Dr. Sher Blog

Over the past three decades, I have met and consulted with tens of thousands of couples seeking treatment for diverse reproductive issues involving infertility and pregnancy loss. The universal thread that I have encountered is people’s hunger for information when they’re facing such situations. Many times, the response I get from patients after discussing their case in depth with them is “I wish I would have understood that before my first (or second) IVF cycle!”

Many people undertake fertility treatment with what they realize later to be very limited information on both their own diagnosis and what their treatment options are. All of my blogs are created to be a source of meaningful and substantive information for those who are considering or currently undergoing fertility treatment. It is my wish that you’ll find something here that will give you additional insight, knowledge, and ultimately, hope.

39 Comments

Anna

Dear dr.Sher

I had my first IVF – short protocol (I have pcos). I got 150 units of Puregon for 7 days,2 days of Ovitrelle, on 9 day I got a stop injection and on 11 day of period I had egg retreival. I had 7 folicles but they where all empty and now I am so worried. When I got the stop injection my folicles where 17mm, is that too small? My Fsh is 6,48 and my lh is 20. Was the choosen protocol suitable for my condition? What is the solution in my case? Should I have a long protocol? Is that common for women with pcos and what can we do about it?

Thank you very much for the answer, it is really amazing that you offer a support for us.

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Dr. Geoffrey Sher

In my opinion, this is likely a protocol issue. There also no such thing as “empty follicles”. When no egg is harvested, it almost always is due to it remaining stuck to the inner lining of the follicle and this happens when the egg is grossly abnormal…see below.

I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• Implications of “Empty Follicle Syndrome and “Premature Luteinization”
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• Taking A Fresh Look at Ovarian Hyperstimulation Syndrome (OHSS), its Presentation, Prevention and Management
• Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
• Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
• “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
• The “Lupron Trigger” to Prevent Severe OHSS: What are the Pro’s and Con’s?
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!
• IUI-Reflecting upon its Use and Misuse : Time for a Serious “Reality Check”.
• Micro-IVF: Often Preferable to Ovarian Stimulation with or Without IUI
• The Role of Gender Selection in IVF.

Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
• Email: Julied@sherivf.com
• Phone: 702-533-2691
 800-780-7437

Geoff Sher

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

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Anna

Does that mean I do not have normal eggs and the same result can appear in the second Ivf?

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Anna

Could you please tell me is there any chance for me to have a baby or i need to start thinking about donor egg? What does it mean that eggs are grossely abnormal?

Dr. Geoffrey Sher

We would need to first discuss in detail!

Geoff Sher

Anna

Could you please tell me is there any chance for me to have a baby or i need to start thinking about donor egg? What does it mean that eggs are grossely abnormal?

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Joey B.Terraza

Hi Dr.Sher,

I am turning 41 on the 22nd this month.I was prescribed Menopur 150,Gonal F 250 for 3 days then increased to 275 until the 7th day+Cetrotide i forgot what day it was started.Last Menopur and Cetrotide dose morning of day 8th,9pm trigger shot HCG taken then retrieval 8-9am the next day,doc retrieved 6 eggs,2 premature,3 fertilized.Received a call on the 5th day not a single turn into blast.I have 1 fibroid doc said will not interfere with pregnancy.Few polyps removed prior to starting cycle.I have appointment for reconsult on 5th of January.Husband is 41 and has low sperm count.I want to know what are your thoughts on my case?I will appreciate it.

Thanks a lot,

Joey

reply
Dr. Geoffrey Sher

While I personally would prefer a different approach to stimulation, in your situation (see below), others would not and I would also have recommended embryo banking of PGS selected, only time will tell.

In my opinion, the protocol used for ovarian stimulation, against the backdrop of age, and ovarian reserve are the drivers of egg quality and egg quality is the most important factor affecting embryo “competency”.
Older women as well as those who (regardless of age) have diminished ovarian reserve (DOR) tend to produce fewer and less “competent” eggs, the main reason for reduced IVF success in such cases. The compromised outcome is largely due to the fact that such women tend to have increased LH biological activity which often results in excessive LH-induced ovarian testosterone production which in turn can have a deleterious effect on egg/embryo “competency”.
Certain ovarian stimulation regimes either promote excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), augment LH/hCG delivered through additional administration (e.g. high dosage menotropins such as Menopur), or fail to protect against body’s own/self-produced LH (e.g. late antagonist protocols where drugs such as Ganirelix/Cetrotide/Orgalutron that are first administered 6-7 days after ovarian stimulation has commenced).
I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of a modified, long pituitary down-regulation protocol (the agonist/antagonist conversion protocol-A/ACP) augmented by adding supplementary human growth hormone (HGH). I further recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing/NGS)-normal blastocysts in such cases. This type of approach will in my opinion, optimize the chance of a viable pregnancy per embryo transfer procedure and provide an opportunity to capitalize on whatever residual ovarian reserve and egg quality still exists, allowing the chance to “make hay while the sun still shines”.
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
• Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Implications of “Empty Follicle Syndrome and “Premature Luteinization”
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.

Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
• Email: Julied@sherivf.com
• Phone: 702-533-2691
 800-780-7437

Geoff Sher

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Geoff Sher

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Yu Li

Dear Dr Sher,
I had contacted you earlier through your blog. I am a 49 year old nulliparous woman who underwent a hysterectomy for endometrial cancer stage 1 which had not responded to conservative treatment with Provera 100mg BD and a Mirena. You had recommended embryo donation. However, I would still like to be considered for IVF using my own eggs prior to considering donated embryos with donated sperm and surrogacy. I never had the opportunity to do that before having the hysterectomy. In your blog you had mentioned that you may be able to use methods to improve the quality of eggs in older mothers. What would that be? What is the success rate? I am keen to try everything possible. Thank you for your help.

reply
Dr. Geoffrey Sher

Unfortunately, this is not an option at 49Y. I strongly urge you to go to egg/embryo donation using a gestational carrier as well. Nothing else is likely to work.

Geoff Sher

reply
smith

Doctor said me Perivitelline space is more in my second ivf , what does that mean? What causes occur

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Dr. Geoffrey Sher

I really do not know what the implication might be! Get more clarification and I will respond!

Geoff Sher

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EH

Hi Dr. Sher,

Thank you for taking the time to help couples struggling with infertility on your blog. Your blog is so helpful and I learn so much from reading your posts.

I have a question for you. My husband (age 30) and I (age 29) just went through our first IVF/ICSI cycle. We planned to do PGS testing at day 5 due to recurrent aneuploid miscarriage (two pregnancies with Turner syndrome). I was stimmed very gently for 8 days with low dose FSH and triggered with 10,000 hCG. They retrieved 14 eggs and all 14 were mature. Nine fertilized normally (2 more fertilized late). Of the 9 normally-fertilized embryos, they all looked good on day 3 and were all between 6-8 cells. By day 5, I had just ONE expanded blastocyst (it was “textbook perfect” looking), one early blast, and 4 morulas. All the morulas and the early blast arrested by day 6. We are shocked and devastated. We sent out the one blast for PGS testing but we do not have the results yet. In your opinion, is this arrest after day 3 likely to be an egg quality issue or a sperm issue? I keep reading that sperm quality issues are a suspect when good looking day 3 embryos arrest by day 5. My husband has a varicocele, with poor morphology (2-3%), low count (10-13 million), and very low motility (19%) and 19% DNA fragmentation. Our karyotypes are normal, and my genetic counselor assured me that in 80% of cases, Turner syndrome is caused by a bad sperm, not a bad egg. Based on our IVF outcome, do you think our sperm could be a serious issue?

reply
Dr. Geoffrey Sher

There could be a male factor, but in the majority of cases, embryo arrest is due to an egg issue. Now that does not mean that your eggs are bad…It could have to do with the protocol used for ovarian stimulation and in a younger woman like you that is usually the case.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Male Factor Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection?
• Varicocele and Male Infertility: When and how should it be treated.
• The Sperm Chromatin Structure Assay (SCSA): A Measure of the Potential of Sperm to Help Propagate a Viable Pregnancy
• IVF for Women Who Have Previously Conceived (Secondary Infertility).
• Implications of “Empty Follicle Syndrome and “Premature Luteinization”
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.

I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

Email: Julied@sherivf.com

OR

Phone: 702-533-2691

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

egg.

reply
EH

Thanks so much for your input! I am actually at one of your clinics and happy there. If this embryo comes back abnormal or normal and doesn’t implant/miscarries, we do have plans to change up the protocol next time.

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Hannah

Dear Dr Sher.

Really hoping you can help and thank you in advance for anything you can help me with.

I am having secondary infertility issues which I think stem from a poor lining following an ERPC for a missed miscarriage i had last year (I have one child prior to this whom i conceived month 2 of trying and then the one i miscarried was conceived on month 1 but sadly as was a partial mole). My periods are now only about 2.5 days and light to moderate bleeding. Before having y child i was on the pill for 10 years so i dont really know what my normal period would be prior to having my child immediately after coming of pill. I am fairly sure i am ovulating (based off ultrasounds and temping and OPK tests) although my progesterone levels and estrogen levels are on the low side. My lining is only reaching a maximum of 6.5mm/7mm even on tamoxiden, which I am currently on month 1 of trying. I am also on cyclogest after ovulation.

