Yes you do!

I suggest you call Rozanne Sher at “Footsteps to Family” for more information. Her # is 702-860-0097.

Geoff Sher

If you’ve undergone in vitro fertilization (IVF) and didn’t achieve a successful pregnancy, you may be wondering why. It’s important to know that IVF outcomes can be unpredictable, but there are factors that can affect your chances. Let’s explore some common reasons for IVF failure in simpler terms.

1. Age: A woman’s age is a significant factor in IVF success. Generally, women under 35 have a higher chance of getting pregnant through IVF, around 35-40% per embryo transfer. However, this success rate decreases as women get older. For women in their mid-forties, the success rate drops to under 5%. This decline is mainly because the quality of eggs decreases as women age, affecting their ability to develop normally.

1. Egg/Embryo Competency: Apart from age, the quality and competency of embryos also affect IVF success. The quality of eggs and embryos is influenced by a woman’s age. However, for older women or those with fewer eggs, the specific IVF protocol used to stimulate the ovaries becomes crucial. A more aggressive approach may be needed to maximize the chances of success. Previously, it was thought that the uterus was better for embryo development than the lab environment. So, early-stage embryos were transferred to the uterus based on their appearance. However, we now know that embryos that have progressed further in development are more likely to be successful. Embryos that don’t reach the blastocyst stage within 5-6 days after fertilization are considered less competent and not suitable for transfer. Additionally, Preimplantation Genetic Sampling / Testing (PGS/T) allows us to check the chromosomes of embryos. This technique helps select the most competent embryos for transfer, especially for older women, those with fewer eggs, repeated IVF failures, and recurrent pregnancy loss.

1. Number of Embryos Transferred: Some people believe that transferring more embryos increases the chances of success. While this may have some truth, it’s essential to know that if the problem lies with the ovarian stimulation protocol, transferring more embryos won’t solve it. Also, transferring more embryos doesn’t fix issues related to embryo implantation dysfunction, such as anatomical or immunologic problems. Moreover, multiple embryos can lead to higher-order multiple pregnancies, which pose risks. To minimize these risks, it’s generally recommended to transfer a maximum of two embryos, or even just one, especially when using eggs from young women.

1. Implantation Dysfunction (ID): Implantation dysfunction is often overlooked as a cause of unexplained IVF failure, especially in young women with normal ovarian reserve and fertile partners. Failure to identify and address these issues can result in repeated IVF failures. If transferring competent embryos repeatedly fails to result in a viable pregnancy, implantation dysfunction should be considered. The most common causes include:

1. 1. Thin Uterine Lining: When the lining of the uterus is too thin, it can affect the embryo’s ability to implant and grow.
   2. Surface Lesions in the Uterus: Polyps, fibroids, or scar tissue in the uterus can interfere with embryo implantation.
   3. Immunologic Implantation Dysfunction (IID): Sometimes, the immune system can mistakenly attack the embryo, preventing successful implantation.
   4. Endocrine/Molecular Endometrial Receptivity Issues: Hormonal or molecular issues in the uterine lining can impact the embryo’s ability to attach and develop.
   5. Ureaplasma Urealyticum (UU) Infection: This infection in the cervical mucous and uterine lining can lead to unexplained early pregnancy loss or IVF failure. Both partners should be tested and treated if positive to prevent transmission.

Certain causes of infertility are difficult or impossible  to reverse, e.g.; advanced age of the woman, severe male infertility, and immunologic implantation dysfunction associated with certain specific genetic factors.

Understanding the common factors contributing to IVF failure can help you have informed discussions with your doctor and make decisions for future attempts. Factors like the number of embryos transferred and implantation dysfunction play significant roles. While success cannot be guaranteed, knowing these factors can guide you in maximizing your chances and addressing potential issues.

I think we should talk. Might I invite you to call my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me.

