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    • Thyroid Autoimmunity & IVF Failure: Linked to Immunologic Implantation Dysfunction?

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      Between 2% and 5% of women of childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss. The condition is 5-10 times more common in women than in men.

      In most cases, hypothyroidism is caused by damage to the thyroid gland resulting from thyroid autoimmunity (TAI) caused by damage done to the thyroid gland by antithyroglobulin and/or antimicrosomal auto-antibodies. The increased prevalence of hypothyroidism and TAI in women is likely the result of a combination of genetic factors, estrogen-related effects and chromosome X abnormalities.

      While being the main cause of hypothyroidism, TAI can be present without any coexisting clinical or hormonal evidence of hypothyroidism. Regardless of whether there is such evidence of hypothyroidism or whether the hormone deficiency has been corrected through thyroid hormone supplementation, women with TAI commonly present with reproductive failure.
      We have reported on the fact (1998, American Journal of Reproductive Immunology) that approximately 50% of women with TAI (regardless of the absence or presence of clinical hypothyroidism) have increased activated Natural Killer cell activity (NKa+) in their blood and that they are the ones that most commonly have reproductive failure.

      Since 50% of women with TAI do not have reproductive failure, it is probably not the presence of antithyroid antibodies themselves that causes reproductive failure. Rather, it is more likely a coexisting presence of NKa+ that causes the problem by damaging the early “root system” of the implanting embryo.

      In some cases of TAI-induced reproductive failure, pregnancy is lost prior to it being diagnosed through blood or urine beta hCG testing (chemical pregnancies) or before ultrasound confirmation (clinical pregnancies). In other cases, the pregnancy may be lost a little later as a clinical miscarriage. We were among the first to demonstrate and report on the association between NKa+ and reproductive failure in women with TAI. We also showed that in such cases, aside from the need (in those with hypothyroidism) to adequately supplement with thyroid hormone replacement, the administration of intravenous gamma globulin (IVIG) or intralipid (IL) therapy in combination with steroids such as dexamethasone or prednisone (starting at least 4-7 days prior to ovulation or egg retrieval) markedly improves IVF birth rates.

      Women with TAI who do NOT have NKa+ do not manifest with reproductive failure and as such do not require or benefit from IVIG or IL +steroid therapy.

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      15 Responses to “Thyroid Autoimmunity & IVF Failure: Linked to Immunologic Implantation Dysfunction?”

      1. Heidi says:

        What would you say to someone who does has TAI, does not have NKa+ and still presents with reproductive failure? Is it advisable to pursue IVIG or IL +steroid therapy, or is it more likely that there is yet another cause for the reproductive failure?

      2. I would not recommend IL/IVIG/steroids in such cases as based on the data they are not at risk of reproductive failure unless thy have NK cells activation.

        Geoff Sher

      3. Jade says:

        Hi Dr Sher,

        Could I get your opinion on whether you would use IVIG or IL treatment for someone with the following test results/history:
        - elevated antithyroid peroxidase antibodies
        - elevated antithyroglobulin antibodies
        - normal thyroid function (no evidence of hypothyroidism)
        - normal levels of NK cells in blood
        - elevated NK cells in uterus
        - repeated IVF failure, including an early miscarriage & a clinical pregnancy.

        Thanks for taking the time to write this blog. It is the most comprehensive and credible source for people who want to better understand their fertility issues.

      4. NK cell concentration is not relevant. It is the NK cell activation as measured by the K-562 target cell test that matters. If that is elevated then intralipid +corticosteroid therapy is best. If there is no NK cell activation then neither intralipid or IVIG is indicated for this problem. However I would advise both alloimmune and other autoimmune tests be done too. See my arrticle elsewhere on this blog relating to immunologic implantation dysfunction.

        Geoff Sher

      5. BMac says:

        I have hypothyroidism and tested positive for thyroid antibodies. After a D&C; to clear out a little scar tissue. My dr. has prescribed asprin and clomid. We tried first month with just intercourse and last month IUI. Neither worked, and I stared my period at least 2 to 4 days early on a regular 28 day cycle. Are their treatments that can aid implantation?

      6. As the above article suggests, you need to do a natural killer cell (NK) activity test (the K-562 target cell test. This can only be adequately done at one of about 3 or 4 Reproductive Immunology Reference Laboratories in the US. The one I recommend is Reproductive Immunology Associates in Van Nuys, CA. Call them. If the NK activity by the K-562 target cell test is increased (>10%) you will need Intralipid therapy

        Feel free to call 800-780-7437 and set up a free medical telephone consultation to discuss.