As well as being under a doctor on the NHS (who has perscribed the tamoxifen) I am seeing a private doctor here in UK who thinks I should instead focus on removing my intramual fundal fibroid removed (2.8mm and sits very close to endometrium) but i am nervous not to rush into laproscopic surgery for this, although i understand my doctor to be an expert in this field and an extremely experienced at this type of surgery. I had this fibroid when i had my child and when I got pregnant with the pregnancy that i miscarried due to it being a partial mole. It was bigger during my pregnancy (4cm) and I understand it is now “calcified”. It pushes down slightly on the endometrium and I am being told mixed things about whether or not i should have it removed. I am finding it impossible to chose what to do- i am so scared of doing any further damage by having it removed but equally aware a fibroid expert has told me it needs to go.

I am wondering what I can do if anything to try and increase the lining or whether i should focus on getting the fibroid removed although i feel this is not the issue as it was there when i fell pregnant bot times before. I am doing accupuncture, taking vitamin E (400 iu), b complex, ubuiqnol and drinking red rasberry leaf tea and pomegranate juice. I keep reading mixed things about l’argenine and vitamin C and am really at a loss to know what I can do to help thicken it or whether I should focus on the fibroid removal.

Any advice would be much appreciated as I am simply at a loss to know what to do. I am scared the tamoxifen may make my fibroid grow but also terrified of having laproscopic surgery in case it causes scarring.

None of my doctors here really seem keen to advise on any viatmins etc that might help and so wondering if you can advise on what i can do to at least try and thicken the lining. Should i take more vitamin E etc?

Many thanks in advance

reply
Dr. Geoffrey Sher

The considerable emotional, physical and financial burden associated with infertility treatment in general and with IVF in specific, demand that factors known to affect outcome be identified and regulated prior to initiating treatment.

Just as a successful garden needs a ”good” seed properly planted in fertile soil to produce healthy plants, successful embryo implantation requires a good seed (genetically “normal” embryo) and fertile soil (receptive uterine lining) to make a healthy baby. I have long used this “Seed/Soil Relationship” analogy to help clarify the critical nature of the interaction between embryo and endometrium in the successful propagation of pregnancy..

There have in the last decade been numerous reports suggesting that certain drugs/supplements (e.g. GCSF) and endometrial receptivity testing/preparation might dramatically improve implantation. As yet, none of these have been proven to be effective. This article addresses the influence of the most relevant and important factors that are known to affect .endometrial receptivity and discusses approaches to treatment:

1. Endometrial thickness
In 1989, I first demonstrated that in both normal and “hormonally stimulated” cycles, preovulatory endometrial thickness as assessed by ultrasound examination, is partially predictive of embryo implantation (pregnancy) potential following IVF. Ideally the endometrium should measure at least 8.0mm in thickness, (but preferably >9mm).

A “poor” endometrial lining is most commonly due to: 1) inflammation of the uterine lining (endometritis) that usually occurs as a result of endometritis (inflammation of the uterine lining that can follow a septic delivery, partial retention of the placenta following delivery, abortion or miscarriage, 2) severe adenomyosis (gross invasion of the uterine muscle by endometrial glandular tissue), 3) multiple fibroid tumors of the uterine wall) 4) prenatal exposure to the synthetic hormone, diethylstilbestrol (DES) and, 5) following >3, consecutive, back to back cycles of clomiphene citrate ovulation induction.

Treatment with vaginal Sildenafil (Viagra): Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and with supplementary estrogen therapy) have yielded disappointing results.

In the mid-90’s I first reported on the finding that thee vaginal administration of Viagra for several days prior to the “hCG trigger “ or progesterone administration enhances uterine blood flow and estrogen delivery to the uterine lining and so improves endometrial thickening. Then In October 2002, I reported on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness and 45% of these women achieved live IVF- births following a single cycle of treatment with Viagra. Nine percent (9%) miscarried. None of the women who had failed to achieve an improvement in endometrial thickness following Viagra therapy, subsequently and who underwent embryo transfers achieved viable pregnancies.

2.Uterine Pathology:
It has long been suspected that anatomical defects of the uterus might result in infertility.
While myomas (fibroids) embedded deep in the uterine wall, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where they distort the uterine cavity, or protrude as submucous polyps through the endometrial lining. It would appear that even small submucous myomas have the potential to prejudice implantation.

Far too many infertile women found to have a partial or complete septum in the uterus are subjected to surgical excision of the septum with a promise that this will enhance subsequent implantation. This is an erroneous belief. Contrary to popular belief, the presence of a septum that partially or completely partitions the uterine cavity, while being responsible (in some cases) for late miscarriages and premature onset of labor, does NOT cause failed implantation.

