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New Methods of In Vitro Fertilization and Gamete Intrafallopian Fetal Transfer

When we talk about assisted reproductive technology, we can see a tremendous number of pregnancies over the years that have been delivered throughout North America; the number is approaching about 10,000 per year in the last reported year and clearly, throughout the world, we are seeing tremendous increases in these pregnancies in vitro fertilization. One of the points that I want to drive home is that the number of multiple pregnancy rates is increasing throughout the world due to this. One of the problems we are running into now is trying to figure out the best way to decrease that dramatic increase in multiple pregnancy rates. When we talk about assisted reproduction, we are really talking about follicular stimulation with gonadotropins, which directly stimulate the ovaries.

There are some patients who have cervical agenesis or atresia due to DES exposure, although we are not seeing that many of those patients. This is the ideal situation for GIFT, because then you can deposit the gametes into the fallopian tubes and actually get fertilization in the tube, get the embryo and then probably do a cesarean section on that patient for delivery.

IVF, GIFT and ZIFT are acronyms. The latest statistics that just came out recently indicate that something like ninety-seven percent of all cycles done nowadays are IVF and only about two or three percent are GIFT and ZIFT. In terms of IVF, the retrieval is done by ultrasound, fertilization occurs in vitro and because of that, micromanipulation is feasible with intracytoplasmic sperm injection (ICSI), or assisted hatching, and so on. The pregnancy rate is about twenty-six percent. With GIFT, it requires a laparoscopy to transfer the gametes, fertilization occurs in vivo, the pregnancy rate is statistically about twenty-nine percent; no micro-manipulation is possible. ZIFT actually requires two procedures.

The main problem with assisted reproductive technologies is expense. When you get into GIFT and ZIFT, you are hitting about $15,000 per cycle versus IVF, which is about $10,000 including drugs, anesthesia and so on. Clearly, the shift has been towards in vitro because it does provide a very comparable pregnancy rate. Obviously, there are programs around the country that advertise much higher pregnancy rates than the twenty-five.

With IVF, we do not have to worry about the fallopian tubes; we get the eggs from the ovaries, add the sperm, get the fertilized embryos in the dish and then transfer the embryos. If we look at the statistics reported by the Society for Assisted Reproductive Technology and more recently, the CDC, we see first of all that the multiple pregnancy rate is forty percent. The take-home pregnancy rate is twenty-six percent. Ectopics do occur, even in in vitro fertilization. If you have a patient who has had multiple ectopics who wants to go through in vitro fertilization.

When we look at male factor related infertility, the indications are pretty much everything, including azoospermia. Ten years ago, we would have said that if you have azoospermia, there is nothing that can be done except for sperm donation. Now, through testicular aspiration of the sperm, we can actually do IVF with intracytoplasmic sperm injection. The congenital absence of the vas deferens involves patients who carry the gene for cystic fibrosis, so they have to be assessed, but essentially, there has been a revolution in the last five to ten years in male factor related infertility in that we can now take a single sperm cell to inject into the oocyte.

With ICSI, a European group looked at ejaculated sperm, epididymal sperm and testicular sperm. Notice first of all that the fertilization rate is pretty much the same and the take-home pregnancy rate is also pretty much the same.

We are trying to get multiple oocytes, we do fertilize all of them, as long as the couple agrees, and we do not necessarily discard excess embryos. We can freeze them. Even though the pregnancy rates are lower than fresh embryo transfer pregnancy rates, they are about seventeen percent around the country. There are a few ectopics; miscarriage rates.

Are there increases in malformation? If you look at the entire IVF population from various countries around the world, you can see that the congenital malformation rate is no greater than in the general population; it is about two to three percent. With these ICSI pregnancies in males who have severe oligoasthenoteratospermia, they probably carry these microdeletions, so what we are now doing is asking those males to have a genetic assessment to see whether indeed they are carrying a microdeletion. If they are, then technically, their male offspring.

