The Guinness Moms?

It would appear that the quest for motherhood is for some, a desire that fails to subside with age. Empowered by new technologies such as IVF treatments, women are increasingly seeking the assistance of fertility clinics to fulfil their aim of bearing a child when their biological clock has ground to a halt. For single women in Japan, however, this type of assistance is not so easy to come by. Strict laws in the field of surrogacy and artificial insemination are imposed due to the country's traditional approach to human reproduction. As a result, fertility treatment is provided almost exclusively to married couples.
Undeterred, a single 60-year old Japanese woman has taken such restrictions into her own hands. The Times newspaper has reported this week that the woman, who wished to remain anonymous, is now in her fifteenth week of pregnancy after travelling to the United States for fertility treatment. She is believed to be the first and oldest single woman to conceive from a donated egg. The use of donated eggs is strictly limited to married couples under a Japanese medical guideline.
After a series of unsuccessful attempts to find a doctor in Japan willing to handle the pregnancy, Yahiro Netsu, a gynaecologist at The Suwa Maternity Clinic in Nagano, central Japan, has stepped in to help. Speaking to the Associated Press, Mr Netsu confessed that the decision had been a tough one, especially as her age and single status meant that the pregnancy was a high risk and an uncertain future for the child. The gynaecologist, however, was won over by the woman's desire to bear a child in spite of her age. He said:'But she wanted a child, and I decided to do all I can to help her through
expected difficulties'.
Although the pregnancy has yet to reach a happy conclusion, Mr Netsu and his patient should take heart from the birth of a healthy baby boy born last summer to a British woman, aged 62. Dr Patricia Rashbrook, a psychiatrist from Lewes, East Sussex, conceived using a donor egg after her fifth attempt at IVF. Her son, nicknamed JJ, weighed a healthy 6 pounds and 10 ounces. But with the trend for older mothers continuing, it would appear that even Dr Rashbrook has been usurped in the trophy for 'The world's oldest mum'. This accolade is believed to go to a 67-year old Spanish woman who gave birth to
twin boys following IVF treatment last year. She is closely followed by Adriana Iliescu, from Romania, who had a daughter called Eliza Maria in January in 2005 at the age of 66.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, affecting an estimated five to ten percent women of reproductive age in India. For women trying to conceive a child, PCOS is a serious, common cause of infertility - nearly half of all female factor infertility cases can be traced to PCOS. New medical insight into the disease has led to treatment options, including insulin-reducing ovulation medication (Clomiphene, Letrozole, Metformin), dietary changes (low glycemic diet) and surgery (ovarian drilling), which have proven successful and allow many women to overcome PCOS and conceive a child naturally, while reducing the risk of miscarriage. Women who undergo treatment for PCOS but are still unable to conceive naturally often turn to assisted reproductive technologies, including IVF, and experience high pregnancy success rates. At Rotunda, our physicians specialize in this common, yet often misunderstood cause of infertility. We work closely with each patient to understand her specific medical case and personal goals, including weight loss, pregnancy or improving general health, and develop a holistic approach to reach those goals. Oftentimes, the road to overcoming PCOS is not an easy one and it takes a strong commitment from both the patient and the physician. The team at Rotunda is committed to supporting our patients every step of the way. I have just published a monograph on "PCOS" which was released by Anshan Publications (www.anshan.co.uk).
Polycystic ovary syndrome is characterized by anovulation (irregular or absent menstrual periods) and hyperandrogenism (elevated serum testosterone and androstenedione). Patients with this syndrome may complain of abnormal bleeding, infertility, obesity, excess hair growth, hair loss and acne. In addition to the clinical and hormonal changes associated with this condition, vaginal ultrasound shows enlarged ovaries with an increased number of small (6-10mm) follicles around the periphery (PCO like ovaries). While ultrasound reveals that polycystic appearing ovaries are commonly seen in up to 20% of women in the reproductive age range, Polycystic Ovary Syndrome (PCOS) is a estimated to affect about half as many or approximately 6-10% of women. The condition appears to have a genetic component and those effected often have both male and female relatives with adult-onset diabetes, obesity, elevated blood triglycerides, high blood pressure and female relatives with infertility, hirsutism and menstrual problems.
