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\

Might I suggest that you contact my assistant, Patti C9onverse at 702-533 2691 mand set up an online consultation with me.

An elevated DHEAS points to either over-ingestion of DHEA supplements or a possible adrenal factor. This needs to be looked into before proceeding any further.

Might I suggest that you contact my assistant, Patti C9onverse at 702-281-7437 mand set up an online consultation with me.

Geoff Sher,

Please re-post in English!

Geoff Sher

To optimize response, all  available hCG receptors in the cells of the follicle should be occupied to insure an optimal response. In many cases, 5,000U hCG wont do the trick.

Since there is no down-side or risk in giving 10,000U there is n in my opinion safer to use this dosage.

If you wsh to discuss your case with me, please call my assistant, Patti Converse (702-533-2691) and set up an online consultation.

Geoff Sher

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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\

I cannot post a detailed protocol here. Your Re is free to call us to discuss this at will (702-533-2691).

• ADDRESSING DIMINISHING OVARIAN RESERVE (DOR) IN IVF

Understanding the impact of ovarian reserve on the success of in vitro fertilization (IVF) is crucial when it comes to reproductive health. This article aims to simplify and clarify these concepts, emphasizing their significance in the selection of ovarian stimulation protocols for IVF. By providing you with this information, we hope to shed light on the importance of considering these factors and making informed decisions regarding fertility treatments.

1. The Role of Eggs in Chromosomal Integrity: In the process of creating a healthy embryo, it is primarily the egg that determines the chromosomal integrity, which is crucial for the embryo’s competency. A competent egg possesses a normal karyotype, increasing the chances of developing into a healthy baby. It’s important to note that not all eggs are competent, and the incidence of irregular chromosome numbers (aneuploidy) increases with age.
2. Meiosis and Fertilization: Following the initiation of the LH surge or the hCG trigger shot, the egg undergoes a process called meiosis, halving its chromosomes to 23. During this process, a structure called the polar body is expelled from the egg, while the remaining chromosomes are retained. The mature sperm, also undergoing meiosis, contributes 23 chromosomes. Fertilization occurs when these chromosomes combine, resulting in a euploid embryo with 46 chromosomes. Only euploid embryos are competent and capable of developing into healthy babies.
3. The Significance of Embryo Ploidy: Embryo ploidy, referring to the numerical chromosomal integrity, is a critical factor in determining embryo competency. Aneuploid embryos, which have an irregular number of chromosomes, are often incompetent and unable to propagate healthy pregnancies. Failed nidation, miscarriages, and chromosomal birth defects can be linked to embryo ploidy issues. Both egg and sperm aneuploidy can contribute, but egg aneuploidy is usually the primary cause.
4. Embryo Development and Competency: Embryos that develop too slowly or too quickly, have abnormal cell counts, contain debris or fragments, or fail to reach the blastocyst stage are often aneuploid and incompetent. Monitoring these developmental aspects can provide valuable insights into embryo competency.
5. Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger

Why IVF should be regarded as treatment of choice for women who have diminished ovarian reserve ( DOR):

Understanding the following factors will go a long way in helping you to make an informed decision and thereby improve the chances of a successful IVF outcome.

1. Ovarian Reserve: While chronological age plays a vital role in determining the quality of eggs and embryos [there is an increased risk of egg aneuploidy (irregular chromosome number) in eggs,  leading to reduced embryo competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
2. Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in both older women or those who (regardless of their age) have DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
3. It is possible to regulate the  decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:

1. Conventional Long Pituitary Down Regulation Protocol:

• Begin birth control pills (BCP) early in the cycle for at least 10 days.
• Three days before stopping BCP, overlap with an agonist like Lupron for three days.
• Continue daily Lupron until menstruation begins.
• Conduct ultrasound and blood estradiol measurements to assess ovarian status.
• Administer FSH-dominant gonadotropin along with Menopur for stimulation.
• Monitor follicle development through ultrasound and blood estradiol measurements.
• Trigger egg maturation using hCG injection, followed by egg retrieval.

1. Agonist/Antagonist Conversion Protocol (A/ACP):

• Similar to the conventional long down regulation protocol but replace the agonist with a GnRH antagonist from the onset of post-BCP menstruation until the trigger day.
• Consider adding supplementary human growth hormone (HGH) for women with DOR.
• Consider using “priming” with estrogen prior to gonadotropin administration

1. Protocols to Avoid in Women with DOR: Certain ovarian stimulation protocols may not be suitable for women with declining ovarian reserve:

• Microdose agonist “flare” protocols
• High dosages of LH-containing fertility drugs such as Menopur
• Testosterone-based supplementation
• DHEA supplementation
• Clomiphene citrate or Letrozole
• Low-dosage hCG triggering or agonist triggering for women with DOR

Preimplantation Genetic Screening/Testing for aneuploidy (PGS/PGTA): PGS/PGTA is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/PGTA significantly improves the success of IVF, in women with DOR.

Understanding the impact of declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Diminished ovarian reserve (DOR) can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. By considering this factor, you can make informed choices and work closely with fertility specialists to optimize your chances of success. Remember, knowledge is power, and being aware of these aspects empowers you to take control of your reproductive journey.

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PLEASE SHARE THIS WITH OTHERS AND HELP SPREAD THE WORD!!

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\

I think I can help here!

Please see my repose to your 2nd post…Same recommendation applies…We should talk.

Geoff Sher