More and more babies are being born after using assisted reproductive technologies (ART). This mainly includes babies being born after in vitro fertilization (IVF) when a woman’s eggs are fertilized with a man’s sperm inside a dish in a laboratory. However other techniques that are under the umbrella of ART are procedures like egg donation, surrogacy and egg freezing. At our annual meeting in the fall of 2016, an estimated 5 million children were born after ART technologies in the previous six years! This increase is thought to be due to increasing access in developing countries and increasing insurance coverage in many locations. According to the Centers for Disease Control and Prevention, about 1% of babies born in the United States each year, so about 60,000, are conceived through ART.
Kari Sproul von Goeben, M.D.
Costs in the U.S. for in vitro fertilization typically range from $10,000 to $18,000 inclusive of medications. Added potential costs include intracytoplasmic sperm injection (severe male factor) $500 – $2000, assisted hatching (patients 38 years and older) $500 – $2000, as well as costs associated with cryopreservation of embryos $500 – $2000. Costs for subsequent thawing and transferring of cryopreserved embryos typically range between $1000 and $3000. Costs most often are not covered by insurance. At the Florida Institute for Reproductive Medicine, our costs have always fallen around the lower end of these ranges. We always strive to provide IVF at the lowest cost possible, making this therapy available to the greatest number of patients.
Infertility patients faced with in vitro fertilization are primarily interested in their chances of taking home a baby from all their IVF embryos. Given the very real concern over multiple pregnancies, i.e. potential significant morbidity and mortality, along with the cost and social difficulties associated with a multiple pregnancy, limiting the number of embryos transferred is appropriate. At the Florida Institute for Reproductive Medicine the majority of our patients are transferred no more than two embryos. Additional embryos are cryopreserved. This brings up the issue of pregnancy rates associated with fresh as well as cryopreserved embryos. IVF programs practicing in the United States are required by law to report their pregnancy data to the CDC each year (http://www.cdc.gov/art/ARTReports.htm). One of the greatest differences in IVF programs is their cryo embryo pregnancy rates. Many programs have very poor results with cryopreserved embryos. For younger patients, less than 35 years of age, who likely will have embryos to cryopreserve, this represents a big disadvantage. Generally, fresh pregnancy rates will be somewhat higher in any program due to selection bias, i.e. when embryos are created, typically the embryologist will select the best looking embryos to transfer fresh, cryopreserving the remaining embryos. At the Florida Institute for Reproductive Medicine our fresh and frozen pregnancy rates have been among the highest in the country. Therefore, when trying to determine the value that a particular IVF program offers, it is important not only to take into consideration the cost, but also the pregnancy rates obtained from both fresh and frozen embryos.
A further consideration is the total number of embryos obtained. This number will vary depending on the patient’s age/ovarian reserve as well as the stimulation protocol, retrieval, and laboratory efficiency. At the Florida Institute for Reproductive Medicine, given the new and aggressive stimulation protocols used, the majority of our patients less than 35 years of age have embryos for at least one cryo IVF transfer, many have embryos available for a second cryo transfer. Therefore, total reproductive potential is the sum of the fresh transfer plus all cryo IVF transfers. Looking at the total reproductive potential in the context of IVF costs, we believe that the Florida Institute for Reproductive Medicine offers one of the greatest IVF values in the country.
Recent headlines have reported that IVF treatment is linked to ovarian tumors based on a recently published study. The findings are not different than was was reported over 10 years ago, and media coverage often misleads the public into making assumptions that may not be true. Many studies in the past have reported positive or no linkages with fertility treatment and ovarian stimulation and future risk of ovarian tumors. This study from the Netherlands was retrospective in nature, meaning that they started with women who had tumors, then looked to see what type of treatments they had. This type of study can possibly find causal linkages between a treatment and an outcome, but are in no way definitive as there are many biases that are introduced. You can breathe a sigh of relief that the study did find no link between IVF and ovarian cancer in a follow up of 15 years time. The only relationship was with possible “borderline” tumors, often called “low malignant potential” tumors. These are not invasive cancer and are not considered pre-cancer tumors, though they can grow like a tumor over time. The prognosis with this tumor is usually very good and tremendously different than with invasive ovarian cancer. Below is a blog from the American Fertility Association that helps to clarify a lot of this information.
