I invite you to contact my Office Manager, Patti Converse (702-533-2691 and set up an  online consultation with me.

Geoff Sher

• IMPLANTATION DYSFUNCTION

Implantation dysfunction is often overlooked as a significant reason for IVF failure. This is especially true when IVF failure is unexplained, or when there are recurring pregnancy losses or underlying issues with the uterus, such as endo-uterine surface lesions, thin uterine lining (endometrium), or immunological factors.

IVF success rates have been improving in the past decade. Currently, in the United States, the average live birth rate per embryo transfer for women under 40 years old using their own eggs is about 2:5 per woman undergoing embryo transfer. However, there is a wide range of success rates among different IVF programs, varying from 20% to almost 50%. Based on these statistics, most women in the United States need to undergo two or more IVF-embryo transfer attempts to have a baby. Many IVF practitioners in the United States attribute the differences in success rates to variations in expertise among embryology laboratories, but this is not entirely accurate. Other factors, such as differences in patient selection, the failure to develop personalized protocols for ovarian stimulation, and the neglect of infectious, anatomical, and immunological factors that affect embryo implantation, are equally important.

Approximately 80% of IVF failures occur due to “embryo incompetency,” mainly caused by ( irregularities in chromosome number (aneuploidy), which is often related to the advancing age of the woman, diminished ovarian reserve ( DOR) but can also be influenced by the ovarian stimulation protocol chosen, and sperm dysfunction (male infertility). However, in around 20% of cases with dysfunction, failure is caused by problems with embryo implantation.

This section will focus on embryo implantation dysfunction and IVF failure which in the vast majority of cases is caused by:

1. Anatomical irregularities of the inner uterine surface:

1. •  Surface lesions such as polyps/fibroids/ scar tissue
   • endometrial thickness

1.  Immunologic Implantation Dysfunction ( IID)lesions

1. • Autoimmune IID
   • Alloimmune IID

1. ANATOMICAL IMPLANTATION DYSFUNCTION
2. a) Surface lesions such as polyps/fibroids/ scar tissue

When there are problems with the structure of the uterus, it can lead to difficulties in getting pregnant. While uterine fibroids usually don’t cause infertility, they can affect fertility when they distort the uterine cavity or protrude through the lining. Even small fibroids located just beneath the lining and protruding into the cavity can decrease the chances of the embryo attaching. Multiple fibroids within the uterine wall that encroach upon the cavity can disrupt blood flow, impair estrogen delivery, and prevent proper thickening of the lining. These issues can be identified through ultrasound during the menstrual cycle’s proliferative phase. Any lesion on the uterine surface, such as submucous fibroids, adhesions, endometrial polyps, or placental polyps, can interfere with implantation by causing a local inflammatory response similar to the effect of an intrauterine contraceptive device (IUD).

Clearly, even small uterine lesions can have a negative impact on implantation. Considering the high costs and emotional toll associated with in vitro fertilization (IVF) and related procedures, it is reasonable to perform diagnostic tests like hysterosalpingography (HSG), fluid ultrasound examination (hysterosonogram), or hysteroscopy before starting IVF. Uterine lesions that can affect implantation often require surgical intervention. In most cases, procedures like dilatation and curettage (D&C) or hysteroscopic resection are sufficient. Rarely a laparotomy may be needed. Such interventions often lead to an improvement in the response of the uterine lining.

Hysterosonogram( HSN/saline ultrasound) is a procedure where a sterile saline solution is injected into the uterus through the cervix using a catheter. Vaginal ultrasound is then used to examine the fluid-filled cavity for any irregularities that might indicate surface lesions like polyps, fibroid tumors, scarring, or a septum. When performed by an expert, HSN is highly effective in detecting even the smallest lesions and can supplant hysteroscopy in certain cases. HSN is less expensive, less invasive/traumatic, and equally effective as hysteroscopy. The only drawback is that if a lesion is found, hysteroscopy may still be needed for treatment.

