New and notable in the infertility field, as well as the laboratory at Pacific Fertility Center, is the introduction of EmbryoGlue, a product used with embryos at the time of transfer to the uterus. As its name suggests, EmbryoGlue is claimed to increase the rate at which embryos implant or stick to the uterus after transfer.
In a typical assisted reproduction scenario, embryos, as well as eggs and sperm, are kept in a nutrient solution, or medium, during their time in the laboratory. This solution contains many ingredients including salts, sugars and antibiotics that help embryos grow in a sterile environment for 3 to 5 days. The solutions are purchased from commercial vendors and several varieties exist. Competition among vendors is fierce and each is actively researching new and improved versions of their products. The IVF laboratory director is responsible for selecting and testing the solution that will be used for patients’ embryos. It is no overstatement to say that the choice of culture medium is fundamental to the success of an IVF cycle, since any compromise on quality could affect the rate at which embryos grow and implant.
When a patient returns to PFC for her embryo transfer procedure, a consultation with the physician and the embryologist will result in a careful decision regarding which embryos to select for transfer. This is a crucial part of an IVF cycle since patients typically transfer between one and four of the available embryos, and it is important to choose the embryos with the greatest potential for implantation. After this decision has been made, the embryos are placed in culture medium and loaded into a fine silicone (plastic) catheter. A Physician then passes the catheter through the patient’s cervix and into the uterus. The small drop of culture medium containing the embryos is gently expelled and the empty catheter is withdrawn.
Traditionally, the medium that is used for embryo transfer has been similar or identical to the solution used for growing the embryos. However, the introduction of EmbryoGlue is purported to bring about a dramatic increase in the rate at which embryos implant after transfer. In clinical trials, implantation rates per embryo increased by 34% and overall pregnancy rates increased by 21% when EmbryoGlue was tested against a more traditional transfer medium.*
Traditionally, the medium that is used for embryo transfer has been similar or identical to the solution used for growing the embryos. However, the introduction of EmbryoGlue is purported to bring about a dramatic increase in the rate at which embryos implant after transfer. In clinical trials, implantation rates per embryo increased by 34% and overall pregnancy rates increased by 21% when EmbryoGlue was tested against a more traditional transfer medium.*
There are several reported benefits to the use of EmbryoGlue. The key component is an enzyme called hyaluronan, which has been shown to increase rates of implantation and fetal development, first in a mouse model, and now in humans. Hyaluronan is naturally found in fluid from follicles, the fallopian tubes and the uterus, so it is claimed to provide a more ‘natural’ environment for the embryos. Hyaluronan production in the uterus is at its highest at the time of embryo implantation, and the enzyme promotes cell to cell contact between the embryo and the uterus. It also dilates the uterine blood vessels, increasing blood supply to the uterus. Lastly, hyaluronan is a viscous sticky solution that more closely resembles the natural secretions of the uterus.
Much media attention has surrounded the launch of this product by its manufacturer Vitrolife (www.vitrolife.com), a company headquartered in Sweden and with a subsidiary in Denver, Colorado. Since patients actively read scientific literature and follow IVF developments on line, and since the FDA has approved this product, there has been much demand for EmbryoGlue. However the study mentioned above is only the first of many that will likely be published on the use of EmbryoGlue. It is important to point out that all studies to date have been performed by researchers affiliated with, and financially supported by the manufacturer. Widespread use of the product will generate more independent studies and help confirm or deny these initial results.
For now, EmbryoGlue is one of the most exciting developments that we, at Pacific Fertility Center, have seen in a few years. We’re cautiously optimistic that it will live up to its reputation since the researchers that developed the product are highly regarded in the scientific community, and the first clinical trial was a well constructed experiment. Nevertheless, in the absence of large scale and independent clinical trials, PFC is not incorporating this product into our standard treatment protocol. While EmbryoGlue is FDA approved for use with human embryos, and we are therefore confident that it does not harm embryos in any way, PFC needs more data on the efficacy of the product before we recommend its use for all patients. Watch this space for regular updates and results from our own patients that choose to have embryos transferred in EmbryoGlue. --Joe Conaghan, PhD, HCLD
*Schoolcraft, W., and others, Fertility and Sterility Vol. 76, (2002).
Joe Conaghan, PhD, HCLD
Best known for his studies on embryo culture, Dr. Conaghan directs a team of eight board certified embryologists. He sets high security standards and provides results that bring national recognition to our PFC laboratory.
