Dr Braverman's response on the lack of stem cells in the womb being the cause of RPL

Dr Braverman responsed on his blog to the lack of stem cells in the womb being the cause of RPL. As he points out,a direct cause for RPL was not demonstrated in the Warwick study.  So he explained it clearly on his blog:

http://www.preventmiscarriage.com/Literature-Review-Blog/2016/March/Defect-in-endometrial-stem-cells-key-player-in-r.aspx

Lack of stem cells to blame for recurrent miscarriages

Date:

March 7, 2016

Source:

University of Warwick

Scientists at the University of Warwick have discovered that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages.

The academics behind the breakthrough are now to start research into a treatment which they believe could bring hope to those who have suffered failed pregnancies.

Professor of Obstetrics & Gynaecology, Jan Brosens led the team who unearthed the link between stem cells and miscarriage. He said: "We have discovered that the lining of the womb in the recurrent miscarriage patients we studied is already defective before pregnancy.

"I can envisage that we will be able to correct these defects before the patient tries to achieve another pregnancy. In fact, this may be the only way to really prevent miscarriages in these cases."

The team found a shortfall of stem cells is the likely cause of accelerated ageing of the lining of the womb which results in the failure of some pregnancies.

Miscarriage is the most common cause of loss; between 15-25% of pregnancies end in miscarriage and one in 100 women trying to conceive suffer recurrent miscarriages, defined as the loss of three or more consecutive pregnancies.

The study, which is a collaboration between the University's Warwick Medical School and Warwick Systems Biology Centre, has been published in the journal Stem Cells.

Miscarriage is the most common cause of loss; between 15-25% of pregnancies end in miscarriage and one in 100 women trying to conceive suffer recurrent miscarriages, defined as the loss of three or more consecutive pregnancies.

The researchers examined tissue samples from the womb lining, donated by 183 women who were being treated at the Implantation Research Clinic, University Hospitals Coventry and Warwickshire NHS Trust.

The team found that an epigenetic signature -- which is typical of stem cells -- was absent in cultures established from womb biopsies taken from women suffering recurrent miscarriages. Indeed, fewer stem cells could be isolated from the lining of the womb from recurrent miscarriage patients when compared to women in the study's control group.

The researchers further found that a stem cell shortage accelerates cellular ageing in the womb. The lining has to renew itself each cycle, each miscarriage and successful birth. This renewal capacity is dependent on resident stem cell population. A shortage of these stem cells in patients suffering recurrent loss is associated with accelerated ageing of the tissue. Ageing cells mount an inflammatory response, which may facilitate implantation of an embryo but is detrimental for its further development.

Professor Brosens added: "After an embryo has implanted, the lining of the uterus develops into a specialised structure called the decidua, and this process can be replicated when cells from the uterus are cultured in the lab.

"Cultured cells from women who had had three or more consecutive miscarriages showed that ageing cells in the lining of the womb don't have the ability to prepare adequately for pregnancy."

Co-author of the study is University of Warwick Professor of Obstetrics and Honorary Consultant at University Hospital Coventry and Warwickshire NHS trust Siobhan Quenby. She said: "The real challenge now is to develop strategies to increase the function of stem cells in the womb lining.

"We will start piloting new interventions to improve the lining of the womb in the spring of 2016. Our focus will be two-fold. First, we wish to improve the screening of women at risk of recurrent miscarriage by developing new endometrial tests. Second, there are a number of drugs and other interventions, such as endometrial 'scratch', a procedure used to help embryos implant more successfully, that have the potential to increase the stem cell populations in the womb lining."

Painful Shoes

Life is a mystery to be lived, not a problem to be solved

Until we tried to have a baby, I pretty much believed that if you want something badly enough in life, you can make it happen. If I didn’t get the job I wanted, I’d just shrug off the rejection and apply for another. If I didn't like where I was living, I'd move.  I've always believed that we choose our own destiny.  I dislike the phrase "It just isn't meant to be". With enough determination and perseverence we can make all our dreams come true. Being in control makes us feel safe. Sometimes when we want something so badly, this control can become obsessive. We will try everything to make it happen. Now, 8 miscarriages and several failed IVF cycles later, the reality has hit me, that some things in our lives we just have no control over. Mainly, life and death. My Reproductive endocrinologist finally admitted that he doesn't know the reason why I keep having losses. He said we may never find the answer as to why. A few years ago, he thought he had an answer. Abnormal chromosomes. He told us that this is usually the case with RPL. I'd had 3 miscarriages from spontaneous conceptions (2 confirmed aneuploid ) and I was afraid of having more. So we embarked on a donor egg program. Excellent grade embryos. I miscarried again. No heartbeat at 8 1/2 weeks. So we had our remaining frozen embryos pre-genetically screened (PGS). One was aneuploid. Ah, maybe there was our answer! We now had three normal embryos. While we were waiting 4 months for the results, I had gotten spontaneously pregnant again and miscarried. Let's not try naturally anymore my Dh and I decided. Crazy, as much as we wanted to have a child, we were now preventing pregnancy. 3 FET's in 2015 resulted in Two chemical pregnanices and a BFN. 
We are still left wondering, why did this happen? There is a reason, but even if we knew what that reason was, it wouldn't guarantee success. Because we just aren't in control of life..and we aren't in control of death either.

