COMING SOON! :"Making a Baby: an MSNBC Special Report"
Portions were filmed at PFC
We will post air date and time as soon as it is available!
Did you know that 343 babies were born as a result of assisted reproduction procedures performed at Pacific Fertility Center in 2002? Of these 343 babies, 98 or 28.6%, were babies conceived after having been stored as a frozen embryo.
This year marks the 20th anniversary of the first successful birth that resulted from human embryo cryopreservation. Since then, thousands of babies have been born worldwide after having undergone embryo cryopreservation. Freezing of excess good quality embryos allows for the transfer of fewer embryos in the stimulated IVF cycle and therefore ensures fewer high-order (triplets or more) multiple births. This process provides patients with a "back-up" should the initial fresh embryo transfer not result in a pregnancy. It is a much lower cost procedure than starting IVF all over again and often is performed with minimal medications. Frozen embryo transfers (FET) have allowed many of our patients to achieve more than one pregnancy from a single cycle of ovarian stimulation.
How safe is embryo cryopreservation? Even after 20 years, there are few studies in the scientific and medical literature concerning outcomes after embryo cryopreservation. However, the few studies that have been published are thus far reassuring.
The four largest studies performed on children conceived after embryo freezing have been done in England, France, Greece and Sweden. In all of these, the authors reported no significant difference in minor or major malformation rates in babies compared to fresh IVF embryo transfers or spontaneously conceived babies. The largest was the Swedish study, which followed 255 children born after embryo cryopreservation up to 18 months of age. Researchers compared them to 255 children born stimulated IVF cycle and therefore ensures fewer high-order (triplets or more) multiple births. This process provides patients with a "back-up" should the initial fresh embryo transfer not result in a pregnancy. It is a much lower cost procedure than starting IVF all over again and often is performed with minimal medications. Frozen embryo transfers (FET) have allowed many of our patients to achieve more than one pregnancy from a single cycle of ovarian stimulation.
How safe is embryo cryopreservation? Even after 20 years, there are few studies in the scientific and medical literature concerning outcomes after embryo cryopreservation. However, the few studies that have been published are thus far reassuring.
The four largest studies performed on children conceived after embryo freezing have been done in England, France, Greece and Sweden. In all of these, the authors reported no significant difference in minor or major mal-formation rates in babies compared to fresh IVF embryo transfers or spontaneously conceived babies. The largest was the Swedish study, which followed 255 children born after embryo cryopreservation up to 18 months of age. Researchers compared them to 255 children born. The longest-term follow-up was conducted in the French study, which followed 82 children, aged 1-9, born after cryopreservation as embryos. The total malformation rate was 3.4%. Incidence of medical and surgical illness was not excessive and scholastic performance in the older children was as expected.
What is the longest time an embryo can remain frozen and still be viable? Just this month, a clinic in Israel reported the birth of healthy twins from a transfer of frozen-thawed embryos that had been cryopreserved for 12 years. Embryos, once frozen, may have unlimited potential for viability, as long as they remain at the extremely low temperatures of liquid nitrogen storage.
At Pacific Fertility Center, we are very proud of our record of success with frozen embryo transfers. We see many healthy children at baby visits that were once stored at PFC as frozen embryos. We believe that the data on safety is reassuring. We see cryopreservation as yet another way for patients to achieve healthy pregnancies through assisted reproduction.
Carolyn Givens, MD
 Dr. Carolyn Givens, MD has been performing frozen embryo transfers for 12 years. She was the first in San Francisco to initiate a successful pregnancy using intracytoplasmic sperm injection (ICSI). She currently directs PFC's Third Party Parenting Program and Co-Directs The Bay Area PGD or Pre-implantation Genetic Diagnosis Program.
References:
Postnatal growth and health in children born after cryopreservation as embryos.
Wennerholm UB, Albertsson-Wikland K, Bergh C, Hamberger L, Niklasson A, Nilsson L, Thiringer K, Wennergren M, Wikland M, Borres MP. Lancet. 1998 Apr 11;351(9109):1085-90.
Perinatal outcome and follow-up of 82 children aged 1-9 years old conceived from cryopreserved embryos. Olivennes F, Schneider Z, Remy V, Blanchet V, Kerbrat V, Fanchin R, Hazout A, Glissant M, Fernandez H, Dehan M, Frydman R. Hum Reprod. 1996 Jul;11(7):1565-8.
Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. Hum Reprod. 1995 Dec;10(12):3332-7.
Follow-up of children conceived from cryopreserved embryos. Sutcliffe AG. Mol Cell Endocrinol. 2000 Nov 27;169(1-2):91-3.
Outcome in children from cryopreserved embryos. Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. St Mary’s Hospital, Manchester. Arch Dis Child. 1995 Apr;72(4):290-3.
Pregnancy and child outcome after assisted reproduction techniques. Tarlatzis BC, Grimbizis G. Hum Reprod. 1999 Sep;14 Suppl 1:231-42.
