Deník *Články o IVF
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The truth about IVF treatment

Infertility clinics have become big business over the last two decades with 20% IVF growth every year, but the technology has failed to deliver. Explore this busy IVF site for more - many pages and video.

IVF couples want human cloning for infertility - video

Ever since the first test-tube baby was born in 1978 there have been hopes that almost every couple could one day have their own children, but the reality is far different. The failure rates with IVF can be appalling in some clinics, yet couples continue to spend a small fortune seeking help because they see it as their only hope.

The IVF industry is powered by photographs of beautiful babies held by proud parents, and being childless is so traumatic for many that almost any cost can seem worth paying. And indeed the birth of a desperately wanted child is a priceless miracle for a couple who have otherwise given up all hope apart from IVF. Every year many thousands of couples become delighted parents through IVF. This is a trully wonderful thing.

Two mums and one dad make one baby

However there have been growing rumbles for some time that parts of the IVF industry are running out of steam with low success rates in some centres, high costs, serious drug-related side effects and poor regulation in some nations, for example over persuading women to "sell" their eggs for free treatment.

Now these fears are confirmed in a damning IVF report by the Centre for Bioethics and Public Policy published.This follows a fierce debate on health rationing with at least one health authority banning infertility treatment on the NHS.

Critics of this decision may be forced to think again. After all, what is the point of pouring large amounts of money into IVF techniques which hardly work? Of course the answer is to invest in clinics that are getting the best results.

Infertility is common and distressing. One in six of all couples seek medical help because of childlessness, and one in twenty will never have a child despite all that medicine can offer. Thus it entangles the emotional and physical lives of tens of thousands of people every year, affecting their sex lives, causing tension in relationships, creating guilt, embarrassment and feelings of shame or inadequacy.

The commonest reason for infertility in women is Pelvic Inflammatory Disease (PID) which now accounts for one in five of all gynaecological admissions.

This chronic and sometimes silent infection is often caused by ly transmitted organisms such as gonorrhoea or chlamydia which can damage the fallopian tubes.

Other causes include infection from abortion, contraceptive coils or giving birth.

Even where damage is slight, surgical repair has a success rate that can be as low as 10-20%. The alternative is IVF where the ovaries are simulated, eggs are collected through an endoscope, fertilised, cultivated and replaced.

Such treatment cycles take place around 30,000 times a year in Britain, at a cost of up to £2,500 each. The industry has a £75 million turnover, yet success rates are so low that if this were any other area of medicine, the IVF clinics would probably be closed down.

Pregnancy rates per IVF cycle of 25% or more are quoted by Dr Mercia Page, Medical Director of Serono Laboratories, which has 80% of the market in infertility drugs. However she admits that this figure is achieved only by "good" clinics with women under forty and men with normal fertility. She said last week that live birth rates "are as good or better per cycle as nature".

Similar claims are made by others in the industry but the reality is that a mere 12.7% of treatment cycles in many clinics actually result in a live birth of a baby, as thousands of couples are discovering to their cost. Even more disturbing is the fact that the birth rates for individual IVF clinics over a six month period can vary from 0% to 50% according to recent reports of the Human Fertilisation and Embryology Authority (HFEA).

There is nothing at all controversial in medical treatments with low success rates: indeed we see it all the time for some kinds of cancers but of course we plough on, striving for better. The difference is that when it comes to IVF in countries like the UK, the treatments are usually private, not covered by state care nor by medical insurance, the couple are paying out of their own pockets, and the pressures are there for clinics to keep busy even when their own success rates are not as good as the people they treat may be hoping. And the treatments are very expensive.

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IVF FAILURE WITH GOOD QUALITY EMBRYOS:“UNEXPLAINED” OR UNDIAGNOSED?