Presently, we do not understand why one woman who demonstrates polycystic appearing ovaries on ultrasound has regular menstrual cycles and no signs of excess androgens while another develops PCOS. One of the major biochemical features of polycystic ovary syndrome is insulin resistance accompanied by compensatory hyperinsulinemia (elevated fasting blood insulin levels). There is increasing data that hyperinsulinemia produces the hyperandrogenism of polycystic ovary syndrome by increasing ovarian androgen production, particularly testosterone and by decreasing the serum sex hormone binding globulin concentration. The high levels of androgenic hormones interfere with the pituitary ovarian axis, leading to increased LH levels, anovulation, amenorrhea, recurrent pregnancy loss, and infertility. Hyperinsulinemia has also been associated high blood pressure and increased clot formation and appears to be a major risk factor for the development of heart disease, stroke and type II diabetes.
There is little agreement when it comes to how PCOS is diagnosed. Most physicians will consider this diagnosis after making sure you do not have other conditions such as Cushing's disease (overactive adrenal gland), thyroid problems, congenital adrenal hyperplasia or increased prolactin production by the pituitary gland. TSH, 17-hydroxyprogesterone, prolactin and a dexamethasone suppression test may be advisable. After reviewing your medical history, your physicians will determine which tests are necessary. If you have irregular or absent menstrual periods, clues from the physical exam will be considered next. Your height and weight will be noted along with any increase facial or body hair or loss of scalp hair, acne and acanthosis nigricans (a discoloration of the skin under the arms, breasts and in the groin). Elevated androgen levels (male hormones), DHEAS or testosterone help make the diagnosis. A two hour insulin and glucose tolerance test will be obtained. Many physicians tell their patients that insulin values are normal, when in fact the value indicates that insulin may be playing a role in stimulating the development of PCOS. Most labs report levels less than 25-30 miu/ml as normal, while in fact, levels over 10miu/ml on a fasting blood sample suggests that PCOS may be related to hyperinsulinism. As women with polycystic ovary syndrome may be a greater risk for other medical conditions, testing for cardiovascular risk factors such as blood lipids should also be carried out.
Traditional treatments have been difficult, expensive and have limited success when used alone. Infertility treatments include weight loss diets, ovulation medications (Clomiphene,Letrozole, Menopur, Gonal-F), ovarian drilling surgery and IVF. Other symptoms have been managed by anti-androgen medication (birth control pills, spironolactone, flutamide or finasteride).
Ovarian drilling can be performed at the time of laparoscopy. A laser fibre or electrosurgical needle is used to puncture the ovary 6-8 times(see picture). This treatment results in a dramatic lowering of male hormones within days. Studies have shown that up to 80% will benefit from such treatment. Many who failed to ovulate with letrozole or metformin therapy will respond when rechallenged with these medications after ovarian drilling. Interestingly, women in these studies who are smokers, rarely responded to the drilling procedure. Side effects are rare, but may result in adhesion formation or ovarian failure if the procedure is performed by an inexperienced surgeon.
For women in the reproductive age range, polycystic ovary syndrome is a serious, common cause of infertility, because of the endocrine abnormalities which accompany elevated insulin levels. There is increasing evidence that this endocrine abnormality can be reversed by treatment with widely available standard medications which are leading medicines used in this country for the treatment of adult onset diabetes, metformin 850 mg two times per day or 1000mg twice daily with meals), Hyponiid (Charak Pharma) (Which is a D-Chiro Inositol containing Indian Ayurvedic Medication) or a combination of these medications. These medications have been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within 10-12 months. They can result in decreased hair loss, diminished facial and body hair growth, normalization of elevated blood pressure, regulation or menses, weight loss, reduction in cardiovascular risk factors, normal fertility, and a reduced risk of miscarriage. We have seen pregnancies result in less than 18 months in women who conceived spontaneously at home. By twenty-four months over 90% of women treated with insulin-lowering agents, diet and exercise will resume regular menses.
The medical literature suggests that the endocrinopathy in most patients with polycystic ovary syndrome can be resolved with insulin lowering therapy. This is clinically very important because the therapy reduces hirsutism, obesity, blood pressure, triglyceride levels, elevated blood clotting factors and facilitates re-establishment of the normal pituitary ovarian cycle, thus often allowing resumption of normal ovulatory cycles and pregnancy. We know the polycystic ovary syndrome is associated with increased risk of heart attack and stroke because of the associated heart attack and stroke risk factors, hypertension, obesity, hyperandrogenism, hypertriglyceridemia, and these are to a large degree resolved by therapy with these medications. Side effects are rare. Although metformin, rosiglitazone and pioglitazone lower elevated blood sugar levels in diabetics, when given to nondiabetic patients, they only lower insulin levels. Blood sugar levels will not change. In fact, episodes of "hypoglycemic attacks" appear to be reduced.
