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New Updated Video: Uterine Septum

Dear Readers,

Yes, it has been quite a while since I’ve written. I hope you all have been well and I am excited to return to the blog sphere. It’s not that I have been slacking; I have been writing extensively in other areas, but I do miss the blog so it’s good to be back.
The attached link is to a patient education piece that I produced on uterine septums, which was accepted and presented at the latest meeting of the American Society of Reproductive Medicine. I am very pleased with this final version and I hope some of you find it helpful.

Patient Education: Uterine Septum Video

More to come!

Frederick Licciardi, M.D.
Professor OGBYN
NYU Langone Medical Center

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Important Final Words on Pre-Implantation Genetic Diagnosis

These past few blogs covering PGD raise a few important issues. There are some well-know fertility centers that are really pushing TE biopsy. The feeling is that the technology has finally become accurate and safe enough.  It may be that doing IVF with PGD leads to a higher pregnancy rate and a lower miscarriage rate.  Plus, if you know you are getting a normal embryo, we can transfer fewer embryos, lowering the rates of twins and triplets.

This all sounds good, however, I think we need just a little more time, but maybe not much more.  In a good center, the pregnancy rate for a woman under 37 years of age is 40-50% without PGD.  PGD adds an invasive procedure. The shell of then embryo has to be opened, usually by a laser beam, then some of the embryo, even if it’s a small piece, has to be chopped away.  We make it sound simple, and so far it seems safe, but no one should promise you all of the safety data is in.  Not to mention the additional costs, which could vary from program to program, but $6,000 is a safe estimate.

In theory, ideally, PGD will be the way to go and everyone doing IVF will have their embryos tested, the pregnancy rates will go up, miscarriage rates will go down and we will say goodbye to IVF twins.   And if the system works really well, in the end this will save money because people will need fewer IVF cycles for success (not to mention the drug cost savings if fewer cycles are needed).

Encouraging news concerning PGD is coming out of the data on miscarriage. Good PGD does decrease the rate of miscarriage. A very high percentage of miscarriages are caused by aneuploidy, which means an abnormality in the number of chromosomes present in the embryo. Just one example of aneuploidy is Down’s syndrome, which is the result of an extra chromosome 21 (also called trisomy 21).  The bulk of PGD is performed looking for aneuploidy.

The reduction of miscarriage rates after PGD has 2 important implications. One is that preventing a woman from having a miscarriage is obviously a welcome idea, as the emotional toll of pregnancy loss is significant. The second is that miscarriage takes time.  While many miscarriages occur early, many women do not suffer their loss until 7-10 weeks, later if the fetus survives to the CVS (10 weeks) or amnio (17 weeks).  When you add in the recovery time of 1-2 months before a woman can try again post-miscarriage, the total time lost could be 2-4 months. This is especially difficult in an older woman whose reproductive time is already limited.

One shortcoming of this technology is that this new method of testing requires a blastocyst. Many IVF programs are still not comfortable growing their embryos to blastocyst; they prefer transferring their embryos on day 3.  These programs will not be able to provide these new services until they become very good a growing embryos out to day 5, which for some clinics could take a very long time.

Lastly, not everyone who wants PGD is a candidate for PGD.  The group that may benefit the best from a PGD cycle is those who are above the average age for reproduction. However in this group, egg production is lower, as is the rate of good (biopsyable) blastocyst formation. So there may be the intention for PGD at cycle start, but if the egg number or embryos quality is low, the option for PGD in that cycle may be lost. Straight IVF may or may not still be a viable option, but at times even those are not possible.  I try to be positive to the end, but it is always necessary to cover all eventualities.

 

Well, that’s quite a bit about PGD. Thanks very much for reading.

Don’t forget to read the disclaimer from 5.17.06.

Dr. Licciardi

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011; 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril. 2006; 85(2):326-32.

 

 

Trends in Pre-implantation Genetic Diagnosis

So what are the new developments increasing interest in PGD?

 

The first is that there is more laboratory expertise on growing the embryos to blastocysts (see blog on blastocyst). These are embryos that have grown not 3, but 5 days in the lab.  As the embryo grows with time, the total number of cells increases from 6-8 to 30-60. Because the cell number is much higher, we can more safely remove more than on cell, maybe 3-5 cells. All of that extra DNA helps us reach much more accurate results.

