Monday, January 31, 2005

Study: In vitro fertilization - IVF - babies are at higher risk for birth defects



A story published a few days ago in The Australian reports that researchers at the Telethon Institute for Child Health Research in Perth, Australia analysed 25 studies from around the world and concluded that in vitro fertilization (IVF) babies consistently showed a 25 to 40 per cent greater risk of abnormalities.

The actual study itself has not been published yet. The authors are quoted however as stating that their study could not determine whehter the increased risk seen was due to in vitro fertilization (IVF) or due to the higher risk population being studied. Several studies have indicated that infertile couples may not be representative of the general population and that underlying factors may predispose them to higher risk of pregnancy complications and/or birth defects.

Interestingly, another study by Kathy Hudson, PhD., of John Hopkins University, reviewed 169 studies on children conceived through in vitro fertilization (IVF). (See Jnauary 6 2005 BLOG entry). She concluded that in vitro fertilization (IVF) babies do not have higher rates of cancer, malformations, psychological or developmental delays.

So which study is to be believed? This is the current difficulty in counseling couples about the possible risks of in vitro fertilization (IVF). At this point there is no clear and conclusive data that in vitro fertilization (IVF) itself poses any special risks for birth defects.

Lets assume for the moment that I am wrong and the new Australian data is correct. The overall risk of birth defects in the general population is about 3%. If the risk is increased by in vitro fertilization (IVF) by 30-40% then the OVERALL risk amongst all in vitro fertilization (IVF) babies is between 4-5%. Stated another way, even if the risk is increased, the chances for baby without defects is over 95%!!. This means that in vitro fertilization (IVF) is still a failry safe procedure.

I am not really ready to concede that the Australian study conslusions are correct, however. In order to settle the issue, we will need a very large study of in vitro fertilization (IVF) patients compared to infertility patients of the same age and same diagnoses who conceived without in vitro fertilization (IVF). This would be a very difficult study to do. In some cases, it would be impossible. For example a woman without fallopian tubes could not conceive without in vitro fertilization (IVF) so you could never have a valid comparison.

Bottom line? Everything we do in this world has some risk associated with it. In vitro fertilization (IVF) is no different. The questions is whether the potential benefits outweigh those risks. This is not something that can be determined by a study. every couple is going to have to make those decisions for themselves.

Wednesday, January 26, 2005

Rh sensitization prevented with IVF and PGD



Background:
Rh sensitization is a complication of pregnancy where a woman can make antibodies against her own baby causing that baby to become sick even while still in the uterus. This occurs when a woman with an Rh negative blood type (A Negative, B negative, AB negative or O negative) conceives a child with a father who has an Rh positive blood type. If the baby turns out to be Rh positive like the father, then the mother's body makes antibodies against the baby's red blood cells. The red blood cells can be destroyed making the baby anemic. In a fetus this can cause a serious condition called hydrops fetalis which can be so severe that the baby dies.

Because the immune system has a "memory" each time a woman is exposed to an Rh positive baby her response gets bigger and more aggressive.

This problem isn't as common as it used to be. The reason is due to the use of a medication called Rhogam. Rh negative mothers who are given the Rhogam injection during and after a pregnancy with an Rh positive baby will be prevented from making the antiboides so that subsequent pregnancies won't be affected.
However, cases of Rh sensitization still occur.

Tuesday, January 25, 2005

Could Leptin be the next fertility medication?



Leptin is a hormone produced in adipose tissue (fat cells). It has been the subject of much study in recent years. Leptin was first discovered in 1994. It is primrily thought of as an appetite and weight regulation hormone. However, leptin also functions to signal the brain and other organs about dangerous states of very low energy availability. Leptin is secreted into the bloodstream in proportion to the amount of energy stored in fat. The leptin is detected by receptors in the brain where it signals how much energy is available. It thereby regulates several key physiological functions that depend on adequate energy balance, including reproduction, metabolism, and bone formation.

We have known for some time that women who have very low body fat and/or those who exercise vigorously, can stop ovulating. Once they stop ovulating, they no longer produce essential hormones like estrogen and their periods can also stop or become infrequent. This condition is called hypothalamic amenorrhea.

Traditionally, in order to acheive pregnancy in these women, we used one of several techniques. First, we might ask the woman to decrease or stop her exercise or try to gain weight. This is usually successful in getting ovulation to return. However, some women are reluctant to try this approach. for them, we would use fertility medications to induce ovulation. This is effective but requires monitoring and has a risk for multiple pregnancy.