It is likely that most surface lesions in the uterine cavity, whether due to an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, have the potential to interfere with implantation by producing a local “inflammatory”- type response, not too dissimilar in nature from that which is caused by a foreign body such as a intrauterine contraceptive device. Unfortunately, a dye X-Ray test (hysterosalpingogram/HSG) will often miss many smaller such lesions. The only reliable methods for diagnosing even the smallest of such lesions, is through the performance of a hysterosongram (HSN),a hysteroscopy or an MRI.

Hysterosonogram (syn. Saline ultrasound): This procedure involves the trans-cervical injection of a physiological saline solution via a catheter, into the uterine cavity. The fluid distended cavity is then examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed correctly, the HSN is highly effective in recognizing even the smallest surface lesions that protrude into the uterine cavity. It is less expensive, less traumatic, and diagnostically, equally reliable as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopic surgical approach to treating the problem..

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general or local anesthesia, with minimal discomfort to the patient. The procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus in order to fully examine the uterine cavity. The uterus is first distended with carbon dioxide gas, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation.

We have observed that approximately 8% of candidates for IVF have intrauterine lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients who have such lesions undergo surgery (D&C and/or hysteroscopic resection) to correct the pathology prior to undergoing IVF. Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia. If so, it should be performed in an outpatient surgical facility or in a conventional operating room.

3. Immunologic factors
The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., the trophoblast), which later becomes the placenta; begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo’s successful growth. Thus, from the very earliest stage of implantation the trophoblast establishes a foundation for the future nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

Considering its importance, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and most importantly activation of uterine natural killer cells (NKa). Presently, these immunologic markers in the blood can be only adequately measured by a handful of highly specialized reproductive immunology laboratories in the United States. I personally use Reproductive Immunology Associates in Van Nuys, CA or Reprosource in Boston, MA.

The Central role of Natural Killer cells: After ovulation and during early pregnancy, NK cells comprise more than 70% of the immune cell population of the uterine lining. NK cells produce a variety of local hormones known cytokines. Uncontrolled, excessive release of certain cytokines (i.e. TH-1 cytokines) is highly toxic to the trophoblast (“root system”) of the embryo” leading to their programmed death (apoptosis) and, subsequently to failed or compromised/dysfunctional implantation. In the following situations NK cells become activated, and start to produce an excess of TH-1 cytokines:

• Autoimmune Implantation Dysfunction: This is most commonly seen in association with a personal or family history of autoimmune diseases such as ith conditions such as Rheumatoid arthritis, hypothyroidism endometriosis and Lupus Erythematosus, Scleroderma, Dermatomyositis etc. It is also encountered in one third of women who have endometriosis (regardless of its severity), and in cases of “unexplained infertility” as well as with recurrent pregnancy loss (RPL).
• Alloimmune implantation dysfunction where the male and female partners share specific genetic (DQ-alpha and/or HLA) similarities This is commonly seen in cases of RPL and in cases of secondary infertility

Activated NK cells (NKa) can be detected through the K-562 target cell blood test and (more recently) through uterine biopsy for TH-1 cytokine activity. Treatment involves selective use of Intralipid (IL) or immunoglobulin (IVIG) therapy combined with oral steroids, initiated more 10-14 days prior to embryo transfer and in most cases of alloimmune implantation dysfunction, the transfer of a single blastocyst at a time.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Why did my IVF Fail
• Secondary Infertility: Addressing the Root Causes
• Uterine Fibroids and Fertility
• Traveling for IVF from Out of State/Country–

I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

Email: Julied@sherivf.com

OR

Phone: 702-533-2691

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

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Dee

Hi Dr. Sher,

What is your opinion of Endometirol Scraping? Do you preform always, never or only in specific cases.

reply
Dr. Geoffrey Sher

I think it is largely an ineffective, unbeneficial maneuver.

Geoff Sher

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maggie

I have PCOS and Hubby has Azoospermia. We are planning to head for ICSI.
Please advise me which protocol should I follow as having PCOS. I was on Clomid for 4 moths in last year. where my response was.
50mg- no mature follicle
100mg – 2 follicles 22,24mm
100mg- 1 follicle 24mm
150mg- 2 follicles 21,21mm

reply
Dr. Geoffrey Sher

Hi Maggie,

Good luck on your IVF-ICSI quests. Your protocol should in large part depend on your ovarian reserve (AMH/basal FSH/basal LH). Most women with PCOS have a very high AMH and are at risk of developing severe ovarian hyperstimulation syndrome (OHSS). However your low follicle yield in response to clomiphene, flies in the face of this. Thus the first order of business would be to detrmine your ovarian reserve.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• Male Factor Infertility
• Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
• Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
• The “Lupron Trigger” to Prevent Severe OHSS: What are the Pro’s and Con’s?
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

reply
dee chan

hi dr sher, i am 25 years old . i did pgs chromosome testing on my embryos and four came back normal. i had two failed embryo transfer. what should i do now ? i have two more embryos left. why did the embryos didn’t implant if they did pgs testing ? my lining , and everything is good. i have two children that was conceived naturally.

