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Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction (IID) in IVF: The Controversy!

by Dr. Geoffrey Sher on March 20, 2016

 “Innovators are rarely received with joy, and established authorities launch into condemnation of newer truths; for at every crossroad to the future are a thousand self-appointed guardians of the past.”

It is an indisputable fact that  thousands of women with “unexplained” infertility/IVF and recurrent pregnancy loss (RPL) have, following selective immunotherapy with Intralipid (IL) or intravenous immunoglobulin (IVIG) in combination with corticosteroids, gone on to have healthy babies. So, why then is there such a “militant obsession” on the part of many, to denounce the entire concept of immunologic factors playing a role in implantation dysfunction?  The most common reason cited is that there are no randomized controlled “gold standard”  studies to support a causal relationship between immunologic implantation dysfunction (IID) and reproductive dysfunction (infertility/failed IVF and early miscarriage)  or the efficacy of immunotherapy to treat the condition.

The double standard: But to single out IID for criticism is a clear example of a double standard since there are no reliable randomized controlled (“gold standard”) studies to validate virtually any IVF, outcome-based treatments currently in general use. It has not even been shown that outcome following IVF is superior to alternatives such as gamete intra-fallopian tube transfer (GIFT) or zygote intra-fallopian tube transfer (ZIFT). Yet, no one would dispute the fact that IVF is far more effective than either of the other alternatives, to the extent that both GIFT and ZIFT are rarely performed any longer and have largely been relegated to the pages of history. Similarly, there are no randomized studies that demonstrate a benefit in using commonly used adjunct procedures such as embryo assisted hatching (AH), embryo co-culturing, nuclear cytoplasmic transfer, uterine scratch, embryo vitrification,  intracytoplasmic sperm injection (ICSI) etc. Yet, many highly ethical and competent IVF practitioners confidently tout some or all of these techniques as being efficacious and beneficial without turning a hair. The truth is that as is the case in many other medical specialties, progress has come has through experience gained by longitudinal studies, not through gold standard statistical testing.

Background: Ordinarily, upon reaching the uterus, the embryo makes itself invisible to uterine natural killer (NK) cells (the predominating immune lymphocytes in the uterine lining). There, provided that the NK cells do not become activated (NKa) and the embryo has a normal configuration of 46 chromosomes (euploid) and is thus “competent”, it will usually gain acceptance, implant and develop into a viable conceptus. However, in some women, the uterine NK cells become activated (NKa) and go “rogue”, confronting the embryo as a “foreign invader”. In response, they (and other uterine immune T-cells) release an excess of TH-1 cytokines (e.g.  TNF-alpha and interferon-gamma) and attack the embryo’s “root system” (trophoblast)   resulting in failed or dysfunctional implantation (i.e.  Failure to conceive or early pregnancy loss).

Uterine NK cells were first identified and described in the mid-90’s and were soon touted as playing a vital role in regulating embryo implantation.  This was soon followed by the determination that under certain conditions, NK cells became activated (NKa) leading to immunologic implantation dysfunction (IID) which could manifest as “unexplained” infertility, “unexplained” IVF failure and recurrent pregnancy loss (RPL). This spawned a lively debate on how to best assess, diagnose and treat the condition.

Why is it that until very recently, there has been a singular inability to reliably evaluate data derived from ART-related studies? To answer this question requires a realization that roughly 80% of ART failures are largely due to  chromosomal numerical irregularities (embryo aneuploidy) which until the recent introduction of full embryo karyotyping (using techniques such as comparative genomic hybridization-CHG or next generation gene sequencing- NGS) was not possible to reliably assess. And, to reliably compare results between groups of IVF patients, it is essential that outcome per embryo transferred be computed. To achieve this requires that the “competency” of the embryos transferred be known prior to embryo transfer so that only chromosomally normal (euploid/”competent”) embryos can be transferred to patients of each group. Since virtually no previously reported clinical, outcome based IVF studies took this critical requirement into consideration virtually negates their validity, making them virtually meaningless.

