The International Council on Infertility Information Dissemination, Inc

Effects of BPA and Phthalates on Conception and Pregnancy

October 14 , 2013

by: ASRM Office of Public Affairs
Published in ASRM Press Release

HIGHLIGHTS FROM THE INTERNATIONAL FEDERATION OF FERTILITY SOCIETIES 21st WORLD CONGRESS ON FERTILITY AND STERILITY AND THE 69th ANNUAL MEETING OF THE AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE

Boston, MA-  Researchers presenting at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine have identified specific effects of bisphenol A (BPA) and phthalates on human reproduction. 

These chemicals are used in the manufacture of plastics and other products, accumulate in the environment and human tissues and are known to be endocrine disruptors.  While evidence is growing that BPA and phthalates influence the success of couples undergoing IVF, less is known about how these chemicals affect couples who are presumed fertile, who are trying to conceive, and how they affect a woman’s ability to sustain a pregnancy. 

In one study, examining BPA and phthalate levels in 501 couples trying to become pregnant, researchers from the National Institute of Child Health and Human Development, Texas A&M Rural School of Public Health, and the New York State Department of Public Health found that phthalate concentrations found in the male partners, but not the females, may be associated with approximately a 20% decline in fecundity.

Couples discontinuing contraception in order to become pregnant were recruited between 2005 and 2009.  They were interviewed at the outset, examined, and all individuals provided urine samples for measuring their BPA and phthalate levels.  In addition, the couples kept journals on intercourse and lifestyle and the women recorded their menstrual cycles and pregnancy test results.

The researchers found that higher BPA concentrations in the female partner did not lead to decreased fecundity and that, in fact, higher concentrations of a certain phthalate were associated with a shorter time to pregnancy.  In the male partners, concentrations of other phthalate chemicals were associated with diminished fecundity and longer time to pregnancy.

O-2  Bisphenol A, Phthalates and Couple Fecundity, The Life Study GM Buck
Louis et al   
 


In another study, researchers from Stanford University, the University of California San Francisco and the University of Missouri found that women with levels of BPA in the highest quartile are at significantly increased risk of having a miscarriage. 

They recruited 114 women having an early pregnancy test at four to five weeks gestation.  The enrollees gave blood to be stored. This was later tested for BPA levels in the women who had given birth and in the women who had had a first trimester miscarriage with testing for chromosomal abnormalities.  Serum BPA concentration levels were ranked in quartiles and the researchers calculated the relative risk of miscarriage for women in each quartile of serum BPA concentration.

Women who had had a miscarriage had higher average BPA levels than those who had live births and the risk of miscarriage increased with increasing levels of BPA in the maternal serum- whether the fetus was chromosomally normal or not.

O-61     Maternal Serum Bisphenol-A (BPA) Level Is Positively Associated with Miscarriage Risk 
RB Lathi et al 

ASRM President Linda Giudice, MD, PhD observed, “Many studies on environmental contaminants’ impact on reproductive capacity have been focused on infertility patients and it is clear that high levels of exposure affect them negatively.  These studies extend our observations to the general population and show that these chemicals are a cause for concern to all of us.”


Also of interest:

Chinese scientists have found that high BPA levels in the follicular fluid of polycystic ovarian syndrome (PCOS) patients may inhibit the activity of a gene in granulosa cells, interrupting the conversion of androgen to estrogen and causing an abnormal accumulation of androgen hormones.

O-42  Bisphenol A (BPA) Induces Abnormal Androgen Accumulation Via Androgen-Androgen Receptor (AR) Mediated CYP19A1 Transcription Inhibition in Granulosa Cells (GC’s)
Pan et al 

Representing more than 50 fertility societies from around the globe, the International Federation of Fertility Societies (IFFS) is the world’s principal international fertility organization. The IFFS was founded in 1951, and held its first congress in New York in 1953. The IFFS mission is to stimulate basic and clinical research, disseminate education and encourage superior clinical care of patients in infertility and reproductive medicine. Website: http://www.iffs-reproduction.org/ 

The American Society for Reproductive Medicine, founded in 1944, is an organization of more than 7,000 physicians, researchers, nurses, technicians and other professionals dedicated to advancing knowledge and expertise in reproductive biology.  Affiliated societies include the Society for Assisted Reproductive Technology, the Society for Male Reproduction and Urology, the Society for Reproductive Endocrinology and Infertility, the Society of Reproductive Surgeons and the Society of Reproductive Biologists and Technologists.


For more information on these press releases, contact:

J. Benjamin Younger Office of Public Affairs
409 12th Street SW, Suite 203
Washington, DC 20024-2188
Tel: (202) 863-2494/Fax: (202) 484-4039

Contact

Eleanor Nicoll
Phone: 240-274-2209
Email: enicoll@asrm-dc.org

 

GIVF's MicroSort: Technology separates the boys from the girls by Keith Blauer, M.D. and David Karabinus, Ph.D., H.C.L.D.

GIVF's MicroSort
Technology separates the boys from the girls 

by Keith Blauer, M.D. and David Karabinus, Ph.D., H.C.L.D. 

 

Many of us know someone who would desperately like to have a girl. Or a boy. Perhaps a couple has several children of one gender already and would like to have another child --- but would only consider doing so if the 50/50 odds could be shifted in favor of the other gender. Or, perhaps a couple is seeking infertility treatment, already has one child, and would prefer that the next child is the other gender. Yet another couple may want to avoid passing a gender-lined genetic disease to their child.

If a scientifically proven method of gender selection existed, these individuals might consider using it. The Genetics & IVF Institute (GIVF) started investigating gender selection technology in the early 1990s. And now the FDA has approved a clinical trial for GIVF's preconception gender selection process, called MicroSort.

When a sperm with a Y chromosome fertilizes an egg, it makes a boy. When an X chromosome bearing sperm fertilizes, it makes a girl. Any given sperm sample contains an even (50/50) amount of X (female) and Y (male) bearing sperm. MicroSort uses a machine called a flow cytometer to sort sperm such that the sorted sperm population is enriched in either X (female) or Y (male) bearing sperm. Once the sperm has been sorted, it can be used with assisted reproductive techniques to achieve a pregnancy. Since it is in a clinical trial, patients must be fully informed of the potential risks and benefits.

 

How does the technology work? 
The separation of male and female sperm is based on the measurable difference in the quantity of genetic material (DNA) they contain. The sperm absorbs a dye, which attaches temporarily to the DNA, or genetic material, inside the individual sperm. When exposed to laser light, the dye fluoresces. Since the X chromosome is larger than the Y, there is more DNA for the dye to attach to and, consequently, the sperm with the X chromosomes will fluoresce more brightly than those with Y chromosomes. The flow cytometer is able to pick up these differences in brightness and separate the sperm as they move through the machine one at a time.

Currently, MicroSort sperm sorting technology improves the chance of a female pregnancy to 89.5 percent after sorting. For a male, MicroSort has improved the chance to 73.6 percent.

 

How does a couple use the sorted sperm to become pregnant? 
The most common method uses the sorted sperm with intrauterine insemination (IUI). The woman is monitored carefully to establish the time of ovulation. Some of this monitoring can occur with her local physician and/or the use of ovulation predictor kits. Insemination is performed very close to the time of ovulation. On the day of ovulation the husband produces a sperm sample, the sperm are sorted for the desired gender, and the insemination with the sorted sperm occurs later that same day.

At the current time, couples must come to the clinic in Fairfax, VA to have their IUI procedures performed with fresh specimens. It is hoped that more U.S. locations will be available soon, making the technology more accessible.

For patients who need additional assistance achieving pregnancy, sorted sperm can be used with IVF. Sperm can be sent frozen, then sorted and returned to a local IVF center, allowing the couple to have IVF close to home. Please refer to the MicroSort website www.microsort.com for a full listing of physicians (collaborators) participating as part of the clinical trial.

MicroSort has accomplished more than 350 pregnancies. Based on the data so far, the likelihood of having a normal, healthy baby is not different from that of the general population.

