A Cheaper Alternative To IVF

A landmark in the development of fertility treatment was announced by doctors yesterday with the birth of the first babies to be conceived using a revolutionary technique that offers a safer, cheaper alternative to IVF. The twin boy and girl, who were born on 18 October at the Radcliffe Infirmary in Oxford, were conceived using In Vitro Maturation (IVM), a method that dispenses with the use of costly fertility drugs, saving up to £1,500 (INR 120,000) on the normal price of treatment. The technique is also safer for the one in three women among those seeking fertility treatment who have polycystic ovaries, a condition that puts them at high risk of dangerous side effects from fertility drugs. Specialists said the development could make in vitro techniques available to more infertile couples by cutting the cost of treatment. Infertility is estimated to affect one in six couples in the UK but IVF costs around £5,000 (INR 400,000) a cycle and treatment is restricted on the NHS!

Tim Child, a consultant gynaecologist at the Oxford Fertility Clinic and senior fellow in reproductive medicine at Oxford University, who led the work, said: "I think it is a safer, cheaper alternative to IVF for all women. However, for many women the success rates are currently much lower. Research in the future will address this." The Oxford Fertility Clinic is the only one in the UK licensed to use the technique: 20 cycles of treatment have been carried out and four other women are currently pregnant, giving a pregnancy rate of 25 per cent. This is expected to improve with further experience. In addition, without the need for drugs, repeating the procedure would be less taxing on the woman. For standard IVF, the Oxford clinic's pregnancy rate is 45 per cent.

The parents of the babies, who have asked to remain anonymous, were delighted, Mr Child said. At birth the boy, born first, weighed 6lb 11oz and the girl weighed 5lb 14oz. "The parents are ecstatic. They have got absolutely stunning twins. They went home on Tuesday to start their new life together. It is wonderful."

In standard IVF, the woman takes fertility drugs for five weeks to stimulate production of her eggs, which are then collected direct from her ovaries under the guidance of ultrasound, before being fertilised in the laboratory. The drugs cost between £600 and £1,500, with charges often higher in London. The procedure is time consuming and uncomfortable and for the third of women with polycystic ovaries there is a one in 10 risk of severe ovarian hyperstimulation syndrome, a dangerous side-effect that in rare cases can prove fatal.

IVM avoids the use of drugs and instead involves collecting eggs from the ovaries while they are still immature. The eggs are then grown in the laboratory for 24 to 48 hours before being fertilised and replaced in the womb. The technique was pioneered by the University of McGill in Montreal, Canada, where Mr Child spent two years researching and developing it before joining the University of Oxford in 2004. It has also been used in Seoul, South Korea, and Scandinavia. To date about 400 babies have been born worldwide using IVM compared with around two million by IVF. At present the Oxford Fertility Clinic is only offering the treatment to women with polycystic ovaries, but in the long term Mr Child said he hoped to offer the procedure to all women. "When we see patients we say these are the options and it is up to them to decide. We are not offering it to women with normal ovaries at present because we don't get enough eggs from them. It depends on the number of resting follicles and with normal ovaries you don't get so many.

"On average we get four eggs from a woman with normal ovaries compared with 16 from one with polycystic ovaries. The procedure involves a process of attrition – two-thirds mature and two-thirds of those fertilise – so you need a decent number to start with." Research on developing the culture medium in which the eggs are matured in the laboratory could reduce the attrition rate so that fewer eggs are needed. The technique could then become suitable for women with normal ovaries, Mr Child said.

A second drawback of the procedure was that eggs grown in culture had a harder outer shell than those matured in the ovary and were more difficult for sperm to penetrate. The eggs had to be fertilised by ICSI – injecting a single sperm directly into the egg. "We hope to develop the culture medium so the egg doesn't mind being grown in the laboratory and we can use ordinary insemination [mixing eggs and sperm so fertilisation occurs naturally]. But in most IVF clinics, 50 per cent of patients are treated with ICSI anyway," he said. "Anything that reduces the cost of IVF, provided it is safe, means treatment could be available to more people. But this is an emerging technology – it is very early days. The most important thing is that patients get proper information so that they can make a decision on what is best for themselves."

