In vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) has made a significant difference in the lives of thousands of couples facing infertility due to severe male factor -- problems within the male reproductive system or the sperm, which account for 40% of all infertility cases. The process of injecting sperm into eggs at the time of in vitro fertilization was developed in 1992 and has now allowed for the birth of thousands of children whose parents would have otherwise not been able to conceive.
Since the IVF with ICSI procedure has a shorter track record, compared to a thirty year plus history for the IVF procedure, scientists and infertility specialists have been carefully monitoring children born utilizing IVF-ICSI. Prior studies of the genetic makeup of children born after being conceived via IVF-ICSI have reported that the risks of chromosomal abnormalities may be slightly increased as compared to natural conception. But these studies have been inconclusive.
However, a new study, presented at the annual meeting of the European Society for Human Reproduction and Embryology in Madrid, Spain this summer, prompted a collective sigh of relief. This extensive study involved 1,500 children from several European countries, who were followed up to age 5. The study was designed to examine both birth defects and mental development differences.
All the children underwent a thorough physical examination, including checking for birth defects, hearing and vision tests and psychological development. Although the rate of birth defects was slightly higher in the IVF-ICSI group at 5 years of age, there were no differences in language or physical skills, and no differences in behavior and temperament. The amount of difference seen in birth defect rates was not considered to be statistically significant enough to warrant concern. Moreover, the lack of difference in developmental skills was clearly an indication that IVF-ICSI children are expected to grow into thriving, healthy children.
The results of this study should be reassuring to parents of children conceived through IVF-ICSI, or those who are considering undergoing this procedure. The vast majority of children that result from the IVF-ICSI process do very well and show no major differences as compared to naturally conceived children.
If you are particularly interested more background and further details of this study, please read further.
-- Carolyn Givens, M.D.
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Dr. Carolyn Givens was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently directs the Third Party Parenting Program and Pacific Fertility Center’s Pre-implantation Genetic Diagnosis (PGD) Program. |
In the general population, the risk of sex chromosome abnormalities is about 2 in every 1000 births (0.2%). With IVF-ICSI, the rate of sex chromosome abnormalities is estimated to be about 6 in every 1000 births (0.6%). These types of abnormal chromosomes can lead to a variety of defects but virtually all chromosomal abnormalities can be diagnosed by prenatal genetic testing (CVS or amniocentesis).
It is not certain that this increased risk is due to the injection procedure itself or whether it is due to the fact that the sperm of men with male factor infertility, being otherwise incapable of fertilization, has a higher percentage harboring chromosomal abnormalities. In fact, recent studies on the chromosomes from embryos created via IVF-ICSI have shown that abnormalities are primarily confined to embryos using sperm from men with the most severe forms of male infertility, usually sperm requiring surgical extraction from the testicles.
This new study focused not only on the sex chromosomal abnormalities but also on the mental development of children conceived with this method. (Prior studies had revealed conflicting results, some showing a slower development in a portion of the children and other studies finding no differences in mental and psychological development.)
Over 1,500 children from Britain, Belgium, Sweden, Denmark and Greece were followed up to age 5. Out of this total, 541 children were conceived through IVF-ICSI, 440 were conceived with IVF without ICSI and 542 were conceived naturally. The children underwent a thorough physical examination, including checking for birth defects, hearing and vision tests and psychological development. Although the rate of birth defects was slightly higher in the IVF-ICSI group (6.4% vs. 2.4%), at 5 years of age, there were no differences in language or physical skills, and no differences in behavior and temperament. The amount of difference seen in birth defect rates was not considered to be statistically significant enough to warrant concern. Moreover, the lack of difference in developmental skills was clearly a significant indication that IVF-ICSI children are expected to grow into thriving, healthy children.
At birth, IVF-ICSI children were similar in birth weight and maturity (only singleton births were included in the study). They were no more likely to have been in the neonatal intensive care unit and the Apgar scores (measuring general health at birth) were similar. However, children conceived with IVF-ICSI were more likely to have undergone mostly minor surgeries, such as kidney and urinary problems, and to have been hospitalized sometime in the first 5 years of life.
