I am 30, my husband is 29. I was diagnosed with PCOS at 15. I had a miscarriage at age 20 at 8 weeks. Last year, I had three miscarriages (one at 6 weeks, 5 weeks and then at 4 weeks). During my work up last year, we did genetic testing. My results were positive for mosaic Turner’s syndrome. This was only positive in less than 50% of my sample. Based on that, we chose to go the route of IVF. I did a retrieval this past July and did PGTA testing. I had 16 eggs retrieved, 12 mature, 9 fertilized, 4 embryos, 3 were genetically normal- 1 was abnormal (mosaic).
In the mean time, we had a spontaneous pregnancy in August. Since then, we have lost the baby (at eight weeks). Based on my PGTA testing, the numbers aren’t awful, and 75% of my embryos were “normal”, one had a genetic abnormality- NOT the chromosome that is linked with Turner’s.
We have tested this tissue from my miscarriage and it showed three different types of chromosomal abnormlities (none of which were Turners related).
I have been on medications (metformin, inositol, CoQ10, prenatals) to improve egg quality for over a year now. When I got pregnant in August of this year, my TSH was high, so I have since been started on Synthroid and taken off of it for normal TSH levels. I take all of my medications religiously. I just don’t understand why this is happening. My husbands tests have all been prestine. I have had a coagulation work up through a naturopath that I saw last year in the midst of my miscarriages, which was normal.
My husband and I have since done ERA/ EMMA/ ALICE which came back normal. I also did the UTIMPRO which is came back unremarkable. I did the Receptiva test which showed the BCL6 as positive, but the CD138 was negative. My fertility team has since let me know that they suspect it is endometriosis.
I am naieve, I know nothing about endometriosis. I am incredibly new to this world. My fertility clinic has decided to move forward with 2 rounds of Lupron (so two months) with Letrozole with the plans to implant at the end of Feb.
Does this sound right? Does this sound like a solid course of action moving forward? Should I be asking for more investigation towards this “suspected” endo. Should I be talking to someone about having the lap surgery to confirm this diagnosis? I am just so lost.
My problem is, I would hate to implant my embryos and have it end up in this same situation, and waste our three healthy embryos. I am just hoping for some guidance.
Answer:
Respectfully, I do not concur with the suggested approach. You have recurrent pregnancy loss. I suggest you read the articles I wrote , below and then seriously consider calling my assistant, Patti Converse at 702-533-to set up an online consultation with me to discuss your case in detail.
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A. 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:
- 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.
- 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:
- 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.
- 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.
- Blood Clotting Disorders: Thrombophilia, a hereditary clotting disorder, can disrupt the blood supply to the developing fetus, leading to pregnancy loss.
- 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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B. WHY IVF SHOULD BE REGARDED AS A TREATMENT OF CHOICE FOR INFERTILE WOMEN WITH ENDOMETRIOSIS.
When women with endometriosis-related infertility seek treatment, they are often advised to try ovarian stimulation with or without intrauterine insemination (IUI) as a first option. However, it’s important to clarify the reality and set the record straight. In vitro fertilization (IVF) offers distinct advantages and a higher chance of success compared to IUI. Let’s explore why IVF should often be considered as the primary approach for women with endometriosis.
- The Toxic Pelvic Factor:
Endometriosis causes the lining of the uterus to grow outside the uterus. As these deposits bleed over time, they release toxins into the pelvic secretions. These toxins coat the peritoneum, the membrane that covers the abdominal and pelvic organs. When eggs are released from the ovaries, they must pass through these toxic secretions to reach the sperm in the fallopian tubes. The toxins alter the egg’s envelopment, making it less receptive to fertilization. This explains why women with endometriosis are far less likely to conceive naturally, following ovulation induction or after surgical attempts to eliminate the condition. Consider the following: .
