— Paolo Memorial Hospital
Paolo Memorial Fertility Center by Superior A.R.TPaolo Memorial Hospital was established 19 May 1972, is one of the nation’s top-ranked private hospitals with general medical practitioners and specialists using modern medical equipment in Thailand including excellent services in Obstetrics and Gynecology and Infertility for 43 years.
Since there has been a significant increase in infertility in the last few years. Paolo Memorail’s expert doctors in collaboration with superior A.R.T give hope to couples with infertility problems. The centre gives infertile patients several fertility options with a personalized approach. Superior A.R.T. offers a high-technology diagnostic assessment ,early intervention and the most advanced IVF.
- PGD-PCR | % Pregnancy/Transfer 63% And % Implantation/Embryo Transferred 56%
- PGD-CGH | % Pregnancy/Transfer 58% And % Implantation/Embryo Transferred 50%
- IVF | Pregnancy Rate for Single Blastocyst Trnsfer % Pregnancy/Transfer 48%
- Frozen Thaw Cycles Survival rate Literature standard 95% Achieved – Superior A.R.T. 97% And Pregnancy Rate 52%
In vitro fertilization (IVF)
What is IVF?
IVF stands for in vitro fertilisation. In vitro literally means ‘in glass’ and with this form of assisted conception, fertilisation takes place in a dish in the laboratory. (At one stage, scientists also used test tubes for fertilisation, hence the term “test tube baby”. Any assisted conception procedure where fertilisation takes place outside the body is a form of IVF. IVF was originally devised to overcome infertility caused by blocked or absent fallopian tubes. Today, IVF is used to treat many more reproductive problems, including irregular ovulation, low sperm count or motility, and unexplained infertility.
How IVF works
Depending on a woman’s age, anywhere between 1 and 30 follicles, known as ‘recruits’, will begin to develop in each menstrual cycle. Whatever her age though, only one of these developing follicles will dominate and ovulate at the level of the hormone FSH that a woman produces naturally. With IVF, the goal is to keep the level of FSH constant, and thus to encourage more of the recruits to develop mature eggs, which are collected surgically under vaginal ultrasound guidance. The eggs are then fertilised in the laboratory, cultured for several days, and then one, or rarely two embryos are transferred back into the woman’s uterus.
The steps in an IVF cycle are:
- Preventing premature ovulation (the LH surge) by shutting down communication between the brain and the ovaries, so that the eggs are not lost before they can be collected
- Stimulating the ovaries with injections of FSH
- Triggering ovulation by replacing the LH surge at mid cycle with an injection of hCG
- Collecting the eggs and sperm
- Culturing embryos in the laboratory
- Transferring the embryo/s
- Supporting the endometrium in the luteal phase with hCG or progesterone
Stimulating the ovaries with injections of FSH
By prescribing a carefully controlled dose of FSH and other hormones and monitoring their effects, your doctor aims to bring to maturity as many of your immediately available follicles as possible, while preventing them from ovulating prematurely. It’s important to understand that no amount of FSH will stimulate more follicles than are available to be recruited. The dose needs to be enough to stop the usual competition that takes place among them, but once that threshold is reached there isn’t a lot of control possible over the number of recruits that will grow. Secondly, using FSH injections does not use up follicles and their eggs any faster than they’re already being used anyway. They actually began their development months earlier. And the non-recruits – those that don’t produce mature eggs – are simply reabsorbed. More is not better when it comes to FSH dosing. If the dose is too high it can be damaging to the eggs and may also put a woman at risk of ovarian hyperstimulation syndrome. The duration of FSH administration is also important. The normal length of the follicular phase generally needs to be made available to the growing follicles, which takes 11 days or more. We usually check a woman’s estrogen level after 3 or 4 days of stimulation. If there does not seem to be much response, the dose of FSH can be increased. If the response has been too brisk, the dose of FSH can be reduced gradually. Patients have their first ultrasound after 7 or 8 days of stimulation. Ultrasonographers who are very familiar with follicle tracking perform the ultrasound examinations. The need for further monitoring will be determined by a woman’s individual response, and may require blood tests and ultrasounds every other day until the follicles reach 18-20mm in diameter, large enough to contain a mature egg.
A ‘natural cycle’
It is possible to have an IVF cycle without having any hormone treatment. This is called a ‘natural cycle’, and just one egg is collected for fertilisation in the laboratory. However, we want to make use of all the eggs that are developing in the month of treatment in order to give you the best chance at pregnancy with just one IVF cycle.
