_Something is not right! See your wife’s OB to confirm that she is indeed carrying a viable pregnancy.

Good luck!

Geoff Sher

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I am attaching online links to two E-books which I 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) “

http://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

Do a quantitative blood hCG test.

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.

____________________________________________________________

I am attaching online links to two E-books which I 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) “

http://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

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You are correct, the Receptiva test is often inconclusive, but would do no harm.  And, unless ultrasound shows endometriotic cysts I would not do a laparoscopy or take Lupron. Rather, I would undergo blood testing for an immunologic implantation dysfunction (IID) specifically looking for antiphospholipid antibodies (APA) and natural killer cell activity (NKa) at one of 3 laboratories in the USA that are capable o doing such testing reliably (I advocate using ReproSource Laboratory in Boston, MA. If you test +ve, it is my opinion that treatment is necessary (see the attached links to books I have written, below which will provide more information.

Endometriosis is a condition that occurs when the uterine lining (endometrium)  grows not only in the interior of the uterus but in other areas, such as the Fallopian tubes, ovaries and the bowel. Endometriosis is a complex condition where, the lack or relative absence of an overt anatomical barrier to fertility often belies the true extent of reproductive problem(s).

All too often the view is expounded that the severity of endometriosis-related infertility is inevitably directly proportionate to the anatomical severity of the disease itself, thereby implying that endometriosis causes infertility primarily by virtue of creating anatomical barriers to fertilization. This over-simplistic and erroneous view is often used to support the performance of many unnecessary surgeries for the removal of small innocuous endometriotic lesions, on the basis of such “treatment” evoking an improvement in subsequent fertility.

It is indisputable that even the mildest form of endometriosis can compromise fertility. It is equally true that, mild to moderate endometriosis is by no means a cause of absolute “sterility”.

Rather, when compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about four to six times less likely to have a successful pregnancy. Endometriosis often goes unnoticed for many years. Such patients are frequently, erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparotomy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.

Women who have endometriosis are far more likely to be infertile. There are several reasons for this:

• First-Ovulation Dysfunction: In about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction. Treatment requires controlled ovarian stimulation (COS). The problem is that the toxic pelvic environment markedly reduces the likelihood that anything other than IVF will enhance pregnancy potential.
• Second- Toxic Pelvic environment that compromises Fertilization Endometriosis is associated with the presence of toxins in the peritoneal secretions. While it is tempting to assert that endometriosis-related infertility is confined to cases with more severe anatomical disease , that normally ovulating women with mild to moderate endometriosis (where the Fallopian tubes are usually patent and free) should  have no difficulty in conceiving once their anatomical disease is addressed surgically, …nothing could be further from the truth. The natural conception rate for healthy young (<35y) ovulating women who are free of endometriosis, is about 15% per month of trying and 70% per year of actively trying to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis  is only about 2-4% per month and approximately 40% after 4 The main reason for this difference is that as the  egg travels from the ovary to the fallopian tube, it is exposed to these peritoneal toxins which compromise the fertilization process. And, this “toxic pelvic influence, cannot be eradicated through surgically removing visible endometriotic deposits in the pelvis or through any medication.  The reason that surgical ablation of endometriotic deposits will not improve pregnancy potential is that  for every deposit observed, there are numerous others that are in the process of developing, which at the time might not be visible (because they are translucent) but  still produce toxins. This also explains why surgery to remove visible endometriotic deposits, controlled ovarian stimulation (COS) with or without intrauterine insemination will usually not improve pregnancy potential. Only IVF, through removing eggs before they are exposed to this toxic pelvic environment, fertilizing them in in the IVF laboratory and then transferring the embryo(s) to the uterus represents the only way to enhance pregnancy potential.
• Third-Pelvic adhesions and Scarring:In its most severe form, endometriosis is associated with scarring and adhesions in the pelvis, resulting in damage to, obstruction or fixation of the fallopian tubes to surrounding structures, thereby preventing the union of sperm and eggs.
• Fourth-Ovarian Endometriomas, Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple. When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary (ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion ovarian endometriomas larger than 1cm need to be removed surgically or though sclerotherapy before embarking on IVF.
• Fifth- Immunologic Implantation Dysfunction (IID). Endometriosis, regardless of its severity is associated with immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa) and cytotoxic lymphocytes (CTL) in about 30% of cases. This is diagnosed by testing the woman’s blood for NKa using the K-562 target cell test or by cytokine analysis, and by doing a blood immunophenotype evaluation. These NKa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most such cases, this will result in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word are actually experiencing repeated undetected “mini-miscarriages”.