Researchers in boston recently studied 14 female athletes who had stopped menstruating on average five-and-a-half years before the start of the study. They had about 40-percent less body fat than the average woman. Eight of the women received leptin, while the others served as controls. After just three months of treatment, women receiving twice-daily leptin supplements resumed menstrual periods, and their ovaries began to function normally. The hormone also significantly improved bone density bone markers in the blood. No change was observed in the control group.

This is pretty exciting stuff. If these results can be confirmed in larger studies and if a pharmaceutical compnay is wlling to put forth the financial risk to do the additional dosing and safety studies then Leptin could become a vialbe treatment option for this group of patients.

Could Leptin be used to treat other ovulation problems like polycystic ovary syndrome - PCOS? This is less certain. Many studies have been conducted trying to determine whether leptin levels are correlated with polycystic ovary syndrome - PCOS but with inconsistent results. Theoretically, however, polycystic ovary syndrome - PCOS patients may have too much Leptin and need a medication which blocks or reduces its effects.

Saturday, January 22, 2005

Three dimensional structure of FSH is detailed - could lead to new drug forms




Whenever you see a publication in the journal Nature, expect something big and important. This is no exception. Wayne A. Hendrickson and his colleague Qing Fan of the Howard Hughes Medical Institute (HHMI) have created detailed images of the reproductive hormone FSH - follicle stimulating hormone and its receptor.

FSH is the hormone which is created in the pituitary and when secreted into the bloodstream serves to stimulate the ovaries or testicles. Like all hormones, FSH "connects" with a receptor on a cell. This "connection" causes changes in the cell that accomplishes some function. Until now, researchers did not understand key details about how FSH interacts with its receptor, largely because the complex had never been crystallized and examined at the molecular level. These researchers set out to produce crystals of the complex to use in determining its structure using a method called x-ray crystallography. With this technique, x-rays are directed through crystals of a protein to be analyzed. The patterns that result are then analyzed using computers to deduce the structure of the molecule under study.

So why should you care about this? Well the key to understanding how hormones work is understanding where and how they act on their receptors. Once this is understood, scientists can devise derivatives.

FSH is available as a fertility medication under the trade name Gonal-F or Follistim. It is administered as a subcutaneous injection on a daily basis.

With greater understanding, you might be able to create a variant of the hormone that acts for a longer period time. What if it were possible to give FSH only once a month and still get the same effect? How great would that be? Another possibility is the creaton of orally active FSH medications. Currently this is impossible because FSH which is a protein gets broken down in the stomache.

Of course, none of this will happen overnight but it is a major breakthrough that will yield benefits for years to come.

Monday, January 17, 2005

67 year old woman delivers twins using In vitro fertilization -IVF and egg donation



Over the weekend, the wire services released a story of a 67 year old Romanian woman who has become the oldest woman in history to deliver a baby. The previous record holder was a 62 year old Italian woman.

Obviously, this woman used donated eggs and possibly also donated sperm though the story wasn't clear on that point. Evidently, she has been trying conceive for nine years which means she was "only" 58 years old when she started trying.

Importantly, she conceived a twin pregnancy but was delivered by cesarean section when one of the twins died in utero.

We know that it is possible to get older women pregnant using egg donation at the same success rate as younger women. We also know that the risk of older women carrying a pregnancy are increased. Specificially, the risk for gestational diabetes, preeclampsia, intrauterine growth restriction and even intrauterine fetal death are all higher. Essentially 100% of these older women deliver by cesarean section.

What we do not know is whether there is an age beyond which

  • Women stop getting pregnant, even with donor eggs

  • The risks of carrying a pregnancy approach an unacceptably high level


  • This case brings that point up since she lost one of the twins. It is impossible to say on the basis of one case that this was due to her age. Younger women can lose a baby also.

    Even if we do beleive that her age increased the risk of fetal death, what then should we do about it? The simple answer is to restrict the age that women can attempt pregnancy at. However, this is a very slippery slope. If we restrict a woman's right to have children based on risk then what do we do about younger women who may be at greater risk because of other problems? Who becomes the judge in deciding who is allowed to have children and who is not?

    This is a question that only society at large can answer and it won't be an easy one

    Saturday, January 08, 2005

    Do In vitro fertilization IVF success rates decline with age? Duhh!




    Yesterday, the CDC released a statement along with the results of the 2002 in vitro fertilization (IVF) statisitcs for U.S. in vitro fertilization (IVF) programs.