BFN

RE phoned me himself to tell me that my beta was negative. He said he doesn't believe my thyroid levels are the issue because although my Free T4 is on the high end of normal at 1.8. He said he would be willing to order the allo-immue testing through Dr Braverman, but he cannot sign the form on his website and doesn't understand why Dr B insists on having his name tied to the clinic's. So I am on my own for getting the immune testing done. Dr Hamersley has ordered the immunology testing for a lady I know. However, the extensive immune panel costs $7,500 which includes Dr B's interpretation. It is not a bad price if we were cycling with his clinic but we are not. Re asked if there should be an allo-immune issue how would Dr B treat it. Possibly intralipids or Ivig, depending on what the immune issue is. My clinic is unwilling to prescribe either of these. Since he had no suggestion as to the next step I suggested maybe donated embryos or donor sperm &egg might work. He then told me that they are starting a donor embryo donation program soon due to the high demand. I will have to talk to the financial councellor and see if we can get a partial refund from the Donor egg program to use towards the Embryo donation program. 

When your RE says there is nothing more that can be done and he suggest a gestational carrier and you are financially drained and know that is not an option.  I just can't explain the feeling of total hopelessness. He said he wished he knew the reason why I keep losing PGS normal embryos but is totally at a loss. We could have transfered more than one embryo at a time and we would have been on cycle #3 by now. But we did eSET each time and that is why it took us almost 2 years to use up our embryos. Why is it always my fault? First bad eggs and now my immune system? Doesn't seem fair. In my defense, Dh said it could be his sperm. RE argued that icsi fixes any issues with sperm morphology. Or perhaps our donor's eggs? After she cycled for us, she was taken out of their database and her eggs were sent to a frozen egg bank. This usually means there were no live births from her eggs.  I asked on several occasions if he could find out this info but he just replied that her after eggs were sent to the egg bank there is no way he could find out any info on her. Makes me wary of choosing another Egg donor.  After our phone conversation, RE wrote me an email saying he would still like to do everything within his power to help us and to keep in mind the Embryo donation program. For the first time since we have been on this journey, I feel like Dh and I have come to the end of the road.

10dp5dt- Thwarted by my thyroid again!

It took a whole week to get my thyroid levels back! Endocrinologist said my TSH jumped from 1.6 before  I started estradiol to 3.2. That was a week ago, so it's probably even higher now! She had doubled my synthroid to 50 mcg but it didn't make much difference since last FET my TSH had jumped to 3.8 when I had the chemical pregnancy. My Thyroid levels were perfect before the stupid estrogen. IVF just isn't for me. When I get pregnant naturally I have abnormal chromosomes.  Can't win. Beyond frustrated! Beta is tomorrow but I know it's going to be negative.

6dp5dt

Transfer was at 2:45pm on Friday so it hasn't been quite 6 days since transfer, but I got a squinter on an IC with FMU at 7am. The lack of symptoms is worrying me. I usually have sore veiny breasts and white CM by now. This time nothing. I felt sharp implantation cramps on the morning of 4dpt, so holding on to hope for that and the faint hpt. It was darker last FET at this point. The 2ww is a killer with this being our last embryo.  Praying.

Transfer day

My transfer was supposed to be at 1:30pm, but due to scheduling mix up because someone having a surgical procedure wasn't told they had to have a full bladder,my transfer was delayed till 2:45! Ironically, I was sitting there with a full bladder from 12;30 -2:40 while we waited for the other patient to fill up hers. I have had lots of procedures so I empathized, when they were asking what her pain was on a scale of 1-10 and she said 9. Eric kept my mind occupied by telling me jokes and being my loveable goofball.  At least I managed not to pee on the doctor. Our transfers have always been on Mondays and this was a Friday so hopefully that change will be a good thing. The biggest change is this was a Natural versus medicated cycle. Here are pics of us at the clinic and our hatching blastocyst. Our last PGS normal embryo. Praying this is the one.

