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Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management: (Case Report)

by Dr. Geoffrey Sher on January 3, 2016

Greetings Dr. Sher!

Just wanted to first thank you for all that you do for women and infertility and I’m truly amazed and grateful at how you are so willingly to share your knowledge and help women achieve pregnancy.

As for me, my background – Diagnosed with endometriosis at age 19 when I lost one ovary/tube. Struggled with recurrent endo and had multiple surgeries for endometriomas. Stayed on continuous BCP for more than 15 years. At about 37 tried a few rounds of in vitro, low slow responder, never made to egg retrieval or transfer. Low AMH. Moved on to donor eggs (frozen eggs from an egg bank). At 41Y I went through an early menopause.

First FET (using embryos derived from banked eggs and partner’s sperm) – standard protocol, BCP, Lupron, esterase, 5 days of doxycycline and PIO. Lining at >11mm at time of transfer, 2 6 hatching embryos, BFN. No symptoms during wait, but experienced painless, but strong uterine contractions/vibrations at about 5-6 days past 6 day transfer. Painless, but very noticeable. Discussed with doctor, doctor said it was gas. Doctor said success usually happens after 1 or 2 tries.

Six months later – Second FET – same protocol, >10mm lining, transferred 2 PGS normal 6 day hatching embryos, BFN. Same uterine vibration/contraction at 4-5 days after transfer strong enough to wake me from my sleep, but not painful. Discussed with doctor that I felt my uterus was literally rejecting the embryos and did not feel it was gas and had not had same feeling since last transfer. Doctor said never heard of symptoms, maybe side effect of PIO. Discussed long history of endometriosis and possible immune issues, doctor said no literature supported correlation. Also discussed if adenomyosis is problem, doctor said normal uterus, no problems with thickening lining. For both cycles, did pre-cycle screening including, pap, checked for uterine polyps and standard STD blood work.

Throughout my infertility, I’ve educated myself, joined forums and found your site and read numerous blogs and feel I have an underlining issue. Went to another RE and did multiple tests for recurrent implantation failure. No elevated NK cells, no lupus, no + ANA, no red flags to the shock of my RE with my long history of Endo. Only found MTFR heterozygous for the C677, elevated homocysteine, low vitamin D, elevated hsCRP. Did MRI of uterus which results showed no issues that would hinder implantation or carrying a child. RE said could do further testing, but feels I have some sort of immune problem and said treatment is usually IL which is cheaper than further testing.

Third FET – BCP, Lupron, endometrial scratch month prior, intralipid (IL) 13 days before transfer, oral estrogen patches, vaginal micronized progesterone, 1ml PIO, 100mg doxycycline 100mg for 5 days, starting 2 days before transfer and 4mg of steroid (Medrol) 4 mg one tablet four times a day for 4 days starting 2 days before transfer, lining at >10mm wee before transfer.. Transferred 2 embryos (not PGS tested)… BFP! First time positive in entire life! HCG at 10 days pass 6 day transfer was 43MIU/ml. Second Beta at 13 days past HCG decreased to 4MIU/ml…a chemical pregnancy

When I did intralipid (IL) prior to transfer, 2-3 days later, I felt like a NEW woman! Getting out of bed in morning wasn’t painful, no painful aching joints. Knees felt great! Not sure if from IL but only thing different in that time frame.

I feel IL 13 days before transfer, 4 days of steroid therapy (Medrol helped me to have a successful implantation, but something caused my uterus again to reject embryo(s) again. Only this time happened later.

Thanks in advance for your time! Your opinion is greatly appreciated!

 

My response: 

There is little doubt in my mind that you have an implantation dysfunction. II respectfully strongly differ from the opinion expressed by your RE. In fact, about 30% of women with endometriosis have an immunologic implantation dysfunction (IID) that is autoimmune in nature and liked to activation of uterine natural killer cells (NKa).

In spite of your telling me that you do not have “increased” NK cells, I believe that you probably do have NKa and the reason for your believing that you do not, is a misunderstanding that it is the concentration of NK cells that matters. There is in fact a big difference between an “increased” concentration of NK cells and “activation” of said cells. The former is irrelevant. In fact, the more NK cells you have, the better. NK cell activation must be measured by the K-562 target cell test. There are but a handful of Reproductive Immunology Reference Laboratories in the United States that are capable of performing the K-562 target cell test, reliably. I use Reproductive Immunology Associates (RIA) in Van Nuys, CA.

This having been said, there are several additional considerations, applicable to your situation:

  1. Even though the fact that you have endometriosis and that almost 1/3 of women with this condition have autoimmune NKa the most likely, you might actually have an alloimmune implantation dysfunction (a “partial or complete DQ alpha match”). The reason why an alloimmune cause must first be identified/excluded is that here, treatment differs substantially from that advocated for autoimmune IID (see below)
  2. The administration of Intralipid alone, is insufficient for optimally addressing NKa. In my opinion, the addition of a steroid (dexamethasone or prednisone) is essential. The administration of such steroid is commenced no later than 10-14 days prior to projected embryo transfer and is slowly tailed off at 10 weeks gestation or with a failed cycle.
  3. It is important to have the right dosage of Intralipid administered. In my opinion, this should be 100ml of 20% of Intralipid diluted in 500cc of physiological (normal) saline and infused over about a 3 hours time period. The first administration should be done about 10-14 days prior to embryo transfer and the second, with a positive beta hCG. In cases of autoimmune implantation dysfunction, no further IL is given. In cases of alloimmune implantation dysfunction (NK activation in combination with DQ alpha/HLA matching of partners, the infusions are ideally repeated every 2-4 weeks until the 22nd week of pregnancy and here, rather than using dexamethasone, I use prednisone.

I urge you to access my new personal website at www.DrGeoffreySherIVF.com   and from there, my new blog. When you get to the “home page” of the Blog, find the “search bar” and type in the following the titles of articles listed below (one at a time) “Click” and you will immediately be taken to these.

  • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
  • Unexplained IVF Failure
  • Endometriosis and Infertility
  • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
  • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
  • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatmen

I hope this helps!

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4 comments

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  • Linda - November 15, 2016 reply

    Hi Dr. Sher, I would love to hear your views on HLA matching? I have been reading reports from Dr. Braverman regarding his treatment for HLA matches (he treats with Neupogen). He believes that even 100% matches can be treated successfully this way and out of his 10 patients with full matches, 8 of those became pregnant and carried to term with having Neupogen as their treatment. I would love to hear your thoughts on this! Is this something you would prescribe for your patients with HLA matches?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 15, 2016 reply

    A total HLA match alone is completely benign and does NOT require immunotherapy unless there is an associated natural killer cell activation (NKa) as reliably measured using the K-562 target cell test. And even then…. there are isolated cases where viable pregnancies do occur, albeit VERY infrequent. Also, I have found that not all HLA matching is relevant. In my experience, occurrence of an intractable immunologic implantation dysfunction (IID) is confined to those cases involving total matching of the HLA, DQ alpha. In such cases, I recommend resorting to the use of non-DQ alpha matching donor sperm with Intralipid/Steroid therapy or the use of a gestational carrier in such cases.I know of no convincing evidence that the use of Neupogen has a beneficial effect in such cases.

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoff Sher

  • Sarah - June 9, 2016 reply

    Does it matter what time period the intralipid is infused for? Mine have usually taken just under 2 hours.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 9, 2016 reply

    Ideally > 3 hours.

    Geoff Sher

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