Advanced Endometriosis: In its most advanced stage, anatomical tubal and ovarian disfiguration is causally linked to the infertility. In such cases, inspection at laparoscopy or laparotomy will usually reveal severe pelvic adhesions, scarring and  endometriomas. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often relatively low on their priority lists. Accordingly, such patients are often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating their symptoms.

Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, Fallopian tubes, bladder surface and on the peritoneal surface, low down  in the pelvis, behind the uterus (in the cul-de-sac). In such cases, the Fallopian tubes are usually opened and functional.

Mild Endometriosis: These are patients who at laparoscopy or laparotomy are found to have no significant distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.

Treatment:

The following basic concepts apply to management of endometriosis-related infertility:

1. Controlled Ovulation stimulation (COS) with/without intrauterine insemination (IUI): Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential, regardless of how sperm reach the Fallopian tube(s). This explains why COS with or without IUI will usually not improve the chances of pregnancy (over no treatment at all) in women with endometriosis. IVF is the only way by which to bypass this problem.
2. Laparoscopy or Laparotomy Surgery aimed at restoring the anatomical integrity of the Fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis many Nor does it address the immunologic implantation dysfunction (IID) often associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age as such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have much more time on their side might consider surgery as a viable option. Approximately 30 -40 percent of women under 35 years of age with endometriosis will conceive within three to four years following corrective pelvic surgery.
3. Sclerotherapy for ovarian endometriomas (“chocolate” cysts).About 20 years ago I introduced “sclerotherapy”, a relatively non-invasive, safe and effective outpatient method to permanently eliminate endometriomas without surgery being required. Sclerotherapy for ovarian endometriomas involves needle aspiration of the liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline hydrochloride into the cyst cavity. Treatment results in disappearance of the lesion within 6-8 weeks, in more than 75% of cases so treated. Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office- based procedure, at low cost, with a low incidence of significant post-procedural pain or complications and the avoidance of the need for laparoscopy or laparotomy.
4. The role of selective immunotherapyMore than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test and/or by testing for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages” Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. Endometriosis-induced NKa is treated with a combination of Intralipid (IL) and steroid  (dexamethasone or prednisone)therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%)  and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa. The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
5. The role of IVF: The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that in cases where the condition is further compromised by an IID associated with NKa and/or for older women(over 35y)  who have  diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

_______________________________________________________________________

I am attaching online links to two E-books which I 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) “

http://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

tht an accredited Reproductive Immunology Laboratory ( I use ReproSource in Boston, MA)for

I am attaching online links to two E-books which I 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) “

http://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

It is a high level but significance depends on when in pregnancy it was taken. An ultrasound done now should rule out a molar pregnancy (which I doubt is the case).

Geoff Sher

To my knowledge,  there is no established relationship!

Geoff Sher

__________________________________________________

I am attaching online links to two E-books which I 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) “

http://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

It is important to nurture and take care of yourself mentally and physically when preparing and going through your IVF journey. This starts with trying to have a positive attitude about what you are about to go through, creating a stress support system for yourself by using tools such as visualization, acupuncture and meditation, eating the right foods taking a few supplements (see below) and balancing exercise with sufficient rest. . Not only will it help your experience but it may also help to increase your chances for IVF success

This article will focus on the role of nutritional supplements in preparing for IVF. You’ve probably wondered whether commercially available fertility supplements could help you achieve your goal. The answer is complex.

Here is my take: Nutrition is indeed a vital prerequisite for optimal reproductive function. However, a well-balanced diet that meets food preferences, coupled with modest vitamin, mineral and antioxidant supplementation (as can be found in many prenatal vitamin preparations) should suffice.

This having been said, conceiving is a delicate process, and eating the right foods is essential to optimize reproductive potential. Indeed, a balanced diet (i.e. a lot of organic and brightly colored foods) will provide most of the nutrients you need. But the truth is that most people do not have a balanced diet and are unwittingly often deficient in important nutrients.