When first starting Metformin, people will often experience upset stomach or diarrhea (usually loosely formed stools) which usually resolves after the first couple of weeks. This side effect can be minimized by taking metformin with the heaviest meal of the day and starting with a low dose. I recommend that our patients start with one 850 mg pill daily the first week and increase to twice a day during the second week. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%) are at a higher risk for a rare side effect of metformin therapy called lactic acidosis, and the drug should be given cautiously, if at all, to such patients. Patients taking metformin should notify their physician and discontinue the medication. Pioglitazone or Rosiglitazone belong to a class of medications called PPAR gamma agonists. They enhance the ability of smooth muscle to metabolize sugar, thereby reducing insulin resistance. The FDA has recently reviewed the safety of troglitazone (and reports that 35 patients out of approximately 1.5 million have either died or required liver transplant.) Therefore Troglitazone has been removed from the market. As the new alternatives to Troglitazone, Rosiglitazone and Pioglitazone are metabolized by different liver enzymes, experience has shown that these medications appear to pose minimal risk of hepatotoxicity.
Transvaginal follicular studies are done to determine if you are ovulating.You will be asked to return three months after initiating therapy. If you have ovulated, therapy may be continued another three months to see if you will conceive. Re-evaluation will include measurements of lab tests that were abnormal at the initial evaluation. If the laboratory studies are still abnormal, metformin may be increased up to 1000 mg three times daily or rosiglitazone may be substituted alongwith addition of higher doses of Hyponiid. If the laboratory studies are normal but ovulation has not occured, a trial of letrozole may be considered. We have seen that women who were unable to ovulate on up to 250 mg of clomiphene ovulate when very low doses of clomiphene or letrozole are used in conjunction with metformin or PPARgamma therapy. Laparoscopic ovarian drilling may be considered for those women where other indications for laparoscopy are present.
While safety during pregnancy has not yet been established, reports have been published of patients who continued on metformin during their entire pregnancy and one who remained on a glitazone have delivered normal babies. There are no reports of abnormal babies in women who conceived using metformin and all resulting babies were normal. Metformin is a category B medication. This means that insufficient human data is available but no credible animal data suggesting a teratogenic (could produce birth defects) risk. Although to the best of our present knowledge the risk of birth defects would be small, it must also be noted that maternal diabetes has been associated with an increased risk of birth defects and the underlying elevated insulin levels may lead to birth defects if not corrected.
While the most prudent policy may be to avoid the use of these medications during pregnancy until more data on pregnancy outcome is available, the risk of miscarriage may be reduced by continuing metformin during the pregnancy. Women with PCOS who conceive either spontaneously or after ovulation induction have a much higher risk of miscarriage. Hypersecretion of LH was thought to cause chromosomally abnormal eggs leading to an increased risk of miscarriage. But a Japanese study found that PCOS was more common in women whose prior loss was associated with normal chromosomes. Others have suggested that high androgen levels may be a contributory factor. Homburg has shown that miscarriage rates after ovulation induction or IVF is decreased when women are pretreated with a GnRH-agonist such as Synarel, Lupron or Zoladex.
Hyperinsulinemia may be a contributing factor in the higher rate of miscarriage. Elevated levels of insulin interfere with the normal balance between factors promoting blood clotting and those promoting breakdown of the clots. Increases in plasminogen activator inhibitor activity (PAI) associated with high insulin levels may result in increased blood clotting at the interface between the uterine lining (endometrium) and the placenta. This could lead to placental insufficiency and miscarriage.
There are no placebo-controlled clinical trials to indicate whether pregnancy outcomes are improved in pregnancies that result from the use of insulin-lowering medications or whether pregnancy outcomes are better in those who continue metformin throughout the pregnancy or those who discontinue. At present there is insufficient data to routinely advise continuation of metformin during pregnancy. As an alternative to continuing metformin therapy, those women with increased risk of abnormal blood clotting may benefit from baby aspirin, folate supplementation and low molecular weight heparin therapy.

