A commentary on the practice of medicine and what lies ahead.

One of the worst things that I realize I do during the TTC process is become too immersed in it. When I was trying to get pregnant, I would google and run pubmed searches till I could practically recite the study results; I chased down every possibility I could think of, and I thought of a lot.Some of that paid off though. I just wish I had done less of it.

The same issues are starting to rear their heads back again now. I've examined practically every study that compares IVF protocols and have obsessively examined those that look at  blastocyst aneuploidy and quality.But anyway, I think I've learned a lot, and I'll be updating both the science of infertility page, and creating a new section on IVF. 

I was talking with my RE's wife (also an RE; a really sweet lady who did my retrieval) about how well this cycle worked out and I commented that a lot of it might have been due to the protocol I tailored for myself (I also tweaked it on the fly) and she joked that I should consult for the more difficult cases, and I quipped back that I would, if I got paid for it. But there is an important take home message here: even among a group of patients labeled "infertile," there are subsets with unique issues. Recognizing those issues, tailoring each protocol individually, being invested in the tiny details, and making changes based on those details as the treatment proceeds may be what is required to optimize your treatment.

As an example, I decided to check LH levels during my treatment (my RE only checks E2). Everybody responds different to both the agonist or the antagonist. I realized that with the antagonist, my LH was getting too suppressed, my E2 was not rising as it should have been (E2 production DOES require LH), and the follicles on the right were lagging (13 mm, as opposed to 19 mm on my left).  I decided to add back LH (in the form of menagon) on the last day of stims. We did not check E2 or follicle growth after that, but the results on egg retrieval day were fabulous; my right ovary had caught up and made even more mature eggs than my left. Was the situation helped by the low-dose LH add back? Impossible to say, but plausible.

Unfortunately, few take such a detail-oriented approach, or have the sort of attitude necessary for such an approach. While patients of a particular disease type fall into into subsets, medical treatments today use a broad strokes approach; the same freaking approach is used to treat everybody who comes your way. I have rarely ever met a doctor who is maverick and intuitive and adjusts the protocol (ANY treatment protocol) on the fly. It takes a rare sort of personality to do that. What REs do when you do not respond (which is the club-on-the-head approach of pushing the stim dose up higher and higher) does not count.

The only doctor I've come in contact with who is truly intuitive and maverick and can to an extent accurately delineate between the shades of grey of human biology is my mother, and the sort of intuitiveness about what is the issue and what may work that she has is extremely uncommon. Her results speak for themselves; she is in a field where the doctors end up doing very little to help their patients, while her methods produce a near to full recovery in a pretty high percentage of her patients. 

Btw, when she was giving me sub-cutaneous injections, we discovered something nifty: Instead of squeezing a wad of skin for sub-cut injections, try stretching the skin out with your fingers; I did not even feel the needle go in. The few times I got the traditional grab-fatty-skin-and-plunge-needle-into-the-pinched-up-wad-of-skin approach (from the nurses at the clinic), it hurt way more.  

Anyway, I digress. Coming back to medical approach and its effect on the success rate, there are some IVF clinics in the world that may show a level of success that surpasses that of their peers, and one of them is CCRM. I visited their webpage for the first time the other day, and I was impressed. Forget about protocol optimization (but please, blog visitors, feel free to talk about your experience with respect to this, it would be very useful), they use an embryoscope that minutely tracks the growth of each embryo, they do PGD, and they freeze their embies one per vial (they have to, if they are doing PGD)...I was practically salivating. But god knows, I don't want to go through another IVF or pregnancy again. Anyway, the time of reckoning is coming up quickly. Transfer to the surrogate occurs on Tuesday.

Then begins an interminably long wait: my RE's clinic believes in testing 12 days after a 5-day blastocyst transfer, which does not seem logical. It would make sense if you were doing a 3-day cleavage embryo transfer (because then you would be testing on the 15th day of embryonic life), but it just prolongs the wait (and the torture) if you want to wait until the 17th day of embryonic life. And given that in every pregnancy (even the one with the Trisomy 4 blastocyst), I had a positive HPT by the 10th day of embryonic life, my RE's assertion that "testing 10 days after 5-day transfer may be too early" cannot be taken seriously. Let us see how putting my foot down goes. But here we go again, soon.