A balanced diet is one that is rich in good quality protein, low in sugar, salt, caffeine and industrially created trans-fats (trans-fatty acids or partially hydrogenated oils) and soy, uncontaminated by heavy metals, free of nicotine, alcohol and recreational drugs. This is why routine supplementation with the following nutrients could enhance preconception readiness:

• Folic acid (400 micrograms daily)
• Vitamins D-3 1,000U daily; Vitamin A (2565 IU daily); B3/Niacin (250mg daily); B6 (6mg -10 mg daily); B12 (12-20 mcg per day); C- (2,000 mg a day for both men and women); E (both sexes should get 150-200U daily); Vitamin D3 (2000U daily)
• Co-enzyme Q10 (400-600mg daily )
• Amino acids such as L-Carnitine (3 grams daily) and L-arginine (1 gram per day )
• Omega 3 fatty acids (2,000mg per day)
• Minerals, mainly zinc (15mg per day); selenium (70-100mcg per day); iron (up to 20mg per day ); magnesium (400mg per day )

There are likely to be significant reproductive health benefits (including enhanced fertility and intrauterine development) associated with the use of nutritional supplements. However there are also certain potential pitfalls associated with their use. Some supplements are not as safe as they would seem. For example, excessive intake of fat-soluble vitamins (A, D, E and K) can even be dangerous to your health and may be associated with fetal malformations.

Additionally, numerous supplements have been found to contain contaminants such as toxic plant materials, heavy metals and even prescription medications that can compromise fetal development. Prior to the passage of the Dietary Supplement Health and Education Act of 1994, supplements (vitamins, minerals, amino acids, and botanicals) were required to demonstrate safety. However, since passage of “the Act”, they are now presumed to be safe until shown otherwise, thus establishing a rather hazardous situation where a typical prenatal vitamin that will provide sufficient vitamins and minerals for a healthy early pregnancy and potentially dangerous supplements can and are being sold in the same store without product liability.

What about the use of dehydroepiandrosterone (DHEA)?  DHEA is a male hormone supplement that is metabolized to androstenedione and testosterone in the ovaries.  While a small amount of ovarian testosterone is needed for optimal follicle and egg development, too much testosterone could be decidedly harmful. DHEA supplements probably won’t do harm if taken by healthy young women who have normal ovarian reserve, but they probably would not derive any benefit either. However, in my opinion, DHEA supplementation could be potentially harmful when taken by women with diminished ovarian reserve (DOR), women who have polycystic ovarian syndrome (PCOS) and older women in their 40’s as such women often already tend to have increased LH-activity, leading to increased ovarian testosterone. Additional ovarian testosterone in such women, could thus potentially compromise follicle development and egg quality/competency.

In summary: Maximizing reproductive performance and optimizing outcome following fertility treatment requires a combined strategy involving a balanced diet (rich in protein, low in sugars, soy and trans-fats), modest nutritional supplementation, limiting/avoiding foods and contaminants that can compromise reproductive potential, and adopting disciplined lifestyle modification such as not smoking, reducing stress, minimizing alcohol intake, avoiding nicotine and recreational drug consumption, and getting down to a healthy weight through diet and exercise.

 Geoff Sher

______________________________________________________________

I am attaching online links to two E-books which I 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) “

http://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

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.

Geoff Sher

_____________________________________________________________________

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) ; http://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\

Our cut off for egg retrievals is 47Y. Frozen embryo transfers….no definitive cut off. See below:

Age should never be a barrier to hope and fulfillment when it comes to IVF. Many women in their early to mid-40s are successfully having IVF babies using their own eggs, especially if they have a good number of eggs left in their ovaries. However, for women with diminished ovarian reserve (DOR) or those over the age of 44, where the chances of success with their own eggs are low, IVF with egg donation can be a highly successful and safe option. Let’s explore why age affects IVF outcomes and discover the possibilities that lie ahead.

The egg plays a crucial role in determining the quality of the embryo, with a “competent” egg having the best chance of developing into a healthy baby. As women age, the chances of having eggs with an irregular number of chromosomes (aneuploid) increase significantly. Fertilizing an aneuploid egg will result in an embryo with an abnormal number of chromosomes, making it unable to develop into a healthy baby.