• EGG/ EMBRYO QUALITY IN IVF & HOW SELECTION OF THE IDEAL PROTOCOL FOR OVARIAN STIMULATION INFLUENCES  EGG/EMBRYO QUALITY AND  OUTCOME.

The journey of in vitro fertilization can be a rollercoaster of emotions for many patients. Often times they have to face the harsh reality that the number and quality of eggs retrieved has fallen short of their expectations. Then, should fertilization of these eggs not propagate  chromosomally normal (euploid), “competent” embryos suitable for transfer to the uterus, many such patients find themselves in a state of emotional distress. They grapple with the inevitable questions of why this happened and how to prevent it from occurring again in the future. This article aims to delve into these queries, providing insights, rational explanations, and therapeutic options. It is an invitation to explore the light at the end of the tunnel. Readers are urged to carefully absorb the entirety of the article in the hope of finding valuable information and renewed hope.

• The Importance of Chromosomal Integrity: While sperm quality is an important factor, egg quality is by far the most important when it comes to the generation of embryos that are capable of propagating healthy babies (“competent”). In this regard, chromosomal integrity of the egg and embryo, although it is not the only factor , is certainly the main determinant of such competency.
• The woman’s age: About two thirds of a woman’s eggs in her twenties or early thirties have the correct number of chromosomes, which is necessary for a healthy pregnancy. As a woman gets older, the percentage of eggs with the right number of chromosomes decreases. By age 40, only about one in every 5-6 eggs is likely to be normal, and by the mid-forties, less than one in ten eggs will be normal.
• Ovarian Reserve (number of available in the ovaries): A woman is born with all the eggs she will ever have. She starts using these eggs when she begins ovulating during puberty. At first, the eggs are used up quickly, but as she gets older, the number of eggs starts to run out. Her brain and pituitary gland try to stimulate the production of more eggs by increasing the output of Follicle Stimulating Hormone (FSH), but unfortunately, this often doesn’t work. When the number of remaining eggs in her ovaries falls below a certain level (which can be different for each woman), her FSH level rises, and production of the ovarian hormone, AMH decreases. This is the start of diminishing ovarian reserve (DOR). Most women experience the onset of DOR in their late 30s or early 40s, but it can happen earlier for some. The lower the ovarian reserve, the lower the AMH level will be, and the fewer eggs will be available for harvesting during IVF-egg retrieval. In such cases, a higher dosage of fertility drugs might be needed to promote better egg production in future attempts. . On the other hand, higher AMH levels mean more eggs are available, and lower doses of fertility drugs are usually needed. DOR is commonly associated with increased bioactivity of pituitary gland-produced LH. This LH activates production of ovarian male hormones (androgens)…predominantly testosterone by ovarian connective tissue (stroma) . While a small amount of  ovarian testosterone is absolutely necessary for optimal follicle and egg development, excessive ovarian testosterone will often access the follicle , and compromise both egg quality and follicle growth and development. In some cases, rapidly increasing  LH-release (“premature LH-surge”) with excessive induced ovarian testosterone can lead to “premature luteinization”  of the follicles with cessation in growth and even to“ premature ovulation”.
• Importance of Individualized Controlled Ovarian Stimulation (COS) Protocol: It’s not surprising that DOR is more common in older women, but regardless of age, having DOR makes a woman’s eggs more likely to be compromised during controlled ovarian stimulation (COS). The choice of the COS protocol is crucial to preventing unintentional harm to egg and embryo quality. The wrong protocol can disrupt normal egg development and increase the risk of abnormal embryos. That’s why it’s important to tailor the COS protocol to each individual’s needs. This helps optimize follicle growth and the quality of eggs and embryos. The timing of certain treatments is also important for successful outcomes.
• Embryo Competency and Blastocyst Development: Embryos that don’t develop into blastocysts by day 6 after fertilization are usually chromosomally abnormal or aneuploid (”incompetent”) and not suitable for transfer. However, not all blastocysts are guaranteed to be normal and capable of developing into a healthy baby. As a woman gets older, the chances of a her embryos being chromosomally normal blastocyst decreases. For example, a blastocyst from a 30-year-old woman is more likely to be normal compared to one from a 40-year-old woman.