Currently, with few exceptions, practitioners of Assisted Reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea that having failed IVF, all that it takes to ultimately succeed is to keep trying over and over using the same recipe is over simplistic. There are numerous non-embryologic factors such as, the woman’s age, poor endometrial receptivity leading to implantation failure, and sub-optimal embryo transfer technique, that are just as likely to be responsible for failed IVF. The considerable emotional, physical and financial burden associated with infertility treatment in general and with IVF in specific, demand that factors known to affect outcome be identified and regulated prior to initiating treatment. This presentation addresses those clinical (non-embryologic) factors that affect IVF outcome, which often fail to be given the required amount of consideration:

• 1.The Woman's Age, Egg Quality and "Ovarian Reserve":

The onset of the climacteric is heralded by gradually increasing blood concentrations of FSH and/decreasing Inhibin B levels, as measured on the 3rd day of a spontaneous menstrual cycle and continue for a number of years (approximately 4-6 years) until virtually all remaining eggs have been used up, at which time ovulation and menstruation ceases altogether, i.e.; the menopause has arrived. The timing of the onset of the climacteric varies from person to person. Genetic factors, exposure to environmental toxins and radiation, disease, drugs and pelvic disease associated with severe peri-ovarian adhesions that compromise blood flow to the ovaries, can all influence the timing of the onset of both the climacteric and the menopause. Most American women will enter the climacteric in their early to mid forties and go into menopause around 45-52yrs.

As a woman advances beyond 30 years of age, her eggs become progressively less likely to be “normal” such that with every advancing year, upon fertilization, her eggs, are less likely to produce embryos with a normal chromosome number and/or structure. Such abnormal embryos are referred to as being aneuploidic. For instance, at age 35 approximately 1 in 4 fertilized eggs will develop into embryos with an abnormal chromosome make-up. About 50% of the embryos derived from a 40-year old woman’s eggs are likely to be aneuploidic. At 43 years, roughly 2 out of 3 embryos are so affected and at 45years the incidence of embryo aneuploidy could be as high as 70-80%. Since it is nature’s intent to preserve the integrity of the species through natural selection, abnormal embryos usually either fail to implant (attach to the uterine lining (in which case the woman would probably not even be aware that she was actually pregnant for a very brief period of time), or it may attach for a period of days or weeks and then be rejected in the first three months of pregnancy as a miscarriage. Infrequently nature will make a mistake and allow a chromosomally defective fetus to continue on to delivery, resulting in a birth (e.g. Down’s syndrome).

The risk of embryo aneuploidy increases with advancing age. This explains why there is a progressive increase in the incidence of infertility, miscarriage, and birth defects that occurs as the age of conception increases progressively as the woman’s age advances beyond 35 years. It also serves to explain why treatment of infertility (regardless of the chosen method) becomes progressively less successful with advancing maternal age.

Since the onset of the advent of the climacteric usually takes place after age 40 years, many physicians erroneously attribute poor egg/embryo quality to a reduction of ovarian responsivity to fertility drugs as evidenced by rising blood levels of FSH. Simply a woman over 40 years, who has entered the climacteric would not only be far more likely to produce fewer follicles/eggs even following the administration of relatively high doses of fertility drugs but because of her age, a higher percentage of her eggs/embryos would be chromosomally abnormal. Accordingly her chances of having a baby using her own eggs would be reduced. Conversely, a woman over 40 years undergoing in vitro fertilization, who has not yet entered the climacteric, might yield many more eggs/embryos, thus allowing for increased availability of eggs/embryos and thereby, the opportunity to select out more and better quality embryos or blastocysts (advanced embryos grown for 5-6 days) for embryo transfer (ET) to her uterus. It should be pointed out that it is embryo/blastocyst quality rather than simply the number transferred to the uterus that influences the incidence of multiple pregnancies. Accordingly, the further the woman’s age has advanced beyond 40 years...the greater the number of embryos or blastocysts (advanced embryos) that could likely be safely transferred to her uterus, without a significant risk of high-order multiple pregnancies (triplets or greater number). It is important to be aware that the only way to optimize IVF birthrates in older women is to increase the number of embryos/blastocysts transferred.

For women whose advancing age and/or ovarian resistance makes having a baby with their own eggs unappealing or unlikely, ovum donation (using donated eggs from a young donor (usually compatible and anonymous) is an excellent option.

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2.Receptivity of the Endometrium:

a)Contour of the uterine cavity

It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of myomas (fibroids) in the uterine wall, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where they distort the uterine cavity, or protrude as submucous polyps through the endometrial lining. It would appear that even small submucous myomas have the potential to prejudice implantation.