    The statement indicated that in vitro fertilization (IVF) success rates decline with increasing age of the female. Well no kidding. The fact that fertility declines with female age has been known for a long time. In particular, it has been known that in vitro fertilization (IVF) success rates decline with age. In fact, every year the CDC has published the clinic success rates the same decrease has been found. This is not news!!

    Friday, January 07, 2005

    ICSI - Intracytoplasmic sperm injection- does not increase miscarriage risk



    A study out of Italy published in the December issue of Fertility and Sterility compared the rate of pregnancy loss - miscarriage - bewtween patients who underwent standard in vitro fertilization - IVF and those who had intracytoplasmic sperm injection - ICSI .

    The study looked at the number of fetuses identified on ultrasound in the second trimester compared to the number identified in the early first trimester.

    The conclusion was that intracytoplasmic sperm injection - ICSI does not increase the risk that a pregnancy will miscarry.

    I think this adds to the growing body of evidence that intracytoplasmic sperm injection - ICSI is as safe as in vitro fertilization - IVF . However, the design of the study does not allow us to determine whether very early miscarriages (those that might occur before a pregnancy can be seen on ultrasound) occur at the same rate. These are referred to as chemical pregnancies and are identified by a positive blood or urine pregnancy test.

    Thursday, January 06, 2005

    Pregnancy after menopause? Not a big deal.




    A report from a British newspaper and picked up by Reuter's indicated that a woman rendered infertile by chemotherpay has delivered a baby without any treatment.

    Why this story made the news is anybody's guess but it is certainly not that newsworthy. It has long been known that premature ovarian failure (premature menopause) can be induced by cancer treatments such as chemotherapy and radiation. It is also known that of all the possible causes of premature menopause, ovarian failure caused by chemotherapy and radiation have the highest rate of remission. In other words, it is the most reversable.

    Studies indicate that women with premature menopause may ovulate and conceive spontaneously in 3-4% of cases. If the menopause was a result of chemotherapy, the rate may be as high as 10-20%.

    Which brings me back to my first point. Why is this is a news story? Probably the medical center where she delivered had a good publicity department. The fact that a Belgian women recently delivered a baby after cancer treatment but with transplantation of a portion of her ovary may also have had something to do with it. Non-medically inclined editors may have thought that this was a similar story which, from the Reuter's report, does not appear to be.

    Health risks for in vitro fertilization - IVF children?




    A study conducted by Kathy Hudson, PhD., who is the director of the Genetics and Public Policy Center at John Hopkins University, reviewed the available medical literature (169 studies) on children conceived through in vitro fertilization (IVF).

    The results are generally reassuring. In vitro fertilization (IVF) babies do not have higher rates of cancer, malformations, psychological or developmental delays.

    Singleton in vitro fertilization (IVF) babies ARE at increased risk for premature birth, low birth rate and death in the first few weeks of life.

    Twin in vitro fertilization (IVF) babies are NOT at any higher risk for these problems than naturally conceived twins. I should mention that twins are at higher risk for these complications compared to singletons and twins are more likely to occur as a result of multiple embryo transfer but in vitro fertilization (IVF) itself does not appear to increase the risk.

    There were two rare genetic disorders, Beckwith-Wiedemann syndrome and Angelman's syndrome that the study made a special comment about. In the case of these two problems, the study found evidence that was "suggestive but not sufficient" to indicate that in vitro fertilization (IVF) may increase the risks of these problems.

    The problem is that these syndromes are both very rare to start with. That makes it very difficult to determine then whether in vitro fertilization (IVF) has any adverse effect. Further study is needed in a much larger study to determine whehter there is a risk.

    There has been alot of information in the media about the possible risks to the babies born through in vitro fertilization (IVF). This study, which is the largest study of its kind, I think is very reassuring.

    There has been some noise in the field about establishing an in vitro fertilization (IVF) registry for children born through in vitro fertilization (IVF) I think it is probably a good idea and may be the only way to answer some of the questions we have about in vitro fertilization (IVF). Opponents say that it violates the privacy of the children in the registry and places a "stigma" on them. I can't argue that but still feel that benefits outweigh the disadvantages.

    Wednesday, January 05, 2005

    Device to improve sperm selection?




    A story in New Scientist Magazine stated a machine being developed at the University of Newcastle in New South Wales is intended to be able to select sperm with less DNA damage.

    The premise is that sperm with normal maturation and therefore less DNA damage is negatively charged. The "sperm sorter" consists of two chambers separated by a filter. After the sperm is injected into the first chamber a voltage is applied across the filter to move sperm to the second chamber.