It is a well-known fact that alcohol and pregnancy don’t mix.
Studies have tied alcohol consumption during pregnancy to increased risk for stillbirth and first trimester miscarriage. Indeed - alcohol abuse by women who are expecting is the number one cause of birth defects, premature births, low birth weight and mental retardation. A shocking 12,000 babies each year are born with Fetal Alcohol Syndrome (FAS) and at least twice that many with the milder Fetal Alcohol Effects (FAE) associated with learning disabilities and lower alcohol intakes.
While the tragedy of FAS is well established, less certain is whether casual consumption of alcohol while trying to conceive either hinders or helps a woman’s chances. Past published studies have been mixed as to whether there is an association between moderate alcohol consumption and waiting time to pregnancy. One study did show decreased probability of conception in women imbibing 1-5 drinks per week. Another study saw no effect of 7 or more drinks per week in younger woman but women over 30 were more likely to be infertile. None of these studies have stratified the data to see if any type of alcohol might benefit or hinder. Yet a recent study drew a mildly positive correlation between moderate wine drinking and pregnancy.
The study, published in the September Journal of Human Reproduction was conducted at the Danish Epidemiology Science Center in Copenhagen by Mette Juhl, who had already researched the impact of moderate alcohol consumption on conception. Her past survey work concluded that moderate consumption of alcohol (up to 7 glasses per week) does not reduce a woman’s chances of purposefully getting pregnant.
For this study, the researcher set out to take a closer look at specific types of alcohol consumed by the 29,844 pregnant women who had participated in the first survey. Researchers discovered that wine drinkers had a nearly 30 percent greater chance than nondrinkers of getting pregnant within one year of trying. Woman who exclusively drank wine became pregnant sooner than those that drank only beer or hard liquor (spirits). Interestingly, drinking all three types of alcohol was associated with the shortest time to pregnancy.
Again, the study confirmed that heavy drinking of spirits actually decreases conception chances. Women who drank more than seven shots per week were 240 percent less likely to conceive. However, it is important to note that many of these women also had other risk factors for subfertility (smoking, greater incidence of pelvic infections or abdominal surgeries).
Ms. Juhl is cautious to point out that it may not be wine consumption per se, causing the increase or decrease in pregnancy success, but rather other lifestyle influences that may go along with wine drinking. For instance, some oenophiles enjoy healthier food than nondrinkers and beer or liquor drinkers. They also are more likely to be of average weight, and practice healthier lifestyle habits. The wine drinkers were less likely to smoke; smoking has been shown to prolong time to conception. Other confounding factors such as caffeine consumption, partner’s age and frequency of intercourse were not evaluated. She cautioned against drinking alcohol specifically to try to conceive, since this benefit was quite mild.
As little as one drink per day in pregnant women has been linked to decreased cognitive performance in their infants. Alcohol can have detrimental effects on the fetus as early as three weeks gestation - before a woman even knows she is pregnant. The "safe" amount of alcohol intake for pregnant women has not been established. Given that wine drinking could just be a proxy for a healthier lifestyle and the known negative effects of alcohol on the fetus, it is premature to encourage the consumption of wine to enhance conception.
For now we at PFC endorse the positions of the Centers of Disease Control (www.cdc.gov/ncbddd) and the American Academy of Pediatrics (www.AAP.org) advising that women attempting pregnancy should abstain from alcohol.
--Isabelle Ryan, MD and Beth Schriock, MD
References:
American Academy of Pediatrics: Preventing Fetal Alcohol Syndrome. www.aap.org/advocacy/chm98pre.htm
CDC: Alcohol Use and Pregnancy. www.cdc.gov/ncbddd
National Institute on Alcohol Abuse and Alcoholism: Fetal Alcohol Exposure and the Brain. www.niaaa.nih.gov/publications/aa50.htm
Barefoot JC, Gronbaek M, Feaganes JR, McPherson RS, Williams RB, Siegler IC. Alcoholic beverage preference, diet, and health habits in the UNC Alumni Heart Study. American J of Clinical Nutrition 2002;76 (2): 466-472.
Bolumar F, Olsen J, Boldsen J. Smoking reduces fecundity: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1996; 143 (6): 578-87.
Bolumar F, Olsen J, Rebagliato M, Bisanti L. Caffeine intake and delayed conception: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1997; 145 (4): 324-34.
