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.
Hi Dr Sher, my husband and I are a full DQ alpha match and l am NK cell positive but are finally pregnant (20 weeks) after doing LIT, and using dexa, clexane, progesterone, aspirin and intralipids. All this support (meds) stops at 24 weeks. Why does it stop then and can I be sure that my body will not reject my baby when the meds stop?
Thanks.
Hi Effie,
This is possible, but very unusual. I would love to see your immune test results and learn where they were conducted. Either way, in my opinion it would be safe to discontinue IL therapy at 24 weeks, but you need to follow whatever advice you receive from your own treating doctor.
Good luck!
Geoff Sher
Geoff Sher
Hi Dr. Sher, Hope you are well ! i wanted to ask you regarding elevated cytokines. I responded better to IVIG infusions than intrallipds meaning my nk cells went down significantly with the IVIG infusions, however it was discovered that my cytokines increased. In this case would humira be of help to reduce the cytokines or do you believe there is an alternate way to reduce cytokines when doing IVIG infusions? thanks !
‘
Good luck!
Geoff Sher
My husband and I have been trying to have children for almost six years. We were with a local RE for over two years of that time, during which we tried different medications, hormone therapies, IUIs, and started the IVF process twice (both times we had to stop the cycle early for various reasons, unrelated to the IVF). I am currently 42 years old, and so obviously, older eggs have been a likely contributor to our lack of success in achieving a viable pregnancy.
That being said, I want to make sure we are not overlooking any other factors that could be causing failure. I have been pregnant twice, and both were spontaneous (in between treatments). The first ended very early, with slow rising hCG and no gestational sac ever present. The second ended as a blighted ovum. My numbers on blood tests have always shown less than stellar values for egg quality. But until recently, these numbers were still not that bad for my age (according to my RE). However, based on a most recent blood test last December, the numbers were considerably worse (AMH 0.6, FSH 24). So we have switched to trying IVF with donor eggs. I had my first donor egg transfer a few weeks ago. We actually went to Europe (Czech Republic) for the cycle, because the cost was so very much cheaper there. I had some immunology tests run prior to the cycle (3 days prior to the donor’s egg retrieval), because I was trying to check out all possibilities. I had a panel which tested for some standard antibodies (anti-sperm, IgM, IgG, etc.). These numbers were all within normal range. Then I had a panel related to NK cells (CD4, CD3, etc.). A few numbers were slightly high, and one was slightly low. The doctor in Europe did not seem particularly concerned, but did have me start taking Fraxiparine injections (comparable to Lovenox here in the US, I believe). He said that we could also do intralipid infusions the next time, but that would need to happen 2-3 days prior to embryo transfer.
I did not get pregnant from that transfer. We have one high quality frozen embryo (and a second that is very poor quality, but we asked them to freeze it as well) that we want to go back for. For financial reasons, we will likely have one more try with the frozen embryos, and possibly one more complete donor cycle after that. So I am trying to decide what course of treatment will give me the best chance for success.
I have read various journal abstracts and/or articles on this matter, and it seems that there are varying opinions on whether things like blood thinners and intralipid infusions are worthwhile. One such article even makes me think that it might be worthwhile to have intercourse several days before the embryo transfer, for Treg expansion? I have also read about the possibility of HLA matching for things like donated organs, and wonder if it would be beneficial or feasible to test for this with an egg donor. I am really desperate to find some answers, and try to increase our chances for success with our next (and possibly last) attempt.
I can send the immunology blood test results if that would help in your assessment.
Thank you so much!
1. Own eggs versus OD:
I understand that you have moved to donor eggs but for the sake of interest let me tell you how you might still be able to use own eggs:
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”.
2. Why IVF fails:
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).
3.Use of Intralipid and steroids but to be effective, should (in my opinion) be combined and initiated 10-14 days prior to ET):
Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid. It is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid), 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).
Possible Mode of Action:
It is thought that fatty acids within the emulsion serve as ligands to activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent. Interestingly, similar to Intralipid 1% Propofol also contains the same concentration of soybean oil, and purified egg phospholipid, with glycerin. Perhaps its use offers a fringe benefit in cases of immunologic implantation dysfunction.
Whatever the exact mechanism of action might be, IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which in my opinion do so by immune modulation of T cells . The combined effect of IL + steroid therapy is thought to suppresses pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha, produced in excess by activated NK cells and cytotoxic T cells.
IL will in about 80% of cases, successfully down-regulats activated natural killer cells (NKa) within 2-3 weeks. In this regard it is likely to be just as effective as IVIg but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
Can in-vitro (laboratory) tests assess for an immediate benefit of IL on Nka?
Since the down-regulation of NKa through IL (or IVIg) therapy can take several weeks to become detectable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.
Treatment of NKa Using IL:
•Autoimmune Implantation Dysfunction: When it comes to NKa in IVF cases complicated by autoimmune implantation dysfunction, the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14 days prior to embryo transfer and repeated once more (only), as soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s) in women under 39Y (who have normal ovarian reserve) is approximately 80%.
