Embryo Transfer & Embryo Implantation
Embryo Transfer & Embryo Implantation:
Embryo transfer is most often done on an outpatient basis. No anesthesia is used, although some women may wish to have a mild sedative. The patient lies on a table or bed, usually with her feet in stirrups. Using a vaginal speculum, the doctor exposes the cervix. One or more embryos suspended in a drop of culture medium are drawn into a transfer catheter, a long, thin sterile tube with a syringe on one end. Gently, the doctor guides the tip of the loaded catheter through the cervix and deposits the fluid contain the embryos into the uterine cavity. The procedure should be done with great care and usually takes between 10 and 20 minutes. Some doctors perform the transfer under ultrasound guidance, to ensure proper placement of the embryos in the uterine cavity. Most doctors advise a few hours of bed rest after the transfer. Most clinics today transfer 2-3 good quality embryos on Day 2 or Day 3.
Embryos are graded according to their appearance and rate of cell-division and good quality embryos are those which have 4-8 cells, of equal size, with clear cytoplasm, and with few fragments. These are called Grade A embryos. Embryos with more fragments are assigned a lower grade, and they usually have a lower chance of implanting. However, the babies who result from these embryos are completely normal, if they do implant successfully. You should ask the doctor to show you your embryos under the microscope. Some times, only embryos of poor quality are available for transfer. While the chance of getting pregnant when only poor quality embryos are transferred, you can be reassured that if a pregnancy results, the children will be normal!
How many embryos to transfer is one of the most difficult decisions facing an IVF patient today. The more the embryos transferred, the greater the chances of getting pregnant. Since the purpose of an IVF cycle is to achieve a pregnancy, then why not transfer as many as possible? However, the price you pay for transferring more embryos are that the risk of a multiple pregnancy increases as well.
In some countries, such as the UK, doctors are allowed to replace a maximum of only 2 embryos, to reduce the risk of high-order multiple births. Some clinics in Scandinavia have now started transferring only one embryo (this is called SET or single embryo transfer) in young women, in order to reduce the risk of a multiple pregnancy. In USA and India, there are no laws, and some clinics will transfer 4 embryos for young patients, and up to 6 for older women – and this number is quite arbitrary.
Doctors have tried to develop an embryo score (based on the number of embryos and embryo quality) in order to predict the chances of a pregnancy after embryo transfer, but this is still not precise. I always tell patients that if IVF technology was perfect, and if every embryo became a baby, we would transfer only one embryo, and I wouldn't need to discuss this with them. Since the technology is still not perfect, and we still cannot predict which embryo will become a baby, there is no easy answer as to how many embryos to transfer. This is why many clinics will allow patients to decide for themselves. This is always a difficult decision, and you need to carefully weigh the pros and cons before making up your mind. There is no right or wrong number – and you need to take the path of least regret.
Transferring more embryos increases the chances of getting pregnant, and also increases the risk of a multiple pregnancy. However, a high-order pregnancy is a complication for which the doctor can perform a selective fetal reduction, in order to reduce this to twins. Not getting pregnant may be a worse outcome for some patients! If embryo freezing facilities are available, then supernumerary embryos can be stored, and this needs to be factored in as well.
The embryo transfer completes the medical treatment in the IVF cycle and most clinics provide "luteal phase support" after the transfer, usually with estrogen tablets and progesterone suppositories, to increase the chances of implantation. However, this period is often the hardest part of an IVF cycle for the patient, because of the agony and suspense of waiting to find out if a pregnancy has occurred. This can be determined by a blood test, which measures the level of the hormone, HCG (human chorionic gonadotropin) only 10 to 14 days after the transfer. For many patients, these 14 days are often the longest days of their life!
A positive beta HCG level ( of more than 10 miU/ml) means you are pregnant, and the doctor will then monitor your pregnancy to confirm it is healthy; intrauterine; and to check how many embryos have implanted.
It is normal to blame yourself for something you may or may not have done during this time if you do not conceive. Therefore, try not to do anything for which you will blame yourself if you do not get pregnant. In general the following guidelines are offered:
- No tub baths or swimming for 48 hours after replacement
- No douching or tampons
- No intercourse or orgasms until the fetal heartbeat is seen on ultrasound, or the pregnancy test is negative
- Do not undertake excessive physical activity such as jogging, aerobics, or tennis
- No heavy lifting
- You may return to "work" after 24 hours of bed rest (getting up for bathroom and meals only) and one to two days of light activity.
It's safe to travel 2-3 days after the transfer.
If you are unsure whether or not to do something, take the "path of least regret". Ask yourself - if I don't get pregnant, will I blame myself for doing this? And if the answer is yes, don't do it!
You may have some vaginal spotting or bleeding prior to your blood test. However, you must have the blood test done, even if you think your period has started. There are no symptoms or signs which will be able to tell you whether or not you are pregnant.
Many doctors used to advise "strict bed rest" after an embryo transfer. However, remember that your physical activity does not affect your chances of getting pregnant. Resting when you are well can be very emotionally taxing, and we encourage patients to lead as normal a life as possible. Many patients are worried that if they cough or sneeze, the embryo will "fall out". However, remember that this is physically impossible, and that if the embryo is going to implant, it will, no matter how much you exert physically. Remember that God has designed the human body with enough sense, that coughing and sneezing will not cause the embryos to "fall out". The uterine cavity is a "potential space", and once the embryos are placed here, they appose to the uterine wall and are not affecting by gravitational forces. I remind patients that it's fine for them to do whatever normal couples would do after having sex - after all, how does it matter to the embryo that it arrives in the uterine cavity in the normal course of events, after the couple had sex, or after spending 2 days in the IVF laboratory and then being transferred into the cavity with a catheter?
