Hyperemesis Gravidarum – Severe Morning Sickness: Are Mitochondria Involved?

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Chandler Marrs
Hyperemesis gravidarum, more commonly known as severe morning sickness, is the type of intractable vomiting that lasts well beyond morning and well after the first trimester. It affects up to 2% percent of all pregnant women and often leads to serious maternal and fetal health complications, including mortality. Although many theories abound, hormone changes and psychosocial stressors among them, the research is extremely limited and, more often than not, steeped in tried and not-so-true aphorisms of the blatantly obvious. Of course hormones play a role and of course stress is involved but neither are requisite to evoke the continuous vomiting experienced by some women.

As a result of our fealty to the obvious, we have no idea what causes the vomiting or how to treat it; leaving women to suffer and their physicians and midwives few tools to alleviate the vomiting. Nevertheless, there are clues from other disciplines and other diseases processes that if we piece them together correctly might point us towards a cause and, more importantly, new treatment options.

If you have followed my work here on Hormones Matter, you’ll know that I spend a lot of time understanding pharmaceutically and environmentally induced damage to the mitochondria. Over the years, I have come to realize that every illness involves the mitochondria in some manner or another. In some instances mitochondrial impairment precipitates illness. In others, it is a consequence of the illness and, in yet other cases, the disease processes involved are a gobbled mess with mitochondrial cascades initially meant to be protective promoting a sort of self-perpetuating damage that is difficult to unwind much less assign fundamental causation. No matter the origins of mitochondrial distress, however, it is my belief that if we look to the mitochondria first we can solve a great number of previously unsolvable disease processes, including hyperemesis.

Outside the Box with Hyperemesis Gravidarum

Not known for coloring within the lines, I often look for clues about disease processes outside the given discipline. So disregarding most of the hyperemesis research, I looked for other ways into this condition. Specifically, I wondered if mitochondrial disorders that cause vomiting independent of pregnancy, like Cyclic Vomiting Syndrome (covered here) or pregnancy complications that fell outside of the hyperemesis classification, but caused severe vomiting nonetheless, such as Acute Fatty Liver of Pregnancy (AFLP), would provide clues and treatment opportunities for severe morning sickness. Indeed, they did.

In both of these disease processes (and a few others), severe, ‘unexplained’ nausea and vomiting are present and, more importantly, share mitochondrial components in the form of deficient fatty acid oxidation. It appears that with Cyclic Vomiting Syndrome (CVS) and AFLP, a critical component of mitochondrial energy production is impaired within the liver (and likely elsewhere) that hinders the liver’s capacity to metabolize fatty acids and detoxify metabolic waste products effectively. When hepatic mitochondria are defunct, liver function is compromised leading to the nausea and vomiting. We get deficits in mitochondrial bioenergetics (made worse by the increased energy demands of pregnancy), but also, a buildup of toxins (energy starved mitochondria cannot clear waste products effectively), and an accumulation of unprocessed fatty acids, all leading to the body’s only mode of clearance, vomiting.

Mitochondrial Fatty Acid Metabolism

The mitochondria take nutrients from food, consume oxygen, and convert those nutrients into a fuel source (adenosine triphosphate ATP) that the cells use to function (learn more). There are two primary mitochondrial fuel pathways (and a whole bunch of secondary and tertiary pathways), one for carbohydrates and the other for fats, disrupt one or both and all sorts of problems arise. Disrupt these pathways in the liver, the organ responsible not only for toxic waste removal but also for glycogen and fatty acid processing and storage, and the problems become exponentially worse. In the case of the severe morning sickness of pregnancy, I suspect that the mitochondrial beta oxidation pathway, the route for turning fatty acids into ATP, is disrupted.

How to Damage Mitochondria: Let Me Count the Ways

Mitochondrial function can be disturbed by a number mechanisms. Sometimes there are heritable genetic mutations, but not always. Heritable genetic mutations are called primary mitochondrial disorders and occur in up to 1 in every 200 individuals. Fortunately, not all mutations result in illness, but when they do, the results are often devastating.