One potential explanation for the differences in the birth defects could also attributed to the mother’s age at conception, as there is clearly a trend towards slightly higher rates of birth defects with maternal age. Also, for unknown reasons, the IVF-ICSI mothers were more likely to have had illnesses during pregnancy. An additional problem with drawing conclusions from the birth defect data was pointed out by Dr. Arne Sunde, chairman of the ESHRE society. In this study, the control group of naturally conceived children was more likely to be skewed towards healthy children, as this group was recruited from mainstream schools. It is likely that some of the children with the most severe birth defects may not be enrolled in regular schools. More data is needed to confirm or refute these results.
Regarding the psychological development findings, one of the researchers of the study, Dr. Susan Golombok from the City University of London stated, "I think we can feel very reassured about children’s social, emotional, and cognitive development up to age 5. If they were doing all right up to age 5, you wouldn’t necessarily expect things to get worse as they grow older. By that time, they are starting school and if they are doing okay, there would be no particular reason to expect problems would suddenly start to manifest."
--Carolyn Givens, M.D.
An almost universal piece of advice from woman-to-woman trying to
conceive is to take a daily dose of folic acid, also called folate. Folic acid
is a B-vitamin that decreases neural tube birth defects by a dramatic 70%.
Women who take 400 micrograms per day of folic acid on top of a
healthy diet while attempting to get pregnant often assume that this is
adequate.
At Pacific Fertility Center, we go one step further, and recommend a prenatal vitamin supplement for our patients undergoing fertility enhancement procedures. Besides the essential dose of folate, prenatals also contain other critical ingredients, such as iron and calcium.Additional iron is important as uterine blood volume builds up. Calcium is needed for a developing fetus, as well as to offset the iron, which impacts calcium absorption.
Some women complain of nausea from swallowing prenatal vitamins, which is usually caused by the iron concentration irritating the stomach lining. One way to overcome this queasiness is to take the pill with a full meal, or in half doses, twice a day. (Best to avoid dairy products, however.) Chewing ginger or sipping ginger tea also helps prevent digestive unease. And as a last resort, you may be a candidate for slow fe, which is an iron supplement designed for extremely slow absorption.
With so many over the counter vitamins available, some may wonder how these differ from prescription-based prenatals. In most cases, prescriptions are written so that insurance companies will cover the cost – there is generally no substantial difference in quality.
Also, it may be overwhelming to determine how prenatal vitamins differ
in quality, given the sheer volume of products in the marketplace. Some
women prefer vitamins with the least amount of flavoring and coloring
additives; with fewer ingredients, absorption may be enhanced.
If you would like to double check whether your prenatal supplement has what
you need, you can compare the label with this list of important ingredients:
Folic acid 400 micrograms (mcg)
Calcium 250 mg
Iron 30 mg
Magnesium 320 mg
Vitamin A 800 mcg (8,000 I.U.)
B6 2.2 mcg
Vitamin C 65 mg
Vitamin D 10 mcg
Vitamin E 10 mcg
Zinc 15 mg
Supplementing your diet with a prenatal vitamin containing these basic
ingredients helps create the building blocks for a successful pregnancy.
Please don’t hesitate to ask your PFC physician if you have any questions.
--Isabelle Ryan, M.D.
A new study, just published in the British Medical Journal has received quite a bit of press attention. This study, conducted at Kaiser Permanente in Northern California, suggests there may be a relationship between the use of aspirin and aspirin- like medications (called non-steroidal anti-inflammatory drugs, or NSAIDs) and first trimester miscarriage. We at PFC took a closer look at the study and determined that it has severe shortcomings.
NSAIDs, including aspirin, ibuprofen, naproxen and others, have not as yet been strictly forbidden during pregnancy, although most doctors, PFC physicians included, recommend acetominophen (Tylenol) if needed for headaches and other minor ailments during pregnancy.
Research has long established the impact of aspirin on women trying to get pregnant. At low doses (e.g. 81 mg), aspirin has markedly different effects on such things as platelet function as compared to higher doses (325-1000 mg). At low doses, some studies have suggested that aspirin may improve uterine blood flow and enhance embryo implantation. At higher doses, NSAIDs may inhibit prostaglandins, substances important for ovulation and implantation. This is the basis upon which we, at PFC, have designed our medication treatment protocol. We suggest patients not take drugs such as ibuprofen and naproxen during treatment, yet we do recommend patients undergoing infertility treatment take a daily baby aspirin.
