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Egg/Embryo Quality: A Critical Consideration in IVF (Part 1)

Dr. Geoffrey Sher Recommends

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When receiving a report of “poor embryo quality” the first inclination is often to point an accusatory finger at the embryology laboratory. This is grossly unfair because the truth of the matter is that while the In Vitro Fertilization (IVF) embryology laboratory plays a pivotal role in the success of an In Vitro Fertilization (IVF) program, it is the IVF doctor that selects the ovarian protocol that drives egg development and, regardless of expertise, no embryologist can make “poor quality eggs” develop into “good quality embryos”.

The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.

In this post, we’ll discuss age related factors that contribute to egg quality. Tomorrow’s post will discuss ovarian stimulation related factors. Age & Egg/Embryo Quality: A woman is born with all the eggs she will ever have.

After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).

One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing, is the detection of a blood FSH level above 9.0 MIU/ml (in association an estradiol level of

Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature spermatazoon ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. With ovulation induction using fertility drugs, the administration of hCG (the hCG “trigger”) mimics the LH surge. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).

Up until a woman reaches her mid thirties, only about 2 in 5 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their

Microscopic Grade alone. Even when turning to conventional chromosomal evaluation of embryos by way of Preimplantation Genetic Diagnosis (PGD) using fluorescence in-situ hybridization (FISH) it remains impossible to differentiate between “competent” and “incompetent” (euploid and aneuploid) embryos reliably. This is because at best, PGD/FISH can only access 12 of the 23 pairs of chromosomes. Thus, even when an embryo tests FISH-“normal,” there remains about a 40%-50% chance that the diagnosis is erroneous. The recent introduction of comparative genomic hybridization (CGH) could change all this. By allowing access to all the chromosomes CGH permits a much more reliable assessment of embryo “competence”. Our research has shown that the transfer of even a single CGH-normal embryo yields better than a 60% chance of a healthy baby. This represents a several-fold improvement over prior methodologies.

The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).

The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.

It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated blood FSH levels. But it is not the elevation in FSH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.

Stay tuned for tomorrow’s post on factors relating to the effect of ovarian stimulation with fertility drugs on egg/embryo quality.

Egg/Embryo Quality: A Critical Consideration in IVF (Part 2)

Tags: Age and Fertility, Controlled Ovarian Hyperstimulation, egg quality, embryo quality, FSH, IVF Authority, LH

20 Responses to “Egg/Embryo Quality: A Critical Consideration in IVF (Part 1)”

Anonymous says:

June 12, 2009 at 6:05 am

thank you adding this blog on egg quality!

any sense for why eggs would have many polar bodies and appear obviously abnormal?

anything i can do/not do to improve the quality of my eggs, i'm 36, and a good responder but most are abnormal and don't grow past day 3.

Reply
coco says:

June 13, 2009 at 3:08 am

Hello Dr. Sher,

In a typical IVF cycle, what percent of a woman's eggs are typically 'normal', and how does this change with age?

How do you know if a poor result is due to age, genetics or poor care?

Thank you

Reply
Geoffrey Sher, MD says:

June 13, 2009 at 8:10 am

When eggs have >1 polar body it is a chromosomal aberation called polyploidy…not much you can do about that.

The most important way to optimize a woman's egg quality is to optimize the ovarian protocol of stimulation. (see Part 2 of the "egg quality" blog posted on Friday!

Geoff Sher

Reply
Geoffrey Sher, MD says:

June 13, 2009 at 8:13 am

Under 35 ..about 40% are normal. At 40, probably 15%-20% and by the mid 40's….. below 10%.

It is usually age that is the predominant factor and also the metod used for ovarian stimulation….See Part 2 of the article, "Embryo quality…" (posted on Friday on this blog)

Geoff Sher

Reply
coco says:

June 14, 2009 at 8:27 am

When eggs have >1 polar body it is a chromosomal aberation called polyploidy…not much you can do about that.

————-

So if the cycle was managed well, most of the eggs were mature and fertilized, then the problem we face seems to be genetic. Is there a chance that one or two of my eggs could be normal. We've done two cycles to date and all eggs appear off.

Reply
Geoffrey Sher, MD says:

June 14, 2009 at 8:36 am

One polar body (PB) is normal. In fact all mature eggs have 1 polar body. However, simply because an egg has 1 PB and is thus mature, does not exclude aneuploidy.

Geoff Sher

Reply
debjani says:

June 21, 2009 at 10:47 pm

I am 38 and my AMH is 25. I have undergone one IVF cycle. 17 eggs retrieved, 9 kept for normal IVF and on 8 ICSI was done. Out of 8 ICSI only 2 embryo formed with 2 and 3 cells on 2nd day. Embryologist told us there is a little hope to conceive.
How should we proceed for the 2nd IVF cycle?

Reply
Geoffrey Sher, MD says:

July 2, 2009 at 10:25 pm

That is really a relatively poor yield of embryos on 17 eggs. Something sounds wrong…possibly relating to the protocol of ovarian stimulation. Read my blog on ovarian stimulation and nthen perhaps go to the SIRM discussion board at haveababy.com and communicate with me from the SIRM-Las Vegas board, there.

