A Step By Step Guide To The IVF Process: Overview

Dear Readers,
I get many  many questions regarding what In Vitro Fertilization (IVF) is and how it works that I thought I would share the information with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.

OVERVIEW:
Before I begin explaining each step, let me give you an overview of IVF. As I mentioned earlier, IVF or "In Vitro Fertilization" is actually a replacement for the natural steps your body would go through in order to get pregnant, and it still relies on many of those natural steps to occur before you become pregnant. “In Vitro” means in the laboratory versus “In Vivo” which means in the body. As I’ll explain, IVF is not all done in the lab. Some parts of the process still are required to be in the body, so in actuality, it is both an “In Vitro” and “In Vivo” procedure.

There are basically nine steps that your body goes through in order to achieve a pregnancy:

(1) Your brain (hypothalamus and pituitary) sends a signal to the ovaries to stimulate the growth of a follicle and maturation of the egg within.

(2) The designated follicle grows, and the egg matures, until it reaches a critical size, whereby there is an LH surge to induce ovulation.

(3) The follicle surface ruptures and an egg is expelled with the rush of fluid within (ovulation) and enters a space behind the uterus called the culdesac, the lowest point in your abdomen.

(4) Through fluid motion (this part is not exactly known so it is my personal belief that this is how it happens), the egg contacts one or the other fimbria of the tube, which is hanging into the culdesac in its natural position, and now lies within this puddle of fluid. The egg is then brought into the tube by the fimbria and tubal motility.

(5) The egg moves into a part of the tube where, hopefully, the live sperm are waiting to attach to the egg, and then fertilization occurs.

(6) The fertilized egg slowly moves down the tube, dividing and forming into a blastocyst.

(7) The blastocyst then enters into the uterine cavity and settles there.

(8) The inner portion of the blastocyst then hatches out of the shell and attaches to the uterine lining.

(9) The uterine lining then engulfs the embryo, which is known as implantation and at this point bHCG begins to be produced.

These are the steps that your body goes through to get pregnant, but does not do it exactly or perfectly each month. That is why it may take several months before a human woman gets pregnant. IVF is basically accomplishing most of these steps for you, NOT doing some artificial process. Yes, it is not within your body, or at least some of it is not, but the same processes have to occur. If you know and understand IVF you can see that IVF basically accomplishes steps 1-7. Two steps then have to occur naturally for pregnancy to occur. So as you can see, IVF is still basically a “natural” process because it still relies on natural processes within your body.

In other words, we give fertility drugs to stimulate the ovaries to grow and mature eggs but the ovaries still have to pick up and process these hormones on their own, and growth and maturation of the eggs still have to occur naturally. We can put the egg and sperm together but fertilization still has to occur by itself. Even ICSI (intra cytoplasmic sperm injection) is only putting the sperm into the egg. The actual fertilization process, the merging of the egg nucleus and sperm nucleus, among other processes; still have to occur on their own. We cannot make that happen. We can put a grown embryo into the uterus but we cannot make it hatch out of its shell, attach to the uterine lining or make the lining engulf the embryo (implant). All of these steps are left up to nature or, as I tell my patients, are in God’s hands and the way He reminds me that I am but His humble servant. This keeps my head and ego from becoming too big!

Many patients are devastated when an IVF cycle fails, because they have the false belief that it is the ultimate and perfected technological way to become pregnant, and therefore works every time. It is certainly more technological but not even close to being the ultimate or perfect method, and it doesn’t work every time. For that reason we cannot achieve 100% pregnancy rates, and much research and technological advances still need to be developed before we will get there. Make no mistake, however, we have improved greatly since the first IVF success with Louise Brown, but that took years to occur as well.