It’s not possible to determine precisely how many eggs a woman has left. However, a doctor can get a sense of her ‘ovarian reserve’ by checking an FSH level and a pelvic ultrasound early in the cycle.
Preventing premature ovulation
Shutting down communication between the brain and the ovaries so that the eggs are not released before they can be collected
This is done using GnRH-analogs, a group of drugs closely related to the natural hormone gonadotrophin releasing hormone (GnRH), a hormone produced by hypothalamus in the brain that controls the release of FSH and LH by the pituitary gland. There are two types of analogs – agonists and antagonists – that prevent an LH surge in different ways. GnRH agonists first cause a flare of FSH and LH as they stimulate and then inhibit, or down regulate, the pituitary. There are two kinds of agonists available in Thailand – a nasal spray and an injection forms. Your doctor will consider which form is suitable for your case. GnRH antagonists are a newer class of injectable medication with the advantage that they drop levels of FSH and LH without first causing the flare, meaning they are given for a much shorter period of time. They are usually started on the sixth day of FSH stimulation. The antagonists, marketed in Thailand as Cetrotide® and Orgalutran®, are a little more expensive than the agonists and are no more effective in preventing the LH surge or in leading to pregnancy. Nonetheless, they may be of value in women who produce only a low number of eggs in an IVF cycle (particularly older women) or for women who prefer the convenience of a shorter treatment time. Which drug your doctor prefers to use will depend on factors such as age, previous response to treatment and convenience.
Replacing the LH surge at mid cycle with an injection of hCG
It’s not presently possible to use synthetic LH to mimic the natural surge, as the duration of action of currently available LH is too short. Using hCG (human chorionic gonadotrophin) to replace the natural LH surge sets in motion everything that makes ovulation happen, causing the egg in the mature follicle to be fertilisable and loosening it from the wall of the follicle so that it comes out with the follicular fluid at egg retrieval. It takes just over 38 hours for ovulation to occur after an injection of hCG. Eggs are mature and can float free from about 34 hours after hCG, giving a four-hour ‘window’ for egg retrieval, which is typically scheduled 36 hours after the hCG trigger. hCG is marketed either as Pregnyl®, a powder or Ovidrel®, delivered in a pre-filled syringe. Your doctor will prescribe the suitable form for your case. Intercourse must be avoided from Day 3 of FSH stimulation, as not all of the eggs might be collected. There is then a small chance of spontaneous conception, which increases the risk of a multiple pregnancy when additional embryos are transferred.
Egg collection involves the aspiration or drainage of the fluid from the pre-ovulatory follicle. The procedure is carried out through the top of the vagina to either side of the cervix, and is guided by a transvaginal ultrasound.
Egg collections are fast and relatively non-invasive operations. At Superior A.R.T. we use a “light” general anaesthetic, it can be likened to a strong sedative. It invokes a minimal degree of muscle relaxation and loss of sensation, and breathing is maintained naturally, although a breathing mask is used to both administer oxygen when required, and to top up the sedation with a ‘gas’ sedation if required.At Superior A.R.T. an anesthesiologist will give you the medicine and closely follow your progress.We use a short-acting intravenous anesthetic agent for the induction of general anesthesia; it has a rapid onset (about 40 seconds) and a short duration of action, allowing patients to wake up, recover, and return to baseline activities and diet sooner than some other sedation agents. If required we use a ‘vapor’ or ‘gas’ to maintain loss of consciousness during surgery when required, eg. where procedure is long or longer than expected. It is inhaled and is a fast-acting, non-irritating anaesthetic agent whose administration has been associated with a smooth, rapid loss of consciousness during inhalation induction and a rapid recovery following discontinuation of anaesthesia.
Following administration of the ‘light’ general anaesthetic, the ovaries are scanned, just as they are during follicle tracking. The follicles are aspirated using a needle passed through the wall of the vagina beside the cervix and into the ovary. Your partner is not permitted in the theatre. There’s often a small amount of bleeding from the wall of the vagina. Other complications such as major bleeding, damage to an internal organ or infection are possible, but rare. After the follicles have been emptied they often fill up again with fluid, so the feeling of fullness may return. Some women also complain of a cramping sensation for a few days following egg collection. This can be relieved with paracetamol (with or without codeine). Side effects are often more marked after the procedure, as the hormone processes following ovulation persist, even though the eggs have been taken out. These side effects include mood changes as before, but also physical effects indicative of heightened ovulation such as pronounced abdominal swelling, breast tenderness and lower abdominal discomfort.