Hysteroscopy is a diagnostic procedure performed in an office setting with minimal discomfort to the patient. It involves inserting a thin, lighted instrument called a hysteroscope through the vagina and cervix into the uterus to examine the uterine cavity. Normal saline is used to distend the uterus during the procedure. Like HSN, hysteroscopy allows for direct visualization of the inside of the uterus to identify defects that could interfere with implantation. We have observed that around one in eight IVF candidates have lesions that need attention before undergoing IVF to optimize the chances of success. I strongly recommend that all patients undergo therapeutic surgery, usually hysteroscopy, to correct any identified issues before proceeding with IVF. Depending on the severity and nature of the problem, hysteroscopy may require general anesthesia and should be performed in a surgical facility equipped for laparotomy if necessary.

1. b) Thickness of the uterine lining (endometrium)

As far back as In 1989, I and my team made an important discovery about using ultrasound to assess the thickness of the endometrium during the late proliferative phase of both “ natural” and hormone-stimulated cycles. The assessment helped predict the chances of conception. We found that an ideal thickness of over 9mm at the time of ovulation , egg retrieval or with the commencement of progesterone therapy in embryo recipient cycles ( e.g., IVF with egg donation, gestational, surrogacy and embryo adoption) was associated with optimal implantation rates, while an endometrial thickness of less than 8 mm was associated with failure to implant or early pregnancy loss in the vast majority of cases. An endometrium measuring <8mm was almost invariably associated with failure to implant or early pregnancy loss in the while an endometrium measuring 8 to 9 mm was regarded as being intermediate, and while pregnancies did occur in this range, the rates were only slightly lower than with an optimal lining of 9 mm

A “poor” uterine lining typically occurs when the innermost layer of the endometrium (basal or germinal endometrium) is unable to respond to estrogen by developing a thick enough outer “functional” layer to support successful embryo implantation and placental development. The “functional” layer, which accounts for two-thirds of the total endometrial thickness, is shed during menstruation if pregnancy does not occur.

The main causes of a poor uterine lining are:

1. Damage to the basal endometrium due to:

1. • Inflammation of the endometrium (endometritis), often resulting from retained products of conception after abortion, miscarriage, or childbirth.
   • Surgical trauma caused by aggressive dilatation and curettage (D&C).

1. Insensitivity of the basal endometrium to estrogen due to:

1. • Prolonged (back to back) use of clomiphene citrate for ovarian stimulation or…
   • Prenatal exposure to diethylstilbestrol (DES), a drug given to prevent miscarriage in the 1960s.

1. Overexposure of the uterine lining to male hormones produced by the ovaries or administered during ovarian stimulation (primarily testosterone):

1. • Older women, women with DOR (poor responders), and women with polycystic ovarian syndrome (PCOS) often have increased biological activity of luteinizing hormone (LH), leading to testosterone overproduction by the ovarian connective tissue (stroma/theca). This effect can be further amplified when certain ovarian stimulation protocols were high doses of menotropins ( e.g., Menopur) are used.

1. Reduced blood flow to the basal endometrium caused by:

1. • Multiple uterine fibroids, especially if they are located beneath the endometrium (submucosal).
   • Uterine adenomyosis, which involves extensive abnormal invasion of endometrial glands into the uterine muscle.

In 1996 I introduced the Vaginal administration of Sildenafil (Viagra) to improve endometrial thickening. The selective administration of Sildenafil has shown great promise in improving uterine blood flow and increasing endometrial thickening in cases of thin endometrial linings. When administered vaginally, it is quickly absorbed and reaches high concentrations in the uterine blood system, diluting as it enters the systemic circulation. This method has been found to have minimal systemic side effects. However, it is important to note that Viagra may not be effective in all cases, as some cases of thin uterine linings may involve permanent damage to the basal endometrium, rendering it unresponsive to estrogen.

Severe endometrial damage leading to poor responsiveness to estrogen can occur in various situations. These include post-pregnancy endometritis (inflammation after childbirth), chronic granulomatous inflammation caused by uterine tuberculosis (rare in the United States), and significant surgical injury to the basal endometrium (which can happen after aggressive D&C procedures).

2. IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

There is a growing recognition that problems with the immune function in the uterus can lead to embryo implantation dysfunction. The failure of proper immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. Some immunologic factors that may contribute to these issues include antiphospholipid antibodies (APA), antithyroid antibodies (ATA) , and activated natural killer cells (NKa).

• Activated natural Killer Cells (NKa):

During ovulation and early pregnancy, the uterine lining is frequented by NK cells and T-cells, which together make up more than 80% of the immune cells in the uterine lining. These cells travel from the bone marrow to the endometrium where they proliferate under hormonal regulation. When exposed to progesterone, they produce TH-1 and TH-2 cytokines. TH-2 cytokines help the trophoblast (embryo’s “root system”) to penetrate the uterine lining, while TH-1 cytokines induce apoptosis (cell suicide), limiting placental development to the inner part of the uterus. The balance between TH1 and TH-2 cytokines is crucial for optimal placental development. NK cells and T-cells contribute to cytokine production. Excessive TH-1 cytokine production is harmful to the trophoblast and endometrial cells, leading to programmed cell death and ultimately to implantation failure. Functional NK cells reach their highest concentration in the endometrium around 6-7days after ovulation or exposure to progesterone, which coincides with the time of embryo implantation. It’s important to note that measuring the concentration of blood NK cells doesn’t reflect NK cell activation (NKa). The activation of NK cells is what matters. In certain conditions like endometriosis, the blood concentration of NK cells may be below normal, but NK cell activation is significantly increased.

There are several laboratory methods to assess NK cell activation (cytotoxicity), including immunohistochemical assessment of uterine NK cells and measuring TH-1 cytokines in the uterus or blood. However, the K-562 target cell blood test remains the gold standard. In this test, NK cells isolated from a woman’s blood are incubated with specific “target cells,” and the percentage of killed target cells is quantified. More than 12% killing indicates a level of NK cell activation that usually requires treatment. Currently, there are only a few Reproductive Immunology Reference Laboratories in the USA capable of reliably performing the K-562 target cell test.

There is a common misconception that adding IL (intralipid) or Intravenous gammaglobulin (IVIg) to NK cells can immediately downregulate NK cell activity. However, neither IL and IVIg cannot significantly suppress already activated NK cells. They are believed to work by regulating NK cell progenitors, which then produce downregulated NK cells. To assess the therapeutic effect, IL/IVIg infusion should be done about 14 days before embryos are transferred to the uterus to ensure a sufficient number of normal functional NK cells are present at the implantation site during embryo transfer. Failure to recognize this reality has led to the erroneous demand from IVF doctors for Reproductive Immunology Reference Laboratories to report on NK cell activity before and immediately after exposure to IVIg or IL at different concentrations. However, since already activated NK cells cannot be deactivated in the laboratory, assessing NKa suppression in this way has little clinical benefit. Even if blood is drawn 10-14 days after IL/IVIg treatment, it would take another 10-14 days to receive the results, which would be too late to be practically advantageous.

• Antiphospholipid Antibodies:

Many women who struggle with IVF failure or recurrent pregnancy loss, as well as those with a personal or family history of autoimmune diseases like lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis, often test positive for antiphospholipid antibodies (APAs). Over 30 years ago, I proposed a treatment for women with positive APA tests. This involved using a low dose of heparin to improve the success of IVF implantation and increase birth rates. Research indicated that heparin could prevent APAs from affecting the embryo’s “root system” ( the trophoblast), thus enhancing implantation. We later discovered that this therapy only benefits women whose APAs target specific phospholipids (phosphatidylethanolamine and phosphatidylserine). Nowadays, longer-acting low molecular weight heparinoids like Lovenox and Clexane have replaced heparin.

• Antithyroid Antibodies ( thyroid peroxidase  -TPO and antithyroglobulin antibodies (TGa)

Between 2% and 5% of women of the 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 (RPL). 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 (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance. It follows that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies. Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids subsequently often results in a significant improvement in reproductive performance in such cases.