Chromosomal abnormalities are the main cause of failed implantation, pregnancy losses, and birth defects. As women get older, the risk of chromosomal abnormalities in embryos rises, leading to lower IVF success rates. Additionally, older women may experience hormonal imbalances that further affect egg quality and development. However, personalized stimulation protocols can help protect egg quality and improve IVF outcomes by regulating hormone production and activity.

When it comes to IVF in older women, selecting the right ovarian stimulation protocol is crucial. Various protocols are available, each tailored to meet individual needs. However, certain protocols should be avoided for older women or those with DOR to optimize chances of success.

I selectively use a variety of ovarian stimulation protocols for ovarian stimulation/IVF in older women and those with DOR :

• The conventional long pituitary down-regulation protocol: This involves administering a GnRH agonist like Lupron or Buserelin for a few days prior to initiating ovarian stimulation with gonadotropins. Then, a combination of FSH-dominant gonadotropin and a small dose of Menopur is administered, and ultrasound and blood tests are done to monitor follicle development. The eggs are triggered for maturation with hCG, and the egg retrieval is scheduled for approximately 36 hours later. This protocol is often preferred for older women who have adequate ovarian reserve (AMH=>1.5ng/ml).
• The agonist/antagonist conversion protocol (A/ACP):, This is similar to the conventional long down-regulation protocol. However, instead of using an agonist, a GnRH antagonist is administered from the onset of stimulation with gonadotropins. This protocol is often preferred for older women who have moderately severe DOR (AMH=0.5-1.5ng/ml).
• A/ACP with Estrogen “priming”; For women with very severe, DORI prescribe  estrogen “priming “with skin estradiol (E2) patches or Estradiol injections administered bi-weekly. For some time before commencing gonadotropin stimulation, in an attempt to enhance ovarian response to stimulation. This protocol is sometimes used in older women who have severe DOR ( <0.5-1.5ng/ml).

In my opinion, the following ovarian stimulation protocols all promote over-exposure to LH-induced ovarian testosterone and are best avoided in older women and women with DOR, undergoing ovarian stimulation for IVF:

• Agonist “flare” protocols, which cause a surge of pituitary-LH at the wrong time.
• High dosages , LH-containing fertility drugs (e.g., menotropins such as Menopur).
• Testosterone-based supplements like Androgel.
• DHEA supplementation: DHEA is converted to testosterone in the ovaries.
• Clomiphene citrate & Letrozole, promote exaggerated pituitary LH release that can result in over-production of ovarian testosterone.
• Triggering egg maturation with too low a dosage of hCG (the ideal dosage is 10,000U of urine derived hCG) andf Recombinant DNA-derived hCG ( the ideal dosage is 500mcg of Ovidrel).

In cases where using their own eggs is no longer viable due to age and severe DOR, using donor eggs provides a fulfilling path to parenthood. Although some may initially hesitate due to the lack of genetic relation, it’s important to understand that the person who gives birth is considered the true biological parent in most cultures and legal systems. Becoming a parent through this connection can bring immense joy and fulfillment, as countless successful cases have shown.

Age may reduce the chances, but it does not eliminate the possibility of having a child through IVF. When IVF with own eggs is not an option, embracing the alternative of egg donation opens doors to highly successful and fulfilling paths to parenthood. It’s time to unlock the possibilities and embark on the journey towards creating a loving family.

 __________________________________________

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) ; http://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\

• 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.

Geoff Sher

___________________________________________________________________

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) ; http://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\

Provided strict criteria are applied…yes, you could use your daughter’s eggs.

Geoff Sher

________________________________________________________________

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) ; http://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\

This is not likely to be a pregnancy. However, to be certain…do a blood pregnancy test.

Geoff Sher

_______________________________________________________

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) ; http://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\

Sjogren Syndrome is likely an autoimmune condition and can be associated with an autoimmune, immunologic implantation dysfunction (IID), in my opinion.See below:

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.

Geoff Sher

________________________________________________________________

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) ; http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

2. 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\

The dosage is 25mg inserted high in the vagina 4 times daily from early in the cycle to the day of hCG or progesterone administration.