Embryo Biopsy

Since the birth of the first baby achieved through conception outside of the human body in 1978, the principles of "in vitro" fertilization and culture have remained the same - careful establishment and maintenance of a well-controlled, sterile environment in which the normal physiology of fertilization and early development can be played out relatively undisturbed to provide healthy embryos for transfer back into the body. During the ensuing two decades, much has been learned, however, about the tolerances of such a system and how this technique can be exploited to treat a widening range of infertility cases. There have been great strides made in development of more appropriate culture media that has enabled embryos to be grown for extended periods of time in culture. Surplus embryos and possibly eggs may now routinely be cryopreserved in liquid nitrogen for use in subsequent attempts at pregnancy. Fertilization itself is no longer a hit-and-miss affair with the advent of assisted fertilization through micromanipulation. Embryos can be micro-manipulated for cell biopsy to determine their genetic status as well as aid in their ability to implant through drilling into their outer shell (assisted hatching). Embryo Biopsy is performed for preimplantation genetic diagnosis (PGD) and enables the screening of both the unfertilized egg by removal of the first polar body, or the fertilized multi-cellular embryo by removal of one or more cells either at the 6-12 cell stage(see picture) or from the trophectoderm of the blastocyst. This material can be probed for both genetic mutations or gross chromosomal errors. This technology remains in its infancy and can be of profound importance clinically, but at this time only for cases with very clear medically-defined needs. The biopsy procedure requires very exacting skills of the IVF laboratory, and the egg or embryo is not entirely free of risk during the procedure. Hence, couples whose offspring have a high chance of inheriting a genetic disorder may have their embryos screened. Women who are at risk of generating eggs with a high risk of chromosomal anomalies can benefit from having their eggs or embryos screened for chromosomal normality.

Risks Associated With Fertility Medications

The controlled "superovulation" techniques used in IVF are designed to stimulate the ovaries to produce several eggs (oocytes) rather than the usual single egg as in a natural cycle. Multiple eggs increase the potential availability of multiple embryos (fertilized eggs) for transfer and ultimately increase the probability of conception. The medications required to boost egg production may include, but are not limited to the following: Lupride/Gonapeptyl (gonadotropin releasing hormone-agonist), Antagon or Cetrotide (gonadotropin releasing hormone-antagonist), Menopur, Bravelle or Gonal-F (FSH, follicle stimulating hormone), GMH(combination of FSH and LH, luteinizing hormone), and Choragon or Ovidrel(hCG, human chorionic gonadotropin). Each is administered by injection only. Most medications are given subcutaneously (beneath the skin), though some are intramuscular injections (into the muscle). Risks associated with injectable fertility medications may include but are not limited to, tenderness, infection, hematoma, and swelling or bruising at the injection site. Risks associated with the medications may include, but are not limited to, allergic reactions, hyperstimulation of the ovaries (mild, moderate or severe), failure of the ovaries to respond and cancellation of the treatment cycle.

There are situations that can occur during a stimulation that may necessitate canceling your IVF cycle and stopping treatment for a period of time. This occurs because the ovaries produce either too many or too few eggs in response to drug stimulation protocol. Although we realize that this can be a big disappointment, at times it is necessary to discontinue the use of the medications to avoid the possibility of complications and to afford you the best chance of future success. If canceling the cycle becomes necessary, you will be told to stop your injections. No hCG injection will be given and no egg retrieval will occur. You will be asked to schedule an appointment with your physician to make decisions regarding future treatment cycles.

When ovulation induction medications are used in fertility therapy, the ovaries are coaxed to produce more than one egg to the point of maturity. Consequently, hormone levels of estrogen and progesterone reach much higher than normal values. When the estrogen level becomes mildly to moderately elevated, side effects that may be experienced include, but are not limited to, fluid retention with slight transient weight gain, nausea, diarrhea, pelvic discomfort due to enlarged cystic ovaries, breast tenderness, mood swings, headache and fatigue.

If the estrogen level rises excessively and hCG is administered to trigger final maturation of the eggs, the following more serious complications may result:

Excessive fluid retention with fluid in the abdomen and/or chest cavity;
Thrombosis of arteries and/or veins (formation of blood clots) which may lead to stroke, embolus, or potentially fatal complications;
Abnormally enlarged ovaries, which have the possibility of rupturing or twisting (a surgical emergency)
Any of the three problems listed above may require prolonged hospitalization.

Given the potential for such severe complications, it is important that we carefully monitor the response to these medications. This monitoring also allows your physician to determine when the eggs are ready for the next stage, oocyte (egg) retrieval. Monitoring includes frequent blood drawing for estradiol (estrogen) and possibly progesterone, LH and FSH levels. These blood tests will take place over approximately a twelve-day period. Risks associated with blood drawing may include, but are not limited to:

Pain at the site of needle stick
Tenderness or infection of the skin
Bruising or scarring of the site of blood draw
Development of a blood clot in the vein (thrombosis, thrombophlebitis)

The second portion of the monitoring phase in IVF involves the use of intravaginal ultrasound to track follicular growth. The eggs develop inside fluid-filled cysts of the ovaries called follicles, which enlarge as the eggs mature. Ultrasound studies usually begin after an estrogen response has been measured and continue on a frequent basis until oocyte (egg) retrieval. The ultrasound studies are performed using a vaginal probe. Vaginal sonograms carry no appreciable risk but may cause slight discomfort, particularly as you near the point of ovulation.