The IVF stimulation protocol has a big impact on the quality of eggs and embryos especially in women with DOR. Unfortunately, many IVF doctors use the same COS “recipe approach” for everyone without considering individual differences. Using personalized protocols can greatly improve the success of IVF. While we can’t change genetics or reverse a woman’s age, a skilled IVF specialist can customize the COS protocol to meet each patient’s specific needs.

GONADOTROPIN RELEASING HORMONE AGONISTS (GNRHA) AND GNRH-ANTAGONISTS:

• Gonadotropin releasing hormone agonists (GnRHa). Examples are  Lupron, Buserelin, Superfact, and Decapeptyl . These are commonly used to launch  ovarian stimulation cycles. They work by initially causing a release of pituitary gonadotropins, followed by a decrease in LH and FSH levels within 4-7 days. This creates a relatively low LH environment when COS begins, which is generally beneficial for egg development. However, if GnRHa are administered starting concomitant with gonadotropin stimulation (see GnRHa –“flare protocol” -below) it can cause an immediate surge in LH release, potentially leading to high levels of ovarian testosterone that can harm egg quality, especially in older women and those with diminished ovarian reserve (DOR).
• Gonadotropin releasing hormone antagonists (GnRH-antagonists) : Examples are Ganirelix, Cetrotide, and Orgalutron. GnRH antagonists (take days   work quickly (within hours) to block pituitary LH release. Their purpose is to prevent excessive LH release during COS. In contrast, the LH-lowering effect of GnRH agonists takes several days to develop. Traditionally, GnRH antagonists are given starting on the 5th-7th day of gonadotropin stimulation. However, in older women and those with DOR, suppressing LH might happen too late to prevent excessive ovarian androgen production that can negatively impact egg development in the early stages of stimulation. That’s why I prefer to administer GnRH-antagonists right from the beginning of gonadotropin administration.

USING BIRTH CONTROL PILLS TO START OVARIAN STIMULATION:

Patients are often told that using birth control pills (BCP) to begin ovarian stimulation will suppress the response of the ovaries. This is true, but only if the BCP is not used correctly. Here’s the explanation:

In natural menstrual cycles and cycles stimulated with fertility drugs, the follicles in the ovaries need to develop receptors that respond to follicle-stimulating hormone (FSH) in order to properly respond to FSH stimulation. Pre-antral follicles (PAFs) do not have these receptors and cannot respond to FSH stimulation. The development of FSH responsivity requires exposure of the pre-antral follicles to FSH for several days, during which they become antral follicles (AFs) and gain the ability to respond to FSH-gonadotropin stimulation. In regular menstrual cycles, the rising FSH levels naturally convert PAFs to AFs. However, the combined BCP suppresses FSH. To counter this suppression, we need to promote increased  FSH production several days before starting COS. This allows the orderly conversion from PAFs to AFs, ensuring proper follicle and egg development.

GnRHa causes an immediate surge in FSH release by the pituitary gland, promoting the conversion from PAF to AF. Therefore, when women take the BCP control pill to launch a cycle of COS, they need to overlap the BCP with a GnRHa for a few days before menstruation. This allows the early recruited PAFs to complete their development and reach the AF stage, so they can respond appropriately to ovarian stimulation. By adjusting the length of time, the woman is on the birth control pill, we can regulate and control the timing of the IVF treatment cycle. Without this step, initiating ovarian stimulation in women coming off birth control pills would be suboptimal.