Back in 1989, I conducted a study that examined how the thickness of a woman’s uterine lining, known as the endometrium, affected the successful implantation of embryos in IVF patients. The study revealed that when the uterine lining measured less than 8mm in thickness by the day of the “hCG trigger” in fresh IVF cycles, or at the start of progesterone therapy in embryo recipient cycles (such as frozen embryo transfers or egg donation IVF), the chances of pregnancy and birth were significantly improved. In my opinion, an ideal estrogen-promoted endometrial lining should measure at least 9mm in thickness, while a lining of 8-9mm is considered “intermediate.” In most cases, an estrogenic lining of less than 8mm is unlikely to result in a viable pregnancy.

A “poor” uterine lining typically occurs when the innermost layer of the endometrium, called the basal or germinal endometrium, fails to respond to estrogen and cannot develop a thick enough outer “functional” layer to support optimal embryo implantation and placenta development. The “functional” layer makes up two-thirds of the total endometrial thickness and is the layer that sheds during menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining include:

1. Damage to the basal endometrium due to:

1. • Inflammation of the endometrium (endometritis) often resulting from retained products of conception after abortion, miscarriage, or birth.
   • Surgical trauma caused by aggressive uterine scraping during procedures like D&C.

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

1. • Prolonged or excessive use of clomiphene citrate.
   • Prenatal exposure to diethylstilbestrol (DES), a drug given to pregnant women in the 1960s to prevent miscarriage.

1. Overexposure of the uterine lining to ovarian male hormones, mainly testosterone, which can occur in older women, women with diminished ovarian reserve, and women with polycystic ovarian syndrome (PCOS) who have increased LH biological activity. This hormonal imbalance leads to the overproduction of testosterone in the ovary’s connective tissue, further exacerbated by certain ovarian stimulation methods used in IVF.
2. Reduced blood flow to the basal endometrium, often caused by:

1. • Multiple uterine fibroids, especially those located beneath the endometrium (submucosal).
   • Uterine adenomyosis, an abnormal invasion of endometrial glands into the uterine muscle.

“The Viagra Connection”

Eighteen years ago, I reported on the successful use of vaginal Sildenafil (Viagra) in treating women with implantation dysfunction caused by thin endometrial linings. This breakthrough led to the birth of the world’s first “Viagra baby.” Since then, thousands of women with thin uterine linings have been treated with Viagra, and many have gone on to have babies after multiple unsuccessful IVF attempts.

Viagra gained popularity in the 1990s as an oral treatment for erectile dysfunction. Inspired by its mechanism of action, which increases penile blood flow through enhanced nitric oxide activity, I investigated whether vaginal administration of Viagra could improve uterine blood flow, deliver more estrogen to the basal endometrium, and promote endometrial thickening. Our findings confirmed that vaginal Viagra achieved these effects, while oral administration did not provide significant benefits. To facilitate treatment, we collaborated with a compound pharmacy to produce vaginal Viagra suppositories.

In our initial trial, four women with a history of poor endometrial development and failed conception underwent IVF treatment combined with vaginal Viagra therapy. The Viagra suppositories were administered four times daily for 8-11 days and stopped 5-7 days before embryo transfer. This treatment resulted in a rapid and significant improvement in uterine blood flow, leading to enhanced endometrial development in all four cases. Three of these women subsequently conceived. In 2002, I expanded the trial to include 105 women with repeated IVF failure due to persistently thin endometrial linings. About 70% of these women responded positively to Viagra therapy, with a notable increase in endometrial thickness. Forty-five percent achieved live births after a single cycle of IVF with Viagra treatment, and the miscarriage rate was only 9%. Women who did not show improvement in endometrial thickness following Viagra treatment did not achieve viable pregnancies.

When administered vaginally, Viagra is quickly absorbed and reaches the uterine blood system in high concentrations. It then dilutes as it enters the systemic circulation, explaining why treatment is virtually free from systemic side effects.

It is important to note that Viagra may not improve endometrial thickness in all cases. Approximately 30-40% of women treated may not experience any improvement. In severe cases of thin uterine linings where the basal endometrium has been permanently damaged and becomes unresponsive to estrogen, Viagra treatment is unlikely to be effective. This can occur due to conditions such as post-pregnancy endometritis, chronic inflammation resulting from uterine tuberculosis (rare in the United States), or extensive surgical damage to the basal endometrium.