Intracytoplasmic Sperm Injection (ICSI)

Through the controlled application of ovarian hyperstimulation, it is current practice to time the retrieval of mature oocytes (eggs) from a woman's ovary. The yield may vary anywhere from one to 30 or more eggs that may be retrieved depending on the responsiveness of the ovaries to the gonadotropins used to stimulate them. These eggs are gathered by the embryologist into an appropriately balanced salt solution and maintained at body temperature (37°C) until such time as they are ready to be inseminated. Meanwhile, a sample of semen containing the sperm destined to be used for each specific set of eggs is collected and processed by cell separation techniques to provide as clean and active a sample of sperm as possible. A major emphasis of the IVF laboratory is directed toward guaranteeing that the correct sperm go with the right eggs through good labeling and check systems. Ultimately, following several hours in culture, eggs and sperm can be mixed and allowed to bind and fertilize in a relatively natural fashion. Depending on the quality and maturity of both eggs and sperm, it is common for fertilization rates to vary considerably relative to the original number of eggs collected. Twenty eggs retrieved in no way guarantees 20 embryos. Likewise, 20 fertilized eggs in no way guarantees that there will be 20 embryos of sufficient quality for both cryopreservation and fresh transfer to the woman's body.

Central to the question of how many embryos are actually utilized in any IVF treatment cycle is the period during which the embryos are cultured in vitro. This can be as little as one day, or up to five in the case of blastocyst growth and transfer. Assuming that culture conditions are relatively optimal, there is less and less reason not to culture embryos throughout their pre-implantation stages to allow the embryos to "select" themselves for transfer or cryopreservation. The blastocyst is the term given to the very last stage of an embryo prior to it implanting into the endometrial lining of the uterus. The poorer the rates of blastocyst growth are, the more restricted the choice of embryo is at this stage of development. In any event, growth of any embryos to the blastocyst stage improves the level of discrimination of embryo viability available to the embryologist, and is key to reducing the numbers of embryos used for uterine transfer. The more confidence a clinic has in the viability of the embryos it transfers, the less need there is for multiple transfers of three or more embryos. Thus with the transfer of three or less embryos, the risk of multiple pregnancies is significantly reduced, in turn minimizing risks of pregnancy loss or fetal abnormalities common in multi-fetal pregnancies.

Micromanipulation is the technique whereby sperm, eggs and embryos can be handled on an inverted microscope stage, performing minute procedures at the microscopic level via joysticks that hydraulically operate glass microtools. Micro-manipulation first saw clinical use in IVF for purposes of assisted fertilization in the treatment of male factor infertility, where fertilization potential was low in cases of poor sperm quality. The ultimate evolution of this approach has been the development of the single sperm injection procedure referred to as Intracytoplasmic Sperm Injection, or ICSI. Sperm of virtually any quality and from any level of the male reproductive tract may be used with the only criterion for use being that the sperm is alive even if it is not moving (motile). Dead sperm may be able to achieve fertilization; however, the DNA or genetic material from such sperm is too degenerate to form a viable embryo. Immature sperm from the testicle or the epididymis can be retrieved for use with ICSI for men who possess no sperm in their ejaculated semen (azoospermia). This azoospermia is either due to an obstruction in the tract (obstructive), or to extremely low production of sperm in the testicle itself (non-obstructive). In certain cases, men may produce sufficient sperm, but they do not survive to the point of ejaculation (necrozoospermia). Consequently, instead of using non-viable sperm from the ejaculate, testicular biopsy will provide a ready source of freshly produced viable sperm.

With the almost unlimited potential to achieve some level of fertilization with ICSI regardless of sperm quality, it would seem that male factor infertility would no longer be of concern. It must be noted, however, that sub-fertility in men can be related to certain numerical and structural defects of the chromosomes and, therefore, there is a strong recommendation for all couples that achieve pregnancies from ICSI to undergo prenatal screening. In certain cases of obstructive azoospermia, there is a higher incidence of cystic fibrosis in the male. Hence, before embarking upon treatment of the more extreme forms of male factor infertility, it is advisable to have some cytogenetic screening performed. Incidentally, very subtle compromise in sperm quality may well be responsible for a marginally lower embryonic viability rate and a slightly higher early miscarriage rate even if such embryos implant. Such observations have led to the suggestion that the technique ICSI itself is at fault; but this misses the point that ICSI per se is not causing the problem, merely facilitating the use of sperm, which under other circumstances would never have even achieved fertilization.