Thus, there are numerous stages to every IVF treatment cycle, each of which must be reached and completed before moving on to the next stage:
- more than one should egg develop
- eggs should mature
- ovulation should not occur before the eggs can be collected
- eggs must be retrieved during the "pick-up"
- sperm must fertilize at least one egg
- Fertilized eggs must divide and grow healthily... and all this so that...
- the embryos might get implanted in the uterus
Think of it as a series of hurdles, all of which have to be cleared, in order to win the race!
The enigma of embryo implantation is why doesn’t every embryo become a baby?
While modern technology is very good at making embryos in the laboratory, we still cannot control the implantation process. We do not know which embryo will become a baby – and this can be very frustrating, for both patients and doctors! Many patients who do not get pregnant after an embryo transfer start believing that their bodies are defective, and that they have "rejected" the embryo. They feel that if they failed to become pregnant even after the doctor transferred 3-4 good quality embryos, that they are flawed. However, you need to remember that embryo implantation is a very complex process, which consists of a series of phases in which the embryo has to appose and attach itself to the maternal endometrium and invade into it.
First, the embryo has to undergo further development, till it reaches the blastocyst stage, when it hatches from its shell, known as the zona.
The hatched blastocyst then needs to implant in the endometrium, and the three phases of implantation are known as apposition, adhesion and invasion, and occur during the period of time known as the implantation window. Apposition, or orientation of the embryo (which is at the blastocyst stage at this time ) within the cavity of the uterus, starts when the cavity has become minimal due to the suction of endometrial fluid by pynopods (small protrusions found on the surface membrane of the cells lining the uterus). Adhesion of the blastocyst is a progressive phenomenon that ties the embryo to the endometrium and is the primary event initiating invasion. Many molecules, such as cytokines, growth factors and cell adhesion proteins called integrins play an important role in this complex process during which the blastocyst and maternal endometrium must undergo an exquisite dialogue. Invasion is a self-controlled proteolytic process that allows the embryonic trophoblast to penetrate deep into the maternal decidua and to invade the endometrial spiral arteries by producing chemicals called proteinases. How implantation is regulated and brought about remains an enigma, but we need to remember that the implantation process is surprisingly inefficient in humans – Nature is not always very competent! After IVF, it’s only about 10%, which means that only 10% of embryos implant successfully to become a baby.
The responsibility for this low efficiency has to be shared between the embryo as well as a defective embryo-endometrium dialogue. We still cannot successfully predict which patient will get pregnant after embryo transfer. We now know that one of the major reasons for failure of the embryo to implant is a genetically abnormal embryo. Basic research on implantation is of great interest today, because embryonic implantation is the major factor limiting in allowing pregnancy after ART, but we still need to learn a lot about this "black hole" in our knowledge, before we can learn to control it!
Many patients blame themselves when they don’t get pregnant after an embryo transfer. They feel that the fact that the embryo did not implant means either that their body is defective; or that it "rejected" the embryo; or that they did not rest enough. However, please do remember that embryo implantation is a complex process, which you cannot influence by your diet or physical activity – so there is no need for you to blame yourself if the embryos do not implant.
Maximizing chances for success women:
- Avoid all unnecessary medications other
(Tylenol). If you are taking other prescription medications check with us prior to beginning your treatment cycle.
- No smoking or alcohol use. Studies show both can result in lower pregnancy rates and a greater risk of miscarriage. Why put yourself through this if you are not doing everything YOU can to insure your success.
- No more than two caffeinated beverages per day.
- Avoid change in diet or weight loss or fad diets during IVF cycle. A healthy well balanced diet works best.
- Refrain from intercourse following embryo replacement until the pregnancy test is done.
- Normal exercise may continue unless enlargement of your ovaries produces discomfort.
- Avoid hot tubs or saunas.
- Fever greater than 100.4 C one to two months prior to IVF treatment may adversely affect sperm quality. Be sure to let us know. If you are sick, please take your temperature and report any febrile illnesses.
- Sitting in hot tubs and saunas is not recommended. Please refrain from this for at least three months prior to treatment.
- Drugs, alcohol, and cigarette smoking should be avoided for three months prior to treatment and at all times during the ongoing IVF treatment cycle to get the best results.
- Abstain from intercourse for at least three days, but not more than seven days prior to collection of semen for egg collection and during treatment.
Embryo Freezing: Embryo Cryopreservation
What is embryo freezing?
Since most IVF programs superovulate patients to grow many eggs, there are often many embryos. Since the risk of multiple pregnancies increases with the number of embryos transferred (and in fact the law in the UK prohibits the transfer of more than 2 embryos to reduce this risk), many patients are left with "spare" or supernumerary embryos. These can be discarded; or used for research.
It is now also possible to freeze these embryos and store them in liquid nitrogen. These stored embryos can then be used later for the same patient - so that she can have another embryo transfer cycle done without having to go through super ovulation and egg collection all over again. Moreover, since this embryo transfer is done in a "natural" cycle (when she is not taking any hormone injections) some doctors believe the receptivity of the uterus to the embryos is better. For women with irregular menstrual cycles, frozen embryo transfer can also be done in a "simulated natural cycle", in which the endometrium is primed to maximize its receptivity to the embryos by using exogenous estrogens and progesterone.