Grandfather Semen Donor

A 72-year-old grandfather will be allowed to act as a sperm donor for his infertile son and daughter-in-law, effectively making any resulting child his father's biological half brother. Although theoretically not illegal, according to the Human Fertility and Embryology Authority, is thought that this is the only time such a case has arisen the UK. The decision to allow the couple to use the grandfather as a sperm donor follows many months of consultation with independent bodies and ethics
committees, says Kamal Ahuja, co-medical director of the London Women's Clinic where the couple are being cared for.Ahuja believes that the couple's wish to have a child that is similar to their own identity is understandable. 'We have made the decision on the basis that the couple have special requirements in that the donor sperm in not acceptable to them', he told the Guardian, UK newspaper. 'That applies to many, many groups of people - some religions [such as Islam] don't condone the use of donor sperm. In this particular case there was a mixture of reasons'.
A spokeswoman for the Human Fertilisation and Embryology Authority (HFEA), which regulates the fertility sector, said it did not need to approve the decision. Donations from family members - such as sisters giving each other their eggs - are allowed under the law, she said. Once a donor has consented to the use of his sperm for fertility treatment, he has no legal or parental rights over any children born using his sperm. Upon reaching the age of 18, the child has the right to find out the identity of their donor father.
However the national sperm donation programme accepts only men aged under 45, raising concerns over the increased risks of miscarriage and genetic mutation associated with the raised paternal age. Allan Pacey, of the British Fertility Society, told the Times London: 'I am sure the couple will have been apprised of the risks, but in my view this is unwise. There is a very
real possibility that this will not work, and the chances of miscarriage are also raised. The chances of a genetic defect or illness become greater too. You could say that if everybody is happy they should go ahead, but God forbid if there if there's a child born with a problem. It would be delicate to explain to that child that it might be the result of its grandfather's
72-year-old sperm'.
According to the BBC, the couple, who are in their 30's and have chosen to remain anonymous, have not yet decided whether they will tell the child the true identify of his or her biological father, although the clinic is positively encouraging them to do so. Any baby born using the sperm would be the grandfather's genetic child and its father's half brother. Preliminary tests suggest the sperm is viable - it is not uncommon for men to continue to produce healthy sperm into their 70s and 80s.Keeping the identity of the child similar to their own was a huge factor. The husband said"Society has also changed its perceptions of what is and what is not acceptable. In this case, keeping the identity of the child similar to ourown was a huge factor. I do not have a brother, which is why I chose my own father to assist."

Empty Follicle Syndrome

The Empty Follicle Syndrome (EFS) is a frustrating condition in which no oocytes (eggs) are retrieved at IVF, even though ultrasound and estradiol measurements showed the presence of many potential follicles. The mechanism responsible for EFS remains obscure. Many hypotheses have been put forward, but none truly explain this syndrome. The most likely cause of EFS is ovarian ageing, as many patients who suffer from EFS are also poor responders. If an EFS cycle does occur during your treatment, please make sure you discuss it thoroughly with your fertility physician. EFS is an infrequent event and has been estimated to occur in between 2 - 7% of IVF cycles. However, the overall risk of recurrence in later IVF cycles is 20% and the risk of recurrence is higher as the age of the patient increases.

