Recurrent Miscarriage Causes: Look Beyond the Woman

Recurrent miscarriages have numerous causes making them difficult to isolate. The causes of recurrent miscarriage may also be multifaceted – and often are.

While the topic of recurrent miscarriage causes has no end in site due to continued research, a major point needs to be addressed which is often overlooked.

Causes of recurrent miscarriages go beyond the condition of the woman and her genetics.

To make this point clearly and succinctly, the following are two causes of recurrent miscarriages that extend beyond the health status of the woman:

  1. Genetics of the Man
  2. Methylation Status of the Fetus

Let’s get into detail.

Genetics of the Man
A Turkish study[1] found that recurrent miscarriage causes “is related to combined parental (not only maternal) thrombophilic gene mutations. . . . heterozygosity of FVL, FVR2, ACE, and ApoE2 genes in both parents play crucial role in RPL (recurrent pregnancy loss) and should be considered as a risk factor in RPL.”

What does this mean?
This means that the genetics passed from the father have a direct connection in the blood clotting risk in the developing child.

What to do?

  • Have your doctor evaluate the placenta and umbilical cord for blood clots
  • Ask for genetic testing for both man and woman
  • Take precautions and talk with your doctor about taking baby aspirin, Lovenox or nattokinase during pregnancy.

Methylation Status of the Developing Child
A study from China[2] published in BMC Medicine states “that defects in DNA maintenance methylation in the embryo, not in the mother, are associated with abnormal embryonic implantation and development. The findings of the current study provide new insights into the etiology of early pregnancy loss (EPL). . . . We also found that disturbance of maintenance methylation with a DNMT1 inhibitor may result in a decreased global DNA methylation level and impaired embryonic development in the mouse model, and inhibit in vitro embryo attachment to endometrial cells.”

What does this mean?
This means that methylation in the developing child is directly correlated to a healthy pregnancy outcome – regardless of the methylation status of the mother or father.

What to do?

  • Support methylation in the father and mother prior to, and during, pregnancy in order to increase the odds of optimizing methylation in the developing child.
  • Identify genetic defects in the methylation pathway, namely MTHFR, in both parents and supplement accordingly in order to bypass the methylation defect thereby increasing the odds of optimizing methylation in the developing child.
  • Identify DNMT inhibitors and have both mother and father cease their use prior to and during pregnancy (for the mother).

What is DNMT and what does DNMT do?
DNMT stands for DNA methyltransferase. DNMT is necessary to help balance methylation.  There are various genes for DNMT and DNMT 1[3] appears to be very significant.

What are DNMT inhibitors?
DNMT inhibitors are compounds which directly or indirectly negatively affect the function of DNMT.  DNMT inhibitors are showing promise in cancer treatment; however, during pregnancy, they are to be avoided.

  • 5-azacytidine
  • 5-aza-2-deoxycitidine
  • zebularine
  • hydralazine
  • epigallocatechin gallate (EGCG)
  • psammaplin A

EGCG as a DNMT Inhibitor
You may not realize that EGCG may be prevalent in your diet.

EGCG is found in green tea.

While green tea in small amounts appears to be beneficial for fertilization, too much is not. An Italian study[4] points out: “Supplementation of 10 microg/ml EGCG during IVF significantly increased the fertilization rate while higher EGCG concentrations (25 microg/ml) decreased the percentage of fertilized oocytes (p<0.05). In conclusion, our data suggest that high EGCG concentrations could affect in vitro maturation and fertilization in pig; it cannot be totally excluded that excessive EGCG concentrations could induce reproductive-related consequences also in vivo.”

A paper written by Jacob Schor, ND[5] elaborates more on the subject of Green Tea in Pregnancy. Dr Schor’s paper discusses the link between EGCG and its ability to inhibit the DHFR enzyme which is needed to convert inactive folate to active forms.

He states, “It seems that EGCG blocks the enzyme dihydrofolate reductase, an enzyme essential for tumor cell growth. Without this enzyme, folic acid is unavailable in the cells. Folic acid is needed for cells to divide. Without folic acid cell division is slowed down. ”

DNMT Antibodies
If an enzyme or any cell has antibodies against it, the potential for partial or complete inhibition exists.

Given the prevalence of autoimmune disease, the potential for DNMT antibodies is important to consider.