Almost 50% of women with antithyroid antibodies do not have activated cytotoxic T lymphocytes (CTL) or natural killer cells (NK cells). This suggests that the antibodies themselves may not be the direct cause of reproductive dysfunction. Instead, the activation of CTL and NK cells, which occurs in about half of the cases with thyroid autoimmunity (TAI), is likely an accompanying phenomenon that damages the early “root system” (trophoblast) of the embryo during implantation.

Treating women who have both antithyroid antibodies and activated NK cells/CTL with intralipid (IL) and steroids improves their chances of successful reproduction. However, women with antithyroid antibodies who do not have activated NK cells/CTL do not require this treatment.

• Treatment Options for IID:

1. Intralipid (IL) Therapy: IL is a mixture of soybean lipid droplets in water, primarily used for providing nutrition. When administered intravenously, IL supplies essential fatty acids that can activate certain receptors in NK cells, reducing their cytotoxic activity and enhancing implantation. IL, combined with corticosteroids, suppresses the overproduction of pro-inflammatory cytokines by NK cells, improving reproductive outcomes. IL is cost-effective and has fewer side effects compared to other treatments like IVIg.
2. Intravenous immunoglobulin-G (IVIg) Therapy:In the past, IVIg was used to down-regulate activated NK cells. However, concerns about viral infections and the high cost led to a decline in its use. IVIg can be effective, but IL has become a more favorable and affordable alternative.
3. Corticosteroid Therapy: Corticosteroids, such as prednisone and dexamethasone, are commonly used in IVF treatment. They have an immunomodulatory effect and reduce TH-1 cytokine production by CTL. When combined with IL or IVIg, corticosteroids enhance the implantation process. Treatment typically starts 10-14 days before embryo transfer and continues until the 10th week of pregnancy.
4. Heparinoid Therapy: Low molecular weight heparin (Clexane, Lovenox)can improve IVF success rates in women with antiphospholipid antibodies (APAs) and may prevent pregnancy loss in certain thrombophilias when used during treatment. It is administered subcutaneously once daily from the start of ovarian stimulation.
5. TH-1 Cytokine Blockers (Enbrel, Humira):TH-1 cytokine blockers have limited effectiveness in the IVF setting and, in my opinion, no compelling evidence supports their use. They may have a role in treating threatened miscarriage caused by CTL/NK cell activation, but not for IVF treatment. TH-1 cytokines are needed for cellular response, during the early phase of implantation, so completely blocking them could hinder normal implantation.
6. Baby Aspirin and IVF:Baby aspirin doesn’t offer much value in treating implantation dysfunction (IID) and may even reduce the chance of success. This is because aspirin thins the blood and increases the risk of bleeding, which can complicate procedures like egg retrieval or embryo transfer during IVF, potentially compromising its success.
7. Leukocyte Immunization Therapy (LIT):LIT involves injecting the male partner’s lymphocytes into the mother to improve the recognition of the embryo as “self” and prevent rejection. LIT can up-regulate Treg cells and down-regulate NK cell activation, improving the balance of TH-1 and TH-2 cells in the uterus. However, the same benefits can be achieved through IL (Intralipid) therapy combined with corticosteroids. IL is more cost-effective, and the use of LIT is prohibited by law in the USA.

Types of Immunologic Implantation Dysfunction (IID) and NK Cell Activation:

1. Autoimmune Implantation Dysfunction: Women with a personal or family history of autoimmune conditions like Rheumatoid arthritis, Lupus Erythematosus, thyroid autoimmune disease (Hashimoto’s disease and thyrotoxicosis), and endometriosis (in about one-third of cases) may experience autoimmune IID. However, autoimmune IID can also occur without any personal or family history of autoimmune diseases. Treatment for NK cell activation in IVF cases complicated by autoimmune IID involves a combination of daily oral dexamethasone from the start of ovarian stimulation until the 10th week of pregnancy, along with 20% intralipid (IL) infusion 10 days to 2 weeks before embryo transfer. With this treatment, the chance of a viable pregnancy occurring within two completed embryo transfer  attempts is approximately 70% for women <40 years old who have  normal ovarian reserve.

