Embryo stages, progression and pregnancy outcomes

November 10, 2010Carole 595 Comments »

Did I mention I love getting blog topic suggestions from my readers? I get in a rut too. So I was happy to find this request in my inbox. “Carole, please could you discuss the various stages and the required number of cells the fertilized egg goes through up until it is vitrified on day 6? Also please could you explain the terms “cleaved”, “compacted”, “non-expanded” blastocysts and possibly give some percentages as to the chance of pregnancy when, e.g. a compacted 6 day blast is transferred.”

This post also gives me the opportunity to thank Dr. Liz Sanders from the Mississippi Fertility Institute and Dr. Robert Shabanowitz from Geisinger Medical Center for their generous permission to use their embryo images in this blog.

First things first. The first embryonic stage is the fertilized egg or zygote stage. Eggs usually show signs of fertilization between 16-18 hours after insemination. What embryologists look for are two well-defined transient structures called pronuclei in the center of the fertilized egg.  In the picture below, the PN look like two chocolate chip cookies inside the egg. These “cookies” contain the male and female DNA and for normal fertilization, there should be exactly two pronuclei or as embryologists like to shorthand, “2PN”.

Normally fertilized egg with a paternal and maternal pronucleus (2PN) visible. Photo courtesy of Dr. Liz Sanders, Mississippi Fertility Center, Jackson, MS.

What is significant about the 2PN stage? This stage is brief, lasting only a few hours and occurring approximately 16-18 hours after insemination. Seeing more than 2PN (say 3, 4, 6PN or more) are all abnormal numbers of pronuclei which can not be corrected and result in an abnormal embryo which may fail to develop further. 3PN zygotes can cleave and continue to develop but will not produce a healthy pregnancy. Embryologists need to identify these abnormally fertilized eggs and remove them from the viable embryo pool.

Some clinics use a zygote scoring system or Z-score based on the appearance of the PNs to try to identify the fertilized eggs that will cleave and progress from this early stage. If the 2PN stage zygote looks like the egg swallowed two chocolate chip cookies, then the tiny spots within each cookie that look like chocolate chips are the nucleoli. Nucleoli are small, typically round granular bodies composed of protein and RNA that are usually associated with a specific chromosomal site, These nucleoli are involved in ribosomal RNA synthesis and the formation of ribosomes.  Characteristics including the number of nucleoli within each pronucleus, the similarity in size of these nucleoli and whether they are lined up along the edges where the “cookies” touch are all factored into the Z-score.  The usefulness of the Z-score is in dispute and is not used by many clinical labs.

Cleavage stages. When the fertilized egg divides for the first time and forms two cells, it has entered the cleavage stage of development. The term “cleaved” simply means that the cell has divided from one cell to two. Divided =cleaved. The cells in the the two-cell embryo continue to divide, creating a four-cell embryo. Each cell in the four cell embryo divides or cleaves again, forming an eight cell embryo. You can watch a great video of development from the fertilized egg to the blastocyst stage on the NIH stem cell website. A note about “days of culture” related to embryo stages: When I refer to day 3 of culture, day zero of culture is egg retrieval day. Signs of fertilization are visible on day 1 of culture. Cleavage to two-cell stage is typically expected on day 2 of culture and cleavage of the embryo to an eight-cell is expected on day 3 of culture. 

What is significant at cleavage stage? Embryologists have long looked for characteristics at this stage which will identify which embryos will go the distance. Characteristics that are favored by embryologists include same sized cells with little or no fragmentation. The four cleavage stage embryos in the picture at the right are a good example of nice cleavage stage embryos on day 3, when the embryo is expected to have cleaved into at least 8 cells. There is some variability in the cell number that we see on day 3. We expect the best prognosis from embryos that have reached 7-12 cells. If the embryo is only two cells on day 3, this is not a good sign and likely indicates the embryo has ceased to grow. Normal embryos have a fairly strict rate of progression which starts at the time of fertilization. If the time of fertilization is delayed (for example, if rescue ICSI is used), the start time of the embryo’s progression program is delayed and the embryo may reach the eight cell on day 4, not day 3 of culture since fertilization occurred a day later than expected.  But except for delays in fertilization, progression should follow an expected predictable rate. Embryos don’t usually speed up to catch up if they are lagging.

Morula stages of development. The morula stage is characterized by a transformation from a loosely associated group of cells to tightly connected cells that are acting more like a tissue. The process by which cells change from loose association to tight association is called compaction. A compacted morula is a group of cells (usually around 30) which have squeezed together inside the zona. This stage is usually seen on day 4 of culture. The photo to the right shows two typical morula stage embryos that have compacted. The name morula comes from mulberry (Latin: morum), perhaps because the morula looks somewhat like a mulberry.

