From Wall Street to Suite 370E – a sad twist to the current credit crisis.

Things are a little slow at AFS this week. Sometimes bad economic news makes people have second thoughts about having kids, but we’re not worried - the urge to reproduce is hard-wired into our species, otherwise there would be some other species reading this. And we ascribe to the King Perry Philosophy of Small Business Economics (he wrote a song called “Keep a Dollar in Your Pocket”). And success rates at the office have never been better. For example, see here:

http://fertilitysuccessrates.com/report/United-States/women-under-35/data.html

But we were a little shaken recently by one of our infertility patients, who announced that she was getting an abortion.

She had been trying to conceive for over 3 years and had undergone about 10 cycles of clomiphene elsewhere before she was referred to us. We bumped up her dose, added an intrauterine insemination, and she got pregnant in her first cycle here. “We didn’t think it would work so quickly!” she said. (Hey, that’s what you pay me for.)

Turns out her husband (who has a chronic medical condition) works at a local car dealership that is letting people go because of slow sales. Family health insurance will be quite expensive when the baby comes, and they may not have jobs. She went to the abortion clinic the other day, but it was too early in the pregnancy to do the procedure, and her blood pressure was really high. (I wonder if her husband is more anxious to take this route than she is – might explain the blood pressure issue, as her pressures were always fine before this.) We tried to talk her out of it, but I don’t think we changed her mind.

There is never a perfect time for a pregnancy, but this seems like irrational thinking to me. It’s a sad time for us.

An ethical dilemma? Infertility and drug addiction

(I sometimes tell this (true) story when talking to medical students or public groups about the ethics of reproductive technology. MPS)

"A couple presented to my office requesting care for infertility and recurrent miscarriages. Within a few visits, it was clear to me and the office staff what the problem was - they were both drug addicts. Their particular addiction was known to increase the risks of infertility and miscarriage, and was associated with a variety of other pregnancy complications. They were in their early 30's and successful in their professions and daily lives. We offered help and strongly recommended that they stop their drug use, but they just wouldn't (or couldn't) do it. How should one proceed in a case such as this?"

Audiences are uniformly unsympathetic towards this couple - no one wants to offer them fertility treatment. Often someone will comment that the situation is appropriate, as drug addicts shouldn't be reproducing anyway. I ask if it matters which drug they are taking, and the answer is "no". Then I reveal that the drug being abused is nicotine - the patients are heavy smokers. At this point some members of the audience become very quiet, as they have packs of cigarettes in their pockets. The rest of the audience usually become less vigorous in their condemnations. No one tries to dispute the harmful effects of smoking on reproduction, but it seems that this addiction is much more socially acceptable than the cocaine or heroine use the audience had in mind.

What ultimately happened with the patients? I finally told them not to come back until they stopped smoking. They never returned.

More fertility questions

Q: "Is there anything else to test a husband for if his count is excellent and they're "strong swimmers"?"

A: Basically, no. You would think that evaluation of male fertility would be very straightforward, since the male gametes are readily available for examination, but this is not so. Just because a sperm has a normal shape and is moving doesn't mean it can fertilize an egg. Many tests have been developed to try to answer this question, and while some advanced sperm tests show a correlation with fertilization capacity in research studies, none of them wind up being clinically useful. Here are some male fertility tests that, in my opinion, fall into this category: hamster egg sperm penetration assay, hemizona assay, strict morphology testing, DNA fragmentation studies. I have seen men who have failed these tests but whose sperm could fertilize a human egg without difficulty. I don't think the tests are worth the expense, and they are seldom covered by insurance.

It turns out that a simple semen analysis is about as good as anything for predicting male fertility. If there are more than 20 million motile sperm in a man's ejaculate, he is probably fertile. If there are less than 10 million, he probably isn't.

Q: "I underwent IVF with ICSI at age 35 after trying for my first pregnancy for 2 years. My husband had a slightly abnormal SA that may be from his previous exposure to chemotherapy (you can comment on that if you'd like). They wanted me to have PGD since I was 35. No thanks, I said. Especially since they were charging $4000 out of pocket.... I knew my chances for an abnormality based on our history and I also trusted nature to take care of any abnormalities they could have picked up with PGD, accepting the consequences if nature didnt....

I got pregnant the first attempt and have a wonderful son after a very traumatic pregnancy (threatened miscarriage, chronic abruption, fetal abnormalities). The genetic testing on my son is all completely normal, however, he does have a syndrome, there is just no test for it....

Are there any abnormalities or genetic syndromes related to IVF with ICSI, or with chemo exposure to the dad?"

