For the video version of this post, click here.

At any given time, there are around 11 million women in the US who are actively taking combined oral contraceptive pills. The first case-report describing a blood-clot in a woman taking the pill was published in 1961, and large epidemiologic studies have since confirmed that the pill increases clot risk, particularly in those who smoke or are above age 35.

But different formulations of oral contraceptives may affect clot risk differently. And here’s where the data gets more interesting. Progrestin-only pills don’t seem to increase clot risk very much, but combined estrogen / progestin pills do. So estrogen seems to be the culprit. Strangely, though, the clot risk seems to differ depending on which progesterone analogue is mixed with the estrogen.

Trying to quantify these risks is really hard.  Many women will use many formulations  over their lifetime, and may go on and off the pill sporadically.

So to study this, you need a really good database. Ideally, an electronic system that is tracking every prescription women get, and all the relevant outcomes. A study appearing in the British Medical Journal uses just that - two large, primary care databases to track the link between various pill formulations and venous thromboembolism.

This was a case-control study.  Identify the cases of VTE, match to controls who didn’t have VTE, and examine how the risk factors differ.

But the devil is in the details. The best way to mess up a case control study is to choose the wrong controls.  The strangest quirk of the BMJ study is that the controls had some different inclusion criteria than the cases.  Potential cases, identified at the time of VTE, were excluded if they had received anticoagulant therapy in the past 42 days.  The controls were excluded if they had EVER received anticoagulant therapy.  This choice would lead to higher-risk people being in the case group, and that could bias the final results.

What the final results showed is that more modern formulations of the pill, so-called 3rd and 4th generation OCPs, had higher risk of VTE than older formulations. Being on one of the older pills increased the risk of VTE by about 2.5 times.  Being on a newer pill upped that risk to around 4 - 5 fold.

Is this effect real? Maybe. It is possible that docs who prescribe newer generation OCPs are more vigilant about VTE symptoms, leading to increased diagnosis.  But regardless, it bears noting that the absolute risk here remains very small. Out of 10,000 women on an older generation pill, 7 will be diagnosed with a VTE compared to 14 on a newer generation pill.

A reasonable strategy may be to prescribe 2nd generation OCPs to women who are concerned about these risks.  Of course, for women who smoke or have significant VTE risk factors, another method of contraception may be easier to swallow.