reply
Dr. Geoffrey Sher

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptl

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report)
• Traveling for IVF from Out of State/Country–
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

reply
Emily

Hi Dr. Sher can you tell me how important is Prolactin levels for implantation success what levels are acceptable ? Thanks

reply
Dr. Geoffrey Sher

Prolactin is a protein hormone (closely related to human growth hormone) that is secreted by specialized cells in the anterior part of the pituitary gland. In addition, the hormone is also produced and secreted by a broad range of other cells in the body, most prominently various immune cells, the brain, and the lining of the uterus. Most cells respond to prolactin. In fact it is hard to identify any tissue that does not have prolactin receptors.

Although prolactin’s major target organ is the breast, where it stimulates development and milk production, the hormone has many other functions. Several hundred different actions have been reported for prolactin.

Immune cells are rich in prolactin receptors and certain types of lymphocytes in fact synthesize and secrete prolactin. These observations suggest that prolactin may to some extent act as a regulator of the body’s immune activity.

In an area in the brain known as the hypothalamus, a chemical called dopamine is released. Dopamine suppresses prolactin synthesis and release by the pituitary gland. As such it acts as a “hypothalamic brake set” causing prolactin only to be secreted when the “brake” is released.

Several other hypothalamic hormones, including thyroid releasing hormone (TRH) and gonadotropin releasing hormone (GnRH) cause an increase in prolactin secretion. Stimulation of the nipples (including but not limited to nursing) leads to hypothalamic activation and prolactin release Estrogens also exerts a positive control over prolactin synthesis and secretion.

Common manifestations of increased prolactin secretion (hyperprolactinemia) in women include amenorrhea (lack of menstrual cycles) and galactorrhea (excessive spontaneous breast secretion). Men with hyperprolactinemia may present with hypogonadism, decreased sex drive, sperm dysfunction resulting in infertility, and with impotence. Such men also can show breast enlargement (gynecomastia), but very rarely have galactorrhea.

Causes: significantly raised blood prolactin levels (>60ng/ml) might point to a prolactin producing pituitary tumor (adenoma) which may be large (macroadenoma), small, or even microscopic (microadenoma). Markedly elevated blood prolactin is also associated with other types of intracranial lesions such as craniopharyngiomas, meningiomas etc. Prolonged treatment with bromocryptine (Parlodel) or related products will usually effectively lower blood prolactin concentration and lead to shrinkage of pituitary adenomas. Such treatment is also safe during pregnancy. Other intracranial lesions causing hyperprolactinemia are usually treated by surgical removal.

Certain drugs (e.g. tranquilizers, ganglion blocker antihypertensives, antidepressants, thiazides and narcotics) can also lead to a significant elevation in blood prolactin. Drug-induced hyperprolactinemia can be reversed by modifying or withdrawing the causative medication. In cases where this cannot safely be done, bromocryptine derivatives can be used.

Elevated Prolactin and female Reproductive Performance: it is important to recognize that even modestly raised prolactin levels (20ng/ml-40ng/ml) can interfere with response of the uterine lining to estrogen (i.e. endometrial proliferation) as well as ovarian follicle growth and development, thereby reducing reproductive potential, and may require treatment with prolactin suppressants such as Parlodel.

Hyperprolactinemia is often an early indicator of impending or existing thyroid hormone deficiency or hypothyroidism (Hashimoto’s disease) which in most cases results from antithyroglobulin and/or antimicrosomal antibodies that attack thyroid hormone producing glands, replacing them with connective tissue. In about 50% of cases where the woman has such thyroid antibodies in her blood (regardless of whether or not they have concomitant hormonal or clinical evidence of thyroid deficiency) she will also have increased natural killer cells activity(NKa). When this happens embryo implantation will likely be impaired and the woman will often present with inability to conceive (“infertility”), unexplained IVF failure, or with recurrent pregnancy loss (RPL).

It is my opinion that all women who manifest with such reproductive problems, women who have a personal or family history of hypothyroidism and those in whom hyperprolactinemia or elevated blood levels of thyroid stimulating hormone (TSH) are detected, be tested for antithyroid antibodies and NKa (using the K-562 target cell assay) and that women found to have such antibodies as well as NKa, undergo selective immunotherapy with Intralipid (IL) infusions plus steroid (prednisone, prednisilone, dexamethasone) therapy to down-regulate NKa. IL is administered intravenously 7-14 days prior to embryo transfer (or about 4-7 days prior to ovulation or egg retrieval) and then repeated once more, immediately upon biochemical confirmation (beta hCG blood test) of embryo implantation. The steroids are continued to the 10th week of pregnancy and then slowly tailed off.