More frequently, researchers are seeing what are called secondary, acquired, or functional mitochondrial damage evoked lifestyle variables. Epigenetic injuries, sometimes from generations past, have become increasingly common routes to disease. Epigenetic injuries do not induce mutations per se, but rather, aberrantly turn on or turn off gene activity that then influences mitochondrial function. Epigenetic activation or deactivation occurs relative to environmental influence, exposure to toxicants, stressors and/or other variables.

Among the least well recognized secondary mitochondrial injuries are those that are purely environmental; cumulative dietary and lifestyle exposures that damage multiple aspects of mitochondrial functioning. Many environmental and pharmaceutical chemicals evoke mitochondrial damage by leaching critical nutrients needed for mitochondrial energy production and other mitochondrial and cellular functions, but they also damage the structural or functional integrity of these organelles. The cumulative damage of everyday exposures when combined with genetic, epigenetic and/or poor dietary choices, render many individuals susceptible to mitochondrial illnesses. I suspect many of the idiopathic pregnancy complications, like hyperemesis, have their roots in mitochondrial dysfunction.

Although most of this paper, and indeed, most of the popular press focuses on mitochondrial bioenergetics, we must keep in mind that the mitochondria regulate a number of other important and endlessly reciprocal cellular functions, namely: steroidogenesis, immune signaling and cell death. Disturbances in mitochondrial bioenergetics, thus, would be expected impair hormone regulation, induce uncontrolled inflammation (chronic inflammatory and autoinflammatory diseases) and initiate tissue and organ injury. Individuals with mitochondrial issues would be expected to have a broad range of subtle and not-so-subtle health issues; many of which are endemic and epidemic in Western cultures.

Clues for Hepatic Mitochondrial Dysfunction in Hyperemesis Gravidarum

Backing up a bit, let’s connect some dots from the AFLP research. From the research on AFLP, we know that a mutation in the mitochondrial enzyme responsible for processing an important mitochondrial transporter evokes some, but not all of the cases of this disease process. Notably, in some women with hyperemesis, the fetus carries the mutation and evokes the vomiting, while mom is simply a heterozygous carrier.

The mutation (L-3-hydroxyacyl-CoA dehydrogenase deficiency – LCHAD) involves an enzyme (carnitine palmitoyltransferase I – CPT I) responsible for synthesizing the protein that acts as key transporter for fatty acids across the mitochondrial membrane. The protein involved is called carnitine.

When a fetus carries the CPT I mutation, the fetus’ inability to metabolize fatty acids and the associated bi-products are kicked back into maternal circulation effectively overriding the mom’s capacity to process these compounds. The increased load on the mom’s liver induces the vomiting, leading, in some cases, to the compensatory reaction of fat deposits within the liver cells – AFLP.  Since AFLP is relatively rare, developing in only 7-10 per every 100,000 pregnancies, is not present in all hyperemesis cases (50% of women with severe vomiting show some liver damage), and the fetal mutation is even rarer, we can deduce that neither AFLP nor the mutations that impair fetal fatty acid metabolism account for the totality of hyperemesis cases or even the morning sickness of early pregnancy.

Nevertheless, this research provides several important clues about hyperemesis. First, given the right set of circumstances, e.g. pregnancy or another high intensity stressor, carriers of a particular mutation may become symptomatic. We often view heterozygous carriers as being asymptomatic or less symptomatic than their homozygous counterparts. This may not be true. We may be simply viewing the symptom status incorrectly. Secondly, mitochondrial fatty acid metabolism is likely impaired and in some manner related to carnitine. Thirdly, maternal hyperemesis may not be a primary mitochondrial disorder in the classical sense (those definitions are changing, however). Even though there are a number of possible genetic mutations involved with the carnitine pathway, most are either severe enough to be identified during infancy (save except CPT II, which may remain latent until adolescence or early adulthood) and/or present differently (with muscular weakness and cardiomyopathy), and therefore preclude them from our differential. For all intents and purposes, hyperemesis presents during pregnancy, mostly in women with no known fatty acid oxidation or carnitine-related mutations, suggesting non-genetic mechanisms at play. In other words, I think we’re looking for functional mitochondrial disturbances in fatty acid metabolism related to carnitine.