•Alloimmune Implantation Dysfunction
oPartial DQ alpha match: IVF patients who have NKa associated with a partial alloimmune implantation dysfunction (DQ alpha match between partners) we use the same IL, infusion as with autoimmune-NKa, only here we prescribe oral prednisone rather than dexamethasone until the 10th week of pregnancy and IL infusions are repeated every 2-4 weeks following the chemical diagnosis of pregnancy until the 24th week. Additionally, (as alluded to elsewhere) in such cases we transfer only a single embryo at a time. This is because in such cases, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Since we presently have no way of determining which embryo carries the matching paternal DQ alpha gene and thus would transfer only one embryo at a time, it follows that the anticipated viable pregnancy rate per cycle will be much lower than with autoimmune implantation dysfunction. It also follows the only way to improve success with a single embryo being transferred would be to perform PGS on the embryos in advance of ET and then selectively transfer a “chromosomally normal-euploid (“competent”) embryos.
oTotal (complete) DQ alpha Match: In cases where the partners have a total alloimmune (DQ alpha) match with accompanying NKa the chance of a viable pregnancy occurring or (if it does) resulting in a live birth at term, is so small as to be an indication for using a non-matching sperm donor or resorting to gestational surrogacy would in our opinion be preferable by far.
Contra-Indications and Cautions with Intralipid Infusion:
IL is only contraindicated in conditions associated with severely disordered fat metabolism (e.g. severe liver damage, acute myocardial infarction and shock,
Rarely, hypersensitivity has been observed in patients allergic to soybean protein, egg yolk and egg whites and where fat metabolism may be disturbed (e.g. renal insufficiency, uncontrolled diabetes, certain metabolic disorders and in cases oif severe infection (sepsis) sepsis
Adverse Reactions During Infusions of IL (rare):
Adverse reactions (rare) reported to occur during and/or following infusion of Intralipid include: transient fever, chills, nausea, vomiting, headache, back or chest pain with dyspnea and cyanosis.
In cases of verified or suspected liver insufficiency, liver function must be closely followed. If increased levels of transaminases, alkaline phosphatases or bilirubin appear, infusion of Intralipid should be withheld or postponed, until normalization is achieved.
Very rare cases of hypersensitivity have been observed in patients allergic to soybean protein, egg yolk and egg whites.
Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes, certain forms of liver insufficiency, metabolic disorders and sepsis.
Administration:
The drip rate is adjusted to 500 ml of a 20% solution should be infused over about 3 hours. The infusion should be started at half the infusion rate during the first 30 minutes, under supervision.
Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid. It is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid), 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).
Possible Mode of Action:
It is thought that fatty acids within the emulsion serve as ligands to activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent. Interestingly, similar to Intralipid 1% Propofol also contains the same concentration of soybean oil, and purified egg phospholipid, with glycerin. Perhaps its use offers a fringe benefit in cases of immunologic implantation dysfunction.
Whatever the exact mechanism of action might be, IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which in my opinion do so by immune modulation of T cells . The combined effect of IL + steroid therapy is thought to suppresses pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha, produced in excess by activated NK cells and cytotoxic T cells.
IL will in about 80% of cases, successfully down-regulats activated natural killer cells (NKa) within 2-3 weeks. In this regard it is likely to be just as effective as IVIg but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
Can in-vitro (laboratory) tests assess for an immediate benefit of IL on Nka?
Since the down-regulation of NKa through IL (or IVIg) therapy can take several weeks to become detectable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.
Treatment of NKa Using IL:
•Autoimmune Implantation Dysfunction: When it comes to NKa in IVF cases complicated by autoimmune implantation dysfunction, the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14 days prior to embryo transfer and repeated once more (only), as soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s) in women under 39Y (who have normal ovarian reserve) is approximately 80%.
•Alloimmune Implantation Dysfunction
oPartial DQ alpha match: IVF patients who have NKa associated with a partial alloimmune implantation dysfunction (DQ alpha match between partners) we use the same IL, infusion as with autoimmune-NKa, only here we prescribe oral prednisone rather than dexamethasone until the 10th week of pregnancy and IL infusions are repeated every 2-4 weeks following the chemical diagnosis of pregnancy until the 24th week. Additionally, (as alluded to elsewhere) in such cases we transfer only a single embryo at a time. This is because in such cases, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Since we presently have no way of determining which embryo carries the matching paternal DQ alpha gene and thus would transfer only one embryo at a time, it follows that the anticipated viable pregnancy rate per cycle will be much lower than with autoimmune implantation dysfunction. It also follows the only way to improve success with a single embryo being transferred would be to perform PGS on the embryos in advance of ET and then selectively transfer a “chromosomally normal-euploid (“competent”) embryos.
oTotal (complete) DQ alpha Match: In cases where the partners have a total alloimmune (DQ alpha) match with accompanying NKa the chance of a viable pregnancy occurring or (if it does) resulting in a live birth at term, is so small as to be an indication for using a non-matching sperm donor or resorting to gestational surrogacy would in our opinion be preferable by far.