PROTOCOLS FOR CONTROLLED OVARIAN STIMULATION (COS):

• GnRH Agonist Ovarian Stimulation Protocols:

• • The long GnRHa protocol: Here, a GnRHa (usually Lupron or Superfact) is given either in a natural cycle, starting 5-7 days before menstruation, overlapping with the BCP for three days. Thereupon,  the pill is stopped, while daily  GnRHa injections continue until menstruation occurs (usually 5-7 days later). The GnRHa causes a rapid rise in FSH and LH levels. This is followed about 3-4 days later , by a progressive decline in FSH and LH to near zero levels,  with a concomitant drop in ovarian estradiol and progesterone. This, in turn triggers uterine withdrawal bleeding (menstruation) within 5-7 days of starting the GnRHa administration. Gonadotropin treatment is then initiated while daily GnRHa injections continue to maintain a relatively low LH environment. Gonadotropin administration continues until the hCG “trigger” (see below).
  • Short GnRH-Agonist (“Flare”) Protocol: This protocol involves starting hormone therapy and using GnRH agonist at the same time. The goal is to boost FSH so that with concomitant stimulation with FSH-gonadotropins  + the GnRHa-induced surge in pituitary gland FSH release, will augment follicle development. However, this surge also leads to a rise in LH levels, which can cause an excessive production of ovarian male hormones (e.g., testosterone). This could potentially adversely affect the quality of eggs, especially in women over 39 years old, those with low ovarian reserve, and women with PCOS or DOR who already have increased LH sensitivity. In this way, these “flare protocols” can potentially decrease the success rates of IVF. While they are generally safe for younger women with normal ovarian reserve, I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.

• GnRH Antagonist-Ovarian Stimulation Protocols:

• • Conventional GnRH Antagonist Protocol: In this approach, daily GnRH antagonist injections are  given from the 5th to the 8th day of COS with gonadotropins to the day of the “trigger” (see below). Accordingly, although rapidly acting to lower LH , this effect of GnRH- antagonist only starts suppressing LH from well into the COS cycle which means the ovarian follicles are left exposed and unshielded from pituitary gland -produced, (endogenous) LH during the first several days of stimulation. This can be harmful, especially in the early stage of COS when eggs and follicles are most vulnerable to the effects of over-produced LH-induced excessive ovarian testosterone. Therefore, I believe the Conventional GnRH Antagonist Protocol is not ideal for older women, those with low ovarian reserve, and women with PCOS who already have elevated LH activity. However, this protocol is acceptable for younger women with normal ovarian reserve, although I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.

It’s important to note that the main reason for using GnRH antagonists is to prevent a premature LH surge, which is associated with poor egg and embryo quality due to follicular exhaustion. However, calling it a “premature LH surge” is misleading because it actually represents the culmination of a progressive increase in LH-induced ovarian testosterone. A better term would be “premature luteinization”. In some such cases, the rise in LH can precipitate “premature ovulation”.

• Agonist/Antagonist Conversion Protocol (A/ACP): I recommend this protocol for many of my patients, especially for older women and those with DOR or PCOS. The woman starts by taking a BCP for 7-10 days. This overlapped with a GnRHa for 3 days and continued until menstruation ensues about 5-7 days later. At this point  she “converts” from the GnRH-agonist to a GnRH-antagonist (Ganirelix, Orgalutron, or Cetrotide). A few days after this conversion from agonist to antagonist, COS with  gonadotropin stimulation starts. Both the antagonist and the gonadotropins are continued together until the hCG trigger. The purpose is to suppress endogenous LH release throughout the COS process and so  avoid over-exposure of follicles and eggs to LH-induced  excessive ovarian testosterone which as previously stated, can compromise egg and follicle growth and development.   Excessive ovarian testosterone can also adversely affect estrogen-induced growth of the uterine lining (endometrium). Unlike GnRH-agonists, antagonists do not suppress ovarian response to the gonadotropin stimulation. This is why the A/ACP is well-suited for older women and those with diminished ovarian reserve.
• A/ACP with estrogen priming: This is a modified version of the A/ACP protocol used for women with very low ovarian reserve (AMH=<0.2ng/ml). Estrogen priming is believed to enhance the response of follicles to gonadotropins. Patients start their treatment cycle by taking a combined birth control pill (BCP) for 7-10 days. After that, they overlap daily administration of a GnRH agonist with the BCP for 3 days. The BCP is then stopped, and the daily agonist continues until menstruation ensues (usually 5-7 days later). At this point, the GnRH agonist is supplanted by daily injections of  GnRH antagonist and  Estradiol (E2) “priming” begins using E2 skin patches or intramuscular estradiol valerate injections twice weekly, while continuing the GnRH antagonist. Seven days after starting the estrogen priming COS begins using recombinant FSHr such as Follistim, Gonal-F or Puregon) +menotropin (e.g., Menopur) . The estrogen “priming” continues to the day of the “trigger” (see below).  Egg retrieval is performed 36 hours after the trigger.