This recent study surveyed 1055 women immediately after their pregnancy was diagnosed, and the women were followed up to 20 weeks of pregnancy. Only 53 women reported using NSAIDs around the time of conception or during pregnancy (5% of those surveyed). Of these, 15 (25%) miscarried. Of the 980 women who reportedly did not use NSAIDs, 149 (15%) miscarried. The 95% confidence interval was 1.0-3.2. When the 95% confidence interval is less than 1.0, the results are not considered statistically significant. Therefore, these results just barely achieved statistical significance. If the study had been able to find more women who had used NSAIDs, it might be more conclusive.
With so few women reporting NSAID use, and with results barely in the statistically significant range, more questions than answers are raised. It is disappointing that the authors did not include the average age of the mothers in their data presentation. Miscarriage is strongly associated with maternal age, as more embryos are genetically abnormal and will likely miscarry, as the mother is older at conception. Is there a possibility that the average age of the women using NSAIDs was greater, by chance or not? The study did not specify the maternal ages or how the data was adjusted to eliminate this potential important bias.
However cautiously we must review these results, PFC will continue to recommend a daily dose of baby aspirin to our patients undergoing infertility treatment. At such a low dose, baby aspirin improves uterine blood flow and this study does not warrant alarm. The primary conclusion from this Kaiser study strongly suggests that further research is needed.
--Carolyn Givens, M.D
Pacific Fertility Center has consolidated into one location. Our smaller Laurel Street office closed on Aug 8, 2003. Dr. Chenette and his patients now enjoy magnificent views of the San Francisco Bay from our sun-filled headquarters, as well as easier parking - a welcome benefit for those navigating the city streets.
This move allows us to create the highest quality embryology and fertility program under one roof. In addition to improving both physician and patient access to resources such as clinical coordinators, nursing staff, fertility counseling, and laboratory/procedure facilities, the consolidation and expansion of our laboratories provides direct benefits to patient care.
The laboratory has increased its handling of embryos for PGD, preimplantation genetic diagnosis, using single-gene testing as well as aneuploidy testing. The latter is a significant development that can help those who experience multiple miscarriages. (See October’s issue coming up for a more detailed lab update). We have upgraded our frozen sperm and embryo facility and purchased 3 new state-of-the-art storage tanks. The new tanks replace more than 20 small tanks that represented the combined storage of our two laboratories. All our frozen specimens have been relocated to the new computer controlled tanks, which offer the most advanced and secure system available for tissue banking. Our continual attention to detail in the laboratory was recognized when once again PFC received the exceptional finding of "no deficiencies" from the College of American Pathologists-American Society for Reproductive Medicine (CAP-ASRM).
As always, your care comes first and it is our goal to make a seamless transition to a single practice location. Please do not hesitate to contact us should have any concerns regarding this transition. We’re excited about the changes here at PFC and look forward to the continued improvement of our center and our on-going role in your care.
Q:
If I use an egg donor, how many embryo transfers can I expect?
A:
PFC maintains detailed records of all treatment procedures and outcomes at our world class laboratory. Nevertheless, the answer to this question is not as straight forward as one might expect. Averages can be summarized, but there are wide swings in the first stage of this procedure - how many eggs a donor can produce. Also, the decision on how many fertilized eggs to implant and how many to freeze can be highly subjective according to the patient.
In 2002, each donor recipient received an average of 23 eggs. But one donor that year failed to produce even a single egg, whereas another donor produced a remarkable 52 eggs. Several successful pregnancies resulted from only a three egg retrieval, so remember, it only takes one healthy embryo to establish a pregnancy!
Once the eggs are retrieved, the fertilization rates are a tad bit more predictable, since most of the donors are in their 20s. In 2002, between 65% - 76% of the retrieved eggs from donors successfully fertilized, depending on whether the donated eggs underwent IVF or IVF-ICSI.
In the next step, the implantation stage, PFC transferred on average 2.3 embryos per patient, and froze on average 7.8 from a single donor cycle. (The average number for freezing would have jumped from 7.8 to nearly 10 if this figure had excluded the 20% of women who did not produce enough eggs for freezing.)
In other words, 80% of donor egg recipients had at least some remaining embryos to freeze after the initial implantation.
And the odds were good for those embryos that entered the deep freeze. Last year, 77% of all thawed embryos were transferred, an improvement over previous years.