Contra-Indications and Cautions with Intralipid Infusion:
IL is only contraindicated in conditions associated with severely disordered fat metabolism (e.g. severe liver damage, acute myocardial infarction and shock,
Rarely, hypersensitivity has been observed in patients allergic to soybean protein, egg yolk and egg whites and where fat metabolism may be disturbed (e.g. renal insufficiency, uncontrolled diabetes, certain metabolic disorders and in cases oif severe infection (sepsis) sepsis
Adverse Reactions During Infusions of IL (rare):
Adverse reactions (rare) reported to occur during and/or following infusion of Intralipid include: transient fever, chills, nausea, vomiting, headache, back or chest pain with dyspnea and cyanosis.
In cases of verified or suspected liver insufficiency, liver function must be closely followed. If increased levels of transaminases, alkaline phosphatases or bilirubin appear, infusion of Intralipid should be withheld or postponed, until normalization is achieved.
Very rare cases of hypersensitivity have been observed in patients allergic to soybean protein, egg yolk and egg whites.
Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes, certain forms of liver insufficiency, metabolic disorders and sepsis.
Administration:
The drip rate is adjusted to 500 ml of a 20% solution should be infused over about 3 hours. The infusion should be started at half the infusion rate during the first 30 minutes, under supervision.
Thank you so much for your response. Certainly a lot to consider! I wanted to send the numbers from my immunology blood work that I had completed 3 days prior to the donor’s egg retrieval. In your opinion, do you think that intralipid infusions or blood thinners would be valuable? I have copied the information for the values that were not in the expected range. I do not know the units.
CD3 in peripheral blood
80.3normal range 30-80
CD4 in peripheral blood
59.2normal range 35-55
CD3-(16+56)+NK cells
5.1normal range 6-22
CD4/CD8
3.44normal range 1-2.5
Hello Dr. Shar,
I am 31 years old and will turn 32 in November. I have Asherman’s Syndrome. I had a termination year ago. I found out I had AS after I tried to conceive for years to no avail. I decided to see a specialist and after an HSG and Ultrasound, she decided that a Hysteroscopy was our best shot. I had the procedure done on 6/2014 and received post –operative Estrogen, antibiotics and had a balloon catheter in for three days. I continued to take the Estrogen until I finally got pregnant after my second cycle. Sadly, there was no heartbeat 7 weeks. I had D&C weeks later due to the “missed” miscarriage. I had Scanty periods for several months but it finally went back to normal ( 24-25 cycle).
On April 2016, I had another hysteroscopy because I was unable to conceive after the D&C. This time around, my doctor decided to place estrogen cream around the balloon catheter, which was suppose to stay in for a week. She placed a gauze inside to keep the cream from coming out. She explained that this method would deliver more estrogen directly into the endometrium. Around 4 days post- op, I started bleeding heavily and passing massive size blood clots the size of my fist. I called the paramedics and was taken to the ER. They did not remove the catheter because they said my doctor was the only one who could remove it. I waited two more days to see my doctor and she removed. She said there was a weird odor which could be an infection, therefore she had me on antibiotics for another 7 days. The pap smear came back negative for an infection but there was still an weird odor.
When I voice my concerns she simply said that I was stressing this “baby issue” too much and that I should consider adoption. I chose to stop going to my doctor because I am not satisfied with the level of care. I also seem to know more about AS than she does. I want to see an actual AS specialist who can give me more treatment options.
It’s been over 4 months since my last hysteroscopy and I have not conceived. I have regular periods, however I continue to spot days after what is suppose to be the last day of my 5 days. Since the surgery, I’ve been spotting (brownish) for up to 4 days after the last day of my cycle. The first month after surgery I was either spotting or bleeding for an entire month. At times, it hurts to have intercourse.
I keep wondering if it was malpractice and the procedure did more harm than good.
I am slowly losing hope.
What can you recommend as my next step?
Thank you.
I don’t think this represents malpractice. However, I do believe we should talk to explore all possibilities before you proceed any further.
Geoff Sher
Hi Dr. Sher,
Your article below seemed to indicate against taking DHEA supplements as it will increase testosterone level.
My doctor, Dr. Gleicher, prescribed me to take DHEA supplements 75 mg per day. Would this supplement harm the quality of my eggs, rather than enhance it? What would be a harmful testosterone level for a 40 year old person like me?
Thanks so much for your quick reply!
Yang Fang
“When too much testosterone gets into the follicular fluid it interferes with egg development, compromises egg maturation and ultimately affects embryo “competence”. When such damaged eggs fertilize (if indeed they are able), the embryos that they propagate are highly unlikely to be “competent.””
Very respectfully, let us just say that my opinion differs strongly from that of Dr Gleicher here.
Geoff Sher