What is significant at this stage? Sometimes embryos get stuck at cleavage stage and never compact. This is a bad sign and the embryo is no longer viable unless it makes this transition. Embryologists like to see that most of the cells are incorporated into the morula. Cells or large fragments that are left outside of the compacted morula are non-viable. In the picture on the right, you can see a little fragmentation between the morula and zona pellucida (the shell) but not too much. These morula look pretty good. Notice that in each picture from fertilized egg to zona, the zona is still about the same size, but the dividing cells within it are getting smaller and smaller with each division.

The blastocyst stage. Reaching the blastocyst stage of development is considered a very favorable sign for implantation and pregnancy. In a typical IVF cycle, some embryos fail to go on at each stage. It is unusual for 100% of a patient’s fertilized eggs to get to blastocyst stage but it can happen. Embryologists talk about expanded blastocysts, non-expanded blastocysts and hatching blastocysts- all stages in the continuum of blastocyst development. By the blastocyst stage, the embryo has reached 50-150 cells and is starting to strain at the confines of the zona pellucida. This straining is not simply due to cell division but also active pumping of fluid by embryo cells into the inner space of the blastocyst, forming a cavity or blastocoel. The filling of this space with fluid expands the blastocyst and we call this embryo an expanded blastocyst. Before creation of this fluid space, the embryo is called non-expanded. You can see a group of blastocysts that have expanded in the photo to the right. The expansion of the blastocyst helps thin the zona and eventually helps to rupture the zona and let the blastocysts escape or hatch from the zona pellucida. In the expanded blastocyst, the embryologist can see the inner cell mass (ICM) within the blastocyst. I have labeled the ball of cells that make up the ICM in the photo. The ICM contains the cells that will give rise to the actual cells of the fetus. The other cells that surround and protect the ICM and line the inner side of the zona pellucida are the trophectoderm cells. The cells of the trophectoderm give rise to the fetal part of the placenta. The mother also provides cells to the placenta. 

What is significant at this stage? The embryo must have a inner cell mass. The absence of an ICM means game over for the embryo since these cells have died off within the blastocyst. These blastocysts are not transferred. The other troublesome sign is when the blastocysts seems to have a low number of cells, suggesting that the transformation program began before cell division was completed, leaving the embryo with an inadequate cell base for development. The blastocyst stage typically occurs on day 5 of culture and we would see hatching early on day five, especially if the zona was hatched earlier for embryo biopsy. Sometimes the blastocyst will not become expanded until day 6. Differences in culture medium or other features between programs may explain why some programs see full expansion and hatching on day 5 and others see this more on day 6. In our program, we expected to see most if not all the embryos in a patients group of embryos reach this stage on day 5.

There’s another interesting feature of blastocysts and that is their ability to expand- and contract. Expanded blastocysts may “collapse” in culture and look unexpanded. With time, the blastocyst will re-pump the fluid and “re-expand”.  A “compacted” blastocyst is likely a transient condition in which the fully pumped up blastocyst has “deflated’. As long as the blastocyst is capable of expansion, this temporary deflation is not a problem. In fact, prior to vitrification, many programs routinely deflate their blastocysts to optimize the vitrification procedure. After freezing and thawing, a sign of recovery is re-inflation or re-expansion of the blastocyst, showing that the embryo is alive and pumping- literally.

In vitro artifact or source of identical twins? Interestingly, one study using time lapse photography of collapsing and re-expanding blastocysts found a connection between the frequency of collapse and the size of collapsing blastocysts and an increasing frequency of monozygotic or identical twins from IVF. Researcher Dianna Payne described her theory that the frequent collapse was a sign of local areas of cell death. The frequent collapses allowed embryonic cells to move and relocate to a second site within the blastocyst, setting up two ICMs that could lead to identical twins. Excessive cycles of  collapse and reexpansion could kill the blastocyst if it becomes unable to expand. In another study, the ability of a blastocyst to reexpand after thawing was used as a predictor of better pregnancy outcomes.

Hatching Blastocysts. The photo to the right shows an empty zona and four fully expanded blastocysts in various stages of hatching. You can see a bubble of cells sticking out (hatching) out of the left side of the top left embryo. Directly below this embryo, you can see an embryo that is completely free of its shell and its empty shell or zona pellucida has floated to the top of the photo. If you look closely, you will notice that the edges of this hatched embryo is irregular and not shiny like those of the blastocysts that are still enclosed by the zona. The two smaller blastocysts to the right of the hatched blastocysts are still expanding, note their relatively smaller size.

