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,
I have one embryo on day 1. I have a choice of transfer on day 2 or wait till day 3. Would day 2 or day 3 be better for transfer and why?
I don’t have a choice to wait till day 5.
I cannot understand why you cannot choose day 5-6 (blastocyst) for transfer. The further out you go, the more confidence you can have of embryo competency and those embryos that don’t reach blastocyst would almost invariably not have propagated a baby had they been transferred earlier, anyway. If going to blastocyst is not an option then the further out you go, the more confidence you can have. So opt for day 3.
With IVF, embryos may be transferred at the cleaved stage, 2 days following fertilization (2-4 cell stage) or 3 days post-fertilization (5-10 cell stage or alternatively, 5-6 days following fertilization, at the blastocyst stage (>100 cells). Blastocyst embryo transfer thus requires extending the embryo culturing duration for an additional 2-3 days.
With blastocyst transfer, the chance of pregnancy is significantly higher than with cleaved embryo transfers. This is because many numerically chromosomally abnormal (aneuploid) embryos arrest in development before they reach the blastocyst stage.
Previously (and to a large extent even today), IVF doctors and embryologists have intuitively believed that the uterus provides a more “natural” and favorable environment for embryo development, than the petri dish and incubator and accordingly have held that the sooner an embryo is transferred to the uterus, the better off it would be. By this belief an embryo transferred as on day 2 -3 post-fertilization rather than as a blastocyst (on day 5 or 6) would have a better chance of resulting in a live birth. We now know this to be erroneous.
Background information: Before the freshly fertilized egg, starts to cleave (divide), it is called a zygote. After the first 24 hours, (Day 1) the embryo has divided into 2 cells. By Day 2 the embryo has 4 cells blastomeres and by the third day, there should be between 6 and 9 cells. Up to that point, embryonic development is under the control of maternal genes in the egg. Around the 8 cell stage, the embryo’s own genes (embryonic genome) begin to take over control of development. By the fourth day, the embryo has between 16 and 32 cells. At this point it looks like a mulberry and is called a morula. Until the morula stage, all of the embryo’s cells are the same and are “totipotential” (i.e. they have the ability to ultimately develop into any tissue or organ type). By day 5 post-fertilization, differentiation of the embryo begins. A fluid-filled cavity blastocoel forms in the center of the conglomerate of blastomeres. This blastocoel will eventually become the amniotic sac and the fluid surrounding the conceptus in the uterus.
The cells around the outside of the morula develop into the trophectoderm, which will eventually form the placenta and fetal membranes, while the cells on the inside of the morula aggregate and group together to form the inner cell mass, which ultimately develops into the fetus. This complex creation is now called a blastocyst. By this stage the embryo comprises more than 100 cells. As the blastocoel fills with fluid, the blastocyst expands, its walls thin out and it eventually breaks through (hatches) its envelopment zona pellucida. The trophectoderm then begins to invade the uterine lining (implantation) by the 6th to 8th day after ovulation (or egg retrieval in the case of IVF treatment).
Human embryos are very fickle. They have specific metabolic requirements in order to survive. The earliest type of artificial embryo culture media developed for IVF purposes was relatively simple in composition and could only support limited embryonic development in the Petri dish and incubator. Thus, the majority of embryos cultured in such media could only survive to the third day, whereupon their development would usually arrest. Subsequent improvements in media composition allowed for more reliable embryo development to the third day…which became and remained the standard time at which embryos were transferred for more than two decades.
In the mid-1990s, researchers in Australia, Scandinavia and the USA simultaneously developed a new generation of culture media that could support the growth of embryos to the fifth or sixth day. This development was based on a clearer appreciation of the metabolic needs of the early embryo. Now, contingent upon the age of the egg provider, approximately 30-40% of morphologically “good quality” day 3 embryos (comprising 5-9 cells with minimal/no fragmentation) can be grown to the blastocyst stage using such advanced culturing methods.
A few years ago I and my research partner, Levent Keskintepe PhD, reported on the fact that embryos that failed to develop into blastocysts were almost always aneuploid and incapable of propagating a viable pregnancy (i.e. “incompetent”). However, not all embryos that developed into expanded blastocyst were chromosomally normal and “competent”. As such, embryos that fail to develop in the laboratory to the expanded blastocyst (advanced preimplantation) stage by day 5-6 post-fertilization, would not have developed into a viable pregnancy had they been transferred to the uterus earlier on in the cleaved stage (day 2-4 post-fertilization). Accordingly, there is in my opinion, little justification for transferring embryos that have not developed into fully expanded blastocysts by day 5-6 post-fertilization. Since many aneuploid (“incompetent” embryos are culled out during the developmental stage, it follows that blastocysts are much more likely to be “competent” than are cleaved, earlier stage embryos. Thus blastocyst transfer reduces the incentive on the part of IVF doctors to transfer multiple embryos in order to bolster their success rates, and the process this reduces the risk of high order multiple pregnancies (triplets or greater) with its incumbent risks to both mother and babies.
