How Medications Cross the Placenta and Affect the Fetus

When a pregnant person takes a medication, it doesn’t just stay in their body. It travels through the bloodstream, reaches the placenta, and can cross over to the developing fetus. This isn’t science fiction-it’s everyday biology. And while some drugs pass through easily, others barely make it. The difference can mean the difference between a healthy baby and serious complications.

The placenta isn’t a wall-it’s a gatekeeper

For decades, doctors thought the placenta acted like a shield, blocking harmful substances from reaching the baby. That idea was shattered in the late 1950s when thousands of babies were born with severe limb defects after their mothers took thalidomide for morning sickness. The drug didn’t just cross the placenta-it caused irreversible damage. Since then, we’ve learned the placenta isn’t a barrier. It’s a selective filter.

At full term, the placenta weighs about half a kilogram, spans 15-20 centimeters across, and has a surface area the size of a small rug-nearly 15 square meters. That’s a lot of space for molecules to move back and forth. But not everything gets through. The placenta uses several mechanisms to decide what passes and what gets blocked.

How drugs actually cross over

There are four main ways medications move from mother to fetus:

• Passive diffusion-the most common route. Small, fat-soluble molecules slip through cell membranes easily. Think alcohol, nicotine, or caffeine. These cross quickly and often reach near-equal levels in mother and baby.
• Active transport-the placenta has special protein pumps that push certain drugs back into the mother’s blood. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two key players. They’re like bouncers at a club, kicking out unwanted guests.
• Facilitated diffusion-some drugs hitch a ride on transporters meant for nutrients. Zidovudine, an HIV drug, uses these to cross efficiently.
• Receptor-mediated endocytosis-larger molecules like antibodies (IgG) are carried in vesicles. This is why some immunotherapies can reach the fetus.

Size matters. Drugs under 500 daltons (Da) cross much more easily. Insulin, at over 5,800 Da, barely gets through. But even small drugs can be blocked if they’re highly bound to proteins in the mother’s blood. Warfarin, for example, is 99% bound-so only 1% is free to cross. That’s why its fetal exposure is low, despite being small and fat-soluble.

What happens when drugs get through?

Once a drug reaches the fetus, its effects depend on two things: the stage of development and the drug’s pharmacology.

In the first trimester, the placenta is more porous. Tight junctions between cells aren’t fully formed, and efflux pumps like P-gp aren’t working at full strength. That means drugs can enter more easily during the critical window of organ formation. A medication that’s safe later in pregnancy might be dangerous early on.

Take SSRIs like sertraline. They cross the placenta with a cord-to-maternal ratio of 0.8 to 1.0-meaning the baby gets almost as much as the mother. About 30% of newborns exposed to these drugs show temporary symptoms like jitteriness, feeding trouble, or breathing issues. These usually resolve within days, but they’re still a sign the drug reached the baby.

Opioids are even more concerning. Methadone reaches fetal levels at 65-75% of maternal concentration. That’s why 60-80% of babies born to mothers on methadone develop neonatal abstinence syndrome-withdrawal symptoms like crying, tremors, and seizures. The same goes for buprenorphine and morphine. These drugs don’t just cross-they stick around in fetal tissues longer than in adults.

Antiepileptic drugs like valproic acid cross easily and are linked to a 10-11% risk of major birth defects-nearly five times higher than the general population. Phenobarbital, another seizure drug, reaches near-equal levels in the fetus. Even though it’s been used for decades, we’re still learning how it affects brain development.

Why some drugs barely make it

Not all drugs are created equal. HIV protease inhibitors like lopinavir and saquinavir are designed to fight viruses, but they’re also stubbornly blocked by placental pumps. In perfused placenta studies, inhibiting P-gp increased lopinavir transfer by 70%. Without that block, fetal levels would be much higher.

That’s actually good news. For drugs that could harm the fetus, the placenta’s efflux systems act as a safety net. But this also means treating infections in pregnancy is harder. If a drug can’t reach the fetus, it can’t treat fetal infections. That’s why researchers are exploring ways to temporarily block these pumps-without risking toxicity.

Chemotherapy drugs like paclitaxel cross at 25-30% efficiency. But when P-gp is inhibited, that jumps to 45-50%. That’s a double-edged sword: better treatment for the fetus, but higher risk of damage. Methotrexate, used for autoimmune conditions and some cancers, barely crosses because the placenta lacks the transporters it needs. That’s why it’s sometimes preferred in early pregnancy-but only under strict supervision.

Research is catching up

For years, scientists relied on animal studies to predict how drugs affect human fetuses. But mouse and rat placentas are structurally different. They’re more permeable. A drug that seems safe in mice might be dangerous in humans.

Now, researchers use dually perfused human placentas-live tissue from C-sections kept alive in the lab. These models show real-time drug transfer. One study found glyburide, a diabetes drug, crossed at just 5.6% efficiency, thanks to BCRP. That matched what was seen in actual human samples.

Even more advanced are placenta-on-a-chip devices-microfluidic systems that mimic the placental barrier using human cells. These can test hundreds of compounds quickly and accurately. One 2022 version matched ex vivo data at 92% accuracy.

The NIH’s Human Placenta Project has also developed non-invasive imaging using radioactive tracers to watch drugs move in real time. For the first time, we can see exactly where a drug goes inside the fetus-like whether it accumulates in the liver or brain.

What this means for pregnant people

If you’re pregnant and taking medication, don’t stop abruptly. But do talk to your doctor. Many drugs are safe. Some aren’t. The key is knowing which ones.

Ask:

• Is this drug necessary?
• Is there a safer alternative?
• What’s the evidence for fetal safety?

The FDA now requires drug labels to include specific data on placental transfer and fetal risk. Look for the Pregnancy and Lactation Labeling Rule (2015) updates. If a drug doesn’t have clear data, that’s a red flag.

Therapeutic drug monitoring is critical for drugs with narrow safety margins-like digoxin or lithium. Even if the placenta doesn’t block them, small changes in maternal dose can lead to big changes in fetal exposure.

And here’s something most people don’t realize: the placenta changes over time. What’s safe at 20 weeks might be riskier at 35 weeks. That’s why guidelines recommend reassessing medication use in each trimester.

The future: targeted therapy or unintended risk?

Scientists are now designing nanoparticles to deliver drugs directly to the fetus-treating conditions like congenital infections or genetic disorders before birth. That’s promising. But these particles can also get stuck in the placenta, triggering inflammation or damaging its function.

A $285 million market is emerging in placental-targeted delivery. But the 2023 International Placenta Society warns: we still can’t reliably predict fetal exposure. Ethical limits on human testing, species differences, and the placenta’s complexity make it hard.

For now, the best approach remains cautious use, careful monitoring, and choosing the lowest effective dose. The placenta is smart. But it’s not perfect. And when it comes to your baby’s development, that’s a risk no one should take lightly.