A look at TMAO, endothelial dysfunction, and the form of choline most prenatal vitamins are getting wrong — from a researcher currently drafting a peer-reviewed paper on the topic.
Preeclampsia is the leading cause of maternal mortality in the developed world.
In the United States, it affects roughly 1 in 12 pregnancies. It is responsible for a substantial portion of preterm births, fetal growth restriction, and emergency cesarean deliveries. It is, by any measure, one of the most consequential pregnancy complications a person can develop.
The pathophysiology has been understood for several decades. Preeclampsia involves endothelial dysfunction, which means thethe inner lining of blood vessels stops working correctly. This, combined with elevated platelet activity, raises the risk of clotting. The cascade affects the placenta, the maternal vasculature, and in severe cases the kidneys, liver, and brain.
What is less widely understood, and what I have spent the last year researching, is that a specific compound your gut microbes produce, called trimethylamine-N-oxide, or TMAO, has emerging mechanistic ties to both endothelial dysfunction and platelet hyperreactivity.
And the synthetic forms of choline in nearly every prenatal vitamin on the market raise TMAO.
I want to walk through what the research currently supports, what remains in the hypothesis stage, and what I believe the implications are for prenatal nutrition.
What TMAO is, briefly
When you consume certain compounds, including L-carnitine from red meat, and synthetic choline salts like choline bitartrate, your gut bacteria can convert them into a metabolite called trimethylamine, or TMA. TMA is then absorbed into the bloodstream and oxidized by the liver into trimethylamine-N-oxide, or TMAO.
TMAO circulates in your blood. It can be measured in plasma and urine. And it has been the subject of intense cardiovascular research over the last fifteen years, beginning with foundational work from Stanley Hazen's group at the Cleveland Clinic.
Here is what that body of research has consistently shown:
Elevated TMAO is associated with cardiovascular events. In multiple large cohort studies, individuals with higher TMAO levels have higher rates of myocardial infarction, stroke, and overall cardiovascular mortality.
TMAO promotes platelet hyperreactivity. Mechanistic studies show that TMAO increases platelet responsiveness to multiple agonists, making blood more likely to clot inappropriately.
TMAO impairs endothelial function. Animal and human studies have shown that elevated TMAO reduces nitric oxide bioavailability and impairs the ability of blood vessels to dilate properly.
TMAO is responsive to dietary inputs. Levels can be raised or lowered based on what you consume and the composition of your gut microbiome.
This is established science. It is not controversial within cardiology.
Where the prenatal nutrition question comes in
Choline is essential in pregnancy. Cornell research from Marie Caudill's group and others has shown that adequate maternal choline supports fetal brain development, neural tube formation, and offspring cognitive performance. The current recommended intake is 450mg daily in pregnancy and 550mg in lactation. Over 90% of pregnant women in the U.S. do not meet these targets through diet alone.
The prenatal industry has responded, correctly mind you, by adding choline to formulations. But the form that has been added in nearly every case is synthetic choline bitartrate, or in newer products, synthetic choline chloride.
In April 2021, Wilcox and colleagues at Cleveland Clinic published a study in the American Journal of Medicine directly comparing the TMAO impact of different choline sources. The design was elegant: participants were given choline bitartrate, phosphatidylcholine from food and supplements (a food-form source), or eggs (the natural source).
The bitartrate group showed significant elevation in fasting TMAO levels.
The food-form arms did not.
The researchers' conclusion was direct: supplementation with synthetic choline bitartrate should be reconsidered.
That was four years ago. Most prenatal vitamins on the market still use synthetic forms of choline.
The connection to preeclampsia
Separately from the cardiovascular literature, a growing body of pregnancy-specific research has examined TMAO in pregnant populations.