IVF#2. The final tally

The results of this round have, frankly, been miraculous-looking. Whether they are actually miraculous (i.e., can produce a drooling, pooping bundle of joy still remains very much a question).

But here we go:

19 eggs, 15 mature, 16 fertilized.
Day 3: 9 eight-celled grade As, 1 five-celled Grade A,  2 six-celled grade Cs. (Plus 1 four-celled and 1 two-celled)
Day 4: 5 embryos are early blasts (!!), 2 reach the morula stage,  2 ten-celled, 4 eight-celled, 1-5-celled (grades AC-CC)
Day 5: 10 blasts!
Five 4AAs, one 3AA, one 2AA, one 1AA, and 2 early blasts (will get the final grade today, when they freeze these last 2 on day 6)

One source says that 40% of "good-looking"embryos make it to blast; Another source says that around 33% of all fertilized eggs make it to the blastocyst stage.

Either way, the results of this cycle are well above average. Last time, the issue was that I had very few mature eggs, but my blastocyst generation rate, from all fertilized eggs, was around 33%, which is dead average.

So why was it so good this time when it was so crappy last time?

More on that later, but this is definately one of those celebrate-becuase-you-bloody-well-can moments. You never know when things will change.

Oh, and I lost my old surrogate and found a new one in the space of 2 hours. And I was lucky enough to find somebody whose cycle began 2 days ago- so a transfer is imminent. More on surrogacy in India soon- have to say, it's SUCH a different set of rules.

More on all of this later, this post has been typed from my phone, so please excuse any typos.

But for now---wheeeeeeeee!!

Decision, and depressed as hell

Thank you all for your input on my last post- I agree with you in that 2 vitrifications should be off the table.  What I was hoping to do was collect the biopsy on day 5, and freeze the biopsied cells. But it looks like that won't be possible, even though I may have been able to get my hands on the materials needed in time.

Doing things in India has the advantage that it won't break the bank, and this is a tremendous advantage that should not be taken lightly. And then, there is the tremendous emotional support that is offered to me by my family.

But one can never have their cake and eat it too- this is a technologically retarded country. NICUs are primitive compared to the setup in the developed world. Fetal DNA analysis from maternal blood (like Sequenom's Tri21 test) during pregnancy is going to take years, if not decades to get here. There is probably one guy who can do a decent aminoicentesis, and I may have to fly my surrogate to another city to find him.  A trophectoderm biopsy is not here yet, or atleast, it is not there with my doctor, who expressed extreme reluctance in doing this procedure. My lack of preparation had an extremely large part to play in this, I just sprung this on him, so he did not have time to prepare, with dummy runs etc.


But there it is- no testing.  I have to just collect whatever grows till day 5, and transfer to the surrogate.

Atleast 40-50% of the day 5 blastocysts  (there was a study definitively showing this) are going to be abnormal. My RE countered that despite such odds, people get pregnant and deliver healthy babies. What was left unsaid was how this is achieved: you transfer multiples. Out of 2 or 3 embryos, 1 may be normal. I'm starting to believe the theory that most women's wombs can distinguish between a normal and abnormal embryo. This may very well be the reason for the high frequency of BFNs in IVF and in natural pregnancies as well. The transfer of 2-3 embryos can also sometimes result in a pregnancy with multiples, which may be slightly or tremendously detrimental to the lifelong health of the resulting children, even if the pregnancy is without complication.

So now, I may have to do what everybody else does: transfer 2 at a time, or I may be doing this for a while, at tremendous cost.  I just have to then pray that if my surrogate gets pregnant, it is with a singelton, not twins. A twin pregnancy is considered high risk in the developed world. Here, given the standards of management, you would have to rely on luck for everything to go ok, and I'm somebody who has had absolutely no luck in this process so far, and now, I have to pray that I find that luck. Scary as hell.

Day 2 report and a difficult decision to make: Need your input!