2. Alloimmune Implantation Dysfunction:NK cell activation occurs when the uterus is exposed to an embryo that shares certain genotypic (HLA/DQ alpha) similarities with the embryo recipient. Humans have 23 pairs of chromosomes: one set from the sperm and one set from the egg that created us. Our sixth pair of chromosomes each contain DQ alpha genes. Again, one of these genes is from the sperm and one is from the egg that created us.

Like the genes for eye color, DQ alpha/HLA gene combinations differ between people. Thus, the male (whose  sperm created an embryo is likely to have different DQ alpha/HLA gene combinations than the potential mother . However, there are rare situations in which the male and the female partners have  DQ-alpha/HLA gene combinations are the same.

The endometrial immune system is programmed to accept embryos with different DQ alpha/HLA gene combinations than its own. This is known as “alloimmune recognition.” So, if the man shares a similar DQ alpha/HLA gene combination with the woman, and his sperm creates an embryo that tries  to implant , her endometrial immune system will see the embryo’s DQ alpha/HLA gene as “too similar” to its own and assume it is a foreign body.

Usually, this will lead to NK/T cell activation, the overproduction of TH-1 cytokines, and reproductive failure (i.e., infertility, and pregnancy loss). The severity with which this occurs is an important determinant of whether total implantation failure will occur or whether there would remain enough residual trophoblastic activity that would allow the pregnancy to limp along until the nutritional supply can no longer meet the demands of the pregnancy, at which point pregnancy loss occurs.

In cases of paternal-maternal DQ alpha/HLA matching, it will often take several pregnancies for NK cell activation to build to the point that women with alloimmune implantation dysfunction will present with clinical evidence of implantation dysfunction. Sometimes it starts off with one or two live births, whereupon NK/T cell activity starts to build, leading to one or more early miscarriages. Eventually the NK/T cell activation is so high that subsequent pregnancies can be lost before the woman is even aware that she was pregnant at all. At this point, she is often diagnosed with secondary, “unexplained” infertility and/or “unexplained” IVF failure.

Alloimmune Implantation Dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/T cell activation.

There are two types of DQ alpha/HLA genetic matching: 

• Partial DQ alpha/HLA genetic matching: Couples who share only one DQ alpha/HLA gene are considered to have a “partial match.” If NK cell activation is also present, this partial match puts the couple at a disadvantage for IVF success. However, it’s important to note that DQ alpha/HLA matching, whether partial or total, does not cause IID without associated NK cell activation. Treatment for partial DQ alpha/HLA match with NK cell activation involves IL infusion and oral prednisone as adjunct therapy. IL infusion is repeated every 2-4 weeks after pregnancy is confirmed and continued until the 24th week of gestation. In these cases, only one embryo is transferred at a time to minimize the risk of NK cell activation.
• Total (Complete) Alloimmune Genetic Matching:A total alloimmune match occurs when the husband’s DQ alpha genotype matches both that of the partner. Although rare, this total match along with NK cell activation significantly reduces the chance of a viable pregnancy resulting in a live birth at term. In some cases, the use of a gestational surrogate may be necessary.

It should be emphasized that poor embryo quality is not always the main cause of reproductive dysfunction and that the complex interaction between embryonic cells and the lining of the uterus  plays a critical role in successful implantation. Women with personal or family histories of autoimmune disease or endometriosis and those with unexplained (often repeated) IVF failure or recurrent pregnancy loss, often have immunologic implantation dysfunction (IID as the underlying cause . For such women, it is important to understand how IID leads to reproductive failure and how selective treatment options such as intralipid (IL), corticosteroid and heparinoid therapy, can dramatically  improve reproductive outcomes. Finally, there is real hope that proper identification and management of IID can  significantly improve the chance of successful reproduction and ultimately contribute to better quality of life after birth.

