnancies: 2.7 (±0.1)

      Lactating or postpartum

      80% of participants were postpartum

      Weight

      Range: 40–100 kg

      Mean: 60.0 kg (±0.4)
      Moggia
      • Moggia A
      • Mischler T
      • Beauquis A
      • Zarate J
      • Torrado M
      • Ferrari F
      • et al.
      Evaluation of the contraceptive efficacy of Quingestanol acetate in daily microdose and post coitum.
      1973ArgentinaQuingestanol acetateNoncomparative studyHighAge

      Range: 15–44 years

      Mean: 26.1 years (±0.2)

      Fertility

      Range number of prior pregnancies: 0–9

      Mean number of prior pregnancies: 2.7 (±0.1)

      Lactating or postpartum

      53.65% of patients lactating

      76% postpartum

      Weight

      Range: 40–100 kg

      Mean 60.1 (±0.3)
      Palacios
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      This study reports on results from two studies; the first of which are already reported in the study by Archer et al. Only results from the second study, and any pooled results, are reported here. **Studies that did not explicitly say they were randomized are categorized as nonrandomized.
      2019Austria, Czech Republic, Germany, Hungary, Poland, Romania, Slovakia and SpainDrospirenone DesogestrelRandomized control trialLowAge

      Drospirenone: Range: 18–45 years; Mean: 28.9 years; Age group: 79.5% were 35 years old or younger

      Desogestrel: Range: 18–45 years; Mean: 28.9 years; Age group: 78% were 35 years old or younger

      Fertility

      Drospirenone:46 % had a previous delivery

      Desogestrel: 45 % had a previous delivery

      Previous Contraceptive Use

      54.7% of Drospirenone users and 58.7% of Desogestrel users had "prior treatment with sex hormones and modulators of the genital system"

      Race

      99.8% of Drospirenone users and 99.7% of Desogestrel users were Caucasian

      Weight

      Drospirenone: BMI range: 16.6–41; Mean BMI: 22.96

      Desogestrel: BMI range: 15.9–38; Mean BMI: 22.82
      Paulsen
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      1974United StatesEthynodiol diacetateRandomized control trialHighAge

      Range: 18–39 years

      Mean: 20.5 years (±2.7)

      Fertility

      5% had a previous pregnancy:

      2.5% had a previous live birth

      Previous Contraceptive Use

      Majority of patients did not have prior experience with oral contraceptives
      Postlethwaite
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      1979United Kingdom
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Ethynodiol diacetateNoncomparative studyHighAge

      Range: 17–48 years
      Rice-Wray
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      1972MexicoLevonorgestrelNoncomparative studyHighAge

      Range: 18–40 years

      Fertility

      All participants of proven fertility

      Previous Contraceptive Use

      None had any steroid therapy for at least 60 days prior to initiating study.
      Scharff

      Scharff H. Clinical experience with d-norgestrel as a continuous microdose. Presented at the Seventh World Congress on Fertility and Sterility, Tokyo, October 1971.

      1971GermanyLevonorgestrelNoncomparative studyHigh
      Sheth
      • Sheth A
      • Jain U
      • Sharma S
      • Adatia A
      • Patankar S
      • Andolsek L
      • et al.
      A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.
      1982India

      Yugoslavia
      Levonorgestrel

      Norethisterone
      Randomized control trialModerateAge

      Range: 18–38

      Levonorgestrel users mean age: 25.7 years (±4.57)

      Norethisterone users mean age: 25.6 (±4.68)

      Previous Contraceptive Use

      No participants had used oral contraceptives within 28 days or long acting injectable hormonal contraceptives within 90 days of starting treatment

      27.4 % of levonorgestrel users had ever used oral contraceptives

      26.8% of Norethisterone users had ever used oral contraceptives
      Shroff
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      1987United KingdomEthynodiol diacetateNoncomparative studyHighAge

      Range: 16–45 years

      Age group:

      72% were 16–34 years old

      28% were 35–47 years old

      Median: 30 years

      Fertility

      75% experienced at least one previous pregnancy

      Previous contraceptive use

      None: 8%

      COCs: 48%

      POPs: 9%

      OCs: (unknown) 1%

      IUCD: 15%

      Other 19%
      Statzer
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      1972United StatesNorgestrelNoncomparative studyHighAge