All but one of my 16 embryos are now 4-celled:


8 are 4-celled As
2 are 4-celled Bs
4 are 4-celled Cs
1 is a 2-celled A (this we can probably write off)

I think there is a good chance I'll get a decent number of blastocysts, of varying grades. This is the sort of thing where I'd want to do an embryo biopsy to see how many are aneuploid.

The issue is, I  was stupid and left it too late, because I did not envision getting anything, after my last experience. The only lab (the Spain-based company Iviomics) doing this in India is not functional yet. We could collect the biopsied cells and freeze them down, but we need a special medium and special tubes to do this.

I just got off the phone with the Spanish guy who is the India head for this organization, and I asked him if we can overnight this from Spain to get here by Day 5 (Sunday). He said he could talk to his people and get back to me.

The other option, which I really don't like, is freeze everything down on day 3, thaw them all, herniate, and biopsy on day 5, and freeze again. This involves double vitrification, which I'm not a fan of.

The other option is going with fate--- just freezing whatever we get on day 5,  transferring and seeing what happens.

Lets hope they can overnight. Even if things work out that ideally, there are still risks: the clinic does not do this routinely.

What would you guys do in my shoes- do the day 5 biopsy on Sunday (if I could get the materials on time) or go with hoping to get lucky?

Myo-Inositol for fertility and PCOS: Share your experiences!

This post is a very long answer to Josie's question in the last post, where she asked me how I picked my myo-insoitol dose. Well here goes my experience with this so far. Just some background information you need: In most studies, women receive 2000 mg myo-inositol twice a day, along with folic acid.

My experience with this supplement:

Despite being aware of the dose used in studies, I arbitrarily went with a lower dose initially, because I was frankly nervous about what it would do. I started with 1000 mg/day, of supplemental (and not the prescription preparation myo-inositol) and things looked great that cycle: I ovulated a bit later (CD 19) than that in my recent cycles (CD 17).

Just FYI, in my pre-vitamin D, pre-supplement days, my best-looking ovulations were on CD 20. Sadly, none of my pregnancies were conceived during these cycles, they happened in shorter, crappier-looking cycles where I ovulated on CD 16. 

Anyway, coming back to the present day, after that first great-looking cycle (with a nearly 16-day luteal phase) where I was taking 1000 mg/day, I shifted to 2000 mg/day, and stuff pretty much went to hell the next cycle, in a manner never seen before - no EWCM, or CM of any sort, no detectable LH surge. I was not even sure I'd ovulated, except my temperature did go up. The luteal phase was a markedly short 11 days.

Alarmed, I shifted back to the 1000-mg dose. The next cycle (still ongoing) is interesting...there was one alarming day where my temperature short up, making me think I had ovulated, and prompting my last post. But happily, I was wrong, I have not misplaced my surge, this turned out to be a nice-looking cycle; got lots of CM, did show a strong surge, ovulated a bit late (on CD 22).

So,phew.It looks like myo-inositol may not be bad for me, but only at low doses. It has changed my O date. Still have not settled into a pattern, but it will be interesting.

How many women, if nothing changes, ovulate on a certain day every month? I'd really like to know.

Also, if you are a PCOSer, or a non-PCOS infertility case on myo inositol, I'd really love to hear your experience. Please do share, sometimes anecdotal information can also be useful!

Also, some information to note, if part of your issue is low progesterone, this may really be something to try out, since both published literature and my experience (with the 1000 mg/day dose, with the longer luteal phase) suggest that this can increase progesterone levels.

Updated: I did an IVF cycle a few months after this post: I took myo-inositol for THREE CYCLES at least, and then went for IVF. Myo-inositol is supposed to increase the percentage of oocytes that are mature at pickup. We got 14 M2 eggs, 2 M1 eggs, and 3 that crapped out, from a total of 19 follicles.All my M2s and my M1s fertilized too. Overall, this was pretty darned amazing: My first IVF, where the protocol used on me was far from ideal, produced 4 M2 and a few M1 eggs out of 11 eggs, and only the M2s (3 out of 4) and none of M1s fertilized, in contrast to my second cycle, where everything did. I attribute the improvement from IVF#1 to IVF#2 to two things: a very different protocol, and maybe, in part, the myo-inositol.