In the picture below, you can see another photograph of a blastocyst in the middle of hatching, half in and half out of its shell. You can see an area in the middle of the embryo that appears more open. This is the blastocoel. Notice how thin and small the zona looks relative to the first photo of the fertilized egg. Some of the newer culture mediums are better designed to allow the natural thinning of the zona in preparation for hatching, making assisted hatching procedures to artificially open a hole in the zona largely unnecessary except for cases in which embryo biopsy is required. Embryo biopsy (removal of one or more cells) from the embryo for genetic analysis requires that a hole is made in the zona at either the eight cell or blastocyst stage embryo.

What does all this embryo progression, embryo scoring and achieving blastocyst stage mean for a person’s chance of pregnancy? Determining which embryo will implant and make a baby is the holy grail of embryology. Evaluation or scoring based on appearance of  the fertilized egg, cleavage stage or blastocyst stage embryos have all been proposed by embryologists to determine which embryos have pregnancy potential and which don’t.  Some clinics have done retrospective studies of embryo progression- a functional test. The embryo progression of sibling embryos was compared from patients who got pregnant to patients who did not get pregnant after day 3 transfer.  Did these sibling embryos stall out or progress to blastocyst stage? Generally speaking, patients whose excess embryos went to blastocyst stage were more likely to get pregnant than those patients whose remaining embryos did not progress to blastocyst stage. So progression is a good functional test of viability and selection of embryos at day 5 of culture is a good tool to identify the embryos that can make it at least that far. Genetic testing for embryonic abnormalities that prevent pregnancy may be the key to identifying the embryos that make babies but those tests are still under development. Testing of embryo metabolism or metabolomics is another promising arena for developing new predictive tools to determine embryo viability.

The bottom line is that even with all embryo characteristics that have been proposed as predictors of implantation and pregnancy, there is not yet one test which accurately predicts which embryos will develop into babies. I am hopeful that a combination of existing evaluation methods and future analytical tests will one day identify those embryos that will produce a healthy pregnancy and child.

© 2010, Carole. All rights reserved.

595 Responses to this entry

  • Carole Says:

    Hi Louise,
    I don’t really understand why they are waiting until day 6 to biopsy. Some programs wait until the embryos are already hatching for biopsy because they don’t have the skills to open the shell and pull out a few cells. There may be another reason they are waiting. As always, you should always feel that you have the right to ask these questions of your IVF team. If their embryo freezing/thawing skills are good, you will probably be in decent shape to have one or two attempts at pregnancy. Good Luck!!! Carole

  • Ingrid Says:

    Dear Carole,
    I need to have some information.
    I had a Fivet in a centre in Prague where they transfer to me 2 morulas even if they told me that they were two blastocysts. I had beta zero.
    Now I still have a morula and an early blasto ( grade 1) that I decided to transfer in another centre because I don’t trust anymore in my previous centre.
    The new centre was really surprised that they thawed these embryos at this stage! The new center was pretty honest and they told me that they thaw only XB or HB, i can go and try but they seemed not to be very optimistic. They told me that they dethawed my embryos the day before and they observe them.
    What do you think? I’m thinking every day if to go and to take these embryos or to start with a new eggs donation.
    Tks a lot for your help

  • Ingrid Vola Says:

    Dear Carole, I need to have some information. I had a Fivet in a centre in Prague where they transfer to me 2 morulas at day 5 ( it was a DE) even if they told me that they were two blastocysts. I had beta zero. Now I still have a frozen morula and an early blasto ( grade 1) that I decided to transfer in another centre because I didn’t trust anymore in my previous centre. The new centre was really surprised that they frozen these embryos at this stage! The new center was pretty honest and they told me that they only froze XB or HB, i can go and try but they seemed not to be very optimistic. They told me that they will thaw my embryos the day before and they observe them. What do you think? I’m thinking every day if to go and to take these embryos or to start with a new eggs donation. Tks a lot for your help Ingrid – See more at: http://fertilitylabinsider.com/2010/11/embryo-stages-progression/#comments

  • May Says:

    Hi Carole,

    Thanks for the informative article. I had my retrieval yesterday at 9:30am and I received my day 1 fertilization report this morning at 9:30am (exactly 24 hours after). Based on the 13 eggs we retrieved, 12 were mature. We did ICSI – 4 were fertilized as of this morning. Another 4 were fertilized but “not at 100% yet”. The nurse said they will be put back into the incubator with the rest of them to see if it will continue to progress. My question is… how likely will these 4 embryos that are not 100% fertilized 24 hours after retrieval continue to grow normally? The nurse didn’t say that these were abnormal, just that they fertilized but not at 100% at the time she called me. Any insight you can give is appreciated. Thank you!