Since pregnancy rates with good-quality frozen-thawed embryos are as good as with fresh embryos, we encourage all our patients to freeze and store their supernumerary embryos, rather than discard them. Freezing is very cost-effective, since transferring frozen-thawed embryos is much less expensive than starting a new cycle, so that it serves as a useful "insurance policy" in case pregnancy does not occur. However, since it is worthwhile freezing only good quality embryos, the option of freezing is a "bonus" which is available to only about 30% of all IVF patients.
About half of all embryos frozen survive the freezing -thaw process. It is reassuring to know that the risk of defects is not increased as a result of freezing. These frozen embryos can be stored for as long as is needed - even for many years. When they are in liquid nitrogen, at a temperature of -196 C, they are in a state of suspended animation, and all metabolic activity at this low temperature stops, so that a frozen embryo is like Sleeping Beauty!
Once stored, embryos can be used by the couple during a later treatment cycle, donated to another couple or removed from storage. These options should only be undertaken after considerable discussion and written consent from the parties concerned.
While we still cannot freeze unfertilised human oocytes efficiently, a new technique called vitrification (which uses ultra-rapid cooling together with an increased concentration of cryoprotectants) may allow us to offer this option to our patients, in the future, allowing the facility of egg storage and egg banking.
Analyzing a failed IVF cycle
If you don’t get pregnant after your IVF attempt, you are likely to be very disappointed and disheartened. However, remember that this is not the end of the road - it’s just the beginning! At the end of the IVF cycle, you need to sit down with your doctor and analyze what you learnt from it. Was the ovarian response good? Was the endometrium receptive? Did fertilization occur? Was the embryo transfer easy and a traumatic? Why didn’t pregnancy occur (the million dollar question, though this is usually a question we still cannot answer!) Can you repeat the same treatment, or do you need to make changes before going in for your next attempt? When can you go in for your next IVF cycle? And even if you do not get pregnant, at least the fact that you attempted IVF should give you peace of mind that you tried your best, using the latest technology medical science has to offer.
The second time around - the next IVF cycle
most doctors would advise you to wait for a month before starting a new cycle. While it is medically possible to do the next cycle immediately, most patients need a break to marshall their emotional strength before starting again. Your doctor may need to modify your treatment, depending upon an assessment of your previous cycle. For example, if the ovarian response was poor, the doctor may advise you to increase the dose of drugs used for superovulation. If fertilization did not occur, you may need to go in for microinjection ( ICSI). If the quality of the embryos was poor, you may be advised to consider a ZIFT rather than IVF. ZIFT will also be advised if the embryo transfer was difficult and traumatic, as this allows us to bypass the cervix and transfer the embryos directly into the fallopian tubes. However, if the cycle was satisfactory, the doctor will often advise you to repeat exactly the same treatment again - and all that it may take to achieve your IVF success is time, patience, and another attempt.
Interestingly, we often find that couples going through a second IVF cycle are much more relaxed and in control. This may be because they are aware of all the medical and procedural minutiae, and are better prepared for these; and also because they have had a chance to establish a personal relationship with the medical team. Also, since they have already faced failure the first time around, many of them are much better able to cope with the stress of IVF, since they are prepared for the worst. With today’s IVF technology, we can confidently reassure any patient that we can help them to get pregnant, provided they have inexhaustible resources of time, money and energy!
Gamete Intrafallopian Transfer GIFT:
GIFT stands for gamete intrafallopian transfer and this used to be a popular alternative to IVF in the past. A gamete is a male or female sex cell - a sperm, or an egg. During GIFT, sperm and eggs are mixed and injected into one or both fallopian tubes. After the gametes have been transferred, fertilization can take place in the fallopian tube as it does in natural, unassisted reproduction. Once fertilized, the embryo travels to the uterus by natural processes.
As in IVF, a GIFT treatment cycle begins with ovulation enhancement which is followed by egg harvest, usually by means of laparoscopy. But the similarity to IVF ends here. In IVF, an embryo is transferred. In GIFT, gametes are transferred.
Only patients with at least one normal, healthy fallopian tube are candidates for GIFT. These include women who have unexplained infertility or mild endometriosis and couples whose infertility results from male, cervical, or immunological factors. Some doctors recommend that couples with male factor infertility proceed with GIFT only if it has been proven that the man's sperm can fertilize the woman's egg either by in vitro fertilization or by past pregnancies.
The basic steps of GIFT
The basic steps of GIFT are superovulation , egg harvest, insemination, and gamete transfer. The eggs are usually harvested during laparoscopy. During this same laparoscopy procedure, which takes about an hour, eggs are mixed with sperm and the gametes are transferred.
The harvested eggs are examined under the microscope and graded for maturity. The selected eggs are placed in individual dishes and combined with sperm (insemination). The sperm are prepared in advance in the same manner as for IVF. Some doctors prefer to allow the dishes to sit for about 10 minutes before the transfer, since during this period the sperm adhere to the zona pellucida of each egg. Many programs load eggs and sperm individually into a catheter and inject them into one or both of the fallopian tubes.
The sperm egg mixture is loaded into a specially designed catheter . This is then directed into the fallopian tube(s) through their fimbrial opening while looking through the laparoscopy. Up to four eggs and sperm may be injected into one or both tubes. Gametes will be transferred only if the fallopian tubes appear healthy. If the surgeon determines that the tubes are unhealthy, IVF should be attempted instead. For this reason, GIFT should be undertaken only at facilities that have the capability to do IVF.