What is Carnitine?

Carnitine is an essential micronutrient derived from the amino acid lysine with the help of methionine (an essential amino acid derived from diet). It is highly expressed in liver, testes and kidney. Dietary carnitine from meats, dairy and other sources yield carnitine. (L-carnitine is biologically active isomer. The research nomenclature varies considerably. For consistency, the word carnitine will be used throughout except when speaking of supplementation, where L-carnitine is more appropriate.) Carnitine is then shuttled off to skeletal and cardiac muscle where fatty acids are used as a primary fuel source. Although it is believed that endogenous carnitine homeostasis is maintained to some extent despite dietary contributions, there are number of conditions that override the internal synthesis of carnitine. These include genetic mutations that limit carnitine synthesis, difficulties with nutrient absorption (leaky gut or bacterial imbalances), kidney dysfunction which limits carnitine re-absorption, pharmacological inhibition of carnitine transporters, and nutrient deficiencies that disrupt any of the many enzymes involved in carnitine biosynthesis or metabolism.

In addition to its direct role in fatty acid metabolism, carnitine is also involved in glucose metabolism (the other major source of mitochondrial ATP) via its potentiating role in the pyruvate dehydrogenase complex, its modulation of  acyl-coenzyme A (CoA) and the storage of acylcarnitine. So when we disrupt carnitine availability, by whatever mechanism, not only is fatty acid metabolism derailed, but the other primary pathways for mitochondrial energy production are negatively impacted, as are the storage and clearance pathways.

Carnitine, Fertility and Pregnancy

We know very little about carnitine during pregnancy except that it generally declines. Below is a review the literature.

In women undergoing in vitro fertilization, higher maternal carnitine concentrations are associated markedly improved fertilization rates and overall better outcomes. Competent fatty acid oxidation is required for oocyte and embryonic development.

During pregnancy maternal carnitine concentrations diminish significantly. Indeed, at delivery, plasma carnitine concentrations have been reported 50% lower than in non-pregnant women. Researchers don’t know why carnitine decreases so much during pregnancy. There is some indication that carnitine concentrations are inversely related to iron status. Iron is needed for carnitine biosynthesis and so the increased demands for iron during pregnancy, if not met, may negatively impact carnitine synthesis. Since carnitine crosses the placental barrier, maternal carnitine deficiency would lead to fetal carnitine deficiency. The research, however, is all but nonexistent.

From animal research, we know that supplementing with L-carnitine, maintains carnitine concentrations across the pregnancy and improves a number of variables associated with reproductie function. Supplementation with L-carnitine also appears to offset liver damage and improve liver function in a mouse model of acetaminophen induced liver toxicity. Similar to the human IVF research mentioned above, L-carnitine supplementation improves oocyte development while increasing overall fatty acid oxidation capabilities.

Carnitine Deficiency with Nutrient Depletion

Population data for carnitine deficiency are unknown but nutrient deficiencies in general are postulated to be non-existent in the developed world, except with poverty. This assumption is erroneous and dangerous in the land of nutrient stripped processed foods. What little data exist for different nutrients, show that a significant portion of the Western population is deficient in one or more nutrients. Nutrient deficiencies impact enzyme function and the mitochondria’s ability to produce ATP and perform other critical functions. Carnitine synthesis alone requires five different enzymes, each with their own nutrient demands. This is in addition carnitine’s requirement for lysine and methionine. Given such demands, it is entirely conceivable, and in fact likely, that Western women come to pregnancy deficient, either marginally or grossly, in any one of the many nutrients involved in the carnitine pathway. Here are just a few.

