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You might have heard that you should use a back-up method of protection if you're taking birth control pills and antibiotics at the same time. You might have even read it on the pill package itself!

And if it's on the packaging, well, you'd assume there's good reason. But... It turns out the majority of reports of this are inconclusive and anecdotal.

In fact, it seems like only one type of antibiotic is actually worth the extra caution. But when you look closely at how birth control pills work, it makes sense that doctors would be worried. Oral contraceptives use hormones to prevent pregnancy.

They include estrogens and progestins, or just progestins alone — though most include some kind of estrogen, because they're better at stopping the pituitary gland from releasing the hormones needed for egg development and preparing the uterus for implantation. Basically, estrogens prevent ovulation really well. Though, they only work if there are enough of them in the blood.

That's why the pills have to be taken every day. But, blood estrogen levels aren't entirely dependent on pills, because your body makes some estrogens, and it can recycle them. Like lots of things, estrogens undergo a process called conjugation in the liver where they're combined with other molecules — often glucuronic acid.

This creates larger compounds that are secreted into the intestines in bile. From there, they get excreted in feces — unless gut bacteria step in. Some bacteria chop off the added bit, thereby converting these chemicals back into active estrogens, which can get reabsorbed.

And research in animal models has suggested this recycling could be important for ensuring blood estrogen levels are high enough for effective contraception. That's where the concern with antibiotics comes from. You see, in theory, antibiotics could kill off some or all of the intestinal bacteria involved in this estrogen recycling program — which could, in theory, make the pills less effective.

The thing is, there just isn't really any evidence this happens. A 2002 review noted that neither estrogen nor progestin levels seem to drop when people take antibiotics. And a 2011 study of 1,330 cases of pregnancies that occurred while people were on birth control found no connection between contraceptive failure and antibiotic use.

Indeed, despite decades of research, a 2018 systematic review failed to find evidence that any of the major classes of antibiotics interfere with birth control. There is one exception to all of this, though: Rifampin, an antibiotic primarily used to prevent and treat tuberculosis. It can cause a notable drop in estrogen levels, and it has been linked to unexpected pregnancies.

But here's the weird part: the way it interferes with birth control has nothing to do with gut bacteria. You see, your liver manages the levels of all sorts of hormones and drugs. So it produces a variety of enzymes that break things down or otherwise prepare them for excretion.

And it just so happens that this particular bacteria-killing compound signals liver cells to ramp up the production of some of these enzymes. Specifically, rifampin increases the activity of cytochrome P450s or CYPs, for short. One of the things they're involved in is the conjugation of estrogens — they prepare the estrogen molecule for the attachment of glucuronic acid and other conjugates.

So by increasing CYPs, rifampin speeds up the conjugation of estrogens — and so much so that it leads to increased excretion of them. Which means its effects may not be limited to oral contraceptives. Other estrogen-containing birth control methods like the patch and the ring could be impacted too, but there hasn't been enough research to say for sure.

And this isn't just about estrogens. CYPs also seem to be involved in the excretion of progestins. And rifampin also increases production of globulin, a protein in your blood that binds circulating progestins and reduces their availability.

So it probably interferes with progestin-only pills, too, though again, more research is needed. In fact, CYPs help your liver deal with a lot of things, so birth control is just one of many drugs that rifampin interferes with. Still, it's not used for a lot of infections — mostly tuberculosis — so the odds are, if you're taking an antibiotic for anything else, it's not going to interfere with your preferred method of contraception.

But some still think it's better to be safe than sorry, which is why the warnings on basically all antibiotics persist. Thanks for watching this episode of SciShow! If you're hungry for more information about antibiotics, might I suggest our video looking at some weird places we might find more of them.

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