Specialists generally agree that pregnancy rates are higher for GIFT than for IVF- in fact, GIFT is about twice as successful as IVF. In part, this may be due to the type of patient accepted into GIFT programs. It may also be because the in vivo tubal environment is more "physiologic" for the gametes and embryo than the in vitro environment.
The advantages of this technique are:
- The fallopian tube acts as the laboratory
- The embryo will reach the uterus at a later stage in its development, as with normal conception.
- The procedure is considered morally acceptable to some religious groups which object to IVF, as conception occurs within the human body.
- The endometrium will also be more receptive to the embryo because of the greater time the embryo takes to reach the uterus.
GIFT & IVF Compared
There are several differences between GIFT and IVF. The most important one is that GIFT requires at least one healthy fallopian tube, whereas IVF is appropriate treatment for women with tubal disease or even no fallopian tubes at all. At present, GIFT requires laparoscopy for transfer, while an IVF treatment cycle can be completed without laparoscopy. This is one of the reasons many IVF clinics no longer offer GIFT, even though it offers a higher pregnancy rate - because they do not have easy access to an operation theatre. Ideally, you should opt for treatment in a clinic which offers all the procedures, so that the doctor can select the one which is best for you, depending upon your individual circumstances.
In the case of GIFT, fertilization occurs unobserved inside the body. With IVF, fertilization takes place in a laboratory dish and can be confirmed visually with a microscope. Visual confirmation of fertilization is especially important in cases of male factor or unexplained infertility. To obtain visual confirmation and still have the greater chance of pregnancy afforded by GIFT, one of the variations of GIFT described later (ZIFT, PROST or TET) may be used, to give the patient the benefit of combining the advantages of both the procedures.
A major disadvantage with conventional GIFT is that a surgical procedure - laparoscopy - is needed to transfer the eggs and sperm into the fallopian tube. Recently, a non-surgical method has been described by Dr. Jansen and Anderson from Sydney IVF, Australia, in which the gametes can be transferred into the fallopian tubes through the vagina and cervix under ultrasound guidance. This requires a special set of catheters which allow the doctor to enter the uterine ends of the fallopian tubes through the cervix. Once the catheters have been accurately positioned - and ultrasound can help in this - the gametes are injected into the tubes. Since this does not involve surgery, the benefits to the patient are obvious - less expense, no hospitalization, no scar and no anesthesia. However, the technique does require much more technical expertise and is still being investigated more thoroughly. Also, the pregnancy rates with the method are less than with conventional laparoscopic GIFT.
ZIFT, zygote intrafallopian transfer, is also called PROST, which stands for pronuclear stage transfer. When a sperm penetrates an egg, the sperm introduces its nuclear material into the egg. Approximately 14 hours after penetration, two distinct pronuclei, one from the sperm and one from the egg, are visible under the microscope. Pronuclei are taken as indicators that fertilization has occurred. A zygote is a fertilized egg before cell division begins. For ZIFT, eggs are removed by transvaginal aspiration and fertilized in a laboratory dish. The next day, when the fertilized eggs have reached the pronuclear stage, the embryos are transferred to the fallopian tubes during laparoscopy.
Approximately 24 hours after a fertilized egg reaches the pronuclear stage, it divides for the first time and becomes a two cell embryo. This cell division is called cleavage. It is at this stage or later that TET, tubal embryo transfer, may be attempted. The fertilized and dividing egg (early cleavage stage embryo) is transferred to the fallopian tube during laparoscopy.
PROST, ZIFT, and TET differ from GIFT in that fertilization takes place in a laboratory dish instead of the fallopian tube. Moreover, they differ from IVF in that the fertilized egg is transferred to the fallopian tube instead of to the uterus. They offer the best of both IVF and GIFT - documentation of fertilization in vitro; and higher pregnancy rates because of tubal transfer. However, the cost of ZIFT, PROST, or TET is usually greater than IVF or GIFT
IVF success rates, blastocyst transfer, and simplifying IVF
The most important question most patients have about IVF and GIFT is: What are my chances of getting pregnant?
This is a difficult question to answer, since there are so many variables involved. Chances of success depend upon:
- The wife's age - chances decline with increasing age - precipitously so over the age of 40
- The reason for the IVF / GIFT - chances of pregnancy decline when IVF is done for male factor infertility
- The quality of the IVF Clinic and its services
- The number of embryos /eggs transferred
- The superovulation regime used
Of course, there are some variables about which nothing can be done - such as the wife's age. But other variables can be controlled to try to maximize chances of a pregnancy! The good news is that with improving IVF technology, pregnancy rates with IVF have increased dramatically.
Pregnancy rates are related directly to how many embryos are transferred. For example, when 3 good quality embryos are transferred, the chance of pregnancy is about 40% in that cycle. The number of embryos transferred needs also to be balanced against the risk of multiple pregnancies, which naturally increases with more embryos.
With this in mind, the Fertility society of Australia recommends that no more than 3 embryos be transferred during any treatment cycle. Studies was done the world over show that the average pregnancy rate per cycle for IVF is about 30 % for most patients; and about 30% for GIFT.