Younger women (under 30 years) and women with absent, irregular, or dysfunctional ovulation, as well as those with polycystic ovarian syndrome (PCOS), are at risk of developing a severe condition called Ovarian Hyperstimulation Syndrome (OHSS), which can be life-threatening. To predict this condition, accurate daily blood E2 level monitoring is required.

TRIGGERING “EGG MATURATION PRIOR TO EGG RETRIEVAL”

• The hCG “trigger”: When it comes to helping eggs mature before retrieval, one of the important decisions the doctor needs to make is choosing the “trigger shot” to facilitate the process. Traditionally, hCG (human chorionic gonadotropin) is derived from the urine of pregnant women (hCGu) while a newer recombinant hCG (hCGr), Ovidrel was recently  introduced. The ideal dosage of hCGu is 10,000U and for Ovidrel, the recommended dosage is 500mcg. Both have the same efficacy. The “trigger” is usually administered by intramuscular injection, 34-36 hours prior to egg retrieval.

Some doctors may choose to lower the dosage of hCG if there is a risk of severe ovarian hyperstimulation syndrome (OHSS). However, I believe that a low dose of hCG (e.g., 5000 units of hCGu or 250 mcg of hCGr ( Ovidrel) might not be enough to optimize egg maturation, especially when there are many follicles. Instead, I suggest using a method called “prolonged coasting” to reduce the risk of OHSS.

• Using GnRH antagonist alone or combined with hCG as the trigger: Some doctors may prefer to use a GnRH- agonist  trigger instead of hCG to reduce the risk of OHSS. The GnRHa “trigger” acts by inducing a “surge of pituitary gland-LH. However, it is difficult to predict the amount of LH that is released in response to a standard agonist trigger. In my opinion, using hCG is a better choice, even in cases of ovarian hyperstimulation, with the condition that “prolonged coasting” is implemented beforehand.
• Combined use of hCG + GnRH agonist: This approach is better than using a GnRH agonist alone but still not as effective as using the appropriate dosage of hCG.
• Timing of the trigger: The trigger shot should be given when the majority of ovarian follicles have reached a size of more than 15 mm, with several follicles measuring 18-22 mm. Follicles larger than 22 mm often contain overdeveloped eggs, while follicles smaller than 15 mm usually have underdeveloped and potentially abnormal eggs.

SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS) & “PROLONGED COASTING”

OHSS is a life-threatening condition that can occur during controlled ovarian stimulation (COS) when the blood E2 (estradiol) level rises too high. It is more common in young women with high ovarian reserve, women with polycystic ovarian syndrome (PCOS), and young women who do not ovulate spontaneously. To prevent OHSS, some doctors may trigger egg maturation earlier, use a lower dosage of hCG, or “trigger” using a GnRHa. However, these approaches can compromise egg and embryo quality and reduce the chances of success.

