Nausea and Vomiting of Pregnancy Is Mitochondrial Dysfunction

The fascinating intersection between pregnancy and mitochondrial dysfunction and what to do about it.

Nausea and vomiting of pregnancy is a hypersensitive reaction to mitochondrial dysfunction in the mother in order to avert greater mitochondrial dysfunction in the more sensitive baby.

In this article, we look at the fascinating intersection between pregnancy and mitochondrial dysfunction and outline what to do to prevent this at least annoying and sometimes devastating phenomenon without trying to interfere with its important protective functions.

Interest in the causes of and solutions to nausea and vomiting in pregnancy focuses on levels of growth differentiation factor 15 (GDF15). While this model is correct, it is incomplete. These models generally ignore the contribution of hydrogen sulfide (H2S), which likely runs in parallel to GDF15 with these two compounds having very interrelated purposes of their signaling.

H2S is a normal, healthy, beneficial signaling compound at low concentrations and a lethal toxin at high concentrations. In between, it stimulates nausea and vomiting in order to create an aversion to whatever is raising its level so that further toxicity can be avoided. Vomiting also may help purge the source of it out of the body.

GDF15 is secreted from the placenta during pregnancy in very large amounts. It travels through the bloodstream and acts on the glial cell–derived neurotrophic factor (GDNF) family receptor α-like protein (GFRAL) in the neurons of the area postrema and solitary tract nucleus in the brain, where it inhibits appetite, induces aversions, and at high levels causes nausea and vomiting.

H2S is similarly made at high concentrations by the placenta. One of its major functions as a normal signaling compound is to signal blood vessel relaxation and the synthesis of new blood vessels. H2S therefore helps vascularize the placenta, and also helps relax the placental vasculature so that it does not tighten up around the fetus and restrict growth.

While H2S from the placenta is very unlikely to reach the brain, H2S rises in response to estrogen, which does reach the brain. H2S is produced locally by the brain, so it is very likely that the rise in estrogen facilitates a local rise in H2S in the brain that acts alongside GDF15 to stimulate food aversions, nausea, and vomiting.

To put these compounds in their proper context, we need to look at the reasons they are produced outside of pregnancy.

In particular, GDF15 rises to levels in mitochondrial disorders that overlap with those levels seen in pregnancy, including the higher levels seen in women with nausea and vomiting. This raises the possibility that mitochondrial dysfunction could massively elevate the amount of GDF15 produced during pregnancy, and it raises the question of why pregnancy and mitochondrial dysfunction would share this characteristic.

GDF15 is synthesized under ordinary conditions in the liver, lung, kidney, and adipose tissue. The levels produced are usually very low, but rise in inflammatory diseases, cardiovascular disease, and obesity. It has actions beyond those involved in producing nausea and vomiting that improve metabolic health. Animal experiments show that it increases lipolysis and thermogenesis, independent of any impacts on food intake. Deleting GDF15 from mice makes them develop late-onset obesity. A synthetic agonist of the GFRAL receptor mimicking GDF15 was able to cause modest weight loss in humans by suppressing appetite without causing any nausea.

GDF15 synthesis is induced by the mitochondrial unfolded protein response and the integrated stress response, which are two pathways for dealing with reactive oxygen species and other damaging compounds that interfere with mitochondrial function. In general, these responses inhibit protein synthesis and increase protein-folding chaperones, while inhibiting food intake and improving the ability to effectively and cleanly burn energy. Thus, it is likely that one of the most basic functions of GDF15 is to inhibit the intake of excessive energy when mitochondria are stressed, until they can improve the capacity to handle that energy.

On the other hand, when one is exposed to an acute toxin that causes nausea and vomiting, the higher level of GDF15 serves to purge the toxin from the body and create an aversion to its current and future exposure.

H2S is produced as part of the hypoxia response. The hypoxia response itself can trigger the integrated stress response, and they each have overlapping triggers and outcomes. However, the hypoxia response is much more concertedly focused on resolving reactive oxygen species that are produced due to “traffic jams” in the respiratory chain where incoming electrons run into blocks, usually but not always due to inadequate oxygen in complex IV. As a result, it stimulates the production of erythropoietin and testosterone, which help build red blood cells; iron absorption and synthesis of hemoglobin, which helps red blood cells deliver oxygen; detox of manganese, which interferes with iron’s role in CoQ10 synthesis and possibly other roles; synthesis of new blood vessels, which deliver oxygen to hypoxic tissues, dormancy of complex I in the respiratory chain, which reduces inflow of new electrons; synthesis of iron-sulfur clusters, which help facilitate movement of electrons through the chain; and increased efficiency of complex IV, which draws electrons toward oxygen to complete their journey.

If these responses bring H2S concentrations back to normal, it is unlikely it builds up to the degree needed to cause nausea and vomiting. However, if they do not, H2S stimulation of aversion, nausea and vomiting could help purge toxins from the body or create an aversion to its current and future exposure just like GDF15.

In fact, given the interrelations of their triggers, it is likely they often — but not always — rise together.

In pregnancy, it makes no sense that it would be adaptive to facilitate decreased appetite. This can be reconciled by considering the other effects pregnancy typically has on appetite.

