INVOcell- Analysis of Risk vs Benefit

November 11, 2014Carole 2 Comments »

Just the other day, I stumbled across an article published on Oct 24, 2014 that discussed a oral presentation presented at the recent ASRM meeting about a low cost IVF alternative called INVOcell. To my surprise, I found comments I made more than two years ago appearing in the current article although no one actually contacted me before they wrote the latest piece. So I thought I would revisit the issue, look at the new data and see whether I can learn to love INVOcell.

What is INVOcell?

INVOcell is IVF without the in-lab culture part. Like IVF, the INVOcell procedure has an ovarian stimulation cycle part to recruit eggs (check). An egg retrieval is performed  to get eggs (check). Eggs and sperm are put together (check), – in a plastic container which is placed in the vagina so the patient can vaginally incubate her gametes. (Whaat?= that’s the INVOCell part).  After 3-5 days, embryos are removed from the container and transferred back to the patient’s uterus.

So, back in 2011 I had two main concerns with this low cost alternative to IVF which I expressed in this post:

Invocell- not nearly IVF

Concern One. If eggs in cumulus and sperm are added to a small culture volume, these other cells will degrade the quality of the culture  medium as they incubate. That is why we remove these excess cells at fertilization check the next morning and place in fresh media. The newest version of the INVOCell technique uses either a very short co-incubation period for sperm and eggs with removal of excess cells before the egg goes into the container or ICSI to minimize the cellular material from the beginning to one egg with a sperm inside. Both of these are good solutions to the media degradation issue and so I am not worried about this any longer.

Concern Two: The fertilization check step is skipped. The window during which normal fertilization can be seen in the form of two pronuclear structures (2PN) inside the egg visible using a microscope happens during the time the egg is incubated in the INVOcell device inside the vagina- so obviously it doesn’t happen. The physician has the option to remove the vaginal device and open it, remove the embryos and check for fertilization but this is not routinely done. After all, the low cost part of INVOcell is due in part to the fact that you don’t do a lot of monitoring and checking during culture (reduced staff) , and don’t need to buy a lot of incubators (reduced equipment overhead since the patient brings her own vagina or that of a good friends to the case). I think INVOcell can be offered at half the price of regular IVF. The stim cycle drugs and physician/nurse time are still expensive but the lab expense can be minimal.

So what’s the big deal with skipping the fertilization check step? 

The reason we don’t skip this step in the IVF lab is because even abnormally fertilized eggs pretty routinely grow into very nice looking blastocysts which can’t make a normal baby but can make trouble if transferred- namely resulting in a molar pregnancy which is one of the complications under the category of gestational trophoblastic disease (GTD) .  Very rarely, a cancer (choriocarcinoma) can arise from GTD.

What causes the most common form of GTD ( hydatiform moles- aka.  molar pregnancies)  which can (rarely) result in choriocarcinomas?

Two types of fertilization errors cause GTD. First, an extra sperm enters the egg, resulting in a 3PN state, DNA from three gametes  (egg, sperm, sperm) instead of two (egg, sperm). Alternatively, the egg can fail to toss out its extra set of chromosomes before a single sperm gets inside- again you have DNA from three gamete sources (2 from the egg plus one sperm) causing a 3PN state instead of the normal 2PN state.

Can we tell if we have a normally fertilized egg or not and remove it from the pool of embryos eligible for transfer?

Yes, traditional IVF procedures require a “fertilization check” step to visually examine the fertilized egg under the microscope during a specific time period (16-20 hrs after sperm are added to the egg) to verify whether 2 pronuclei are visible (normal 2PN state) or more than two are visible (abnormal 3PN) state.

The INVOCell procedure does not include a check for 2PN status.

How often does gestational trophoblastic disease happen? From the American Cancer Society link:

Gestational trophoblastic disease (GTD) occurs in about 1 pregnancy out of 1,000 in the United States. Most of these are hydatidiform moles.

How often does GTD convert into a cancer? From the National Cancer Institute link:

The reported incidence of choriocarcinoma, the most aggressive form of GTD, in the United States is about 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is about 0.18 per 100,000 women between the ages of 15 years and 49 years.[2]

So the incidence of this across all pregnancies (natural and presumably some from IVF in this sample)  is relatively rare.

So why worry about GTD at all?

One reason I am not 100% relieved at this low incidence rate is that we don’t actually know what the rate of molar pregnancy is in IVF patients. I do know that in my experience, we could expect to have a least one molar pregnancy a year in our program.

What was the clinical outcome for IVF patients with a molar pregnancy? These patients had a D&C and then they were counseled not to attempt pregnancy for another 12 months just in case some of the cellular material was retained and could result in an undiagnosed choriocarcinoma. Molar pregnancy was a relatively infrequent event, but something that was treated very seriously when it happened.