WE really need to talk. I invite you to contact my Office Manager, Patti Converse (702-533-2691 and set up an  online consultation with me.

• UNDERSTANDING RECURRENT PREGNANCY LOSS ( RPL): CAUSES AND SOLUTIONS.

When it comes to reproduction, humans face challenges compared to other mammals. A significant number of fertilized eggs in humans do not result in live births, with up to 75% failing to develop, and around 30% of pregnancies ending within the first 10 weeks  (first trimester). Recurrent pregnancy loss (RPL) refers to two or more consecutive failed pregnancies, which is relatively rare, affecting less than 5% of women for two losses and only 1% for three or more losses. Understanding the causes of pregnancy loss and finding solutions is crucial for those affected. This article aims to explain the different types of pregnancy loss and shed light on potential causes.

Types of Pregnancy Loss: Pregnancy loss can occur at various stages, leading to different classifications:

1. Early Pregnancy Loss: Also known as a miscarriage, this typically happens in the first trimester. Early pregnancy losses are usually sporadic, not recurring. In over 70% of cases, these losses are due to chromosomal abnormalities in the embryo, where there are more or fewer than the normal 46 chromosomes. Therefore, they are not likely to be repetitive.
2. Late Pregnancy Loss: Late pregnancy losses occur after the first trimester (12th week) and are less common (1% of pregnancies). They often result from anatomical abnormalities in the uterus or cervix. Weakness in the cervix, known as cervical incompetence, is a frequent cause. Other factors include developmental abnormalities of the uterus, uterine fibroid tumors, intrauterine growth retardation, placental abruption, premature rupture of membranes, and premature labor.

Causes of Recurrent Pregnancy Loss (RPL): Recurrent pregnancy loss refers to multiple consecutive miscarriages. While chromosomal abnormalities are a leading cause of sporadic early pregnancy losses, RPL cases are mostly attributed to non-chromosomal factors. Some possible causes include:

1. Uterine Environment Problems: Issues with the uterine environment can prevent a normal embryo from properly implanting and developing. These problems may include inadequate thickening of the uterine lining, irregularities in the uterine cavity (such as polyps, fibroid tumors, scarring, or adenomyosis), hormonal imbalances (progesterone deficiency or luteal phase defects), and deficient blood flow to the uterine lining.
2. Immunologic Implantation Dysfunction (IID): IID is a significant cause of RPL, contributing to 75% of cases where chromosomally normal embryos fail to implant. It involves the immune system’s response to pregnancy, which can interfere with successful implantation.
3. Blood Clotting Disorders: Thrombophilia, a hereditary clotting disorder, can disrupt the blood supply to the developing fetus, leading to pregnancy loss.
4. Genetic and Structural Abnormalities: Genetic abnormalities are rare causes of RPL, while structural chromosomal abnormalities occur infrequently (1%). Unbalanced translocation, where part of one chromosome detaches and fuses with another, can lead to pregnancy loss. Studies also suggest that damaged sperm DNA can negatively impact fetal development and result in miscarriage.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION AND RPL:

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 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 natural killer cells (NKa) and cytotoxic lymphocytes (CTL B) 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 Antiphospholipid antibody (APA) panel Antinuclear antibody (ANA) panel Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies) Reproductive immunophenotype Natural killer cell activity (NKa) assay (i.e., K562 target cell test) 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 intralipid (IL), intravenous immunoglobulin-G (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: When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed and in cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.  The reason for IVF being a preferred approach when immunotherapy is indicated is that in order to be effective, 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 screening/ testing (PGS/T), with tests such as next generation gene sequencing (NGS), can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGS/T requires IVF to provide access to embryos for testing. There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha gene matching ( where there is a complete genotyping match between the male and female partners) 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. Conclusion:

Understanding the causes of pregnancy loss is crucial for individuals experiencing recurrent miscarriages. While chromosomal abnormalities are a common cause of sporadic early pregnancy losses, other factors such as uterine environment problems, immunologic implantation dysfunction, blood clotting disorders, and genetic or structural abnormalities can contribute to recurrent losses. By identifying the underlying cause, healthcare professionals can provide appropriate interventions and support to improve the chances of a successful pregnancy. 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.

