We assessed the available evidence regarding adverse effects on surrogate and patient-important health outcomes of third- and fourth-generation combined oral contraceptives among premenopausal women. We performed a systematic review and meta-analysis including randomized controlled trials and observational studies comparing third- and fourth-generation combined oral contraceptives with other generation contraceptives or placebo. Studies that enrolled women aged 15 to 50 years, with at least three cycles of intervention and 6 months of follow-up were included. A total of 33 studies comprising 629,783 women were included. Low-density lipoprotein cholesterol levels were significantly lower in fourth-generation oral contraceptives (mean differences (MD): −0.24 mmol/L; [95% CI −0.39 to −0.08]), while total cholesterol was significantly increased in levonorgestrel users when compared to third-generation oral contraceptives (MD: 0.27 mmol/L; [95% CI 0.04 to 0.50]). A decreased arterial thrombosis incidence was shown in fourth-generation oral contraceptive users, as compared to levonorgestrel (incidence rate ratio (IRR): 0.41; [95% CI 0.19 to 0.86]). No difference was found in the occurrence of deep venous thrombosis between fourth-generation oral contraceptives and levonorgestrel users (IRR: 0.91; [95% CI 0.66 to 1.27]; p = 0.60; I2 = 0%). Regarding the remaining outcomes, data were heterogeneous and showed no clear difference. In premenopausal women, the use of third- and fourth-generation oral contraceptives is associated with an improved lipid profile and lower risk of arterial thrombosis. Data were inconclusive regarding the rest of outcomes assessed. This review was registered in PROSPERO with CRD42020211133.
de WitAEBooijSHGiltayEJ, et al. Association of use of oral contraceptives with depressive symptoms among adolescents and young women. JAMA Psychiatry2019; 77(1): 52–59.
BeralVHermonCKayC, et al., Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study. BMJ1999; 318(7176): 96–100.
4.
HatcherRAGuillebaudJ. The pill: combined oral contraceptives. In: Ardent Media (ed.) Contraceptive technology. Irvington, NJ: Irvington Publishers, 1998, pp. 405–466.
5.
GaspardULambotteR. Metabolic impact of current estrogen-progestins and cardiovascular consequences. Bull Mem Acad R Med Belg1991; 146(8–10): 334335.
6.
LeblancESLawsA. Benefits and risks of third-generation oral contraceptives. J Gen Intern Med1999; 14(10): 625–632.
7.
StadelBV. Oral contraceptives and cardiovascular disease. N Engl J Med1981; 305(11): 612–618.
8.
VandenbrouckeJPRosingJBloemenkampKWM, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med2001; 344(20): 1527–1535.
9.
DhontM. History of oral contraception. Eur J Contracept Reprod Health Care2010; 15(Suppl 2): S12–S18.
10.
LidegaardØLøkkegaardESvendsenAL, et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ2009; 339: b2890.
11.
van Hylckama VliegAHelmerhorstFMVandenbrouckeJP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ2009; 339: b2921.
12.
BasdevantAPelissierCConardJ, et al. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women. Contraception1991; 44(6): 599–605.
13.
HazardMCClavetMChapignacA, et al., Effects of progestogens on lipemia and lipolysis in rat: effects of progesterone, megestrol acetate, norethindrone acetate, and nomegestrol acetate. Fundam Clin Pharmacol1987; 1(4): 233–242.
14.
CampagnoliCAmbroggioSLotanoMR, et al. Progestogen use in women approaching the menopause and breast cancer risk. Maturitas2009; 62(4): 338–342.
15.
FabreAFournierAMesrineS, et al. Progestagens use before menopause and breast cancer risk according to histology and hormone receptors. Cancer Epidemiol Biomarkers Prev2008; 17(10): 2723–2728.
16.
SchaffirJWorlyBLGurTL. Combined hormonal contraception and its effects on mood: a critical review. Eur J Contracept Reprod Health Care2016; 21(5): 347–355.
17.
O’ConnellK.DavisARKernsJ. Oral contraceptives: side effects and depression in adolescent girls. Contraception2007; 75(4): 299–304.
18.
HuberLRBHogueCJSteinAD, et al. Contraceptive use and discontinuation: findings from the contraceptive history, initiation, and choice study. Am J Obstet Gynecol2006; 194(5): 1290–1295.
19.
ArieS. French doctors are told to restrict use of third and fourth generation oral contraceptives. BMJ2013; 346: f121.
20.
BitzerJAmyJJBeerthuizenR, et al. Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism. Eur J Contracept Reprod Health Care2013; 18(3): 143–147.
21.
BurkmanRSchlesselmanJJZiemanM. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol2004; 190(4 Suppl): S5–S22.
22.
DingerJCHeinemannLAJKühl-HabichD. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception2007; 75(5): 344–354.
23.
MoherDLiberatiATetzlaffJ, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ2009; 339: b2535.
24.
McGinnTWyerPCNewmanTB, et al. Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic). CMAJ2004; 171(11): 1369–1373.