Your Superior A.R.T. embryologist is located in the adjoining embryology laboratory. As the follicles are emptied the collected fluid is passed to the embryologist, who using a powerful microscope, begins locating and extracting the eggs, transferring them to special plastic dishes ready to be incubated.
After your procedure, we will take you to the recovery room. Your partner can be with you after you wake. Since you’ve had a light general anaesthesia, make arrangements for an adult to be responsible for you and to accompany you home. Do not plan to drive yourself or travel alone; it’s unsafe to do so, no matter how well you feel. Be sure not to carry out any critical activities – such as driving a car, operating machinery, or signing important documents – for 24 hours from the time of your anaesthesia. It is not usually necessary to take time off work on the days following the procedures, but if you feel that you need a medical certificate, you can discuss this with the nurses. If the male partner has an PESA or TESA operation at the same time as the female partner has her egg pick-up, you will need a third person to take you home. In the very unlikely event that further surgery is needed for your safety, Superior A.R.T. day surgeries are fully equipped to handle emergencies.
Soon after egg collection the male partner has his role to play and will be asked to proceed to one of our collecting rooms. It is also possible to collect at home, if you live within an hour of the lab. Sperm can be frozen in advance of the day of egg collection if you anticipate difficulties. Superior A.R.T. scientists look for two things in a sperm sample – freshness, and the quality of sperm. To ensure that the sperm is fresh we recommend ejaculation on the same day as the hCG trigger. To maximise the quantity of sperm, ejaculation should then be avoided until after the egg collection.
Culturing the embryos in the laboratory
After collection, the eggs and sperm are brought to the laboratory where the eggs will be fertilised and the embryos cultured for 5 days. In conventional IVF, about 50,000 to 100,000 washed sperm are left in a small plastic dish with the eggs. The sperm spend the next few hours getting through the layers of cumulus cells, and hopefully one sperm will successfully fertilise the egg. By the next day – some 15 hours after introducing the sperm to the eggs – the scientists will check to see if the eggs have fertilised by looking for the presence of pronuclei. In normal fertilisation there should be 2 pronuclei – one from the sperm and one from the egg. Not all eggs will fertilise normally, which is common. We consider it a good result if 80% of the eggs collected have two pronuclei on Day 1.
Intracytoplasmic sperm injection (ICSI)
Intracytoplasmic sperm injection (ICSI) can be used to fertilise eggs when your doctor thinks there is a decreased chance of fertilisation occurring with conventional IVF, either because of problems with low sperm numbers or low sperm motility, or because of other barriers to the fertilisation process such as sperm antibodies or previous failure to fertilise through IVF. A single sperm is injected into each egg. The sperm is selected mainly on the basis of its normal shape and size.
Once fertilisation has occurred, the embryo will divide and rapidly increase in cell number over the next few days. By Day 4, the cells have divided rapidly but the embryo has not yet increased in size. It is now compacting (you cannot distinguish the cells) and is called a morula. If the embryo survives to Day 5 – the blastocyst stage – it will contain between 75 and 100 cells. It is a 3-dimensional ball of outer cells (the trophectoderm) surrounding a fluid-filled cyst in which an inner group of cells, the inner cell mass can be seen. The trophectoderm will go on to form the placenta, membranes and umbilical cord, while the inner cell mass will become the baby. We cannot tell the difference between a good embryo and a bad embryo just by looking at them. Embryos at the best of times are busy transforming and repairing themselves, so can develop fragmentation (which is when small bits of cells are pinched off during division) or vacuoles, which are small spaces within the substance of the cells. The significance of these changes is not known and many fragmented and vacuolated embryos can go on to form perfectly healthy pregnancies. While many embryos can survive 2 or 3 days to reach the 4-6 cell stage, only the strongest will have the ability to keep developing into a blastocyst and then a baby. One way of identifying the better embryos, therefore, is to let them grow a little longer in the laboratory and to transfer them at the blastocyst stage. It is a good way of determining which embryos have the most developmental potential. Our world-leading success with blastocyst culture and implantation means that blastocyst transfer is standard at Superior A.R.T. centre. An embryo needs two things to reach Day 5: enough energy, and normal chromosomes.
An embryos energy supply comes from tiny structures inside its cells called mitochondria. The embryo needs to survive on the energy produced by the mitochondria it inherits from the egg until it has implanted and formed a placenta. Because all the mitochondria in an embryo come from the egg they are inherited from the mother. And because women are born with all their eggs for their lifetime already formed, the mitochondria in your eggs are as old as the eggs themselves.