Possible Nutritional Culprits in Functional Carnitine Defiency

Endogenous carnitine synthesis requires methionine. Methione concentrations in foods have steadily decreased (by as much as 60%) in parallel with the increase in glysophate (Roundup) used in conventional agricultural practices. Methionine synthesis also requires vitamin B12a nutrient deficiency common with the Western diet and exacerbated by many medications.

One of the only accepted treatments said to reduce the nausea in hyper-emetic women is vitamin B6 supplementation. Vitamin B6 is involved in carnitine synthesis. It is also an important anti-inflammatory, especially in the central nervous system.

The other nutrients required to maintain active enzymes for carnitine synthesis include: iron, niacin (B3) and vitamin C.

Finally, with pregnancy in general, but especially, with pregnancies involving severe nausea vomiting, the risk of nutritional deficits is exacerbated as the intake of nutrients diminishes. Not only would we expect carnitine depletion but deficits in many of the other vitamins and minerals required by the mitochondria to produce ATP either via fatty acid metabolism or via glucose metabolism. The vomiting itself depletes nutrient stores, and thus, becomes self-propagating; fewer nutrients > more vomiting, more vomiting  > fewer nutrients.

Connecting the Dots: Potential Treatment Options for Hyperemesis Gravidarum

Thus far, the clues point to some sort of functional, epigenetic, or even an unrecognized, but latent, genetic derailment of fatty acid metabolism involving carnitine. The deficit in carnitine then precipites the severe morning sickness of pregnancy known as hyperemesis gravidarum. The nausea and vomiting worsen nutrient deficiencies and continue the cascade. If this is true, and I think it is, then the question becomes, can we support the carnitine system and mitochondrial function in general, to alleviate or completely eliminate the vomiting. I think we can.

I mentioned cyclic vomiting syndrome in the early sections of this post but haven’t spent any time on the topic. It is from the cyclic vomiting research that we find our treatment options. Specifically, Dr. Richard Boles has successfully treated pediatric patients who have cyclic vomiting syndrome with L-carnitine and Co-Enzyme Q10 (CoQ10), as have others. Indeed, we have personal experience with Dr. Boles’ work, as the daughter of one our writers had treatment refractory cyclic vomiting syndrome; that is, until the L-carnitine and coQ10 eliminated the constant vomiting. Cyclic vomiting syndrome is believed to be a mitochondrial disorder falling under a category of disorders called dysautonomias. And though a specific mitochondrial genotype has not been linked to CVS, Dr. Boles’ clinical data shows a clear association with mitochondrial fatty acid oxidation (L-carnitine supplementation) and the electron transport function (coQ10 supplementation).

Other Bits and Pieces

Fatty acid and carbohydrate metabolism within the mitochondria are closely tied to each other, with multiple interleaving levels of reciprocity. Both pathways demand nutrients to power their enzymes. A nutrient that is particularly high on food chain for mitochondrial function, is vitamin B1 or thiamine. We’ve written about thiamine deficiency repeatedly, as it seems to be leached from the mitochondria by a number of medications and vaccines and is implicated in a wide variety of adverse medication reactions. As a core nutrient in the pyruvate dehydrogenase enzymes, thiamine is critical for ATP production. Thiamine is also critical for fatty acid metabolism. A borderline thiamine deficiency would impair fatty acid metabolism and is linked to hyperemesis related liver damage and Wernicke’s Encephalopathy. Thiamine deficiency also impairs brainstem control of vomiting, thereby exacerbating the already difficult-to-control pregnancy hyperemesis. Thiamine supplementation should also be considered for hyperemesis gravidarum. Our own Dr. Lonsdale tells us that he has used thiamine in clinical practice to reduce cyclic vomiting in pediatric patients. The research on hyperemesis gravidarum, however, is extremely limited, focusing solely on the use of thiamine to curb the effects of hyperemesis-induced Werknicke’s syndrome.

