At this stage of pregnancy, the levels do not rise as fast as earlier on. I think this is perfectly acceptable…/However an US done in 1-2 weeks should be definitive!

Good luck!

Geoff Sher

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TIMING AND INTERPRETATION OF hCG BLOOD PREGNANCY TESTS

Geoffrey Sher MD

Going through IVF is a major investment, emotionally, physically, and financially, for every patient or couple. One of the most crucial moments is receiving the result of the blood test for human chorionic gonadotropin (hCG) pregnancy. It’s a big deal! The days after the embryo transfer, waiting for this result, can be extremely stressful. That’s why it’s crucial for the IVF doctor and staff to handle this information with care and professionalism. They should be accessible to the patient/couple and provide results promptly and sensitively.

Testing urine or blood to check for human chorionic gonadotropin (hCG) is the best way to confirm pregnancy. Urine tests are cheaper and more commonly used. They are also more convenient because they can be done anywhere. However, blood tests are more reliable and sensitive than urine tests. They can detect pregnancy earlier and at lower hCG levels. Blood tests are also more accurate and can track changes in hCG levels over time. Urine tests can detect hCG when blood levels are above 20IU, which is about 16-18 days after ovulation or 2-3 days after a missed period. Blood tests can measure any concentration of hCG about 12-13 days after ovulation.

Detecting hCG in the blood early on and tracking its increase is especially useful for women undergoing fertility treatments like controlled ovarian stimulation or in vitro fertilization. The sooner hCG is detected and measured, the more information can be gathered about the success of implantation and the health of the developing embryo.

Typically, two beta hCG blood tests are done, spaced 2-4 days apart. It’s best to wait for the results of the second test before reporting on the pregnancy. This is because an initial result can change, even from equivocal or negative to positive. Sometimes a normal embryo takes longer to implant, and the hCG level can be initially low or undetectable. Regardless of the initial level, the test should be repeated after two days to check for a significant rise in hCG. A significant rise usually indicates that an embryo is implanting, which suggests a possible pregnancy. Waiting for the second test result helps avoid conveying false hope or disappointment.

It’s important to note that beta hCG levels don’t double every two days throughout pregnancy. Once the levels rise above 4,000U, they tend to increase more slowly. Except in specific cases like IVF using an egg donor or transfer of genetically tested embryos, the birth rate following IVF in younger women is around 40% per embryo transfer. Patients need to have realistic expectations and should be informed about how and when they will receive the news, as well as counseling in case of a negative outcome.

When an embryo starts to implant, it releases the pregnancy hormone hCG into the woman’s bloodstream. Around 12 days after egg retrieval, 9 days after a day 3 embryo transfer, or 7 days after a blastocyst transfer, a woman should have a quantitative beta hCG blood pregnancy test performed. By that time, most of the hCG injected to prepare the eggs for retrieval should have cleared from the bloodstream. So, if the test detects more than 10 IU of hCG per ml of blood, it indicates that the embryo has attempted to implant. In third-party IVF (e.g., ovum donation, gestational surrogacy, embryo adoption, or frozen embryo transfers), no hCG trigger is administered, so any amount of hCG detected in the blood is considered significant.

Sometimes, there is a slow initial rise in hCG between the first and second tests (failure to double every 48 hours). In such cases, a third and sometimes a fourth hCG test should be done at two-day intervals. A failure to double on the third and/or fourth test is a poor sign and could indicate a failed or dysfunctional implantation. In some cases, a progressively slow rising hCG level might indicate an ectopic pregnancy, which requires additional testing and follow-up.

In certain situations, the first beta hCG level starts high, drops with the second test, and then starts doubling again. This could suggest that initially, multiple embryos started to implant but only one survived to continue a healthy implantation.

It’s customary for the IVF clinic staff to inform the patient/couple and the referring physician about the hCG pregnancy test results. Often, the IVF physician or nurse-coordinator coordinates with the referring physician to arrange all necessary pregnancy tests. If the patient/couple prefer to make their own arrangements, the program should provide detailed instructions.

In some cases, when the two blood pregnancy tests show that one or more embryos are implanting, certain programs recommend daily injections of progesterone or the use of vaginal hormone suppositories for several weeks to support the implantation process. Others give hCG injections three times a week until the pregnancy can be confirmed by ultrasound examination. Some IVF programs don’t prescribe any hormones after the embryo transfer.