- Ovulation induction with or without intrauterine insemination (IUI) is commonly recommended for women with mild to moderately severe endometriosis. However, while fertility drugs can stimulate the growth of multiple follicles, ovulatory women (including those with mild to moderately severe endometriosis) usually ovulate only one egg a time. Therefore, the use of fertility drugs in such cases doesn’t significantly improve pregnancy potential.
- Surgery to remove endometriotic deposits or adhesions: Surgical removal of visible endometriotic lesions in mild to moderate endometriosis does not usually improve pregnancy potential significantly. This is because endometriosis is an ongoing process, with new lesions constantly developing. Even after the visible lesions are removed, invisible lesions continue to release toxins that can compromise natural fertilization. In contrast, IVF bypasses the toxic pelvic environment by retrieving eggs from the ovaries, fertilizing them outside the body, and transferring resulting embryos to the uterus. This makes IVF the preferred treatment for endometriosis-related infertility.
- The Immunologic Factor:
Approximately one third of women with endometriosis also have an immunologic implantation dysfunction (IID) related to the activation of uterine natural killer cells (NKa). This requires selective immunotherapy with Intralipid infusions or heparinoids, which can be effectively implemented in combination with IVF.
- Ovarian endometriomas :
Women, who have advanced endometriosis, often have endometriotic ovarian cysts, known as endometriomas. These cysts contain decomposed menstrual blood that looks like melted chocolate. Hence the name “chocolate cysts”. These space-occupying lesions inside the ovaries can activate ovarian connective tissue (stroma or theca) resulting in an overproduction of male hormones (especially testosterone). An excess of ovarian testosterone can severely compromise follicle and egg development in the affected ovary. Endometriomas of >1 cm in size should in my opinion be addressed because in my opinion, they can and do adversely affect the quality of eggs produced in the affected ovary. We confirmed this effect in a study where we evaluated egg quality in a number of women who had one or more endometriomas involving one ovary while the contralateral ovary was unaffected. We were able to show that those eggs aspirated from follicles in the endometrioma-affected ovary were of markedly reduced quality (and, the embryos and blastocysts they propagated were fewer in number and of markedly reduced quality as compared to those harvested from the un affected ovary.
- Conventional surgical treatment performed to remove endometriomas involvers laparoscopy or laparotomy with aspiration of the cyst content followed by complete removal and/or ablation/obliteration of the cyst wall. This should be done at least 6 weeks in advance of egg retrieval, in my opinion. Such treatment is associated with pain and a risk of surgical complications.
- An alternative approach which I and my colleagues first reported on more than 2 decades ago, known as Ovarian Sclerotherapy is a highly effective, inexpensive and safe outpatient method for treating endometriomas in women planning to undergo IVF. The process involves needle aspiration of the “chocolate colored” liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline hydrochloride into the cyst cavity. Such treatment will, more than 75% of the time result in disappearance of the lesion within 6-8 weeks. Ovarian sclerotherapy can be performed under local anesthesia or under conscious sedation. It is a safe and effective alternative to surgery for definitive treatment of recurrent ovarian endometriomas in a select group of patients planning to undergo IVF. It is in my opinion, unfortunate that Ovarian Sclerotherapy is not readily available in this country.
I am not suggesting that all women with infertility-related endometriosis should automatically resort to IVF. Quite to the contrary…. In spite of having reduced fertility potential, many women with mild to moderate endometriosis can and do go on to conceive on their own (without treatment). It is just that the chance of this happening is so is much lower than normal.
IVF is by far the most successful approach to dealing with endometriosis-related infertility , especially when it comes to women above the age of 35 years, those who have moderate or severe disease and for women who have DOR. Understanding how endometriosis affects IVF outcomes can help make informed decisions about treatment. By providing a more favorable environment for fertilization and implantation. IVF offers much higher success rates when compared to ovulation induction with or without IUI or surgical correction. Simply put……If you’re facing infertility due to endometriosis, it’s worth considering IVF as the first line of treatment to increase your chances of having a baby
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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:
- From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf
- 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\
