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Maternal hypertension and cardiovascular medications dysregulate placental arterial tone

This study demonstrates that maternal hypertension and the use of various cardiovascular medications, including labetalol and bisoprolol, can dysregulate human fetoplacental vascular tone and reactivity, potentially compromising placental perfusion and fetal outcomes.

Original authors: Teresa Tropea, Elizabeth C. Cottrell, Raianne Wallworth, Nardeen Khalil, Edward D. Johnstone, Jenny E. Myers, Paul Brownbill

Published 2026-06-29

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Teresa Tropea, Elizabeth C. Cottrell, Raianne Wallworth, Nardeen Khalil, Edward D. Johnstone, Jenny E. Myers, Paul Brownbill

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

The Big Picture: The Placenta as a "Traffic Control Center"

Imagine the placenta as a busy highway interchange connecting the mother's body to the baby. The arteries in this interchange (specifically the "Chorionic Plate Arteries" or CPAs) act like the traffic lights and road width. Their job is to stay open and relaxed to let a steady stream of oxygen and nutrients flow to the baby.

If these "roads" get too tight (constricted), the baby gets less fuel. If they are too loose, the mother's blood pressure might drop too low. The balance is delicate.

This study asked a simple question: When pregnant women take heart or blood pressure medications, do those drugs accidentally jam the traffic or clear the roads in the baby's highway?

The Experiment: Testing the Roads

The researchers took samples of these "highway roads" from placentas after birth. They tested them in a lab using two main scenarios:

The "Fresh Paint" Test (Acute Exposure): They took healthy roads and dipped them in different medications one by one to see what happened immediately.
The "Wear and Tear" Test (Chronic Exposure): They looked at roads from women who had high blood pressure or heart issues during their entire pregnancy, some of whom were on medication and some who weren't. They wanted to see if the roads had changed permanently.

What They Found

1. The "Relaxing" Drugs (Calcium Channel Blockers)

The Drugs: Amlodipine and Nifedipine.
The Analogy: Think of these drugs as gentle road wideners. When the researchers put these on the healthy roads, the roads immediately relaxed and opened up wider.
The Result: These drugs work exactly as intended in the placenta—they help blood flow.

2. The "Confusing" Drugs (Adrenergic Medications)

The Drugs: Labetalol, Methyldopa, and Bisoprolol.
The Analogy: These are like traffic signals that are stuck on "Stop" or are sending mixed messages.
- Labetalol & Methyldopa: Instead of relaxing the roads, these actually made the healthy roads tighten up (constrict) more than usual. It's like a drug meant to lower blood pressure accidentally squeezing the highway shut in the lab.
- Bisoprolol: This drug didn't immediately squeeze the road shut, but it kept the road "stiff" and prevented it from relaxing when it needed to. It was like a road that refused to open up even when traffic was light.

3. The "Stiff" Roads of High Blood Pressure

The Finding: The roads from women who had high blood pressure (even without medication) were already stiffer and less responsive than healthy roads. They didn't squeeze as hard when asked, and they didn't relax as well when given a "relax" signal.
The Surprise: Adding medication to these already-stiff roads didn't make them much worse or much better in the lab. The high blood pressure itself seemed to be the main reason the roads were damaged, not necessarily the pills.

4. The Special Case of Bisoprolol

The Finding: Women taking Bisoprolol (a heart medication) had the most noticeable issues. Their placental roads were significantly worse at relaxing.
The Analogy: Imagine a rubber band that has been stretched for a long time; it loses its snap. The study suggests that being on Bisoprolol during pregnancy might make the placental "rubber bands" lose their ability to stretch and relax, potentially making it harder for the baby to get nutrients.

The "So What?" (Without Overpromising)

The paper concludes with a few key takeaways, but it is very careful not to say "This drug is dangerous" or "This drug is safe" for every patient.

The Placenta is Unique: What happens in the mother's main body (systemic circulation) doesn't always happen in the baby's highway (placental circulation). A drug that relaxes a mother's arm artery might tighten a baby's placental artery.
High Blood Pressure is the Real Culprit: The study found that the mother's high blood pressure itself damages the placental roads more than the medications do.
Bisoprolol Needs More Study: Because Bisoprolol showed the strongest negative effect on the placenta's ability to relax in the lab, the authors say we need more research to understand why this happens and to weigh the risks carefully.

Summary Analogy

Think of the pregnancy as a construction project building a house (the baby).

High Blood Pressure is like a storm that damages the scaffolding (the placenta).
Calcium Channel Blockers are like workers who fix the scaffolding by loosening the bolts.
Labetalol and Methyldopa are like workers who, while trying to fix the storm damage, accidentally tighten a few bolts, making the scaffolding stiffer.
Bisoprolol is like a worker who leaves the scaffolding rigid and unable to move, which might make it harder to deliver materials to the house.

The researchers are telling us: "We know the storm (high blood pressure) is bad for the scaffolding. We also know that some of the tools (medications) we use to fix the storm might have unexpected side effects on the scaffolding itself. We need to study these tools more closely to make sure we aren't accidentally making the job harder for the baby."