Jacobson JL, Jacobson SW, Sokol RJ, Martier SS, Ager JW, Kaplan-Estrin MG. Teratogenic effects of alcohol on infant development. Alcohol Clin Exp Res. 1993; 17 (1): 174-83.
Jensen TK, Hjollund NH, Henriksen TB, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde JP, Skakkebaek NE, Olsen J. Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy. BMJ. 1998; 317: 505-510.
Juhl M, Andersen AM, Gronbaek M, Olsen J. Moderate alcohol consumption and waiting time to pregnancy. Human Reproduction. 2001; 16 ( 12) 2705-2709.
Juhl M, Olsen J, Andersen AM, Gronbaek M. Intake of wine, beer, and spirits and waiting time to pregnancy. Human Reproduction. 2003; 19 (9): 1967-1971.
Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake during pregnancy and the risk of stillbirth and death in the first year of life. Am J Epidemiol. 2002; 155 (4): 305-12.
Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ. Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol. 2002; 37 (1): 87-92.
Rosenberg A. Brain Damage Caused by Prenatal Alcohol Exposure. Scientific American. July/August 1996; 42-51
Despite the overwhelming success of In Vitro Fertilization (IVF) in helping couples to conceive in the past 25 years, there remains a group of women for whom there is no obvious explanation for repeated IVF failures. This has led to hundreds of theories, most debated and subsequently discarded, to explain these inexplicable, yet relatively uncommon embryo implantation failures.
One popular theory that lingers is that the implantation process is facilitated in part by the maternal immune system, acting at the contact point of the uterine lining and the normal embryo. While there is little doubt that many biological processes are likely at work here, the exact mechanisms of embryo implantation remain poorly understood. More basic research is underway to further understanding of this complex process.
Taking off on this theory that some abnormality in the immune system is responsible for implantation failures, some IVF practitioners will run a battery of tests for antibodies to phospholipid molecules on their IVF patients. These phospholipids are everywhere on cell surfaces. At high levels, such as with some auto-immune diseases, the presence of antibodies to phospholipids can lead to clotting disorders and sometimes repeated, mostly second trimester pregnancy losses. Much more controversial is the question of whether or not anti-phospholipid antibodies play any direct role in inhibiting embryo implantation. Approximately 9% of normal fertile women can be found to have anti-phospholipid antibodies in their blood.
A well designed study from 1997 by Denis and colleagues found that in a large number of patients undergoing IVF, the presence or absence of these anti-phospholipid antibodies prior to treatment had no effect on IVF outcome. This is why the majority of reproductive endocrinology and infertility specialists, including Pacific Fertility Center, do not run anti-phospholipid antibody tests on their infertility patients. But some IVF practitioners routinely run these tests and, based on the presence of any positive titers of antibodies, will prescribe a regimen of twice daily injections of heparin and a tablet of children’s aspirin daily. Heparin is a blood thinner and is known to inhibit the binding of anti-phospholipid antibodies to phospholipids on cell membranes.
Prior studies examining heparin use have resulted in conflicting findings, some studies showing amazing benefits and others finding none at all. Most of the prior studies had design limitations that made it difficult to form firm conclusions. This conflict, coupled with the inherent potential risks of heparin use, have limited the use of this controversial therapy to a very small number of centers.
A new study, recently published in the August issue of Fertility and Sterility (an official professional journal) may finally put the debate to rest. The study was designed as a randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with prior in vitro fertilization failure, and with positive signs of anti-phospholipid antibodies or anti-nuclear antibodies. This study protocol is considered the "gold standard" design for a clinical trial and when performed as designed, the results are very hard to dispute.
Basically, some of the women, all of whom had had at least 10 embryos transferred over several prior IVF cycles and who had no known explanation for the implantation failure, were randomly assigned to receive either heparin and aspirin or a placebo (blank) during their IVF or frozen embryo transfer cycle. Neither the researchers nor the patients were aware whether or not the patient was receiving the active drug until the study was completed, to eliminate any potential study biases.
For the women receiving heparin and aspirin, a total of 296 embryos were transferred. This resulted in 20 cases with positive fetal heartbeats on early ultrasound (7%). For the placebo group, 259 total embryos were transferred and there were 22 positive fetal heartbeats (8%). Keep in mind that these patients had been through several prior IVF attempts so their overall chances for success would be low to start with. The live birth rate for the heparin and aspirin group was 6% and was 7% for the placebo group. There was no statistical difference in these numbers.