How can a patient interpret this figure? For example, let us consider a 30 year old patient with irreparable tubal damage who goes through one IVF cycle. She can look at the pregnancy rate figure of 30 %. In two ways a success rate of 30 % means there is a 70 % chance she will not get pregnant. On the other hand, if she takes no treatment, her chance of getting pregnant is zero. The IVF cycle has increased this to 30 % - no one can do any better than this today!
Of course, for the couple who gets a baby, it's a 100% baby - and for the one who fails, its 0% - so for the individual patient, it's really not a question of statistics! Each IVF treatment cycle is a bit like taking a gamble - and you need to hope for the best and prepare for the worst!
IVF and GIFT treatment should not be considered to be a single shot affair. Patients should plan ( mentally at least !) to go through at least 3 to 4 cycles to give themselves a fair chance of getting pregnant. With 4 treatment cycles, the chance of getting pregnant (the cumulative conception rate) is about 70 %. What this means, is that even though the chance of getting pregnant in a single cycle may never be more than 40%, over 4 cycles, the chances increase to 70% because the success rate is cumulative.
Thus, let us assume the pregnancy rate for IVF at a clinic is 30%. If 10 patients start an IVF cycle, 3 will get pregnant, leaving 7 patients. If these 7 do another IVF cycle, another 30% (2.1 patients - so let's say another 2) will conceive. If the remaining 5 do another cycle, 1 more will get pregnant; and at the end of the 4th cycle, 1 more will conceive; so that of the 10 patients who started, 7 will have got pregnant in 4 attempts. This is because the chances of getting pregnant in the next IVF cycle do not decrease just because a pregnancy has not occurred in the previous cycle - so the best bet would be to keep on trying.
Theoretically, we could reassure every couple taking IVF treatment that they would get pregnant - provided they were willing to go through as many cycles as were required, till they hit the jackpot! Of course, one has to set a limit somewhere, and the decision when to stop is something which only the couple can make for themselves. After more than 6 failed IVF cycles, the chance for a pregnancy with IVF does decline.
Games IVF Clinics Play with Pregnancy Rates
Of course, some clinics have much better pregnancy rates - and others much worse. Nevertheless, many clinics will quote inflated rates - and this can mislead patients! Unfortunately, in India there is no central registry or monitoring of IVF clinics, so that you pretty much have to trust what the doctor tells you. In many countries in the West, the law mandates that IVF clinics provide their pregnancy rates to a central authority - thus ensuring that IVF clinics maintain high standards and quality control. This is very helpful for patients.
Different programmes define success in various ways. To most couples, success is a baby, not a pregnancy - so that what needs to be determined is the "take home baby rate". Some clinics quote pregnancy rates when describing their success rates - and these can be considerably higher than the live birth rate, depending upon how a pregnancy is defined. Thus, some programs define pregnancy when the pregnancy test is positive; others define pregnancy as a fetus seen on ultrasound.
So called biochemical pregnancies are also fairly common after IVF. These are pregnancies confirmed by blood and urine tests but in which the embryo does not develop beyond the earliest stage. No gestational sac and no fetus is seen on ultrasound examination. Counting biochemical pregnancies will, of course, inflate the pregnancy rate.
Other ways of juggling with pregnancy rates include: accepting only patients who have a good chance of getting pregnant or selectively reporting pregnancy rates achieved in younger women (and excluding other patients from data analysis).
Most good programs today express their pregnancy rate as the number of babies born per treatment cycle, and this is the figure you should be looking at.
One of the major problems with IVF today is the low pregnancy rate after successful embryo transfer. The reason why such few embryos implant successfully (only 1 of 10 embryos will become a baby) is one of the things we really do not understand today. Dr. Cohen from New York believes this is because the surrounding shell of the embryo (called the zona pellucida) hardens when it is cultured in the laboratory. They therefore use "embryo surgery" called zona drilling or assisted hatching to "soften" the shell of the embryo, and they believe this helps to increase pregnancy rates by improving implantation rates, since embryo hatching is facilitated. This can be done using an acid (acid Tyrode’s) or with a laser.
Assisted Hatching: The embryo is held securely, and a carefully controlled stream of acid is blown through a fine pipette in order to drill a hole in the zona (shell). If you click on the picture, you can watch a video of how we do a laser-assisted embryo hatch in our clinic
Embryo surgery has also been used for embryo biopsy, for preimplantation genetic diagnosis, in which single cells are removed from the developing embryo, to make sure the embryos are healthy and have no genetic disease.
Embryo multiplication, by removing some of the cells from the embryo and allowing them to divide, can allow doctors to "multiply" the number of embryos formed in vitro. The new embryos can then be coated with a new shell (zona) and then transferred into the uterus. This could help to increase the chances of pregnancy is women who can produce only a small number of embryos.
Other scientists feel that the reason for the poor implantation is the poor quality of the embryo cultured in vitro. They have therefore tried to improve embryo quality in the laboratory by trying to provide it with more natural ("physiological") culture conditions. This is done by a method called co-culture in which the embryo is cultured along with "feeder cells" in the culture dish.
These cells provide the embryo with the extra nourishment they need for better growth. Better pregnancy rates are claimed with co-cultured embryos as compared to embryos grown under traditional IVF conditions.
Some patients going through IVF grow lots of eggs, but persistently form poor embryos which fail to implant. In some of them, this may be because they have a problem in their cytoplasm (the area within the shell of the egg that lies outside of the nucleus) - either in their mitochondria or the cell-division apparatus. Dr Cohen hypothesised that it should be possible to correct this problem by replacing just the cytoplasm of the egg, instead of the whole egg, thus keeping the mother's own genetic contribution (the DNA contained in the nucleus) to the baby intact. This high-tech method is called cytoplasmic transfer, and uses cytoplasm donated from the healthy eggs of another woman.