To date, Empty Follicle Syndrome (EFS) has only been reported in GnRH agonist down-regulated IVF cycles. Some cases have been successfully treated by changing the batch, or by repeating the dose of hCG. A case of EFS was reported recently on PubMed in both GnRH antagonist and GnRH agonist down-regulated IVF cycles when final oocyte maturation was triggered using urinary hCG (u-hCG). Failure to retrieve oocytes occurred, despite administration of a further dose of u-hCG from a different batch and a delayed repeated oocyte recovery performed in the second GnRH agonist down-regulated cycle. A successful oocyte recovery cycle was achieved after triggering of an endogenous gonadotrophin surge using GnRH agonist in an antagonist down-regulated cycle. Nine oocytes were readily retrieved from 10 follicles, at 36 h after GnRH agonist administration, and eight of these fertilized normally. Two good quality embryos were used for fresh transfer and four were cryopreserved for future use. The authors concluded that EFS can occur in GnRH antagonist down-regulated IVF cycles, and can be successfully treated by triggering a natural gonadotrophin surge using GnRH agonist in the absence of any response to previous treatment methods. This represents a novel therapeutic modality for this uncommon but frustrating condition.

Another paper reports experience with three IVF cycles in which no oocytes were collected. In all cases, an additional IVF cycle was performed. The ovarian stimulation protocol, ultrasound and hormonal surveillance methods, human chorionic gonadotrophin timing and oocyte retrieval technique were similar in all patients. The assessment of additional cycles demonstrated a poor response in terms of oocyte quality, since the number of mature oocytes was low despite the high number of oocytes collected. Thus, the data suggest that in these patients, EFS should be considered as a borderline form of poor response to ovarian stimulation. If this is confirmed, EFS should be a recurrent event and an empty cycle could be a good predictor that a subsequent stimulated cycle will be an unfavourable.

A group from UK recently reported five cases in which no oocytes were retrieved after standard ovarian stimulation for in-vitro fertilization (IVF), and in which it was found that mistakes had been made at the time of human chorionic gonadotrophin (HCG) administration. In all five cases, oocyte retrieval was achieved after injecting HCG, when necessary, and reprogramming aspiration 24–36 h later. A mean of 7 ± 3.2 MII oocytes were recovered per patient and 3.2 ± 0.8 embryos were transferred. Three clinical pregnancies were obtained, and four healthy infants were born. In their program, these were the only cases of empty follicle syndrome (EFS) that appeared over a total of 1118 cycles, and were all explained by human error in the administration of HCG. Our experience too shows that human error could be considered a significant factor in the aetiology of empty follicle syndrome, and that EFS may be in part avoided by taking simple preventive measures.

A novel method of rescuing empty follicle syndrome (EFS) was recently published and provides evidence that it is a drug-related problem rather than a clinical dysfunction. In a preliminary study the authors from UK established that in EFS the serum beta-human chorionic gonadotrophin (beta-HCG) concentrations 36 h after HCG administration never exceeded 10 mIU/ ml. beta-HCG concentrations were thus used to confirm EFS when oocytes were not retrieved from one ovary after controlled ovarian hyperstimulation. The procedure was suspended leaving intact all follicles in the second, ovary. After confirmation of EFS, a second HCG from a different batch was administered and 36 h later mature oocytes were retrieved from the intact ovary, suggesting a fault with the HCG previously administered. Three patients have been treated in this way. In the first case, four out of five mature eggs were fertilized after intracytoplasmic sperm injection (ICSI) resulting in the transfer of three top grade (grade 1) embryos. In the second case all seven mature oocytes fertilized after in-vitro fertilization (IVF) and three grade 1 embryos were transferred resulting in a twin pregnancy, now delivered. In the third case, five out of nine oocytes were fertilized after ICSI and one out of the three treated with high insemination concentration IVF fertilized, resulting in the transfer of three ICSI embryos.

We suspected hCG batch-to-batch consistency a couple of times with our own cases, but could never confirm the above. Would love other clinics to post their experiences here.

Weekend Punjabi Puttar Joke

Bill Gates was looking for a new Chairman for Microsoft Europe and
organized an enormous session to interview a suitable candidate.