Sixteen years ago when my wife and I did IVF, she was 37 years old, and her statistical chances were about 12-15% but now a 37 year old in my center has a 65% chance of pregnancy per cycle. We have improved greatly and come a long way. We can now help a couple acheive a pregnancy where previously there would have been no other option but adoption. IVF is certainly better than trying naturally because more steps are accomplished, whereas in natural cycles, the body does not always do each and every step correctly. For example, ovulation may occur but the egg may never find the fimbria so that month pregnancy will not occur. Just to put things in perspective, a 37 year old has a 5% chance of pregnancy per month of trying by natural means. When trying naturally, women have to keep trying for several months before a pregnancy occurs. In fact it will take 85% of women under 30 years old 8 to 12 months to achieve a pregnancy. In the same way, because IVF is just replicating the process, it can take several attempts before the body does its part of the process correctly. In my center 55% of patients (not adjusted for age), achieve pregnancy in their first attempt. Most patients will be pregnant by three attempts rather than the 12 months it may take to achieve a pregnancy naturally.

We will continue this discussion soon with the next installment, "Step One: Stimulation".

Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA
http://www.montereybayivf.com/

Severe Allergy To Progesterone During IVF Cycles

QUESTION:

Dr. Ramirez, I have a problem with progesterone but my symptoms are not typical of an allergic reaction. My husband and I have done 3 IVF cycles, all failed. They were all chemical pregnancies

1st cycle: The day after the first progesterone in ethyl oleate injection, I developed chills, a high fever, blood pressure drop and an elevated heart rate. The doctor thought it was an infection but the lab results were negative. I was then switched to Endometrin which caused intense vaginal itching and burning. So the RE put me on Crinone which also resulted in intense burning and terrible headaches.

2nd cycle: I was put on compounded progesterone capsules. After 5 days, I developed severe redness, swelling and pain. So I was then put on compounded suppositories which looked like white bullets. These caused burning and bleeding. The RE then had me try progesterone in sesame oil injection. About an hour after the shot, I became flushed and felt like I was going to pass out. I also developed a fever, drop in blood pressure and an increase in my heart rate.

We then did a mock cycle with the compounded progesterone capsules along with Zyrtec and Singulair. When the vaginal redness, swelling and pain returned, I was put on Benadryl. Unfortunately, that didn't work either.

3rd cycle: The RE had me do daily HCG injections along with oral Prometrium 200 mg three times daily. I had no problems with that protocol but it was not successful in achieving a pregnancy.

Prior to my mock cycle, an allergist tested the various progesterones to which I had an adverse reaction. The prick test was negative for all but the intra-dermal shots induced a wheal (9 & 10) and flare (both 12).

Is there a way to either prevent symptoms from developing or are there other progesterones which will not induce a reaction in the first place? Thank you! S. from Michigan

ANSWER: Hello S. from Michigan,

I think that you should avoid compounded progesterone. Instead, you could try an injectable progesterone made with an oil other than sesame oil so that would be one option, or a pharmaceutical formulated progesterone such as Crinone 8% or Endometrin would be alternatives. I use a pharmacy called MDR who makes an progesterone in a different oil that is less viscous and more easy to inject. I presume that the injectable that was tested by your allergist was with sesame oil. It is most likely that the allergen was the "oil" and not the progesterone itself, since the oil is a protein. You might want to have him check that.

Crinone and Endometrin are both used vaginally which has been shown to be the optimal method for delivering progesterone to the endometrium. Oral progesterones have been shown to be ineffective because most of the drug is lost in the first pass through the liver. Only injectable, vaginal or dermal have been shown to be effective.

Although there are no pharmaceutical companies that sell transdermal progesterone products on the market, there are a lot available through health stores and the internet, and also can be compounded. I don't use them so can't attest to their effectiveness or dosage but have seen some studies looking at them. It is possible that MDR can compound one for you.

The alternative for luteal phase support would be low dose HCG injections, like your RE has done. That has been shown to be effective. As a last resort, a surrogate could be used. Although expensive, it is an alternative that some of my patients have used with success when they could not carry the pregnancy for whatever reason.

Good Luck,
Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

3-D Animation Of The IVF Process

A very nice 3-D animation on In Vitro Fertilization from Schering-Plough (2009).  It details the procedure as well as the fertilization process.

IUTPI: Is It A Better Method Of Intra Uterine Insemination?