The formulation of new laboratory culture media - the liquid in which the embryo is grown in vitro - has made it possible to "grow" embryos in vitro beyond the typical 2 to 3 day state of development , till they become blastocysts. A blastocyst is the final stage of the embryo’s development before it hatches out of its shell (zona pellucida) and implants in the uterine wall.
Initial studies suggest that transfer of the embryo on day 5, at the blastocyst stage, may yield higher pregnancy rates. There may be two possible reasons for this. Firstly, transfer of the blastocyst to the uterus may be more physiologically appropriate, since this mimics nature more closely, so that the implantation rate may be higher. Also, waiting till the blastocyst stage allows the doctor to select the "best" embryos, since unhealthy embryos are likely to die (arrest) before they reach this stage.
Blastocyst transfer also significantly reduces the possibility of potentially dangerous high-order multiple births, such as triplets. Higher implantation rates allow doctors to transfer fewer blastocysts - perhaps only one - reducing or avoiding multiple births and their associated problems. Supernumerary blastocysts can also be successfully cryopreserved with resulting pregnancies after thawing.
While blastocyst transfer is a very promising advance for patients who grow lots of eggs (good ovarian responders), its utility for the difficult patient - the poor ovarian responder - is still debatable. This is because if there are few eggs, there is a very real risk that none of them may develop to the blastocyst stage. All of them may "arrest", so that there are no embryos available for transfer. Every patient needs to balance these risks and benefits, depending upon the clinic’s experience and success rate.
Some people might ask whether all this is relevant to Indian conditions. While these technologic refinements are very exciting, IVF clinics in India should also focus on simplifying IVF technology - so that it can be made more affordable for the average Indian couple. Advances which have occurred which have helped to simplify IVF and make it more easily available include the following.
Intravaginal culture: This is a technique for IVF, which provides the same rate of fertilization which conventional IVF does, at a fraction of the cost. In this method, which was first described by Dr. Ranoux of France in 1984, the eggs and sperm are placed in a sterile vial which is then sealed and placed in the woman's vagina. Thus, the woman acts like her own incubator, since she keeps her eggs and embryos at body temperature. Since expensive laboratory equipment is not needed, this is much cheaper - than and as effective as conventional IVF!
Natural cycle IVF: Natural cycle IVF is much less expensive because it does away with the high expense of gonadotropin injections used for superovulation. In this method, the single egg which the woman grows in her unstimulated ovulatory cycle is used for IVF. While the pregnancy rate is lower, the expense (and the stress of IVF) is much less! Interestingly, "gentler" IVF is becoming increasingly popular in the West as well. Many doctors are very critical of the large amounts of hormones which are being used in traditional IVF in order to produce large quantities of eggs. Gentler ovarian stimulation (using only clomiphene or smaller doses of HMG) has also become popular once again, since it reduces the risks of complications, such as ovarian hyperstimulation and multiple pregnancies.
Transport IVF: Transport IVF is a recent innovation pioneered in the Netherlands; and by Dr. Kingsland of UK. In this, the egg retrieval is performed by the gynecologist in his own clinic or hospital; and the eggs (in the follicular fluid) are then transported to a central IVF laboratory by the husband in a portable incubator. Insemination, fertilization and embryo transfer take place in the central laboratory. This method allows gynecologists to take an active part in their patients' treatment; ensures high quality, since all laboratory procedures are performed in a central laboratory; and also minimizes patient inconvenience ( since superovulation and egg retrieval are done by the local gynecologist, the number of visits the patient has to make to the IVF Center are minimized.)
Egg Donor Program & Donor Embryos
What about using donor sperm, donor eggs and donor embryos in an IVF cycle?
Donor Sperms, Donor Eggs and Donor Embryos
Couples with no sperm or eggs can undergo IVF and GIFT with the use of donor sperm or eggs.
For IVF, cryopreserved donor sperm are processed in the same way as fresh sperm. In some cases of female infertility, fertilization may be attempted first with the husband's sperm, and if this fails, donor sperm may be used in a second attempt. Alternatively, if several eggs are aspirated, some may be inseminated with the partner's sperm and some with donor sperm.
Donor eggs: can be used in GIFT or IVF for women who have no eggs (ovarian failure) but who do have a healthy uterus. For GIFT, the woman must also have at least one functional fallopian tube. In GIFT, the donor's eggs are mixed with sperm from the husband. This mixture is injected into the patient's fallopian tubes, while hormone supplements prepare the uterus and aid in the initiation of pregnancy. For IVF, an embryo resulting from the fertilization of a donor egg and the husband's sperm is placed inside the patient's uterus.
A couple may also choose to use donor eggs if the woman has a genetic disease that could be passed on to a child. Donor eggs can also be used in some cases of long standing infertility when other procedures have failed - for example, women with many previous unsuccessful IVF cycles. The use of egg donation is now becoming increasingly commoner, as older women are seeking infertility treatment. Since the chance of a pregnancy in the older woman depends directly upon the quality of her eggs, many older women opt to use donor eggs from younger women - which increase their pregnancy rates dramatically. This also creates headline news, for example, when a menopausal woman has given birth with donor eggs. In rare cases, when both the man and woman are infertile, donor sperm and donor eggs have been used together.
