Sixty years of the combined oral contraceptive pill

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Discovery and development of the pill

Progesterone was first synthesised in the 1950s and was licensed as an oral contraceptive in 1960

1951: Carl Djerassi, a chemist at pharmaceutical company Syntex, creates a progesterone pill by synthesising hormones from yams

1952: Chemist Frank Colton at the pharmaceutical company Searle also develops a synthetic progesterone pill

1954: Biologist Gregory Pincus and gynecologist John Rock conduct the first human trials on 50 women in the US. The pill is contaminated with oestrogen during synthesis but purifying it leads to breakthrough bleeding so it is retained

1956: After large clinical trials in Puerto Rico, the pill is found to be 100% effective

1957: Enovid 10mg (9.85mg norethynodrel and 150µg mestranol; Searle) is approved by the US Food and Drug Administration (FDA) for “menstrual irregularities”. It is released onto the British market as Enavid

1960: The FDA approves contraception as an additional indication for Enovid 10mg

1961: Conovid 5mg is approved by the British Family Planning Association. Serious concerns are raised after three fatal cases of blood clots in women taking COCs

1967: Epidemiological studies link the pill with thrombosis

1970s: Second generation pills are launched, which contain lower amounts of hormones

1974: Free contraception is introduced in the UK leading to increased uptake

1980s: Third generation pills are launched to reduce androgenic and metabolic side effects

1995: The UK Committee on Safety of Medicines says third generation COCs should not be used first line because of the risk of blood clots. This “pill scare” is thought to lead to an increase of 9% in the abortion rate in 1996

1999: The Medicines Commission says third generation pills can be prescribed first line after all

2001: The EMA reviews third generation COCs and confirms a small increased risk of VTE compared with second generation pills. Fourth generation COCs are released

2009: The first COC containing the oestrogen estrodiol is launched

2013: The EMA reviews third and fourth generation COCs and concludes that their benefits continue to outweigh their risks, and the well-known risk of VTE with all COCs is small

Contraindications and interactions

Women should not take the combined oral contraceptive pill if they:

• are pregnant
• smoke and are 35 or older
• stopped smoking less than a year ago and are 35 or older
• are very overweight

Or if they have or have had:

• a blood clot
• a heart abnormality or heart disease, including high blood pressure
• severe migraines, especially with aura (warning symptoms)
• breast cancer
• disease of the gallbladder or liver
• diabetes with complications or diabetes for the past 20 years

The following medicines can interact with combined oral contraceptive pills:

• antibiotics (rifabutin, rifampicin)
• antiepileptics (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, topiramate)
• antiretrovirals (ritonavir, ritonavir-boosted protease inhibitors, efavirenz, nevirapine)
• antidepressants (St John’s wort)
• others (modafinil, bosentan, aprepitant)