        Geoff Sher

      7. cycladesgr10 says:

        My wife has hypothyroidism and tested positive for thyroid antibodies. After our first IVF cycle now is pregnant (4 weeks). she now takes adequately supplement with thyroid hormone replacement.
        Do you recommend to make the K-562 target cell test in order to decide to proceed or not to Intralipid therapy?

      8. nknightmare says:

        Hi Dr Sher,
        I’ve been diagnosed with high NK cell activity recently as the cause of my implantation failures but my doctor believe the progesterone i was using should suppress nk activity. (with normal cgh embryos) I have heard of intralipid therapy but my doctor does not believe in intralipid and claims that progesterone and intralipid perform the same function of suppressing these cells. Please advise. I am about to start a third cycle. Should I change my RE or is she right?

        • Geoffrey Sher says:

          Respectfully…Progesterone will NOT reduce NK cell activation at all. Alas, in ny opinion, if you do not treat this effectively, you will be unlikely to achieve a pregnancy.

          Might I recommend that you go to the home page on this site, find a “search bar” in the upper right hand column and type in the following subjects into the bar and it will take you to all the relevant articles I posted there.

           “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
           “IVF success: Factors that influence outcome”
           “A Personalized, Stepwise Approach to IVF At SIRM” (Parts 1 &2 posted in on March, 2012)
           Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted March, 21st 2012)

          You might consider calling 800-780-7437 or 702-699-7437 to set up a web-based video conference or a telephone consultation with me (which is free if you reside in the U.S.A or in Canada) so we might discuss your case in detail.

          Geoff Sher

      9. Need help says:

        helllo Dr Sher,

        Immunological test have confirmed that I have autoimmune problems causing elevated nk cell activity. This explains why I haven’t had a successful pregnancy. My current clinic doesn’t provide intralipid therapy but are able to turn around cgh results within 24hours on day 6. Also, I have taken a lot of time off work and cannot do a lot of out of state travel. Is it possible to do my egg retrieval and cgh testing with my local clinic and travel down to your clinic in Vegas for intralipid therapy and FET?

        Thanks.

        • Geoffrey Sher says:

          That would not work but why don’t you call 800-780-7437 ASAP and set up a consultation with me to discuss. I can almost certainly help here.

          Geoff Sher

      10. Stephanie says:

        I have been struggling with Graves Disease and have had two RAIs to dissolve my thyroid. I am now hypothyroid and on synthroid. I just went through IVF and my TSH was right at the cutoff for my RE. At ET the transferred three 8 cell grade A 3-day embryos. At my first HCG 14 days after ET, I had a very low 1st HCG (10) but my second “progressed appropriately (doubled over 48 hours to 44 in 4 days)”. I was wondering if hypothyroid could of caused my body to delay implantation and could it still produce a healthy pregnancy?

        • Geoffrey Sher says:

          Yes you could be fine. However, if you have an autoimmune condition with antithyroid antibodies, then please know that about 50% of women who have such antibodies will have activated uterine natural killer cells (NKa that would compromise embryo implantation.

          Good luck!

          Geoff Sher

      11. Ria says:

        Hi doc,

        I am 31 now and I have had 5 IVF failures due to implantation problem.
        I have ATA > 1300 and hypothyroid taking eltroxin.
        My doc gave me IVIG in two cycles, but the issue I had with IVIG was I developed fever which lasted 2-3 hours on the 6th day of Transfer of day 2 embryos.
        What cud be the cause of fever, my both cycles also failed? IVIG given was 5 gm and 15 gm in each.

        thnx doc.

        • Geoffrey Sher says:

          IVIG can cause a reactive fever and of course this is not ideal for implantation. Today we have supplanted IVIG with Intralipid.

          Thank you for taking the time to provide all that information.

          Please go to the home page of this blog (www.IVFauthority.com ). When you get to the look for a “search bar” in the upper right hand corner. Type in the following subjects into the bar and it will take you to all the relevant articles I posted there.

           “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
           “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
           “Agonist/Antagonist Conversion Protocol”
           “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
           “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
           “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
           “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
           “IVF success: Factors that influence outcome”
           “Autoimmune Thyroid Disease and IVF”

          Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada) so we can discuss your case in detail.. While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.

          Geoff Sher

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