After contemplating how to make my blog posts more helpful to patients with unexplained IVF failures, I have decided to profile the case histories of a number of patients who sought my input after having failed at IVF (often repeatedly). I will try to identify the various potentially remediable reasons for failure, and then make specific recommendations as to how I personally would address (or have addressed) these issues. In some cases, the patients underwent subsequent treatment with me, in which case I have indicated the details and outcome of their treatment.
To make this exercise useful, I have decided to discuss these cases in specific categories that will highlight often overlooked factors that can lead to (unnecessary) IVF failure.
Cases will be presented in three categories:
- Women who ended up with poor quality eggs/embryos.
a. Younger women with normal or exaggerated ovarian reserve
b. Older women (over age 39) with normal and/or diminished ovarian reserve (DOR)
- Women who failed to conceive because of embryo implantation dysfunction
- IVF failures following third party IVF (Egg Donation and Gestational Surrogacy)
Please note that the case reports and commentaries will include links to other articles on this site that will hopefully expand on the explanations given.
The first three posts in this series will address Category 1.a – younger women who ended up with poor quality eggs/embryos.
Today’s post profiles a patient with Polycystic Ovarian Syndrome (PCOS) and the various effects of this condition (along with the prescribed IVF protocols) on egg/embryo quality. Friday’s post will discuss a case in which poor egg/embryo quality was due to an occult male factor infertility issue. Next Tuesday I will post case #3, which will detail a patient with poor egg/embryo quality due to advanced endometriosis.
In coming weeks, I will address more cases under the current heading and will then go on to cases involving the other categories listed above.
Case History #1
“Ann” aged 34 years had been trying to conceive for 3 years. She had never conceived previously (Primary Infertility) in spite of having a fertile male partner, undergoing four attempts at intrauterine insemination using clomiphene citrate (Serophene) for induction of ovulation, and 2 prior IVF procedures. Her menstrual periods were grossly irregular with cycles ranging from 20–35 days apart. Her day-3 blood hormone levels were as follows: Follicle Stimulating Hormone (FSH): 4.5 MIU/ml; Luteinizing Hormone (LH): 9.1 MIU/ml; Estradiol (E2): 62pg/ml; Antimullerian Hormone (AMH): 5.6
Ann had been diagnosed with Polycystic Ovarian Syndrome (PCOS). Both of her IVF treatment cycles (prior to consulting with me) involved ovarian stimulation with Menopur and Ganirelix (beginning on day 6 of stimulation). By the time of the hCG trigger (7-8 days after stimulation started) most of her 40+ follicles were still somewhat under-developed measuring 15-17mm in mean diameter, having not yet attained optimal size (18-22mm), and her peak blood [E2] exceeded 6,000 pg/ml. She was told that she needed to be triggered with hCG at that time to stop the process of follicle growth, which would prevent her blood [E2] from spiraling out of control and potentially causing her to develop the life-endangering condition of Severe Ovarian Hyperstimulation Syndrome (OHSS). In both of these prior cycles, only about 40% of the follicles yielded eggs at the time of egg retrieval. Many of her eggs were immature (MI’s), and those that were mature (MII’s), yielded poor quality embryos after fertilization by ICSI.
She had developed moderately severe ovarian hyperstimulation (abdominal fluid collection, backache and some difficulty in breathing) prior to the embryo transfer (ET), which in both cycles involved the transfer of three (3) day-3, poor quality embryos to her uterus. She did not conceive, but her ovarian hyperstimulation got worse in the ensuing days. She experienced a reduction in urine output, diarrhea, worsening abdominal pain, and progressively more difficult breathing. These symptoms and signs, along with abnormal blood tests pointed to OHSS, which is a life-threatening condition, which fortunately, in the absence of pregnancy is self-limiting and disappears 10-14 days after the hCG shot. Thus, since she did not conceive, she recovered about 10 days later.
In my opinion, the reason for the poor egg/embryo quality in these two IVF cycles preceding her final attempt with us, was likely due to the IVF stimulation protocol that was used, as well as premature timing of the hCG trigger. In my experience, women with elevated basal blood [LH] do poorly on protocols that do not down-regulate the LH before and during the stimulation cycle (women with PCOS commonly have elevated blood [LH]). Since the “antagonist” (Ganirelix) was only commenced six days after the stimulation was initiated with Menopur, by the time it suppressed her high pituitary LH production, her eggs had already been exposed to excessive LH-induced ovarian male hormones or androgens (mainly testosterone). It was probably this that had a deleterious effect on her developing eggs and subsequently on her embryo quality.
In addition, because her eggs developed poorly, many of them remained firmly attached to the inner walls of her follicles and could not be retrieved. This would serve to explain why she had so many “empty follicles”. It also probably explains the low percentage of mature (MII) eggs produced in prior cycles and her subsequent poor quality embryos that ultimately led to failed IVF. In addition, Menopur (which aside from FSH also contains 50% LH/hCG) was not the ideal gonadotropin to use in this case, because the additional LH would simply add more “fuel to the fire”.
Another factor here is that the hCG trigger was administered relatively early in her cycle, such that her follicles did not have sufficient time to develop optimally before the process of development was abruptly arrested by the trigger. This was clearly done deliberately in an attempt to reduce the risk of OHSS developing…unsuccessfully in this case.
The patient subsequently went through a cycle of COS with me. We prepared Ann for an IVF cycle by starting her on a birth control pill and thereupon, given that she was a “high responder,” we put her on a low-dosage, long pituitary down-regulation protocol with Follistim and Luveris to properly maintain a low LH. She produced 47 follicles which by day 8 of stimulation were (14m-16mm) and her [E2] was 2700pg/ml. At this point I commenced the “prolonged coasting” process by discontinuing the gonadotropins while maintaining the daily “agonist” (Lupron) injections. This would give her follicles and eggs an opportunity to develop optimally (18-22mm) before administering the hCG trigger. Her blood [E2] rose and peaked at 7700pg/ml by day 9 and then began to fall, reaching below 2,500pg threshold by day 12. At this point the follicles were mostly 18-22mm in mean diameter and I administered 10,000U of hCG (Profasi) to trigger ovulation. We retrieved 42 eggs, 34 of which were mature (MII’s) and were fertilized using ICSI. Thirty-one (31) MII’s fertilized and by day-3 post-ICSI, most were 6-9 cells. By day-6, we counted 11 expanded blastocysts and transferred two of these into her uterus. She conceived with a singleton and at this time is nearing the end of the 1st trimester and is doing well. This treatment approach likely prevented OHSS and helped optimize embryo quality.
Addendum:It is important to understand that IVF is an ART-Science blend and not all practitioners agree on the same strategies.Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.Feel free to present your case history in the comments and I will do my best to offer my opinion.