What are in vitro fertilization (IVF) and embryo transfer?

Introducing IVF - In Vitro Fertilization (UK Fertilisation)

IVF literally means fertilization outside the body. In vitro (Latin: within the glass) refers to the technique of performing a given biological procedure in a controlled environment outside of a living organism; for example in a test tube. IVF means that the eggs are fertilized outside the body. IVF treatment involves removing eggs from the ovary, fertilizing them in the laboratory with sperm and replacing them into the woman's uterus. IVF treatments are highly confidential.

Louise Brown - The first IVF baby - 1979

Louise's mother had blocked fallopian tubes. Success rates to open blocked fallopian tubes was always low. Some women have had both tubes removed because of ectopic pregnancies. IVF was originally developed to allow women with such problems to achieve pregnancy. IVF has also proven to be effective for other causes of infertility including endometriosis and unexplained infertility or a combination of infertility factors. IVF can be the last hope for the one in seven couples in the UK who have trouble conceiving. Some couples with male factor infertility achieved conception with IVF. A further development of IVF - ICSI (intracytoplasmic sperm injection) involves the usual IVF type protocol but instead of allowing the eggs to fertilize by themselves in a dish of sperm, an embryologist injects a single sperm into each egg. Around 6,000 babies a year are born in the UK to otherwise infertile couples as a result of in vitro fertilization (IVF). This means that one baby in a hundred is conceived by IVF.

Recommended Book:

 In Pursuit of Parenthood: Experiences of IVF

What are In Vitro Fertilization and Embryo Transfer?

An IVF treatment cycle involves the collection of eggs from the ovaries. Each egg is placed in a special dish together with sperm to facilitate fertilization and early development of embryos. Eggs, sperm and embryos are very sensitive and they are cared for by embryologists who ensure that they are nurtured in the most perfect environment within special incubators. About two days after egg collection, embryos (Figure 10.2) are transferred into the uterus.

IVF was initially developed for women who had severe tubal disease or who had their Fallopian tubes removed but this treatment has also proved successful for unexplained infertility and male factor infertility. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed.A typical IVF treatment cycle is outlined in (Figure 10.3). Originally, eggs were collected laparoscopically (laparoscopy) but we now collect the eggs by ultrasound guidance usually through the vagina.

Figure 10.3  An IVF Treatment Protocol

The IVF pioneers collected just one egg immediately before ovulation but now we use gonadotrophin injections to increase the number of eggs available for collection (superovulation). Natural gonadotrophin release from the pituitary is suppressed (down regulation) by GnRH (gonadotrophins) to prevent ovulation before the eggs are collected. Ultrasound and hormone assays are required to optimise follicular development. In the UK a maximum of three embryos can be transferred into the uterine cavity usually two days after egg collection.

IVF is a complicated treatment requiring dedication from highly trained clinical and embryology staff. In the UK, clinics offering IVF require a licence from a government appointed body 'The Human Embryology and Fertilisation Authority' who monitor the work of IVF units. On average, there is a 20% to 30% success rate associated with IVF. This means that there will be an IVF failure for 70 -80 % of treatment cycles. The issue of birth defects remains a controversial topic in IVF. From a theoretical point of view, doctors and scientists are selecting gametes and embryos which is against the biological vogue favouring natural selection. Evidence on IVF thus far has been largely reassuring.  

IVF has been a major breakthrough in treating infertility and is responsible for the birth of more than 500,000 healthy children around the world.

An IVF treatment cycle is divided into five main stages:

Egg production

Egg recovery

Insemination

Embryo transfer

Luteal phase - supplementation

Egg Production In IVF

IVF drugs are used to produce several eggs during one cycle. The majority of IVF cycle protocols employ superovulation whereby there is an increased production of a larger-than-normal number of eggs for fertilization. The drugs used to stimulate the ovaries are called gonadotrophins and include Pergonal, Metrodin, Follistim and Gonal-F. They are injected daily and the response is monitored by ultrasound and oestrogen levels. To prevent spontaneous ovulation (egg release) in an IVF cycle, GnRH analogues are employed.

Egg Recovery In IVF

During an IVF treatment cycle, eggs are removed from the ovary just before ovulation. HCG is injected approximately 36 hours before planned egg collection. The egg collection can be performed either under general anaesthetic or by sedation. You may find the procedure fine and have no discomfort or you may find that you can be uncomfortable afterwards. Paracetomol can be taken to ease any pain. The Egg Collection can take anything from 20 minutes to an hour but you wont know anything about it!  When you come round from either the anaesthetic or sedation the hospital will tell you how many eggs they managed to aspirate from the follicles.

Pictures of IVF Egg Recovery. An ultrasound probe is introduced vaginally and a fine needle guided into the follicles to collect the ova. With superovulation several follicles become evident at ultrasound. The collected eggs are transferred to the embryologist, a scientist with special training in nurturing the precious IVF gametes (eggs and sperm)

Generally, on the same day of your egg collection, your partner will be asked to provide a sperm sample, unless one has already been collected and stored.

