You are currently browsing the Dr Licciardi blog archives for May, 2007.

Ectopic Pregnancy

Hello again.
I want to start with the real story and discuss the details next time. Many of you will relate to this because it covers many aspects of ectopic pregnancy.
The patient is a very nice married woman, young and healthy. She had been trying for about a year and her basic problem was lack of ovulation. She did a couple of Clomid cycles before meeting me, and since all of her testing was negative we felt that a few more Clomid IUI cycles would be best for her. The subsequent cycles looked good on paper, but no pregnancy resulted, therefore she wished to proceed to IVF.
Being young with many resting follicles, we started on a relatively low dose of FSH, 150 units, which worked out well. She made many eggs and had 2 above average embryos transferred, with no luck. Actually, her first beta was positive, but over the next 2 weeks it rose and quickly fell. For her second IVF we modified the protocol a little, she again made many eggs, and had embryos that looked a little better. 2 were frozen.
Her first beta was 10, a low number. 6 days later it went to 198, and 5 days after that it fell to 141. So we were not sure where the pregnancy was, uterus or tube, and as hard as it is not to have a normal pregnancy, when things don’t look good, a falling beta can be a relief. But, she came back a week later and the beta was up to 1108: bummer. Usually, once it starts to fall it continues to do so, a rise like this is unusual, and can’t be good.
Ultrasound showed a small ectopic without a fetal pole or heartbeat and there was no internal bleeding. After reviewing the options, she received methotrexate, which I told her had a 90% cure rate with one injection. All looked ok, however her next hCG level was even higher. Her ultrasound remained unchanged and she was not bleeding, so the decision was made to give another methotrexate injection, which I told her takes care of the problem most of the time. Her next beta was slightly lower, but the others following showed a nice decrease. We were on our way to resolution.
Unfortunately she had a trip planned out of the country to see her relatives and I had to tell her she could not travel. So this poor woman started her IVF cycle mid March, and two months later was still getting treatment for a pregnancy that was doing nothing but delaying any other treatments and worrying her with the low possibility of rupture despite treatment and falling betas.
And then what happened? Despite her beta falling to ¼ of the previous levels, she ruptured the tube, developed internal bleeding and needed emergency laparoscopy to remove her tube.
What a pile up of bad circumstances. Any of her events taken alone (the low beta at her first pregnancy test, multiple methotrexate treatments, the long uncertain waiting time, the cancelled trip, the surgery, the loss of a tube) are tough on anyone. But to get all of this happening to the same person over a relatively short period of time is excessive.
She will take a break and then continue on, she has some nice frozen embryos and things still look good. She is young, makes plenty of eggs, has nice embryos and we remain very hopeful for success.
We will go through some details about ectopics next time. I would like to thank this woman for giving the ok to tell her story. I think many other women will be able to relate to and learn from her ordeal.
Dr. Licciardi

References:

  • Barnhardt KT et al.  Diagnosis of Ectopic pregnancy.  Obstet Gynecol. Dec 1994; 84:1010-1015.
  • Stovall,TG et al. Ectopic pregnancy, diagnostic and therapeutic algorithms minimizing surgical intervention. J Repro Med. Oct 1993;38:807-812
  • Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol 2006; 107(2 Pt 1):399-413.

More About PGD

So should you have PGD? Well, this is between you and your doctor. Hopefully this blog will help you in your discussion with him/her. Let me start by saying that there is a place for PGD. There are some patients that are clearly candidates, and many children have been born as a result. I am very happy for those of you who have had PGD successfully. The problem is in saying that if it’s good for some, it’s good for all.
We already said that PGD is not all it’s cracked up to be. How could that be? Isn’t IVF science cutting edge? Yes it is, but it’s not perfected and here are some of the pitfalls.

Mosaicism. In basic biology it is taught that the cells of the early embryo are identical. Since it all starts from the DNA of the fertilized egg, as the cells divide they all have the same DNA. Well, this is usually the case, but often enough, there is mosaicism, meaning that some cells have one type of DNA and other cells have different DNA. For example, in an 8 cell embryo, it’s possible to have some cells that cause Down’s Syndrome (this is an extra chromosome 21) and some cells can be normal. Just to back up, almost all of us have 23 pairs of chromosomes, for a total of 46. If an embryo is missing at least one, or had an extra 1, we generally call this aneuploidy. Aueuploidy is the genetic problem related to aging. Down’s is an extra chromosome 21, but any of the chromosomes affected in the same way, either an extra or missing. Getting back to PGD, if the embryo has 2 normal cells, and 6 abnormal cells, and the biopsy plucks off a normal cell, this mostly abnormal embryo will be transferred, probably producing no pregnancy. If the embryo is mostly normal and an abnormal cell is tested, that embryo will not get transferred, yet it may have produced a normal child.

Embryo Damage. This is very hard to quantitate, but embryo biopsy is a rather invasive procedure. So it may be that removing 1/8 of the embryo reduces its viability.

Testing Error. Even when done correctly in experienced hands, error happens. Meaning the lab says the cell is normal when it is abnormal, and visa versa. The error rate is low, but if many embryos are tested the chance of an error per case increases.