What often goes unrecognized is that treatment of hypothyroidism with thyroid hormone replacement alone, while resolving the hormonal imbalance associated with hypothyroidism will usually not resolve associated reproductive dysfunction due to associated immunolgic imlantation dysfunction.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Traveling for IVF from Out of State/Country–
• A personalized, stepwise approach to IVF
• How Many Embryos Should be Transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF
• Measuring and Interpreting Blood hCG to Assess Pregnancy Viability Following ART Treatments.
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

reply
Emily

Thanks dr. Sher my level is 22.9 ng/ml for my fet I will be on steroids and intralipids do you think I need parlodel as well? Thanks

reply
Dr. Geoffrey Sher

In my opinion…no you do not need Parlodel at a prolactin level of 23ng/ml. However, discuss with your personal RE. Also, look in to your TSH level, and if >3.0 MIU/ml, check antithyroid antibodies as well as natural killer cell activation (by the K-562 target cell test.

Good luck!

Geoff Sher

Geoff Sher

reply
Rachel

Hi Dr. Sher,
Thank you so much for your blog! I’ve been reading it for some time and thought I would seek your opinion. I am 34 y/o. Started trying to conceive at age 32, became pregnant after only two months. Miscarriage at 5+3. After that miscarriage, I began having luteal phase spotting with each cycle (but still regular, 28 day cycles with regular ovulation on first response tests). Chemical pregnancy a few months later. Due to my abnormal bleeding, I started seeing a fertility clinic about 6 months after that first miscarriage. Started several months of luteal phase progesterone suppositories and did a few timed intercourse cycles. Then tried letrozole for one of the timed cycles, then had IUI with letrozole and gonol. Our second IUI was with letrozole and menopure and was successful but I miscarried again at 7 weeks. We had excellent stimulation with the IUI cycles, achieving 2-3 great looking follicles each time. After that miscarriage, we tried an antagonist IVF protocol with gonol and menopure (OCP prior to starting the drugs), got only 5 follicles that matured, retrieved 2 but none made it to blast. Second IVF cycle was a micro-dose flare protocol that was cancelled due to poor response and converted to IUI. My AMH came back VERY low at 0.13, my FSH has been as high as 12 but is typically about 9. My antral follicle count ranges from 7-11. My sonohystogram is normal. My lining is typically quite thin. No male factor present.

So there’s a synopsis of the past year and a half for us….any suggestions for our next protocol? I’m hopeful despite our terrible numbers that we’ll be successful as I’m relatively young (at least in the fertility world!) and I’ve been pregnant 3 times already.

Any advice you can offer is much appreciated!

reply
Dr. Geoffrey Sher

Hi Rachel1

There are two issues here. The first and the most concerning is your declining ovarian reserve. This needs a revised approach to your stimulation protocol and quickly, before it is too late. In my opinion, “microdose” (“flare”) Lupron protocols,and high dosage Menopur protocols, should best not be used in women with DOR (see below). It surges LH and with it ovarian testosterone as the stimulation begins and this can have a deleterious effect on egg quality/competency…especially in older women and also in women such as yourself who have DOR. You need a modified, robust, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts, to make hay while the sun still shines.

The second issue is your prior recurrent pregnancy loss.When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

• Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
• Immunologic testing to include:
a) Antiphospholipid antibody (APA) panel
b) Antinuclear antibody (ANA) panel
c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d) Reproductive immunophenotype
e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f) Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.

Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

• Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
• Immunologic testing to include:
a) Antiphospholipid antibody (APA) panel
b) Antinuclear antibody (ANA) panel
c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d) Reproductive immunophenotype
e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f) Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.

Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

• Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
• Immunologic testing to include:
a) Antiphospholipid antibody (APA) panel
b) Antinuclear antibody (ANA) panel
c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d) Reproductive immunophenotype
e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f) Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.

Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate?
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Why did my IVF Fail
• Recurrent Pregnancy Loss (RPL): Why do I keep losing my Pregnancies?
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report)
• Traveling for IVF from Out of State/Country–
• A personalized, stepwise approach to IVF
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

reply
Alyssa

Dr Sher,
This is going to be a bit lengthy. I am so thankful and grateful for your expertise. I am a ball of stress right now. I will try to shorten this up as much as possible.