Unfortunately, it is still not possible to freeze and store eggs on a routine basis - they are too fragile! This is why fresh eggs need to be used for donor egg treatments. These may come either from another infertile patient; or a volunteer egg donor; or a friend or relative, who offers to donate eggs.
Egg donation for IVF or GIFT requires the egg donor to undergo ovulation induction and ovum aspiration. The donation of eggs carries more risk and inconvenience to the donor than does the donation of sperm.
The use of donor eggs requires that the cycles of the donor and the recipient be closely synchronized. This requires treatment of the recipient, so that her endometrium is primed and is receptive to the embryos at the time of transfer.
For amenorrheic women with ovarian failure, this can be achieved by treating them with exogenous estrogens and progesterone. Other women who are cycling need to be downregulated with GnRH analogs before starting treatment with exogenous estrogens.
In the future, it is possible in the future those scientists will discover ways to collect and store immature eggs. This may make "egg banks" a reality, and considerably simplify the technique of egg donation.
Couples with both a sperm and an egg problem can also use donor embryos. Since embryos can be stored, some infertile couples going through an IVF cycle, who have chosen to freeze their supernumerary embryos for themselves, are willing to donate their surplus frozen embryos to other infertile couples when they get pregnant. Since donor eggs are still so hard to come by, many couples may choose to resort to using donor embryos, since these are much more easily available. You can think of donor embryo treatment as very similar to adopting a baby - with the difference that you are carrying the pregnancy and giving birth to the baby!
Some couples are worried that if they use donor eggs or donor embryos, their body will "reject" them, because these are genetically foreign. However, remember that all embryos are genetically foreign to the mother, because half the genetic material comes from the father! The uterus is an "immunologically privileged" site, and donor embryos have as good a chance of implanting as normal embryos.
Risks and complications of IVF
Risks and complications of IVF and GIFT
Many couples are still worried that babies born after IVF are abnormal or weak. You need to remember that in one sense there is nothing "artificial" about these babies - they aren’t synthetic babies which are being manufactured in the laboratory! Remember that IVF is a form of assisted reproductive technology, where technology is being used to assist Nature to accomplish what it has failed to do for the infertile couple! Over a hundred thousand babies have now been born after IVF treatment, and the risk for birth defects is not increased after IVF treatment.
most worrisome complication of IVF is that of ovarian hyperstimulation syndrome
(OHSS), because of superovulation. The cause of "hyperstimulation
syndrome" is that superovulated ovaries contain many follicles which are
loaded with estrogen. After ovulation, a huge amount of estrogen-rich fluid is
poured directly out of the enlarged and fragile ovaries into the abdominal
cavity. This fluid also contains chemicals like kallikrein-kinin and VEGF
(vascular endothelial growth factor), which then coat the lining of the abdominal cavity (called the peritoneum) and cause it to become very permeable (leaky).
Fluid (serum) literally pours out of your bloodstream into the peritoneal cavity because of the "leakiness" of the abdominal cavity’s lining. The ovaries balloon in size, your abdomen swells, you get lightheaded with relatively low blood pressure, and you may get dizzy because of the decreased blood volume. Many women will have mild degrees of hyperstimulation syndrome with a little bit of lower abdominal swelling, discomfort, and dizziness. This does not require hospitalization, just bed rest at home. It is only the rare, severe cases that require hospitalization.
The occasional patient today who develops severe hyperstimulation must go into the hospital, have intravenous fluids for several days, and wait for her ovaries to reduce in size and for her body to readjust. Some patients may even need to be admitted into an intensive care unit for monitoring and observation, since this can be life-threatening.
At one time this was a very dangerous condition only because it was not fully understood. We now know that by putting a small "paracentesis" catheter into the abdomen and draining all of this fluid, the patient is made much more comfortable, she can breathe more easily, and by getting rid of this estrogen irritation, fluid leakage into the abdomen slows down dramatically. Thus, even in the very rare cases of severe hyperstimulation syndrome, knowledgeable treatment makes the likelihood of any dangerous outcome very remote.
In our clinic, we prevent OHSS by carefully aspirating each and every follicle at the time of egg retrieval, and flushing it repeatedly with a double-lumen needle, until it collapses completely. By removing the follicular cells which are responsible for producing VEGF and causing OHSS, we have been able to prevent OHSS very successfully in our clinic by using this novel technique.
Interestingly, the worst cases of hyperstimulation syndrome occur when a woman becomes pregnant. This is because her placenta is making HCG and stimulating the ovaries to continue to pour out large amounts of estrogen-rich fluid. So although it is a very unpleasant side effect to endure, hyperstimulation syndrome often means good news.
If you grow too many follicles ( more than 25) , or if your estradiol level is very high, the doctor may be forced to cancel the IVF cycle, because of the high risk you run of developing ovarian hyperstimulation syndrome. In some clinics, doctors can salvage this cycle by collecting all the eggs and freezing all the embryos. Since the embryos are not transferred, the risk of hyperstimulation is reduced; and the frozen embryos can then be transferred in a future cycle.
Complications can also occur during the egg harvest procedure. The removal of eggs through an aspirating needle entails a slight risk of bleeding, infection, and damage to the bowel, bladder, or a blood vessel.