Twin delivery following 12 years of human embryo cryopreservation: case report. Revel A, Safran A, Laufer N, Lewin A, Reubinov BE, Simon A. Hum Reprod. 2004 Feb;19(2):328-9.
After my husband and I learned that we had no chance to become pregnant by natural means, we began to investigate IVF/TESE (sperm obtained by biopsy of the testes) with ICSI (Intracytoplasmic sperm injection) as a way to realize our dream of starting a family. We expected the procedures to be challenging to our bodies, minds, and finances.
We were also concerned about the frequency of twin and triplet births with IVF. As much as we hoped to have a child, we wanted to do everything we could to provide the best start for our child-to-be. We wanted to optimize our chances for a healthy full-term singleton pregnancy, natural childbirth, and breastfeeding, if we could become pregnant.
Dr. Carolyn Givens patiently answered our many questions about IVF and embryo cryopreservation and supported us when we made a choice that was quite unusual at the time: we requested that only one embryo be placed in my uterus during the IVF cycle and that any remaining embryos be frozen. I was 34 at the time and had never been pregnant.
We had the exceptional fortune that our first IVF/ICSI cycle in August of 1997 produced 13 beautiful embryos, and our transfer of a single fresh 3-day-old embryo during that cycle resulted in the birth of our son Benjamin nine months later.
 Eight-cell embryo
I was still breastfeeding Ben in 2001 when we decided to try for a second pregnancy. Dr. Givens transferred a single 8-cell frozen embryo during an unmedicated natural cycle. We had explained to Ben that there was a little, little baby in Mommy's tummy that we hoped might grow to be his brother or sister. About a week after the transfer, Ben said, "Mommy, the little, little baby in your tummy is crying." A few days later, my period began, and I felt like crying too.
The next month, Dr. Givens transferred another frozen embryo, also without medication. Ben thought this embryo was happy, and he was right: she grew to be his sister Charlotte.
When we were considering the choice to have our embryos transferred one at a time, we were glad to learn that the expense of frozen embryo transfers was only a small fraction of that for the IVF/ICSI procedures. I found embryo transfers performed by Dr. Givens to be gentle and comfortable. Dr. Givens' respect for our individual preferences made our infertility treatments a very positive experience. Our children have brought us unimaginable happiness.
--- Camille, Redwood City
Most couples going through IVF or frozen embryo transfer choose to transfer at least two embryos in order to improve the chances of conception with any one embryo transfer procedure. As Camille's story indicates, however, in younger patients with nice embryo quality and overall good chances for success, electing to transfer a single embryo is a viable option to avoid the risks of multiple gestation pregnancy. It also illustrates the benefits of embryo cryopreservation for having more than one child with a single IVF stimulation cycle. Carolyn Givens, MD
Q:
Can vaginal Viagra increase my odds of having a successful IVF cycle?
A:
Some fertility physicians turn to vaginal Viagra as a tool to improve uterine function. However, there is a great deal of skepticism about the use of Viagra for fertility patients.
One of the key parameters we monitor during a fertility treatment cycle is the development of the endometrial lining: both thickness and pattern. Our aim is to achieve a lining with a minimum thickness of >=7mm, and a trilaminar (or triple) pattern of the endometrial layers, by the day of HCG administration. For some patients, we cannot obtain this type of a lining, despite various hormonal manipulations.
For these patients, and even many without endometrial lining issues, we will typically recommend that she take a baby aspirin per day (81 mg) starting with gonadotropin stimulation. The rational for the use of baby aspirin is that on a micro-vascular level, vasodilation and decreased blood platelet aggregation occurs and therefore improves blood flow to the uterine lining, providing a lining with functional improvement. Blood platelets are the blood cells, which promote blood clotting. Two well designed studies confirm the benefit of baby aspirin use in improving pregnancy rates for patients with endometrial linings <8mm. It is important to note that the lining does not necessarily thicken with the use of baby aspirin - this is a qualitative improvement. It is also important to take only a baby aspirin, NOT a full dose aspirin.
Some fertility practitioners have suggested that Viagra vaginal suppositories for women, which are also a vasodilator, may provide improvements in pregnancy rates in the same way baby aspirin does. It needs to be noted however, that Viagra as a vasodilator works via a different mechanism compared to aspirin. While these claims have been made, well designed studies have yet to prove this. In the interim, Viagra should be used with caution.
--- Isabelle Ryan, MD
More and more patients undergoing fertility treatment ask about incorporating acupuncture and Chinese herbal medicine treatment with their IVF cycle. Some patients are especially inquisitive after reading Lifang Liang's recently published book Acupuncture and IVF: Increase IVF Success by 40-60%. For most patients going through the struggle of infertility, this title proposes a provocative and enticing claim.
