New generation contraceptive pills
This article focuses on the different generations of the combined pill, why they were developed and the differences between them.
The first contraceptive pill was developed in the 1950s, and since then a lot has happened. There are now over 30 different brands of combined contraceptive pills, all of which work in the same way as the original pill, but contain different combinations of hormones.
In addition to the combined pill, hormonal contraception can now also be used as a skin patch (Evra) and vaginal ring (Nuvaring).
There are also progestogen-only pills, initially termed 'mini pills' but now called POP (progestogen-only pill) which contain only one progestogen hormone, usually desogestrel.
Why develop different generations of the combined pill?
There are two main reasons for developing so many different combined pills:
- To try to improve patient safety on the pill.
- To minimise pill side effects.
Over time, as new pill formulations were developed, newer synthetic hormones were incorporated. Many of the changes made were to the progestogen constituent of the pill, but more recently, combined pills have been developed with newer oestrogens too.
Combined pills are often defined by the generation of the pill, with the newer, later generations having slightly different side effects. Lists do vary, but below is one classification often used.
First, second, third, and fourth generation pills
- First generation pills contained the oestrogen mestranol. They also contained the progestogens norethindrone or norethnodrel. These are no longer in general use. A mestranol pill with the progestogen norethisterone is still available as Norinyl-1.
- Second generation pills contain the oestrogen ethinylestradiol with either the progestogen levonorgestrel or norethisterone.
- Third generation pills also contain the oestrogen ethinylestradiol but combined with the progestogen desogestrel, or gestodene, or norgestimate.
- Fourth generation pills contain either the same synthetic oestrogen ethinylestradiol, plus a new progestogen drospirenone or a different natural oestrogen either estradiol hemihydrate with the progestogen nomegestrol acetate, or estradiol valerate and the progestogen dienogest.
A table of combined pill brands and pill generation classification
|First generation mestranol
|Second generation ethinylestradiol
|Third generation ethinylestradiol
|Fourth generation ethinylestradiol/estradiol
Microgynon 30 ED
See also CHC active ingredients comparisons.
Combined pills from all four generations work in the same way, by suppressing ovulation (egg production from the ovaries) and are all very similar in terms of efficacy to stop women becoming pregnant, being up to 99% effective at preventing pregnancy when taken correctly.
The combined pill and thrombosis
Soon after the combined pill was first marketed, there were reports linking the pill to thrombosis. This is a medical condition in which blood clots form spontaneously, often in the deep veins of the legs, a deep vein thrombosis (DVT). The blood clot may then travel to the lungs causing a pulmonary embolus (PE). Very rarely, blood clots may also spontaneously form within an artery and this can lead to a heart attack or stroke.
The level of risk of thrombosis in women is linked to their oestrogen levels. Oestrogen levels vary naturally and in particular rise significantly during pregnancy.
Other factors which increase the risk of thrombosis include:
- Previous DVT.
- Cancer and chemotherapy.
- Being overweight/obese (fat cells produce oestrogen).
- Family history of disorders causing increased clotting.
- Immobility, e.g. bedbound, prolonged travel (over 4 hours).
- After childbirth - natural physiological changes occur in the body to limit blood loss during delivery. These changes have the side effect of increasing the risk of unintended clots, e.g. DVT and PE.
Thrombosis is a serious medical condition, which although treatable, may occasionally be fatal.
Why should the pill cause thrombosis?
There are two hormones in the pill – oestrogen and progestogen. The oestrogen in the majority of pills has (almost always) been a synthetic oestrogen called ethinylestradiol (EE). The progestogen component was specifically changed between brands. However, some fourth generation pills nowadays do contain new, natural oestrogens.
Ethinylestradiol stimulates blood clotting factors and increases platelet stickiness, predisposing users to develop a clot. The progestogen in the combined pill however is also important, because this oestrogen clotting effect is modified by the particular type of progestogen. In second generation pills, levonorgestrel and norethisterone seem to counteract this effect better than desogestrel and gestodene in third generation pills. Hence second generation pills have a slightly lowered risk of thrombosis. The difference however is very small and the overall risk is still very slight especially when compared to the risk from pregnancy or childbirth.
It's now over 50 years since the first pills were prescribed in the UK, meaning there is a wealth of clinical experience with its use. In most original first generation pills, each pill contained 3-4 times as much oestrogen and progestogen as in most modern pills. The clinical debate about which pills cause the highest or lowest risk of thrombosis is ever present, but the current consensus of opinion is presented below.
What is the risk of a thrombosis on the combined pill?
The Faculty of Sexual and Reproductive Healthcare (FSRH) summarise the current evidence about the risk of thrombosis and use of hormonal contraception in a 2019 Clinical guideline: Combined Hormonal Contraception.
The Faculty underlined the numerous advantages and benefits of taking combined hormonal contraception. This now includes not only the pill, but also the contraceptive patch (Evra) and the vaginal ring (Nuvaring).
The benefits and risks should be clearly weighed up for each individual before prescribing any contraception. Women wishing to take the combined pill, the patch or the vaginal ring, should be informed about the small increased risk of a thrombosis associated with the use of these products.
Because of the higher risk of thrombosis with third generation pills and in pills with higher oestrogen content, the FSRH recommends that women over 40 are best to start with a second generation pill, such as Microgynon 30.