HONESTLY, i DO NOT RECOMMEND TRANSFECTING ANEUPLOID EMBRYOS.

SORRY!

GEOFF SHER

Between 2% and 5% of women of the 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 of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and 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 is more often present independent of coexisting clinical or hormonal features of hypothyroidism. Regardless of whether or not hormonal or clinical evidence of hypothyroidism is present or whether a woman with Hashimoto’s disease is successfully treated with thyroid hormone supplementation, women who have thyroid antibodies are often afflicted with reproductive dysfunction (infertility and early or late pregnancy loss).

We reported on the fact that 47% of women with TAI (regardless of the absence or presence of clinical hypothyroidism) have CTL and activated NKa cells and that such women often present with reproductive dysfunction. We also reported that appropriate treatment with IL and steroids, often results in viable pregnancies in such cases.

 The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo.

Geoffrey Sher MD

702-533-2691

• FROZEN EMBRYO TRANSFER : ONE PREFERRED APPROACH AT SFS.

Two decades ago, when women went through IVF (in vitro fertilization), they usually had their embryos put in the uterus right after the eggs were collected in the same cycle (known as “Fresh” Embryo Transfer). Freezing embryos at that time was risky, with about 30% not surviving the process, and those that did had lower chances of successfully implanting and growing a healthy pregnancy compared to fresh embryos. This was because the slow freezing process led to ice forming within the embryo’s cells, harming them.

But things changed with a new, faster freezing method called vitrification. With vitrification, embryos are frozen so quickly that ice crystals don’t have a chance to form. More than 90% of embryos survive this process in excellent condition, just like they were before freezing, giving them a better chance to develop into healthy pregnancies.

Modern advancements in frozen embryo transfers (FET) have shown great promise, possibly even surpassing the success rates of transferring “fresh” embryos. This improvement likely isn’t because of the freezing process itself, but rather due to two key factors:

1. a) FET often involves transferring blastocysts that have been carefully tested and selected through preimplantation genetic screening (PGS)/preimplantation genetic testing for aneuploidy ( PGT-A) , increasing the chances of a successful pregnancy compared to “fresh” transfers where such selection is not done.
2. b) The hormone replacement therapy (HRT) used for FET helps prepare the uterus optimally for implantation, improving the overall conditions for a healthy pregnancy compared to the ovarian stimulation with fertility drugs used in Fresh IVF cycles.

Considering these factors, FET offers several clear advantages:

• Safe storage of extra embryos for future transfers.
• Flexibility to delay transfers for additional testing or to avoid complications.
• Preserving embryos for selective transfer in cases of advanced maternal age or diminished ovarian reserve (DOR).
• Convenience in assisted reproductive services involving third-party parenting, like egg donation or gestational surrogacy.

These advancements provide hope and options for couples seeking successful IVF journeys and healthy outcomes for growing families.

The advent of PGS/PGT heralded a major advance in IVF as it enables us to choose the healthiest embryos for transfer to the uterus, thereby significantly boosting the chances of a successful pregnancy. The performance of PGS/PGTA virtually mandates that advanced embryos ( blastocysts) be biopsied 5-6 days after fertilization and that an additional period of 10 days be allowed for genetic testing to be performed. It follows that such blastocysts be vitrified and stored for FET to be performed in a later cycle. 

For women who are older or have a lower number of eggs (diminished ovarian reserve-DOR ), as well as those who have faced repeated pregnancy loss or IVF failure, PGS/ PGT-A can be a game-changer. It helps identify the best embryos for successful transfer. However, for younger women who tend to have normal egg reserves, and because of their youth produce a larger number of quality eggs/ embryos the benefits of PGS might not be necessary.