Tumors of low malignant potential
Posted by Corey Whelan on Oct 27, 2011 with 1 Comments
http://www.theafa.org/blog/tumors-of-low-malignant-potential/
A new study out of the Netherlands and published in Human Reproduction is making the news today. It is entitled “Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort”. Reuters picked it up as “Fertility treatment raises tumor risk in study”.
It is of course understandable that The AFA’s phones have been ringing off the hook. Women are alarmed by this report. Briefly, I wanted to share a few facts about the study and urge you to please relax while you read this.
This long term study compared women who had done in vitro fertilization (IVF) with two other groups of women; 1)the general population, and 2)sub fertile women who had not done IVF. The researchers reported an increased risk level for the IVF group of developing borderline ovarian tumors. The research also showed that the overall incidence of invasive ovarian cancer was not significantly elevated, but increased with longer follow up.
The important thing to note here is that borderline ovarian tumors are actually cysts of low malignant potential. I am not minimizing the value of this study However, the term as is being reported in Reuters and picked up by media outlets, that women are twice as likely to develop ovarian cancer after IVF, is misleading. Patient’s individual risk of getting ovarian cancer if they do IVF is not 50% higher than it would be were they not undergoing treatment. The increased risk of acquiring invasive ovarian cancer for this group is around 1.76% greater after 15 years. If you however, put together the statistics for borderline ovarian tumors along with the statistics for ovarian malignancies, the rate goes up to 4.23%. That being said, we don’t want women to wind up in either group if they can help it.
I reached out to Dan Potter, M.D. to get his opinion on the study. His comments, verbatim, were:
“This is no different than the study that was published here in the U.S. about 10 years ago. The lead author is an epidemiologist. Oftimes in studies such as this, the researcher starts with the conclusion they wish to arrive at and then they work backward to prove it. I’m not saying that’s what happened here, but these are the most problematic issues that I see in this study.
- They linked all of the ‘malignancies’ in the registry to patients in the two study groups (IVF and non-IVF) regardless of whether they returned the surveys or not. This creates a falsely high incidence. They compared them to ‘general population rates’ who basically have the equivalent of a survey return rate of 100%. See how they appeared to start at the conclusion and work backwards?
- Borderline tumors, also known as tumors of ‘low malignant potential’ or LMP are not malignancies. There is no such thing as ‘invasive cancer’ and ‘non-invasive cancer’. Cancer is invasive. Borderline tumors are not cancer and while not benign have low malignant potential. The 5 year survival rate of borderline serous tumors (the most common type) is ….…100%.
- They seem to speak of ‘invasive cancer’ and consider the borderline tumors ‘non-invasive’ cancer. The definition of malignancy is invasion so this simply does not make sense from a medical perspective.
- Their control group is women diagnosed with infertility that did not do IVF. They did not stratify these patients as to whether they became pregnant or whether they were on the birth control pill, both known protective factors. In fact, there is not control for whether the patient even had a hysterectomy or oophorectomy for endometriosis. It is hard to get ovarian cancer when you do not have ovaries. Prior use of fertility drugs in the controls may have led to pregnancy so that they did not pursue IVF. Pregnancy, BCPs, oophorectomy are all protective.
- There were 19,146 patients in the IVF group and 28 ‘invasive cancers’. Using their methodology they would have expected 21. Both of these number are very high compared to what we would expect in the US (about 10x higher). Not sure why they diagnose it more frequently there.”
So, to sum it up. You should absolutely discuss this study with your physician and weigh your own personal risk, based on medical and family history and genetic background. And, if you want to talk about it, please feel free to call.
Comments:
Great news about fertility treatment from the Netherlands!