The bottom line on this study is that even with positive anti-phospholipid antibody tests, women with repeated IVF failures were no more likely to conceive if they received a treatment regimen with heparin and aspirin or with nothing at all. This study provides Class A medical evidence that recommendations to use heparin for infertility must be viewed very cautiously, as heparin’s effect on certain patients can be even detrimental to their overall health. For more information regarding the use of low-dose aspirin while attempting conception, please see our Sept. ’03 issue of Fertility Flash. --Carolyn Givens, M.D
Q:
Hi - I have severe painful endometriosis, am 34, otherwise healthy and fit with one failed fresh IVF cycle and one failed frozen transfer. Is there anyway I can help the process of implantation? And could the endometriosis be preventing the implantation? Many thanks for your help.
A:
Endometriosis is the condition where tissue that forms the uterine cavity lining each month (and is shed as menstrual flow is now growing outside of the uterine cavity. This extra-uterine tissue is most commonly found around the ovaries, fallopian tubes, and outer layer of the uterus.
In general, the negative affects of endometriosis are due to processes occurring in the pelvis. These negative affects make the pelvic fluid more hostile to eggs and sperm. Therefore, the negative pregnancy affects are limited to the processes that are occurring in this pelvic environment (egg bathed by pelvic fluid as they are ovulated, fallopian tubes bathed by pelvic fluid and impacting fertilization and early embryo development). The uterine cavity itself seems to be protected from these negative affects. For patients who need to proceed to IVF, we bypass the "pelvic environment" and all steps which would be occurring in the pelvis are now occurring in the laboratory (egg recovery, fertilization, early embryo development). The uterus is protected from the negative pelvic affects, so pregnancy rates are the same for endometriosis patients, as they are for other patients who need IVF.
Exceptions to this would be patients with adenomyosis. Adenomyosis is a benign condition characterized by the endometrium lining growing INTO the muscular layer of the uterus, instead of just staying confined to the uterine cavity.
The other exception is for patients who have endometriomas (endometriosis ovarian cysts filled with thick, dark brown blood). These can impact egg quality, so it is not uncommon that if you have endometriomas, it might take a few more IVF cycles than the average to achieve a successful pregnancy. -Isabelle Ryan, MD
---Joe Conaghan, Ph.D
My husband and I had always wanted children, but did not marry until age 40 (we are the same age). My mother had seven healthy children, the last one at age 40, so I had always assumed I would have no problem conceiving a child. We tried for several years, then had some tests done at my gynecologist's suggestion. A few problems were corrected, and we tried for another year, using an ovulation predictor kit. Finally, at age 45, we turned to Dr. Ryan for help.
We tried artificial insemination once, without success, and then immediately chose IVF with a donor egg, due to our age. We wanted the healthiest donor we could find, and we luckily found a woman similar to me in ethnic background, appearance, and many interests and traits. At age 46, we were blessed with a beautiful, very healthy full-term baby girl on our first IVF cycle. She is very active and alert, and ahead in most developmental milestones, yet doesn't sleep as many hours as the average baby, so we have our hands full.
Because I gave up my career to become a stay-at-home mom, we are now stretched financially. Due to our circumstances and age, when our baby was 5 months old we made the difficult decision to not try for more children. Having decided this, we wanted to give some other couple the chance to become parents, and give our apparently very healthy embryos a chance to develop into fetuses, and, hopefully, babies (born to people who want children as much as we do, but may not have the ability to conceive their own or pay donor, agency and donor meds fees). So with the help of Dr. Ryan, we put our 17 embryos up for adoption.
--L.F., Belmont, CA
It is our policy to match the extraordinary generosity of some of our patients, like the couple above, with eligible PFC patients who have tried to conceive, but have more or less reached the end of their rope. Everyone’s circumstances are unique. Stay tuned to this column in the next couple of months to find out more about how embryo adoption benefits infertile couples!
--Isabelle Ryan, MD
In response to questions about new developments, fertility studies covered by the media as well as news pertaining to our center, we are thrilled to launch Fertility FlashSM.
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New! Stress Reduction for Infertility Workshop
January 24th and 25th, taught by Peggy Orlin, MFT and Allison Chamberlain, RN. Call to register 888-834-3095.
PFC’s Free Seminar
Our next seminar is Wednesday November 19th from 6:30 to 8:30 PM.
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