While there is no direct research identifying DNMT antibodies and their effect on DNMT function, one must suspect they exist in nature – because DNMT antibodies certainly exist in the laboratory.[6]

What do to about potential DNMT Antibodies?

  • Eliminate gluten from your diet, especially wheat
  • Identify potential food intolerances and remove them
  • Supplement with effective probiotics
  • Obtain and maintain vitamin D3 levels around 45 to 50

Remove the Inhibition of DNMT by Folate
By ingesting foods high in folate or supplementing with methylfolate and folinic acid, DNMT inhibition may be lessened.

A Chinese study[7] researched the effects of maternal folic acid in newborn piglets. They found that “Real-time PCR indicated that gene expression of … DNMT1 were lower in IUGR piglets but could be elevated by maternal folic acid supplementation”

Bottom Line of Recurrent Miscarriage Causes:

  1. Recurrent miscarriage causes are not completely due to the status of the woman
  2. Paternal genetics should be considered – especially clotting disorders and MTHFR
  3. DNMT inhibitors must be avoided
  4. Optimize DNMT while pregnant with food folate, methylfolate and folinic acid
  5. Optimize methylation in man and woman prior to becoming pregnant

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13 Responses to “Recurrent Miscarriage Causes: Look Beyond the Woman”

  1. eb April 15, 2012 at 9:41 pm # Reply

    I found this very helpful! I have two healthy girls and am 17 weeks pregnant now. However in trying to get pregnant with this baby had three very early miscarriages. My OB tested me for MTHFR, and I turned out to be homozygous. I am being treated for both this, and a potential luetal phase defect (progesterone supplements up to week 12) so it is impossible to discern which is either in isolation or combination is responsible for getting us this far into the pregnancy, but I am thankful to have been tested for this gene and trying to modify it to the extent that I can. Estimated due date of late September–keeping my fingers crossed!

  2. Emily April 21, 2012 at 1:21 am # Reply

    Thank you for your information! I have had two miscarriages in the last 6 months…one at 13 weeks and one at 15 weeks. I have been pregnant previously twice with no issues at all in the pregnancies. I just had blood work done and everything was normal except I am heterozygous mthfr (c677t). I am meeting with a reproductive endocrinologist in a few days to discuss possible treatments and moving forward.

    This has been such a traumatic time and my husband and I both agree that if we do not determine an issue that has some form of treatment to help lessen the likelihood of this happening again we do not think we will move forward in trying to conceive again….but I really would like to have another child.

    All that being said, what questions would you recommend I bring to the RE next week?

    We are expecting that they will also do blood work on my husband but that has not been done at this time.

    With both of the losses, there was testing completed. I did not ever see the reports but was told that both of the babies appeared to have no chromosomal issues. Would the standard pathology reports have included information on this mutation? Just wondering if I would be able to tell from those reports if the babies carried the mutation and possibly either were homozygous or compound heterozygous as a result of my husband having a mutation.

    Any thoughts or suggestions would be greatly appreciated.

    Thanks,

    Emily

  3. Cal Crilly April 24, 2012 at 2:15 am # Reply

    This may help.
    Ben has mentioned the possible methylation problems and yes green tea is an anticancer compound and not good for babies, green tea will prevent placental attachment to the fetus.

    Allergies to cell recognition HLA antigens can cause miscarriage.

    “Anti-paternal HLA-antibodies are considered a harmless phenomenon during most pregnancies, whereas their role in recurrent miscarriage (RM) patients is disputed.”

    “In conclusion, HLA-antibodies are significantly more frequent in secondary RM patients with a firstborn boy than in other RM patients and controls. The presence of these antibodies in early pregnancy is associated with a reduced chance of a live birth.”
    The presence of HLA-antibodies in recurrent miscarriage patients is associated with a reduced chance of a live birth
    http://www.jrijournal.org/article/PIIS0165037810001014/abstract?rss=yes

    If the father doesn’t get enough vitamin D or sunlight as well as sleep (melatonin) they may not create enough TGF-beta to be present on the sperm and allergies to the HLA-DR can happen.
    The mother also needs enough sunlight or vitamin D to prevent allergies, sleep too.

    This is off a science TV show here in Australia back in 2004.

    “The detective hunt was closing in…The molecule crucial to tolerance must be within seminal fluid, but Sarah still had to find it.

    Finally her team pinpointed a protein called TGFbeta in the semen. A protein with a previously unsuspected role in the internal war of the sexes.