At the age of 28, had my first pregnancy. It ended up being a blighted ovum and I had to have a D&C. Tried for another year and nothing. My fsh was 10.1 (not sure why) my amh was 3.97 and I had 25+ follicles. Did my first round of IVF in 2014 at the age of 29. Retrieved 22 eggs, 8 were mature, 8 fertilized. Put in a day 3 grade A embryo… cycle failed. Did a frozen the following month of two 8 cell grade A embryo. at 6 weeks we saw two heartbeats. At 8.5 weeks, again two heartbeats. Baby A’s Sac was measuring really far behind but when I questioned it, no one would answer.
At 20 weeks, we found out that baby A had passed around 9.5 weeks. I also ended up with a DVT in my left groin at 30 weeks and was treated with lovenox.
FF to Jan 2016. Did a frozen embryo transfer. Positive pregnancy test. My cycle was manipulated with estrace and progesterone. My estrogen dropped after the pregnancy was confirmed. It was 1,700 a few days later it dropped to 200, a few days later, back up to 1,800 and the last two draws have been around 250. HCG increasing substantially. Well, Last Tuesday, I was 5 weeks 5 days, I Started bleeding heavily.. went in for a scan and everything was good and measuring appropriately. There was blood in my uterine cavity but they had no idea why.. possibly the lovenox. Went home, rested and bleeding stopped. three days later, the bleeding started again but this time, I passed two extremely large clots. I thought that was it. I went to the dr for another scan ( I was 6 weeks 1 day). I couldn’t believe it when there was a heartbeat of 106.. My dr cannot explain any of this. I am so scared and confused. My morning sickness is awful and my fatigue is so bad. I just don’t know how to feel.

reply
Dr. Geoffrey Sher

I am so sorry that you are going through all this.You certainly are on a roller coaster. Clearly you are having a sub-chorionic bleed.This could absorb and hopefully it will do so over the next month or two. After this pregnancy is over (be it successful or not), I would suggest that you be evaluated thoroughly for an implantation dysfunction (anatomical or immunologic). I wish I could be more helpful, but there is probably nothing that can be done at this time. You just have to wait it out. In the interim, be sure to follow the advice of your treating doctor.

G-d bless!

Geoff Sher

reply
Emily

Doctor sher I followed your long protocol for people with pcos ended up coasting for 5 days had over 40 follicles but only got 6 mature eggs can u maybe explain to me why this might be. I was Devasted when they told me .7 were over 22 mm about 16 were between 14 and 22 mm.

reply
Dr. Geoffrey Sher

First, coasting is not a magic formula. Success absolutely depends on implementation. This relates to the dosage and type of fertility drugs used , but most importantly when the coasting was started. IT MUST be initiated not before an E2 of >2500pg/ml is reached in association with >50% of follicles measuring between 14 and 16mm. If you wait until later than this point to initiate the coast (i.e. when most follicles are >16mm), the follicles will grow too large (by the time of the hCG trigger) and the eggs they harbor will be dysmature (immature or mature but of poor quality). If the coast is started prior to 50% of follicles having reached 14mm in diameter, the eggs will be poor quality too. Then comes the important requirement that the E2 be allowed to drop to below 2500pg before the “trigger is initiated. Finally the trigger must be with 10,000U HCG or 500mcg of Ovidrel…not less …nor should a Lupron trigger be used.

In most cases the type of outcome you experienced will have to do with less than optimal implementation. This having been said, even with optimal “coasting” technique, women with PCOS have poorer egg quality that is genetically based and will have a lower percentage of healthy eggs no matter what you do. Not all cases with PCOS respond the same way!

To give you a better insight into the concept of egg immaturity/postmaturity/dysmaturity:

One commonly hears patients undergoing IVF state that they had too many “immature eggs”, and suggesting that had more time been allotted to ovarian stimulation with fertility drugs, this might not have happened. Nothing could be further from the truth. In fact, the duration of ovarian stimulation is rarely the cause of egg “immaturity”. More often than not, it can be attributable to the use of an unsuitable protocol for ovarian stimulation, especially in cases of advanced maternal age, diminished ovarian reserve and in cases of polycystic ovarian syndrome (PCOS). This article takes a look at the implications of “Egg Maturation” and its role in IVF outcome.

Background

Within 38-42 hours of the onset of the spontaneous LH surge in normally ovulating women (or following the administration of human chorionic gonadotropin (hCG) to women undergoing ovarian stimulation with fertility drugs), the total number of chromosomes in the egg nucleus is reduced through a process known as meiosis or “maturational division”. The purpose of meiosis is to halve the total number of chromosomes from 46 (the normal human genomic number) to 23 by expelling them in a membranous envelopment known as the 1st polar body (PB-1). The PBI comes to lie in a narrow space (the viteline space) which is located between the egg’s outer shell (zona pellucida) and the membrane that surrounds the inner egg substance (the oolema) where it can often be identified microscopically.