 

Who qualifies for gender selection by MicroSort? 
Currently couples must be in one of two categories. A couple with a history of an X-linked disease, where the woman is a known carrier, may qualify for free treatment with MicroSort. Examples of such disorders include hemophilia and Duchenne muscular dystrophy. Other couples can choose to use MicroSort for family balancing. Family balancing couples must be married, the wife must be between ages 18 and 39, and they must have at least one child and be selecting for the less represented gender of children in their family.

 

Is MicroSort here to stay? 
MicroSort is the only scientifically verifiable method of pre-conception gender selection. It is showing positive results after more than 350 pregnancies. For couples today who are considering options for having a family, especially those with chromosome-linked concerns, MicroSort gender selection is of serious interest. As the science continues to improve and centers open in other locations, we expect that MicroSort will become a routine part of family planning.

 

PGD: The Next Step in Pregnancy Enhancement and Disease Prevention or the Search for the Holy Grail of Infertility Treatment by Carlene W. Elsner, M.D., Z. Peter Nagy, M.D., Ph.D, and Amy E. Jones, M.S.

PGD:  The Next Step in Pregnancy Enhancement and Disease Prevention or the Search for the Holy Grail of Infertility Treatment

Carlene W. Elsner, M.D., Z. Peter Nagy, M.D., Ph.D, and Amy E. Jones, M.S.

 

Preimplantion Genetic Diagnosis (PGD) makes it possible to detect genetic abnormalities in the embryo prior to embryo transfer. This technology offers huge potential for improvement in outcomes of IVF treatment, including improved pregnancy rates, reduced miscarriage rates, and avoidance of an ever expanding list of genetic abnormalities. With each passing year, more can be learned about an embryo and its ultimate development potential from a single cell.

 

BACKGROUND

Before PGD was available, chromosomal abnormalities in the conceptus could not be detected until the pregnancy was already established. Prenatal diagnosis of chromosomal abnormalities in the fetus prior to birth has been in use for many years. It is currently recommended for all pregnant women over the age of 35, because the risk of maternal age related genetic abnormalities begins to rise at this age. Fetal cells are obtained for culture either by chorionic villus sampling or amniocentesis. These procedures are typically performed in the late 1st trimester or in the early 2nd trimester of pregnancy. A relatively large number of fetal cells can be safely obtained at this time and tested to determine a full karyotype (testing of all 23 chromosome pairs) of the fetus as well as detection of single gene defects and translocations is possible. If an abnormality is detected, abortion can then be performed to terminate the pregnancy and avoid the birth of an abnormal child. However, couples who want children, find the concept of abortion emotionally difficult if not ethically impossible.

With PGD, there is the possibility to detect many, but not all, genetic abnormalities in the embryo before the pregnancy is established. This helps to avoid the need for many therapeutic abortions and reduces the risk of maternal age related miscarriage in older women. As a woman ages, the likelihood of becoming pregnant in any given cycle declines and the miscarriage rate rises. Every time a pregnancy is terminated or miscarried, the woman loses 3-6 months of precious time needed to complete her family plans. Older women cannot afford that lost time. By age 40, at least 50% of a woman’s embryos will be chromosomally abnormal (Munne et al.). With the use of PGD, abnormal embryos are eliminated from the group of embryos selected for replacement into the uterus or cryopreservation, so these pregnancies are never established. Clearly, PGD is a giant step forward in our ability to help women have healthy babies.

PGD can also be used to detect many genetic diseases that are a result of single gene defects occurring in some families. In these families, the risk of having an abnormal child is not related to maternal age, but to which genes are inherited from the mother and father. Usually, in these cases, both parents have one normal gene and one abnormal recessive gene. Each parent is healthy. For the disease to occur, the child must inherit the abnormal gene from both parents. PGD can detect which embryos have the disease (two abnormal genes), which are normal (two normal genes), and which are carriers (one normal and one abnormal gene) like the parents. This information can be used in the selection of which embryos to replace in the mother’s uterus and which are appropriate for cryopreservation. PGD offers the potential of eliminating these diseases altogether.

In addition to women with known genetic diseases in the family and older women at risk for maternal age related genetic abnormalities, there are two other groups who may benefit from PGD. Seventy percent of embryos may be abnormal in women under 35 who have a history of repeated unexplained miscarriage (Simon et al.). A similar percentage of abnormal embryos (70% has also been reported in a group of women with multiple failed IVF cycles (Pehlivan et al.). PGD should be discussed with both of these groups of women before additional IVF treatments are performed, so that the best embryos can be selected for transfer.

 

TECHNIQUES OF BIOPSY

The development of microtechnology that makes it possible to test for chromosomes or single genes in a single cell has made PGD a reality. Testing can be performed either on the 1st and 2nd polar bodies of the egg or on a single cell extracted from the embryo at the 6-8 cell stage (day 3 of embryonic life) or on the embryo at the blastocyst stage (day 5 of embryonic life).

Polar body biopsy involves the analysis of genetic material extruded from the egg during meiosis. The 1stpolar body is formed with maturation of the egg, and the 2nd is formed during the process of fertilization. Both of these structures contain chromosomes that have been excluded from the embryo during its formation and, therefore, may be analyzed without risking damage to the embryo itself. Then, the chromosomal makeup of the egg may be determined by inference.

Embryo biopsy involves the removal of a single cell from an embryo after fertilization at the 6-8 cell stage of development, just after compaction (the process by which the cells of the embryo attach to one another) has occurred. Biopsy can be done at this time without damage to the embryo because one single cell can be removed through a small opening created in the zona pellucida without fear that the rest of the embryo might escape through the opening. Analysis of this cell can then give information on not only the maternal, but also the paternal genetic contribution to the embryo. Blastocyst biopsy is a possible alternative to day 3 embryo biopsy. It is not used very widely because it is technically more challenging and also because it may not always provide an interpretable result. Both polar body biopsy and embryo biopsy are in current usage.

 

TECHNIQUES OF ANALYSIS

Two techniques are available to test the genetic material (DNA) obtained in the biopsy. They cannot both be done on the same sample obtained from a single cell, so a choice must be made. Fluorescent in situ hybridization (FISH) is used to test for an abnormal number of chromosomes within the embryonic cell. Polymerase chain reaction (PCR) technology can detect an abnormality within a single gene on a chromosome pair, but PCR does not test for extra or absent chromosomes as does FISH. Some diseases are caused by aneuploidy (extra or absent chromosomes) and others are caused by single gene defects.

 A normal human cell contains 23 chromosome pairs. Fluorescent in situ hybridization (FISH) is used to test for aneuploidy. It involves attaching color coded fluorescent tags to chromosome pairs from a single cell removed from an embryo and fixed on a slide. When examined microscopically, two fluorescent signals indicate the normal diploid state. Three signals indicate trisomy, and one signal, monosomy for the particular chromosome studied. Currently, in our laboratory, testing is available for 9 chromosomes, X, Y, 13, 15, 16, 17, 18, 21, and 22. This technology detects Down’s syndrome (trisomy 21), Turner’s syndrome (45XO), Klinefelter’s syndrome (47XXY), and a myriad of other abnormalities involving extra or absent chromosomes.

When the abnormality to be detected is limited to a single abnormal gene on a single chromosomal pair, polymerase chain reaction (PCR) technology is used to amplify segments of DNA to make possible the detection of defects using the minute amount of DNA in a single cell. Some of these abnormal genes contain extra copies of a 3 base sequence (triplet repeat) that make them bigger than the normal gene, i.e. Fragile X. The number of these repeated sequences is variable, so each abnormality is unique. Other abnormal genes may have a portion of the gene deleted, i.e. cystic fibrosis. Therefore each test must be tailored to fit the couple and the exact abnormality to be detected. The test sample DNA from the embryo is then run along with DNA from each parent to detect the presence or absence of the defective gene. This technology is used for the detection of

normal, carrier, and affected embryos for diseases like Tay Sach’s disease, cystic fibrosis, Duchenne’s muscular dystrophy, Fragile X and an ever expanding list of diseases caused by single gene defects. Genetic matching (HLA typing) can be combined with PCR in families with children with Fanconi’s anemia to detect embryos that are both normal and an HLA match for the affected child so, after the birth of the normal child, stem cells from the normal child can be used to save the life of the sick child.