    In one test of the machine,using semen from medical students, 20 percent of sperm made it into the second chamber. This "select sperm" had only half as much DNA damage as the sperm in the first chamber.

    Without having actually seen the data, I am very suspicious about this. My big concern is how they were determining whether sperem had DNA damage. Recently there has been alot of interest in sperm DNA damage testing. The most popular of these tests, the Sperm Chromatin Structure Analysis (SCSA) initially had some very enouraging studies suggesting that it could identify men less able to produce a pregnancy.

    However, at the fall 2004 meeting of the American Society for Reproductive Medicine (ASRM), there were three studies from three separate groups which failed to find any benefit to the test.

    It leaves considerable question as to whether identification of sperm with more or less DNA damage makes any difference. Some will argue that it is only logical that choosing sperm with less DNA damage would work better. This is not necessarily so. Cells such as eggs contain mechanisms to repeair DNA damage. Maybe the differences we find are clinically unimportant.

    If anyone has a complete copy of the New Scientist article, please email me.

    Bedrest after in vitro fertilization (IVF) not necessary

    I hear it all the time. My patients correspond with in vitro fertilization (IVF) patients at another program. "Their doctor says they have to go on bed rest after the embryo transfer or it won't work." I have always thought this was baloney. Now more proof that it is baloney.
    A recent study of 378 women who were undergoing in vitro fertilization (IVF) were randomly assigned to rest for either 1 or 24 hours following an in vitro fertilization (IVF) embryo transfer. The 1-hour rest group had a rate of 21.5 percent, whereas the 24-hour rest group had a rate of 18.2 percent. Actually, the implantation rate per embryo in the 1-hour rest group was 14.4 percent, which was higher than the 9 percent rate seen in the 24-hour rest group.
    Previous studies have all reached the same conclusion. Resting after an in vitro fertilization (IVF) embryo transfer does nothing to improve the pregnancy rate. This makes good sense since women who achieve pregnancy spontaneously do not rest so why would it be necessary after in in vitro fertilization (IVF).
    Also, since implantation does not occur until day 7 or 8, a day or two of rest after a day 3 embryo transfer would seem to be ridiculous. Now I couldn't argue if someone was recommending five days of rest, that study has never been done but programs that stick by this do not recommend rest for that long.
    Bottom line? Rest if you want to but if you don't it won't hurt your chances.

    Tuesday, January 04, 2005

    Alternatives to glucophage for treating insulin resistance




    For women with polycystic ovary syndrome - PCOS, insulin resistance is a common finding. In addition, many of these women do not respond to clomiphene citrate (Clomid resistance). For these reasons, many women are now treated with a diabetes medication known as glucophage (metformin) which works, in part, to reduce insulin resistance and improves the chances for ovulating spontaneously or with Clomid. However, many women will have side effects from glucophage such as bloating, cramping, diarrhea, flatulence and nausea. The most serious complication of glucophage is lactic acidosis which is a rare but potentially life threatening condition.

    Acarbose is another medication used to treat diabetes. Acarbose is an alpha-Glycosidase inhibitor. It works by reducing the absorption of monosaccharides (simple sugars) through intestines and minimize the increase in blood sugar and insulin seen after meals. Serious side-effects of acarbose are rare and
    although it shares many of the gastrointestinal side effects as glucophage, lactic acidosis is not a problem with this drug.

    In a recent study, researchers looked at 30 women with polycystic ovary syndrome - PCOS who did not previously respond to clomid. The women were divided into two groups. One group received acarbose and clomid. The other group received glucophage and clomid.

    By the end of three months, the women taking acarbose lost more weight than the glucophage group. Both groups showed a similar improvement in the number of women who ovulated. There were 15 women in each in group and they were studies for three months so there was a possibility of 45 ovulatory cycles (15 x 3). The acarbose group had 20 ovulations and the glucophage group had 24 ovulations. The incidence of side effects were the same in both groups and there were no serios adverse effects in either group.

    In summary, it seems that acarbose could provide a reasonable alternative to glucophage for treating insulin resistance in polycystic ovary syndrome - PCOS patients, though the expected benefits are minimal. This was a small study so there isn't nearly as much data showing a positive effect as exists for glucophage at the moment. Acarbose did not have a better ovulation rate than glucophage so the main benefit comes down to a lower risk of lactic acidosis which is a very rare complication anyway.

    I would think of acarbose as a second line drug for the time being. If first line drugs like glucophage or Actos or Avandia were not tolerated or ineffective than trying something like acarbose might be reasonable.