Final Thoughts

Although there is little direct evidence linking a functional carnitine deficiency in pregnancy to hyperemesis gravidarum, there are a enough indirect data to suggest this may be a mechanism worth investigating. If this work bears fruit, L-carnitine, CoQ10, thiamine, vitamin B6 and likely other nutrients may be all that are needed to alleviate the nausea and vomiting across pregnancy.

Please note, I am not a medical doctor and this should not be construed as medical advice. Please speak to your healthcare practitioner before beginning any treatment protocol.

If there are any physicians or midwives who have used L-carnitine in patients with hyperemesis, please comment below.

This post was published originally on Hormones Matter on July 22, 2015.

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20 Comments

  1. I suffered HG both pregnancies back in 1995 /99. I have since found out I an homozygous for MTHFR 677 and I believe the fact that I took folic acid (as instructed) before and during both pregnancies caused / exacerbated the HG. Both children are also homozygous for MTHFR677. Thankfully avoiding folic acid (bread) etc and correct supplementation of B vitamins and we all have improved health wise.

    1. Very interesting many mothers I come across have this MTHFR677 and advoiding folic acid helped ! I actually was taking extra doses before pregnancy to prevent birth defect ! I need to research this !
      Thank you
      Starr Andrews StrongHGactivist

  2. I had CVS before Hyperemesis Gravidarum and had the most severe case of Hyperemesis Gravidarum that I have known . I vomited 100 X a day to the point my eyes would bleed . Vomiting 98-101 non stop was normal for me even on IV fluids and 16 NG IV push Zofran . I love your work . For years I have said Mito was involved in CVS and Hyperemesis Gravidarum Were connected. When I found out about the RYR2 factor I was actually thrilled . Please continue to research your theories are wonderful and right on track there’s no one like you that I met out there that thinks outside the box as I do . I’m not a medical doctor but a hardcore HG activist and advocate . I love to talk with you more !

    Starr Andrews Strong HGactivist

    1. That sounds absolutely horrible. I think CVS and HG are woefully under-recognized. I am not familiar with RYR2 factor but will look into it. As an activist, if you’d like to share your work here, we’re always looking for writers. So many topics deserve much more attention than we can give them. This is one of them.

  3. I suffered from HG in my second pregnancy. I could not get out of bed for 16 weeks. I could not care for my family. Zero energy. Today my son, after 8.5 mo “investigation” was diagnosed with carnitine uptake disorder. This is all very fascinating to me and I too am going to dig deeper into this. Today was a difficult day but I am happy to hear that this genetic condition is treatable.

    1. Vanessa, that is very interesting that your son has the carnitine disorder. Was there any indication of this or any fatty liver disease during the pregnancy. Please dig deeper and let us know what you learn. If you’re interested in sharing your story on the blog we’d be interested in publishing it.

  4. This article on a possible link between mitochondria and hyperemesis gravidarum is the most plausible explanation for this debilitating illness I have read. One symptom of HG, which is not often mentioned, is complete exercise intolerance. The need to preserve every ounce of energy in your body because normal everyday actions are so impossibly difficult. This symptom is not easily measured by medical professionals and HG is difficult to explain without reference to the complicated effects of pregnancy hormones on systems and metabolism.

  5. Charles Darwin suffered from an inherited pathological mtDNA mutation. His mother, among other ailments, suffered from hyperemesis of pregnancy. Her mother in turn was chronically unwell and nearly died with what was almost certainly fatty liver of pregnancy after a spontaneous abortion.
    If interested Google: ‘Hayman thesis UniMelb’, which brings up an abstract, then click on ‘view/open’.
    Would be interesting to survey mothers who had hyperemesis to see if their children have any disability, such as CVS, migraine or excessive motion sickness.

