Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Dear Dr Sher, I’ve been pregnant 3 times. In 2015, with an IVF day 3 fresh transfer in Cornell no immune treatment just prednisolone. Only 2 embryos made it to day 3 (8 and 9 cells). Normal baby no issues in pregnancy. Then in 2017, an IUI in Asia (miscarriage at 7 weeks due to trisomy 13). Then another IVF day 3 transfer (no frozen embryos) and miscarriage in 2017 (no D&C).
We have the results of the Chicago NK (attached) assay full panel (%cd19+cells, cd5+ is high, TNF:a-IL10 (CD3+ CD4) is also high). First one is 17.4 and second is 34.7, so slightly higher than the upper limit of the expected range. No testing after the Intralipid or IVIG treatment.
I also consulted with Dr Gleicher in 2018 in NY. He recommended using clexane and a higher dose of prednisolone. No issues according to the results. No PCOS. He recommended using DHEA.
I’ve been doing IVF for a couple of years overseas and recently I transferred 2 PGTa tested embryos with my RE in Asia (in the last transfer no immune protocol). My endometrial lining has been a recent new complication since December 2018. In the last transfer, it reached 7.5 and then decreased to 6.5, back to 7 and was at 6.8 at the time of the transfer. During these cycles, my RE recommended using estrogen and progesterone. The estrofem 2mg is once a day for 4 days (oral and vaginal) and then twice a day for 5 days (each time is one oral and one vaginal). With this protocol the estrogen levels (Estradiol) reached 1552 pgml (2 days after transfer) and Progesterone was 13.9 ngml. The medicated transfer follows the ERA test results of 5 days +2 hrs (ERA test was done with intralipids). Progesterone is a suppository Endometrin 100mg 2 times per day, then was increased to 3 times per day. My RE also recommends using prednisolone (10mcg for 5 days until the transfer and 25mcg until the pregnancy test). After transfer, my RE adds another progesterone Duphaston (1 tab 3 times daily). I read that dexamethasone might be better than prednisone.
We have tried one transfer with IVIG (1 transfer, pgta tested embryo), another 2 transfers with intralipids (1 transfer, pgta tested embryo). All these transfers also include Humira, Clexane (40mg injection), prednisolone and plaquenil (200mg 2 times daily). Viagra 2 times per day. Cardiprin 100mg. Metformin 500mg 2 times daily. The trigger shot is Ovidrel 500mcg. Humira and Clexane is done before the transfer, and we continue with Clexane until pregnancy test.
We didn’t use the immune suppressants during the last transfer due to the coronavirus circulating globally. For the last IFF cycle (DEC 2019), the stimulation was based on pergoveris and gonalF and we got 4 good PGTA embryos and 2 didn’t amplify. We transferred 2 embryos in March 2020 (FET) based on the ERA test results (includes intralipids).
My RE does not want to make a transfer this cycle, and he recommended reaching out to you to do something different. We are following a natural cycle and monitoring the lining, hopefully it will reach 8+mm as it was in 2018.
We are wondering if we should consider a FET during a natural cycle (current cycle and if it reaches the threshold for the lining) and also if we should be using Neupogen injections, or if the problem is the embryo quality (all the transfers in 2019 are PGTA tested) or if the main issue is the lining. We are also wondering if we should consider a DQ-Alpha and HLA gene testing. My husband is originally from Asia and I’m originally from Spain.
Thanks for your help in advance.
Hi Carol!
There are a few issues:
1. Thickness of the endometrium, prior to the “trigger” or starting progesterone (if you are on an FET)must be at least 8mm (preferably >9mm). Less than 8mm, is in my opinion rarely associated with a viable baby. At 6-7mm your lining is deficient. To try to improve it would require compounded vaginal Viagra (sildenafil), 25mg X 4 per day starting after the period ends and discontinued at the time of the “trigger” or progesterone administration. Administration of more estradiol alone, will rarely work as evidenced by your report that even with an [E2] of 1500pg/ml your endometrial thickness was still not adequate. If both Viagra + Estradiol (preferably administered by injection every 3 days (Delestrogen)or transdermally (Vivelle skin patches) fails to optimise the lining, then you might have an intractable problem, perhaps caused by clinical or sub-clinical postpartum or post-abortal endometritis. A hysteroscopy would be helpful in trying to identify intrauterine synechea (scarring) which if present would be an argument in favor of the endometritis diagnosis.
Immunologic Implantation Dysfunction (IID):
The fact that you had a baby , while making the diagnosis of autoimmune IID less likely, does NOT out a variety of IID known as alloimmune implantation dysfunction where there is a DQ alpha/HLA genotypic match (see below—under “management of IID). This typically can occur after a normal birth. It requires very individualized management and will reduce the chance of success, even with using Intralipid/steroids or IVIG/steroids which is the standard treatment for the “autoimmune variety”.
3. Embryo aneuploidy:
Short of a translocation (diagnosable by karyotyping both you and your husband, the other consideration is whether the numerical chromosomal integrity of the embryos transferred was abnormal (aneuploid). Aneuploidy increases with advancing age and can be impacted on by the protocol used for ovarian stimulation. I suggest that IF you do another fresh retrieval, all blastocysts be tested for their chromosomal integrity, using PGS/PGT. By the way, while pregnancies are reported after re-testing frozen blastocysts, the chance of success can be compromised by the traumatic effect on such embruyos resulrting from rthe thaw-test-refreeze-rethaw for FET, process.
Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented.