In both of these techniques, embryos are biopsied on day 3. The cell removed is then tested. Testing can be very time consuming and may require up to two days to complete. Normal embryos are replaced in the woman’s uterus on the afternoon of day 4 or the morning of day 5. If a pregnancy is established, chorionic villus sampling or amniocentesis is still recommended because it is not possible to detect all chromosomal abnormalities with current technology.

 

THE FUTURE

Microarray technology currently under development offers the opportunity to test for all 23 chromosome pairs at once. Additionally, it provides the possibility to screen the complete genetic information of the embryo, facilitating the prevention of genetically inheritable diseases. This exciting new technology is not yet sensitive enough for use with the minute amounts of DNA in a single cell, but research continues in this area. When microarray technology can be adapted for use in single cells, it may represent the next major breakthrough in PGD.

 

Carlene W. Elsner, M.D. is a reproductive endocrinologist at Reproductive Biology  Associates in Atlanta Georgia.
Phone: 404-843-3064 or Toll Free 1-888-RBA-4IVF

Email: rba-online@rba-online.com

Website: http://www.rba-online.com

 

Z. Peter Nagy, M.D., Ph.D. is the scientific and laboratory director and Amy E. Jones M.S. is the laboratory supervisor at Reproductive Biology Associates.

 

REFERENCES

Munne, S., Alikani, M., Tomkin, G., Grifo, J., and Cohen, J.. Embryo morphology, developmental rates, and maternal age are correlated with chromosomal abnormalities. Fertil. Steril. 64[2], 382-391. 1995.

 

Pehlivan, T., Rubio, C., Rodrigo, L., Romero, J., Remohi, J., Simon, C., and Pellicier, A..Impact of preimplantion genetic diagnosis on IVF outcome in implantation failure patients. Reprod. Bio. Online. 6[2], 232-237. 2003.

 

Rubio, C., Simon, C., Vidal, F., Rodrigo, L., Pehlivan T., Remohi, J., and Pellicer, A.. Chromosomal abnormalities and embryo development in recurrent miscarriage couples.

Hum. Reprod. 18[1], 182-188. 2003.    

 

Infertility and Multiple Pregnancy: Can you have too much of a good thing? by Serena Chen, M.D.

Infertility and Multiple Pregnancy: 
Can you have too much of a good thing? 
by Serena Chen, M.D.

In general, the best way to reduce multiple births is to transfer only single embryos. In order to do that without dramatically lowering the overall pregnancy rate, implantation rates need to be increased. Implantation rate is the potential of a single embryo to result in a pregnancy and is calculated by taking the total number of gestational sacs divided by the total number of embryos replaced. Implantation rate is always lower than the pregnancy rate because the vast majority of IVF procedures involve the transfer of more than one embryo. The higher the implantation rate, the lower the number of embryos needed to achieve pregnancy, and the lower the multiple birth rate.

Improvements in various techniques used in the laboratory have led to gradually improving pregnancy rates across the country. Improved techniques of embryo culture, assisted hatching and fragment removal are being used more widely. As embryologists gain experience, implantation rates have improved. Again, improvements in implantation rates will ultimately allow physicians to replace fewer and fewer embryos, maintain or improve the overall pregnancy rate and someday, eliminate the risk of high order multiple pregnancy.

 

EMBRYO FREEZING
Cryopreservation or freezing of embryos is another technique that can be used to reduce multiple births. Cryopreservation is widely available and can help decrease the pressure to transfer large numbers of embryos by allowing a couple to freeze extra embryos for use at a later date. The disadvantages of cryopreservation are that some embryos will not survive the freeze-thaw process and previously frozen embryos may have less pregnancy potential than "fresh" embryos. However, there does not appear to be any increase in the rate of birth defects or miscarriages in pregnancies conceived using frozen-thawed embryos. As this technology continues to improve, with better freeze-thaw survival rates and better pregnancy rates, it will become a more powerful tool to help reduce multiple births.

 

PREIMPLANTATION GENETIC DIAGNOSIS (PGD)
Preimplantation genetic diagnosis (PGD), or the genetic analysis of embryos prior to transfer into the body is an exciting new technology that could help reduce multiple births. PGD can be used to look for chromosomal aneuploidy (abnormal numbers of chromosomes) in the embryo. This condition can lead to infertility, miscarriages and birth defects (an extra chromosome 21 causes Down's Syndrome). As a woman gets older, the chance that her embryos are chromosomally abnormal increases dramatically. In older women, the ability of the embryologist to select the embryos most likely to result in a pregnancy decreases markedly. This occurs because a higher proportion of the embryos are chromosomally abnormal and because most chromosomal abnormalities do not cause any changes in the embryos appearance. So a very high quality embryo can be very abnormal genetically. Because of the higher rate of chromosomal abnormalites, the implantation rate of the embryos decreases. By using PGD to select the chromosomally normal embryos, the implantation rate of the embryos that are selected is increased. The higher the implantation rate, the lower the number of embryos needed to achieve pregnancy and the lower the multiple birth rate. At this time, PGD can analyze only a limited number of chromosomes and only a few centers worldwide have significant experience in this technique. However, studies performed at Saint Barnabas have already demonstrated that PGD can improve pregnancy rates in women over 35, and dramatically lower the miscarriage rates. Ultimately, as the technique improves, PGD may allow us to offer all patients a single embryo transfer, eliminating the multiple pregnancy problem without sacrificing a high pregnancy rate.

 

CONCLUSION
Despite what many infertile couples think, it is possible to have too much of a good thing. Multiple pregnancies involve reward and risk. High order multiple pregnancy can result in serious complications for both the mother and the babies. There are various techniques available to try and minimize these risks. Couples should discuss these techniques with their doctor to decide how or whether to use them in their individual treatment plan.

 

Serena Chen, M.D. is Director, Division of Reproductive Endocrine Department of Obstetrics and Gynecology Saint Barnabas Medical Center and the Director, Ovum Donation Institute for Reproductive Medicine and Science at Saint Barnabas East Wing Suite 403 94 Old Short Hills Road, Livingston, NJ 07039
Tel 973 322 8286. Email Dr. Chen

 

Pregnancy and Multiple Gestation Rates after Transfer of Two Versus Three Blastocysts

Article Title: "Two-blastocyst transfer has similar pregnancy rates and a decreased multiple gestation rate compared with three-blastocyst transfer"

Authors and Affiliations: Amin A. Milki, Jeffrey D. Fisch, and Barry Behr, Department of Gynecology and Obstetrics, Stanford University School of Medicine.

 

Summarized by Christine M. Schroeder, Ph.D.

In IVF, transfer of more embryos is often associated with a higher chance of pregnancy. However, transferring more embryos also confers an elevated risk of multiple pregnancy. Blastocyst transfer may provide at least a partial solution to this dilemma, because blastocysts have higher implantation rates than day 3 embryos. Because of the higher implantation rates, not as many blastocysts have to be transferred back to the uterus in order to achieve satisfactory pregnancy rates.

The authors of the current study began offering fresh blastocyst transfer routinely to patients who are at risk for multiple gestations in January 1998. All patients were advised to transfer only two blastocysts; however, patients willing to undergo selective reduction were allowed to transfer up to three blastocysts. Despite this fairly conservative policy, the clinic noticed that the proportion of multiple pregnancies at their clinic increased. Due to the fact that there was little information on the issue of multiple pregnancy and the number of blastocysts transferred, the authors decided to compare the two and three day blastocyst transfers.

The study was retrospective, which means that the researchers went back and reviewed the cases of women who had undergone two- and three-blastocyst transfers; in other words, patients were not randomly assigned to type of transfer. Twenty-nine patients had two blastocysts transferred (the 2B group) and 24 had three transferred (the 3B group). Despite the fact that they had not been randomly assigned to treatment, the 2B and 3B groups were similar in age (35.1 years average), the number of previous IVF cycles, the number of oocytes retrieved, the number of embryos on day 3, and the number of blastocysts that ultimately developed. Patients with embryos fertilized conventionally and via ICSI were both included in the study.