    Sarah Robertson:
    ‘What the TGF Beta does is interact with the female immune system to say that these molecules in the semen are not dangerous, that these are friend, not foe.’

    Narration:
    Incredibly, they’d found the agent that over time, negotiates the truce between the male DNA and the female immune system.

    Sarah Robertson:
    ‘It really is an extraordinary moment actually when you put all the pieces together and suddenly it all makes sense. That was really exciting.’

    Narration:
    But most exciting for Sarah was that at last they could understand why couples like Natalie and Tim have such unexplained difficulties – miscarriages, infertility, pre-eclampsia.

    She is now discovering that a number of men lack sufficient TGF Beta to create tolerance”
    Sperm Tolerance
    http://www.abc.net.au/catalyst/stories/s1097423.htm

    They did a show recently too where men who were allergic to their own sperm were cured of the allergy by taking vitamin B3.
    I presume this would help women with the allergies to HLA antigens but guessing there.
    I’ve taken B3 for years and cod liver oil in winter to stop skin allergies.
    The link is not child friendly so here’s the quote (:

    “NARRATION
    Now you may be wondering why Victor is not feeling unwell after producing his semen sample. About a year ago, he found an internet forum where men from all over the world would discuss the same illness. Someone online suggested he take niacin, a type of vitamin B. He did so, one hour before orgasm, and miraculously he didn’t get sick.

    Victor Pavia Reina
    It just, it has improved my life in all sense, as in I’m more confident about everything, I enjoy life, you know.

    NARRATION
    But if Victor doesn’t take the niacin, his flu-like symptoms return, and that’s why Dr Waldinger warns this is not a permanent fix.”

    So Niacin or B3 (I use Nicotinamide) may help HLA allergies and miscarriage.
    Vitamin D as well.
    The study that indicates Vitamin D (sunlight) and sleep is needed for TGF-beta is this one.

    ‘Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures.’

    Vitamin A is a growth vitamin and TGF-beta slows uncontrolled growth and is a signal hormone for creating collagen while vitamin D helps to differentiate cells once started so is needed to guide fetal cells.
    So vitamin D needs to be balanced with adequate vitamin A.

    So people know a few more clues to the subject.

    • Dr Ben April 24, 2012 at 4:10 am # Reply

      Cal –

      Interesting comment.

      I do not agree though with the niacin aspect especially during pregnancy unless there is a definite overmethylation aspect going on. Niacin uses up SAMe and miscarriage or pregnancy issues can be caused by hypomethylation (undermethylation).

      I havent looked by Curcumin may help lower TGF beta – and probiotics.

      • Dr Ben April 24, 2012 at 4:13 am # Reply

        I just looked it up – Curcumin does indeed lower TGF beta – here is one study
        http://www.ncbi.nlm.nih.gov/pubmed/20160437

      • Cal Crilly April 24, 2012 at 5:53 am # Reply

        Oh it does get confusing, curcumin is great for leukemia and cancer but not for when pregnant as it inhibits angiogenesis and would create preeclampsia.
        Preeclampsia seems to be a problem with creating the blood supply to the fetus but has many aspects of miscarriage.
        Interesting thought then that perhaps turmeric should be avoided as turmeric has curcumin in it.
        This means raw pineapple should not be eaten too, pineapple, green tea and turmeric along with olive leaf extract are potent anti-cancer substances as they stop tumour attachment.
        You’ll find anything that that affects tumour attachment can affect fetal attachment too.

        Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin
        http://cgd.aacrjournals.org/cgi/content/abstract/9/4/305

        In the study on men having low TGF-beta it shows having adequate levels of TGF-beta will reduce the allergies so you want TGF-beta there.

        To try and simplify the way I see it, Vitamin D (sunlight) and melatonin (sleep) are needed for creating TGF-beta in the body and reducing allergy problems to a fetus or the father’s HLA genes which may be in the fetus.

        The sunlight aspect is so forgotten so that is my main thought.

        Maternal Vitamin D Deficiency Increases the Risk of Preeclampsia
        http://jcem.endojournals.org/content/92/9/3517.abstract

        The Niacin may be good for men’s allergies but yes as you say can get in the way of the methylation nutrients and when you take it can cause flushing.
        So B3 is best not taken if pregnant as you say.

