How to Prevent Preeclampsia Part I: Connecting the K2 Dots

We don’t know the exact cause of preeclampsia or eclampsia, and current treatments are only moderately effective. Many women who develop it will deliver preterm. Since is a severe progression of preeclampsia which involves seizures, we will only be using the term “preeclampsia.” Converging evidence suggests that supplementation with certain vitamins, micronutrients, minerals, antioxidants, and amino acids could prevent or possibly treat preeclampsia and eclampsia. We will be discussing the evidence that supports each, and make a case for the theory that nutritional deficiencies are the cause, therefore nutritional therapy is the treatment. This post is about Vitamin K2, and future posts will cover the other nutritional therapies.

Vitamin K2

Vitamin K2 (also known as MK-7 and menaquinone) is a little understood and little known vitamin and cofactor. It plays a major role the proper absorption of calcium, the prevention of atherosclerosis, suppressing inflammation caused by oxidative stress, reducing the risk of type 2 diabetes, increasing insulin sensitivity, and many other processes which we are still uncovering. Right now there isn’t even a test that is used as the “gold standard” method for assessing total Vitamin K status. What we do know, is that most people are not getting enough of it from the foods here in America.
Let us take a look at some of the risk factors and lab values associated with preeclampsia and eclampsia (according to WebMD, 2018) and connect them to K2 deficiency.

Risk Factor #1: Preexisting Protein C or Protein S deficiency

Protein C and Protein S are both Vitamin K dependent proteins. This means that the body requires Vitamin K to be able to activate Protein C and Protein S. Protein C is made primarily in the liver, but 50% of protein S is made in the endothelial cells of the vascular walls (Frannsen et al., 2017). Vitamin K1 activates coagulation factors in the liver, but vitamin K2 activates the vitamin K dependent proteins that exist extrahepatically (outside the liver) (Frannsen et al., 2017). If a vitamin K deficiency exists, than Protein C or Protein S deficiency will also exist. If protein C or protein S deficiency is a risk factor for eclampsia, it is certainly possible then that the root cause is actually vitamin K2 deficiency. 

I was diagnosed with “mild” protien S deficiency after having three miscarriages.  I did not know then what I know now.  I had to take aspirin to be able to maintain the pregnancy.  If I had known better, I would have replenished my K2 before trying again.  I was never tested for K2 deficiency and did not even know it could be a possible cause at the time.  I will be writing about recurrent miscarriage in the near future and will certainly discuss this further.

Another K dependent protein: Matrix Gla Protein

Another vitamin K dependent protein is Matrix Gla Protein (MGP). Vitamin K2 activates MGP, and vitamin K2 deficiency leads to circulation of unactivated MGP. There is clear evidence that it plays a role in calcium balance and the calcification of arteries, which means it inevitably plays a role in the development of high blood pressure. MGP research is still in its infancy, and it seems most of the research being done in the field of cardiology or nephrology. I was unable to find any research on dephospho-uncarboxylated (inactive) MGP levels in preeclamptic women. However, an interesting study conducted just months ago discovered that MGP exists in uterine smooth muscle tissue. In comparison to non-pregnant women, there is more MGP in the uterine tissue of pregnant women (Ackerman et al., 2018). Since uterine contractions utilize calcium, and MGP plays a role in calcium metabolism and is found in uterine tissue, perhaps deficiency in K2 resulting in deficiency of the active form of MGP plays a larger role in preeclampsia or preterm labor? As studies unfold, we shall see.

Risk Factor #2: Diabetes and Gestational Diabetes

According to Chen et al., (2018), vitamin K2 supplementation substantially reduces the risk of Type 2 Diabetes. K2 supplementation increases insulin sensitivity, improves insulin resistance, and reduces inflammation which are all characteristic in Type 2 Diabetes (Chen et al., 2018). Of course, a high carbohydrate diet is the number one contributor to the development of diabetes (Type 2 and gestational), but if K2 supplementation reduces risk, it certainly stands to reason that K2 deficiency would contribute to diabetes development as well.

Risk Factors #3 – #6 Obesity, Advanced Maternal Age, Non-White Race, Chronic Hypertension

Additional risk factors for preeclampsia include obesity(3), advanced maternal age(4), non-white race(5), chronic hypertension(6); all of which are also associated with insulin resistance (Mudd & Weissgerber, 2015). Compared to women who have normal blood pressure during pregnancy, women who develop preeclampsia are more insulin resistant prior to pregnancy, in the first and second pregnancy trimesters, and for years after pregnancy. Since K2 is known to reduce insulin resistance, women who are planning for pregnancy could supplement with K2 to improve insulin sensitivity and thus reduce preeclampsia risk–especially those with a personal or family history of preeclampsia (Mudd & Weissbgerber, 2015).

