Science Pulse    Can Stress Decrease Outcome of IVF Cycle?

Researchers from the UC San Diego Dept. of Family and Preventive Medicine, working with a number of IVF centers, tried to assess the impact of patient worries on their IVF outcomes Konoff-Cohen et al, Fert Ster: Vol 81, No 4, 982-988). In this prospective study, 151 women completed questionnaires pre and post IVF or GIFT treatment regarding their concerns about medical aspects of their treatment (not achieving desired results, side effects, surgery, anesthesia, not enough information, pain, recovery) and financial aspects (missing work, finances). It is important to note that only the questionnaires completed pre-treatment provided data for this study, since not enough post-treatment questionnaires were returned.

Women who were concerned about the medical aspect of the procedures had 20% fewer eggs retrieved and 19% fewer fertilized, than women who were less inclined to worry about it. Women who were concerned about missing work had 30% fewer eggs fertilized. Those who were very concerned about the financial implications of their treatment cycle had a greater risk of not achieving a live birth. These results were adjusted for different variables that could also affect success rates such as age, race, smoking, type of infertility, previous treatment attempts, and prior live births. However, other important predictors of outcome were not adjusted for, such as FSH and antral follicle count.

While these findings may appear to show dramatic differences, it is important to note that these differences (20-30% fewer eggs, 19% fewer fertilized) clinically represented a decrease of only ONE fewer embryo transferred. The greatest decrease was seen in women > 35 yrs old, and those who had already done a treatment cycle.

This study represents an interesting look at the issues of personal concerns and IVF/GIFT outcomes, and calls for further studies to understand the potential physiological effects that may mediate these outcomes. Other related studies are also worth noting.

For instance, a well-done study (Domar), which we described in the November/December 2003 issue of Fertility Flash, has shown that women participating in support groups while in IVF treatment seem to have increased pregnancy rates. A recently published study (Facchinetti) has looked at changes in physiological markers (heart rate, blood pressure, cortisol levels) in women undergoing IVF treatment and participating in support groups, showing evidence of physiological changes for those in support groups. These physiological changes are consistent with those seem in lower stress situations.

These collective studies suggest that one can best prepare for IVF by being as informed as possible about expectations of one's treatment cycle (treatment procedures and financial impact). It may also be helpful to consider joining a support group. Fertility clinics can help patients by trying to alleviate patient's concerns and making the IVF experience as smooth as possible.
- Isabelle Ryan, MD
Dr. Isabelle Ryan, recognized by prestigious medical associations for her pioneering research, offers her patients a combination of clinical expertise and warm personal care. She has developed an interest in treating those with the diagnosis of unexplained infertility and endometriosis. Dr. Ryan serves as Director of PFC’s Third Party Parenting Program and Associate Medical Director.

From Us to You    PFC's New IVF Incubator Chambers

The Petri dishes with embryos are maintained in incubators at body temperature, 37° C, providing an environment that is to their liking. The incubators do not contain ordinary "air", but a special gas mixture that has more carbon dioxide and less oxygen than room air.

Although the embryos are kept under special conditions in the incubators for their entire time in the laboratory, we occasionally have to retrieve them to observe how they are developing, or to perform procedures such as assisted hatching. We also must remove them from the incubators when we get them ready for the actual embryo transfer.

Outside of the incubator, the embryos are observed using microscopes that have heated stages to maintain their ideal temperature. In fact, the ambient temperature of the laboratory is kept as high as tolerable by the staff. However, the room air cannot be changed to perfectly suit the embryos. For this reason, the time spent working with the embryos outside of the incubators is kept as brief as possible.

In our constant drive to create a more embryo-friendly environment, we have recently acquired 2 IVF incubator chambers that are fully mobile and will allow us to observe and work on embryos in optimal conditions while they are outside of the regular incubators. These chambers are almost identical to the special care baby incubators in hospitals. They are essentially transparent chambers that allow us to precisely control the environment around the embryos while allowing us to work on and observe them. With openings for our hands, the incubators contain a microscope and other necessary equipment, and enough space for us to work in. In performing an embryo transfer, for example, the embryos can be loaded into the transfer catheter while still being maintained in their special environment. The whole chamber can then be rolled close to the procedure room where the transfer is going to be performed.

The acquisition of these new chambers won't change any of the procedures that we perform in the laboratory, nor change IVF treatment in any way. However, for those procedures that require us to remove embryos from the regular incubators, we can maintain the precise environment that embryos like. This may seem like a small benefit, but growing embryos successfully requires rigorous and meticulous attention to detail. Small changes in the environment that may appear insignificant can easily make a difference in the embryo's ability to thrive and eventually implant in the uterus after transfer.
-- Joe Conaghan, PhD, HCLD

Ask the Experts    Everything to Know About Clomiphene - aka Clomid

Q:
Is Clomid always the drug of first resort for treating infertility?

A:
Clomiphene citrate, aka "Clomid," is in a class of drugs known as anti-estrogens, meaning it binds to estrogen receptors in the hypothalamus region of the brain responsible for reproduction. As such, clomiphene fools the brain into thinking that there is little or no circulating estrogen in the bloodstream, and so the brain signals the pituitary gland to secrete more follicle stimulating hormone (FSH).