How might we in the future, reliably establish value and efficacy of selective immunotherapy in IVF?  In order to be reliable and representative, any study to assess a benefit of immunotherapy in women with IID would require that, demographically and clinically identical NKa positive patients, all of whom would be treated by the same physician using the same stimulation protocols, be randomly assigned to one of two groups. Group 1 would receive the designated immunotherapy regime and Group 2, would not. To be reliable, all variables that could affect outcome, would need to be kept constant. Only “competent” (euploid) blastocysts would be eligible for transfer and results would be reported as viable birth per embryo transferred.

Clinical Reproductive immunology is a very complex field which most IVF physicians do not take the time to try and understand. Most, simply follow the party line and dismissively reject the concept out of hand. So, when patients tell me that “My RE does not believe in immunologic factors causing infertility, IVF failure or Recurrent pregnancy loss”,  I advise them, to go back and ask the doctor that gave this answer for a clear explanation as to what it is that he/she does not believe. I submit to you, that in most cases a rational answer will not be forthcoming.

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  • Carmen - November 17, 2016 reply

    Hello Dr. Sher,
    I have a 16 year old son that I conceived naturally. My spouse and I tried to have more children but we were unsuccessful (low sperm motility). I just turned 37 and I have had 3 failed transfers 2 were fresh and 1 FET. I have 6 more embryos which we have froze. My doctor has done many different tests on me and I have had a hysteroscopy and a biopsy to make sure nothing is wrong with me. He has not performed the NK test is this something I should ask him to perform? I am new to your website and blogs and I have learned a lot already. I would like to know what other tests I should ask my doctor to perform on me? Any help is greatly appreciated. Thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 17, 2016 reply

    While Primary infertility refers to the inability of a woman who has never been pregnant in the past, to conceive, Secondary Infertility is defined as an inability to conceive more than 1 year after having conceived in the past. Most patients find it difficult to accept the fact that having once been able to conceive they are now unable to do so. When confronted with the proposition that they need IVF, women who have Secondary Infertility find it harder to accept than do those who have Primary Infertility. It commonly raises issues of guilt, a declining sense of self-worth and ultimately self-recrimination impacting rational decision making, family dynamics that involve partners and siblings and relatives. The fact is that secondary infertility can be just as difficult for individuals and family to deal with as primary infertility.
    There are several factors that contribute to the problem of Secondary Infertility. These include:
    • Social and marital factors: In this modern day and age where at least one in two marriages ends in divorce, it is not surprising that there would be an inevitable hiatus in childbearing. This often results in a considerable delay in re-initiating family building. Since the biological clock keeps on ticking in the interim, advancing age can, and often does, have a profound effect on a woman’s ability to subsequently conceive and successfully complete a pregnancy. In my experience, this is one of the most common reasons for secondary infertility. In addition, by the time a decision is made to enter a new relationship, many men and women will have undergone a prior sterilization procedure which now needs to be addressed. To make matters worse, many such men and women first opt for surgical reversal of their occlusive surgery, only to learn in the end that the procedures were not successful, and they now need to consider in vitro fertilization (IVF) in one form or another.

    • Financial factors: Here, the cost of raising a child often weighs heavily, especially in this present tough economic climate. This is becoming more of an issue as women playing an ever increasing role as a primary bread winner.

    • Career demands: There can be little doubt that when it comes to climbing the career ladder, women are considerably disadvantaged by the fact that pregnancy and the immediate demands of child rearing take away from their ability to compete with men. As such, many women choose to delay having another child until such time as they have been able to make up for prior lost opportunity.

    • Medical barriers to fertility: Certain common medical conditions, while not absolutely precluding pregnancy, make it much more difficult to conceive.
    • Endometriosis: It is not uncommon for women with endometriosis to achieve a pregnancy, but find difficulty in doing so again at a later date. The reason for this is that while most women with endometriosis have patent fallopian tubes, the environment surrounding their tubes is compromised due to pelvic toxins that are produced by the endometriotic implants. These toxins compromise egg fertilization potential, making it more difficult for sperm in the fallopian tube to fertilize the egg upon its arrival there. As such, endometriosis is one of the commonest causes of secondary infertility.