These pitfalls get magnified when a woman produces few eggs. The biggest risk here is that the one good embryo gets damaged or is misdiagnosed as abnormal.
So the most important question you have to ask is, “will PGD increase my chances of having a baby?” If your doctor says, “Yes, absolutely”, or “most of our patients are getting PGD”, get another opinion.
The bottom line is that the medical community is not so sure yet if PGD increases pregnancy rates. Theoretically it should, but in practice nothing has been proven yet. It is possible that PGD will reduce the chance of miscarriage, and there are some studies to show this is the case, but there is other research showing it may not.
And what about the cost? My partner Dr. Berkeley brought up a great point. For the extra cost of 2 PGDs, you can pay for another IVF cycle.
Just to repeat, I have patients who do PGD, but they make the choice after getting whatever information I can give them.
Please read disclaimer 5/17/06.
Dr. Licciardi

p.s. I have recently heard of programs that freeze the embryos of poor responding patients over a few cycles to get a batch big enough to biopsy all at once. It sounds a little extreme to me, but I can’t really comment until I see the results published. Just remember, a frozen embryo is not a good as a fresh.

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., 2011. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 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.

3 Good Stories About 2 Opinions

So how was your week? Mine was fine thank you. I was very busy, saw many patients, but I want to tell you about 3 who I hope are better off after the second opinion.

The first was a young woman who gets her period very infrequently. She had a HSG that showed bilateral proximal occlusion. She was told she needed to go directly to either laparoscopy/hysteroscopy to fix her tubes, or to IVF to bypass her non-functioning tubes. If you need a little background on this subject please check my blog archives. In fact, she read the blog and wanted my opinion. I told her the same thing I discussed in my blog, namely, she needed to have another HSG at a place where back-up tubal cannulation could be performed if necessary. Sure enough, the repeat HSG showed non-blocked tubes, no further procedures were necessary. We started Clomid to increase the frequency of ovulation and I am happy to report her last cycle was successful. She didn’t need surgery or IVF.

The second was a woman with multiple miscarriages and an abnormal uterine ultrasound. She was told by one doctor she had a bicornuate uterus. Another said it was a little arcuate but not a problem, essentially normal. If you need more background there are a few past blogs on this subject. I examined her, performed my own ultrasound, and ordered the MRI. My feelings were she had a septum. The ultrasounds and MRI did not make the diagnosis perfectly clear, so I recommended a laparoscopy and hysteroscopy. Sure enough, she had a very large septum, which I recently corrected. She asked me how there could be such difference of opinion.

The third was a woman who was trying for about 7 months and went to see a fertility doctor. The HSG report said there was tubal blockage. Not looking at the film, the doctor told her the tubes were not repairable and she needed to go directly to IVF. After some failed cycles she understandably decided to revisit the tubal issue. I looked at her film and felt one tube was perfectly fine and the other had possible proximal tubal occlusion. Because of a history of mild endometriosis, we decided upon a laparoscopy. Sure enough the tubes were perfectly normal. She asked me why the other doctor said her tubes were no good.

So want do these stories have in common? Even in the world of well trained reproductive endocrinologists, in the world’s most sophisticated cities, opinions can vary considerably and even be diametrically opposed. This puts a big burden on the patient. It is a burden to get a second opinion but it’s even a bigger challenge to decide which diagnosis or plan is correct. When I tell patients that I disagree with their other opinion they are really stuck. I say use the second opinion to your advantage, and get a third if necessary. I’ll get into trying to pick the right doctor in another blog. I still owe your more on PGD.

The PGD Paradox

The next couple of blogs will be about the downside of PGD.

PGD: Pre-Implantation Genetic Diagnosis, otherwise known as Embryo Biopsy.

A day 3 embryo is ideally 8 cells. One of the cells can be removed and the DNA in the cell can be analyzed. If the cell is normal, we can transfer the embryo into the woman’s uterus. If it is abnormal it will not get transferred. Now it can be a little more complicated. Some centers are biopsying polar bodies, and some talk of testing blastocysts; but the great majority of the biopsies are done on day 3.
PGD is mostly performed for 2 indications. One is to look for genetic diseases. Here, one or both parents carry genes that will lead to illness in the child, so they undergo PGD to identify the embryos without the abnormal gene or genes.
The second is to look for aneuploidy, which means an abnormal number of chromosomes. This is the problem that occurs with age related infertility and miscarriage. You’ve heard of Down’s syndrome, which is when the child has an extra chromosome 21. But we have 23 pairs of chromosomes, so if an embryo gets one too few or one to many of any of the chromosomes, the embryo may be abnormal. In these cases, the embryo may just not implant, or it could grow early on and miscarry, or in rare cases it could turn into an abnormal baby.
Aneuploidy testing is the most common indication for PGD, and for good reason. Women who want to increase their chances of becoming pregnant, or want to reduce their chance of miscarrying an abnormal fetus, can do in vitro fertilization, get their embryos tested using PGD, and transfer the good embryos.
The problem is that PGD for aneuploidy has not been as helpful in improving pregnancy rates and reducing miscarriage as we had hoped, thus the paradox. If you were a patient undergoing IVF, had a good stimulation, normal uterus, nice embryos and no pregnancy, what explanation would you get from your doctor? He or she would probably tell you that although they looked good, your embryos were probably genetically abnormal. This tells me that if you were to do PGD, and had only the normal embryos transferred, you should expect a very very high pregnancy rate. Unfortunately, this is not the case. I’ll talk about possible reasons why next time. As usual, please read 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., 2011. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 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.