The study, a large cohort of Dutch women with infertility, showed that
the incidence of invasive ovarian cancer was NOT increased in either IVF
treated women or Non-IVF subfertile women followed for up to 15 years
after treatment.
The study of 19,146 women who underwent IVF and 6,006 women treated with
lesser forms of fertility therapy over a period of 13 years, found 28
and 9 women respectively developed invasive ovarian cancer, (37 cases /
25,152 women) a rate that was the same as the general population in the
Netherlands.
9 of the 28 cases of invasive ovarian cancer found in IVF treated women
occurred beyond the initial 15 year observation period when the authors
would have expected to find approximately 3. No medical information
about other exposures that these women may have had during those
intervening years was accessible.
Borderline ovarian tumors, a non-lethal ovarian growth that may never
become cancer but may require surgery, were seen more frequently in
women who underwent IVF compared to Non-IVF subfertile women.
There are many risk factors for ovarian cancer and non-lethal borderline
ovarian tumors independent of treatment including infertility itself,
use of exogenous hormones; lifestyle factors; and family history of
cancer. The current study obtained this critical information by
questionnaire.
A limitation of the study is that while 71% of the subjects who
underwent IVF returned the 23 page questionnaire, less than half (48%)
of those who received lesser treatment responded.
Factors known to decrease the incidence of invasive ovarian cancer
including pregnancy and the use of oral contraceptives, now commonly
used in conjunction with IVF treatment, were not independently assessed.
Alan Penzias, MD
Five of the Most Important Questions to Ask
1) Ask to see the program’s official CDC pregnancy statistics.
The Wyden Bill requires that all IVF programs report their results to the CDC yearly. While this is a law, it is not enforced by any significant penalty. Treatment centers that do not report their data know they cannot be audited. These clinics may be reporting erroneous data. They may be transferring excessive numbers of embryos to achieve pregnancy. Transferring excessive numbers of embryos leads to high rates of multiples, resulting in potentially serious morbidity and mortality to the babies and Mom. Often programs have good fresh IVF transfer rates, but poor results with cryopreserved embryos. Pregnancies from cryopreserved embryos can add a tremendous amount to a couple’s cumulative chance of having a baby. Again, ask to see official CDC take home cryo IVF pregnancy rates.
2) Ask if the clinic has regular office hours on Saturdays and Sundays.
Infertility is time specific. If the clinic is not operating seven days a week, care, i.e. inseminations, IVF retrievals and transfers are often being compromised.
3) Ask if the embryology lab is headed up by an embryologist certified as a highly complex lab director (HCLD).
This certification is given to embryologists who have obtained an advanced degree of training and equipment knowledge and have passed a rigorous certification exam. Ask if the center has a secured facility for storage of your cryopreserved sperm, eggs, or embryos. Ask how often liquid nitrogen tanks are filled and checked. There should be documentation of these checks. Ask if the program has a back up alarm system.
4) Ask about cost for IVF.
Typically IVF costs range anywhere from $10,000 to $18,000 inclusive of medications. Ask if there are additional charges for intracytoplasmic sperm injection (ICSI), typical cost $500 to $1000. For assisted hatching, typically $500 to $1500, and whether cryopreservation, typically $500 to $1500, is included in the cost estimate. Costs to do a subsequent cryo IVF transfer cycle range from $1000 to $3000.
5) Ask if the physicians at the clinic are board certified or board eligible in Reproductive Endocrinology/Infertility.
Reproductive Endocrinology/Infertility subspecialists are OB/GYNs who have gone on to do two or three more years of subspecialty training in Reproductive Medicine. To maintain board certification subspecialists must continue to keep up with important medical advances and take a re-certification exam yearly.
Answers to these five questions will go a long way in directing you to one of the better IVF programs in your area. Do your homework – chances are your referring physician has no knowledge of these five issues.
A female has the maximum number of eggs she will ever have as a fetus in utero at 20 weeks gestation, approximately 20 million. During the last 20 weeks of in utero development, over 90% of the eggs will be lost, forming scars in the ovary. At the time of birth, there are about a million eggs. At puberty, when the brain-ovarian axis matures and ovulation begins, a few hundred thousand eggs remain. The process of egg loss is known as atresia, and will continue until the last egg is released – menopause.