25.
BalshemHHelfandMSchünemannHJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol2011; 64(4): 401–406.
26.
HigginsJPTLiTDeeksJJ. Chapter 6: Choosing effects measures and computing estimates of effects. In: HigginsJPTLiTDeeksJJ (eds) Cochrane handbook for systematic reviews of interventions. 2nd ed. Chichester, UK: John Wiley & Sons, 2020, pp. 143–176.
27.
HigginsJPTEldridgeSMLiT. Chapter 23: Including variants on randomized trials. In: HigginsJPTEldridgeSMLiT (eds). Cochrane handbook for systematic reviews of interventions. 2nd ed. Chichester, UK: John Wiley & Sons, 2020, pp. 569–593.
AmiriMNahidiFBidhendi-YarandiR, et al. A comparison of the effects of oral contraceptives on the clinical and biochemical manifestations of polycystic ovary syndrome: a crossover randomized controlled trial. Hum Reprod2020; 35(1): 175–186.
30.
AmiriMNahidiFYarandiRB, et al. Effects of oral contraceptives on the quality of life of women with polycystic ovary syndrome: a crossover randomized controlled trial. Health Qual Life Outcomes2020; 18(1): 293.
31.
AmiriMRahmatiMHedayatiM, et al. Effects of oral contraceptives on serum concentrations of adipokines and adiposity indices of women with polycystic ovary syndrome: a randomized controlled trial. J Endocrinol Invest2021; 44(3): 567–580.
32.
ApterDZimmermanYBeekmanL, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception2016; 94(4): 366–373.
33.
ApterDZimmermanYBeekmanL, et al. Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur J Contracept Reprod Health Care2017; 22(4): 260–267.
34.
DingerJBardenheuerKHeinemannK. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception2014; 89(4): 253–263.
35.
KellySDaviesEFearnsS, et al. Effects of oral contraceptives containing ethinyl estradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women. Clin Drug Investig2010; 30(5): 325–336.
36.
OelkersWFoidartJMDombroviczN, et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab1995; 80(6): 1816–1821.
37.
PodfigurnaAMeczekalskiBPetragliaF, et al. Clinical, hormonal and metabolic parameters in women with PCOS with different combined oral contraceptives (containing chlormadinone acetate versus drospirenone). J Endocrinol Invest2020; 43(4): 483–492.
38.
AhrendtHJMakalováDParkeS, et al. Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel. Contraception2009; 80(5): 436–444.
39.
DingerJMöhnerSHeinemannK. Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives. Contraception2016; 93(5): 378–385.
40.
FraserISRömerTParkeS, et al. Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial. Hum Reprod2011; 26(10): 2698–2708.
41.
JungeWMellingerUParkS, et al. Metabolic and haemostatic effects of estradiol valeratedienogest, a novel oral contraceptive: a randomized, open-label, single-centre study. Clin Drug Investig2011; 31(8): 573–584.
42.
WongwananurukTPanichyawatNPanchaleeT, et al. Comparison of change in body weight between contraception containing 30-μg ethinyl estradiol/2-mg chlormadinone acetate or 30-μg ethinyl estradiol/3-mg drospirenone: a randomised controlled trial. Eur J Contracept Reprod Health Care2020; 25(1): 43–48.
43.
YildizhanRGokceAIYildizhanB, et al. Comparison of the effects of chlormadinone acetate versus drospirenone containing oral contraceptives on metabolic and hormonal parameters in women with PCOS for a period of two-year follow-up. Gynecol Endocrinol2015; 31(5): 396–400.
44.
WiegratzILeeJHKutscheraE, et al. Effect of dienogest-containing oral contraceptives on lipid metabolism. Contraception2002; 65(3): 223–229.
45.
ÅgrenUMAnttilaMMäenpää-LiukkoK, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinyl estradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care2011; 16(6): 444–457.
46.
YuQZhouYSuturinaL, et al., Efficacy and safety of estradiol valerate/dienogest for the management of heavy menstrual bleeding: a multicenter, double-blind, randomized, placebo-controlled, phase III clinical trial. J Womens Health2018; 27(10): 1225–1232.
47.
HirvonenEStenmanUHMälkönenM, et al. New natural oestradiol/cyproterone acetate oral contraceptive for pre-menopausal women. Maturitas1988; 10(3): 201–213.
48.
HoPCLiuWTKwanMS. Serum lipids in Chinese patients using oral contraceptive pills. Contraception1990; 41(1): 55–61.
49.
JickHKayeJAVasilakis-ScaramozzaC, et al. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis. BMJ2000; 321(7270): 1190–1195.
50.
KatzHIKempersSAkinMD, et al. Effect of a desogestrel-containing oral contraceptive on the skin. Eur J Contracept Reprod Health Care2000; 5(4): 248–255.
51.