Appetite is regulated in large part by two opposing peptides in the hypothalamus, proopiomelanocortin (POMC) which inhibits appetite largely through being metabolized to the peptide hormone melanocyte-stimulating hormone (MSH), and agouti-related peptide (AgRP), which stimulates appetite. MSH not only inhibits appetite, but it also increases lipolysis. Adipose tissue makes the hormone leptin in proportion to its mass, and leptin levels rise after meals in proportion to their caloric load. Leptin then acts on the hypothalamus, in proportion to the efficiency of ATP extraction from available food energy within the hypothalamus, to increase POMC and decrease AgRP. Thus, as body fat and caloric intake decline, the drop in leptin helps stimulate appetite and fat storage. As body fat and caloric intake rise, the rise in leptin helps suppress appetite and increase adipose lipolysis.

During pregnancy, the placenta makes soluble leptin receptors, which bind to leptin and prevent it from entering the brain. This decreases POMC and increases AgRP, leading to increased fat accretion, especially in the second trimester. After giving birth, these changes quickly reverse, allowing the accreted fat to be shed.

Thus, in pregnancy, the anorexic effect of H2S and GDF15 is opposed by placentally driven leptin resistance, which makes net appetite go up instead of down.

However, the rise in GDF15 and H2S increases the sensitivity to previously programmed food aversions, which causes the mother to reduce her exposure to toxins that could interfere with the massive anabolic response that is needed.

The massive increase in energy demand likely communicates this through relative “mitochondrial dysfunction,” meaning an inability of mitochondria to meet that demand without systemic adjustments to increase blood supply and nutrient intake while decreasing toxin intake.

Evolutionary biology literature tends to argue that the aversive response is meant to target teratogens that cause birth defects. However, it is difficult to imagine how it would be possible for two molecules — or even their more complex triggers and targets — that do nothing other than turn up the aversive tone to make the brain “know” what is teratogenic and what is not. This seems to require a mystical appeal to a universal human consciousness within which there is some historical record of what has caused birth defects across all time and space.

It is, further, difficult to conceive of how the mother could have developed aversions specifically to teratogens in the past unless they were also toxic to the mother herself.

Rather, it is likely that most things that are toxic to the baby are also toxic to the mother, but at much higher doses, and that increased aversion is meant to drive the mother to avoid toxic exposures in general.

The brain’s ability to know what is toxic is not perfect, but in general the brain tries to match aversions to toxic exposures and it overall works. Most teratogens are mitochondrial toxins, and most mitochondrial toxins are teratogens. There are exceptions, but broadly speaking teratogens are toxic to adults at some concentration and vice versa.

What to Do About Nausea and Vomiting In Pregnancy

Thus, the solution to nausea, vomiting, and pregnancy likely is to optimize mitochondrial function and to remove any impairments in the clearance of hydrogen sulfide or the triggers of its formation.

The FDA-approved treatment for nausea and vomiting of pregnancy is a combination of the pyridoxine form of vitamin B6 and the antihistamine doxylamine. Other treatments used include other antihistamines, steroids, antiemetics, and ginger.

Vitamin B6 binds to sulfite and hydrogen sulfide so can help mop it up. However, it is one of the vitamins with a toxicity syndrome — which I covered in This is What Causes Vitamin B6 Toxicity — so a blunt tool for the job and not without risk.

The drugs used here are shooting the messenger.

Shutting down your vomiting response to allow your body to overlook mitochondrial dysfunction doesn’t fix your mitochondria. I am not saying no one should ever use these to relieve suffering, they just clearly aren’t fixing the problem.

Ginger is a complex food with complex actions. It may help move food along through the GI tract, lessening a need to expel it out the way it came in, but it also may improve mitochondrial function in many ways.

If ginger doesn’t do the trick, though, it is likely you need to address your idiosyncratic limitations in mitochondrial function and sulfur metabolism.

Anyone with unresolved and unexplained nausea, including that of pregnancy, should run the Sulfur Protocol:

Click Here for The Sulfur Protocol

Since GDF15 rises in response to different triggers that are more specific to mitochondrial dysfunction and more generalizable across the breadth of idiosyncratic forms of mitochondrial dysfunction and does not always parallel H2S accumulation, anyone trying to solve a difficult case of nausea and vomiting of pregnancy should run Mitome:

Click Here to Get Mitome

Mitome reflects a year and a half of deep research into the causes of many different patterns of mitochondrial dysfunction, fused with my own cross-referencing over 100 sets of respiratory chain data with comprehensive whole genome sequencing and biochemical data (amino acids, organic acids, vitamins, minerals, and other markers) to distill ways of inferring causal patterns and effective actionable protocols from repeatable patterns within the respiratory chain data when used on its own. Mitome can be used to infer three important patterns in sulfur metabolism, including whether there appears to be increased sulfur flux, which of several different points is limiting sulfur detoxification, and whether you need more CoQ10 or should instead try an unnatural analog of CoQ10 called MitoQ that handles sulfur in a completely different manner, yet happens to be a miracle for the select few that need it. Mitome also simplifies this for you by automatically constructing your protocol for you.

Have you suffered through nausea and vomiting in pregnancy? What helped you?

Let me know in the comments.