IVF - Egg Insemmination

The oocytes (eggs) are incubated for 3-6 hours before insemination in Petri dishes. On day 2, approximately 48 hours post egg collection, the embryos are graded from Grade 1 to 5 - Grade 1 embryos are the best.

Embryo Transfer in an IVF cycle

The endometrial thickness is a factor in the success of IVF treatment. In medicated frozen embryo cycles, an endometrial thickness of 9-14 mm measured on the day of P supplementation is associated with higher implantation and pregnancy rates compared with an endometrial thickness of 7-8 mm.⁰⁸⁰²

The selected embryos are transferred to a 15% patient's serum dish and labelled for transfer. The patient is taken into the treatment room adjacent to the embryology laboratory and placed in the lithotomy position. A vaginal speculum is inserted and the cervix wiped with sterile water. A catheter pre-loaded with the embryos is introduced through the cervix into the endometrial cavity. The position of the catheter is checked by abdominal ultrasound. The embryos are slowly discharged from the catheter. The catheter is then carefully removed and checked to see that all the embyos have been released. If there are spare embryos, they can be frozen and kept in reserve for you.

A randomized control trial was performed to test the hypothesis that using abdominal ultrasound at the time of embryo transfer to guide replacement, improved pregnancy rates by at least 5%. There was no difference in clinical pregnancy or live birth rates between the two groups. The clinical pregnancy rate for ultrasound-guided embryo transfer was 22% and for non-ultrasound-guided embryo transfer was 23% (odds ratio: 0.96; 95% confidence interval: 0.79-1.18).

 A randomized controlled clinical trial of 2295 ultrasound-guided embryo transfers.(2008-04)

 The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles.(2008-02)

IVF - Single or Double Embryo Transfer?

It has been common practice for IVF programmes to boost the pregnancy rate by placing multiple embryos during embryo transfer. The more embryos replaced during IVF, the greater the chance of pregnancy but there is also an increased chance of multiple pregnancy. In the early days, many embryos were transferred in each IVF cycle and, although this boosted pregnancy rates, triplets, quads and even higher order pregnancies occasionally occurred.

At first it may seem wonderful for a couple with infertility to have a bonus of two babies rather than one, but there is sadly additional costs that may have to be met. All the complications of pregnancy are increased in a twin pregnancy. There are increased risks of miscarriage, premature delivery and operative delivery including caesarean section. Premature delivery is associated with increased chances of morbidity and perinatal mortality (loss of a baby before delivery or in the first week after delivery.^{0001, 0201, 0602}. Whereas one pregnancy in a hundred will have been conceived by assisted conception in the UK and other developed countries, it has been estimated that 50% of babies requiring care in a special care baby unit are IVF babies. For higher order pregnancy, the risks increase exponentially. To reduce the risks of higher order pregnancies, the option of selective termination of pregnancy was developed.

Successful outcome with IVF has increased as techniques have been refined. At one time, authorities with the power to do so, placed restrictions allowing replacement of just three embryos and then two. For example, in 2001, The Human and Embryology Authority (HFEA), which administers IVF clinics in the UK, decided to reduce the number of embryos that can normally be transferred from three to two. The multiple pregnancy rate for IVF in Europe still approaches one in four.⁰⁶⁰¹  Now, the question is addressed as to whether only one embryo should be transferred.   

In women younger than 36 years, single embryo transfer followed by transfer of another single frozen embryo when initial treatment has failed results in similar livebirth rates but with lower incidence of multiple pregnancy.⁰⁴⁰² The cost effectiveness of repeated cycles of elective single embryo transfer may be better than double embryo transfer because of the savings from reduced twin pregnancies.⁹⁸⁰¹

The case for elective single has been contested.⁰⁶⁰⁴ It is likely that single embryo transfer will replace double embryo transfer when there would be a high chance of multiple pregnancy^{0401,0501,0701} although even in those aged 36-39 the elective single embryo transfer policy can still be applied reducing the risk of multiple birth and increasing the safety of assisted reproduction technique (ART) in this age group. ⁰⁶⁰³

Luteal phase - supplementation

Luteal phase supplementation in IVF-stimulated cycles, both in gonadotropin releasing hormone agonist and antagonist protocols, is considered an essential requirement for optimal success rates. The date of initiation and discontinuation of supplemented hormones is not adequately studied in the literature. In most major controlled and randomized studies, there are no significant differences in success rates with progesterone supplementation alone, progesterone and estradiol, progesterone and human chorionic gonadotropin, and human chorionic gonadotropin alone. Success rates seem similar with intramuscular and vaginal progesterone administration with patient preference for the vaginal route. The optimal dose of progesterone has not been studied in a scientific way in the literature. The use of gonadotropin releasing hormone agonists for luteal phase supplementation in antagonist cycles appears to be promising, and is worthy of further investigation.⁰⁸⁰³

Luteal supplementation in in vitro fertilization: more questions than answers.(2008-03)

IVF Costs

NICE guidelines published in 2004 recommend that suitable couples receive up to three cycles of IVF treatment on the NHS. Only 18% of IVF treatment is funded by the NHS and waiting times can differ greatly. The majority of IVF treatment cycles are undertaken privately and the IVF clinics should provide their patients full details of all likely treatment costs before they start a treatment cycle. The typical cost of one IVF cycle at a private clinic is £2,500.