Analysis of the results indicated that:

  • The 2B and 3B groups both had implantation rates of 47 percent.
  • Pregnancy was defined as two positive rising hCG tests taken two days apart. The pregnancy rate in the 2B group was 73 percent and in the 3B group, it was 76 percent.
  • Viable pregnancy was defined as visualized fetal cardiac activity at seven and nine weeks gestation. The viable pregnancy rate in the 2B group was 58 percent, and the viable pregnancy rate in the 3B group was 62 percent.
  • The twin pregnancy rate in the 2B group was 39 percent, and the twin pregnancy rate in the 3B group was 50 percent
  • The triplet pregnancy rate in the 2B group was zero percent, and the triplet pregnancy rate in the 3B group was 29 percent

 

Thus, over three fourths of the pregnancies in the 3B group - 79 percent - were multiple gestations, compared to 39 percent in the 2B group. Additionally, none of the multiple gestations in the 2B group were triplet gestations, whereas 36 percent of the 3B group pregnancies were triplet gestations.

Thus, two blastocyst transfers sharply reduce the risk of multiple gestation, with no compromise in overall pregnancy rate. Based on these results, the researchers strongly recommend that patients be encouraged to transfer only two blastocysts.

 

Historical Implications for Today’s Embryo Transfer: Day 3 Vs. Day 5 by G. John Garrisi, Ph.D.

A discussion of the optimal day for embryo transfer is, in its essence, a discussion of the IVF laboratory environment, and the ability of human embryos to respond in a "normal" way to the artificially created embryo culture system. The option to transfer embryos from the laboratory back to the patient beyond the third day of development has been relatively recently developed; it is an effective option only where there is impeccable control of laboratory culture conditions. The advent of Day 5 embryo transfer has added a new element to the available treatment options for infertile couples.

The following basic description of preimplantation embryo development will support the ensuing discussion of the timing of embryo transfer. Oocytes (eggs) and sperm are united on Day 0 in the IVF laboratory. On Day 1, normally fertilized 1–cell embryos, called zygotes, are observed. On Day 2, embryos are typically seen at the 2 – 5 cell stage (depending in part on the timing of observation). On Day 3, normally developing embryos may have from 4 to 10 cells; 6-8 cell stages are most common. The cells of the embryo (called blastomeres) continue to divide, and on Day 4 the embryo is called a morula; at this stage, the cell number may be difficult to determine because of continued division and a developmental process called compaction. By Day 5, many embryos will reach the blastocyst stage, characterized by an expanded, fluid-filled cavity and a localized group of specialized cells called the inner cell mass. In some cases, normal embryos will not reach the blastocyst stage until Day 6 of culture.

Historical aspects of embryo culture and transfer provide an interesting framework for a discussion of the relative benefits of embryo transfer on Day 3 or Day 5.

 

Historical Considerations

The determination of the optimal day for embryo transfer after in vitro fertilization has been a critical consideration for more than two decades. In the 1980’s, the decision-making process involved balancing two components: 1) the capability of the laboratory to provide an adequate environment for embryo development and 2) the increased amount of information that was available when the embryos were allowed to develop in the laboratory for a longer period. The increased information available with extended culture times allowed the selection of higher quality embryos for transfer, as well as facilitating the development of future patient-specific treatment plans. While these considerations are as important today as ever, we now have an additional interest in identifying the embryos that are most likely to implant as we attempt to minimize multiple pregnancies by reducing the number of embryos transferred.

 

1980’s

In the earliest IVF procedures, it was most common to transfer embryos on Day 2. When more embryos were available than could be safely transferred, the embryos were, in many cases, selected simply on the basis of cell number: 4-celled embryos were selected before 2 or 3-celled embryos. In many labs, the embryos were not examined with high power microscopes; consequently, it was impossible to identify sub-cellular features that may have assisted the embryo selection process.

During those early years, it was not uncommon for an IVF program that was experiencing difficulty to transfer embryos on Day 1, immediately after the determination of normal fertilization. We learned quite early on that the uterine environment, while not the natural location of early embryo stages (human embryos develop in the Fallopian tube until Day 6 or 7) is conducive to embryo development. The idea in these cases was to move the embryos out of the suboptimal laboratory environment as soon as possible. This concept spawned the development of a new procedure – gamete intra-fallopian transfer (GIFT). During this procedure, eggs and sperm were surgically transferred to the Fallopian tube, ostensibly to take advantage of the tubal micro-environment that would be natural for the gametes and resulting embryos. In retrospect, it is much more likely that this procedure was effective because it avoided the necessity of culturing embryos in the sub-optimal laboratory conditions of the day. Indeed, while many IVF labs today bear little resemblance to those of the early and mid-80’s, the principle that early embryo transfer may be beneficial to some patients with a history of very poor embryo development conditions still holds.

The first successful blastocyst culture system was developed by Jacques Cohen and his colleagues at Bourn Hall, England, in 1985. Although pregnancy rates after blastocyst culture were higher than after transfer of cleavage-stage embryos, the demands of this type of embryo culture system made it difficult for other laboratories to adopt blastocyst culture and Day 5 transfer at that time. In the late 80’s and early 90’s, though, Dr. Cohen’s group (then at Cornell Medical Center) pioneered the practice of transferring embryos on Day 3. While it stretched the limits of the prevailing culture procedures, Cohen showed that careful attention to quality control parameters allowed the development of healthy Day 3 embryos in vitro. The ability to observe embryos on Day 3, coupled with the recognition of morphologic features of Day 3 embryos visible at high microscopic power, allowed the Cohen group to identify embryos with increased implantation potential. To a large extent, it was Day 3 culture, coupled with other developments such as assisted hatching, which resulted in the quantum increase in the pregnancy rates that became achievable with IVF in the early 90’s, first demonstrated by the Cohen lab and soon thereafter in other leading IVF centers.

 

1990’s

As implantation rates improved, so did multiple implantations. Consequently, several of the leading IVF centers began to reduce the numbers of embryos that were transferred, in order to decrease multiple gestations and the attendant risks and complications. The trick was to decrease the number of embryos transferred without decreasing the overall pregnancy rate. Two general approaches were taken to achieve this goal, sometimes concurrently. In the first, embryos were cultured beyond Day 3, in order to obtain even more information about the fitness of each. The second approach was to make demonstrable correlations between discrete microscopic features of embryos at different stages of development and subsequent implantation and pregnancy. The successful aspects of both of these approaches are applied today in many IVF centers.

Through the mid- to late-90’s, a number of groups attempted media and culture changes that would make culture to the blastocyst stage feasible. Chief among the laboratory scientists to develop new media to better support human embryo development in vitro was Dr. David Gardner, who, with Dr. Bill Schoolcraft, developed and applied a system of sequential culture media for blastocyst culture. Several of the principles developed by Dr. Gardener and others have now been embodied in a new generation of culture media. These media formulations have made it possible for a reasonably high percentage of embryos to develop to the blastocyst stage in vitro.

Other studies have focused on key features of cleavage stage embryos that indicate high implantation potential. Several groups identified and confirmed the importance of features such as normal pronuclear appearance the zygote stage, ideal cleavage rates, the importance of single nuclei in blastomeres, and the impact of cell fragmentation. The assessment of these indicators and many others have led in recent years to further increases pregnancy rates, and, as a separate benefit, facilitated wider applications of assisted reproductive technologies to patients that were heretofore not very good candidates for IVF treatment. Further, as the ability of embryologists to identify healthy embryos improved, it became increasingly possible, indeed for many practitioners necessary, to utilize this capability to make reductions in the number of transferred embryos. In fact, a review of the CDC reports of IVF outcomes for many of the leading IVF centers shows a yearly decline in average number of embryos transferred to patients in each age group.