In my practice, I sometimes recommend combining vaginal Viagra administration with oral Terbutaline (5mg). Viagra relaxes the muscle walls of uterine spiral arteries, while terbutaline relaxes the uterine muscle itself. The combination of these medications synergistically enhances blood flow through the uterus, improving estrogen delivery to the endometrial lining. However, it’s important to monitor potential side effects of Terbutaline such as agitation, tremors, and palpitations. Women with cardiac disease or irregular heartbeat should not use Terbutaline.

Approximately 75% of women with thin uterine linings respond positively to treatment within 2-3 days. Those who do not respond well often have severe inner ( (basal) endometrial lining damage, where improved uterine blood flow cannot stimulate a positive response. Such cases are commonly associated with previous pregnancy-related endometrial inflammation, occurring after abortions, infected vaginal deliveries, or cesarean sections.

Viagra therapy has been a game-changer for thousands of women with thin uterine linings, allowing them to successfully overcome infertility and build their families.

Geoff Sher

________________________________________________________________

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) ; http://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\

_

Understanding the impact of age and 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 older women an those 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. Age and Ovarian Reserve: Chronological age plays a vital role in determining the quality of eggs and embryos. As women age, there is an increased risk of aneuploidy (abnormal chromosome numbers) in eggs and embryos, leading to reduced 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 older women or those with DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
3. Individualized Ovarian Stimulation Protocols: Although age is a significant factor in aneuploidy, it is possible to prevent further 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 for Older Women or Those with DOR: Certain ovarian stimulation protocols may not be suitable for older women or those 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(PGS/T): PGS/T is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/T significantly improves the success of IVF, especially in older women or those with DOR.

Understanding the impact of advancing age and declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Age-related factors can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. Diminished ovarian reserve (DOR) further complicates the process. By considering these factors, 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.

Geoff Sher

______________________________________________________________________

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) ; http://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\

Yes we do! However, to be honest, I am not a true believer.

Geoff Sher

_______________________________________________________________

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) ; http://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\

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

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

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

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

1. 1. Anatomical irregularities of the inner uterine surface:
2. a) Surface lesions such as polyps/fibroids/ scar tissue
3. b)endometrial thickness
4.  
5. 2. Immunologic Implantation Dysfunction ( IID)lesions
6. a)Autoimmune IID
7. b) Alloimmune IID

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

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

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

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

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

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

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

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

The main causes of a poor uterine lining are:

1. Damage to the basal endometrium due to:

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

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

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

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

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

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

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

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

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

1. IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

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

• Activated natural Killer Cells (NKa):

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

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

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

• Antiphospholipid Antibodies:

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

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

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance. It follows that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies. Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids subsequently often results in a significant improvement in reproductive performance in such cases.

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

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

• Treatment Options for IID:

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

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

1. 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.

 Geoff Sher

________________________________________________________________

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) ; http://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\

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) ; http://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\

That is not sufficient to disrupt your cycle…in my opinion.

Discuss with your treating RE.

Geoff Sher

__________________________________________________________

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) ; http://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\

Yes indeed I do!

_____________________________________________

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) ; http://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\

Frozen transfer of PGS-normal blastocyst  is preferable in my opinion. With regard toi stimulation, consider the following:

Understanding the impact of age and 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 older women an those 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. Age and Ovarian Reserve: Chronological age plays a vital role in determining the quality of eggs and embryos. As women age, there is an increased risk of aneuploidy (abnormal chromosome numbers) in eggs and embryos, leading to reduced 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 older women or those with DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
3. Individualized Ovarian Stimulation Protocols: Although age is a significant factor in aneuploidy, it is possible to prevent further 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 for Older Women or Those with DOR: Certain ovarian stimulation protocols may not be suitable for older women or those 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(PGS/T): PGS/T is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/T significantly improves the success of IVF, especially in older women or those with DOR.

Understanding the impact of advancing age and declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Age-related factors can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. Diminished ovarian reserve (DOR) further complicates the process. By considering these factors, 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.

______________________________________________

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) ; http://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\