FET CD 20- Final lining check

My RE was pleased with my u/s this morning and said he recommends we go ahead and transfer tomorrow at 1:30 pm. The thinnest measurement he got for my lining was 8.8mm and 12mm in the thicker area. I asked if that could be due to the adenomyosis, but he said he didn't see any muscle thickening or evidence of that like he saw cycle day 21 last month. I had prepared myself for bad news so it was a nice surprise.

FET CD 14- Ovulated on my own

Something weird is going on with my lining.  The nurse practitioner who measured it yesterday said it was only 6.8!? My heart sank. RE measured it at 9.8 yesterday and so he said that couldn't be possible so he redid the u/s. He measured 7.8. Not much better. :( He said once ovulation happens, lining does not get any thicker on a natural cycle. My regular RE said it could thicken a bit now that I started estradiol. I ovulated on my own yesterday so didn't need the Ovidrel trigger. I also felt O pain. Today RE measured it at 6.8 but it was 9 in some areas. I don't know if the adnomyosis is causing this?  My cycle may have to be cancelled if lining keep thinning. RE said it wouldn't be the biopsy because it is usually beneficial for implantation.  I had a great lining last month at 9.5.  I have to go for bloodwork & ultrasound again Thursday 3rd. The day before scheduled transfer day.  I am so tired from all these early morning appointments.  I should have transferred last month when I had a 9.5 lining instead of wasting it on the endometrial biopsy for the stupid ERA.

FET CD day 12

Lining was 9.8 this morning. E2 is 511. Even better than last cycle on this day. My nurse said she is confidant I will ovulate on my own again and not need the Ovidrel trigger. Last Thanksgiving eve I was in the hospital for bleeding and rhogam shot and then miscarried 2nd December.  This year FET date is set for 4th December. So weird how dates play out. I was not expecting to transfer during the holidays. Feeling excited and nervous. Praying out last embryo is our take home baby.

Invalid ERA result

I got bad news from my RE. He said my biopsy result was INVALID for the ERA because there was too much tissue collected in ratio to the preservative in the test tube! RE thought more would be better but not in this case. I am used to disappointments by now but sheesh, I got maternal cell contamination for my 8 week loss last summer, now again an invalid result. RE was apologetic and he assured me that Ivigen would give me a refund for the $870. Doesn't give me back the 2 months I lost though. I asked him what he thought of doing an extra day of PIO for next transfer. He understood me not wanting to do another biopsy since there would most likely be a 3rd biopsy needed should the result be pre-receptive. He agreed. Trying to find the silver lining in this bad luck situation, I asked my nurse since I am on cycle day 11 and haven't ovulated yet could we try for a natural cycle transfer this month.I have been doing opk's to keep tabs on my Lh surge. She calculated when I would have my FET approx 3rd Dec and she said luck would have it they have an opening that day! So I start my natural cycle for FET tomorrow CD 12. Hopefully my lining will be thick enough. I have been drinking pom juice and raspberry tea, taking lArginine, vit e and wobenzym n. The same as last cycle. Good thing I continued taking the prednisolone to keep my inflammation down and then increased the dose to 20 mg a week ago. We were going to NTNP this month. This time last year I got a spontaneous bfp but I miscarried because I hadn't met with Dr H. yet then. Now that I have the prednisolone and lovenox. I will always wonder if this protocol would have helped me save that pregnancy.

ERA- Endometrial biopsy-CD 21

I had my endometrial biopsy for my ERA today. Startling discovery when my RE did my 21 day ultrasound. He said I have Adenomyosis! (yes in addition to endometriosis which I had excised in May this year) It's a mild case that he said shouldn't affect my getting pregnant. I know quite alot about adenomyosis because my close friend since childhood has it. It makes a woman's body produce too much estrogen. This makes me angry because my 4 medicated ivf cycles probably caused my adenomyosis in the first place!!! That explains why my body reacted so adversley to the del estrogen injections. I was already producing too much estrogen. Back to my childhood friend. She went for her 19 week utrasound where she was supposed to find out the gender. Sadly her baby's heartbeat was gone. :(  she said she heard it with the doppler just 2 days before :(  I am devastated for her. Not feeling much hope for myself now since she is the same age as me (44). 