Vitamin D3 and Calcium levels

According to Devi et al., (2014) the modification of calcium metabolism during pregnancy could be a potential cause of pre-eclampsia. Devi et al. (2017) also state that magnesium metabolism could play a role as well (and I believe it plays a major role) but magnesium will be covered in a later post. Malas (2001) explained that low calcium levels during pregnancy are widely documented and there is a relationship between low calcium levels and high blood pressure during pregnancy. Malas also proposes that calcium supplementation could be used as prophylaxis or treatment for high blood pressure during pregnancy. I disagree. I believe most people do get plenty of calcium in their diets.
I have read quite a lot of conflicting information pertaining to the idea that vitamin D supplementation reduces the risk (and even treats) preeclampsia. I am not convinced that Vitamin D supplementation alone can do this for all preeclamptic women if there is a disturbance in calcium metabolism.

According to Dwarkanath et al. (2017), while there is a correlation between low vitamin D levels and preeclampsia, clinical trials to date have been unable to show an independent effect of vitamin D supplementation in preventing PE. Vitamin D supplementation alone reduces preeclampsia some of the time, but not all of the time.

I am not saying that women with a Vitamin D deficiency should not supplement vitamin D3, I am saying that it is more complicated than that. Without concurrent supplementation of K2, vitamin D does something very scary. It removes circulating calcium and deposits it into the arteries which hardens them and narrows their opening. The hardening of the arteries does not allow for full expansion of those vessels when blood pressure rises, which leads to what we know as high blood pressure and cardiovascular disease.

To be clear, if there is a deficiency in the other fat soluble vitamins A and K2, vitamin D won’t be able to do it’s job. Vitamins A, D, and K work synergistically. In fact, taking only vitamin D increases the body’s demand for both A and K2; and if deficiency in K2 exists then the higher level of Vitamin D accelerates the calcification of the arteries as seen in people with K2 deficiencies. (Rheame-Bleue, 2012).

Further, magnesium activates vitamin D, so if magnesium deficiency exists, that would essentially nullify vitamin D supplementation resulting in higher levels of only the inactive form that does nothing to improve calcium balance or prevent high blood pressure. Remember that I said half of your K2 exists in the vasculature. Vascular K2 holds calcium’s hand and delivers it to where it belongs (mostly the bones), thus preventing calcium from staying in the arteries where vitamin D left it. From there, activated vitamin D will promote proper calcium absorption.

Why does this matter in preeclampsia?

It is important to realize that calcium plays a direct role in vasodilation (the dilation of blood vessels, which decreases blood pressure), though we won’t get into the specific mechanisms here.

In a study on calcium and essential hypertension (high blood pressure in people without a known cause for it), Arifuddin et al. (2012) points out many studies have found significantly elevated intracellular calcium levels in people with high blood pressure, but low serum blood levels. Similarly, preeclamptic women (when compared to pregnant women without high blood pressure) also have significantly low serum calcium levels (Devi, 2014); and not surprisingly, they also have significantly elevated intracellular calcium (Barenbrock, 2000). Coincidence? I think not.

There is clearly a disruption in proper metabolism of calcium, not a calcium deficiency. Bild et al. (1997) confirmed this in a study that concluded “calcium supplementation during pregnancy did not prevent preeclampsia [or] pregnancy-associated hypertension.”

Perhaps K2, vitamin A, and magnesium are indeed the missing links between why vitamin D works sometimes but not all the time to prevent or reduce preeclampsia.

Also concerning is that perhaps for preeclamptic women, vitamin D supplementation without K2 supplementation is contributing to their higher chances of developing cardiovascular disease years later. Again, although some of this data seems to shine a negative light on vitamin D, Vitamin D is not the enemy here. With proper intake of magnesium and A and K2, Vitamin D supplementation is beneficial. I will post more on the benefits of vitamin D (especially the kind we get from sun exposure) for preeclamptic women at a later date.

Placental calcification and uteroplacental arterial blood flow in preeclampsia

At this point you understand that K2 prevents calcification of the vasculature through its actions on calcium itself as well as on vitamin K dependent proteins such as MGP. And we also know that MGP exists in uterine tissue. We have also noted that women with preeclampsia are at significantly increased risk for developing cardiovascular disease in the future. I propose that preeclampsia does not cause cardiovascular disease, but the mechanisms involved in cardiovascular disease could very well cause preeclampsia. Placental calcification, tissue death, and reduced uteroplacental blood flow are characteristic of preeclampsia. Benson et al. (2018) confirms: “The placenta is a highly vascularized organ, and it is likely that other mechanisms common to vascular calcification [like in atherosclerosis] are involved.”  Is placental calcification similar if not the same as the calcification of cardiovascular arteries?  Yes.  A placental infarct an area of dead tissue due to blocked circulation in the area.  That sounds nearly identical to the definition of a heart attack.  Is a placental infarct like a heart attack for the placenta? It certainly seems that way to me.