  • Carole Says:

    Hi May,
    I don’t understand the “not at 100% yet” comment either. Your egg is either fertilized or not fertilized. Since ICSI was used, there should be pretty synchronized fertilization and a fairly tight window to see all fertilized, especially since all but one were mature at time of ICSI. You have every right to ask them to clarify what they mean. Good Luck!! Carole

  • Carole Says:

    Hi Ingrid,
    It might be worth it to let the new lab thaw and observe the embryos with a plan to transfer them if they continue to grow. You can always start with a fresh cycle if this does not work. Good Luck!! Carole

  • Ingrid Says:

    Dear Dr. Carole,
    thank you for your prompt reply.
    I forgot to ask you if you suggest me a PGD in my next DE fresh cycle or not!
    I had a natural pregnancy at the age of 43 but M/C ( 9+4) due to chromosomal abnormalities
    DE Beta zero
    DE ( frozen embryos) ectopic pregnancy
    Natural pregnancy at the age of 45 M/C due to Trisomy 18.
    The caryotipe of my husband is perfect. Anyway, Do you think it’s better to do also the Array -CGH or this is not the case?
    Thank you so much for your help!

  • Carole Says:

    Hi Ingrid,
    At 45, your risk of producing eggs- and thus embryos- with chromosomal abnormalities is very high so yes, PGD is probably a good idea- if you are using your own eggs. Array-CGH is better than older methods. You may, however, find that all your embryos are abnormal which would be upsetting but if it gives you some insights into the possibility of pregnancy with your own eggs, it might be worth it- just so that you can try something else . IF you are using donor eggs from a young donor, PGD is generally not ordered, because the risk of chormosomal abnormalities are much lower. Good Luck!! Carole

  • Ingrid Says:

    Dear Dr Carole,
    Ref my message dated 29th february, ref the early blasto and the morula, I went in the new centre for the Ket.
    So, they told me that they thawed the embryos the night before and that they were viable! They gave to me the 15pc of chances with my early blasto that became grade 2 and the compacted morula! I was sceptic about the CM but the Dr suggested me to transfer also it!
    In the paper they gave to me there is written: day 5 1EB/2 1 CM/3! What do you think? Do you confirm the 15pc of the center?

  • Carole Says:

    HI Ingrid,
    Yes, we have had pregnancies with compacted morulas, as long as they are stage appropriate- that is – they become compacted morulas on or about day 4 to day 4.5. IF they are much slower or faster than that, it suggests a problem with the embryo. The chances of pregnancy arising from a given embryo is dependent on a huge numbers of factors, egg quality, embryo quality both contribute to embryo quality. The embryo needs to be healthy and the uterine environmnet needs to be able to accept the embryo so there are a lot of moving parts. On top of all that, the technical staff must be capable and well trained because there are opportunities to screw up every step of the process. So their 15% is based on their experience with their patients at their clinic. I think 15% is low but it may very well be what you can expect based on their past data with patients similar to you. Also, this is the second of two embryos transferred; the other is an expanded blast so that one alone should give you a decent chance of pregnancy. Good Luck! Carole

  • Ingrid Says:

    Dear Carole,
    tks for your reply.
    The other was an early blasto. Anyway, my beta were zero.
    I will try with a fresh cycle in this new center.
    I know that they only transfer Exbanded blastos or in hatching blastos.
    I hope it will be the good opportunity.
    Tks a lot for your suggestions and your patience

  • Natasha Says:

    Dear Dr Carole ,
    I had a 3 day transfer of 2 – 12 cell embryos . 1 was already starting to compact .. Toward morula stage . My question is , are these viewed as good quality or ” problematic” ? I had hope this would be it – however 2 no blood test follow up today shows a drop in estrogen and I’ve been placed in estradiol … I’ve read various articles that point to both . I am now in my 2ww period and today is day 8 after the transfer and of course out of lack patience a hpt indicated negative result , I’m not too hopeful as I feel more Pms symptoms than anything else including acne breakouts which normally occur before my cycle – so things aren’t looking good . Should I just give up at this point ? 12 cells can’t make it – best I’ve had after 4 Ivf attempts . Last attempt had 9 embryos ( 2 @ 10 cell , 2 @ 8 cell and rest were 7 cell on day 3) that ended in 8 week D&C which showed extra chromosome … I did get pregnant naturally last September – resumed in chemical, pregnancy and poor results on Ivf before that .. Is it too late ? I’m 41 will be 42 in November . Partner is 30 yr. what’s ur opinion ?