When RE found the "adenomyosis" His first reaction was quite annoying. "This thing is growing" he said. Then he turns to me like a kid who has found a hidden treasure in the sand and says "It looks like a pregnancy...but it probably isn't". Not the kind of thing you tell a woman who has had 8 losses and doing donor egg ivf.  So he had me do a pee pregnancy test just in case.  All this time in my head I am thinking ..but we used birth control. I couldn't be pregnant..so what was the RE seeing in my uterus? Maybe the ghost of the pregnancy I had last November? I am only cycle day 21. How could he see a pregnancy on an u/s even if I had conceived. I should have told him smugly when he said it wasn't  a pregnancy.."well I have gotten naturally pregnant several times including last November" Not that I expect him to remember but it almost makes me feel like getting pregnant naturally again just to remind him I can get pregnant without his help! I know, a bit irrational, but the nerve of him you know?  Pregnancy test was of course negative. If he really thought it was a pregnancy on cycle day 21, why not order a beta? Urine hpt would not show positive that early. My beta from my chemical was zeroin Sept. I just don't understand Re's.

After the biopsy he said Ivigen recommends a second biopsy. I really don't want to delay embryo transfer by another month and pay another $900. *sigh* If I get a "pre-receptive result" That will be good enough for me. Then we will know we need to add an extra day of pregesterone, Natural cycle requires so much bloodwork and u/s. I will do it for transfer but not for another ERA. I also told him that I was disappointed in the "natural cycle" I thought natural meant only progesterone supplementation without estrogen which I want to avoid.  He said it would be risky to do it without. I said no way if I get pregnant am I doing estrogen until week 12. I have known other women who did a natural cycle without estrogen. So we compromised and I will only have to estrace from cycle day 16 until BFP. Then I can discontinue and only do Progesterone.

ERA-CD 15

Another blood work and ultrasound appointment yesterday morning and today. My poor veins are shot, Good news though, that 23.9 follie is gone and they saw corpeus luteum so I ovulated on my own and wont need the ovidrel trigger injection! Bloodwork confirmed it and I felt ovulation cramping last night too so I was pretty sure I ovulated. Endometrial biopsy is scheduled for 11/11. I'm So relieved it doesn't fall on a weekend so Dr M will be doing my procedure as I hoped. I can't always be unlucky. I start my vag estrogen and PIO tomorrow

ERA- CD 14- (Ovulation)

Yesterday and today more blood draws and ultrasounds. My lining is 9.5. I think the person measuring on Sunday was being generous with her 9.9 measurement.  Tomorrow will be the 6th office visit for this Natural cycle so far  and I have to go back in again tomorrow! At least they detected my LH surge to day Maybe I won't need that Ovidrel trigger that's sitting in my fridge afterall! My follie is 23.3 and ready to pop! I am feeling some cramping on my right ovary. Unusual because it's usually the left. I was beginning to think my right ovary was blocked or something. Nurse said estrogen is dropping and progesterone is rising  indicating ovulation is happening soon. Thank goodness! I am tired of having to leave at 6:30 am every morning to get there for 7:30. Hopefully this will be the last before my ERA biopsy. My nurse cracks me up. She said I am her first natural cycle and she doesn't want me to feel like I am the experiment. I am the teacher lol

ERA- Natural cycle-CD 11

I had another ultrasound and bloodwork today. I have 9.9 lining so far. All my transfers I've had 7.8 -8.6 which is good but this is excellent and no del estrogen hormone injections to thicken lining! E2-254 and LH- 4.32. RE was worried at my age that my lining would not get more than a 6. He said he would have to cancel a natural cycle that was less than a 6.  Well he will be surprised when he gets my results. I'll start PIO in a few days. This is a mock cycle but they are doing everything the way it will be for the cycle I do embryo transfer.I am so glad I am doing a natural cycle with no Estrogen because that is the medication that affected my thyroid. Feeling hopeful and considering doing a December transfer if ERA results come back receptive. I have another appointment on Tuesday.

ERA- CD 9 Bloodwork & ultrasound

My Lining is 7.8 on CD 9.  Bloodwork results- LH-  4.32 and E2- 119. Nurse said I have one follicle growing nicely so I go back on Sunday. Hoping that I ovulate on my own so I don't need the ovidrel (hcg trigger) injection. This ERA cycle is like a mock cycle. I will start PIO injections and estrace after I ovulate. Not sure when in relation to the biopsy procedure. Re said biopsy would be 7 days after ovulation. Loving this "Natural cycle" so far and that  I can skip the 3 weeks of del estrogen injections. That awful vaginal burning( allergic reaction in) was the worst and I am sure it was my body telling me something was wrong. Plus each bottle was $490 a bottle out of pocket.