“The hallmark placental lesion in preeclampsia is acute atherosclerosis of the decidual arteries.” – Coppage & Sibai, The Global Library of Women’s Medicine, 2008

(Decidual arteries supply blood to the uterus.)

“Atherosclerosis” is a term more commonly heard when talking about heart disease.  Usually we think about atherosclerosis as something that takes a long time to set in.  However, considering the rapid life cycle of the placenta (it grows and dies extremely rapidly through pregnancy then after birth), it is completely logical to suspect that a vitamin K2 deficiency also contributes to the calcification of the placental vasculature (blood vessels) be it placental, the blood flow from the mother to the placenta, or the blood flow from the fetus to the placenta. In fact, in the article titled Placental Vascular Calcification and Cardiovascular Health: It Is Time to Determine How Much of Maternal and Offspring Health Is Written in Stone, Benson et al. (2018) demonstrate the evidence suggests that placental calcification may be linked to inflammation and gestational cardiovascular symptoms; and they emphasize “further investigation is needed to delineate associations between preeclampsia, placental calcification, and vascular calcification in order to evaluate the potential diagnostic value of placental calcification in both acute and long-term cardiovascular health.” I couldn’t agree more. And one strongly supported association that must be investigated is the role of Vitamin K2 in preeclampsia.

Systemic inflammation in preeclamptic women

There are many inflammatory markers, but for the sake of being brief lets just discuss one: Interleukin-6. Don’t let the science sounding name scare you. Put simply, it is a small protein that stimulates an immune response, and the immune response is inflammatory.
According to Basar et al., (2008) “numerous reports indicate that the plasma of preeclamptic patients contains elevated levels of interleukin-6.” A study conducted by Chen, et al. (2012) in which preeclamptic women and healthy women in matching gestational periods revealed:

The levels of interleukin-6 in blood were significantly increased in women with preeclampsia in early onset and late onset preeclampsia compared to healthy pregnant women. In addition, the levels of interleukin-6 were significantly increased in women with severe preeclampsia, but not with mild preeclampsia compared to healthy pregnant women matched for gestational period.

Vitamin K2 plays a role in inhibiting interleukin-6. If vitamin K2 deficiency exists, then the preeclamptic woman is missing an important modulator of her immune system that plays a role in controlling systemic inflammation.

Do you have a K2 deficiency?

But how do you know if you have a K2 deficiency? Right now, there is no one specific K2 test, but high “undercarboxylated calcium” is a biomarker for K2 deficiency. I have never tested myself. In my opinion, since K2 has such an excellent safety profile and has so many benefits, I take it regardless because I know I am not getting enough from my diet. However, if you have a history of preeclampsia, have been recently diagnosed with preeclampsia, or have a family history and are planning a pregnancy, it might be a good idea to check it just for peace of mind.

The best food source for vitamin K that works for me is ghee (clarified butter). The more yellow the butter, the more K2 it contains. It must be from pasture raised/grass fed cows that feed on fast growing grass at peak season. The brand I use after much trial and error is this one: Pure Indian Foods Organic Ghee. You can also buy it from their website: www.pureindianfoods.com.

I could not find any studies that evaluated levels of undercarboxylated osteocalcin (a marker for K2 deficiency) in preeclamptic women. This surprised me, because it seems so obvious that it needs to be investigated. Perhaps no such study has been done? If any of my readers find one or know of one, please email it to me directly.

Finally . . .

Could it be this simple? Could one simple and highly safe vitamin supplement really prevent preeclampsia and save thousands of lives? Could this have been right under our noses all this time? Could vitamin K2 be the one common denominator (the root cause, if you will) among the majority of preeclampsia risk factors? Sure it could. I believe existing studies are demonstrating all the right answers; perhaps they’re just not asking the right question.

An excellent book to read more about K2 is Vitamin K2 and the Calcium Paradox: How a Little Known Vitamin Could Save Your Life.