I have gotten emails asking about a good supplement: I would recommend this (see above),
which combines myo-insoitol and folic acid, and appears to have been used by many women with PCOS successfully.

On myo-inositol and new blogs

First, lets get the annoying news out of the way- I seem to have mislaid my LH surge. The ONE thing, which is dependably seen in every cycle ever the past 3 years, is gone. I can't see a pattern anymore; I did ovulate last month based on a temperature rise, but it was a shitty cycle in that there was no CM, and the LH was an itsy-bitsy 12 days. GRR. 

Given all the stuff I do, I have to say that I'm really good at figuring out what is responsible for which effect, and this one I'm blaming on myo-inositol (down from 2000 mg/day, to 1000 mg/day). Its playing havoc with my cycle. Its freaking amazing for my skin. Definitely cause for shaking my fist at the universe.

I'm not going to give up on it just yet through; I'm going to keep taking it over the next 2 months and see if things change/settle down, and maybe I'll keep taking it till IVF anyway, and just use a trigger. 

The amazingly frustrating part is that myo-inositol is supposed to do GOOD things

• It is great at fixing the issues in women with PCOS. It can, to a large extent, shown by multiple studies, fix acne and hirsuteism, bring down LH and androgens (definitely doing that with me) and restore ovulation in women with PCOS.
• It can increase the proportion of mature oozytes at pickup during IVF (!!!!).

 I'm not sure what to do. Yes, my cycle looks utterly shitty now, and what I took for gospel truth--that if you had perfect cycles, you would have good eggs--has not held true for me. Sure, I got pregnant almost everytime I tried with my natural cycle, but something was off, 2 out of 3 times, my eggs may have been aneuploid. So maybe the lower LH is good, and such crappy cycles may actually get me live babies. Unlikely, but knows right?

Plus, I like what its done for my skin. Don't want to stop taking it, at my current lowish dose, ever.

So there is my current conundrum. I'm ok despite it though. I really, really relax during my breaks from TTC, I have to say. Probably because TTC itself is such stress, and has never got me good news yet, not trying to make a baby makes me feel so much more better. Its like when the dentist stops drilling on the tooth with the exposed nerve. It is too bad I'm determined to have a child, and TTC will have to recommence at some point.

The other news is that I will be starting a wellness blog using my real name and identity. Having a widely- read blog is good for me professionally, given that I've started building a career in scientific communication. The face-palm moment arrives when I realize I've started a blog that is visited by people all over the word, has gone over 200,000 page views, shows up quickly in Google searches, and I most definitely cannot list it on my LinkedIn page about it because too much of it deals with deeply personal issues.

What I'm going to start doing, is take away all the science from here slowly, and move it to there, and incorporate it into the general health topics I will discuss. So there, I'll be talking about infertility, autoimmunity, fibromyalgia, autism, discussions on healthy practices, etc. What I do best is gather, assimilate and distill scientific information, and I flatter myself in saying that I do it rather well.  

When the new blog is started- most of the science on this blog (the stuff on vitamin D,  the science of infertility page) will go away. People who want the address of that blog, will have to contact me on an individual basis. I'm a little (actually very) leery about people linking the real me to all the deeply personal information that is on here, so I will have to think about how to handle things. Would have been so easy to just put a link on this site, but nothing in life is straightforward is it?

All about CGH microarray- part II

A continuation from my previous post, this discusses the pros and cons of CGH microarray. If there is anything I have missed out, please bring it up here.

2 kinds of embryo biopsies:
First a little background, and its going to get technical. You can biopsy a developing embryo at 2 points- around day 3, where you pull out a single blastomere, and on day 5-6, after the blastocyst has begun hatching- here you can get out multiple cells. The latter is called a trophectoderm biopsy.

A blastomere biopsy on day 3 is more harmful to the embryo, because "removal of one or two cells from a six- to eight-cell embryo on day 3 depletes the embryonic mass by 12.5%–25% or more, risking the inadvertent removal of critical cells from the embryo, especially if attempting to improve diagnostic certainty by taking more than one cell for testing." Also, with a single cell biopsy on day 3, you have a significant chance on missing out on mosaicism, a condition where chromosomal errors can be introduced during cell division after fertilization, at any point. The earlier the mosaicism is introduced, obviously, the greater impact it would have.  