WHO SHOULD UNDERGO IID TESTING?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
•A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy)
•A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
•“Unexplained” infertility
•Recurrent pregnancy loss (RPL)
•A history of having miscarried a conceptus that, upon testing of products of conception, was found to have a normal numerical chromosomal configuration (euploid).
•Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
oFor Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
oFor Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of Intralipid (IL) /immunoglobulin-G IVIG) can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later. In addition, to be effective, IL/IVIG therapy needs to be combined with steroid (dexamethasone/prednisone/prednisolone) therapy to down-regulates (often) concomitantly activated T-cells.
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.
•The Role of 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) Why did my IVF Fail
•Recurrent Pregnancy Loss (RPL): Why do I keep losing my PregnanciesGenetically Testing Embryos for IVF
•Staggered IVF
•Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
•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.
•IVF: Selecting the Best Quality Embryos to Transfer
•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?
•Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
•Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
•Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
•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
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ADDENDUM: PLEASE READ!!
ADDENDUM: PLEASE READ!!
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Geoff Sher
Hi Dr. Sher – thank you for your unbelievable service to the world.
I’m pregnant (34) with an untested embryo. My starting beta was 579 and my second beta 4 days later was 4100.
How likely is it that this embryo is normal versus abnormal based upon the fact that it implanted and that the betas are so high? I’m currently 5 weeks along and know I cannot test for genetic abnormalities until week 9, so I’m trying to fill the time void with some level of reassurance. Thank you!
Hi iz,
Congratulations!
This looks very promising!
Good luck!
Geoff Sher
Hi Dr Sher,
I’d love to hear your thoughts on whether the following PGS NGS tested blastocyst would be suitable to consider transferring;
46;del(4)(q34.1-qter) aneuploid:deletion on long arm of chromosome 4.
If so, what sort of prenatal screening should I do if successful? NIPT? Amniocentesis?
Considering my options as elective surgery is winding down in Australia bc of Coronavirus.
I would consider transferring this embryo. As long as you undertake to do CVS or amniocentesis in the event of a pregnancy, so as to enable you to consider terminating the pregnancy in the event of a chromosomally compromised conceptus.
Geoff Sher
Hi Dr. Sher,
I am 29 years old and am currently doing IUI treatment. This is my third and final IUI before the clinic suggests IVF. The first round of IUI I had a positive test and blood test, but quickly had a chemical pregnancy a few days later. The second IUI was negative. This last IUI was positive. I am currently 6 weeks and 5 days, throughout this pregnancy my hcg has risen significantly but never doubled in the 48 hour range. The clinic has always told me it was rising slower but still in the appropriate range. Last week around 6 weeks or so they did a vaginal ultrasound. Everything was in the correct place, however they said the embryo was a little on the small side, but still in appropriate range. I had a follow up ultrasound today, the doctor said to prepare for a miscarriage and asked if I wanted to set up a D&C, as no heart beat was detected. I did not feel comfortable with doing this. My husband and I are aware this is not a good prognosis, but felt it was too soon to end it. What are your thoughts?
There should be no harm in delaying a decision for a week or so!
Good luck!
Geoff Sher
Can you explain the benefit of “Estrace priming”? Is this different than what you mention as the birth control pill. Would Estrace priming go well with these protocols: a long-pituitary down regulation GnRH agonist protocol or a GnRH antagonist protocol (with the antagonist started with the FSH)? Advanced maternal age. Thank you
Estrogen priming can help certain women who have VERY diminished ovarian response. My preference is to administer transdermal or parenteral (by injection SC) estradiol so that it reaches the systemic circulation directly and thereby the ovaries. Oral estrogen first passes through the liver via the portal system) where it is altered before reaching the systemic circulation, so in my opinion oral estrogen priming is not optimal. Then, as far as estrace is concerned, I perfer not to use it as a disproportional percentage may be metabolized to estrone which is not ideal. If oral estradiol is used, my preference would be to take estradiol valerate (Progynova) which does not as readily convert to to estrone.
My protocol for E2 priming is a combination is to prescribe ransdermal vivelle skin patches, overlappee with an agonist in the last few days, followed at the onset of the period by SC estradiol valerate (Delestrogen) twice weekly until the “trigger”.
Good luck
Geoff Sher
Hi Dr Geoffrey Sher,
I recently underwent and IVF with a failed transfer.
I’m 35 years old, my FSH 9, AMH 13,5. Prolactin, TSH including T4 were all normal. I have bilateral Endometriomas both measuring approx 3cm each, and couple of small fibroids which are not distorting the uterus.
My protocol was:
Gonapeptyl 3.75 injection to suppress ovaries
Menopur 450iu for 13 days
Gonasi hCG 10,000iu for follicular maturation
Cyclogest 400mg pesseries starting on the morning of the egg collection, one in the morning and one in the evening
The outcome was 7 eggs collected, 3 fertilised. I had day 3 transfer- 1-8 cell and 1-6 cell embroys, both perfect shape. 3 rd embryo had 7 cells but shape wise wasn’t as perfect as the two transfered however it was good enough to freeze.
Unfortunately embies didn’t take in as started bleeding 2 days before testing( 12dpt).
My questions are:
1. Was my progesterone level not high enough to support the implantation since I started bleeding before testing?
2. Should I be put on natural killer cells medication to suppress the Endo inflammation and support the implantation success?
3. Should my testosterone or DHEA Level be tested as well since I have endometriosis and fibroids ( estrogen dominant condition) to support potentially better egg production during the cycle? If not, Can I still take DHEA daily before my next cycle?
Thank you so much in advance!