Tuesday, August 28, 2007

The Rise (and Fall?) of Preimplantation Genetic Screening

In vitro fertilization (IVF) success rates are lower in older women, and embryos obtained with IVF in older women are more likely to be chromosomally abnormal. When donor eggs from younger women are used, the age-related differences in IVF success disappear. Perhaps if the chromosomally normal embryos of older women could be identified and selected for transfer during an IVF cycle, IVF success would be higher in these patients. This is the rationale of preimplantation genetic screening (PGS), and it makes perfect sense. This technique has become aggressively marketed in the IVF community as a way to boost IVF success rates in older women. However, in my own program, we don’t offer it, mainly because it hasn’t been proven effective to my satisfaction.

In a recent study performed in the Netherlands, more than 400 infertile women 35 through 41 years of age who were scheduled for IVF were randomly assigned to having IVF with or without PGS, for up to three cycles. It turned out that the continuing pregnancy rate was lower in the group who got PGS. This is the second study of its type to show such results. Why isn’t PGS helping?

Maybe the people who did the embryo biopsies weren’t very skilled, or perhaps the ovarian stimulation protocols didn’t yield enough embryos to make a difference. One of the randomized studies has been criticized because two cells were removed from each embryo. However, it is likely that the benefit of PGS is overcome by the damage that occurs when performing the embryo biopsy. Also, some people think that the chromosome count of a single cell is not representative of the rest of embryo; that is, there may be a high degree of mosaicism in preimplantation embryos, and the embryos identified as abnormal by PGS could actually result in normal infants

In any case, I think it is the responsibility of IVF programs that perform PGS to better document the benefit of this procedure before they make patients (or their insurance companies) pay for it.


Tuesday, August 21, 2007

How big is too big for in vitro fertilization?

We recently heard of someone (in another state) who died from complications of egg retrieval. This is an extremely rare event (the risk is about 1 per 100,000 cases; compare this to the risk of maternal death with pregnancy, about 1 in 10,000). Although the details aren’t entirely clear, it sounded like the patient’s obesity played a role in her demise. It made us wonder, should we have a weight limit for egg retrievals?

Our procedure table for egg retrievals has a weight limit of 500 pounds, but rather than just setting a weight limit, a better way of considering obesity is by looking at the body mass index (BMI), calculated by dividing the weight in kilograms by the square of the height in meters. Individuals with a BMI of 25 to 29.9 are considered overweight; individuals with a BMI of 30 or more are considered obese, and those with a BMI of 40 or more are considered morbidly (or extremely) obese. According to recent surveys, about a third of all adults in the US are obese, and about 5 to 10 million people in the US are morbidly obese.

Obesity is associated with increased risks of a number of diseases, including hypertension, type 2 diabetes, coronary heart disease, stroke, and … infertility. Obese patients have higher complication rates from anesthesia and surgery, especially those with morbid obesity. Therefore, we have decided not to perform egg retrievals on women with a BMI of 40 or above.


Monday, August 6, 2007

Does a hysterosalpingogram make you more fertile?

A hysterosalpingogram (HSG) is a procedure in which dye that blocks X-rays (radio-opaque dye) is injected through the cervix to see if the uterine cavity is normal and the fallopian tubes are open. An HSG is part of the basic infertility investigation. There are two kinds of HSG dye: oil-soluble dye, and water-soluble dye. More than forty years ago, a radiologist reported that when HSG dye was switched from oil-soluble dye to water-soluble dye, the pregnancy rate over the next 12 months in patients who had had the HSG dropped from 41% to 27%. When the use of oil-soluble dye was resumed, the pregnancy rate rose to 44%. It seems that using oil-soluble HSG dye increases the chance of subsequent pregnancy, but many physicians are either unaware of this effect, or choose to ignore it. I think this is an opportunity missed.

The only oil-soluble HSG dye in current use in the US is Ethiodol. Studies have shown that the subsequent pregnancy rates are twice as high when Ethiodol is used compared to when a water-soluble dye is used. This effect seems to be most pronounced in women with unexplained infertility or endometriosis. The reason for the beneficial effect is uncertain, but one study showed that Ethiodol altered the function of peritoneal macrophages, white blood cells that are normally found the peritoneal fluid (fluid that can be found in the pelvis around the ovaries and fallopian tubes). In women with endometriosis, peritoneal macrophages gobble up sperm, and this may be part of the reason for infertility in women with this disorder. In any case, the fertility-promoting effect of oil-soluble HSG dye seems pretty clear to me, and I think most every infertile woman getting an HSG should have this dye used. Nevertheless, in the hospital where I do most of my HSGs, I notice that most of the other physicians are using water-soluble dye, not Ethiodol, when they do an HSG. Why is this?

There are several reasons why oil-soluble dye is not used more frequently. First of all, there are some studies which failed to show the beneficial effect of oil-soluble dye. The problem here is that most (but not all) of these studies didn’t have enough patients to show the effect; that is, the sample size was too small. However, when you combine data from all the studies in one analysis, the beneficial effect can be detected. This is called meta-analysis, and it is a controversial statistical technique, but I believe it is valid in this setting.

Secondly, some physicians are concerned that there is a higher incidence of complications when an HSG is done using oil-soluble contrast dye. There have been serious complications, even deaths, associated with HSGs, using both water-soluble and oil-soluble dyes. Most of these problems occurred more than forty years ago, before the use of fluoroscopy (X-ray video) to monitor the dye injection. At that time, a very thick, viscous HSG dye was in use, and when this was inadvertently injected into the bloodstream, serious complications could occur. The last death from an HSG was thought to have occurred in the 1960’s. Recently, in a series of over 1,000 HSGs performed with oil-soluble dye using fluoroscopy, no serious reactions were reported. In my opinion, using oil-soluble dye is no riskier than using water-soluble dye. Oil-soluble HSG dye is incompatible with some catheters used to perform the procedure, but there are plenty of alternative catheters that don’t have this problem.

Probably the most significant reason why more people don’t use oil-soluble HSG dye is that it is more expensive. A 10 mL ampule of Ethiodol retails for about $90, whereas the same amount of water-soluble dye (such as Omnipaque-300) is about half the price. In my experience, most radiologists are not familiar with the fertility-promoting effect of oil-soluble HSG dye (ironic, since one of the early reports was from a radiologist), and the radiologist if often the one directing purchase of the supplies. However, if you figure that extra $45 doubles your pregnancy rate, this becomes one of the most cost-effective treatments for infertility available.

If you are an infertility patient planning to have an HSG, and you want to convince your doctor to use oil-soluble contrast medium, you’ll probably need a better reference than this blog to convince him/her. I suggest you go to the library and get the following references, or just print off the abstracts from PubMed:

Watson A, Vandekerckhove P, Lilford R, Vail A, Brosens I, Hughes E. A meta-analysis of the therapeutic role of oil soluble contrast media at hysterosalpingography: a surprising result? Fertility and Sterility 1994 Mar;61(3):470-7.

Luttjeboer F, Harada T, Hughes E, Johnson N, Lilford R, Mol BWJ. Tubal flushing for subfertility. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD003718. DOI: 10.1002/14651858.CD003718.pub3.

Johnson NP, Farquhar CM, Hadden WE, Suckling J, Yu Y and Sadler L .The FLUSH trial—Flushing with lipiodol for unexplained (and endometriosis-related) subfertility by hysterosalpingography: a randomized trial. Human Reproduction 2004; 19, 2043–2051.