    • Tubal damage due to prior pelvic inflammatory disease: In first world countries, the early and often indiscriminate use of antibiotics for the slightest symptom has led to the point where an acute attack of pelvic inflammatory disease is often masked. As such, less than 30% of American women with tubal damage have knowledge that their tubes are compromised and that they might have subsequent difficulty in conceiving. Since, in many such cases the tubal damage will not have totally blocked both tubes, some of the women so affected might experience a pregnancy but have difficulty in conceiving again later down the line.

    • Dysfunctional ovulation: Since ovulation as well as normal hormonal support of the early implanting embryo are both essential for a healthy pregnancy to occur, it follows that women with irregular or dysfunctional ovulation (e.g., polycystic ovarian syndrome – PCOS, persistent follicular luteal phase deficiencies or post birth control pill ovulatory problems) might sporadically conceive and thereupon find it difficult to do achieve another pregnancy later on.

    • Immunologic Implantation Dysfunction (IID): has become ever more apparent that immunologic factors play an important role in achieving healthy implantation. Women with endometriosis (regardless of its severity), those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis and thyroid autoimmunity (TAI), and some cases where the man and the woman share certain genetic similarities involving DQ alpha and HLA genotype (alloimmune implantation dysfunction), will have activated T cells (cytotoxic lymphocytes) and natural killer cells (NKa)CTL/NK cells that can inhibit or compromise healthy implantation. This is an often overlooked cause of secondary infertility. Most such autoimmune/alloimmune cases require selective immunotherapy and IVF.

    • Anti-sperm Antibodies: Although infrequent, some cases of secondary infertility might also be caused by the woman harboring anti-sperm antibodies. In such cases IVF is mandated.

    • Previous post-pregnancy uterine inflammation: Retention of products of conception after the birth of a child, miscarriage, or abortion can so damage the uterine lining as to result in subsequent implantation failure. Unless specifically looked for, this will usually be unknown to the patient, who will simply present with secondary infertility. Treatment is often difficult because such patients might not respond adequately to surgical removal of intrauterine scar tissue or to hormonal or Viagra therapy.

    Male immunologic factors: Most men who have undergone a previous vasectomy more than 10 years earlier, will have anti-sperm antibodies that will interfere with fertilization. Such cases require IVF with intracytoplasmic sperm injection (ICSI). Here we offer a few words of caution to men who are considering undergoing surgical reversal of vasectomy. Always first have a test done to exclude the presence of circulating anti-sperm antibodies, because in such cases, even if the reversal is successfully performed, they will not be able to initiate a pregnancy without IVF/ICSI.

    Whatever the cause, Secondary Infertility often affects older couples disproportionately, creating a sense of urgency and even desperation in achieving a viable pregnancy before time runs out. It is for this reason that IVF becomes the treatment of choice in such cases. However, even IVF becomes progressively less successful with advancing age of the woman (whose eggs are being fertilized). In such cases it is important for the couple to be realistic with regard to their expectations. Here, options that include embryo banking and egg donation should be carefully considered.

    Finally, whenever a regularly ovulating younger woman (under 36 years of age) with patent fallopian tubes is diagnosed with secondary infertility, it is essential to consider underlying endometriosis or non-obstructive tubal disease as a possible cause. In such cases, IVF often becomes the treatment of choice.

    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.
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • IVF Failure and Implantation Dysfunction:
    • 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!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF

    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.

  • Gillian - June 3, 2016 reply

    Hi Dr. Sher, I think your blog is wonderful and so informative! I have a question on immune protocols, my clinic would not be immune specialists but they are very willing to prescribe immune medication. I have implantation dysfunction (4 failed cycles with excellent embryos) and have had all the standard immune bloods done and nothing has shown up, We can’t afford the deeper immune bloods at present as it is very expensive where I live so my clinic are willing to treat me as a precaution. I will be on intralipids a week before transfer, on the morning of transfer and then again after a positive hpt, also clexane and .5mg steriods per day until 12 weeks. Would this be a standard immune protocol do you think? I look forward to hearing from you!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 3, 2016 reply

    I guess empiric treatment with IL and steroids is better than no treatment. However, I do not espouse to treating without a diagnosis, especially in cases of immunologic implantation dysfunction (IID) because the cause of NK cell activation can be alloimmune or autoimmune and the treatment would differ in the former. Finally the IL should be administered 7-10 days prior to ET and it should be combined with steroid therapy. I administer 0.75mg dexamethasone daily, starting at the begining of fertility homrmone therapy.
    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and 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)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!