 

2000’s

So, with this background, how do we use our accumulated knowledge to optimize pregnancy rates? There are now many studies that have documented impressively high pregnancy rates for patients that have Day 5 embryo transfers – in many cases, the increased pregnancy rates have been achieved along with a reduction in multiple pregnancy rates. Some IVF programs have responded by adopting the new blastocyst culture techniques in total, and offer Day 5 transfer to most, if not all, of their patients. Certainly, the transition to this type of protocol must have improved outcomes in these IVF programs, or the new procedures would have been abandoned. High pregnancy rates, with reduced multiple pregnancy rates, are achievable with blastocyst transfer on Day 5.

However, despite the success of blastocyst culture protocols, there are several reasons to avoid blastocyst culture. The applicability of blastocyst culture, like most of the rest of the assisted reproductive technologies, turns out to be highly dependant on individual patient and embryo factors. Drs. Gardner and Schoolcraft, among others, have amply demonstrated that blastocyst culture is advantageous for aselected group of patients. Conversely, a number of well-controlled studies have now been performed, at IRMS and elsewhere, that have shown that application of blastocyst culture to randomly chosen patients does not increase pregnancy rates. These two sets of data, taken together, have led to the conclusion that while blastocyst culture may benefit some patients, there is a large subset of IVF patients that would be better served with embryo transfer at the Day 3 stage.

 

Day 3 vs. Day 5: Current Considerations

The key consideration in defining the applicability of blastocyst culture is the understanding that today’s improved culture conditions still do not perfectly mimic the natural environment of gametes and preimplantation embryos. That is, IVF laboratory culture conditions do not provide all of the growth and development factors that exist in the Fallopian tube. The circumstances that made GIFT a good alterative to IVF 20 years ago still exist today – just to a lesser extent. Embryos will even develop better in the uterine environment (one step removed from the Fallopian tube) than in our most advanced, well controlled culture system. As a result, the natural attrition that is characteristic of human preimplantation embryo development is increased when the embryos are developing in vitro. A small percentage of embryos that arrest between Day 1 and Day 2in vitro would have continued to develop had they been transferred to the uterus on Day 1. As preimplantation development proceeds, it is likely that a greater percentage of embryos arrests at each succeeding developmental stage. With time, the embryo becomes a more complex organism; as it increases in complexity, it places ever greater demands on the culture system.

So, why don’t we replace all embryos on Day 1? For almost all patients, the benefits of selecting embryos based on morphologic indicators on Day 3 far outweigh the risk of embryo arrest (although it could be argued that some patients with only 1 or 2 embryos on Day 1 would benefit from an immediate transfer). In many IVF centers, more than 90% of embryos continue to develop in vitro until Day 3. So, embryo transfer on Day 3 allows selection based on a host of criteria, while minimizing the risk of compromising embryo quality.

These considerations differ beyond Day 3, however - most programs report blastocyst development rates in the neighborhood of 50%, so there is considerable embryo loss between Day 3 and Day 5. There is a subgroup of Day 5 embryo transfer patients that either fail to have an embryo transfer because of embryo arrest between Day 3 and Day 5, or have a less-than-ideal transfer of morulae or suboptimal blastocysts. Some practioners explain this phenomenon by asserting that the embryos that arrest in vitro between Day 3 and Day 5 were destined to have arrested in the uterus had they been transferred. There is no data to support this assertion. There is indirect data, however, collected at IRMS and elsewhere, that shows convincingly that a portion of embryos that arrest in vitroafter Day 3 would not have arrested had they been transferred on Day 3. Specific classes of embryos that develop to normal blastocysts at a very low rate when held in vitro were studied. When embryos of these classes were transferred on Day 3, the proportion that implanted and contributed to term pregnancies was greater than the percentage that developed to blastocyst in the group that was held in vitro until Day 5.

Blastocyst culture is then, to some extent, a survival test. The embryos are challenged by the conditions present in the blastocyst culture system, and the fittest are able to continue development and become normal blastocysts. In the process, some embryos with implantation potential are lost. An additional consequence of culturing all embryos to the blastocyst stage, and accepting the attendant embryo loss, is that significantly fewer embryos are available for cryopreservation.

 

Finding Your Assisted Reproduction Program by Diane Michelsen, J.D., M.S.W.

Finding Your Assisted Reproductive Program

Diane Michelsen, J.D., M.S.W.

(From INCIID Insights Newsletter - Published April 2005)

 

The idea that it takes a village to raise a child has now been supplemented with the concept that with assisted reproduction, it takes a village to create a child.  And when you learn that you need to add a third person (donor or a surrogate), it sometimes feels as if the village has now become a small city.  So how do you negotiate the maze of “streets” the city presents?  The purpose of this article is to offer you a map so you can find that special donor or gestational carrier.

 

Most people turn to preexisting programs rather finding an individual, and performing the  screening, legal work and coordination functions themselves.  The consequences of mistakes in assisted reproduction are very serious. You need to be certain that each party’s rights, obligations and expectations are clearly laid out and important legal issues such as behavioral restrictions, future contact, identity and confidentiality, medical expenses and liability for complications, monies and taxation of monies, and parental rights are addressed.  A reputable program and knowledgeable attorney1 will make it very clear who the parents of this child will be, and who is responsible for what. 

 

Just as not all attorneys are knowledgeable in this area, NOT all assisted reproductive programs are reputable. Anyone can open an agency; there is currently no requirement of education, experience, insurance, bonding, or licensing.  So sometimes people open an agency because they see this as an interesting opportunity or because they have participated in an assisted reproduction arrangement; other times the program’s founder has a genuine long-term interest and participation in the field. Many, many assisted reproduction programs advertise they will assist you in finding surrogates, gestational carriers and donors and will orchestrate the entire process.  However, it is important to know that there are no set standards for operators of  assisted reproduction programs; additionally, there is no licensing or oversight agency.  So you need to be certain that the program you choose will not abscond with your funds and have the backing to be able to complete their duties.

 

We recommend you ask your reproductive endocrinologist for referrals, do contact Resolve or a similar group knowledgeable about assisted reproduction to see if they have consumer feedback to share.  Naturally, check internet resources (Surrogacy.com, OPTS.com.) 

 

To assist you in comparing resources, whether referrals or internet or phonebook, the following questions will be helpful.

 

1.  Philosophy:  What is the program’s philosophy about assisted reproduction?  Do the program's attitudes match yours, and/or is the program willing to adjust to your desires and needs?  Does the program have strong beliefs about anonymity or disclosure of identities?  What about future access for sharing of medical information or contact for the child?  How will this play out in the future for you? 

 

2.  Expertise:  What is the program/program director’s familiarity with assisted reproduction, from both a people base and a legal base?  Is the program director experienced, knowledgeable and competent?  Are there references for the program or the director?   How long has the program been in operation? What are the program statistics?  How many assisted reproduction matters does the program work with each year?  How many reproduction matters have been initiated?  How many have been successful? Has the program or program director ever been sued?  If so, for what and what was the outcome?  Does the program/program director have anything to lose if they breach their fee agreement or provide a less than adequate standard of care?  Does anyone have any licenses on the line?

 

3. Fee Agreements: Who is the client of the program? The duty or service the agency is going to provide to whom should be clearly spelled out in your initial fee agreement so you really know what you are going to be paying for. 

 

4.  Contracts:  Does the program draft the agreements/contracts between you and the donor or carrier?  Are these custom contracts or the agency’s prewritten standard contract?  Is there any room for negotiation?  Are there measurable time frames for when duties will be performed?  If the program/attorney does not represent only you, then does separate outside counsel review the contracts on your behalf and on the behalf of the donor/carrier and if so, who pays these costs?

 

5.  Adjudication of Parentage:  Does the program provide for a judicial determination of parentage of the child?  Is there a determination as to when and where  the action will be brought?  Are the attorney fees and court costs covered or are they additional? 