Patients with appropriate doubling of hCG levels within two days after frozen embryo transfer (FET) or third-party IVF procedures such as surrogacy or egg donation may receive estradiol and progesterone injections, often along with vaginal hormone suppositories, for 10 weeks after the implantation is diagnosed by blood pregnancy testing.

A positive Beta hCG blood pregnancy test indicates the possibility of conception, but ultrasound confirmation is needed to confirm the pregnancy. Until then, it is referred to as a “chemical pregnancy.” Only when ultrasound examination confirms the presence of a gestational sac, clinical examination establishes a viable pregnancy, or after abortion when products of conception are detected, is it called a clinical intrauterine pregnancy.

A significantly elevated  hCG blood level without concomitant detection of an gestational sac inside the uterus by ultrasound after 5 weeks gestation raises the suspicion of an ectopic (tubal) pregnancy.

The risk of miscarriage gradually decreases once a viable clinical pregnancy is diagnosed (a conceptus with a regular heartbeat of 110-180 beats per minute). From this point onward, the risk of miscarriage is usually 10- 15% for women under 40 years old and around 35% for women in their early forties.

Dealing with successful IVF cases is relatively easy as everyone feels happy and validated. The real challenge lies in handling unsuccessful cases. Setting rational expectations from the beginning is crucial. In some cases (fortunately rare), emotional pressure may overwhelm the patient/couple, leading to a need for counseling or psychiatric therapy. I always advise my patients that receiving optimal care doesn’t always guarantee the desired outcome. There are many variables beyond our control, especially the unpredictable nature of fate. With around 36 years of experience in this field, I strongly believe that when it comes to IVF, the saying “man proposes while God disposes” always holds.

There are a few important things to consider when interpreting blood hCG levels. Levels can vary widely, ranging from 5mIU/ml to over 400mIU/ml, 10 days after ovulation or egg retrieval. The levels double every 48-72 hours until the 6th week of pregnancy, after which the doubling rate slows down to about 96 hours. By the end of the 1st trimester, hCG levels reach 13,000-290,000 IU and then slowly decline to around 26,000-300,000 IU at full term. Here are the average hCG levels during the first trimester:

• 3 weeks after the last menstrual period (LMP): 5-50 IU
• 4 weeks LMP: 5-426 IU
• 5 weeks LMP: 18-7,340 IU
• 6 weeks LMP: 1,080-56,500 IU
• 7-8 weeks LMP: 7,650-229,000 IU
• 9-12 weeks LMP: 25,700-288,000 IU

Most doctors wait until around the 7th week to perform an ultrasound to confirm pregnancy. By that time, the heartbeat should be clearly visible, providing a more reliable assessment of the pregnancy’s viability.

In some cases, blood hCG levels can be unusually high or increase faster than normal. This could indicate multiple pregnancies or a molar pregnancy. Rarely, conditions unrelated to pregnancy, such as certain ovarian tumors or cancers, can cause detectable hCG levels in both blood and urine.

To summarize, testing urine or blood for hCG is the most reliable way to confirm pregnancy. Urine tests are more common and convenient, while blood tests are more accurate and can detect pregnancy earlier. Tracking hCG levels in the blood is especially important for women undergoing fertility treatments. It’s essential to wait for the results of a second blood test before confirming pregnancy to avoid false hope or disappointment. Interpreting hCG levels requires considering various factors, and doctors usually perform an ultrasound around the 7th week for a more accurate assessment. Unusually high hCG levels may indicate multiple pregnancies or other conditions unrelated to pregnancy. Providing sensitive and timely communication of results is crucial for IVF clinics to support patients through the emotional journey.

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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\

_______________________________________________________________________________________________________________________________

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\

IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?

Geoffrey Sher MD

Older women and those who have diminished ovarian reserve (DOR) have greater difficulty in conceiving naturally or through assisted reproductive technology (ART). This is largely due to an inevitable increase in egg aneuploidy (numerical chromosome irregularity). However, although less significant than the rising increase in egg aneuploidy, advancing age and DOR are both also associated with non-chromosomal egg deterioration involving a decline in mitochondrial activity as well  as a progressive reduction in the  ability of the granulosa cells that line the inside of the follicle to respond to FSH stimulation.