A 2019 study by Wang and colleagues published in Frontiers in Cellular and Infection Microbiology found that women who developed preeclampsia had significantly elevated plasma TMAO levels compared to controls, alongside altered gut microbiome composition. A 2019 nested case-control study published in the Journal of Clinical Endocrinology and Metabolism found that elevated TMAO in early pregnancy was associated with significantly increased risk of gestational diabetes. A 2017 study in Arteriosclerosis, Thrombosis, and Vascular Biology showed that perinatal exposure to elevated maternal TMAO exacerbated atherosclerotic lesions in offspring later in life.
Each of these studies, on its own, is suggestive rather than conclusive. Taken together, they describe a coherent mechanism:
- Synthetic choline supplementation raises TMAO
- Elevated TMAO promotes endothelial dysfunction and platelet hyperreactivity
- Endothelial dysfunction and platelet hyperreactivity are central to preeclampsia pathophysiology
- Therefore, synthetic choline supplementation may contribute to preeclampsia risk in vulnerable populations
This is the hypothesis I am writing about in my paper. It is supported by mechanism. It is supported by observational data. It is consistent with what we know about cardiovascular biology. It has not been definitively proven through a prospective randomized controlled trial — and I want to be careful to say that openly.
But the mechanism is strong enough to warrant a clinical shift now. The risk of being wrong about the hypothesis, in this case, is minimal — there is no downside to using food-form choline instead of synthetic choline bitartrate. The risk of being right about it, and waiting another decade for definitive trials, is meaningful.
What this means for what you take every morning
Find the choline line on your current prenatal. Look at the form in parentheses.
If it says choline bitartrate — that is the synthetic form that the 2021 study showed raises TMAO.
If it says choline chloride — that is another synthetic form. It has not been studied as extensively in the TMAO literature, but still can raise TMAO, it works through the same natural metabolic pathway and is reasonable to suspect of similar effects.
If it says phosphatidylcholine, phosphorylcholine, or sunflower lecithin — that is a food-form choline. The 2021 study did not show TMAO elevation from food-form sources.
If your prenatal does not specify the form, if it simply lists "choline 200mg" with no parenthetical, assume it is bitartrate. That is the industry default.
This is not a recommendation to stop taking your prenatal. Choline is essential in pregnancy and most women do not get enough. What it is, is an argument that the form of choline in your prenatal matters more than the conversation has acknowledged.
What Tend uses
Tend uses a food-aligned form of choline called CholineAid — a phosphorylcholine compound that enters the same metabolic pathway as choline from food, without raising TMAO.
We have always used food-aligned choline because of the body of research I have been describing here. It has always been the most consequential ingredient decision of our product, and it cost us margin.
We made this decision because the science has moved, even if the rest of the industry has not.
A note on the broader context
The conversation about synthetic versus food-form nutrition is not unique to choline. The same pattern, a synthetic form being chosen because of cost and shelf stability, despite emerging evidence that the bioavailable form behaves differently, this applies to folate, to iron, to many B vitamins, and to other nutrients. We have written about folate and iron in previous posts. The pattern repeats.
I think the prenatal industry will move toward food-form nutrition over the next decade. The science is increasingly difficult to ignore. The question is whether you wait for the industry to catch up, or you make the change in your own routine now.
That is the choice my paper is making the case for.
Studies cited
- Wilcox J, Skye SM, Graham B, et al. Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial. American Journal of Medicine, 2021.
- Wang J, Gu X, Yang J, Wei Y, Zhao Y. Gut Microbiota Dysbiosis and Increased Plasma LPS and TMAO Levels in Patients With Preeclampsia. Frontiers in Cellular and Infection Microbiology, 2019.
- Huo X, Li J, Cao YF, et al. Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study. Journal of Clinical Endocrinology and Metabolism, 2019.
- Trenteseaux C, Gaston AT, Aguesse A, et al. Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids. Arteriosclerosis, Thrombosis, and Vascular Biology, 2017.
- Caudill MA, Strupp BJ, Muscalu L, Nevins JEH, Canfield RL. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed. FASEB Journal, 2018.
- Nam HS. Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide. Journal of Stroke, 2019.
- Hazen SL, Wang Z. Intestinal microbial metabolism of L-carnitine. Nature Medicine, 2013.