It is likely that any surface lesion in the uterine cavity, whether an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by a foreign body such as a intrauterine contraceptive device. Unfortunately, a hysterosalpingogram (HSG) will miss the diagnosis in approximately 20% of cases. The only reliable methods for diagnosing even the smallest of such lesions, is through the performance of a sonohysterogram (fluid ultrasound) or by hysteroscopy.

Sonohysterography [syn; Fluid ultrasonography (FUS)]
Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem, anyway.

Hysteroscopy
Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus in order to fully examine the uterine cavity. The uterus is first distended with carbon dioxide gas, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF has lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology. Prior to IVF. Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and in such cases should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.

b) Endometrial thickness

In 1989, we were first to show that in both normal and "stimulated " cycles, preovulatory endometrial thickness and ultrasound appearance, is predictive of embryo implantation (pregnancy) potential following In Vitro Fertilization/Embryo Transfer (IVF/ET). With conventional IVF (where the woman receives fertility drugs and has her own fresh embryos transferred to her uterus), there needs to be a 9mm sagital thickness (Grade 2) and a triple line appearance (Grade A) accordingly, a Grade 2A lining is optimal in such cases. Anything less is associated with about a five- (5) fold reduction in live birth rate per ET. A possible exception may apply in cases of third party embryo Recipients (Ovum donation, IVF-Surrogacy) and in cases of Frozen embryo transfers (i.e., where the recipient receives supplementary estrogen/progesterone and not gonadotropins, to prepare the uterine lining. Here, a lining of 8mm thickness seems to be adequate.

A “poor” endometrial lining most commonly occurs in women with a history of unexplained recurrent IVF failures or early recurrent miscarriages and is usually attributable to: 1) inflammation of the uterine lining (endometrium), i.e., endometritis (occurring following a septic delivery, abortion or miscarriage, 2) adenomyosis (gross invasion of the uterine muscle by endometrial glandular tissue), 3) multiple fibroid tumors of the uterine wall) 4) prenatal exposure to the synthetic hormone, diethylstilbestrol( DES)and, 5) in women who have received clomiphene citrate (Clomid, Serophene) for at least 3 months in a row without a resting cycle (this effect is self-reversible within 4-6weeks of discontinuing clomiphene).

Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results. We recently reported on the ability of vaginally administered Viagra to significantly enhance uterine blood flow and estrogen delivery to the endometrium and thereby improve endometrial development. In the process many women with intractably poor endometrial development have achieved healthy pregnancies.

Immunologic factors

The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblast), which later becomes the placenta, begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a "cross talk" through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

Considering its importance, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and, perhaps most importantly, activated natural killer cells (NKa). Presently, these immunologic markers can be adequately measured by only a few (less than a half dozen) highly specialized reproductive immunology laboratories in the United States, from patient blood samples.

• The presence of APAs in male factor cases appears to bear no relationship to IVF outcome;
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with IVIg
• More than 75% of APA+ women who have increased NK cell activity also harbor a PE and/or a PS antibodies

Cytotoxic Lymphocytes (CTLs)
CTLs release “toxins”(perforins and granzymes) and TH-1 cytokines that counter the humoral, TH-2 cytokine response that is a necessary prerequisite for B-cells to produce antibodies. The “toxins” and TH-I cytokines damage or kill the cells that form the outer layers of the embryo’s root system”(i.e.; the trophoblast). By pitting their TH-1 response against the counter-effect of humoral TH-2 cytokines, both CTL’s and activated NK-cells (Nka) regulate and control the degree to which the trophoblast ( placenta) invades the uterine wall as well as the tolerance and acceptance by the uterus of the foreign fetal “transplant” (allographt). Studies have shown that women who experience recurrent pregnancy miscarriages have significantly raised levels of CTL’s, Nka’s and TH-1 Cytokines (the so called “embryotoxic factor”) in their uterine linings as well as in the peripheral blood.