Each month when the menstrual cycle begins, a number of eggs start to develop – this group of eggs can vary in size from one to as many as thirty or forty eggs, depending on the number of eggs an individual is born with and her age. With each reproductive cycle the entire group of eggs starts to develop; one egg out of this group develops to maturity and is released, i.e. ovulates, but the entire cohort of eggs is lost. On rare occasions, more than one egg may ovulate, bringing about the opportunity for a multiple pregnancy. This process of egg loss continues until menopause. Typically, five to six years before menopause, cycles will become increasingly irregular as the quality of eggs that are released are often poor and may not produce enough estrogen to trigger ovulation.
Some individuals are born with much lower numbers of eggs. These individuals are at risk for premature menopause – sometimes this occurs as early as the teenage years. It is unknown why some women are born with fewer eggs, but likely is a function of genetics, i.e. menopause is often closely timed to maternal menopause. The time of menopause can be influenced by a number of environmental factors, including surgeries, radiation, chemotherapy and smoking. Starting your period early does not accelerate menopause. Likewise, being on birth control pills, which prevents ovulation, does not delay menopause. Again, there is a programmed loss of eggs each month.
Am I at risk for premature menopause?
It is important to identify those individuals that may be at risk for early menopause, not only for fertility concerns, but also for potential hormone replacement needs. There are three primary means to guesstimate ovarian, i.e. egg, reserve:
Age
Age can be looked at as a rather crude guesstimate of remaining ovarian reserve, as some individuals are born with much greater numbers of eggs than others. Certainly it is true that on average a 20-year-old is going to have far greater ovarian reserve than a 30-year-old, who would be expected to have far greater ovarian reserve than a 40-year-old.
Again, because of differences in the number of eggs someone is born with and potentially harmful environmental factors, there can be considerable variability in ovarian reserve at any age. More accurate assessments of ovarian reserve include:
Hormonal Tests
Day 3 FSH/estradiol levels
Inhibin levels
Clomiphene citrate challenge tests
Antimullerian hormone
Ultrasound Assessment of Ovary
Counting the number of egg/follicle units in the ovary, “antral follicle count” early in the cycle, typically days 2-4.
Combining different ovarian reserve tests is likely to give a more accurate assessment of ovarian reserve. Ovarian reserve can decrease abruptly in some individuals, likely representing an accelerated period of atresia, much like what happens in the second half of intrauterine development. This is relatively common and can be seen in patients whose mother had an early menopause or who have been exposed to chemotherapeutic drugs, radiation, or destructive ovarian surgeries. For others there are no obvious causes. If an individual is at increased risk for accelerated egg loss, it is important to do regular ovarian reserve testing, especially if future fertility is a concern.
Fertility Preservation Options
Oocyte Cryopreservation
Oocyte cryopreservation is a relatively new, exciting technology for those individuals who do not have a male partner or who are uncertain as to whether they will stay with their current partner. Worldwide, there are approximately 1500 babies born from frozen eggs. Because of the limited number of babies born and relatively short follow up on these children, this technology should still be considered research and therefore should be carried out under an IRB (Institutional Review Board) protocol. The institutional review board serves to review results from oocyte cryopreservation both in terms of efficacy and safety. There are many programs throughout the country advertising egg freezing. Many of these programs have had little or no success. It is, therefore, important to ask some key questions when trying to identify a competent institution. Namely, the number of babies that have been born from that particular embryology lab, not an affiliated lab or program. Ask the number of eggs that were frozen to achieve these pregnancies, thereby getting an idea of efficacy. The number of eggs available to an individual less than age 35 years of age or younger, on average, will vary typically between 8 and 16 each month. For those individuals 36 and above, the cohort size is likely to be reduced, averaging between 5 and 12. Ovarian reserve testing, again, will give a better estimate of individual egg number. Depending on the efficiency of the program and an individual’s ovarian reserve, more than one stimulation cycle may be necessary to have a realistic chance for pregnancy. Programs involved with oocyte cryopreservation should maintain a registry as to any birth defects or any development problems.