Question:

My wife and I are trying for a child for almost a year now and a doctor recommended us this new method of intrauterine insemination, IUTPI (IntraUterine TuboPeritoneal Insemination). I would like to ask you if you have heard about it and of course what is your opinion about it?? You can find the link below.

Thank you. G. from Greece

http://www.iutpi.eu/en.html

Answer:

Hello G. from Greece,

The goal of insemination has ALWAYS been to allow the sperm to travel into the tubes. That is because fertilization has to occur in the tubes. The technique that is offered by this Physician is NOT innovative and has not been proven better than current techniques in my opinion. He is using a larger concentration of the injected pellet (1 ml vs 0.3 ml) which certainly increases the availability of the fluid to get into the tube but I would anticipate that it will cause increased discomfort and cramping similar to doing an HSG (hysterosalpingogram). Is that more effective? A No. 0.3 ml is sufficient to get fluid into the tube with minimum discomfort. He also states that he uses a clamp to prevent reflux, which I am sure needs to be done because of the large amount of fluid being injected. Otherwise the majority of it will flow out.

IUI is dependent on many factors, the least of which is getting sperm to the tube. The success of IUI is mainly dependent on timing, the ovulation of more than one eggs so that there is an increased chance of an egg getting into the tube (getting into the tube is not automatic), fertilization of the egg by the sperm, quality of the egg, development of the egg into a good embryo, travel of the embryo into the uterus, hatching and extrusion of the embryo from its shell, attachment of the embryo to the uterine lining and growth of the lining around the embryo (implantation).

How is the IUTPI helping those steps? None that I can see. A standard IUI, if done properly, should give you equal chance of pregnancy because sperm delivery is the same. In my clinic, I have had a consistently 33-43% pregnancy rate per patient using proper technique but that is also dependent on factors such as the woman's age and the cause for her fertility problems.

Thanks for the question.

Good Luck,
Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

Recurrent Pregnancy Loss (RPL) Workup Shows MTHFR: What Next?

Question:

Dear Dr. Ramirez,

I am 31 years old and have had 3 chemical pregnancies in the past 12 months. They have run a slew of genetic testing and a RPL (recurrent pregnancy loss) workup and all has come back normal with exception to the MTHFR test. I have tested positive for 1 copy of the MTHFR mutation. The nurse told me that because I was considered heterozygous that this was not a big deal. They prescribed me with a high dosage of Folic Acid. She said that it was likely not contributing to the repeat losses. I have been reading online and while the homozygous mutations seem to be more serious, there seem to be mixed reviews on whether this can contribute to early miscarriage.

Do you prescribe Lovenox or Heparin in this type of situation (only 1 copy?) Should I be concerned about this and demand that they treat it somehow? It doesn't seem like they are planning on doing anything besides the folic acid.

Also, given that this test has come back as it did, is there any other testing that you would reccommend that may be related to this? I am a little frustrated because this test was not originaly included in the work up and I had heard about it from online research and specifically requested it.

I just want to make sure that I am not missing anything.

Thank you,

D. from Boston

Answer:

Hello D. from the U.S. (Massachusetts),

The treatment for MTHFR (Methylenetetrahydrofolate reductase), is increased Folic acid (for more information MTHFR.net). But with your history of recurrent pregnancy loss or RPL, I usually will add the following to my patients, although there is not clear research backing it up if you are immunologically negative:

1. Low dose aspirin 81 mg starting with the start of the cycle

2. Low dose heparin 2000 units bid starting with the start of the cycle (you can substitute lovenox but it is more expensive).

3. Medrol 16 mg starting with the beginning of the cycle until ovulation then decrease to 8 mg

4. Increase progesterone supplementation of either Crinone 8% per day or Endometrin 100 mg three times per day starting after ovulation.

This cocktail has been shown to be effective in recurrent miscarriages (see Reproductive Immunology Associates for further information regarding immunological causes of miscarriage). My presumption is that you have had immunological testing, specifically antiphospholipid antibodies?

I hope this helps!

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A