A trophectoderm biopsy on day 6 appears to have 2 advantages over a blastomere biopsy on day 3-- a) it is potentially less damaging to the embryo (you remove a much lower percentage of the total number of cells, and one lab, who had done this a gazillion times and were now expert at this, clearly, reported that "after allowing for blastocele reconstitution" the majority of their embryos survived their freeze-thaw) and b) It has a  much higher chance (but is not a 100% reliable obviously), of catching out on mosaicism.

Ok- those technicalities being explained,  my RE wisely chose a trophectoderm biopsy, so lets move on to the pros and cons of that, with CGH micrroarray thrown in.

Cons

Damage to the embryo during biopsy: The more the lack of experience of the tech doing this, the higher the possibility of damage, or so i think--correct me if I'm wrong, it does not seem like a simple procedure, no idea what the learning curve is like. Additionally, there are different options of herniating the zona pellucida(?) prior to biopsy, and some may be safer than others, it depends on available technology.

Obviously, as stated above a trophoectoderm biopsy is better than a blastomere biopsy, because you take less from the embryo. But the risk remains that you can damage the embryo, worst case, none of your chromosomal normals might survive the thaw. Or they might be able to survive, but might have a lower chance of implanting. My mother had a unique worry: that there would be flawed development of the baby due to embryo biopsy.  Nothing I've read shows any indication of abnormalities in any children resulting from biopsy (there have been 700 children born from blastomere biopsy worldwide in 2005, apparently). There are plenty of logical reasons to think it decreases your chances of having viable embryos in itself, and based on the hardiness of the embryo and the skill/experience of the tech doing this delicate procedure, may even result in your IVF cycle producing zero clinical pregnancies. That, I think is the worst case scenario, and its one I've considered.I think my final decision will be made after considering the experience my clinic has had with this procedure. If I'm one the first people they try it with, I'll be aware before I decide, one way or the other. 

It does not eliminate the possibility of mosaicism: Obviously, a trophectoderm biopsy is your best chance of detecting this, while it is not foolproof. Again, it comes down to the luck of the draw and about overall risk reduction of pregnancy loss. My goal is to eliminate as many aneuploids as possible. I know that I may not be able to get them all.

Limitations of the technique itself:  My RE bought this one up- its a new-ish procedure, with limitations. In the very best hands with the very best luck, its limits of detection are possibly microdeletions/microinsertions. Still room for things to go wrong. But right now, I'm considering it only for its core ability- the ability to detect gross aneuploidy. Good enough for me.

Practical issues: I'm doing this in India, where CGH microarray is not offered as a procedure (I hope some enterprising individual comes across this and decides to start this as a business venture, sometime soon, though its not going to happen for me). So we are doing it in a clinic where this is not usually done (and I am deeply and utterly grateful for their willingness to take this on), then will be attempting to ship DNA across continents (So much can go wrong there), then I have to find a lab willing to do this, who accepts extracted, amplified DNA from another country as raw material for this procedure (anybody who has had this done, can you tell me the name of your lab?) CCRM girls, this is done in house (right?)
Right now, I just know of  24suretest (in England) and CCRM.

Pros:

It would definitely improve the chances of success. One study reported that after taking into account aneuploidy and mosaicism, over 50 % of the generated embryos of 'young women'  were chromosomally abnormal.  Clearly, age does not protect you fully.  And I'm young (in that I appear to have plenty of eggs left, with excellent FSH, AMH, estradiol and AFC--similar to that of any egg donor), and I make eggs capable of fertilization and implantation, and 2 out of my 3 eggs may have been chromosomally abnormal.

If 40 % of the embryos generated through IVF are aneuploid (and embryo grade is not much of an indicator of whether am embryo is euploid or not!) then I would need some serious luck to avoid having a surrogate go through loss. Both my RE and my mother were of the thought process that, if my surrogate went through one loss, or more, it would be something easily borne, because it is not me going through the pregnancy. I think everybody was startled when I burst into tears at the very thought of my surrogate losing the pregnancy--and the 20 week amnio time point was under discussion here. I think women who have lost babies will completely understand my horrified reaction, while others would think--- its not your body, so what is the matter? To that, I'm going to say, its still your child. So you will be devastated each and every time it happens, especially if you get to the point of 20 weeks, where your hopes have really been built up. For people having gone through the process of using a surrogate, if you could address how you felt at the thought of anything happening to the surrogate pregnancy in the comments section, that would be very useful.