 

6.  Money Issues:  What services are provided and for what services do you need to hire someone else? What is the total cost, including necessary outside services,  for the outcome you wish?  Does the program accept credit cards?  Under what circumstances is a refund or partial refund granted?  Does the program handle an escrow/trust account for the donor or surrogate or gestational carrier? Are the funds insured?  What happens to this money if there is a disagreement as to whether funds should be released?

 

7.  Accessibility:  Does the program return phone calls or emails, and if so, when?  Does the office keep you up-to-date and involved in your case?  Are copies of relevant correspondence or documents regularly sent to you? When your program coordinator is away from the office, is another knowledgeable coordinator on hand to answer your specific questions and concerns?

 

8.  Physical Plant/ Personalities:  Is there a real brick and mortar office or just a mail drop or kitchen table or email address?  It is important to find a program which will still be in business or which at least can be physically found if there is a difficulty.  And the last question, are the personnel of the agency pleasant people who help you to feel at ease?  Your relationship may well extend over a year’s time, before, during and after the pregnancy.  It should be clear that the program will provide you with competent, thoughtful and caring service, and that the personnel are committed to working diligently on your behalf.

 

Diane Michelsen, J.D., M.S.W. is an INCIID professional member.

Watch the interview about adoption & surrogacy with Diane here

Contact:

Diane Michelsen JD, MSW 
Law Offices of Dianne Michelsen

Phone: (925) 945-1880
Fax: (925) 933-6807

Email Michelsen

http://www.FamilyFormation.com 
 


1 An attorney who has drafted and reviewed at least 12 donor contracts and at least six gestational carrier contracts and/or is a member of the American Academy of Adoption Attorneys Assisted Reproduction Section.

 

Achieving a Successful Outcome Through Intrauterine Insemination and Ovulation Induction by Scott M. Slayden,MD, Joe B. Massey, MD

Achieving a Successful Outcome
Through Intrauterine Insemination and 
Ovulation Induction 
by Scott M. Slayden,MD
Joe B. Massey, MD

Last Updated: March 14, 2006
Page: 1 

 

Drs. Slayden and Massey are physicians 
Reproductive Biology Associates
Atlanta, Georgia

 

June 9, 2005 - The United States Census Bureau has released our country's latest census results indicating a total U.S. population of nearly 300 million. This statistic suggests that exceptional fertility is an inherent trait of the human species - this is far from the truth. With peak normal pregnancy rates of only 15 - 25% per month between the ages of 18 -35, it is no wonder that, as a species, we are particularly devastated by conditions leading to subfertility. In fact, it is not at all unusual for an otherwise healthy but subfertile couple to experience a pregnancy rate less than 5% per month. Oftentimes, we are left with unanswered questions and frustration when an infertility investigation in such couples uncovers no particular abnormality - ie: open tubes (normal HSG), normal natural ovulation each month, and a normal semen analysis. Although a subsequent laparoscopy may uncover stage I-II endometriosis or a repeat semen analysis may reveal mild abnormalities, it still seems that patients experiencing such subtle problems are the ones who "should have been pregnant".  If this situation sounds familiar, please read further to understand how the use of intrauterine insemination (IUI) and ancillary technologies such as ovulation induction (OI), PAF sperm treatment and more can raise pregnancy rates back to baseline levels and beyond.

 

NATURAL EVENTS

Natural conception results when adequate numbers of normal motile sperm are deposited in the vagina and become activated (capacitated) while traversing through normal cervical mucus. Of the 100 - 200 million sperm found in a typical ejaculate, 50% are motile and only 0.1% ever reach the end of the tubes where fertilization of a single egg occurs. When these and other hurdles are taken into consideration (sperm count, cervical mucus interactions, sperm attrition, and timing) it is no small miracle that successful union of sperm and egg occurs at all.

 IUI is a technique that addresses the inefficiency associated with many of these natural hurdles by increasing the probability that appropriate numbers of sperm will be present around an egg (or eggs) at the appropriate time. Ovulation induction (OI) involves the use of fertility drugs to increase the number of eggs to serve as targets for sperm during an IUI procedure. Generally speaking, OI techniques can increase monthly egg production and correct undiagnosed ovulation defects but may not correct poor egg quality. Nonetheless, success or failure of OI often relies on the random chance that some of the additional eggs produced per cycle are of better quality than the single egg generated in a natural cycle. The following sections will review the three basic situations where OI- IUI may provide benefits to infertility patients:

I.  Male factor infertility 
II. Unexplained infertility
III. Endometriosis.

 

I.      Male Factor Infertility - it takes more than one 

Within each sperm head, a small enzyme filled area called the acrosome awaits the call to action. The acrosome is filled with enzymes that degrade the cells (cumulus) and membrane (zona pellucida) around an egg so that fertilization can occur. A single sperm provides a negligible amount of enzymatic activity to have any impact on the fertilization process. In actuality, it takes many thousands to millions of activated healthy sperm to "dissolve" a pathway to the inner egg membrane so that a single sperm can penetrate and fertilize the egg. So, an important concept to understand relates to the total number of motile sperm (TMI) available to interact with the egg. This number is a product of the semen volume (mL), sperm count per mL, and the percent of sperm moving (motility).

 

Normal sperm shapes (morphology) are also very important although they are not part of the calculated final TMI. Abnormalities of any one of these parameters may or may not drop the total number of available sperm below a threshold level where conception rates will suffer. A second important concept to be aware of relates to sperm function - or lack thereof. As will be discussed below, diminished sperm function may be partly to blame for the low pregnancy rates seen in male factor couples despite seeing enhanced numbers of motile sperm through IUI techniques.

 

Preparation of semen for IUI will enrich the final sample with the most motile sperm. Thus, the endpoint of an IUI prepared semen sample is the total motile inseminating count (TMI). For male factor infertility patients undergoing IUI, a TMI   2-5 million is preferred. Unfortunately, a maximum pregnancy rate of only 10% per attempt (cycle) is seen even if a good TMI is generated. Thus, couples experiencing male factor infertility need to be prepared to undergo 3-4 IUI cycles before and consider moving on to IVF if they desire a better pregnancy rate. Alternatively, immediate progression to IVF (without preceding IUI) should be considered when a very low TMI is encountered (< 1 million/ml) or significant male factor infertility coexists with either female age >35 year range or female pelvic pathology such as endometriosis. (1)

 

Considering the disappointment and cost associated with multiple unsuccessful IUI cycles, we are constantly searching for new ways to predict which male factor infertility patients will conceive with IUI versus IVF. Evaluation of sperm function is one method of evaluation. Traditionally, sperm function tests have served this purpose, with the hamster egg sperm penetration analysis (SPA) being the most popular. However, the SPA is expensive and may fail to predict outcome. Thus, we are currently evaluating the hyaluron binding assay (HBA) - a new, less expensive sperm function test. (2) We are hopeful that the HBA may predict outcomes more effectively than the SPA and subsequently allow us to better individualize therapy. However, it remains to be seen whether patients with abnormal HBA results should seriously consider pursuing IVF with ICSI instead of spending their resources on 3-4 months of IUI therapy.  

 

IUI PROTOCOLS & TECHNIQUES ENHANCE OUTCOME

Timing of IUI in relationship to ovulation appears to be critical - conception will not occur if exposure to sperm occurs >24 hours after ovulation. (3) However, there is controversy regarding the need for absolutely precise IUI timing as long as the procedure is performed within this time constraint. Nonetheless, many clinics utilize ultrasound follicular monitoring combined with urinary LH surge testing to predict the appropriate timing of the IUI procedure. Detection of a natural LH surge should be noted when follicles have reached their maximal diameter of 18-24 mm. Sometimes, a natural LH surge fails to occur, particularly when gonadotropin (FSH) injections are given to stimulate ovulation.

 

In these cases, a single hCG injection is given as a substitute for the natural LH surge when follicles have reached a mature size. Otherwise, ovulation will usually occur 12-24 hours after a natural LH surge is detected in urine or 38-44 hours after a single hCG injection. Thus, an IUI is usually scheduled the morning after an LH surge or approximately 36 hours after a patient self-administered evening hCG injection.