As mentioned earlier on, the older the egg provider, the lower the chance that her fertilized eggs with develop into blastocysts. In fact, in spite of the introduction of specialized culture systems and other new techniques, at best (even in younger women) 40% of “good quality” day 3 embryos (those that are 6-9 cells and have little fragmentation) will develop into expanded blastocysts by day 5-6 post-fertilization in younger women. And the blastocyst conversion rate declines rapidly as the woman ages beyond 35 years, such that by age 40 years, the conversion rate is about 15-20% and by 43 years of age it is <10-15%. Since blastocysts are much more likely than cleaved embryos to implant following embryo transfer (ET), the transfer of 1-2 good quality blastocysts will in any age category, proportionately yield a far better IVF success rate
The new found ability to safely freeze blastocysts using a new ultra-rapid process known as vitrification which does not compromise their subsequent (post-thaw) ability to propagate a viable pregnancy, has led to many IVF programs to preferentially cryobank vitrified blastocysts for transfer in one or more subsequent frozen embryo transfer (FET) cycles. Also, the introduction of Preimplantation genetic sampling (PGS) with full numerical chromosomal assessment (full karyotyping) using methods such as comparative genomic hybridization (CGH) and next generation gene sequencing or (NGS) now permits the identification and selective transfer of only the most competent blastocysts, thereby improving IVF outcome substantially. This allows many older women and those with diminished ovarian reserve(DOR) who are averse to doing egg donation-IVF, to have their embryos biopsied and then bank (stockpile) their embryos over several cycles, in the hope of subsequently transferring only those that are determined through PGS to be the most “competent” ones
For all these reasons (and there are probably many others) most IVF centers of excellence have graduated from transferring cleaved embryos to blastocyst transfers.
Other than patient preference and easing pressure on doctor and/or patient, there is in my view seldom a justification for transferring embryos on day 2 or day 3. In light of the aforementioned revelations and developments I therefore hold that blastocyst transfer should be the embryo transfer method of choice.
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
?800-780-7437
Geoff Sher
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.
Dear Dr Sher,
I am 40 years old and my FSH and LH are normal, my testosterone and my DHEAS are low.
In your opinion, do you think a little bit of LH in the form of Menopur is essential (or maybe you would prefer to say useful) for egg maturation and egg quality, if adding Menopur in during the last 2-3 days of a short, antagonist cycle (where otherwise only gonal f is being used)? Or would you say on an antagonist cycle it would be better to stick with an FSH product like Gonal F only?
I understand you prefer an agonist/antagonist conversion protocol, but my Czech clinic doesn’t do it. So an answer about the above short antagonist cycle would be so much appreciated.
In my opinion, a small amount of Menopur (37.5U-75U daily wadded, would be preferred.
Geoff Sher
Hello Dr ,
I have undergone 4 IVF cycles 2 fresh and 2 frozen .The first fresh and frozen cycle resulted in missed miscarriage.The last 2 cycles after around 8 to 10 days after embryo transfer I developed severe itching and hives all over the body .The hives used to disappear after few minutes but re appear in other areas after i scratch that area.I was on crinone gel ,progestrone injection ,Aspirin and estrabet tablets after transfer.Do you think i might be suffering from IID.The itching and hives continued for few weeks after I stopped all medicine after negative beta HCG in last 2 cycles
There is no relationship between IID and cutaneous allergies, in my opinion.
Geoff Sher
Dear Dr. Geoffrey
From the moment IVIG enters the blood stream what are its mechanisms? What journey will it take in order to reach the NK cells and become effective. I understand IVIG has many mechanisms dependant on its usage but I just wanted some more information in relation to fertility and its uses during RPL.
Warm Regards
Clare
I no longer use IVIG. It has all but been supplanted by Intralipid/steroid therapy. However, in answer to your question, both intralipid and IVIG work by down-regulating activation of natural killer cells to bring their TH-1 and TH-2 cytokine activity into equilibrium.
Geoff Sher
Hi Dr. Sher… after many failed Cycles due to DOR.. I have finally produced 5 follicles but my progesterone was 7 and estrogen 236 ..the dr. Said to wait 2 days and redo blood test. ..I have also been taking spironolactone for acne and had a hunch that this was causing the elevated progesterone.. So I did not take it the next day and the progesterone was actually even higher.. But the estrogen was under 100.. The doctor said to continue the cycle since I do have more follicles than usual.. Do you know of a way that I can reduce progesterone? Any pills out there that’d do the trick? Is it safe to go ahead and continue the cycle? Should I continue taking spironolactone? The doctor said to stop but it doesn’t make sense to me since it actually raised the progesterone by stopping.. In general it seems like it masks the FSH levels as well since while I was on spironolactone my FSH was very low even though I have DOR but then when I stopped taking it for 2 months and was tested again my FSH was super high. . I would be grateful if you can share your thoughts..
Hi Rachel,
The FSH is simply a rough measure of ovarian reserve. It does not directly influence the ovarian reserve itself. It is the effect and not the cause. I can tell you that at this point, trying to influence estrogen/progesterone is not likely to be effective. It is all about starting off with the ideal protocol. I think the spironolactone is probably not a factor here.
In my opinion, the protocol used for ovarian stimulation, against the backdrop of age, and ovarian reserve are the drivers of egg quality and egg quality is the most important factor affecting embryo “competency”.
Women who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the effect of DOR, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can in my opinion, make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.I try to avoid using such protocols/regimes (especially) in women with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy
Please visit my new Blog on this very site, https://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
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
• 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.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• 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.
• 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?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• Traveling for IVF from Out of State/Country–
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview
I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:
Email: Julied@sherivf.com
OR
Phone: 702-533-2691
800-780-7437
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.
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