      Range: 15–44 years

      Fertility

      All participants demonstrated fertility. Previous pregnancies ranged from 1 to 9

      Previous contraceptive use

      Subjects have taken no oral or injectable contraceptive for 90 days or more

      In some cases, subjects switched directly from Oral (norgestrel 0.5 mg and ethinyl estradiol 0.05 mg) to microdose norgestrel

      Race

      14% White

      86% Black
      Tejuja
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      1974IndiaNorgestrelNonrandomized comparative study (comparing two doses)ModerateAge

      50 μg Norgestrel users: 79.2% between 20 and 29 years old

      75 μg Norgestrel users: 80.1% between 20 and 29 years old

      Fertility

      50 μg Norgestrel users: >99% of participants had had at least one pregnancy

      75 μg Norgestrel users: >99% of participants had had at least one pregnancy

      Lactating or postpartum

      50 μg Norgestrel users: 27.2% had lactational amenorrhea prior to commencement of the study

      75 μg Norgestrel users: 29.8% had lactational amenorrhea prior to commencement of the study

      Weight

      50 μg Norgestrel users' average weight: 43.4 kg

      75 μg Norgestrel users' average weight: 44.7 kg
      Tyler
      • Tyler ET.
      Studies of “mini-micro” contraceptive doses of a new progestrogen.
      1968United StatesNorgestrelNonrandomized comparative study (comparing two doses)High
      Vessey
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      1972YugoslaviaChlormadinone acetate

      Norethisterone acetate

      Norgestrel
      Randomized control trialModerateAge

      Chlormadinone acetate users' mean age: 30.4 years

      Norethisterone acetate users' mean age: 30 years

      Norgestrel users' mean age: 30.1

      Fertility

      All participants of proven fertility

      Chlormadinone acetate users mean number of full term births: 1.7

      Norethisterone acetate users' mean number of full term births: 1.8

      Norgestrel users' mean number of full term births: 1.8

      Weight

      Chlormadinone acetate users' mean weight: 65.8 kg

      Norethisterone acetate users' mean weight: 65.6

      Norgestrel users' mean weight: 66.1 kg
      Vessey
      • Vessey M
      • Lawless M
      • Yeates D
      • McPherson K.
      Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness.
      1985United KingdomNorethisterone

      Norgestrel

      Levonorgestrel

      Ethynodial diacetate
      Nonrandomized comparative study (comparing different POP formulations)ModerateAge

      Range: 25–39 years

      Marital Status

      All participants were married

      Race

      All participants were White
      Whyte
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      1973CanadaNorethindroneNoncomparative studyHighAge

      Mean: 23.3 years

      Fertility

      98% of participants had at least one previous pregnancy

      Previous Contraceptive Use

      All participants had previously used a type of oral contraceptive

      Other

      One third of patients were either contraindicated to estrogen or found the combined pill unacceptable due to side effects. The remaining sample had never used any oral contraceptive before and had no contraindications to a combined or progestin-only pill.
      Zañartu
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      1968Chile
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Chlormadinone acetateNonrandomized comparative study (comparing two groups of participants of different socio-economic statuses)HighAge

      Minimum: 16 years

      Fertility

      All participants had been pregnant at least once

      Lactating or postpartum

      110 women started use after childbirth while lactating and/or experiencing amenorrhea

      Other

      45 women were came from families with an above-average income

      345 were from low-income groups

      Combined oral contraceptives or sequential oral contraception was either poorly tolerated or not acceptable to all women from low-income group and in the majority (40) among women from families with an above-average income
      Zanartu
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      1974Chile
      Study location was not reported in the article so the country where researchers were based are listed instead.
      Ethynodiol diacetate



      Norgestrienone
      Nonrandomized comparative study (comparing different formulations among two different groups of patients -continuous use with precoital use)HighAge