 

Preparation of a semen sample with Platelet Activating Factor (PAF) for IUI takes approximately 2 hours. Our standard technique washes sperm from seminal fluid using several centrifugation steps. The washed sperm are then incubated with platelet activating factor (PAF) for 15 minutes to enhance motility. In our non-male factor patient population, we demonstrated that PAF incubation increased pregnancy rates to 30% per cycle versus 18% per cycle in non-PAF treated samples. (4) 

 

Our continued observations of a subgroup of IUI patients receiving follitropin-beta OI (FSH injections administered by a pen device) has demonstrated a surprisingly high pregnancy rates of 48% per cycle. (5) This data is particularly exciting when it is compared to and found to exceed the national IVF pregnancy rate of 42.5% noted by the CDC in 2002. (6) Unfortunately, IUI pregnancy rates for male-factor patients were not improved with the PAF wash, with pregnancy rates hovering around 10% per cycle. Nonetheless, we are hopeful that our continued research on PAF treatment will demonstrate benefits for male factor patients too.

 

Dual IUI's - Traditionally, patients undergo a single IUI per cycle. However, some studies have shown improved pregnancy rates when dual IUI's are used. (7,8,9) Thus, for the past several years, we have encouraged this technique for patients with normal semen parameters (non-male factor patients). In this technique, ovulation is triggered with a nighttime hCG shot and the first IUI is performed the next day and the second, more important IUI is performed the following day approximately 36 hours after hCG administration. Some patients will choose to undergo a single IUI per cycle as a cost savings measure. In these cases, a single IUI is performed approximately 36 hours after a nighttime hCG shot or 12-24 hours after a positive urinary LH surge is detected. 
 
Ovulation Induction - Based on the majority of available medical evidence, we strongly encourage treating the wife with fertility drugs (ovulation induction) so that more eggs are available during the IUI process. Pregnancy rates are clearly enhanced by this combination when compared to IUI in natural (unstimulated) cycles. (10) For some patient categories, use of FSH injections (gonadotropins) will result in higher pregnancy rates than use of clomid. Again, ultrasound monitoring should be used to determine that an appropriate number of mature follicles are produced (2-4 generally) and to enhance timing of the IUI procedure - usually with an hCG injection.

 

It is a basic premise of OI-IUI cycles that some risk of multiple pregnancy must be taken in order to achieve a reasonable per cycle pregnancy rate. This risk is a direct result of the extra eggs produced - the more produced, the greater the pregnancy rate and the greater the risk of triplets and above. Ultrasound monitoring further allows us to counsel our patients about their multiple pregnancy risks based on the number of follicles counted. However, all methods of predicting multiple pregnancy are inherently imprecise. Patients need to maintain awareness of this situation and realize that IVF with controlled limited embryo transfer continues to be the most effective method of generating high pregnancy rates while greatly minimizing the risk of triplets or more. 

 

II. UNEXPLAINED INFERTILITY: 
Using OI-IUI to Enhance Pregnancy Rates in Ovulatory Women with Open Tubes

Unexplained infertility is a relatively common diagnosis that occurs when the basic infertility investigation fails to uncover any problems. This situation is found primarily among infertile women with regular, ovulatory menstrual cycles. By definition, the semen analysis and HSG are normal, there is no known cervical factor, and normal findings at laparoscopy have been noted. In actuality, there may be clinically subtle but functionally major defects in sperm function, cervical hostility, tubal dysfunction, abnormal sperm-egg interaction, poor egg quality, genetic, environmental and implantation defects. The watchword here is "functionality" which is inherently difficult to test in a meaningful, accurate fashion. Without treatment, pregnancy rates are usually less than 10% per cycle. Following, IUI with OI will be discussed as a proven method of enhancing pregnancy rates in patients with unexplained infertility.

 

1.  Using IUI to compensate for Possible Undiagnosed Sperm Function Defects

It may be recalled that in normal cases, interaction of the sperm with cervical mucus results in sperm capacitation. Without capacitation, the sperm cannot attain maximal motility and cannot undergo the release of their acrosomal enzymes near the egg (acrosome reaction). Because it is not practical to test for capacitation, many fertility specialists rely on the ability of IUI preparation techniques to induce capacitation.  It is this effect, combined with the increased numbers of sperm introduced into the uterine cavity, that may explain some of the benefit of performing IUI in unexplained infertility patients.

2.   Using IUI to Bypass Hostile Cervical Mucus
 
Patients with unexplained infertility may have "hostile" cervical mucus that can be easily bypassed by IUI. In the past, a postcoital test (PCT) was performed to diagnose this condition. However, more recently, the PCT has fallen into general disfavor due to its inherent inaccuracies and patient inconvenience. In fact, IUI has become so effective for unexplained infertility that evaluation for abnormal "hostile" cervical mucus is now usually bypassed in favor of moving directly to IUI.

3. Utilizing OI-IUI to Compensate for Possible Poor Egg Quality

Ovulation induction with a goal of producing multiple eggs per month can be helpful for patients with unexplained infertility. Treatment with this goal in mind can compress several months of "natural" fertility into one month, thereby enhancing pregnancy rates. It is theorized that compressing all of this reproductive capacity into one month somehow compensates for an undiagnosed egg quality issue. Many patients wonder if they have poor quality eggs and are aware that the "Day 3 FSH Level" and the" Clomiphene Citrate Challenge Test - CCCT" are tests for inherent ovarian reserve problems or poor egg quality. (11) Day 3 Estradiol levels, inhibin levels, ovarian volume measurements and basal antral follicle counts (BAF) may also provide similar information. If any one of these tests is abnormal in a patient >35 years old, an egg problem probably exists and the infertility case is no longer "unexplained". However, these tests have limitations. For example, an abnormal single test in a woman <35 years old may have less clinical significance than expected whereas a normal test in women at any age doesn't always confirm normal egg quality. Alternatively, poor egg quality is usually suggested by the presence of multiple abnormal tests.

Again, stimulation of multiple eggs may produce a higher pregnancy rate in these patients and IUI clearly adds to the success rate. (10) Thus, for many patients with unexplained infertility we advise pursuing 2-3 cycles of OI-IUI prior to undergoing IVF, especially if they are less than 35 years old. Generally speaking, FSH shots (gonadotropins)/IUI generate higher pregnancy rates than clomid/IUI. A relatively new treatment protocol utilizing the aromatase inhibitor letrozole (Femara) is being investigated as a non-FDA approved OI regimen. When combined with gonadotropin injections and IUI, Letrozole is emerging as another powerful choice in our armamentarium. (12,13) Ultimately, the increasing number of regimens available will allow us to tailor therapy to a patient's individual needs with respect to her economic situation and willingness to risk multiple pregnancy. Although a generalization, the following table provides some information regarding our clinical experience with some of these ovulation induction regimens:

 

Table 1.  PROTOCOLS FOR OI-IUI CYCLES

Protocol

Pregnancy

Rate

Cost

Multiple PPr  Preg Rate

Clomid/IUI

Good

Low

Low
to mod

FSH/IUI

Highest

Highest

Highest

Femara + FSH/IUI

High

Mod

Highest

Femara/IUI

Good to Moderate

Low

Lowest

4.  Utilizing OI-IUI to Compensate for Possible Abnormal Ovulation and Luteal phase Defects

Unexplained infertility patients may experience subtle ovulation deficiencies that include the lack of an appropriate LH surge or a luteal phase defect (LPD). These abnormalities can be very difficult to diagnose and may therefore fall into the category of unexplained infertility. Fortunately, the use of ovulation induction (OI) with hCG ovulation triggering (artificial LH surge injection) can treat the majority of these problems resulting in increased pregnancy rates. Additionally, some clinicians use progesterone to supplement a possibly deficient luteal phase while others rely on the enhanced natural progesterone production resulting from the use of OI medications to produce similar results. 
 