    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

    Gillian - June 3, 2016 reply

    Thank you for your reply! It makes perfect sense. You are a wealth of knowledge so thank you and I love your blog 🙂

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 3, 2016 reply

    Thank you kindly Gillian and…good luck!

    Geoff Sher

  • Jennifer - May 18, 2016 reply

    Hello Dr. Sher,
    I am 33 and have had 4 natural mc over the last several years and most recently had my first ivf cycle that ended with a 6 week miscarriage of twins. I have know mthfr, and high nk cells which were tested last year to be (cd56/16) at 27%. My current reproductive endocrinologist is saying this miscarriage is due to my nk cells and I need to consider a surrogate. Unfortunately my current doctor doesn’t believe in ivig or intralipid therapy and only had me on prednisone, lovenox, folic acid, pre-natal, progesterone shots and estradiol. We had all our embryos pgs tested and all frozen on day 5, that turned out to be all Grade A quality and normal and have a total of 9 left to use. Can you tell me in your opinion if women with high NK cells need to use surrogates in many cases ? Also I am located in Florida, do you see patients out of state for treatment via Skype or phone or do they have to travel to you for any treatment? Thanks

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - May 18, 2016 reply

    Respectfully, I am confused and confounded by your being denied access to selective immmunotherapy for what clearly is an immunologic implantation issue. I do agree that it is not likely that the MTHFR mutation is causing these losses.And yes..ABSOLUTELY, I do treat patients from out of state and country. In fact 70% of my patients travel to Las Vegas for treatment with me.

    When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
    Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
    • Early pregnancy loss (first trimester)
    • Late pregnancy loss (after the first trimester)
    • Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
    • Early pregnancy losses usually occur sporadically (are not repetitive).
    In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
    Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
    There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
    Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
    Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
    1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
    • Inadequate thickening of the uterine lining
    • Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
    • Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
    • Deficient blood flow to the uterine lining (thin uterine lining).
    • Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
    • Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
    2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

    IMMUNOLOGIC IMPLANTATION DYSFUNCTION
    Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
    But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
    Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
    Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

    Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
    However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
    DIAGNOSING THE CAUSE OF RPL
    In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
    Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

    • Karyotyping (chromosome analysis) both prospective parents
    • Assessment of the karyotype of products of conception derived from previous miscarriage specimens
    • Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
    • Hysterosalpingogram (dye X-ray test)
    • Hysteroscopic evaluation of the uterine cavity
    • Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
    • Immunologic testing to include:
    a) Antiphospholipid antibody (APA) panel
    b) Antinuclear antibody (ANA) panel
    c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
    d) Reproductive immunophenotype
    e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
    f) Alloimmune testing of both the male and female partners
    TREATMENT OF RPL
    Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
    Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
    Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.

    Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
    Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
    The Use of IVF in the Treatment of RPL
    In the following circumstances, IVF is the preferred option:
    1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
    2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
    The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
    Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
    There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
    The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

    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.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • 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)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF
    • Progesterone-Estrogen Hormonal supplementation in IVF: How Does it Work and What is its Value?

    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.

  • Teresa - April 8, 2016 reply

    Hello Dr Sher. I had 2 miscarriages at 7/8 wks. I then saw a fertility endocrinologist and learned that I had an elevated # of Natural Killer T Cells. When I become pregnant (naturally) the 3rd time. I did 3 rounds of IL starting around 5wks from LMC and continued every 3 or 4 wks until passed the first trimester. I was told that after the first trimester, the baby was large enough for the Natural Killer Cells to recognize the baby as what it was an not attack it. The pregnancy was successful. I am now pregnant again and doing the same 3 IL treatments in the 1st trimester. However, now my doctor wants me to get tested again before the 3rd IL treatment and if my killer cells are still elevated, continue getting a 4th… 5th… IL treatment. My concern is that these treatments are costly and this is very different from what I was told last time. I’m looking for a 2nd opinion. TIA.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 8, 2016 reply

    I congratulate you and your doctor for implementing the right treatment and for the excellent outcome. However, I very respectfully (in my opinion) do not think that protracted IL infusions are necessary or helpful.