When it comes to creating a reserve of embryos through “Embryo Banking,” FET is mandatory and ground-breaking. Here, multiple IVF cycles are conducted over an extended period of time allowing for the collection and banking of a good number of advanced ( usually PGS/PGT-A tested)  embryos ( blastocysts) for future dispensation. Once we’ve gathered a promising group of such embryos, well-timed FETs can be undertaken, significantly improving the chances of a successful pregnancy and reducing the risk of miscarriage.

Through these advancements, we are able to offer greater  hope and possibilities to those on their journey to parenthood, making IVF an even more effective and accessible option.

Let’s break down the process to prepare the uterus for a frozen embryo transfer (FET) in simpler terms:

• Cycle Start: To begin, the recipient takes birth control pills (like Marvelon, Desogen ,Lo-Estrin etc.,)for about 10 days. The patient commences 0.75mg Dexamethasone daily OR 10mg prednisone BID at cycle start. This is continued to the 10^th week of pregnancy (tailed off from the 8^th to 10^th week) or as soon as pregnancy is ruled out
• Hormone Kickstart: After 10 days, they start another medication called Lupron/Lucrin/decapeptyl/ Superfact/ Buserelin  through a shot.
•  Monitoring Progress: The doctors keep an eye on the progress by doing ultrasounds and blood tests to make sure things are on track.
• Boosting Hormones: Delestrogen 4mg IM is injected, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact, Decapeptyl-induced menstruation. Blood is drawn on Monday and Thursday for measurement of blood [E2].  This allows for planned adjustment of the E2V dosage scheduled for the next day. The objective is to achieve a plasma E2 concentration of 500-1,000pg/ml and an endometrial lining of >8mm, as assessed by ultrasound examination done after 10 days of estrogen exposure i.e., a day after the 3^rd dosage of Delestrogen.  The twice weekly, final (adjusted) dosage of E2V is continued until the 10^th week of pregnancy or until  pregnancy is discounted by blood testing or by an ultrasound examination. Dexamethasone/Prednisone is  0.75 mg is taken (as above) and oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation.
• Antibiotic prophylaxis: Patients also receive Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.
• Luteal support: commences on day-1 , 6 days prior to the FET, with intramuscular progesterone in oil (PIO) at an initial dose of 75-100  mg (-Day 1). Daily administration- is continued until late in  the evening of Day 5 ( I suggest 10.00PM-11.00PM) . Daily PIO (75mg-100mg) is continued until the 10^th week of pregnancy, or until a blood pregnancy test/negative ultrasound (after the 6-7^th gestational week), discounts a viable pregnancy. Also, commencing on the day following the FET, the patient inserts one (1) vaginal progesterone suppository (100 mg) in the morning  + 2mg E2V vaginal suppository (in the evening) and this is continued until the 10^th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination after the 6-7^th gestational week.

• Timing the  FET: This  is performed as early as possible on the morning of Day-6
• Blood pregnancy Testing:  Blood pregnancy tests are performed 13 days and 15 days after the first PIO injection was given  

*Note: In cases where intramuscular progesterone administration is not well tolerated, we tend to use a vaginal  gel known as Crinone8%. This gel is used twice a day (morning and evening) until the day of the embryo transfer.

• Preparing for Transfer: On the morning of the embryo transfer, we pause using the gel but resume it in the evening. The day after the transfer, we continue using the gel twice a day. . If the blood pregnancy tests show a positive result and 2-3 weeks later an ultrasound examination confirms a viable pregnancy, the Crinone 8%  gel is continued twice daily up to the 10th week of pregnancy

Regime for Thawing and Transferring Cryopreserved Embryos/Blastocysts:

Patients undergoing FET with cryopreserved embryos/ blastocysts will have their embryos thawed and transferred by the following regimen.

• Monitoring Pregnancy: Regular check-ups and tests are done to confirm if the pregnancy is successful.

Please email my office Manager Patti Converse at concierge@sherIVF.com and set up an onlne consultation with me.

Geoff Sher