Also worth mentioning is that a prenatal vitamin that contains K2 is hard to find. Even the popular Garden of Life and New Chapter brands do not have it. I personally used Garden of Life for both of my pregnancies (unfortunately both were before I knew about the benefits of K2). After an extensive search I found one brand that does include it: Naturelo Prenatal Whole Food Multivitamin. I believe all pregnant women should supplement K2.  Off topic, but I also like that Naturelo’s prenatal has folate from food sources rather than the synthetic form of folic acid. The Vitamin K2 supplement that I personally use is made by YounGlo Research: they are 100 mcg K2 per capsule and I take at minimum two per day. Since K2 is fat soluble, I like that this brand uses coconut oil as a carrier oil. They also smell really good (though I’m not sure why) and are inexpensive compared to other brands. If you get them, you will see what I mean. I also give them to my children at a lower dose to help improve their dental health and overall bone development.  Another product that I use for my daughter who cannot swallow pills yet is Go Nutrients D3/K2 drops, however I usually just open the capsule from YounGlo Research into her mouth.

Again, Vitamin K2 is certainly not the only supplement that could prevent preeclampsia. Please subscribe for free to this blog and stay tuned for my next post, which will be discussing the link between magnesium deficiency and preeclampsia/eclampsia. This is going to be a multi-post series focusing on preeclampsia prevention.

If you have any questions or comments, or if you feel it is necessary to correct something that you read here, feel free to do so below. I appreciate any and all of your contributions. If you think this post could help a friend, share it. You just might change their life.

This article will be updated as I learn new information.

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References

Ackerman, W., Buhimschi, C., Buhimschi I., Kellert, B., Stetson, B., & Summerfield, T. (2018). Decreased myometrial expression of matrix-Gla protein (MGP) is associated with preterm and term laboring state. Retrieved from https://www.ajog.org/article/S0002-9378(17)31915-4/fulltext

Arifuddin, M., Hazari, M., Muzzakar, S., Reddy, V. (2012). Serum calcium level in hypertension. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503375/

Barenbrock, M., Hausberg, M., Louwen, F., Kisters, K., Kosch, M., & Rahn, K. (2000). Membrane, intracellular, and plasma magnesium and calcium concentrations in preeclampsia. Retrieved from https://watermark.silverchair.com/

Benson, C., Chavkin, N., Chin, M., Frasch, M., & Wallingford, M. (2018). Placental Vascular Calcification and Cardiovascular Health: It Is Time to Determine How Much of Maternal and Offspring Health Is Written in Stone. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090024/

Bild, D., Catalano, P., Clemens, J., Curet, L., DerSimonian, R., Esterlitz, J. . . . Raymond, E. (1997). Trial of calcium to prevent preeclampsia. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9211675

Basar, M., Buhimschi, C., Buhimschi, I., Huang, J., Kayisli, U., Krikun, G. . . . Yen, C. (2008). Preeclampsia-Related Inflammatory Cytokines Regulate Interleukin-6 Expression in Human Decidual Cells. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408417/

Chen, J., Duan, L., Li, S., & Li, Y. Retrieved from https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(17)31256-1/fulltext

Chen, Q., Gao, Y., Lau, S., Shen, F., Yin, Y., & Xiao, J. (2012). The increased maternal serum levels of IL-6 are associated with the severity and onset of preeclampsia. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22921280

Coppage, K, Sibai, B. (2008). Preeclampsia and eclampsia. Retrieved from https://www.glowm.com/section_view/heading/Preeclampsia%20and%20Eclampsia/item/158

Devi, U., Kanagal, D., Kumari, S., Shetty, H., Shetty, P., & Rajesh, A. (2014). Levels of Serum Calcium and Magnesium in Pre-eclamptic and Normal Pregnancy: A Study from Coastal India. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149110/

Dwarkanath, P., Gala, P., Kurpad, A., Larkin, H., Mehta, S., & Purswani, J. (2017). The role of vitamin D in pre-eclampsia: a systematic review. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513133/

Frannsen, F., Janssens, W., Janssen, R., Piscaer, I., Vermeer, C., & Wouters, E. (2017) Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases? Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683584/

Harris, M., Henderson, B., Hodges, S., Hopper, P., Meghji, S., Poole, S., & Reddi, K. (1995). Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/7640347

Malas, M., Shurideh, Z. (2001). Does serum calcium in pre-eclampsia and normal pregnancy differ? Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11744944

Mudd, L., & Weissgerber, T. (2015). Preeclampsia and diabetes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317712/

Rheaume-Bleue, K. (2012). Vitamin K2 and the Calcium Paradox: How a Little Known Vitamin Could Save Your Life. New York City, NY: Harper

WebMD. (2018). Eclampsia. Retrieved from https://emedicine.medscape.com/article/253960-overview#a15

Author: Elena Mazzella, RN BSN

I am passionate about taking care of people, but I am even more passionate about helping people take care of themselves.

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