Embryos must also have the right genetic makeup to develop normally. In humans, genes are contained in 23 pairs of chromosomes. An incorrect number of chromosomes leads to failure of an embryo to implant or to progress to a normal birth. Pregnancy is a great filter of abnormal embryos. When chromosome analysis is performed on cells from Day 3 embryos, studies have shown that only one third will have the normal number. If an embryo progresses to Day 5 and becomes a blastocyst, it has a two-thirds chance of being chromosomally normal. 90% of chromosomally abnormal pregnancies will miscarry in the first trimester. 93% of chromosomally normal pregnancies will continue to term.
An embryo transfer to the uterus is usually straightforward and painless: no more (or less) uncomfortable than having a Pap smear. After a speculum is placed in the vagina, a fine plastic catheter that has been loaded with the embryo is passed through the cervix into the uterus. Many people think that the uterus looks like it does in most diagrams, with a cave-like interior in which transferred embryos can rattle around and even fall out! In reality, the endometrial cavity is a potential space. In fact, the front and back walls of the uterus are in contact like two slices of bread with jam in the middle; the embryo is like a raspberry seed wedged in between. No matter what you do, it won’t fall out!
After the embryo transfer
The effects of the hCG injection wear off within a week and the ovaries may not produce enough progesterone on their own to support a pregnancy. Extra doses of hCG (Pregnyl®), or progesterone (Crinone® or Cyclogest® vaginal tablet) are required until the outcome of the cycle is known. A pregnancy test is not reliable until 16 days after egg collection. This can be the most nerve-racking time of the whole treatment cycle. Many people will feel simultaneously elated (there’s a new chance of pregnancy) and deflated (there is much less to do compared with before the egg retrieval, there is less information and, unless you have specific questions, there is much less contact with people at the clinic).
“The two-week wait”
Once all the stages of the IVF cycle have been completed, there’s nothing more to be done than wait for the time to pass before the results – whether or not the pregnancy has started – are known. Some refer to this time as the dreaded “two week wait”, because such a protracted period of uncertainty after so much forward activity can be stressful. Our counsellors, nurse coordinators and your doctor are all available to help during this time.
After ovarian stimulation and egg pick-up, there are often more embryos than the one or two needed for transfer in that cycle. If there are healthy-looking embryos left over from the IVF cycle they may be placed in cryo-storage. By freezing these embryos, you have the chance to attempt pregnancy more than once after only one stimulated cycle. Note that not all unused embryos are suitable for freezing. At Superior A.R.T. we use a method called vitrification to freeze and cryo-store embryos. Vitrification is an ultra-rapid cooling technique which allows embryos to be efficiently cryo-preserved without any damaging ice formation; therefore this method improves survival upon re-thawing. Compared to conventional freezing, vitrification is cost-effective, time-effective, and shows significantly better results in terms of survival and pregnancy rates following thawing. Vitrification, used in conjunction with blastocyst culture and single embryo transfer, significantly improves the chance of a pregnancy from a single stimulation cycle while avoiding the complications of multiple pregnancies. Vitrifying and storing embryos reduces the amount of hormone treatment you receive and also the number of times your ovaries are stimulated. Some people have two or three embryo transfers after just one stimulated cycle. Frozen embryo cycles involve either monitoring your menstrual cycle for ovulation and transferring the embryo at the right time or using sequential medication to mimic the hormones of a natural cycle.
Risks, cancellations and side effects
Things to be aware of with IVF
To help you understand what you can expect to encounter during your treatment, you need to be aware that things do not always go according to either desire or plan. Some problems are temporary setbacks or conditions; others can take a considerable emotional and physical toll.
Ovarian hyperstimulation syndrome (OHSS)
It’s normal for the ovary to produce fluid in the abdomen as a follicle grows, and to bleed at ovulation. And it’s normal for a corpus luteum to form in the ovary and become cystic in the second half of the cycle. Pain can accompany ovulation and the formation of the corpus luteum, while premenstrual tension can cause bloating, irritability, depression and breast pain. When the ovaries are stimulated to increase the numbers of follicles, as occurs in IVF, all these events and their symptoms can be more pronounced than you might expect in a natural cycle. There are three classifications of OHSS severity:
- Mild OHSS – accompanied by enough pelvic pain in the luteal phase to cause a woman to want to rest in bed for a day or two. This occurs in 1 in 30 stimulations.
- Moderate OHSS – requires a hospital stay, mainly for observation and to enable us to give adequate relief of pain. This occurs in about 1 in 250 stimulations.