      Mean:28.8

      Range: 18–41

      Fertility

      Mean parity:5.5
      low asterisk Study location was not reported in the article so the country where researchers were based are listed instead.
      ^ This study reports on results from two studies; the first of which are already reported in the study by Archer et al. Only results from the second study, and any pooled results, are reported here. **Studies that did not explicitly say they were randomized are categorized as nonrandomized.
      low asterisklow asterisklow asterisk Korver T is listed as the corresponding author. The study was written by a collaborative study group.
      Data on study participant characteristics varied widely: age (reported by 44 studies) [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      ,
      • Lakha F
      • Ho P
      • Van der Spuy Z
      • Dada K
      • Elton R
      • Glasier A
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Aznar-Ramos R
      • Giner-Velázquez J
      • Martínez-Manautou J.
      Contraceptive efficacy of single and divided doses of chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Cortes-Gallegos V
      • Aznar R
      • Rojas B
      • Guitterez-Najar A
      • et al.
      Daily progestogen for contraception: a clinical study.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      ,
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      ,
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      ,
      • Moggia A
      • Mischler T
      • Beauquis A
      • Zarate J
      • Torrado M
      • Ferrari F
      • et al.
      Evaluation of the contraceptive efficacy of Quingestanol acetate in daily microdose and post coitum.
      ,
      • Paulsen ML
      • Varaday A
      • Brown BW
      • Kalman SM.
      A randomized contraceptive trial comparing a daily progestogen with a combined oral contraceptive steroid.
      ,
      • Postlethwaite DL.
      Pregnancy rate of a progestogen oral contraceptive.
      ,
      • Bernstein GS
      • Seward P.
      Daily chlormadinone acetate as an oral contraceptive.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,
      • Sheth A
      • Jain U
      • Sharma S
      • Adatia A
      • Patankar S
      • Andolsek L
      • et al.
      A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.
      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ,
      • Vessey M
      • Lawless M
      • Yeates D
      • McPherson K.
      Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      ,
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ,
      • Broome M
      • Fotherby K.
      Clinical experience with the progestogen-only pill.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ] and fertility (reported by 40 studies) [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Cox H.
      Progestogen-only oral contraceptives.
      ,
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.
      ,
      • Howard G
      • Elstein M
      • Blair M
      • Morris N.
      Low-dose continuous chlormadinone acetate as an oral contraceptive.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Jubhari S
      • Lane ME
      • Sobrero AJ.
      Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Korba V
      • Paulson S.
      Five years of fertility control with microdose norgestrel: an updated clinical review.
      ,
      • Korver T.
      A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 μg/day or levonorgestrel 30 μg/day: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Maqueo M
      • Mischler TW
      • Berman E.
      The evaluation of quingestanol acetate as a low dose oral contraceptive.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      ,
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      ,
      • Moggia A V
      • Mischler T
      • Berman E
      • Beauquis A
      • Torrrado M
      • Koremblitt E.
      Evaluation of the contraceptive efficacy of quingestanol acetate (W 4540) when administered as an oral low-dose conraceptive in the puerperium.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      ,
      • Zanartu J
      • Dabancens A
      • Oberti C
      • Rodriquez-Bravo R
      • Garcia-Huidobro M.
      Low-dosage oral progestogens to control fertility. I. Clinical investigation.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      ,
      • Jick SS
      • Hagberg KW
      • Kaye JA
      • Jick H.
      The risk of unintended pregnancies in users of the contraceptive patch compared to users of oral contraceptives in the UK General Practice Research Database.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ] were most frequently reported. Although studies reported ages differently (range, average age, maximum age, or a mix of these measures), ages ranged from 13 to 54 years. Studies also measured fertility in various ways, including number of previous pregnancies, number of living children, and number of live births. Twenty-seven studies noted that all or most participants (between 75% and 99%) had proven to be fertile [