A: Whether fertility treatment causes birth defects has been debated for many years. People are still arguing about whether clomiphene causes birth defects, even though the drug has been on the market for more than 30 years. The development of in vitro fertilization has renewed interest in this matter. Several studies have shown that children conceived with IVF have a higher incidence of birth defects, but the defect found is not consistent among all the studies. More recently, it was suggested that IVF caused certain "imprinting" disorders by altering methylation of DNA due to culture of the embryos outside of the body. However, a larger study failed to confirm this.

Why all the conflicting results? I think a lot of it has to do with the nature of the IVF patients, and how a control population is chosen for study. Infertile women are different from the general population of pregnant women: they are older, of different ethnicity and socio-economic status, and their infertility problem is often associated with other problems that may affect pregnancy outcome (for example, the association betweeen polycystic ovary syndrome and diabetes). In my opinion, there is no convincing evidence showing that IVF (or clomiphene, or any other fertility treatment) causes birth defects.

There are two exceptions to this. (1) IVF for male factor infertility is more likely to yield a child (if male) that will be infertile himself. (2) The incidence of cystic fibrosis is higher in children of men with congenital absence of the vas deferens who conceive by IVF. In both of these cases, it isn't the fertility procedure that causes the defect, but rather the underlying problem.

SEX! and other FAQs

A former patient with a particularly wry sense of humor has observed that this blog is a bit dry. I can’t help it – when patients see me in the office, I try to inject a little humor into the visit in order to put them at ease (you must admit that some aspects of infertility treatment can be funny), but it’s hard to be light-hearted when putting things down on paper (or rather, on a screen) for everyone to see.

There is something to be said for a sense of humor. It’s a coping mechanism of sorts, kind of like prayer or meditation. It worked for my patient, anyway, and we enjoy her periodic visits to show off her baby. JT, this blog is dedicated to you.

Q: How often should I have sex if I’m trying to get pregnant?

MPS: It’s the number-one question of infertile patients, and I’m amazed at how much misinformation there is about it. First of all, NO ONE HAS EVER SHOWN THAT HAVING TOO MUCH SEX WILL DECREASE YOUR CHANCES OF CONCEIVING, assuming that we are dealing with intercourse that ends with ejaculation into the vagina. Yes, I know semen quality declines with frequent ejaculation, but hey, those sperm are going where they need to go. In more than 20 years of practice, I have never seen a couple who presented with infertility due to having too much sex – I challenge you to find such a case. If you want to do it every day, be my guest. However, anything more than about three times a week is for recreational purposes only. Sperm survive in the female genital tract about 2 or 3 days near the time of ovulation, so more than every other day will not improve your chance of pregnancy. Now, if you look around in the medical literature, you can find papers that show increased pregnancy rates with more frequent intercourse, up to five times a week, but those investigators didn’t account for the fact that younger couples are more likely to have sex, and are more likely to get pregnant as well. When you control for age, maximal fertility tops out at about three times a week. I tell patients that if you having 28-day cycles you should have sex at least three times a week between days 10 and 20. I think that doing it every other day is bit too regimented, but some people find that schedule helps them stay focused.

Often, infertile couples are burned out on sex by the time they see me. They work hard, they are tired when they get home, and they’re sick of doing it like bunnies month after month. I think if you want to pick the ONE DAY to have sex the entire month, use an ovulation prediction kit, and have sex the night the kit turns positive. You can achieve success almost as good as with the three-times-a-week regimen if you do it that way. (See below for more info about ovulation predictor kits.)

Q: Someone told me I should elevate my hips on a pillow after sex. Will this help me get pregnant?

MPS: If pillows were required for reproduction, our species would have long since died out. I am not aware of any study showing improved pregnancy rates with post-coital hip elevation. Here’s what I recommend: after sex, lie there for five minutes or so, then get up and go to the bathroom to empty your bladder (this is good hygiene for preventing bladder infections). Yes, fluid is going to leak out, but that’s ok.

Q: What kind of ovulation prediction kit should I use?

MPS: Several years ago, Consumer Reports did a study on ovulation prediction kits. I was impressed at how much difference in quality there was among the brands out there. The winner in that evaluation was a product called Clearblue Easy (it used to be called Clearplan Easy), and a newer version called Clearblue Easy Digital is even better – that’s the one I recommend. (By the way, I have no financial interest in this product.) We use these kits to time artificial inseminations and post-coital tests, and they work quite well.

Most ovulation predictor kits detect a surge of luteinizing hormone (LH) in the urine. This is the hormonal trigger that tells the ovary to release the egg. However, there are some other products out there that claim to predict ovulation by detecting changes in saliva, vaginal discharge, or sweat. One product even claims a 65% improvement over urine LH kits, but in my opinion, no one has ever shown these products to be as good as a quality LH kit, and I don’t recommend them.

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.

MPS

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.

MPS

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.

MPS