Getting older women and those with DOR to respond optimally to ovarian stimulation often represents a serious challenge. Many will fail to respond adequately to standard ovarian stimulation regimens, requiring any individualized and strategic approach to ovarian stimulation…. one that regulates and limits exposure of ovarian follicles and eggs to LH-induced local male hormones (predominantly testosterone). This, in my opinion is best addressed by using a modified long pituitary down regulation protocol with an agonist (e.g. Lupron/Buserelin/Superfact) coming off a birth control pill. Thereupon, as soon as the period starts, the agonist is supplanted by an antagonist (e.g. Cetrotide/Orgalutron/Ganirelix) and stimulation with recombinant FSH (Follistim/Gonal-F/Puregon) along with a small amount of menotropin (e.g. Menopur) until t optimal follicle development prompts initiation of the hCG trigger. More than 15 years ago, I reported on the observation that in some women with severe DOR, the addition of intramuscular administration of estradiol valerate (i.e. Delestrogen) prior to and during gonadotropin stimulation (i.e. “estrogen priming”) is capable of further enhancing follicle growth .

More recently, researchers have shown that the administration of human growth hormone (HGH), as an adjunct to ovarian stimulation, can enhance follicle response in older women and those with DOR. Two basic mechanisms have been proposed: a) enhanced response to FSH by up-regulating the FSH receptors on follicular granulosa cells and, b) through a direct effect of HGH on the egg itself whereby mitochondrial activity is enhanced.  Human eggs do have receptors to HGH but eggs retrieved from older women show decreased expression of such receptors (as well as a reduced amount of functional mitochondria. It was recently observed that some such women treated with HGH, show a marked increase in egg functional mitochondria along with improved egg quality.

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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 would all-but stop worrying at this stage`.

Geoff Sher

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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\

Within the 1st week of the period starting.

One often hears the expressed opinion that the BCP suppresses response to ovarian stimulation. This is not the case, provided that the BCP is overlapped with administration of an agonist (e.g. Lupron, Buserelin, Superfact) for several days leading up to the start of menstruation and the initiation of ovarian stimulation cycle with gonadotropin drugs. If the latter precaution is not taken, and the cycle of stimulation is initiated coming directly off the BCP the response will often be blunted and subsequent egg quality could be adversely affected. The explanation for this is that in natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors . Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists (e.g. Lupron, Buserelin, Superfact) , cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why, women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.

Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be  completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S.This is where overlapping the BCP with an agonist (e.g. Lupron/Superfact/Buserelin) comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will  (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal

I believe it to be essential regardless of the protocol of COS protocol being contemplated, for women who launching ovarian stimulation coming off a BCP to overlap with an agonist for several days in advance of initiating ovarian stimulation with the onset of menstruation,

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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\

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In my opinion, in the absence oft certain thrombophilias, or a history of thromboembolism,  heparin therapy for suspected immunologic implantation dysfunction (IID) s rarely required beyond the 10th week.

In the world of assisted reproduction, when IVF fails repeatedly or without explanation, it’s often assumed that poor embryo quality is the main culprit. However, this view oversimplifies the situation. The process of embryo implantation, which begins about six or seven days after fertilization, involves a complex interaction between embryonic cells and the lining of the uterus. These specialized cells, called trophoblasts, eventually become the placenta. When the trophoblasts meet the uterine lining, they engage in a communication process with immune cells through hormone-like substances called cytokines. This interaction plays a critical role in supporting the successful growth of the embryo. From the earliest stages, the trophoblasts establish the foundation for the exchange of nutrients, hormones, and oxygen between the mother and the baby. The process of implantation not only ensures the survival of early pregnancy but also contributes to the quality of life after birth.

There are numerous uterine factors that can impede embryo implantation potential. However, the vast majority relate to the following three (3) factors:

1. Thin uterine lining (endometrium) . A lining that is <8mm in thickness at the time of ovulation, and/ or the administration of progesterone
2. Irregularity the inner surface of the uterine cavity (caused by protruding sub-mucous fibroids, scar  tissue or polyps )

• Immunologic factors that compromise implantation

Of these 3 factors, the one most commonly overlooked (largely because of the highly complex nature of the problem) is immunologic implantation dysfunction (IID), a common cause of “unexplained (often repeated) IVF failure and recurrent pregnancy loss. This article will focus on the one that most commonly is overlooked ….namely, 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 6-7 days 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 IVIg to NK cells can immediately downregulate NK cell activity. However, 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 Immunologic Implantation Dysfunction (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.

1. 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.
2. 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.
   • 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.

____________________________________________________________

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\

Please re-post in English!

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\