The use of ICSI is now routinely applied to a range of clinical situations wherever there is a possibility that conventional in vitro fertilization may be suppressed or not occur. Such situations include the following: idiopathic or unexplained fertility; hyper-responsive ovarian stimulation cases where egg quality may be reduced; post-thaw sperm samples that survive poorly; post-thaw egg insemination; generation of embryos for pre-implantation genetic screening where embryos "clean" from any extraneous contaminating sperm is needed; or, indeed, any case where there is an extreme need to maximize normal fertilization, for example, when a woman has only a few eggs retrieved. It is possible to "rescue" cases following complete failed conventional fertilization with ICSI. The viability potential of these "late-fertilized" embryos is approximately half of timely fertilized embryos; nevertheless, they do generate successful live births. ICSI has become such a common feature of IVF therapy that it is fast becoming the insemination technique of choice.

Two Lawyers

Two lawyers had been life long friends: they were partners and shared everything , including their hot-blooded secretary . 

One day the secretary announced she was pregnant. They told her not to worry and assured her that they would pay all medical costs and would act as co-fathers when the child was born and provide all expenses thereafter. 

The day of delivery arrived. Both the lawyers were at the hospital pacing the floor in the waiting room. Finally one of them said, "I can't take this, I'm going down to sit in my car and wait there. Please come down and tell me as soon as the child is born!" 

The partner agreed to do that. About an hour later the partner approached the car with a very grave look on his face. 

"What happened ?" asked the waiting car occupant. 

The other partner announced, "They were twins and mine died!"


The Italian Don

An old Italian Mafia Don is dying and he calls his grandson to his bed!"
Lissin-a me. I wanna for you to taka my chrome plated 38 revolver so you will always remember me."
"But grandpa, I really don't lika guns. Howzabout you leava me your Rolex watch instead?"

"Looka here sonnie. Somma day you gonna runna da business.....you gonna have a beautifula wife, lotsa money, a biga home and maybe a couple a bambinos."

"Somma day you gonna comma home and maybe find you wife inna bed with another man.

Whadda you gonna do then....... pointa to you watch and say "Times up"?"

Blastocyst Embryo Transfer

Blastocyst transfer achieved the first IVF human pregnancy. Blastocyst transfer is claimed to be more physiological than pronucleate or cleaved-embryo transfer is as it mimics nature more closely. As the embryo advances in the development, after 5-6 days it becomes a blastocyst(see picture). This has an outer thin layer of cells, which will later form the placenta, and an inner cell mass, which will develop into the fetus. A blastocyst has about 120 cells. A blastocyst gives a better idea of the competence of an embryo and has a higher chance of implantation than a cleaved embryo. In conventional culture medium, about 20% of embryos will develop into blastocysts. Recently, the use of sequential culture medium (the embryos are cultured in different media according to their stage of growth) has enabled a larger number of embryos to develop into blastocysts. However, up to 40% of patients will not grow blastocysts and will not have blastocyst embryo transfer. The rationale behind a blastocyst transfer is that an embryo, which has failed to reach the blastocyst stage, would be unlikely to have resulted in a pregnancy. However, if it reaches the blastocyst stage it has about 50% chance of implanting. So the improved implantation rates following blastocyst transfer is due to selection of the best embryos.
Why then do 50% of the blastocysts fail to implant? A defective blastocyst (e.g. chromosomal abnormalities) is a possible cause; a non-receptive endometrium is another cause. Blastocyst embryo transfer into the uterine cavity is performed about 5-6 days after egg collection. Transfer of one or two blastocysts is recommended to avoid high-order multiple pregnancies. Supernumerary blastocysts can be frozen for future use.
Blastocyst transfer is recommended for patients who had repeatedly failed to achieve a pregnancy following the transfer of good quality cleaved embryos (If the embryo arrests and did not develop to blastocyst, this may indicate a potential egg problem). Patients who wish to achieve a pregnancy without the risk of multiple pregnancies will benefit from a single blastocyst transfer. Patients who do not wish to have their spare embryos frozen for whatever reasons may be advised to have blastocyst transfer. About 10% of the embryos that fail to develop to blastocyst in vitro may have done so if replaced inside the womb on day 2 or 3. Up to 40% of patients will not have blastocysts available for transfer. Freezing spare blastocysts is not as good as freezing cleaved embryos. But, with the advent of Vitrification, high pregnancy rates have been reported from countries such as Spain & Japan. We, at Rotunda have just embarked upon our Vitrification Program, which is as yet in a nascent stage