5000 hopeful candidates assemble in a large room. One candidate is Santa
Singh.

Bill Gates thanks all the candidates for coming and then asks all those who
do not know JAVA to leave.

2000 people leave the room.

Santa says to himself, "I do not know JAVA, but I have nothing to lose if I
stay. I'll give it a try".


Bill Gates asks the candidates who have never had experience of managing
more than 100 people to leave.

Another 2000 people leave the room.

Santa says to himself "I have never managed anybody by myself, but I have
nothing to lose if I stay. What can happen to me?" So he stays.


Then Bill Gates asks candidates who do not have management diplomas to
leave.

500 people leave the room.

Santa says to himself, "I left school at 15, but what have I got to lose?"
So he stays in the room.


Lastly, Bill Gates asks the candidates who do not speak Serbo - Croat to
leave.

498 people leave the room.

Santa says to himself, "I do not speak a singlr word of Serbo - Croat, but
what do I have to lose?"
So he stays and finds himself with one other candidate.


Everyone else has gone. Bill Gates now joins them and says
"Apparently you are the only two candidates who speak Serbo - Croat, so I'd
now like to hear you have a conversation together in that language."

Calmly, Santa turns to the other candidate and says "Hor Paape, ki haal
chaal?"

The other candidate answers "O vadiya veere, tu sunaa". Bolo Ta Ra Ra Ra:)

Tubal Transfer Procedures

The Tubal Embryo Transfer (TET) procedure involves the transfer of embryos that are more advanced in development than those in ZIFT i.e. cleaved embryos. The aim is to achieve fertilization in-vitro (in the laboratory) and then replace the cleaved embryos in the Fallopian tube, the normal site for fertilization. It is suitable only for women who have at least one healthy Fallopian tube. TET is carried out as a day-case procedure under a general anesthetic, using laparoscopy(see picture). You may experience some abdominal discomfort and pain for a few days after the procedure, but painkillers can relieve this. The main groups of patients selected for TET procedure are women who are keen to have gamete intra-Fallopian transfer (GIFT) but where there is doubt about the chance of fertilization, and women who encountered difficulties in previous embryo transfers through the cervix. The success rate for TET is in the region of 25-40% per embryo transfer, but varies depending on many factors such as the woman's age and the number of embryos transferred, etc.

The ZIFT procedure involves the transfer of embryos (zygotes) into the Fallopian tube 24 hours after fertilization. The aim is to achieve fertilization in-vitro (in the laboratory) and then replace the early embryos in the Fallopian tube, the normal site for fertilization. ZIFT offers the best of both IVF and GIFT procedures. It is suitable only for women who have at least one healthy Fallopian tube. ZIFT is carried out as a day-case procedure under a general anesthetic, using laparoscopy. You may experience some abdominal discomfort and pain for a few days after the procedure, but painkillers can relieve this. The main groups of patients selected for ZIFT procedure are women who are keen to have gamete intra-Fallopian transfer (GIFT) but where there is doubt about the chance of fertilization, and women who encountered difficulties in previous embryo transfers through the cervix. If the quality of the embryo's in a preceding IVF cycle was poor, some fertility specialists will advise the patient to have ZIFT rather than IVF.

Gamete Intra-Fallopian Transfer (GIFT) is a procedure in which the eggs are mixed with sperm and the mixture is then injected into the Fallopian tube. It is suitable for women who have at least one healthy Fallopian tube. The aim of GIFT is to allow fertilization to occur in the right place and implantation at the right time. There are selected groups of patients to whom gamete intra-Fallopian transfer (GIFT) is recommended:
a)Couples with unexplained infertility.
b)Women with minimal endometriosis.
c)Men with infertility problem (not severe).
d)Couples who have had failed donor insemination.
e)Where transcervical embryo transfer is impossible and the patient has one healthy tube.