---Joe Conaghan, Ph.D
Gary and I were married in 1994. It was a fairytale romance and we knew we wanted children so we did not bother using contraception. But after two years we started getting anxious. We started actively trying by taking basal temperatures and timing ovulation. In my early 30th’s I went to the doctor for tests. He said I did not ovulate and that my ovaries made little eggs, not one big egg that a woman needs to ovulate. He prescribed Clomid.
On my second cycle of Clomid, I got pregnant. We were so happy. Then I had a miscarriage at nine weeks. It was the most horrible experience of my life. We knew we had to keep trying and we did.
We tried two more cycles of Clomid, but in conjunction with insemination (IUI). Gary held my hand each time, and again weeks later when I cried because it didn’t work.
Then our doctor suggested we see a specialist in the city. This specialist did not do IVF, but we didn’t think we needed it. So we had new hope. This time I had injections. We went through ten cycles of these shots with inseminations (IUI) for over two years. I had many tests during that time to confirm ovulation and Gary’s sperm quality. Each time the pregnancy test came back negative, I cried.
My grief was enormous but my desire to have a baby grew stronger. Then we were told we would need IVF.
I researched fertility doctors in the bay area. Some offer miracles but are not board certified. Several phone calls led me to Carolyn Givens at Pacific Fertility Center. It was the best referral I ever got.
I met with Dr. Givens and explained my situation and medical history. She said she believed she could help. She gave me a timeline and procedure to follow. It included shots again, but this time we would do IVF.
The day of retrieval came quickly. I kissed Gary, went under and woke up looking at his face. The transfer took place 3 days later. Gary held my hand just like all those times before, except this time they put three healthy embryos inside of me.
I will always remember the feeling when the nurse called me and said "Good News! It’s positive!" After years and years of pills, test, shots, crying when it was negative, and avoiding the baby aisles in stores and mothers with carriages because my pain was so deep, I became pregnant.
I will always remember Dr. Givens and the other doctors, nurses and staff at PFC. I really liked the way the staff at PFC always treated me with respect, kindness and professionalism. They helped us to have our baby girl and to finally live "happily ever after!"
-- Kim, San Francisco, CA
1. A fertilized oocyte (egg)
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This is a fertilized oocyte (egg) 22 hours after the egg retrieval procedure. The egg is the large cell within the thick shell, and its characteristic feature is the 2 nuclei in the center. One of these is the egg’s own nucleus containing the mother’s DNA. The other results from enlargement of the sperm head and contains genetic material from the father. Prior to the sperm’s arrival, the egg discarded ½ of its DNA, and this is visible as some small fragments at the 12 o' clock position, between the egg and the shell. |
2. An 8 cell embryo
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This 8 cell embryo is 48 hours older than the embryo in picture # 1. Once an egg is fertilized, it divides into two cells within 12 hours. It then again divides to give 4 cells and again to 8. These later rounds of cell division take about 16 hours each. Consequently, when patients come for embryo transfer 3 days after their retrieval, embryos with the greatest potential will have 6 to 8 cells. This is the time that embryos naturally travel from the fallopian tube into the uterus so it is the perfect time for transfer. |
3. A 6 day old Blastocyst
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This is a 6 day old blastocyst. It is almost twice the size of the embryos in pictures 1 and 2 (this picture was taken using half the magnification). After the 8-cell stage, fluid accumulates in the center of the embryo between the cells. As this fluid filled cavity expands, cells are pushed to the outside and the embryo expands within its shell. Most of the cells in the embryo are in a single layer around the cavity. These are the cells that will make up the placenta and they are already making the pregnancy hormone, human chorionic gonadotrophin (hCG). The remaining cells, organized in a small ball at the 6 o clock position in this picture, will become the fetus.
---Joe Conaghan, Ph.D., Director, ART Laboratories |
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.
To receive our newsletter via email or post, please call 888-834-3095 or email us at Newsletter@PacificFertility.com and place "subscribe" in the subject line. This mailing list remains confidential and will not be lent or sold to anyone.
On October 30th, Dr. Isabelle Ryan will be speaking from to 8:30 PM on Fibroids and Endometriosis as part of CPMC’s Mini Medical School on Women's Health This six-week educational program focusing on women's health is designed to offer the public some of the basic medical facts learned by first-year medical students. It is part of a six-session program offered at their Davies Campus.
PFC’s Free Seminar Our next seminar is Wednesday October15th from 6:30 to 8:30 PM. Please click "seminar" to register or call 888-834-3095.
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