    1. I had hyperemesis during both of my pregnancies, one in 2011/12 and the other in 2015. My first son, now 4, started having vomiting issues 9 mos. ago, and the same pattern has followed every 1-2 mos for the last 9 mos. I am suspecting CVS as he meets nearly all of the signs. I just happened upon this article as I googled ‘HG and CVS’, because I couldn’t help but wonder about a connection. I wish I would have come across this discovery sooner, but better late than never. I will be digging into this deeper.

      1. Neither hyperemesis nor CVS are as well researched as they should. Do look at our articles on CVS. The daughter of one of our writers (Philippa Bridge-Cook) had severe CVS until we stumbled upon the work a pediatric geneticist Dr. Richard Boles. His work showed that coQ10 and l-carnitine were able to treat CVS successfully. Philippa’s daughter has been using those supplements now for several years and has been largely free of the vomiting whereas before the supplements was suffering greatly. Her entire story is on the blog. Keep us posted.

    2. I also wanted to add that while I don’t have a history of CVS or migraine as an adult or child, I have always been plagued by motion sickness. It also appears that I may have a MTHFR genetic mutation, not sure if there is a correlation.

    3. Many mothers have CVS before pregnancy get Hyperemesis Gravidarum , or get Hyperemesis Gravidarum and get CVS after or have Hyperemesis Gravidarum and their child has CVS . More needs to be research on the RYR2 factor that the her foundation found the link of CVS and Hyperemesis Gravidarum . The connection is real but more people need to look into this !
      Being a CVS sufferer since I was 15 years of age the symptoms and feeling of cvs and Hyperemesis Gravidarum are identical!

  6. This post may be too technical for many people. I agree completely with the principles that are given but I may be able to simplify it to give a direction for anyone with this disease called hyperemesis gravidarum. It has always been tacitly accepted that emesis (vomiting) in pregnancy is a normal phenomenon. Hyperemesis is used to indicate that the vomiting is excessive. As readers on this post know, I have talked a great deal about thiamine and perhaps it will surprise noone that I have to indicate its use here. Recently I received an email from a specialist in ob/gyn by the name of John B.Irwin M.D. Now at the age of 92 he is long since retired but from our correspondence I became aware that he was very frustrated by his many years of attempting to describe the advantages of thiamine in pregnancy. He sent me a copy of his book which is entitled “The Natural Way to a Trouble-Free Pregnancy” published by Aslan publishing, 2490 Black Rock Turnpike, #342 Fairfield CT 06825. I will not steal his thunder because it is a book that any pregnant woman should have, but I will give you some quotes: “I will describe how large doses of thiamine (100 mg daily) have been essentially 100% effective in preventing toxemia of pregnancy in my patients”. In his book he does not mention hyperemesis but I have had personal experience with this. Some years ago I saw a patient with hyperemesis who could not even keep water down. I gave her a series of water-soluble vitamins intravenously and she went home completely free of vomiting for she was an out-of-town patient. Later on in the pregnancy the vomiting returned and she received another short course of intravenous vitamins with the same result. The last time that I saw her was only because she came to show me the baby. What we are saying here is that the present dose of obstetric vitamins is ridiculously too low. Dr. Irwin in his book, addresses the use of vitamin supplements in pregnancy. Lastly, I want to say that the lower part of the brain which contains a center called the vomiting center, is exquisitely sensitive to thiamine deficiency. A healthy dose of thiamine and magnesium with a well-rounded multivitamin seems to be a necessity in pregnancy

    1. This is really interesting. I am a doctor but I also suffered from HG in my first pregnancy so I have done a lot of research in preparation for a 2nd pregnancy. What would be the recommended dose of magnesium?

    2. What doses were you giving her ? How much was she vomiting ? I am very intrigued by this! I ended up with a severe thiamine deficiency while suffering from Hyperemesis Gravidarum and almost died of (WE) I would vomit 98 hours at a time without a break ! This post is not to technical for me, writing a book on Hyperemesis Gravidarum and my journey and interested in how much she was vomiting as nothing seemed to stop my vomiting even 16 mg of Zofran at one time along with other meds !

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