  • Amanda Garza Says:

    I am 36 & husband is 52. I just went through my 1st unsuccessful IVF using ICSI. I was on stim meds for 10 days, 150 menopur and 300 Follistim daily. Last 5 days 250 Ganirelix.They retrieved 10 eggs, 7 were mature, 3 fertilized and 1 fertilized late. Day 3: Out of the 4 embryos, two of them graded poor (4 cells) and two of them fair ( 6 cell & 8 cell w/ fragmentation & uneven cells). Today, day 6…they called & told me my 4 embryos stalled in the cellular stage so I have nothing to biopsy & freeze. We will meet with Dr next week to go over everything. What questions should I ask? I am new to this and not educated on the topic. I have been reading as much as I can to familiarize myself but feel lost. This cycle cost almost $20,000 and we want to try again but I am not sure if I should stay with current Dr or try somewhere else. Any advice would be greatly appreciated. Thanks in advance.

  • Carole Says:

    HI Amanda,
    I am sorry you are having such a difficult time. First,check out your current clinic’s pregnancy and live birth rates at http://www.sart.org. Compare the clinics near you to the national average success rates. Don’t go to clinics that are worse than average for women in your age group. The cycle you describe is complicated and requires the clinics to be skilled at ovarian stimulation of older patients, good ICSI technique, good cellular culture technique. It will be difficult to determine whether the poor results you had are entirely due to technical issues, patient issues or a combination. You can ask about their level of experience (frequency and/or experience ) with these techniques. You want to hear that they have several years experience and also confirm that they have better than average pregnancy rates if you continue with them. In the end, you have to calculate the odds and decide whether you can afford to continue down this path to parenthood or want to pursue another path. Good Luck!!! Carole

  • Carole Says:

    Hi Natasha,
    I am sorry you are having such a hard time. I think that the problems you describe are common and, unfortunately, can be explained by increased aneuploidy (abnormal chromosome number) in eggs from older women. I think IVF is not working very well for you. It may be time to consider alternative paths to parenthood- embryo adoption, donor egg, child adoption. Good Luck with whatever you decide! Carole

  • Ann Says:

    I had a day 3 embryo transfer of 4 embi 3 ×10 cell and 1×8 cell all grade A,am worried about the grading since I heard a perfect embryo should be 8 cells on day 3,what are my chances with these embryo this is my 2nd attempt on ivf

  • Ingrid Says:

    Hi Carole,
    I would like to know what do you think of embryoglue? In my clinic it costs 250 euros but they don’t suggest it to me! I had 2 cycles failed( but we didn’t good embryos from ED) . Do you suggest it to me? It’s my 3rd ED and this is with a fresh transfer.
    Tks a lot

  • Carole Says:

    I would not worry too much about 10 cells on day 3- that is close enough to 8 cells, particularly when you consider that the timing of fertilization – the “start time” for development- will vary by some hours in a group of embryos. Please be optimistic at this point. I wish you Much Good Luck!! Carole

  • Carole Says:

    HI Ingrid,
    Embryo Glue might be beneficial. A Cochrane Review of 17 clinical studies with almost 4000 patients suggested that the use of adherence agents like embryo glue may be beneficial. you can read the article here: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007421.pub3/abstract We used it in our lab and were pleased with the results.I think if you can afford it, it is unlikely to hurt your chances and may help. Good Luck!! Carole

  • TG Says:

    Hi Carole, I had a 5-day transfer 9 days ago and I find a slight spotting this morning, is this mean everything is over? My pregnancy test is scheduled day after tomorrow..please advise.



  • Carole Says:

    Hi TG,
    I would continue to follow your doctor’s directions and take the pregnancy test as scheduled. Please do not hesitate to follow-up with your doctor with these questions. Good Luck!! Carole

  • Amanda Says:

    Hi Carole,

    I just did my 3rd frozen round of IVF, but the pics of the embryos look diff this time around. I don’t see the fluid sac, the part that would be the fetus, ect. I was wondering if I sent you pics if you would have an opinion about them. I’m wondering if they didn’t let them progress long enough before transferring to make sure they were a good grade or what?

  • Amanda Says:

    hmm testing out to see if my comment went through, I’m not seeing it.

  • Carole Says:

    HI Amanda,
    It may be that the embryos are morula stage- the stage just before the fluid filled cavity is created. If the embryo is healthy and the uterine environment is ready, a transferred morula will implant so I wouldn’t worry about transferring a morula. Since this is a thawed embryo, the other possibility is that the embryo hasn’t fully expanded in culture. Expansion is a handy indicator that the embryo is alive after transfer but not seeing it does not mean that the embryo is dead, just that the transfer happened before the embryo expanded. If alive, it will expand after transfer as well. The other thing is that sometimes the embryologist takes pics of all the thawed embryos early in the day and at the time of transfer hours later, they see that expansion has indeed occurred but they don’t take a second picture- but may well have made a note in the chart that expansion was visible. By all means, ask these questions of your embryologist to be sure but what you describe is not necessarily concerning. Good Luck!! Carole

  • Fathima Says:

    I had egg retrieval done earlier this week, 15 eggs obtained.
    But the embryologist results say, all the eggs are of poor quality, amorphous in shape. On Day 1, only 1 had fertilized with 2 PN. Six of the eggs had degenerated. Few had fertilized but abnormally.
    By Day 3, there were 3 fertilized, one 8-cell, one 9-cell, one in compact state, all of Grade 2, their best being grade 1.
    At this stage, they had done freezing. We had plans to do PGS, but we were informed that, minimum 6-8 embryos in number are required, for PGS to be done, is it correct?