There are various anecdotal reports of molar pregnancies in the published literature but I couldn’t find any  national statistics in the incidence of molar pregnancies arising from IVF. Yet, almost every program will, if asked, tell you that yes, they  have had IVF patients with molar pregnancies – and this is under regular IVF protocols in which  3PN embryos are routinely detected and removed from the groups of normal embryos for transfer.

So what can we expect if we skip this step? Will increased use of INVOcell unwittingly lead to the transfer of more abnormal 3PNs – some of which may implant and cause GTD?

Although we may not know the incidence of molar pregnancies in US IVF programs, I know that 3PNs are commonly present among the normally fertilized eggs of many of our patients. How do I know this? I know this because my lab would freeze these non-clinical embryos on a weekly basis (with patient permission) to use these as embryos for technical training. Techs could practice moving embryos from dish to dish or practice freezing or thawing them. We had 3PNs every week to freeze. We pulled them out of the clinical transfer pool but they were routinely arising in our culture system. They made great practice cells because they looked so normal.

So if we don’t look for them in the INVOcell system, does that mean they don’t happen?

My first post back in 2011- caused a big reaction on the part of a reader “Boris”. I took the bait and responded to him in a second, snarky post.INVOcell post strikes a nerve. It’s hard to tell who was suffering from more nerve pain- me or Boris.

In any case, more than two years after my last INVOcell post, earlier this month at the ASRM meeting in Honolulu, data from a small US study was presented that showed encouraging results with INVOcell compared side by side with regular IVF. You can decide if the new data warrants the exuberant headline from the  ASRM press release “Intravaginal incubation of embryos is safe and could save patients money.”

This new INVOcell study was presented by Dr. Kevin Doody from Bedford, Texas as an oral presentation at the meeting. The ASRM abstract data is presented below and  the entire abstract can be found at this link.  There’s not a lot there about how the INVOcell procedure was done except for this: “After a 2-4 hour co-incubation with sperm, up to 10 eggs were placed into the INVOcell device or into traditional incubators. After 5 days, one or two embryos were transferred into the uterus.” Since the window for fertilization check is after 16-20 hours, it’s probably correct to say that fertilization check step is still not part of the INVOcell procedure.

Incubator INVOcell
Number of cycles (patients) 16 17
Mean age 32.3 (26-38) 32.8 (26-38)
Mean body weight (pounds) 162.0 (121-207) 151.5 (109-184)
Mean number of oocytes inseminated 7.6 (1-10) 6.7 (3-10)
Mean number of embryos transferred 1.8 1.65
Mean blastocyst quality score (BQS) 27.24 26.14
Ongoing pregnancy rate /cycle 62.5% 58.8%

The patients in the study are fairly young (on average less than 35) and there were 16 patients in the Incubator method and 17 in the INVOcell method. Statistically speaking, 17 test patients is probably insufficient to detect the risk of GTD.

According to the Medscape article, another clinician, Dr. Lucena, in Bogota, Columbia says that she has seen no adverse outcomes in approximately 500 cycles, which while encouraging is probably still not enough cycles to detect an increased risk of GTD. It is also possible that other factors like advanced maternal age, may make a patient more prone to producing 3PN embryos. We just don’t know enough yet.

These early results are promising in that these patients had very comparable pregnancy rates between regular IVF and INVOcell. The FDA has not approved INVOcell yet for routine use in the US, but one INVOcell clinical trial(2011) is listed on the US government list of clinical trials.

I would be happier if we had more data and I would be ecstatic if we had some test to tell that these embryos are normal when they are removed from INVOcell culture and before they are used clinically. In theory,  genetic testing could be performed on INVOcell embryos but that would make INVOCell more expensive.

Is INVOcell safe? I don’t know. Most of the time when you drive around in a car without seat belts, no harm done. But sometimes, if you are unlucky, you can have preventable injuries if the car does crash. I would rather see more patients have access to insurance policies that pay for traditional IVF that has all the safety features, rather than encourage patients to use a cheaper procedure which may be riskier. Most patients will have no trouble but a few may have very bad trouble. In the end, it boils down to an analysis of risk vs. benefit. If you are enrolled in a clinical trial with INVOcell, hopefully the risk of GTD –as much as can be known- will be disclosed to you before you take part in a trial and you can decide:  Do you feel lucky?

 

Disclosure: As an ex- embryologist,  I have no financial interest in the performance of  EITHER regular IVF or INVOcell. As a patient advocate, I am always hoping for better infertility treatments and better access to these treatments for patients.

© 2014, Carole. All rights reserved.

2 Responses to this entry

  • Nick Says:

    Can you please post a link to the current article that used your comments from a past article? I’m actually interested to read both articles, the two that share the same comments.

  • Carole Says:

    Hi Nick,
    The Medscape article is the first link in the post- click on the work “article” that is a different color. My two previous blog posts are also linked- just click on the names above, “INVOcell, not nearly IVF” and “INVOcell strikes a nerve”. etc. It’s all there. Carole

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