Most obstetricians and gynecologists are faced with the situation of delivering these babies. In the majority of instances, these will be singleton pregnancies. Let's look at what happens obstetrically to these IVF pregnancies. Let's look at singleton IVF pregnancies in terms of bleeding, hypertension, previa, IUGR, distress and cesarean as compared to spontaneous delivery. This is data from England which shows markedly increased bleeding.

The people who are reporting seventy to eighty percent take-home pregnancy rates are not blastocyst transfers. Most of those are transfers of multiple embryos, so without regard to how many multiples they are getting, they are interested in publishing that high pregnancy rate, because that is what is going to bring in more patients. The question to ask of those

When you look at multiple pregnancy rates for various procedures - IVF, GIFT, ZIFT, egg donation, you can see thirty to forty percent. The figure that bothers me the most is for egg donation; the multiple pregnancy rate is forty percent. Who gets egg donation? Most of the women who get egg donation are between 40 and 60. How good is it for these women to be carrying triplets or even twins? These are very high-risk pregnancies. Clearly, we must come up with alternatives to deal with this issue. Unfortunately, one of the alternatives that has been used

The next alternative has been blastocyst transfer. Blastocyst transfer theoretically makes perfectly good sense. You can just transfer one or two, you know that the embryos are healthy and that everything is going well. Indeed, the pregnancy rates are quite high. The problem is that if you take one hundred women and plan to do a blastocyst transfer, you may not get but twenty to forty of those women to get to blastocyst transfer, because the loss rate of those embryos is

The other issue that I want to discuss is that of advancing maternal age. Most of the patients in my practice are an average age of about 38. What can we do for these patients? First of all, you in your practice can do some testing based on the fact that the pituitary, through FSH, drives ovarian production of follicles as well as hormones. The two main hormones from the ovary are going to be inhibin, which feeds back to the pituitary, and estradiol, which feeds back to the

If you look at basal FSH levels, as FSH levels increase, you see dramatic drops in pregnancy. By the time the FSH is over 25, you get a less than five percent delivery rate. Clearly, the FSH level is important. The assay that was used here is a different assay than is being used nowadays. Most programs now are using a cutoff of about 10 for the FSH to look at women that will actually do well in terms of delivery rates.

What about maternal age? I alluded to the fact that overall, for in vitro, the take-home pregnancy rate is twenty-six percent. But what about women 40 and over. As I told you, a lot of my patients are approaching 40. They come in and say that they saw in the paper that the pregnancy rate is fifty percent in such and such program, so they are ready to go. Unfortunately, I have to

Assisted hatching has been used in the past. It involves essentially thinning of the zona pellucida so the embryos can then hatch out and implant a little bit easier. What we know about this technique is that it can improve the pregnancy rate in some women, especially if the zona

Looking at oocyte donation data, take-home pregnancy rates are almost forty percent. Some people have reported rates as high as fifty percent. Essentially, the fertility of the woman depends on the age of the donor. If you have a woman who is donating at age 20, that is going to give you an incredible pregnancy rate. There are a few ectopics and miscarriages, but the multiple pregnancy rate is forty percent. If you have a woman over 40 who now has triplets, that

When we talk about future directions, there is quite a bit going on, but just to touch on some of the issues, we are trying to understand what causes endometrial receptivity. Various growth factors and so on are involved, but we do not know at this point how to modulate them so as to improve overall receptivity. There have been attempts at using a glue where the embryos are

Cryopreservation is getting to the point where rates are starting to improve, although we still see about a ten percent drop in pregnancy rates between fresh cycles and frozen cycles, so we are not quite up to par. The newest think that I'm sure you have heard about is the freezing of oocytes. All of the medical students at the University of Illinois are coming to me and saying that they are ready to freeze their eggs at any time so they can be ready when they want to have

ICSI micromanipulation is clearly the way to go for most male factor related infertility. Assisted hatching technology is actually being used with the micropipette to do essentially what we would call genetic engineering, where we are transplanting nuclear material from an older patient into the cytoplasm of a younger patient. There have actually been about five patients who had this

Preimplantation genetic diagnosis is now taking off. There are a few programs around the world doing this. If you talk to the geneticists, it is still considered experimental in that there is a lot of