    Also, i am having doubt, that from the 15 eggs retrieved, only 3 had fertilized normally, remaining 12 eggs either degenerated or fertilized abnormally, can the status of these 12 eggs be taken as a pointer to the implantation success for the 3 fertilized embryos in the future?

  • Carole Says:

    Hi Fathima,
    I am sorry you are having such trouble with IVF.
    RE: “we were informed that, minimum 6-8 embryos in number are required, for PGS to be done, is it correct?” This is a clinic policy. Technically, you can do PGS on one embryo. My guess is that they have had experience that if there are less than 6 embryos, the odds of finding a good embryo for the client and achieving a pregnancy is poor and the client is unhappy with the cycle and the cost associated with the cycle. You could probably insist they do it but if they have historically poor results in their lab with fewer than 6 embryos, you likely will be unhappy with the outcome.
    RE: “can the status of these 12 eggs be taken as a pointer to the implantation success for the 3 fertilized embryos in the future?”, there are many reasons for poor outcome, and it can be due to issues that the patient and partner have and/or problems with the clinic. If you are using a US clinic , you can check their pregnancy and live birth outcomes at sart.org http://sart.org/Find_A_Clinic/ and compare your clinic to the national average: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0 In my opinion, if I am the patient, I would only go to clinics that had better than average rates for women in my age group. While any clinic can have a problem with a particular cycle, your odds are improved with a clinic that generally has better than average outcomes. IF the clinic is better than average, than the odds are that patient and partner factors are probably playing a bigger role. It is concerning that your first cycle had such poor results. IF this cycle does not work and your doctor suggests another cycle, I would press him on what he will do different in a second cycle. A better stimulation protocol may be very helpful. The first cycle can provide helpful hints for improvement. If you are over 35 years old, and more so if you are over 38 years, this outcome is much more likely to be repeated in a second cycle because eggs are more likely to have abnormal chromosomes as the women ages. In that case, I would seriously consider alternative paths to parenthood because IVF is not serving you well. Good Luck with whatever you decide!! Carole

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  • Jen Says:

    I had 2 compacting modules transferred on day 5, one was starting to cavitate. How much lower of a percentage of pregnancy would this be than if the transfer had been with 2 blasts?

  • Carole Says:

    Hi Jen,
    Compacting morulas can make babies, no problem. It’s helpful to know that when the sperm is added to eggs in the lab, not all eggs are simultaneously fertilized so the start clock is different for each–what looks like a half day lag might just be a half day lag in when fertilization occurred. Good Luck! Carole

  • Sarah Says:

    Hi Carole,
    I’ve just completed a third IVF cycle, (first two unsuccessful fresh transfers.) This time we are doing everything different. Sending 3 frozen embryos for PGS and whatever we have from this cycle as well. The roundup for this cycle was: 14 eggs retrieved, 11 mature, 5 fertilized with ICSI. My clinic also uses assisted hatching because of my age (42). I got the call yesterday (Day 5) with these stats: 1 at 3 cell, 1 at 6 cell, 1 at 7 cell and two at 8 cell. My nurse said they wanted to let them grow another day. I’m sure the 3 cell will not have a good outcome. Are the others hopeless at this point? They did not call me today with any update. Thoughts?
    Thank you,

  • Carole Says:

    Hi Sarah,
    I am sorry you are having such a difficult time. Unfortunately, the outcomes you are seeing are exactly what one can expect for your age group. I really wish physicians would do a better job of explaining that at 42, even if you manage to produce and retrieve a good number of eggs- as in your case- the odds are that most of the eggs –if not all of them- will have an abnormal number of chromosomes(aneuploidy), which could explain that very poor progression . This is a normal side effect of living to 42- there is nothing you can do to prevent this normal ageing process on your eggs. On day 5, normal embryos would be at blastocyst stage. Even the 8 cells are two days behind at this point. Honestly, as hard as it is to contemplate, your best chance of having a child are via egg donation, embryo “adoption” or traditional adoption. I would recommend using your financial and emotional resources on something that is more likely to give you what you want- a child. I wish you all the best in whatever you decide going forward. Carole

  • Shelby Says:

    Hi Carole I am turning 40 yrs old in a month and this is my IVF#2. I just recently had my 3 day tranfer of 2 embryos with 1 of them 6 cell average and the other 1 a 7 cell above average. Retrieved 10 which 9 are mature and where fertilised via ICSI. All 9 were fertilised when I got the call the next am after retrieval ,Only 3 has divided.2nd day I got a call and was I was told out of 3 that divided 1 arrested so they ae doing a 3 day tranfer with the 2 embryo remaning . So, I had my transfer yesterdayBefire yhe transfer RE talked to us and told us that he find it find it strange that after he called me the 2nd day after retrieval abt my embryos, he noticed that the other 5 that were fertilised but did not divide the 1st day, did not arrest but instead started cleaving the 2nd day after retrieval.He said this rarely happens and he finds it strange.He said he is keeping them and watch them and let me know how they will progress.Day 4 after retrieval I got a call and the RE told me out of 5 remaining embryos 3 has divided into 5 cells and morphology wise they look above average.The other 2 is a 2 cell and a 3 cell.My question is is it possible that a fertilized eggs can have a day late in cleaving and still turn into a good embryo and can be freezed for future transfer?

  • Shelby Says:

    Carole this is just a continuation of my 1st post.My 1st IVF was August last year,collected 9 eggs all fertilized via ICSI but only 2 survived on the 3rd day and had transferred both but they did not implant.I have a daughter by yhe way conceived naturally she is now 10.Looking forward to your answer.
    Thank you ?

  • Carole Says:

    Hi Shelby,
    Slow embryo progression is troubling because it can be a sign of aneuploidy, which is just a fancy way of saying that somewhere along the way , during egg development , or after fertilization, during chromosome replication and division, the chromosomes didn’t split properly and the number of chromosomes in the cell is either too many or too few than the normal number. Depending on the chromosome involved, it causes a variety of problems for the embryo- including failure to go on. So it is not great. At 40, your risk of aneuploidy is elevated simply due to age. You can live as healthy as possible and it won’t make much difference. Female fertility declines after 35, and declines more rapidly after 40 so if this cycle does not work, I would recommend thinking carefully if you want to continue on with IVF. IVF is not being very kind to you. If your embryos are not where they are expected to be – 8 cell on day 3, blastocyst on day 5, it is unlikely to work. There are many paths to parenthood and IVF may not be the one for you. I wish you all the best as you move forward. Carole

  • joy Says:

    hi carole,
    I’m 42 and had my ovum pick up last feb.28,2017. we got 5 eggs but 1 was atretic. Of the remaining 4, 1 was inseminated while the 3 injected (icsi). On day 5 only 1 of the embryos reached the blastocyst stage and it’s grade 1. The blastocyst was frozen and we were waiting for my 2nd cycle for it to be put back in the uterus. I’ve been asking regarding the result from my RE and clinic but was not given satisfactory explanation. I hope you can shed some light to my questions.
    1. is the grade 1 blastocyst a good stage that may result to a pregnancy?
    2. what does grade 1 means pertaining to the success of the IVF?
    3. will my blastocyst still divide/mature while being frozen?

  • Some tips for having a better conversation with your IVF Lab · Circle + Bloom™ Says:

    […] Embryo stages, progression and pregnancy outcomes […]

  • Sarah Says:

    Hi Carole,
    Thanks for the nice article.
    I am 45, living in Australia. I have got 7 eggs on the last Monday after going through IVF plan. The fertility clinic contacted me on Tuesday and let me know that 5 of them were fertilized successfully. Then they contacted me on Saturday (4-5 days after fertilization), notifying me that all fertilized eggs are growing nicely, some better than the others but all look all right. Today (Monday) two days after their last call they contacted me with the updated news to tell me that all of the 5 fertilized eggs are not growing/dividing at the speed they expected. They said they were going to give them a couple of days more time until Wednesday to see if they have “good quality” (this was the exact word she used) or not, and if they don’t, they can not keep them for longer period of time.
    I am a neuroscientist, and I may don’t know very much about fertilization progress in vitro, but It doesn’t sound scientifically right to me that al the well fertilized, well growing eggs for the first couple of days, stopped their progress at the same time and together.
    Would you please give me any idea, or comments about it.

    Thanks very much.