 

The second has to do with the way we test the DNA.  The DNA amplification techniques have improved, as have the techniques for identifying important areas in the DNA.

 

An advantage of blastocyst biopsy is that in a good blastocyst, we can tell by looking which cells will be the embryo (the inner cell mass) and which will be the placenta (the trophectoderm- thus the term trophectoderm biopsy, also called TE biopsy for short).  Naturally, at the time of the biopsy, it is the placental cells we take as not to interfere with the fetal cells. Taking a few extra cells from the placenta is much less harmful than taking cells needed for the fetus.

 

Another advantage of performing the biopsy on day 5 is that mosaicism is much less of a problem in a blastocyst. (The last blog explains mosacism), The cells we get on day 5 more accurately reflect the DNA status of the embryo as a whole.   We are not sure why mosacisism is less of a problem on day 5, it may be that it’s common for an embryo to start off with some abnormal cells, but with time the normal cells outgrow the bad ones.

 

One downside to TE biopsy is that in most cases, the results of the biopsy take 1-3 days to process. We do not want a day 5 embryo growing extra days in the lab waiting for the results. Therefore, we usually freeze the blastocysts just after the biopsy, get the results a few days later, and then have the patient come back the next month for a thaw cycle.  This gives the patient a one month delay, which may or not be an important factor, depending on the expectations of the patient.  There are some programs that offer same cycle PGD biopsy and transfer, but usually those women with only the fastest growing and best looking are candidates for the same cycle process.

 

Patients are naturally concerned about embryo freezing, as is it is mostly true that embryos in a frozen cycle have lower pregnancy rates than when the embryos are transferred when fresh.  However, there may be some very explainable reasons why freezing normal blastocysts may not be problematic.  In a standard fresh cycle, the best embryos are transferred. While the extra embryos may look very good, the best ones go back originally, leaving the left overs for the frozen cycle, and this could explain the lower rates.  In a PGD cycle, even the best embryos are frozen, upping the odds for a successful cycle after the thaw.  Also, at least from what I have seen, normal embryos seem to thaw and freeze very well. So if you know you have a good one in the freezer odds are good that it will survive the freeze and thaw and have good potential for success.

 

In addition, freezing techniques have really blossomed in the past few years.  Most programs have moved to vitrification (the fast freezing method), and embryos do have better outcomes when preserved this way.

 

On top of all of this, there are some doctors who believe that all embryos, even without biopsy, should be frozen. There is the revival of an old theory that the endometrium of an IVF cycle is not ideal for implantation, possibly due to excessive estrogen levels caused by the fertility drugs. Others feel that the relationship between the timing of ovulation and embryo transfer is altered with IVF, lowering the ability of the embryo to implant.  I’m not so sure about theses theories, but I am raising the point here to say that a frozen embryo cycle is not necessarily a bad thing.

 

There are still a few more points about PGD that I will go over next time.

 

Thanks for reading, and don’t forget the disclaimer 5.17.06

 

Dr. Licciardi

 

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011; 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril. 2006; 85(2):326-32.

 