IVF is very stressful with highs and lows which means you can become very emotionally drained. There are emotional costs as well as financial cost implications. Most IVF units have counsellors with the experience to assist you to cope with this stress.

An increasing number of fertility specialists and centres offer acupuncture as a part of their IVF protocol, or maintain a list of acupuncturists specialising in infertility. Scientific evidence does not seem to support acupuncture as a means of improving pregnancy rates although it may assist with relaxation.^{0601, 0801}

Natural cycle and Mild IVF

Natural cycle IVF involves collecting and fertilising the one egg that you release during your normal monthly cycle. This avoids the side effects of fertility drugs and you are less likely to have twins or triplets. Costs are much lower with natural cycle and mild IVF as expensive drugs are not used.

As techniques for nurturing the early embryo advance, success rates with single egg collection approach those for stimulated cycles. Natural rather than stimulated in vitro fertilization might be a potential treatment for patients of advanced age when stimulated in vitro fertilization has been repeatedly unsuccessful.⁰⁸⁰⁵

Natural IVF cycles may be desirable for women with repeated failures by stimulated IVF cycles.(2008-05)

Egg Donation and Egg Sharing

Some women are unable to produce healthy eggs either because they have reached their menopause early, they are approaching their menopause (Figure 10.7) or because their eggs carry abnormal genes. The only realistic chance of a successful pregnancy in these circumstances is if another woman donates some of her eggs. There are some remarkable women who, for altruistic reasons, come forward voluntarily and go through the regimen for IVF egg collection and donation. Egg donors should usually be aged 35 years or less.

Figure 10.7

The demand for egg donation greatly exceeds supplies. There are many women who have healthy eggs and need IVF but for economic reasons IVF is beyond them. The combined requirements of funding for IVF for the less privileged and of others for egg donors has led to the development of eggs sharing. If a woman requiring egg donation will fund the two treatments, she may receive perhaps half the eggs provided by the woman who hasQuality eggs but cannot afford the treatment.

Some pertinent ethical challenges in egg sharing have largely been overlooked.

To maximize the number of retrievable oocytes, prospective egg-sharers are often restricted to younger women with indications for either male-factor or mild female-factor sub-fertility.

Recently, there is increasing evidence that such group of patients would do better either with natural cycle or minimal ovarian stimulation. The quality of the fewer oocytes retrieved is better and there is also improved endometrial receptivity for embryo implantation. Moreover, high gonadotrophin dosages are associated with increased health risks and expensive medical fees.

Hence, there could be an irony because such good prognosis patients may not require a discount if they had instead opted for nil or low dosages of expensive gonadotrophins.

Secondly, there is a dire lack of guidelines and regulations specifying the appropriate discounts in medical fees given to egg-sharing patients.

Thirdly, there must be rigorous auditing to ensure that the amount of financial subsidy given to the egg-sharing patient is exactly equal to the surplus medical fees billed to the recipient patient, or this might lead to profiteering by fertility clinics and doctors.

Lastly, the abolishment of donor anonymity in many countries has potentially more ramifications for prospective egg-sharing patients, as compared to non-patient donors.

Egg sharing in return for subsidized fertility treatment-ethical challenges and pitfalls.(2008-01)

Counselling couples and donors for oocyte donation: The decision to use either known or anonymous oocytes. (2000-01)

Crinone 8% (90 mg)* given once daily for progesterone replacement therapy in donor egg cycles. (1999-01)

Gamete donation: Ethical implications for donors (1999-02)

Cumulative conception and live birth rates after oocyte donation: Implications regarding endometrial receptivity (1997-01)

Low-dose aspirin for oocyte donation recipients with a thin endometrium: Prospective, randomized study (1997-02)

Some psychological aspects of oocyte donation from known donors on altruistic basis (1997-03)

Age of the uterus does not affect pregnancy or implantation rates; a study of egg donation in women of different ages sharing oocytes from the same donor (1997-04)

What are the effects of anonymity and secrecy on the welfare of the child in gamete donation? (1997-05)

Oocyte donation to women of advanced reproductive age: Pregnancy results and obstetrical outcomes in patients 45 years and older (1996-01)

Oocyte donation program: Pregnancy and implantation rates in women of different ages sharing oocytes from single donor (1996-02)

Improvement of pregnancy rates with oocyte donation in older recipients with the addition of progesterone vaginal suppositories (1993)

IVF Support Groups

www.IVFconnections.com IVF Connections connects people going through IVF to information, support, and others going through the same experiences. IVF Connections features IVF bulletin boards, IVF questions and answers, IVF stories, IVF links and an IVF in Canada section.
IVF Connections was founded in February 1999 with just a few bulletin boards. They now have over 150.

www.fertilityfriends.co.uk supports assisted conception, parenting, adoption and surrogacy. This is a Non-Profit UK Registered Company dedicated to providing free support services.

www.fertilityconnect.com They provide information and support for couples having trouble in conceiving and offer information on IVF, IUI, ICSI, and other infertility treatments.

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