Geoff Sher

Reply
Carolina says:

April 24, 2010 at 2:45 pm

I'm am 26 years old. After one laparascopy to remove my left tube for an etopic pregnancy, fallowing after that I had two more laps and numerous blood work, and procedures done to determine the cause of my infertility. They didn't find nothing and said it was unexplained and it could be because of my long periods 28-39, and hence I don't make quality eggs. I am going through IVF and supposed to transfer in two days. My ER retrieved 19, 8 mature, 6 fertilised, and ONLY 2 are growing. My nurse told me "It's an egg quality problem". I always new this in my heart that I had this. I have been trying for 6 years now. Why is this happening to me?

Reply
Cathy says:

June 14, 2010 at 2:27 pm

Is it possible to retrieve any left over eggs from a post menopausal women?

Reply
Geoffrey Sher, MD says:

June 16, 2010 at 4:54 pm

I am afraid not!

Geoff Sher

Reply
mamaisbjorn says:

June 28, 2010 at 7:20 pm

I will be 44 in about a month. I have completed 90% of pre-IVF screens and results are normal. My current cycle day 2 FSH was 18 and 2 months ago had to cancel a flare-micor dose Lupron IVF cycle due to lack of follicles. Based on yours and SIRM's experiences, what would be my chance of having a life birth with my own eggs with IVF? Thank you.

Reply
Geoffrey Sher, MD says:

June 29, 2010 at 1:11 pm

So sorry. First the chances at 44 with dimiished ovarian reserve are poor. You really need an egg donor.

However, if in spite of this you want to try again, then in my opinion, the last protocol I would recommend is a flare protocol. Women over 40 and women with reduced ovarian reserve do poorly on this. You need an agonist/antagonist conversion protocol with estrogen priming (LA10-e2v).Please see the relevant article on this, elsewhere on this blog.

If you wish to discuss further with me, feel free to call 702-619-7437 for a free consultation.

Geoff Sher

Reply
The Mystical and Practical Lawyer says:

September 7, 2010 at 6:44 am

Dr. Sher

5 IVFs have resulted in an average fertilization rate with ICSI of about 30% with only two cycles making it to Day 5 (2 blasts and one morula). I am a good responder (no less than 15 eggs per cycle). Last cycle, 9 fertilized out of 18 and all but one arrested before Day 5. One poor grade morula was transferred. My current doctor says my husband (35 – low counts) and I (33 – PCOS) are genetically "incompatible" and are incapable of success through our own gametes. Do you ever come to this conclusion after such repeated failures?

Reply
Geoffrey Sher, MD says:

September 7, 2010 at 11:28 am

Respectfuully, I cannot conceive of that explanation being correct. This could have to do with the fine tuning the protocols for ovarian stimulation.

Please read elsewhere in this blog on this issue.

Also consider calling 800-780-7437 for a free medical telepgone consultation to discuss indepth.

Geoff Sher

Reply
hopeful says:

September 20, 2010 at 9:00 am

Dr. Sher,

I am a healthy 37 year old and conceived for the first time at 35 with a trisomy 18 baby that I carried until 17 weeks (D and E). Since then I have conceived 2 more times both ending in early miscarriage. We just got back from my first IVF cycle. I had 11 eggs retrieved of which 8 were mature. ICSI was used on all 8 and 5 fertilized. On day 3 all were dividing normaly and biopsied for CGH testing. On day 5 all came back with chromosomal abmormalities (some with multiple). We were told by doctor that we should not try IVF again due to bad egg quality. I have been told that my reserve is excellent and all my pre IVF testing came back great, so there was no reason to expect such a poor outcome. We were told that our best option is egg donor. Can you give me any other information? I am a healthy 37 year old and dont understand why eggs are bad.

Reply
Sarah says:

September 20, 2010 at 6:36 pm

Hi Dr. Sher,

I am 34 years old and my husband is 35. I have had 3 miscarriages at 10 weeks or earlier and 2 chemical pregnancies (both following IUIs using follistim). I produced 4 follicles using 150 units of follistim a day and 5 follicles using 225 units. My day 3 FSH is 12.8, and my RE feels that explains our poor outcome so far. She feels that we should do microdose flare IVF as our next step.

After reading about your thoughts on the MDL protocol, I'm uncertain as to whether or not this is the best course for us. We're 100% self-pay, and I'd hate to waste our hard-earned cash on a protocol that's unlikely to give us a good outcome.

Thank you very much for your thoughts,
-Sarah

Reply
Andrea says:

January 18, 2011 at 1:24 pm

Hi, Dr. Sher. I had 2 ivf cycle failed. the first one i had 10 eggs which 3 were fertilized , and 2 transfered with no sucess. the second i had 11 eggs and 5 fertilized but only 2 survived , my MD said i had fragmentation, and poor quality eggs, do you think it is possible to have a better outcome?how?

Reply
5c0cbb68-6185-11e0-89be-000f20980440 says:

April 7, 2011 at 7:10 pm

Hi Dr, I had IVF cycle and we have 4 embryos of poor quality and 1 of high quality. According to our PGD results the high quality embryo is a polyploid but according to our embryologist that is best we have and she recommends transferring that. According to her, this particular embryo can be termed "normal" by a different lab. We are concerned about any birth defects if we transfer the polyploid embryo. Please advice

Reply
- Geoffrey Sher MD says:
  
  April 5, 2012 at 2:28 am
  
  Respectfully, I would NOT advise that this embryo be transferred. It is abnormal, no matter how “good” it looks!
  
  Geoff Sher
  
  Reply

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