Dr M finally got the gender from my last Chemical pregnancy. Normal Boy. Our first boy. All the others (from donor egg) have been girls. Funny because I had nicknamed him "Little Eric"

I have been doing my "Restoring fertility yoga" dvd again and Eric is teasing me about the breath of fire lol He imitates the drumbeats to a tee when I have the volume turned down. He cracks me up. I used to cue it up daily for 3 yrs in a row. I realized how much time has passed since I started it back in 2011 by the length of their hair! Mine was like Wendy Yu's when I started. Now even after cutting it 5 inches it's longer than the one lady's with the mid-back length. 

CD 1 finally!

Finally! After 40 long days of waiting for my period after my chemical pregnancy. I start bloodwork and ultrasound for ERA cycle starting CD 9. Since I am trying to avoid del estrogen, will be doing a a natural cycle. Not looking forward to the every other day trips to my clinic for monitoring to detect my LH surge. Last time I did OPK's a year ago, I was surging CD 12 so fingers crossed my LH surge is early which means less ultrasounds!

October 15th- pregnancy and infant loss remembrance day

Tonight, Eric and I lit 8 candles for the Wave of light remembrance. One of the candles, had a flame that was much taller than the others and was "dancing"around and I could feel a strong presence in the room as though spirits were  trying to communicate with us.  Eric asked which baby did that candle represent and I replied "George/Georgia". In the photo I took, you can see an orb next to that candle on the upper left!

WTF appoint with RE

RE had a cancellation so we went in an hour earlier and we were his last patients for the day. So appointment ended up being over 30 mins. It was not rushed at all so after covering all the concerns I had, he even chatted about some things he learnt at a seminar he recently attended. When we arrived he asked what I had on my mind and since I always like to get his point of view first before expressing my concerns/dislikes, I asked him his thoughts as to why this FET failed.  He admitted that the problem was most likely was an immune issue as I have said all along. With my ANA now negative with the immune therapy, I am really distraught that I've had another chemical. He agreed to let me have a a "natural cycle". He agreed we have nothing to lose since I will either have an adequate lining and they will transfer or they will cancel. He didn't say anything about cancelling if it fell on a weekend like he did when I asked about natural cycle before. so I didn't bring it up either.He said transfer would have to be next cycle though because they don't like transfer to be that soon after saline sono. So this month I will do opk's to see if I am still surging around day 12 like I was a few months ago. He thought it was good that I have been monitoring my ovulation when not on BCP.

I also want to have the Endometrial receptivity array (ERA) test done. They are finally offering it at my clinic. RE said this will delay me by a month because it takes a cycle to do the biopsy and testing.  I have noticed that my LH surge has gotten earlier (CD 12 instead of CD 14). So perhaps my earlier ovulation also means that my implantation window is earlier? RE said it certainly won't hurt ( the biopsy itself I know will hurt physically yes but ykwim)

http://www.ivigen.com/tests/endometrial-receptivity-test-era/

I asked him about the possibility of mitochondrial errors in the egg.  He it was a possibility. I asked about IVIGEN's Mitoscore test for embryos. He said it was a controversial topic. He said that mitochondrial testing on embryo as well as endometrial transplant (3rd party IVF) is illegal in the US. The UK has approved it (they are always the ones to make breakthroughs regarding fertility) so hopefully the US will follow in their footsteps soon.   DH said he doesn't have much faith in our donor's eggs. RE replied that this is understandable after 4 failed FET's. Well, I am not giving up on our underdog "BB"frostie.  He/she is genetically normal and I feel they have a good chance if I just let my body do what it does naturally and keep my thyroid under control. All of the eggs couldn't possibly have gotten mitochondrial errors right?!


As to the gender of our last loss, he didn't have the result yet. *groan* He explained (emphasizing that this did not apply to us) that no-one could agree on when it was ok to reveal gender, 1st u/s or later. Since it is a guarantee program,they cannot risk telling their patients sooner might stop their meds if the embryo might not be the gender they wanted. Obviously in my case, I just want to know because I had a chemical and it was too early to test POC.

I wrote Dr H. (MFM) an email asking her to order thryoid bloodwork for me next week and to renew my synthroid prescription. She responded that she would. Since Dr H will be monitoring my thyroid, I didn't even bring up my thyroid with RE, other then to say that the reason I wanted to do a natural cycle was to avoid taking the del estrogen because it messes up my thyroid levels.  I have done hormone replacement replacement therapy protocol 4 times! My thyroid has reacted adversely to it and that was proven this last FET. So I am happy to be having my natural cycle finally!