- Severe OHSS – in about 1 in 1000 stimulations there’s enough fluid in either the abdomen or the chest to be of serious medical concern.
OHSS is a self-limited condition and the ovaries will almost always completely recover.
We occasionally find that the ovaries fail to stimulate, and cancelling the cycle may be recommended. Less than 5% of cycles are cancelled. A cycle might be cancelled because:
- Your follicles are not responding to hormone treatment
- Your follicles are over-responding to the hormones, risking hyperstimulation
- Uterine problems such as fibroids or polyps are unexpectedly detected on ultrasound
- Personal reasons.
If you’re at risk of hyperstimulation or if a problem is discovered in the uterus, your doctor might suggest that you have a freeze-all cycle rather than cancel the cycle completely. In a freeze-all cycle, the eggs are collected and fertilised then cryo-stored. Because pregnancy or further hormone injections will worsen the risk of ovarian hyperstimulation syndrome (OHSS), a freeze-all cycle is a safer option. This gives the ovaries time to settle down before attempting pregnancy at a later date. When returning for the frozen transfers, there is no need to have any stimulation of the ovaries at all.
Multiple pregnancy risk
At Superior A.R.T., we would like to help you grow your family one healthy baby at a time. So as a rule, we only transfer one embryo. The risk of a twin pregnancy after a single blastocyst transfer is around 2%. In certain circumstances, such as older age of the woman or previous unsuccessful treatment, we will consider transferring two embryos. If you’ve had trouble conceiving, the idea of having two babies at one time might seem like a blessing. However, the death rate of twins between 5 and 9 months of pregnancy is 6 times that for single baby pregnancies, while the mortality rate from IVF twins following birth is 4.5% or nearly 1 in 20. In 2002, Sydney IVF undertook a study in a special subset of couples who had several high quality embryos suitable for both transfer and freezing. They compared the ‘take home baby’ rate in women under 38 who had two embryos transferred during the fresh cycle with those who had one embryo transferred fresh. Both groups later had frozen embryo transfer cycles if they needed them. The end result was the same: approximately 70% of women in both groups took home a baby after one stimulated cycle. However, five babies died from premature delivery among the IVF treatments where fresh embryos had been transferred two-at-a-time.
Risks of medications
Since ovarian stimulation medications were first used decades ago, there has been concern that their use might increase the risk of cancer. Several large studies have now found that the rates of cancers among women who have used infertility drugs are not significantly different from the rest of the population. There is no evidence to date that the drugs used in assisted conception causes either breast or ovarian cancer.
No fertilisation; no embryo development; no implantation
Fertilisation can fail, and fertilised eggs can fail to divide or undergo cleavage properly. The reason can lie with the sperm (usually fertilisation failure rather than cleavage failure), with the egg, or both. And sometimes it can lie with the lab. Fertilisation can fail when not enough sperm attach to the egg’s surrounding coat. This can happen because the number of healthy sperm is too low, or because there are antisperm antibodies that prevent sperm from attaching. Either way, future cycles can overcome this problem by using ICSI. In addition, fertilisation and/or cleavage might fail if the follicles from which the eggs were extracted had begun to fail prior to egg collection. This can be an inherent problem with the ovaries, or it can result from suboptimal stimulation. Most embryos that fail to implant and/or fail to result in a baby (even though they might look normal in the lab) fail through a combination of intrinsic and extrinsic shortcomings. Intrinsic shortcomings might be based on insufficient metabolic energy or an abnormal chromosome count. Extrinsic shortcomings might occur during follicular stimulation or during laboratory handling.
Stresses associated with infertility
IVF treatment can be stressful and intrusive. There are various reasons for this including:
- Demands of stimulated treatment (daily injections, the need for blood tests early in the day, ultrasounds etc)
- Stresses associated with procedures (having an invasive procedure; the discomfort sometimes experienced; providing a semen sample on the day of the egg pick-up)
- Stresses associated with periods of waiting (such as waiting for fertilisation results; pre-embryo checks; and the long wait between transfer and pregnancy test, then the wait for the pregnancy test result)
- The possibility of treatment not being successful.
Luckily, stress itself does not jeopardise the chance of IVF working. Many people have remarked that they have felt worn down by the stresses and the losses associated with infertility. It’s not uncommon for people to experience grief in response to the many losses experienced, as well as other emotional responses such as depression and anxiety. With this in mind, you should be aware that Superior A.R.T. provides counselling services that can greatly assist in managing this emotional impact.