It would potentially decrease time required for success: Lets start with the assumption that around 40% of my embryos will be aneuploid. I line up one surrogate. Transfer one embryo (I refuse to do multiple embryo transfers to one surrogate).  If its aneuploid, best case, we lose around 3 months.Worst case, its something that we don't detect for 20 weeks (again, bloody scary prospect for the mother, while the general audience thinks this is not a big deal). Then, we repeat the process again. If we get unlucky, it would really be a while before we hit on a winning combination. I want to stay in India around 3-4 years maximally. I also want any children I have to spend atleast the first formative 2 years of their lives around my family---which means, for my 2 plans to mesh, this has to work quickly. While IVF with PGS does not guarantee this---I could totally lose a chromosomally normal embryo, at 5 months, for multiple reasons, it reduces the overall risk of pregnancy loss.

A valuable learning experience: If we embark on this road, everybody involved could learn a lot, even if no pregnancy results from this IVF cycle.  I could learn more about the nature of my embryos. The person doing this should get valuable laboratory experience at this technique. If this entire IVF fails, the only commodity that would be definitively lost is money and time. The time would smart, but the money? We spend money on so many things, so many of them relatively inconsequential that I'm not going to feel bad about spending money on this, even if it fails utterly. My mom wants to get me a diamond set worth around a million rupees for the wedding. The possibility of a baby is definitely something priceless, and this venture may set us back around 1/5th of that price, so I'm not going to quibble about it.

This is a post utterly open to lively comment and debate. I hope there is some of that, and more importantly feedback on available facilities (in the US, or anywhere else) that do this routinely and are willing to accept samples and my $$$.  I know a lot of people, from everywhere, read this blog. I hope that will come in useful here!

All about CGH microarray---part 1

I had my visit with my RE yesterday, with my parents in tow. Coming back to India, with the difficult choices to be made, I had expected no step of this process to be easy, and that was proven right with a vengeance yesterday. And its not even a process that should be easy, these are extremely difficult decisions, with a great deal of grey area and a lot of room for arguing pros and cons for any particular fork in the road. Unexpectedly, the point I had expected to be the sticking one, surrogacy, was more easily settled, but another point provided a great deal of debate-- that of genetically testing the IVF-generated embryos.

First, lets segue to another point, that of treatment choice in itself. Both my RE and the MFM specialist I saw in the US gave me the impression that of all the treatment options they would offer as the first choice, an IUI conception (probably with ovulation-inducing drugs thrown in) would be a top choice, and possibly, many of you reading would also agree. This stems from the finding that even women who have had 5 losses have a good chance (is it 50%?) of carrying to term in the next round. This is where the patient and the doctor part ways I think. The patient looks at a 50% risk of going through the hell they went through previously, and may balk, for good reason, I should add. Nobody who has not experienced that reason, personally, (being a truly empathetic audience is not good enough), will  understand why.

I personally, am invested in making the risk of miscarrying/late loss lower. That is all I'm about. I'd love to eliminate that risk entirely, but I know all I can do is make the risk as low as practically and economically possible (and everybody's capabilities here are different), but I can never, ever, despite the best laid plans and all the plotting, planning, testing and novel approaches (IVF, PGS and surrogacy included), can I make that risk go away. Despite all you account for, things can go wrong in yet another way, I am so blindingly, painfully aware of that, far more so now, than 2 years ago.

My doctor proposed a novel  exercise, and its one that is pretty useful and logical- consider and write out the 'cons' of pre-genetic screening of embryos.  I'm doing that, but more for my parent's benefit (they need to understand why I'm proposing this, instead of following the doctor's advice), I'm also going to write a 'Pros' list. This list of pros and cons should be useful for anybody who is at the cusp of this difficult decision. This is coming up in the next post...stay tuned.