4)Antithyroid Antibodies (ATA)
A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility). We have previously reported on the ability to double IVF birth rates through the administration of IVIg to ATA+ patients. IVIg therapy should be initiated prior to initiation of treatment with fertility drugs, and should be administered one more time after pregnancy is diagnosed. About 50% of women who harbor ATAs also test Nka positive. The risk of implantation failure in ATA positive women appears to be confined to cases where ATAs coexist with Nka. IVIg therapy should be confined to such cases.

THERAPEUTIC IMMUNOMODULATION

1)Corticosteroid Therapy (Prednisone, Prenisolone and Dexamethazone) Steroid therapy is routine in most IVF programs. Some advocates use daily oral methyl prednisolone .We prescribe oral dexamethazone commencing about ten days prior to initiating ovarian stimulation with gonadotropins, and continuing until the diagnosis of pregnancy, whereupon, in the event of a negative test (Beta HCG or ultrasound), the dosage is tapered over a period of seven to ten days, and then discontinued. Pregnant patients continue treatment through the first trimester. Steroids are believed to act by inhibiting the cellular immune response

2)Heparin
There is compelling evidence that the subcutaneous administration of heparin (at a dosage of 5000 U twice daily) to women undergoing IVF for female causes of infertility who test positive for APAs, but negative for NK activation), significantly improves IVF birth rates. Heparin administration is withheld on the day of egg retrieval until immediately following embryo transfer, whereupon it is recommenced and continued until the 8th week of pregnancy. Heparin is thought to act by repelling APAs from the surface of the trophoblast (early "root system" of the embryo). Provided that platelet counts are normal, are checked on a regular basis, and heparin is withheld on the day of egg retrieval, its administration is virtually risk-free.

3)Intravenous Immunoglobulin G (IVIg)
Intravenous Immunoglobulin G (IVIG) is a sterile protein preparation derived from human blood. Every effort has been made to ensure that it is free of bacterial and viral contamination. There are basically four ways in which IVIG is believed to offset or counter the anti-implantation effects associated with reproductive immunologic deficiencies. First, it is a potent suppressor of activated (toxic) Natural Killer cells (NKa). Second, IVIG reduces the activity of CTL’s ( activated T-cells), which are major producers of TH1 cytokines ("toxins") that can damage the early implanting conceptus. Third, IVIG is believed to suppress the ability of B cells to produce damaging autoantibodies such as APAs and antithyroid antibodies (ATA) and, Fourth, IVIG contains anti-idiotype antibodies that directly counter many of the damaging effects of autoantibodies (antibodies that attack the bodies own cells), such as antiphospholipid antibodies (APAs), thereby protecting the early "root system” of the embryo/conceptus from damage.

IVIG has had some undeserved bad press. Since it is a blood derivative, the thought of administering it in an era where HIV is rampant, is frightening to most. However, consider the following: IVIG products available in the United States and the United Kingdom are subject to the most stringent controls and scrutiny. According to the manufacturers of IVIG, there has not been a single case of HIV viral transmission in more than two million administrations and there have only been a few isolated cases of Hepatitis C. This is not surprising since IVIG is derived from the very same blood pool used for transfusion purposes, and since millions of units of blood have been administered in the United States over the last 7 years without any reports of HIV transmission. The IVIG available in the U.S is thoroughly tested .We hold, that if administered properly by qualified medical personnel, and the appropriate precautions are taken, IVIG, currently used in this country, is virtually devoid of viral contamination. We recommend that IVIG for increased NKa be administered at least 7 days prior to embryo/blastocyst transfer.

The selective use of immunotherapy has, on numerous occasions, enabled us to achieve successful pregnancy in patients who had previously suffered repeated IVF failures (4 or more). Many such patients had previously been advised, not to try again with their own eggs. We are able to report IVF births occurring in numerous cases, where the woman had previously experienced more than ten (10) IVF failures. One such case involved a 42-year-old woman who was successful with us (using her own eggs) following 22 consecutive prior IVF failures. We believe that such results could not have been achieved without access to selective immunomodulation.Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Endometriosis
• Unexplained infertility or
• A family history of autoimmune diseases (e.g. rheumatoid arthritis, lupus erythematosus & hypothyroidism).