While acupuncture is based on an ancient medical tradition, current studies are trying to clarify the physiological basis for treatment results. Some indicate that the benefits of acupuncture may be mediated by opioid-types of proteins in the central nervous system. Some of the proteins affect gonadotropin secretion from the pituitary (brain), and therefore could impact menstrual cyclicity to help regulate ovulation. Others propose that blood flow to the pelvic organs may be improved through mechanisms other than the central nervous system therefore improving fertility. And yet others propose there might be a psychosomatic benefit.
While all these theories are intriguing, a true understanding of the benefit of acupuncture and its impact on fertility will not be elucidated until the execution of several well designed studies (large numbers of patients, randomized controlled trials).
To date, there is only one such study (Paulus et al, Fertil Steril. 2002 Apr;77(4):721-4), which was conducted in Germany. While this study revealed an improvement in pregnancy rates, there are a number of issues with the study itself, which calls for cautious interpretation of the final results (an improvement in pregnancy rates from 26% to 42% - 61.5% improvement rate). For instance, the study was weakened by a low baseline pregnancy rate (26.3%) in a young patient population (early 30yo). Statistically, it is much easier to show an improvement in pregnancy rate, when the baseline pregnancy rate is so low. This finding may not hold true if this study was performed in an IVF center where the pregnancy rates in young patients was closer to 50% (which is what we expect for patients in their early 30s). More importantly, when studying such complex questions, a clear understanding will not be obtained, and claims of improvement cannot be made, until a number of well designed studies are performed and the majority of results echo a similar theme (either positive or negative).
In her book, Lifang Liang presents a nice overview of the theories behind Chinese Medicine, as well as various herbal treatments available for fertility patients, and their proposed effects. She then presents a number of "Case Histories", illustrating the use of both herbal therapies and acupuncture. While these are quite interesting, they are anecdotal stories, and do not represent a scientific study to evaluate the role of acupuncture and infertility. The above study by Paulus et al is mentioned in the book, and seems to be the basis for the claim of a 40-60% increase in IVF success rates. As mentioned, this claim should be taken with caution.
All of us who serve patients with fertility treatment, whether trained in Western or Chinese medicine, are looking for the best possible outcome for our patients. It would be wonderful if indeed there was a combination of various treatment approaches which, when practiced together, could provide the best "cocktail". However, the exact role that acupuncture plays is currently an unanswered question, until more well-designed studies are performed. We look forward to such studies, to better define the role of acupuncture and herbal remedies in the treatment of infertility.
--- Isabelle Ryan, MD
| 1. Embryos are stepped through increasing (freeze) or decreasing (thaw) antifreeze concentrations in a 4-well plate. |
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| 2. Once saturated with antifreeze, the embryos are loaded into small straws. |
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| 3. The straws are placed in a controlled- rate freezer. |
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| 4. Once frozen, the embryos are placed in state-of-the-art, computer controlled storage tanks. |
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| 5. The straws snap into labeled metal canes. They are barely visible through the mist of the cooling nitrogen gas. |
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| 6. After thawing, it is not unusual to see one or more dead cells in an embryo. Arrow is to 1dead cell in 4-cell embryo. |
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To successfully freeze, or cryopreserve any cell, its water must first be removed. Otherwise, the water expands into ice crystals as it freezes, and this process bursts or kills the cell. To maintain embryo viability during cryopreservation, the embryo is bathed in antifreeze, which draws the water out of the cells while the antifreeze enters. (1) Made with propylene glycol supplemented with sucrose, the antifreeze is not harmful in any way, provided the embryos are kept cool.
After this first step, the embryos are loaded into small straws (2) and placed in a controlled-rate freezer, which cools the embryos at a rate of -0.3°C/minute until they reach a temperature of
-38°C. (3) Then they are placed in, and stored in liquid nitrogen at -196°C. (4,5)
To thaw the embryos, the straw(s) are first warmed to room temperature and the embryos unloaded into a Petri dish. Then they are stepped through decreasing concentrations of antifreeze until eventually all the antifreeze has been removed and the embryos have been rehydrated. (1)
There is tremendous variability in how well embryos tolerate the freeze/thaw procedure, although surprisingly, it has little to do with the quality of the embryos at the time of freezing. A poor quality embryo will endure the process just as well as a good quality one. However, since poor quality embryos have a very low possibility of implanting, they are often not worth freezing.
While every care is taken to protect the embryos during the process, some embryos will have one or more burst cells (6) after they have been thawed. This cell loss results either from puncture by tiny ice shards around the embryo or from rupture as water rapidly enters the cell during thawing.
In 2003, over 80% of embryos survived freezing and thawing with one or more cells intact. On average, 2 out of every 3 cells in an embryo tolerated the process, and we consider an embryo with 50% or more of their cells surviving as having a normal chance of implanting after transfer. If an embryo thaws with fewer than 50% of its cells alive, we usually recommend thawing another embryo if one is available. At PFC 66% of embryos thaw with 50% or more of their cells intact.
--- Joe Conaghan, PhD
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