Technical Summary: Maternal Hypertension and Cardiovascular Medications Dysregulate Placental Arterial Tone

Problem Statement
Cardiovascular disease, particularly hypertension, is a leading cause of maternal mortality and poor pregnancy outcomes. While antihypertensive medications (including calcium channel blockers, $\alpha$ - and $\beta$ -adrenergic receptor antagonists, and agonists) are prescribed to manage maternal blood pressure and protect the maternal cardiovascular system, these drugs cross the placental barrier. Their entry into the fetoplacental circulation poses a risk of altering placental vascular tone and perfusion, potentially contributing to fetal growth restriction (FGR) and small-for-gestational-age (SGA) outcomes. Currently, there is limited mechanistic evidence regarding how specific classes of these medications affect human fetoplacental vascular reactivity, leaving clinicians with minimal guidance for evidence-based prescribing that balances maternal safety with fetal well-being.

Methodology
The study utilized human chorionic plate arteries (CPAs) isolated from placentas to assess vascular function via wire myography. The research was divided into two primary experimental objectives:

Acute Ex Vivo Exposure: CPAs from normotensive women were pre-constricted using the thromboxane A2 mimetic U46619. The acute, concentration-dependent effects of seven cardiovascular medications were tested: amlodipine and nifedipine (Ca $^{2+}$ channel blockers, CCBs); labetalol ( $\alpha$ / $\beta$ -antagonist); methyldopa ( $\alpha_2$ -agonist); doxazosin ( $\alpha_1$ -antagonist); and bisoprolol and nebivolol ( $\beta_1$ -antagonists). Concentrations were based on known or estimated fetal venous plasma levels.
Chronic In Vivo Exposure: CPAs were isolated from women with chronic hypertension or cardiac disease who had been exposed to these medications throughout pregnancy. Vascular reactivity was assessed by measuring vasoconstriction responses to high potassium physiological solution (KPSS) and U46619, and vasorelaxation responses to the nitric oxide (NO) donor sodium nitroprusside (SNP).

The study cohort included 107 participants, categorized by maternal condition (normotensive, untreated hypertensive, medicated hypertensive, or cardiac disease) and specific medication exposure (amlodipine, nifedipine, labetalol, bisoprolol, or combinations).

Key Results

Acute Drug Effects on Normotensive Arteries:
- Vasorelaxation: Acute exposure to amlodipine, nifedipine, doxazosin, and nebivolol promoted significant vasorelaxation in pre-constricted CPAs. Amlodipine showed the most potent effect (31.9% maximum vasodilatory effect).
- Vasoconstriction/Impaired Relaxation: In contrast, labetalol, methyldopa, and bisoprolol increased vasoconstriction relative to controls. Bisoprolol specifically maintained a higher level of pre-constriction tension over time compared to controls, suggesting a lack of vasorelaxation or a sustained constrictive phenotype.
Impact of Maternal Hypertension:
- Maternal hypertension itself significantly reduced CPA reactivity. Compared to normotensive controls, arteries from untreated hypertensive women showed diminished vasoconstriction to KPSS and U46619, as well as reduced vasorelaxation to SNP.
- This impairment in vascular function was observed regardless of whether the women were treated with CCBs (amlodipine or nifedipine), suggesting the underlying hypertensive pathology, rather than the medication, was the primary driver of reduced reactivity in these groups.
Impact of Specific Medications (Chronic Exposure):
- Labetalol: Treatment with labetalol (alone or combined with CCBs) did not significantly worsen the vascular dysfunction associated with hypertension. However, the labetalol group still exhibited reduced vasoconstriction and relaxation compared to normotensive controls, consistent with the underlying hypertensive effect.
- Bisoprolol: This group exhibited the most distinct vascular phenotype. Chronic in vivo exposure to bisoprolol was associated with significantly reduced vasoconstriction to U46619 and a marked reduction (~26%) in maximal vasorelaxation to SNP compared to normotensive controls. Notably, the bisoprolol cohort had the highest rates of SGA (38%) and fetal growth restriction.

Significance and Claims
The authors claim this is the first study to directly compare the effects of maternal hypertension and common antihypertensive/cardiac medications on human fetoplacental vascular function. The study establishes that:

Maternal Hypertension Dysregulates Placental Tone: The underlying disease state of hypertension impairs the ability of fetoplacental arteries to constrict and relax, independent of medication exposure.
Medication Class Matters: While CCBs act as vasodilators in the fetoplacental circulation, adrenergic agents have divergent effects. Specifically, bisoprolol is identified as having the most pronounced negative impact on vascular reactivity, inducing a vasoconstrictive phenotype and impairing NO-mediated relaxation.
Clinical Implications: The findings suggest that the increased risks of adverse perinatal outcomes (such as FGR and SGA) observed in women with cardiovascular disease may be attributable to dysregulated placental perfusion caused by the underlying disease and potentially exacerbated by specific medications like bisoprolol.

The paper concludes that while these medications are necessary for maternal safety, the differential effects on fetoplacental vascular tone—particularly the impairment caused by bisoprolol—warrant further mechanistic investigation and clinical correlation to guide evidence-based prescribing. The authors emphasize that current data is insufficient to fully disentangle the effects of the underlying maternal disease from the drug effects, highlighting the need for future studies to clarify risk-benefit profiles.