    Geoff Sher

  • Verity Willcocks - April 3, 2016 reply

    Dear Dr Sher,
    I have a four year old son conceived through our first ICSI (low motility) with no immunes. Since then we had a chemical pregnancy in 2014 (following another ICSI and treatment for high TNFa with 4 shots of humira, steroids and clexane beforehand), and another failed fresh ICSI (no humira as tnfa tested at 29 six months after last humira jab, but steroids, clexane and intralipids). I am 42 in August and have never been pregnant naturally. I have just done tests for LAD – found to be low, Dqa (no match) and Kir (missing all three receptors). Neupogen has been recommended for the Kirs and LIT for the low LAD – I live in the UK where this is legal (I assume!). I am questioning whether to do this as it takes a long time – two shots three weeks apart, then retesting 4 weeks later, and I am desperate to get on with what will be our last cycle due to my age. My doc has said that high cytokines are more of an issue than my low LAD. I also have some raised NKs. I am wondering whether to do thrombophilia and antibody tests – ANA, APA, antihistone etc – but I can’t help wondering if I must be OK on some things as I managed to have my son without a problem (once I got pregnant)? Or can your body stop making antibodies? What do you think of LIT? There are patients who think this has been the key to achieving a pregnancy. Thank you in advance for your reply – it’s very generous of you to answer people’s questions. Best wishes, Verity

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 3, 2016 reply

    I am not a believer in LIT therapy.If it has any role at all, then it would be for alloimmune implantation dysfunction (seebelow). I also think Humira is counter-productive (see below). If there is NKa+, then in my opinion treatment is best achieved using Intralipid + corticosteroids (see below).

    More important at 42y is the the need for using a very selective and individualized approach to ovarian stimulation to try and protect egg integrity during stimulation.Rather, in my opinion, I think you need a modified, robust, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts, to make hay while the sun still shines.

    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and 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

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors•
    . 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)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy

    • Implications of “Empty Follicle Syndrome and “Premature Luteinization”
    • Premature Luteinization (“the premature LH surge): Why it Happens and how it can be Prevented.
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    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

  • Melissa - March 27, 2016 reply

    Hello Dr Sher,
    I know it is difficult to comment unless an extensive history is noted but I am currently 5 weeks and 5 days pregnant post FET. I transferred 2 day six embryos and one day five embryo. My third beta was 9,720 and I have an extensive history of chemical pregnancies/missed miscarriages. My last two losses were found to be chromosomally normal and I was only given .75 dexamethasone and some Intralipids during those cycles.
    Currently, I have received 3 IVIG infusions and am on 20mg prednisone and 40mg lovenox bid.
    I have normal cytokines but I do have elevated NK cells, low LAD, hashimotos, anti ovarian antibodies, some antiphospholipid antibodies and pcos.
    I also take metformin, synthroid, low dose asprin and prenatals.
    My question is: what is your typical ivig infusion schedule?
    Since already having had 3 infusions so far should I now start infusing every 28 days or in your experience is it more prudent to test my levels and infuse as needed even if it’s every 2 weeks? Any advise is so very much appreciated since my past embryos have stopped developing in the sixth week during past pregnancies.
    Again, thank you for any guidance. Melissa

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 27, 2016 reply

    I do not do >2 IL or IVIG infusions (not both…either or and there is in my opinion no benefit in using IVIG over IL. The second and final infusion is done with confirmation of a +ve beta hCG test. There is no benefit in cases of autoimmune NKa to go beyond this in my opinion.

    Good luck!

    Geoff Sher

  • Tiffany - March 21, 2016 reply

    Hello! I am curious as to what your thoughts on LIT are? Also, vitamin D deficiency and inflammation. My husband and I are in the process of making embryos (retrieval is Wednesday) but we have decided to not transfer right away. We are doing PGS for the first time but I am concerned that even if we do get healthy embryos, is my body ever going to be able to implant successfully? Is there any information about using gestational carriers being more successful with women such as myself?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 21, 2016 reply

    Hi Tiffany,

    You do not need LIT…besides it is banned in this country. There are far better and less risky alternatives. However, I cannot advise you authoritatively without access to much more information.

    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    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
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    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

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