        Missing the methylation gene and having low folate also raises homocysteine and inflammation as a result. That sort of long term inflammation due to unrecognised MTHFR1 problems seems to manifest in all sorts of problems like coeliac and autoimmune/allergy problems so adjusting for MTHFR1 is a big part of it all.

        I did a lot of reading on this lately as South African ladies have up to 18% preeclampsia.
        I concluded they have low dietary levels of B12, Folate, B6 and during South African winters can get low levels of sunlight and vitamin D.
        They don’t have the MTHFR1 problems but get into trouble anyway due to deficient diets that cause the same hypomethylation of the DNA with hypertension from homocysteine.
        And low vitamin D or sunlight causing allergies.

        Nice to be able to mention it here, thanks Ben.

  4. Patricia April 25, 2012 at 7:51 pm # Reply

    Hello-
    I am interested to hear how you are being treated for the MTHFR mutation. I am homozygotic with the C677T mutation. I have 1 healthy son and have had 7 1st trimester miscarriages in the past 3 years in varying weeks (7-13). I have been treated with baby aspirin and folic acid and my reproductive endocrinologist is going to start lovenox with the next pregnancy.
    They were reluctant at first and did not really feel that the mutation was the cause of the miscarriages as my homocystene levels are within normal range.
    Any input on this would be great.
    Thank you

    • Ellen April 27, 2012 at 10:54 pm # Reply

      I am currently being treated with baby aspirin and 2mg of folic in addition to my prenatal vitamin which has an additional 800 mcg. I started both pre-ovulation. I am currently 18 weeks and feeling the baby kick as I type, so I am hopeful and praying! Good luck to you!

  5. Carolina August 23, 2012 at 8:41 am # Reply

    Thanks for this website. Helps to see a little light at the end of the tunnel for those women like me that are in this terrible and distressing experience of repeat abortions. I have had 3 recurrent miscarriages and I´m heterozygote in MTHFR and XII Factor. In my last pregnancy I had heparin, but the end was the same. No doctor has been able to give me any recommendations for the next pregnancy, just try again.

    I would like if possible to make you a question: in case the fetus is homozygote in MTHFR, how could you treat him to prevent his death in the uterus? I mean, is the heparin or the baby aspirin enough to prevent the death of a homozygous fetus? Is there any other treatment that you can have to prevent this?

    Thank you so much for your work and your effort on this issue, most of the doctors in many countries are totally blind and ignorant about this important issue, so your job and the job of all these scientists that you quote, is crucial to help people like me who feel abandoned by medicine.

    • Dr Ben August 23, 2012 at 3:43 pm # Reply

      Carolina –

      If you are supporting your MTHFR mutation properly and are also addressing other potential causes, it is possible to reduce risk of miscarriage to your developing child.

      You will need a good doctor to dig further and evaluate:
      – thyroid
      – estrogen/progesterone
      – adrenals
      – lifestyle/diet
      – etc

      Please read this article on Prenatal Supplementation with MTHFR.

      Lovenox and baby aspirin are the two most commonly recommended blood thinners during pregnancy for reducing clotting risk. Both may be needed.

  6. Rose October 25, 2014 at 12:26 pm # Reply

    Hi Dr Ben, PLEASE I AM DESPERATE NEED OF HELP FOR MY SISTER WHO HAS JUST HAD HER 11th MISCARRIAGE. She has not tried to get pregnant in over a year, cleansed her body, gluten free dairy free. She has been taking the supplements of Metformin 1500 mg, Metanx, Vitamin neevo prenatal,vitamin B6 B12 in all active form, and an aspirin before being pregnant. Doctor put her on lovenox 1 time a day this pregnacy. NO ONE IN NEW YORK KNOWS ABOUT THE MTHFR GENES. She was put on cynthroid 100mg to keep TSH DOWN BUT DOES NOT HAVE A THYROID PROBLEM. I will give you a history of both my sister and brother in law and I ask PLEASE give us some advice.
    My sister has a history of ANA POSITIVE. HOMOZYGOUS FOR C677T with normal homocysteine levels. 2 copies of the 4g allele in PA1. Positive anti annexing.

    My brother in law is heterozygous for 1 copy of c677t, 1 copy A1298c and Herero for G20210 in the prothrombin factor, 2 gene at elevated risk for venous thrombosis, positive for 2 copies of 4g variant and is homozygous 1. This is what we have from doctors results. Please if you have any advice please help us if they will be ever to have a child together with all these MTHFR GENES. Thank you in advance.

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