Florida Institute for Reproductive Medicine has been involved with oocyte cryopreservation since 1998. To date, we have had 63 babies born from frozen eggs. On average, we have required ten mature eggs to produce a healthy ongoing pregnancy in mothers 35 years or less. For individuals 36-38, we are requiring on average fourteen mature eggs. We do not offer oocyte cryopreservation for individuals over the age of 38, as the great majority of these individuals will have low ovarian reserve and a very high percentage of poor quality eggs, i.e. they are unlikely to benefit from cryopreservation.
Pre-embryo or embryo fertility preservation
This is an appropriate option for those individuals who are in a stable relationship. In general, if there is any concern about potentially discarding an embryo, the option of cryopreserving pre-embryos should be considered. Freezing a pre-embryo is, in essence, freezing male and female nuclear material that are close to each other but have not combined to form an individual. Pre-embryo and embryo cryopreservation have been available since the mid-1980’s. There have been hundreds of thousands of babies born from both pre-embryos and embryos. There is a large body of reassuring health data, on babies born from (pre)embryos. Fertility rates with (pre)embryos vary tremendously depending on the reproductive medicine program. Each advanced reproductive medicine program in the United States is required by law to report their data to the CDC; therefore, before considering an individual program, check with the CDC registry (www.cdc.gov/ART/ART2011) on the program’s cryo IVF data.
Costs for oocyte cryopreservation as well as (pre)embryo cryopreservation should mimic those of a typical IVF cycle; the steps are basically the same. Ongoing storage costs will typically vary from $100 – $400 per year.
We currently do not perform PGD (preimplantation genetic diagnosis/screening) for the sole reason of gender selection. In those patients who are undergoing PGD for other medical indicated reasons, then sex is sometimes also determined at the same time. Some diseases are transmitted through only one sex, thus in those cases, gender selection can be applied.
Many patients have heard of IVF (In vitro fertilization), and may even be facing IVF in their effort to conceive. However, many do not know exactly what is involved. This will hopefully give a quick overview of a typical IVF cycle.
General
The basic idea in IVF is to give the patient a large amount of gonadotropins (the hormones from the brain that stimulate egg development) to cause the development of many follicles (the ovarian cysts that each contain an egg). The hormones used must all be given as injections, as they do not come in pill form. The injections are given just under the skin like an insulin injection that a diabetic person might take. Once the follicles are fully developed, which usually takes 10-12 days of medication, the eggs are retrieved through an in-office procedure. The eggs are given to the embryology lab where they are fertilized with sperm, and allowed to grow for 3-5 days. At that point, the embryo(s) are transferred back into her uterus through a small catheter (tube).
Stimulation Protocols
There are several basic plans (protocols) for performing ovarian stimulation for IVF. There have been numerous variations reported over the years, but primarily two or three basic standard types have proven to be the most successful. The differences between any of the protocols are subtle. It is usually only through the judgment of the physician that it can be determined which protocol will be most suitable for a particular patient.
The two protocols that have been time-tested and most often used are termed “Agonist Protocols” and “Antagonist Protocols”. These terms refer to the type of medication that serves to prevent your body from trying to prematurely ovulate or release the developing eggs. In both protocols, the stimulation medication (FSH and LH) are used for a total of 10-12 days.
Though it may sound counterproductive, it is helpful to use a birth control pill for at least one cycle before starting the IVF medications. This serves to keep the ovaries quiet and prevent any cyst formation that may later interfere with the IVF cycle.
In an Agonist Protocol, a hormone (called a GnRH-agonist) is used to prevent the brain from trying to prematurely ovulating the developing follicles. This is usually started during the last week of the birth control pills, and continued daily up until the point of egg retrieval. The stimulation medications (FSH and LH) are started after being on the GnRH Agonist for approximately one week.