KaunitzAM. Efficacy, cycle control, and safety of two triphasic oral contraceptives: CyclessaTM (desogestrel/ethinyl estradiol) and Ortho-Novum® 7/7/7 (norethindrone/ethinyl estradiol): a randomized clinical trial. Contraception2000; 61(5): 295–302.
52.
KnoppRHBroylesFECheungM, et al. Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception2001; 63(1): 1–11.
53.
MoreauCTrussellJGilbertF, et al. Oral contraceptive tolerance: does the type of pill matter?Obstet Gynecol2007; 109(6): 1277–1285.
54.
PrasadRNVLiewDRatnamSS. Comparative metabolic effects of three types of combined oral contraceptive pills in Chinese women. Contraception1989; 39(1): 21–35.
55.
SanamMZibaO. Desogestrel + ethinyl estradiol versus levonorgestrel + ethinyl estradiol. Which one has better affect on acne, hirsutism, and weight change. Saudi Med J2011; 32(1): 23–26.
56.
WinklerUHFergusonHMuldersJAPA. Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 μg ethinyl estradiol. Contraception2004; 69(6): 469–476.
57.
WinklerUHRöhmPHöschenK. An open-label, comparative study of the effects of a dose-reduced oral contraceptive containing 0.02 mg ethinyl estradiol/2 mg chlormadinone acetate on hemostatic parameters and lipid and carbohydrate metabolism variables. Contraception2010; 81(5): 391–400.
58.
FaitTBuryakDCirstoiuM-M, et al. Needs and preferences of women users of oral contraceptives in selected countries in Central and Eastern Europe. Drugs Context2018; 7: 212510.
59.
LoudonNBKirkmanRJEDewsburyJA. A double-blind comparison of the efficacy and acceptability of Femodene and Microgynon-30. Eur J Obstet Gynecol Reprod Biol1990; 34(3): 257–266.
60.
JanaudARouffyJUpmalisD, et al., A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet Gynecol Scand Suppl1992; 156: 33–38.
61.
Weber-DiehlFLehnertJLachnitU. Comparison of two triphasic oral contraceptives containing either gestodene or norethindrone: a randomized, controlled trial. Contraception1993; 48: 291–301.
62.
SulakPLippmanJSiuC, et al. Clinical comparison of triphasic norgestimate/35 μg ethinyl estradiol and monophasic norethindrone acetate/20 μg ethinyl estradiol: cycle control, lipid effects, and user satisfaction. Contraception1999; 59(3): 161–166.
63.
SangthawanMTaneepanichskulS. A comparative study of monophasic oral contraceptives containing either drospirenone 3 mg or levonorgestrel 150 μg on premenstrual symptoms. Contraception2005; 71(1): 1–7.
64.
Silva-BermudezLSTolozaFJKPerez-MatosMC, et al., Effects of oral contraceptives on metabolic parameters in adult premenopausal women: a meta-analysis. Endocr Connect2020; 9(10): 978–998.
65.
GalloMFLopezLMGrimesDA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev2014; 29(1): CD003987.
66.
FSRH guideline (January 2019) combined hormonal contraception (revision due by January 2024). BMJ Sex Reprod Health2019; 45: 1–93.
67.
SteenlandMWZapataLBBrahmiD, et al. Appropriate follow up to detect potential adverse events after initiation of select contraceptive methods: a systematic review. Contraception2013; 87: 611–624.
68.
KharbandaEOParkerEDSinaikoAR, et al., Initiation of oral contraceptives and changes in blood pressure and body mass index in healthy adolescents. J Pediatr2014; 165(5): 1029–1033.
69.
ArowojoluAOGalloMFLopezLM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev2012; 7: CD004425.
70.
RoachREJHelmerhorstFMLijferingWM, et al. Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev2015; 8: CD011054.
71.
AkersAYGoldMABorreroS, et al. Providers’ perspectives on challenges to contraceptive counseling in primary care settings. J Womens Health2010; 19(6): 1163–1170.
72.
AmyJ-JTripathiV. Contraception for women: an evidence based overview. BMJ2009; 339: b2895.
73.
MoosMKBartholomewNELohrKN. Counseling in the clinical setting to prevent unintended pregnancy: an evidence-based research agenda. Contraception2003; 67(2): 115–132.
74.
LeemanL. Medical barriers to effective contraception. Obstet Gynecol Clin North Am2007; 34(1): 19–29, vii.
75.
RosenbergMJWaughMS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol1998; 179(3 Pt 1): 577–582.
76.
DehlendorfCFoxESobelL, et al. Patient-centered contraceptive counseling: evidence to inform practice. Curr Obstet Gynecol Rep2016; 5(1): 55–63.
77.
DehlendorfCLevyKKelleyA, et al. Women’s preferences for contraceptive counseling and decision making. Contraception2013; 88(2): 250–256.
78.
FoxEReynaAMalcolmNM, et al. Client preferences for contraceptive counseling: a systematic review. Am J Prev Med2018; 55(5): 691–702.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
