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.
Hello Dr Sher. I am 38 years old and have always suffered from Endometriosis. I have had two unsuccessful IVF cycles in the past.
My most recent and third IVF cycle resulted in 4 grade A and 2 grade B embryos, which were frozen in December ’15. I had gone to see my OB-GYN on 18th April ’16 which was my CD13. I had not taken any medications during this cycle as this was not supposed to be the ET month. My doctor scanned me and discovered that I had a 10.3mm endometrium with a 0.6 ng/ml progesterone and a large 22 mm follicle on the left ovary. She said that the endometrium thickness is very good and she thinks that this is the prefect natural cycle for ET. She administered a 2000IU HCG injection and asked me to return for a scan and progesterone blood work on 21st April i.e. CD16. She planned to transfer three embryos on 23rd April (CD18), My progesterone level on 21st April turned out to be 3.0 ng/ml and she informed me that she will have to cancel the ET due to a ‘progesterone surge’. I am confused – how could she not see this coming because I was clearly going to ovulate in day or two when she scanned me on CD13. Didn’t the HCG shot aid in bringing the progesterone up? Please let me know your thoughts. Thanks in advance.
Just a small addition. I have been having pain and discomfort in my left ovary since the HCG shot. This is more severe than ovulation pain. Thanks again.
Very respectfully, I very much favor doing an FET in hormone replacement cycles when the endometrium can much more precisely be prepared than in natural cycle FET’s.
Geoff Sher
Hello Dr. Sher – I was wondering if you had any feedback on my situation. I am almost 38, and have been TTC #2 for a full year. I got pregnant the second month trying with my first born son at age 34. We started again when he turned 2 (I was almost 37) and got pregnant the first month trying. I miscarried – U/S suggested growth stopped around 6.5 weeks, but wasn’t discovered until 9 weeks, followed by D&C. We were asked to wait 1 cycle, and I did. We got pregnant again the first month trying. I miscarried a second time – U/S suggested growth stopped around 7 weeks, discovered at 9 weeks, followed by D&C. The beta HCGs were decent but not great for this pregnancy – 1832 on 22dpo with a progesterone of 12.3, and 3386 on 24dpo. The karyotyping revealed 47XY (trisomy 15). We were asked to wait 3 cycles, and did partial RPL testing. I had a mixed positive ANA (1:320), borderline anti-ds DNA (10) and indeterminate anti-cardiolipin IgM. A rheumatologist determined I did not have lupus (although I have had Raynaud’s my whole life). I was put on baby aspirin and progesterone (100mg suppositories starting after HPT+, a very strong one at 12dpo). The beta HCG was 26,000 at 23dpo, my OB saw no need to repeat. But we miscarried a third time at 7 weeks discovered immediately, waited a week to confirm no heartbeat and then D&C. The karyotyping was inconclusive (46XX). None of the miscarriages were molar pregnancies and I resumed normal cycles within 28-32 days.
I have since seen 4 REs and had additional testing done. All anti-cardiolipin, anti-beta2glycoprotein, and lupus anticoagulant tests are now negative; prolactin is normal (10). Day 3 of my first true cycle after my second miscarriage had an FSH of 15.1 and undetectable (<20) E2. Day 3 of my second true cycle after my third miscarriage had an FSH of 7.9 but high E2 (96). That same cycle, I had an AMH of 0.875, but an antral follicle count of 15. After the follicle count and a saline infusion sonogram to exclude adhesions, polyps, or fibroids the RE guessed my AMH would be around 2.0, so this was a surprise to everyone. However, endometrial biopsy identified chronic endometritis and I am on doxycycline 100mg twice daily (I was never given doxy after any of my 3 in-office D&Cs, so maybe not surprising). My TSH has risen from its typical 1.4-1.6 range, to 2.0, although that high value was taken around 8am after 11 hours fasting in the winter instead of the mid to late afternoon, so I’m not sure if that accounts for the discrepancy. I show normal anti-TPO (17.8). Goiter runs on my paternal side, and late menopause/late childbearing runs on my maternal side. I ovulate very regularly around day 12-13 of a 26 day cycle and show a clear biphasic BBT pattern. My BMI is 20.5, and I run or do yoga 5-6 days a week, and acupuncture most weeks. I supplement with 400 mg ubiquinol, prenatals that include bioavailable forms of folate and B12, DHA, vitamin D, and 25 mg of DHEA (I see you do not recommend that last supplement). I have also greatly reduced the amount of gluten and cow’s milk in my diet.
My husband’s semen analysis parameters were poor – low volume (1.6 ml), count 99 million/ml or more, 48% motility or more, 76 million or more motile, forward progression 2-2.5, viscosity 1, ph 8, normal morphology 8% or more, 3hpf round cells, 2 agglutination. That being said, the sample was taken 50 minutes prior to delivery and, unfortunately, not kept in a shirt pocket en route.
My questions are:
1. We are trying to decide whether to go immediately to IVF with PGS, or to try medicated IUI cycles first to try and push out a smaller number of eggs (3-4) on the odds that 1 in 4 might be normal. Do you think one of these is a far better idea than the other, not considering cost differences?
2. Would you be concerned about my thyroid function?
3. Am I overlooking anything obvious that could improve my chances? All 4 of the REs I have seen do not test for immune issues and generally seem to think my issues are due to ovarian aging. It seems like something else is at play though, perhaps an overly hospitable endometrium (or would that be unlikely given chronic endometritis)?
Thank you!
I strongly suspect that aside from your more recent development of DOR which requires avery individualized approach to ovarian stimulation, even tough you do have a child, you probably also have an implantation dysfunction which could very likely be due to an alloimmune cause (see below).
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?
•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
•Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
•Traveling for IVF from Out of State/Country–
•A personalized, stepwise approach to 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
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
Hi Katrina,
We will need to consult 1 on 1 for me to be able to understand more about your case and be of help to uyou. I do not do telephone consultations for new patients. I only consult at a distance by Skype. Frankly, I do conduct Skype consultation all over the world, including with patients from France. There should be no difficulty in us connecting. Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up a 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
Geoff Sher
Hi doc
I am a 34yrs old woman Marrued for 7 yrs. My husband is 39yrs old
I started on with assisted reproductive techniques from 2013…which includes 3-4 Iui attempts and 7 IVF. one of which has been a fresh transfer and others frozen. Out of these I conceived once in 2014 which resulted in blighted ovum subsequently terminated. I conceived again in March 2016 making Me approximately 9 wks pregnant now…but my embryo has not got the cardiac activity as per usg dated 19th April. I have got monochorionic diamniotic twins. .size 8mm and 6mm. Why is this happening and what should I do. Rest of all ivf and iui attempts had resulted in implantation failures. This time and one attempt before that (Oct 2015) I had been transfered frozen blastocyst.
Kindly help
Hi Urvee,
You probably need to repeat the ultrasound examination within a week before reaching any conclusions about this cycle and your present disposition.
Good luck and please keep me in the loop!
Geoff Sher
Dear dr.sher
i am planning to undergo ivf trial after 3 months..
I am breastfeeding 13 months baby currently ..
Iam pcos patient..not ovulating on my own..
Since delivering my baby i had 3 periods..i.e menstruation every 2 months..
Is having prolactin hormone in my system going to affect ivf outcomes?!
Does it affect egg/ embryo /linning quality?!
If i have to wean..how many months before ivf do i have to stop breastfeeding?!
Unless your prolactin is markedly raised (>30ng/ml) it likely will not severely affect IVF success. I suggest you wait for at least 2 full menstrual cycles to ensue after weaning from the breast before doing IVF.
Geoff Sher