Why Clomid is So Common
Many women are prescribed clomiphene empirically, that is, without a specific cause, in hopes of enhancing fertility. For most women, this strategy is fine because clomiphene is a safe and inexpensive medication. However, no real benefit may be gained unless the clomiphene induces the ovulation of more than one follicle (or egg).

Furthermore, as clomiphene is an anti-estrogen, for some women, it may bind to estrogen receptors in the uterine lining and cause it to be too thin, prohibiting pregnancy. To avert this, we perform at least one ultrasound in each clomiphene treatment cycle to check for normal endometrial thickness and hopefully, two or three follicles. We also have our patients monitor for their own LH surge with an over-the-counter ovulation predictor kit. Intercourse or intrauterine insemination is planned accordingly.

Best Candidates
Clomiphene is targeted to patients who do not ovulate regularly, especially if they have a condition known as polycystic ovarian syndrome or PCOS. These women have normally functioning ovaries but do not go through proper signaling of the brain to the pituitary and do not make adequate FSH and LH to induce ovulation. In these women, a small dose of clomiphene can trigger just enough FSH to accomplish ovulation of a single egg.

While most women with PCOS will respond to clomiphene and ovulate, some will require the addition of an insulin sensitizing medication to enhance response. If a woman does not respond to clomiphene, she may have very low FSH and estrogen levels, a condition known as hypothalamic anovulation. These patients usually require injectable FSH to induce ovulation.

Normal Ovulators
Women who ovulate normally are also candidates for clomiphene to improve the hormonal response of their ovulatory cycles. If she is found to have a low luteal phase progesterone level, she may benefit from clomiphene making higher levels of progesterone to support embryo implantation. Unfortunately, many women are diagnosed with low progesterone because they are advised to check the level on "day 21" of the cycle. But because they don't have an exact 28 day cycle, the monitoring isn't exactly in the middle of the luteal, or post-ovulation phase of the cycle. A better way to do this is to have a patient use an ovulation predictor kit and have the progesterone level drawn 7 days after the LH surge. If this level is 10 ng/ml or greater, the level is normal and there is no "luteal phase defect."

Who Should Avoid Clomid
In general, we recommend that women 35 and older skip the Clomid step and consider more aggressive treatment, such as injectable FSH with intrauterine insemination or even in vitro fertilization. Women who experience a thinning of the uterine lining should not be given clomiphene.

Potential Side Effects
Many women will experience no side effects while others experience side effects similar to those seen in early menopause: hot flashes and irritability. These are rarely bothersome enough to discontinue treatment. Women who experience a rare side effect of significant visual changes (flashing lights) are advised to discontinue treatment immediately. Regarding risk of multiple pregnancy, Clomid doesn't have a large impact; the risk of twins is about 5% and triplets or more is 1% or less, depending on the patient's age.
-- Carolyn Givens, MD

Patient Odyssey    PCOS and Success with Clomid - Times Two

Four years ago my husband and I decided that we were finally ready to have children. We had been together for over ten years. When we decided to start to try to get pregnant and I stopped taking the pill, we anticipated it might take a few months for my period to start and my cycle to become regular. After many months, I had not had my period and was still not pregnant. Still, we optimistically had sex, thinking that I might get pregnant even without having my period. We had heard and read that it was possible. More months went by. I spoke to my gynecologist who said that it might take a while. Still more months went by.

After almost a year, I went back to my gynecologist to try to uncover what was going on. She advised that I could start taking Clomid to assist with the pregnancy. My understanding was that I would not be able to take Clomid indefinitely until I got pregnant, and I wanted to understand the underlying problem and diagnose it before I started taking drugs. Luckily for us, I had a family member who was able to advise us to seek help from a fertility specialist and even found out the names of the top specialists in San Francisco. I then found out that before I could see one, I would need to jump through a series of hoops. The first one was to try to get my doctor to identify the right tests I would need to take to get the referral to the specialists. After many phone calls to my doctor's office and insurance company, I was finally able to identify and take the right tests. This took a couple of more months, after which I was diagnosed with polycystic ovarian syndrome.

The diagnosis was frightening to me at first. As it turned out, I had a mild case, and it did not interfere with my ability to get pregnant. Rather, Dr. Givens identified a very simple but elegant way to help me. She prescribed Clomid and monitored my ovulation. I was not able to detect ovulation with a home test, but Dr. Givens could see the egg maturing with ultrasounds. At the critical point, when I was about to ovulate, Dr. Givens prescribed a shot of HCG and said that my husband and I could have intercourse in the next 48 hours. It worked. This same approach worked with both pregnancies on the first cycle. We are fortunate to have found an excellent doctor and cannot underestimate the power of the expertise of Dr. Givens.
-- LK (name withheld upon author's request)

Once women with polycystic ovarian syndrome are successfully induced to ovulate with medications such as Clomid, it is likely that pregnancy will follow, if all else is normal. Sometimes Clomid alone will not work and ultrasound monitoring and appropriate timing of hCG injections will complete the ovulatory process. My patient, LK, is young and she only needed a little extra help to ovulate. She was very fortunate to conceive on the first try with both of her pregnancies. It is more typical that it may take 3-6 cycles of ovulation induction to achieve a pregnancy. Nonetheless, we are delighted that LK was able to have her family with a relatively low-tech approach.-- Carolyn Givens, MD

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-- Best regards from all of us at Pacific Fertility Center.