The procedure is carried out as a day case surgery under a general anaesthetic, and involves making three small cuts in the abdomen. Fertility drugs are used to stimulate the ovaries, monitoring is also carried out as with IVF treatment. Eggs may be collected either by a vaginal ultrasound scan or laparoscopically using a fine needle and gentle suction.Once the eggs are collected, they are examined under the microscope for quality. The best eggs are then mixed with washed and prepared sperm in a small volume of culture medium. The end of the fallopian tube is grasped gently and a guided fine canula is passed through the fimbrial end of the tube(see picture). The mixture of the eggs and sperm is then deposited into the Fallopian tube. In most cases, three or four eggs are usually transferred per cycle. Any spare eggs that are collected may be fertilized in-vitro and the resulting embryos are frozen (if they are of good quality to freeze) for later embryo replacement. After the GIFT procedure, the patient is usually given hormonal supplements, in the form of tablets, pessaries, gel or injection to help the implantation of embryos.The success rate after GIFT is similar to that of in-vitro fertilization (IVF) treatment. Some specialists claim a higher success rate with GIFT compared to IVF.

More recently, attempts have been made to simplify the procedure by collecting the eggs by vaginal ultrasound and injecting the egg and sperm mixture into the tube via the cervix using a special catheter. The procedure is usually performed under ultrasound guidance. The reported pregnancy rates with this method are less than that with conventional laparoscopy GIFT.

Last week, we did a big Tubal Transfer Procedures Workshop at the Prince Aly Khan Hospital IVF Center (www.testtubebabyclinic.com) where we performed the above procedures on 9 patients. We have made a teaching DVD of the same to teach post-graduates which will be released at the World Congress on Fallopian Tubes to be held at Kolkata from 18-21 October 2007. You can access the meeting homepage on www.sisab.net/tubes2007

Frozen Embryo Transfer

Embryo freezing is a well-established form of assisted conception treatment. An increasing number of IVF clinics worldwide are now able to freeze spare embryos for later transfer. The first frozen embryo baby was born in 1984. Embryo cryopreservation allows multiple embryo transfers from a single egg collection and improves the chances of livebirth. Amongst the advantages of embryo cryopreservation are maximizing the potential for conception for IVF and prevent wastage of viable normal spare embryos. Perhaps this is the most important advantage of cryopreservation. Approximately 50% of women may have spare embryos available for freezing. In some clinics, the pregnancy and live birth rates with frozen-thawed embryo transfer is as high as those achieved with fresh embryo transfer. Freezing all embryos for subsequent transfer may be advised for women who are at a high risk of developing severe ovarian hyperstimulation syndrome following ovarian stimulation for in-vitro fertilization (IVF).

Embryo Freezing is also resorted to when embryo implantation may be compromised in cases such as the presence of endometrial polyps, poor endometrial development, break through bleeding near the time of embryo transfer or illness as also difficulty encountered at fresh embryo transfer e.g. cervical stenosis (inability to pass through the cervical canal because the cervix is narrowed or scarred, etc). Cryopreservation of embryos is very important to be incorporated in the egg donation programs. It is not always possible to synchronize the recipient’s cycle with that of the egg donor. In some countries, it is mandatory to freeze all embryos created from donated eggs, quarantined for a period of six months and until the donor have a repeat negative screening tests. As a result of successful cryopreservation programs, frozen embryos have also become available for donation to infertile couples.

Embryos can be frozen at any stage (pronucleate, early cleaved and blastocyst) if they are of good quality. Embryos are stored in batches of one or more embryos depending on the number of embryos that are likely to be transferred into the uterus at a later date. Embryos are mixed with a cryoprotectant fluid (to protect embryos from damage during freezing process). Then, the mixture is put either in a plastic straw or a glass ampoule and stored in liquid nitrogen at a very low temperature –196°C using a specialized programmable machine. Thawing of embryo involves removing the embryos from the liquid nitrogen, thaw at room temperature, remove the cryoprotectant fluid and mix the embryo in a special culture media. The mixture is then kept in the incubator ready for transfer.

If the embryos were frozen at cleaved stage or blastocyst, they can be thawed and replaced in the same day. However, if they were frozen at the two-pronucleate stage, then they are thawed on the day before and cultured overnight to allow them to divide and are replaced when they become 2-4 cell embryo (s). Different countries have different regulation concerning the length of time that embryos can be frozen. In the United Kingdom, embryos can be stored for a maximum of 10 years. India is yet to define the upper limit of storage.