In an Antagonist Protocol, the stimulation medication is started once the menses following the birth control pill cycle occurs. After 4-6 days of stimulation medication, another hormone is started (a GnRH-antagonist), which prevents premature ovulation of the developing follicles. This is also continued until the point of egg retrieval.
Cycle Monitoring
The initial dose of medication is chosen by the physician based on several factors, including the patient’s age, previous IVF experience, and hormone levels. Usually the dosages of stimulation medications will be adjusted during the stimulation phase based on the results of close monitoring which includes a pelvic ultrasound and hormone measurements. This monitoring is performed at baseline before starting stimulation, and after the first 3-5 days of stimulation medications. From that point on, an ultrasound and estrogen blood level is usually performed every 2-3 days until the time of retrieval, for a total of 4-5 monitoring visits.
Once the majority of the ovarian follicles reach the proper size (usually 17-19 mm in diameter), a separate medication is given (hCG- human chorionic gonadotropin). This serves to “trigger” the eggs, causing the eggs to genetically awaken from their idle state, continue development, and become “mature” or able to be fertilized and develop into an embryo.
Egg Retrieval
The hCG medication is given with specific timing. If the eggs are not retrieved, they would be ovulated and released. This timing is such that the egg retrieval occurs just several hours before the eggs would be released. The egg retrieval occurs in our certified operating room located within our office. Anesthesia medication is administered through an IV placed in an arm vein. This allows the patient to be fully relaxed and comfortable during the procedure. A pelvic ultrasound is performed as usual, and ultrasound guidance is used to guide a needle into each ovary allowing the fluid (containing the egg) in every follicle to be removed. After the eggs are carefully removed, they are given to the embryologist (the laboratory scientist specially trained in handling eggs and embryos). The entire retrieval usually takes about 15-30 minutes, and the patient goes home once fully recovered from the anesthesia (about 45 minutes later).
Fertilization and Embryo Culture
Once the eggs are retrieved, they are fertilized several hours later. This is usually done by mixing the eggs with the sperm. In cases of male fertility issues, an individual sperm may be directly injected into each egg. The fertilized eggs then start the process of dividing. They are grown (cultured) in a very closely monitored and controlled setting which allows for the optimal environment for the early embryos. They are assessed on the second day after retrieval, and depending on several factors, a decision will be made by the physician to either transfer the embryos on the following day (Day 3), or allow them to grow for an additional two days and transfer them on Day 5.
Embryo Transfer
When the day comes for the embryo transfer, you will return to the office. The transfer will take place in another room specifically used for this purpose which is located next to the embryology lab. The transfer is a simple and painless procedure that does not require any type of anesthesia. It is very similar to having a pap smear performed. During the transfer procedure, a small catheter (tube) containing the embryos is carefully inserted through the cervix and into the uterine cavity. This is guided with an ultrasound to ensure that they are gently placed in the proper location. After the transfer, the patient relaxes for approximately 15 minutes then is able to go home. Once placed in the uterus, the embryos cannot “fall” out or dislodge.
After the Embryo Transfer
After the retrieval and transfer, hormone supplementation (using progesterone) is continued to provide extra support for the pregnancy. Progesterone is available in several forms including injection, vaginal tablets, and vaginal creams. A blood pregnancy test is performed about 14-16 days after the egg retrieval. Once a pregnancy test is positive, an ultrasound is performed approximately 3 weeks later, at which time we should be able to detect a heartbeat in the embryo. Progesterone is continued for an additional 2-3 weeks after the detection of a heartbeat.
Summary
At first glance, the steps of IVF appear very complicated. However, our entire team of physicians, nurses, and staff will work to guide you step-by-step through the entire process. Having a dedicated team available and on call 24-hours a day ensures that you have a continuous support network at your fingertips. The entire time-frame from the start of a birth control pill until the pregnancy test is approximately 7 weeks, during which specific IVF medications are used for 4 weeks. IVF is not necessary for every couple, but it is always the fastest route to a pregnancy.