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Foss GL
      • Fotherby K.
      Long-term use of daily administration of low doses of norgestrel as an oral contraceptive.
      ,
      • Foss GL
      • Svendsen EK
      • Fotherby K
      • Richards DJ.
      Contraceptive action of continuous low doses of norgestrel.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Jeppsson S
      • Kullander S.
      Experience with chlormadinone acetate in continuous low dose as an oral contraceptive.
      ,
      • Kesserü E
      • Larrañaga A
      • Hurtado H
      • Benavides G.
      Fertility control by continuous administration of d-Norgestrel, 0.03 mg.
      ,
      • Laurie RE
      • Korba VD.
      Fertility control with continuous microdose norgestrel.
      ,
      • Lawson JP
      • Bradshaw FR.
      Experience with norethisterone 0.35 mg. as an oral contraceptive - a preliminary report.
      ,
      • Martinez-Manautou J
      • Giner-Velasquez J
      • Rudel H.
      Continuous progestogen contraception: a dose relationship study with chlormadinone acetate.
      ,
      • Martinez-Manautou J
      • Cortez V
      • Giner J
      • Aznar R
      • Casasola J
      • Rudel H.
      Low doses of progestogen as an approach to fertility control.
      ,
      • McQuarrie H.
      The clinical evaluation of norethindrone in cyclic and continous regimens.
      ,
      • Mears E
      • Vessey MP
      • Andolsek L
      • Oven A.
      Preliminary evaluation of four oral contraceptives containing only progestogens.
      ,
      • Moggia A
      • Harris G
      • Dunson T
      • Diaz R
      • Moggia M
      • Ferrer M
      • et al.
      A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina.
      ,
      • Rice-Wray E
      • Beristain II
      • Cervantes A.
      Clinical study of a continuous daily micro-dose progestogen contraceptive–d-norgestrel.
      ,
      • Shroff NE
      • Pearce MY
      • Stratford ME
      • Wilkinson PD.
      Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
      ,
      • Tejuja S
      • Saxena NC
      • Choudhury SD
      • Malhotra U.
      Experience with 50 mcg and 75 mcg dl-norgestrel as a mini-pill in India.
      ,
      • Vessey MP
      • Mears E
      • Andolšek L
      • Ogrinc-Oven M
      Randomised double-blind trial of four oral progestagen-only contraceptives.
      ,
      • Whyte JC
      • Pooransingh CS.
      Low dosage progestagen as an oral contraceptive: a clinical study.
      ,
      • Zañartu J
      • Rodriguez-Moore G
      • Pupkin M
      • Salas O
      • Guerrero R.
      Antifertility effect of continuous low-dosage oral progestogen therapy.
      ,
      • Statzer D.
      Daily microdose norgestrel as a contraceptive: a preliminary report.
      ,
      • Cerais A
      • Abdel Aziz F
      • El Dirdire S
      A study of a progestogen only oral contraceptive for lactating women in Khartoum, Sudan.
      ,
      • Board J.
      Continuous norethindrone, 0.35 mg, as an oral contraceptive agent.
      ,
      • Board J.
      Contraception with norethindrone 0.35 mg administered continuously.
      ,
      • Butler C
      • Hill H.
      Chlormadinone acetate as oral contraceptive.
      ]. We included other commonly reported participant characteristics in Table 1.
      Thirty-six studies [
      • Palacios S
      • Colli E
      • Regidor PA
      Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.
      ,
      • Apelo R
      • Veloso I.
      Clinical experience with microdose d-Norgestrel as an oral contraceptive.
      ,
      • Canto TE
      • Vera L
      • Polanco LE
      • Colven CE.
      Mini-pill in lactating women.
      ,
      • Christie G.
      Chlormadinone acetate 0-5 mg. A report on its effectiveness in continuous use as an oral contraceptive.
      ,
      • Cox H.
      Progestogen-only oral contraceptives.
      ,
      • Dunson TR
      • McLaurin VL
      • Grubb GS
      • Rosman AW.
      A multicenter clinical trial of a progestin-only oral contraceptive in lactating women.
      ,
      • Eckstein P
      • Whitby M
      • Fotherby K
      • Butler C
      • Mukherjee TK
      • Burnett JBC
      • et al.
      Clinical and laboratory findings in a trial of norgestrel, a low-does progestogen-only contraceptive.
      ,
      • Hawkins DF
      • Benster B.
      A comparative study of three low dose progestogens, chlormadinone acetate, megestrol acetate and norethisterone, as oral contraceptives.
      ,
      • Heinen G
      • Rindt W
      • Yeboa J
      • Umla H.
      Hormonal contraception with 0.5 mg chlormadinone acetate by continuous administration.
      ,
      • Hernandez-Torres A.
      Preliminary evaluation of fertility control with continuous microdose norgestrel.
      ,
      • Archer DF
      • Ahrendt HJ
      • Drouin D.
      Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability.