Infertility

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Chapter 17 Infertility

Infertility 358

Causes of Female Factor Infertility 359

Causes of Male Factor Infertility 359

Investigations 360

Investigations in the Primary Setting 360

Investigations in the Secondary Setting 360

Evidence of Ovulation 361

Features Suggestive of Ovulation 361

Tests that Confirm the Occurrence of Ovulation 362

Seminal Analysis 364

Tests which Confirm Normal Sperm Production 364

Sperm Production Tests 365

Abnormalities in Sperm Production 366

Sperm Function Tests 367

Postcoital Test 367

Measurement of Antisperm Antibodies 367

In Vitro Assessment of Fertilisation Ability of Sperm 367

Abnormal Sperm Function 367

Tests of Tubal Patency 368

Requirements for the Assessment of Tubal Patency 369

Contraindications to the Assessment of Tubal Patency 369

Assisted Conception 370

Assisted Reproduction Techniques 370

Fertility Drugs 371

Tubal Surgery 373

Efficacy 373

Side Effects 373

Assisted Conception 380

Counselling 380

Infertility

Approximately one in seven couples has difficulties in conceiving. In general, 80% of the couples who have regular sexual intercourse and do not use contraception will get pregnant within a year. The majority of the remaining 20% achieve a pregnancy within 2 years of trying.

Percentage of couples pregnant after varying time periods of unprotected intercourse (Gutmacher 1965)

Definitions

Primary infertility is a condition where a couple, who have had no previous pregnancies, are unable to conceive.

Secondary infertility is a condition where a couple, who have had at least one previous pregnancy that may have ended in a livebirth, stillbirth, miscarriage, ectopic pregnancy or induced abortion, are unable to conceive.

Aetiology of Infertility Lifestyle factors such as heavy smoking or being significantly over- or underweight and stress can adversely affect both male and female fertility.

Infertility

Causes of female factor infertility

With increasing age, women become less fertile.

There are many causes of infertility (see below). Sometimes, failure to conceive can be due to a combination of factors. However, in approximately 30% of cases, a clear cause is never established.

Unexplained infertility	28%
Male factor infertility	21%
Ovulatory disorders	18%
Tubal disease	14%
Endometriosis	6%
Coital problems	5%
Cervical factors	3%

Other factors that may play a part include chronic medical conditions such as diabetes, epilepsy and thyroid and bowel diseases.

Investigations

Investigations in the primary setting

When a couple presents to their general practitioner with the issue of infertility, these initial investigations should be carried out.

Female partner	Cervical smear test.
	Urine test for Chlamydia (this can cause blockages of the fallopian tube).
	Serum progesterone level to check ovulation. This is taken 1 week prior to menstruation, hence day 21 for a 28-day cycle or day 28 for a 35-day cycle (see below).
	Rubella immunity – if rubella is contracted during the first 3 months of pregnancy it can seriously harm the developing fetus Women who are not immune to rubella should be vaccinated, and advised to avoid pregnancy for 3 months.
	Measuring serum FSH (follicle stimulating hormone), LH (luteinising hormone) and oestradiol to identify hormone imbalances or possible early menopause.
Male partner	Semenalysis to check for abnormalities of the sperm such as number, motility, and morphology (see below).
Male partner	Urine test for Chlamydia, which, in addition to being a known cause of infertility in women, can also affect sperm function and male fertility.

Investigations in the secondary setting

These are done in the context of a tertiary fertility clinic and after the primary investigations have been carried out. Some or all of the following tests will be done:

Female partner	Measuring serum FSH, LH and oestradiol to identify hormone imbalances or possible early menopause.
	Serum progesterone level to check ovulation. This is taken 1 week prior to menstruation, hence day 21 for a 28-day cycle or day 28 for a 35-day cycle.
	A pelvic ultrasound scan to look at uterine and ovarian anatomy.
	Serial ultrasound tracking of the ovaries for looking at developing follicles (see below).
	Checking of tubal patency – either by hysterosalpingogram, hysteron-contrast sonography or laparoscopic hydrotubation.
	Diagnostic laparoscopy – to check for problems with tubal and uterine anatomy.
	Hysteroscopy – to check for uterine conditions such as fibroids or polyps
	Endometrial biopsy (in rare cases) see below.
Male partner	Semenalysis to check for abnormalities of the sperm such as number, motility and morphology (see below).
Male partner	Sperm antibody test to check for protein molecules that may prevent sperm from fertilising an egg.

Evidence of ovulation

Features suggestive of ovulation

1. Clinical symptoms and signs

Regular menstruation is usually associated with ovulation, however, no clinical symptoms or signs are sufficiently reliable to confirm ovulation. Supportive laboratory tests are always required.

2. Changes in basal body temperature

The secretion of progesterone by the corpus luteum induces a rise of around 0.5 °C in basal body temperature (BBT). If BBT is recorded throughout the menstrual cycle, a fall in temperature is often observed at the time of the LH surge. Charts typical of those generated by A) a woman with a normal ovulatory cycle, and B) a woman with an anovulatory cycle, are shown below. The differences in BBT between ovulatory and anovulatory women are not sufficiently consistent for a diagnosis of ovulation to be made without further tests.

A. Normal BBT chart from an ovulating woman

B. Abnormal BBT chart from a woman who is not ovulating

Tests that confirm the occurrence of ovulation

1. Serum progesterone levels

Estimation of serum progesterone is a simple method for confirming ovulation. Progesterone is produced by the corpus luteum and its levels reach a peak in the mid-luteal phase (i.e. 7 days prior to menstruation). If the measured serum progesterone levels are low, this may indicate either that the patient is not ovulating, or that the blood sample was withdrawn at an inappropriate time in the cycle. Information about the time of the subsequent menstrual period is required to accurately interpret the relevance of serum progesterone levels.

2. Endometrial biopsy

The presence of a secretory endometrium confirms that ovulation has taken place. Under the influence of progesterone, the endometrial glands dilate, and secretory vacuoles may be observed within the glandular cells. If an endometrial biopsy is taken in the luteal phase and examined histologically, secretory changes can be observed. A biopsy of the endometrium is a relatively invasive process, but it gives useful information, especially if sensitive progesterone assays are unavailable.

3. Serial ovarian ultrasound

Over the course of the menstrual cycle, an ovarian follicle develops, grows to 20 mm and the oöcyte is then released at ovulation. This process can be visualised by a transvaginal ultrasound examination every 2–3 days during the follicular, ovulatory and early luteal phases. This procedure is too invasive and expensive to be used in an unselected population of women complaining of infertility. However, it is often used to monitor the number and size of the developing ovarian follicles in women undergoing ovulation induction. The serial ultrasound is the only method of detecting the luteinised unruptured follicle syndrome (LUF).

Early follicular phase (no ovarian follicle visible on ultrasound).

Mid-follicular phase (12 mm follicle visible on ultrasound).

Immediate pre-ovulatory phase (ovarian follicle on 20 mm diameter).

Seminal analysis

Tests which confirm normal sperm production

Semen Analysis

A basic semen analysis assesses the number, morphology and motility of spermatozoa. The patient is asked to provide a sample (usually by masturbation), which should be analysed within 2 hours of production. The sample should be kept warm (15–38 °C) during the interval from production to analysis. Abstinence from sexual activity for a period of 2–3 days is required before submitting a sample for analysis; otherwise an abnormally low count may be recorded. The patient should also be advised to keep the sample away from spermicidal agents, such as those in condoms.

The criteria for normal spermatogenesis may vary from laboratory to laboratory. The WHO criteria are shown below:

1. Volume: ≥2 ml

2. Concentration: ≥20 million/ml

3. Motility: ≥50% with forward motility (within 60 min of ejaculation)

4. Morphology: ≥30% normal forms

5. White blood cells: <1 million/ml

Normal human sperm (from transmission electron micrograph).

Abnormal sperm (from scanning electron micrograph).

Sperm production tests

Spermatogenesis takes at least 72 days. Events such as viral infection may influence the result. For completeness and accuracy two samples should be analyzed each taken at least 3 months apart.

Semen analysis is conventionally performed by a trained technician using a microscope with a heated stage. More recently, computerised forms of semen analysis have become available which have the advantages of speed, reproducibility and cost-effectiveness.

Sperm movement analysed by a computerised image analysis system: a linear progressive tracks of a non-capacitated sperm population; b high amplitude, non-progressive tracks of a hyperactivated, capacitated sperm population.

Abnormalities in sperm production

The causes of abnormalities in sperm production include:

1. Acute and chronic infection of the male genital tract. Gonococcal and coliform infections respond to antibiotics but chronic prostatitis can be difficult to treat. Spermatozoa are reduced in number and tend to be malformed and non-motile.

Chlamydial infection may be found in both partners. Sperm motility is reduced, causing infertility. Both partners should be treated and follow-up examinations of the ejaculate carried out.

Viral infections can be important, especially mumps. Testicular atrophy may follow this infection.

2. Immunological reactions in the form of auto-antibodies occur in a variable number of men (3–12%). Formation of these antisperm antibodies may be stimulated by infection or by injury, but in most cases the cause is obscure. Steroids in short courses may be helpful.

3. Environmental factors

These include social habits such as smoking, alcohol and drugs.

Also included under this heading are occupational hazards such as working with heavy metals, welding processes, exposure to high temperatures, pesticides and radioactive materials.

The list of occupations involving substances that are toxic to sperm count is remarkably long:

Agriculture and gardening – handling pesticides, weed killers.

Car industry, painters, battery workers, domestic decorators, smelters – all using lead products.

Textile industry – exposure to carbon disulphide.

Plastic manufacturing – exposure to chlorinated biphenyls.

Grain storage – exposure to benzine hexachloride.

A large number of therapeutic agents also affect spermatogenesis.

1. Chemotherapeutic agents – these depress sperm production and cause germinal epithelial aplasia. Rising FSH levels are an indication of these changes.

2. Sulfasalazine reduces sperm motility and number. These effects are reversed if treatment is stopped.

3. Cimetidine, spironolactone and ketoconazole interfere with androgen action and may affect spermatogenesis.

4. Anabolic steroids profoundly depress spermatogenesis, but the effect is reversible when the drug is withdrawn.

5. Antihypertensive drugs, antidepressants and some sedatives cause impotence and may depress sperm count or motility.

6. Nitofurantoin, antimalarial drugs and corticosteroids depress spermatogenesis.

Sperm function tests

Other tests which may be used to assess sperm function:

Postcoital test

The postcoital test assesses the ability of sperm to penetrate the human cervical mucus. Healthy sperm are able to swim through the cervical mucus secreted at mid-cycle. To perform the test, the couple is advised to have intercourse mid-cycle, and a sample of the cervical mucus is obtained 9–24 h later. The presence of ≥20 motile sperm per high powered field (400× magnification) indicates a positive result.

Positive postcoital test showing presence of ≥20 motile sperm in one high powered field.

Although the postcoital test is still widely used, the requirement for careful timing of intercourse and cervical mucus recovery means that the test can be difficult to perform. An alternative is to assess the distance travelled by sperm through a layer of ‘artificial mucus’, normally, a polymer of hyaluronic acid. This test is more easily quantified, and when used in combination with antisperm antibodies, gives similar information.

Measurement of antisperm antibodies

Antisperm antibodies may be found in the serum, seminal fluid or the cervical mucus. Each of these may adversely affect fertility. Many tests have been devised to assess antisperm antibodies. The immunobead test (IBT) detects both IgA and IgG antibodies. In the presence of antisperm antibodies, polyacrylamide beads covered with bound antibody react with the spermatozoa. The test has good sensitivity and specificity, and this test can also be used to identify the antisperm antibody binding site – antibodies bound to the head of the sperm have the most serious effect on fertility.

In vitro Assessment of fertilisation ability of sperm

In practice, many couples with male factor infertility are treated with in vitro fertilisation (IVF). Some sperm are so abnormal that they are unable to fertilise the egg in vitro, and this will be detected during the course of a conventional IVF regimen. More specialised treatment, such as intracytoplasmic sperm injection (ICSI), may then be required.

Abnormal sperm function

Spermatogenesis may be adversely affected by conditions such as a viral illness; hence it is important to obtain two samples of sperm, more than 3 months, apart for complete analysis. Persistent abnormalities in spermatogenesis are rarely treated successfully without recourse to assisted reproductive technologies. Further investigation and treatment of such men is outside the scope of this book, but these should be considered before assisted reproduction technologies are embarked upon.

Tests of tubal patency

1. Laparoscopic hydrotubation

Tubal patency can be assessed at laparoscopy. A cannula is inserted into the cervix, and 5–20 ml of methylene blue dye is injected into the cavity of the uterus. If the fallopian tubes are patent, the dye can be seen spilling out of the end of each tube. An important advantage of laparoscopic hydrotubation is that it enables inspection of the pelvic organs during the procedure. Conditions such as pelvic adhesions and endometriosis, both of which may reduce fertility, can be noted. The major disadvantage of laparoscopy is that it is an operative procedure that requires a general anaesthetic.

2. Hysterosalpingography

Hysterosalpingography is the radiological visualisation of the genital tract after the injection of a radio-opaque contrast medium through the cervix. Hysterosalpingography may be a useful supplementary test in women who have tubal blockage that is demonstrated at laparoscopy. Hysterosalpingography allows the site of tubal blockage to be determined, which is helpful if surgery is contemplated.

This is a normal salpingogram. Note: 1. The anteverted uterus is foreshortened. 2. The long thin tubal outline. 3. The ill-defined shadow of peritoneal spill. 4. Cervico-vaginal leakage.

3. Hysterosalpingo-contrast sonography.

Tubal patency can also be assessed by an ultrasound examination. A solution containing galactose microparticles, visible on ultrasound, is injected though the cervix. If the fallopian tubes are patent, the solution can be observed passing along the tubes and out through the fimbrial ends.

4. Falloposcopy

Advances in imaging techniques have allowed the manufacture of hysteroscopes that are small enough to be passed into the fallopian tube. Internal tube morphology can be directly assessed. This procedure is only available in specialised centres, but it can be combined with operative treatments to relieve fallopian tube blockage.

Requirements for the assessment of tubal patency

1. The patient should have a clear understanding of the procedure that is going to be performed.

2. To avoid inadvertently performing the procedure when the patient is pregnant, the procedure should be done during the first half of the menstrual cycle, or may be done at any phase of a cycle if adequate contraceptive precautions have been taken.

Contraindications to the assessment of tubal patency

1. Pregnancy or possible pregnancy.

2. Active pelvic or vaginal infection.

Assisted conception

Pre-Pregnancy Infection Screening

Prior to the storage of patient sperm, eggs or embryos a number of screening tests are carried out to assess the risk of contamination. These include HIV 1 and 2 (anti-HIV – 1, 2), hepatitis B (HBsAg/Anti-HBc) and hepatitis C (anti-HCV-Ab).

Folic Acid Administration

Folic acid is thought to reduce the risk of neural tube defects in the offspring of pregnant women. All women planning a pregnancy should be advised to commence folic acid.

Fertility drugs

Fertility drugs

These are used for inducing ovulation. Some women may become pregnant with these drugs alone, or alternatively, these may be used in combination with other treatments such as IVF or IUI. Commonly used drugs include:

1. Clomiphene

Clomiphene is a non-steroidal antioestrogen. It has complex actions, including an oestrogen-agonistic activity at the endometrium. The major effect of clomiphene is at the hypothalamus, and it induces ovulation by increasing pituitary gonadotrophin production. Its side effects include hot flushes, mood swings, nausea, breast tenderness, insomnia, increased urination, heavy periods, spots and weight gain. The risk of ovarian cancer can also increase slightly if it is taken for over a year.

This is an oral insulin sensitising medication that helps stimulate ovulation in women with the polycystic ovarian syndrome. Potential side effects of this drug include nausea, vomiting, diarrhoea, abdominal pain, a metallic taste, itching, allergic reactions and rarely hepatitis.

3. Gonadatrophin releasing hormone analogues (GnRHa)

This is administered by a small pump, which injects pulses of the drug into the bloodstream. It is used mainly in ovulation failure caused by a lack of GnRH. Possible side effects include abdominal pain, nausea, vomiting, heavy periods and headaches.

4. Gonadotrophins

Follicle stimulating hormone (FSH), Gonal-f and Puregon

Luteinising hormone (LH), such as Menogon, Menopur and Merional

The use of gonadotrophins to induce ovulation should only be carried out in specialised centres. The patient should be monitored by ovarian ultrasound (to determine the number of follicles and their diameter) combined with serum or urinary oestrogen assays. These drugs are generally used before treatment cycles during assisted conception, or for polycystic ovary syndrome in which clomiphene has not been effective. They are administered as once-daily injections and act by stimulating follicle production in the ovaries. When the follicles are mature (as deemed by ovarian tracking), an injection of human chorionic gonadotrophin hormone (hCG) is given to trigger the release of an egg(s). Ovarian hyperstimulation syndrome (OHSS), risk of multiple pregnancies when used for ovulation induction, allergic reactions and skin reactions are the potential side effects.

5. GnRH analogues/pituitary agonists (nafarelin, buserelin and goserelin)

These are administered via nasal sprays, daily injections, or as monthly depot injections. They downregulate the ovarian cycle which results in low levels of FSH, LH and oestradiol. They are often used before an IVF cycle is commenced. Some side effects include hot flushes, night sweats, headaches, vaginal dryness, mood swings, changes in breast size, acne and muscle aches.

6. Gonadotrophin releasing hormone antagonists (cetrotide and orgalutran)

These are given daily by subcutaneous injection and simultaneously with FSH injections. These drugs act by blocking the release of LH and are administered while the ovaries are stimulated to produce eggs, in readiness for IVF treatment. Possible side effects include nausea, headache, injection site reactions, dizziness and malaise.

7. Progesterone (Cyclogest, Gestone, Crinone, Progynova)

This is generally given after the hCG injection or on the day the embryos are returned to the womb. Its purpose is to prepare the endometrium for nurturing an embryo. This may help maintain the pregnancy after IVF or IUI.

8. Bromocriptine and carbergoline

These tablets reduce high levels of prolactin, which can be a cause of subfertility. Side effects include nausea, headache, constipation, dry mouth, skin reactions, hair loss and a lowering of the voice.

Tubal surgery

When tubal disease has been confirmed, tubal patency may be improved by surgery. The best results are obtained when surgery is performed by an operator trained in these techniques, using an operating microscope. Surgery may be performed laparoscopically, or as an open procedure. The aim of surgery is to restore tubal patency and mobility. However, the restoration of tubal patency does not guarantee pregnancy, since tubal function (e.g. the movement of cilia) may have been permanently destroyed or impaired.

Laparoscopic salpingostomy with laser or diathermy to (a) incise the tube and scar the serosa to cause (b) eversion of the mucosa.

Efficacy

The efficacy of tubal surgery depends on the extent of the pre-existing disease and on the particular procedure that is carried out. The best results are achieved after surgery for sterilisation reversal as pregnancy rates as high as 60%, have been reported. However, with severe disease, the cumulative pregnancy rate at 24 months after surgery is low at 10%, which is a little greater than could have been expected after no treatment.

Side effects

– complications of surgery

– increased risk of ectopic pregnancy during a future pregnancy.

Assisted conception techniques

In vitro fertilisation

This technique involves the fertilisation of human oöcytes ‘in vitro’. The eggs are harvested from ovarian follicles that are approximately 20 mm in diameter (i.e. immediately before ovulation). The eggs are then placed in a culture medium, in an incubator, and fertilised several hours later. Gonadotrophins are commonly employed to increase the number of pre-ovulatory oocytes available for collection. The use of a GnRH analogue allows better control of the timing of egg collection.

Indications for in vitro Fertilisation

1. Unexplained infertility when anatomy and function appear to be normal, and all treatable causes of infertility have been eliminated.

2. Tubal disease.

3. Lack of success with other techniques such as fertility drugs alone or IUI.

4. Minor degrees of male subfertility, for example, when the sperm count is low, but not so low that fertilisation is impossible (see ICSI).

Example of a Treatment Schedule

Suppression of the Natural Monthly Hormone Cycle

The patient is usually given a GnRH analogue, which blocks the pituitary receptors and stops the normal production of GnRH.

Boosting the Egg Supply

Once the natural cycle has been suppressed, a FSH (e.g. human menopausal gonadotrophin, hMG) is administered by daily injection.

Follicle Tracking

This is done by a transvaginal ultrasound scanning which helps monitor follicular growth. When the follicles reach 20 mm in diameter, ovulation is imminent. At this point, an injection of hCG is given to facilitate the egg maturation process.

The diagram shows the sequence of hormone treatments, and the much improved luteal progesterone profile (•) compared with the normal (shaded).

Collection of Eggs

Egg collection is carried out by a transvaginal ultrasound-guided aspiration of the ovarian follicles. Light sedation may be required for this process.

Egg Fertilisation

The eggs and sperm are then cultured, in vitro, for 16–20 h to allow fertilisation to occur. The fertilised eggs (embryos) are then grown to the 4–8 cell stage. The best one, or two, embryos are then chosen for transfer back to the uterus.

Human egg, 18 h after fertilisationTwo pronuclear bodies (one from the sperm and one from the egg itself)

Normal human embryo at the 4 cell stage 48 h after fertilisation and ready for transfer back to the uterus

After egg collection, progesterone is often given to prepare the lining of the womb for embryo transfer. This can be in the form of pessaries, an injection or a gel.

Embryo Transfer

For women under 40 years of age, one or two embryos can be transferred. If the woman is over 40, however, a maximum of three embryos can be used. A restriction on the number of embryos used is to prevent multiple births and its associated risks. Any remaining embryos can be frozen for future IVF attempts, if they are suitable.

Risks of IVF Treatment

(1) Side effects of hormonal therapy – hot flushes, mood changes, headaches, restlessness.

(2) Multiple births (twins, triplets or more) – this is the single greatest health risk associated with fertility treatment. The Human Fertilisation and Embryology Authority (HFEA) has imposed restrictions on the number of embryos that can be transferred during IVF in order to reduce the number of multiple births. Multiple births carry risks for both the mother and fetuses. The babies are more likely to be premature and tend to have below-normal birth weight. The perinatal mortality rate has been shown to be four times greater in twins compared to singletons, and for triplets, the risk is seven times greater than for singletons. In addition, the risk of cerebral palsy is five times higher for twins and 18 times higher for triplets, compared to singletons.

(3) Ovarian hyperstimulation syndrome

The ovarian hyperstimulation syndrome is a potentially dangerous overreaction to certain drugs that are used to stimulate ovarian follicle production. It is characterised by a sudden increase in vascular permeability with a massive extravascular exudate. The condition is categorised into mild, moderate and severe disease. In severe disease, there is evidence of intravascular loss, with ascites and pleural effusion. The resulting haemoconcentration can lead to hepatorenal failure and thrombosis. The condition can be fatal and should be carefully managed by fluid balance, thromboprophylaxis and, where necessary, dialysis and paracentesis. The mainstay of management is prevention, which involves careful monitoring of ovarian stimulation and a withholding of hCG in women at risk.

(4) Ectopic pregnancy – there is a higher chance of this occurring after IVF (especially in the context of tubal disease) when compared to a spontaneous conception.

Efficacy

The success of IVF is dependent on the age of the female partner, the indications for treatment, the number of embryos replaced and the skill of the IVF treatment centre. The cumulative conception rate, after three treatment cycles, varies from over 40% (in women aged 20–24) to 20% (in women aged 40–45). The live birth rate is considerably lower at around 30% (in women aged 20–24) to less than 15% (in women aged 40–45).

Intrauterine insemination (IUI)

IUI involves a laboratory procedure that separates fast-moving sperm from more sluggish or non-moving sperm. The fast-moving sperm are then placed into the woman’s womb, close to the time of ovulation, when the egg is released from the ovary in the middle of the monthly cycle. Prior to IUI, it is essential that fallopian tubes are proven to be patent. IUI can be carried out with or without the use of fertility drugs.

Intracytoplasmic sperm injection (ICSI)

ICSI involves the injection of a single sperm into an egg. This technique is used when, in the male partner, the sperm count is so low, or if the sperm function is so abnormal, that they would not normally be able to fertilise an egg, either in vitro or in vivo.

Donor conception

Donor conception involves using sperm, eggs or embryos from donors. DI uses sperm from a donor to achieve conception. Sperm donors are screened for sexually transmitted diseases and some genetic disorders. In DI, sperm from the donor is placed into the cervix at the time of ovulation.

Donor eggs are fertilised in vitro, frozen, and placed in a recipient who has been treated with oestrogens and progesterones, as described above. Such treatment may be useful in women with premature menopause.

Gamete intrafallopian transfer (GIFT)

GIFT involves the replacement of harvested sperm and eggs into the fallopian tube, before fertilisation occurs. The advantage of this technique is that the expertise of an embryologist is not required. Clearly, GIFT is unsuitable for women with tubal disease. Pregnancy rates are similar to those achieved by conventional IVF. However, the clinical guidelines on fertility, issued by NICE (the National Institute for Health and Clinical Excellence) state: ‘There is insufficient evidence to recommend the use of GIFT … in preference to IVF in couples with unexplained fertility problems or male factor fertility problems.’

In vitro maturation (IVM)

With IVM, eggs are removed from the ovaries and collected when they are still immature. They are then matured in the laboratory, before being fertilised. The difference between IVM and conventional IVF is that the eggs are immature when they are collected. This means that the woman does not need to take as many drugs before the eggs can be collected as she might if using conventional IVF, wherein mature eggs are collected. This is a useful technique, particularly in patients who are susceptible to developing the ovarian hyperstimulation syndrome.

Reproductive immunology

Reproductive immunology (still in its infancy) is a method which offers treatments aimed at the patient’s immune system, in an effort to sustain a pregnancy. The theory behind this is that the natural killer (NK) cells, found within the endometrium, may be attacking the implanting embryo, thus resulting in miscarriage. Uterine NK cells are present in large numbers in the wall of the womb at implantation and in the early months of pregnancy. They appear to facilitate the placental link between the mother and the fetus – the mechanism of this is, however, not clear.

Treatments to ‘suppress NK cells’, offered by some clinics, include high-dose steroids, intravenous immunoglobulin and tumour necrosis factor-a (TNF) blocking agents. These treatments are not licensed for use in reproductive medicine. As with all medical interventions, they carry risks and potential side effects.

Pre-implantation genetic diagnosis (PIGD)

PIGD testing involves carrying out tests on embryos, created through IVF or ICSI, to detect certain inherited conditions or abnormalities. The embryo is grown in the laboratory for 2–3 days until the cells have divided and the embryo consists of around eight cells. An embryologist then removes one or two of the cells (blastomeres) from the embryo. The cells are tested to see if the embryo from which they were removed contains the gene that causes a genetic condition in the family. Embryos unaffected by the condition are transferred to the womb for development. Any suitable remaining unaffected embryos can be frozen for later use. Those embryos that are affected by the condition are allowed to perish. Another method, known as the trophectoderm biopsy, is also available, wherein the embryo is allowed to develop for 5–6 days such that there are 100–150 cells. At this stage, cells within an embryo have separated into two types: cells which will form the fetus (inner cell mass) and cells which will form the placenta (trophectoderm). More cells can be removed at this stage (from the trophectoderm) without compromising the viability of the embryo, possibly leading to a more accurate test.

Assisted conception

HFEA (Human Fertilisation and Embryology Authority)

HFEA was created by an act of the UK parliament in 1990. Its function is to license and monitor clinics that carry out ART (e.g. IVF, DI, etc.). The HFEA inspects each clinic on an annual basis. It also lays down criteria on what is considered as acceptable treatment (e.g. women under the age of 40 can have either one or two embryos transferred (if however, the woman is 40, or over, a maximum of three can be used) it requires clinics to make counselling facilities available to patients; it forbids the payment of donors, etc.). In other countries (e.g. the USA), there are no legal restraints on treatment; however, clinics have an ethical obligation to treat their patients with clinical, rather than commercial, principles in mind.

Counselling

Infertility is not just a medical condition, as it also affects the couple’s perceptions of themselves as individuals, their relationship and their functioning in society. The use of assisted reproductive technologies, such as IVF, has allowed many couples to bear children when they could not conceive naturally. However, these technologies may be a mixed blessing – they are stressful to undergo and are by no means completely effective.

It is important, while dealing with subfertile couples, to give them an accurate description of the cause of their infertility and their prognosis, both with and without treatment. The efficacy and the side effects of the various treatment options should be discussed. In addition to this detailed medical information, the couple should be encouraged to explore their feelings about their situation. The use of professionals with counselling skills is invaluable, and, indeed, the provision of counselling facilities is required by the HFEA, as a prerequisite for their licensing of ART providers.

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