Miscarriage, Infertility, Antibodies and the Immune System

We are entering the world of unknowns. You will see me contradict myself a bit, but I will try to explain why.
I will start by saying that no one has ever shown well that any of this matters at all. There have been no good studies showing that antibodies of any type have an effect on the ability of someone to get pregnant or keep the pregnancy (outside of the women with Anti-phospholipid Syndrome mentioned last time). Now I know there are small studies out there proving x, y, and z, and some of you have been treated with success, but as far as large well designed studies showing antibodies matter, they don’t exist. The same is true for levels or activity of natural killer cells, platelet activation, factor 5, protein c and s, and the list goes on and on. In fact, the American Society of Reproductive Medicine has put out a statement saying treating abnormalities of anti-cardiolipin antibodies is not recommended.
So if having the antibodies or clotting issues may not matter, how will treatment help? Good question. Many of you know that blood-thinning drugs, like heparin, fragmin, Lovenox, are given to tons of women. Also IVIG, which is supposed to lower the immune response, is given out rather frequently. But again, no one has ever shown well that these drugs are doing anything. This is hard for me to deal with because it would be very easy to the right study. Just give 100 women Lovenox and 100 none, and look for a difference. The same for IVIG. I am sure that the practices that use this stuff like water could easily do a study.
And these drugs are not risk free. You can bleed from blood thinners and there may be unknown risks of IVIG, which is made by pooling human serum.
So here is the contradiction. I do have a very small group of patients who are getting these treatments from other doctors. Why, because they are in the hole of last resort. They have tried for a long time without success. They feel good that a doctor has found a possible problem and feel good that something is being done. I am sure many of you are in the same hole. And guess what, some of them get pregnant and have a baby. If they didn’t get the treatment, would they have had the baby? Probably, but we will never really know.
I know there will be many detailed questions on this topic but this is about as far as I can go. There are too many unknowns, and not enough proof.
If you are considering these treatments, be sure your talk to your doctor about possible risks, and remember to see disclaimer 5/17/06. Dr. Licciardi

References:

  • Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006; (2): CD000112.
  • Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev. 2009 Jan 21 ;(1):CD004734.
  • Stephenson MD, Kutteh WH, Purkiss S, Librach C, Schultz P, Houlihan E, Liao C. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod. 2010 Sep; 25(9):2203-9.

Miscarriage and the Immune System (antibodies)

As many of you have noticed, I have been avoiding this one. It’s just too controversial. Actually, there are many known facts but very little data.
Let’s start with what we know. We know that there are people out there who have high levels of antibodies who have miscarriages. Who are these people? They have the “anti-phospholipid syndrome”. Which is? A condition whereby the body makes antibodies against its own cells. We all have antibodies that help us fight disease and none of us would be here if it were not for antibodies. Some, probably many of us, have extra antibodies that don’t fight disease, but rather fight ourselves. These are auto-antibodies. Probably the most common are the thyroid antibodies; antibodies that the body makes that attack the thyroid gland. Up to 10% of women have thyroid disease, and the vast majority is due to antibodies against the thyroid that slowly destroy the gland making it under-active (Hashimoto’s Thyroiditis). Grave’s Disease is thyroid antibody condition that makes the thyroid overactive. There are many other autoimmune diseases, such as Rheumatoid Arthritis, that occurs when the body makes antibodies against the cells of our joints.
Phospholipids are large molecules that are on the surface of most of our cells, so as you could imagine, antibodies that help destroy phospholpids can’t be a good thing. In patients with the Antiphospholipid Syndrome (APS), these antibodies somehow affect the blood clotting system (we don’t exactly know how). These people are very prone to large blood clots in their arteries and veins. And it’s not just the vessels of the legs and pelvis, but the arms, neck and brain can also get dangerous clots. Now the placenta also has large blood vessels and vascular spaces. In patients with true APS, clots can form between the uterus and the placenta, reducing or stopping blood flow, and this causes miscarriage. This is what we know, and this is about all we know. As you will see next time, we know very little about clotting and miscarriage in women who do not have APS.
So where does Lupus come in? Well now we are getting into some overlap and probably a little confusion. Patients with lupus can have antiphospholipids, but not necessarily the full APS. Patients with Lupus usually have other autoantibodies that attack DNA, again not a good thing. Here almost all types of the body’s cells (brain cells, joint cells, kidney cells, joint cells, to name a few) can be affected. One of the blood tests for APS is called the Lupus Anticoagulant test. So some women have both, some have one or the other, and some can have a mix. And in case you were wondering, cardiolpins are a type of phospholipid, so anticardiolipins are another type of antiphospholipid antibodies.
Next time we will tighten this up and talk about what this all means to some one with miscarriages and abnormal clotting tests.

References:

  • Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; (2):CD002859.
  • Practice bulletin no. 132: antiphospholipid syndrome. Obstet Gynecol. 2012 Dec; 120(6):1514-21.
  • Ernest JM, Marshburn PB, Kutteh WH. Obstetric antiphospholipid syndrome: an update on pathophysiology and management. Semin Reprod Med. 2011 Nov; 29(6):522-39.
  • Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med. 2012 Jan; 14(1):39-50.