The first step to transfer embryos from one centre to another is to write to the centre which has the couple's embryos stored in order to release the embryos. Consent from both partners is required. The couple will need to take responsibility of the embryos once they leave the center. The embryos are transferred using a small liquid nitrogen container specially designed.
Not all embryos survive the freezing and thawing process. In a good freezing program, a survival rate of 75-80% should be expected. Therefore, it may be necessary to thaw out several embryos to get two or three good embryos to replace. Damage of embryos does occur as a result of freezing, not during the storage but during the cooling and thawing process. It is important that both the couple and the clinic to keep in contact with regard their frozen embryos. Most IVF clinics will send an annual reminder letter to patients who have frozen embryos stored.

The letter usually offer a couple five choices:

Continue storage for a further period of time.
Arrange for embryo transfer treatment cycle before the expiry date.
Allow embryos to perish by interfering with the thawing process.
Donate embryos to ethically approved research.
Donate embryos to infertile couple.

Frozen/thawed embryos may be transferred into the uterus in a natural cycle, a hormone replacement cycle or a stimulated cycle. In general, the three methods have similar pregnancy and live birth rates. A Natural cycle is usually recommended in young women with regular menstrual cycles and ovulation. It involves serial ultrasound scans to check the development of the follicle and endometrium, blood tests to check the levels of hormone LH, estrogen and progesterone. Embryo transfer is usually performed about 3-4 days after the LH surge (2-3 days after ovulation). The woman is given no drugs until the day of embryo transfer. On the day of embryo transfer, the woman may start a course of progesterone pessaries or tablets to support the luteal phase. Natural cycles have the advantages of a naturally prepared endometrium and reduced cost. The disadvantages of natural cycle frozen embryo transfer is the risk of failure of ovulation. Also, the date of ovulation can not be predicted.

Hormone replacement cycle with or without GnRh agonist is usually recommended for older women, woman without ovaries or non-functioning ovaries, women with irregular infrequent menstrual cycles or ovulation. It involves giving estrogen in the form of tablets or skin batches and later adds progesterone in the form of tablets, pessaries, gel or injection. Different IVF clinics have different protocols for giving these medications and in some women GnRh agonists may be given in addition to hormone replacement to "switch off" any hormone production by the ovaries which may interfere with the treatment. After embryo transfer, both estrogen and progesterone are continued until the pregnancy test. In the test is positive, the woman should continue the medication for a further 8-10 weeks. Hormone replacement cycle allows accurate programng the date of embryo transfer and ensures that the endometrium is adequately prepared to receive the embryos.

Stimulated cycle is where fertility drugs such as clomifene tablets or FSH injection is given aiming to produce one or two follicles. When the follicle is mature and the endometrium developed satisfactorily, hCG injection is given to induce ovulation. Embryo transfer is usually performed 2-3 days after the ovulation. This regimen is usually recommended for women do not ovulate regularly and did not respond to hormone replacement treatment in a previous cycle.

The success rates depend on many factors; mainly the woman’s age and number of embryos transferred. The outcome of pregnancies resulted from frozen embryo transfer is similar to fresh embryo transfer in the incidence of biochemical pregnancy, blighted ovum, early and late miscarriage, ectopic pregnancy, preterm deliveries and term deliveries. To date there is no evidence that babies born after frozen embryo transfer have any increased incidence of congenital abnormality.

There are several ethical and moral issues surrounding the embryo freezing process. These include the following:

Fate of the stored embryos on the death of couple - 'orphaned' embryos.
Ownership of the embryos if the couple divorce.
Safety of embryo freezing.
Concern that the length of time embryos have been kept in storage might have a detrimental effect on the outcome of frozen embryo transfer and possible increase in fetal abnormalities. However, no long-term studies have been carried out since the age of the oldest child born as a result of frozen embryo transfer is only 14 years. In addition, there is no evidence that extended storage is detrimental to the outcome of treatment.