To protect against the risk of OHSS while optimizing egg quality, Physicians can use one of two options. The first is “prolonged coasting,” a procedure I introduced more than three decades ago. It involves stopping gonadotropin therapy while continuing to administer the GnRHa until the risk of OHSS has decreased. The precise timing of “prolonged coasting” is critical. It should be initiated when follicles have reached a specific size accompanied and the  blood estradiol has reached a certain peak.  The second option is to avoid fresh embryo transfer and freeze all “competent” embryos for later frozen embryo transfers (FETs) at a time when the risk of OHSS has subsided. By implementing these strategies, both egg/embryo quality and maternal well-being can be maximized.

In the journey of fertility, a woman is blessed with a limited number of eggs, like precious treasures awaiting their time. As she blossoms into womanhood, these eggs are gradually used, and the reserves start to fade. Yet, the power of hope and science intertwines, as we strive to support the development of these eggs through personalized treatment. We recognize that each woman is unique, and tailoring the protocol to her individual needs can unlock the path to success. We embrace the delicate timing, understanding that not all embryos are destined for greatness. With age, the odds may shift, but our dedication remains steadfast, along with our ultimate objective, which is  to do everything possible to propagate  of a normal pregnancy while optimizing the  quality of that life after birth and all times, minimizing risk to the prospective parents.

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• Premature Luteinization: A Hurdle in Ovarian Stimulation

Premature luteinization, is a condition where a progressive increase in LH (luteinizing hormone) disrupts the development and maturation of follicles and eggs before the planned hCG trigger is initiated. This phenomenon is not an isolated occurrence; it results from a series of ovarian events, often affecting susceptible women, particularly older women and those with diminished ovarian reserve (DOR). It is more likely to happen when the ovarian stimulation protocol fails to keep LH levels low throughout the stimulation process.

Once premature luteinization sets in during a stimulation cycle, it cannot be reversed by altering the ongoing stimulation or by administering GnRH antagonists like Ganirelix, Cetrotide, or Orgalutron midway through the cycle in the hope of rescuing the developing eggs. Unfortunately, once it starts, the cycle is likely to fail. This condition raises the risk of premature ovulation, unsuccessful egg retrieval (referred to as “empty follicle syndrome”), and the occurrence of chromosomal abnormalities in eggs and embryos.

This issue is most commonly observed in older women and those with severe DOR. However, its impact can be mitigated through personalized and strategic protocols for controlled ovarian stimulation (COS), along with optimizing the type, timing, and dosage of the “hCG trigger shot.”

Typically, the “trigger shot” is administered after optimal ovarian stimulation to initiate meiosis (reproductive division) within  36- 40 hours, reducing the chromosome count from 46 to 23. Additionally, it enables the egg to detach from the follicle wall for easy retrieval.

Older women and those with DOR tend to have higher levels of biologically active LH, which promotes the production of excessive male hormones ( predominantly, testosterone) by ovarian connective tissue. A controlled amount of testosterone is necessary for healthy follicle development and egg development ( oogenesis)  induced by FSH (follicle-stimulating hormone). Excessive LH activity can result in overproduction of ovarian testosterone, compromising oogenesis and leading to a higher likelihood of chromosomal abnormalities in eggs following meiosis.

Women with increased LH activity due to age or DOR are particularly vulnerable to the effects of prolonged exposure to LH-induced ovarian testosterone. Medications or protocols that further stimulate pituitary LH release, contain LH or hCG, or promote increased exposure to the woman’s own pituitary LH can be detrimental.

To address this issue effectively, it is crucial to tailor COS protocols, choose the appropriate hCG trigger dosage and type, and administer it at the right time. For urinary-derived hCG (such as Novarel, Pregnyl, and Profasi), 10,000U is the ideal dosage. When using recombinant DNA-derived hCG (like Ovidrel), 500mcg is recommended. Using lower dosages can increase the risk of egg chromosomal abnormalities and affect the overall outcome of IVF treatments.

Please re-post in English!

Geoff Sher

Please re-post in English!

Geoff Sher

I suggest you  call my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me to discuss.

Geoff Sher

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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.

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Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; https://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\