The PB-1 soon undergoes degeneration and, within a few days of meiosis having been completed, disintegrates and absorbs completely. An egg with a microscopically detected PB-1, is referred to as being “mature” (M-II). An “immature” egg (M-I) is one that has failed to undergo maturational division (meiosis) and thus has all 46 chromosomes intact. In this form, the immature egg is incapable of propagating a healthy embryo (see below).

In order to be capable of fertilizing an egg, the sperm must likewise undergo meiosis, the purpose of which is to reduce its chromosome number from 46 to 23. Upon fertilization of the M-II egg with a mature spermatozoon, the resulting embryo will have a chromosome number equal to the combined contribution by both egg and sperm. The objective is for fertilization to involve an egg and a spermatozoon that each have precisely 23 chromosomes, such that the resulting embryo will contain precisely 46 chromosomes (euploid) and thus be “competent” to propagate a normal baby. Embryos with more or less than 46 chromosomes (aneuploid) are “incompetent” and generally either arrest during development, fail to implant normally, are lost in early miscarriage, or will result in a chromosomal developmental defect such as Down syndrome. In more than 70% of cases, embryo aneuploidy (“incompetence”) is the direct result of the egg (rather than the sperm) undergoing abnormal maturation that results in there being more than or less than 23 chromosomes prior to fertilization.

The confirmation microscopically that an egg is “mature”, in no way insures that it has precisely 23 chromosomes. In fact, in humans, more often than not, M-II eggs will indeed have more than or less than 23 chromosomes (aneuploid eggs) and accordingly be incapable of propagating euploid embryos following fertilization. This propensity increases with advancing age and in the presence of certain conditions such as polycystic ovarian syndrome (PCOS), but can also be aggravated by the use of suboptimal protocols for ovarian stimulation (especially when it comes to women who have diminished ovarian reserve). This is why it is so important to be highly individualized in selecting the protocol used for ovarian stimulation in such cases.

To recap….the detection by microscopy, of a PB-1 situated immediately under the egg’s zona pellucida, indicates that maturational division (meiosis) has been completed. BUT it does NOT provide assurance that chromosome segregation has been orderly (i.e. that precisely 23 chromosomes remain in the egg nucleus) and that the egg is “euploid”. The presence of even one more or one less than 23 chromosomes is referred to as egg “aneuploidy”… a condition that almost always results in failed embryo development, failed implantation, miscarriage or a chromosomal birth defects such as Down’s syndrome. As it turns out, even in younger women, half to two thirds of M-II eggs are aneuploid and this incidence increases rapidly with advancing age beyond 35 years.

Another interesting fact is that an embryo that fails to reach the blastocyst stage is almost invariably aneuploid (“incompetent”) and is thus doomed from the get-go. On the other hand, embryos that do make it to the blastocyst stage, while being much more likely to be euploid, are often aneuploid and incompetent. Even in young women with normal ovarian reserve, less than 50% of blastocysts will be aneuploid and percentage increases progressively with advancing age. And this incidence can be further influenced by the protocol used for ovarian stimulation as well as the timing and dosage of the hCG used to “trigger” egg meiosis at the end of the stimulation process. When the hCG trigger is administered too early or too late, or too low a dosage of hCG is administered (5,000U rather than 10,000U of hCGu or 250mcg rather than 500mcg of hCG-Ovidrel), the egg might not be developmentally positioned to undergo orderly meiosis. The result could be an increase in the percentage of immature (M-I) or mature M-II (but aneuploid), eggs.

The terms “immature” and “post-mature” as applied to eggs, are thus often erroneously interpreted as meaning that the eggs were harvested too early, and that performing the egg retrieval a day or two later would have prevented this problem. This suggestion infers that M-I eggs result from their being harvested before they were developmentally ready to enter meiosis. This inference is completely erroneous. In fact, as previously stated, an M-I egg could just as easily have resulted from delaying the hCG trigger too long or from using the wrong timing or dosage. Likewise, a “post-mature” egg can result just as readily from administering hCG too early as too late. For these reasons, the terms “immature” and “post-mature,” as applied to eggs, should be supplanted by the term “dysmature” which simply implies that the M-1 or M-2 egg in question is maldeveloped, aneuploid and “incompetent”.

Finally, it is important to bear in mind that severely aneuploid eggs often remain densely attached to the inner wall of the follicle and fail to loosen sufficiently from surrounding cells during follicle aspiration. When this affects most or all available follicles, this condition is often referred to as “Empty Follicle Syndrome (EFS)”. It is an erroneous diagnosis because a follicle requires an egg to grow. The more likely explanation is severe egg “dysmaturity”.

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
• Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

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Laura

Hello Dr Sher,
I was wondering if there are any instances where you recommend a higher dose than 0.75mg of dex for autoimmune (w/o alloimune) ID? In instances of repeated IVF failure despite good embryos with immune protocol? Or is this dose always consistent regardless? Thank you

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