  • Carole Says:

    HI Sarah,
    I am so sorry you are having such a hard time. What puzzles me is that the embryos were doing great 4-5 days after fertilization, but then they cultured them for two more days taking them to day 7. The vast majority of clinics would transfer the embryos on day 5 or day 6. Even the best embryos in the world need to be frozen or go into a uterus after being in culture 5-6 days–they don’t survive in culture by 8 with current culture media. We don’t know how to successfully culture embryos past day 6. I would ask them what their pregnancy rates are with transfer on day 5, 6 or 7 for women in your age group??? IF they looked good on day 5, why didn’t they transfer then? I think if you ever do this again, PLEASE find another clinic. The other issue is that they may have exaggerated your chances of pregnancy at the age of 45. in the US, the chance of a women who is over 42 ya achieving pregnancy with her own eggs is very low- less than 4%. At age 45, I would expect even worse luck with your own eggs. I don’t want to upset you, but using donor eggs or adoption are both much more likely to work for you. Most women in your age group would be counseled about these unfortunate statistics. Based on what you told me, it appears that they are not operating within what is considered standard practice. I wish you all the best going forward. Please get a second opinion from another clinic. Good Luck! Carole

  • Zula Says:

    Am 36 years, did IVF due to blocked tubes. Transferred frozen embroy on Thursday but Dr said the first embroy thawed but did not multiply and the second one thawed but was multiplying slowly. So we transferred that one which was slow at multiplication. Am just confused, does multiplication mean re-expansion or it rexpended and the issue was about multiplication of cells!! Am confused. But the culture was for 2 hours.

  • Carole Says:

    Hi Zula,
    You will need to ask your doctor to be sure, but I suspect that they are referring to “expansion” of the blastocyst after re-warming. A blastocyst is the normal stage of development that is reached after 5 days in culture. The blastocyst has a central space and it expands by pumping fluid into the central space. Prior to freezing, the space is purposefully collapsed to allow more efficient freezing. After re-warming, as the embryo re-vives, it begins to pump fluid again and it expands like a deflated balloon being pumped through air. This usually takes 1-2 hours after re-warming. Good Luck! Carole

  • Mona Says:

    Hi Carole , I had my first IVF cycle and 3 eggs fertilised normally. At day 3 the embryos were 8 cells grade 2, 12+ cells grade 2, and 11 cells grade 1. I was then called on day 5 to be told two had reached early blastocyst stage and the other was just cells and they would give it one more day. Then today they called to say none of the embryos had made it to blastocyst stage and when I asked why they said they had arrested development and some cells had turned ‘black’ and they were discarding them. I am confused as they seemed to be doing well and wonder if there was something wrong with the embroys or could it possibly be the culture. I was initially advised to do frozen cycles but now wonder even if they do develop will they thaw and be suitable as I was told there is no difference between frozen or fresh embryo transfer. I have an appointment to discuss with the clinic further and wanted your advice on pertinent questions to ask about what could have gone wrong in the later stages, should I still have frozen cycle ( with PGS) and also would an earlier embryo transfer increase my chances if they were initially looking good? Thank you

  • Steef Says:

    Hi Carole,

    First, thanks for the information you provide it helps us a lot and is very useful to understand the process more detailed.
    My wife recently had her 2nd cycle at an IVF clinic in Russia.
    She has PCOS, nevertheless, 31eggs were retrieved, 20 naturally fertilized, 1 frozen day 5 blast (quality 2BB).

    Doctor says PCOS patients suffer from possible low egg quality and that it might be because of that the cycle turned out with dissapointing results.

    1 frozen egg, trophectoderm biopsy and assisted hatching was done. Now will be send for PGS testing.

    We are considering to perhaps do another cycle, but doubting the clinics skills as the results were so low.

    Any advice you could give us? There are no live birth rates and pregnancies online available, but the clinic says they are good. It’s a trust issue, or is there any specific things I can ask to check for more confirmation? Thanks in advance!

  • Carole Says:

    Hi Steef,
    It is difficult for me to give you much relevant advice since I have no experience with Russian clinics. From my experience with PCOS patients, it is not uncommon to retrieve a very large number of eggs, but then see only a few fertilize. Physicians tend to learn from each stimulation how the patient responds and can tweak subsequent cycles. You might ask your doctor how he might adjust the stimulation for the next cycle for your wife. If he doesn’t have any plans to change anything, you might try another doctor. Wishing you much good luck to you and your wife. Carole

  • Yong KM Says:

    Dear Carole.

    Like to seek your kind advice.
    My wife did her 1st IVF cycle at age 40.
    Retrieved 9 eggs, 8 fertilized, 7 growing ( update at day 3).
    Day 5: 3 reached blastocyst, remaining 4 embryo appear arrested. 1 of the 3 blastocyst biopsied and other 2 blastocyst appear slow growing.
    Day 6; 2nd blastocyst biopsied and 3rd blastocyst arrested.
    We sent the 2 for PGS test and waiting for result.

    the embryologist find it strange that the 3rd blastocyst was arrested. Is that common or rare ?

    is day 6 blastocyst likely to have any problem compared to the day 5 embryo ?

    Look forward to hearing from you.

  • Yong KM Says:

    Dear Carole,

    Like to ask how common will a day 5 blastocyst get arrested on day 6 ?

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