III.     ENDOMETRIOSIS: Improving Pregnancy Rates with OI-IUI
 
Endometriosis is diagnosed when endometrial implants are visualized within the pelvis during laparoscopic evaluation. The abnormal growth of endometrial tissue in the pelvis causes an inflammatory condition that may be toxic to sperm, eggs, and embryos. Infertility results when inflammation either produces severe scarring (Stage III-IV Endo) or leaves the pelvis undamaged but nonetheless inhospitable to conception (Stage I-II Endo). Sperm survivability within the female reproductive tract may be greatly diminished.

 

It takes a surprisingly small amount of endometriosis to significantly impair pregnancy rates. (14) Ovulatory patients with a normal basic infertility investigation are often found to harbor endometriosis at high frequencies. In other words, we suspect endometriosis in the patient who "should be pregnant". Although useful in predicting a successful diagnosis, a history of painful menses or painful intercourse need not be present. A family association is frequently absent in confirmed cases.

 

For many patients, particularly ones in their early 30's and beyond, laparoscopic evaluation without actual surgical treatment of disease (laser vaporization, excision, or cautery) followed by observation simply isn't effective therapy. Pregnancy rates as low as 2.5% per month have been reported when using this ultra-conservative approach. Moreover, pregnancy rates of only 5% per month may be seen if the disease is actually vaporized at the time of laparoscopic diagnosis and not followed by OI-IUI therapy. (14) Thus, once endometriosis is suspected, we generally advise laparoscopic diagnosis with simultaneous vaporization of the disease implants immediately followed by OI-IUI for several cycles in patients with lower stage disease. Pregnancy rates over 17% per month may be attained with this management strategy, particularly with Stage I- II disease. (15) IVF is recommended if pregnancy doesn't result after 2-4 appropriately responsive OI/IUI cycles in the post-operative interval. Generally speaking, more surgery or use of depot-Lupron do not enhance pregnancy rates in this situation. Patients with Stage III-IV disease are treated surgically but will usually require IVF instead of OI-IUI to achieve reasonable pregnancy rates.

 

SUMMARY

Our practice has achieved remarkable success with our IUI program by adopting a detailed and fairly aggressive management approach with these cycles. We advise ovarian stimulation in conjunction with IUI for the majority of our patients. Using dual IUI's and PAF sperm treatment has increased pregnancy rates in our patient population. Patients with suspected endometriosis may have higher pregnancy rates when the disorder is diagnosed and treated with laparoscopic surgery early in the course of therapy. We also direct some patients rapidly towards IVF if their prognosis with IUI appears to be poor. Other patients may choose IVF instead of IUI if they desire the highest pregnancy rate possible.  In other words, IUI can be very successful if used in the correct patient population and much less rewarding if used in an inappropriate patient population. We are hopeful that continued research will enable more patients to achieve conception through use of enhanced IUI techniques.

REFERENCES

1. Dickey et al. Fertil Steril 71(4):684-9, 1999.
2. Roudebush et al. New England Fertility Society Annual Meeting 2004.
3. Wilcox et al. New England Jour Med 333(23):1517-21. 1995.
4. Roudebush et al. Fertil Steril 82(1) 2004.
5. Roudebush et al. in print; Abstract of annual ASRM meeting, 2005.
6. www.cdc.gov/reproductivehealth/ART02/
7. Ragni et al. Fertil Steril 72(4):619, 1999.
8. Silverberg et al. Fertil Steril 57(2):357, 1992.
9. Matilsky et al. Journal Andrology 19(5):603, 1998.
10. Guzick et al. NEJM 340(3):177, 1999.
11. Scott et al. Fertil Steril 63:1, 1995. 
12. Mitwally et al. Hum Repro 18(8):1588-97, 2003.
13. De Ziegler. Hum Repro 18(8):1598-1602, 2003.
14. Marcoux et al, NEJM 337(4):217, 1997.
15. Guzick et al. Fertil Steril 70(2):207, 1998.

 

Help Now Online

Help Now Online
Web Site Offers Help for Couples Struggling with Infertility
By Linda Davey
 

 

As originally published in the July, 1996 issue of Today's Dallas Woman Magazine 
 
For couples struggling with infertility, finding support and information regarding diagnosis, research and treatment can often be a frustrating experience. While traditional resources, such as media, physicians, local support groups, libraries, and bookstores provide good information on well-established and conventional treatments, they often can't stay current with the latest cutting-edge in the world of infertility Superhighway.

A quick search of the World Wide Web using a comprehensive search about such as Yahoo!, Web Crawler, Infoseek Guide, Lycos, Excite, or Alta Vista will yield nearly 200 Websites that provide information on infertility. Culling through all this information may seem daunting at first glance, but the search engine will usually rank the sites in order of relevancy. Additionally, online services such as America Online and Prodigy have very active bulletin boards specifically for subscribers who wish to post information about their ongoing infertility battles, and both services provide access to alt.infertility and misc.health infertility, the Internet's computer bulletin boards, commonly referred to as newsgroups.

In addition to accessing personal stories and treatment information from hundreds of others struggling with infertility, you may ask and answer questions, send private E-mail, post your own infertility story, and join an E-mail group comprised of others who share the same medical diagnosis. If you are an online "newbie," you can choose to "lurk," that is, read posts anonymously without participating. Subscribers to online services may also participate in regularly scheduled, "real time" chats.

During my own search for information in Cyberspace, following my fourth pregnancy loss in as many years, I met two other women actively participating on bulletin boards. Together we established the InterNational Council on Infertility Information Dissemination (INCIID--- pronounced "inside"). INCIID is a nonprofit organization dedicated to providing consumers with information regarding the causes and treatments of infertility and pregnancy loss. INCIID reaches its audience primarily through Cyberspace.

The Web site features an extensive list of fertility acronyms and terms, basic testing information, a reading list and a growing series of fact sheets and articles on cutting-edge technologies and treatments authored or edited by acknowledged leaders in the field of infertility. Topics include immunology and recurrent pregnancy loss, micromanipulation and male factor infertility, insurance coverage for infertility, predicting implantation success via ultrasound screening, and information on evaluating clinics. The organization currently has members from seven countries around the world and is working with other organizations to establish more ties internationally, including a mirror Web site in the United Kingdom. You can find INCIID on the Web at http://www.inciid.org/.
 
 
Editor's note: There's a happy ending to this story for the founders of INCIID. For some mysterious reason, creating the web site served as the catalyst of creation for the trio. Up until that point, between the three of them, they had suffered 12 pregnancy losses over 16 years of infertility. Within three weeks of creating INCIID, they each discovered they were pregnant. In the summer of 1995, Linda Davey and her partner, Terry Grant, both delivered their "miracle babies" on the same day; Nancy Hemenway of Arlington, VA, delivered her first child two and a half weeks later.

The InterNational Council on Infertility Information Dissemination (INCIID --- pronounced "inside") is a nonprofit organization dedicated to educating infertile couples about the latest methods to diagnose, treat and prevent infertility and pregnancy loss.  With traffic exceeding 23,000 accesses daily, site maintenance becomes expensive. If you value the information and support provided and would like to see INCIID continue to grow, please consider becoming an INCIID Sustaining Member.

 

NOVARELTM HCG ADDED TO FERRING INFERTILITY LINE

A Ferring Pharmaceuticals News Release

Contact: Laura Moulder

(203) 762-8833


 

NOVARELTM HCG ADDED TO FERRING INFERTILITY LINE

 

TARRYTOWN, NY – Ferring Pharmaceuticals broadens its line of infertility products with the addition of Novarelä (Chorionic Gonadotropin for Injection, USP). Designed to mimic the action of pituitary luteinizing hormone (LH), Novarel is used during ovulation induction therapy to trigger egg release. It can also be used in men to stimulate testosterone production.

 

"The introduction of Novarel is part of our ongoing commitment to provide therapeutically equivalent, cost-effective treatment alternatives to the reproductive community and their patients," says Wayne Anderson, president, Ferring Pharmaceuticals.

 

Novarel is available by prescription in 10 mL multiple dose vials containing 10,000 USP units with accompanying diluent.

 

For more information about Novarel, and/or infertility and its treatment, contact Ferring Pharmaceuticals at 888/337-7464.

 

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