The risk of thrombosis in women using the combined pill, patch or ring is set out in the table below.
|Risk of thrombosis
|Non user and non pregnant
|2 per 10,000 women per year
|Second generation pills containing levonorgestrel, norethisterone, or norgestimate
|5-7 per 10,000 women per year
|Third generation pills containing desogestrel or gestodene
|9-12 per 10,000 women per year
|Evra and Nuvaring containing norelgestromin or etonogestrel
|6-12 per 10,000 women per year
|Fourth generation pills containing drospirinone
|9-12 per 10,000 women per year
|Fourth generation pills containing nomegestrel or dienogest
|Data not yet available
|29 per 10,000 women per year
|300-400 per 10,000 women per year
From the table you can see that you are far more likely to have a blood clot in pregnancy or after having a baby, than you are on the pill.
In addition, the chance of dying if you have a thrombosis is less than 1%.
To keep it simple, in terms of thrombosis, it seems that the third generation pills may have a slightly higher risk of thrombosis than the second generation pills, but the difference in risk is small. So long as you accept the risk at 6-12 per 10,000 users, you can use any combined pill you like. This risk is still significantly less than the risk of thrombosis in pregnancy and after childbirth.
To stay healthy on the pill, it's important to keep your risk factors for thrombosis as low as possible.
- Stop smoking.
- Try to maintain a healthy weight – ideal BMI is 21-25. (If you have a BMI of 35 or over you will not be allowed to continue on the pill.)
- Have regular pill checks – including blood pressure checks.
- Stay active – let the doctor know if you have reduced mobility, or for example planned surgery.
- Follow advice on long haul flights.
What are the advantages of the newer generation pills?
Possibly fewer side effects? Up to 30% of women may discontinue their pills within the first 3 months, often because of side effects. Third generation pills may be associated with less in the way of some side effects. Because the progestogens desogestrel, norgestimate, and gestodene are less androgenic (male-type), using these types of pills may cause less in the way of androgenic side effects (study data), e.g. mood swings, acne, bloating, and PMT (premenstrual tension) type symptoms. A small study has shown an improvement in bleeding pattern with third generation pills but better research is still needed.
How common are side effects on the pill really? Interestingly, side effects due directly to taking the pill, may not be as common as they are made out to be. It is important to note that in some studies using combined pills and placebo (dummy) pills, where neither the investigator nor the study participant knew what they were taking, there were similar numbers of side effects in the group taking the placebo pills.
Non-contraceptive benefits - one of the reasons for taking the pill may be to obtain non-contraceptive benefits such as improved acne, less mood swings, bloating, and PMT. The combined pill reduces painful, heavy periods. It is also a good treatment for women with polycystic ovarian syndrome, endometriosis, and some other gynaecological disorders. In the long term there is less risk of developing ovarian or womb cancer in women who have taken the combined pill.
The anti-androgenic effect of the progestogen in fourth generation pills may be very helpful to treat a lot of these symptoms, for example, at improving acne. Specific pills used to treat acne are Yasmin (drospirenone), and a similar alternative is Dianette (cyproterone acetate). (There are specific recommendations for using Dianette which are beyond the scope of this text. If you want to take Dianette you must discuss this with your regular doctor.)
No clear association with weight gain - the early combined contraceptive pills with their very high levels of oestrogen were more likely to cause weight gain through the combined effects of fluid retention and increasing the appetite. Modern pills contain much less oestrogen. There is no clear evidence that taking any of the modern combined pills actually causes weight gain. This is often not believed, but medical research has shown that women naturally gain weight as they age, whether they use a hormonal method of contraception, or a copper IUD (plastic and copper - no hormones).
If you have put on weight whilst on the pill, the lower 20 microgram oestrogen dose pills - e.g. Gedarel 20, Mercilon, Eloine, Femodette, Millinette - may seem a more logical choice. These contain 30% less oestrogen than most standard combined contraceptive pills, but they are just as effective as a contraceptive.
Natural oestrogen in the fourth generation pill. Some fourth generation pills have been developed containing natural oestrogen in the hope they may prove safer with long-term use. There is not yet enough clinical evidence to substantiate this but they are often used by women who prefer 'natural' hormones, or who have had oestrogenic side effects on other pills (nausea, vomiting, breast tenderness). They can be a good solution if you have tried various other pills and not got on well with them.
Second generation pills have the lowest risk of thrombosis, but the difference is slight and there are benefits in terms of fewer side effects, when taking third or fourth generation pills. In particular fourth generation pills can lead to an improvement in acne.
There is no documented difference in reliability between the different generations of combined pill, but the reliability does depend on the pills being taken consistently and correctly. Long-Acting Reversible Contraception (LARC) in the form of coils, implants and injections can provide more reliable contraception.
Weight gain has long been thought to be associated with combined pill taking but with modern low dose pills there is no evidence of this.
If you are medically eligible, there is a wide choice of combined contraceptive pills, and most women are able to find a pill which suits them.Buy Combined Pill
- FSRH, 2020, Clinical Guideline: Combined Hormonal Contraception, accessed 17 October 2022
- FSRH, 2019, UK MEC, accessed 17 October 2022
- NICE, 2019, Combined oral contraceptive, accessed 17 October 2022
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