In all techniques of assisted reproductive technology, the chance of multiple pregnancies is increased when more than one embryo or egg is transferred. Although some would consider having twins to be a happy result, there are many problems associated with multiple pregnancies, and problems become progressively more severe and common with triplets and each additional fetus thereafter. Women carrying a multiple pregnancy may need to spend weeks or even months in bed or in the hospital. There may be enormous bills for the prolonged and intensive care for premature babies. There is also a greater risk of late miscarriages or premature delivery in multiple pregnancies.
A recent treatment option for women with multiple pregnancies is that of selective fetal reduction, in which one or more of the fetuses is selectively destroyed (usually by injecting the toxic chemical, potassium chloride, into its heart under ultrasound guidance). In most cases, the killed fetus is then reabsorbed by the body - and the other fetuses continue to grow. Of course, the risk of all the fetuses being lost because of a miscarriage (as a result of inadvertent trauma during the procedure) is also present, and is about 10% in experienced hands.
There is approximately a five percent chance of an ectopic pregnancy with IVF and GIFT. This is not because of the procedure, but rather because women going through IVF already have damaged tubes, which predisposes them to having an ectopic.
IVF is physically demanding - and stressful! The effects of blood tests, anesthetic and operation are tough on your body. Hormone stimulation causes lethargy and fatigue, notwithstanding the sometimes extensive travelling required each day. Some people find treatment conflicts with their employment or other commitments.
A final risk is not physical, but psychological. The major risk for most patients is that even after spending all the time, money and energy required for a treatment cycle, they will not get pregnant. Couples undergoing IVF and GIFT have described the experience as an emotional roller coaster. The treatments are lengthy, involved, and costly. These procedures often create high expectations but are more likely to fail than to succeed in a given cycle.
The unsuccessful couples will feel frustrated in their quest for pregnancy. It is common to feel angry, isolated, and resentful toward both the spouse and the medical team. At times, this feeling of frustration leads to depression and feelings of low self-esteem. The support of friends and family members is very important at this time.
The danger of overtreatment and undertreatmen
IVF techniques have now become well established, and most towns in India have one or more IVF clinics today. This is all for the best, because infertile couples no longer need to travel long distances for IVF treatment. However, because offering IVF has become a fashionable trend, there are now too many IVF clinics in competition with each other. Many of these clinics are poorly equipped, and the staff inadequately trained, with the results that pregnancy rates are poor. Many clinics have started, and then closed down in a few months, without being able to achieve even a single pregnancy - dashing many patients’ hopes in the process. Unfortunately, this often means that all IVF clinics start getting a bad reputation. In order to protect yourself, it’s a good idea to ask the clinic staff to actually show you the embryos under the microscope. Most good clinics do this routinely, and some even offer video records. Not only is this reassuring for the patient, it also helps them to "bond" with the embryos!
Another danger of too many IVF clinics is the risk of overtreatment. In order to remain profitable, many clinics now offer IVF to infertile couples as a treatment of first choice (rather than reserving it for patients who truly need it). While this does help them to keep their financial bottomline healthy and to increase their pregnancy rates (since many of these patients are young couples, who never needed IVF in the first place!), it is an inappropriate use of limited medical resources. IVF treatment should be reserved only for patients who really need it. Paradoxically, while rich patients end up getting IVF even when they don’t need it, poor patients are often deprived of this treatment even though they need it, because of the expense involved. Unfortunately, the Government still does not consider that providing infertility treatment should be a part of its family planning program. Hopefully, this will change in the future, and providing infertility services will be seen to be a part of comprehensive reproductive care services. This will provide many more infertile couples access to assisted reproductive technology.
Supporting each other
You may not be able to comfort each other enough at times of disappointment, especially when you are both upset. If you don't have a family or a friend who can provide support (without pressure), then the positive and sensitive assistance was offered by a support group may be very suitable, either in the short term or longer. Yet other people may seek the more specialized assistance of a counselor, who is either attached to the clinic or based in the community.
Going through an IVF cycle can be very stressful, and you need to be prepared for the ups and downs. Many clinics have found that optimistic and well-prepared patients do have better pregnancy rates, and counseling and emotional support can be very helpful in improving your chances of getting pregnant!
Every time you start a cycle, you have to hope for the best and be prepared for the worst. It literally is like gambling - and hoping that you hit the jackpot! Many patients find the first cycle the most stressful - and find it much easier to do a second cycle, because they are more in control and understand much better what they are going through.
If you judge the outcome of an IVF cycle only on the basis of whether or not you get pregnant, then with the limitations of today’s technology, you are more likely to be disappointed than otherwise. However, do remember that each cycle also provides you with valuable information, such as whether the sperm fertilize the egg or not, so that you can plan your future course of treatment. Going through an IVF cycle can also give you peace of mind that you tried your best!
Selecting an IVF/GIFT Program
There are now over 300 IVF clinics in India, so how do you go about selecting the best? This can be difficult and confusing, but remember that when selecting an IVF program, information is crucial. Important points for consideration include the qualifications and experience of personnel, types of patients being treated, support services available, cost, convenience, and rate of successful pregnancies. Older programs have established live birth rates based on years of experience. Although new programs won't have as much experience and may still be determining their live birth rates, their personnel may be equally qualified.
The range of services offered by an IVF program should be carefully considered. Not all programs are equipped to provide all services, such as tubal transfer, ZIFT, sperm donors, ICSI and cryopreservation of embryos. It is best to select a full-service clinic, which offers all the possible treatment options, so that the one which is best for you can be used.
The above considerations and answers to the following questions, which may be asked of the program, will help you make an informed decision when choosing an IVF/GIFT program.