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Investigation of the infertile couple for 2 assisted conception

Amir Lass
Normal fertility is usually defined as achieving a pregnancy within 2 years by regular coital exposure'. It is estimated that about 90% of couples will achieve pregnancy in the first year and 95% in 2 years. Therefore, 8—10% of couples world-wide experience some form of infertility problem2. There are variations in the incidence of infertility in different regions and countries3. Although the prevalence of infertility has probably remained constant in the last rv.'o decades, attendance of patients for fertility treatment has increased dramatically all over the world with, in parallel, the creation of more new fertility centers. In the UK alone there are currently 76 centers performing more than 30 000 IVF cycles a year4. This observation is probably the result of the higher profile of infertility issues in the public arena, manifested by intensive coverage in newspapers, magazines, radio and television programs. Moreover, the abundance of treatment facilities and easier access to fertility specialists has increased the awareness of patients and health-care providers to seek expert assistance much sooner. Only in a minority of cases is one partner completely sterile, meaning that there is no possibility of a natural pregnancy occurring (i.e. azoospermia, bilateral tubal occlusion, absence of uterus, anovulation); therefore fertilityimpairment is seen in both partners more frequently than expected5. their general practitioner, gynecologist or andrologist after completion of basic infertility investigations. A substantial proportion of these patients have already undergone some infertility' treatment such as ovulation induction, inrrauterine insemination or tubal surgery. Moreover, some couples have had treatment by in vitro fertilization (IVF) cycles in other centers. We encourage both partners to attend the primary consultation in the Clinic together and thoroughly investigate them as a unit. \Vc ask them to supply any relevant information and test results that are in their possession, with a covering letter from their general practitioner or consultant. In this interview, a detailed family and medical history is obtained to rule out other health problems. Due attention is given to exclude conditions that can contribute ro the infertility', such as diabetes mellitus, endocrinopachies or autoimmune disorders. The menstrual history is recorded and any previous investigations and pregnancies are noted. Although sometimes embarrassing, it is important to verify the frequency of intercourse and the timing of these occurrences related to the menstrual cycle. It is also important to explore any sexual problems such as impotence or premature ejaculation. It is still surprising that inappropriate intercourse due to biological or sexual problems or lack of knowledge contributes up to 6% of the causes of infertility. It is not rare to discover that some couples with sexual problems present themselves as suffering from infertility. A complete physical and pelvic examination of the female and genital examination of the male are an integral part of the primary consultation. Our policy is to assess the patients promptly, without"8' unnecessary repetition of previous examinations and tQ offer the appropriate treatment to the right patients. The

Most patients are referred for assisted conception treatment in a tertiary center such as Bourn Hall Clinic by


Temperature recordings are still a mainstay of many infertility clinics and something which many infertile women may use before seeking the advice of a general medical practitioner. Couples are routinely required to be tested for human immunodeficiency virus (HIV) within the 6 months preceding treatment. reduce the chance of conceiving. Furthermore. she is strongly advised to be immunized before continuing with fertility treatment. A biphasic temperature chart indicates that at least some progesterone is being produced. The hemoglobin is estimated and should be more than 10 g before IVF is embarked upon. Asterisks mark the tests thai are considered essential. if the test is negative and she is resident in the UK. Patients whose BMI is not in the recommended range are referred to a dietitian in order to achieve that goal before they are allowed to continue with assisted conception treatment. estradiol* ovarian volume by ultrasound Ovarian reserve Sperm Tubal and factors Uterus hysterosalpingogram laparoscopy hysterosalpingogram ultrasound* hysteroscopy D & C with histology ofendometrium Doppler scan of uterine arteries LH. Such charts are rarely 'textbook' in result. but only serial ultrasound scans or fortuitous direct inspection will confirm that the dominant follicle has ruptured. there is the possibility that the egg may still be trapped within peritoneal 14 . testing of the luteinizing hormone (LH) surge'and serial ultrasound scans. Ovulation estradiol. General condition The woman's body mass index (BMI) should be in the range of 20—30. some may notice a lack of correspondence between cervical mucus changes. The most common means of assessing ovulation in the menstruating woman include: basal temperature recordings. the rest are optional. and a luteal phase plateau suggests that the progesterone output is satisfactory. and increase the risks involved in anesthesia and surgical retrieval of oocytes6-7. hepatitis B virus (HBV) and hepatitis C virus (HCV) antibodies. Where relevant. while multiple peaks may indicate 'luteal phase deficiency'. temperature response and the LH surge10. increase pregnancy complications and neonatal morbidity. patients do not always find them easy to interpret. Both being overweight and underweight can affect normal ovularion.In Vitro Fertilization and Assisted Reproduction basic groups of investigations required are shown in Table 1. Similarly. it is essential that they have been tested for Table 1 Investigation of infertility. D & C. depending on clinical necessity General body mass index* HIV antibodies* hepatitis B and C antibodies* hemoglobin* basal temperature charts cycle day 2—6: serum LH. FSH. follicle stimulating hormone. and they are offered the option of counselling regarding the implication of this blood test. FSH. cervical mucus changes. and are notoriously difficult for couples to interpret in deciding on the best time for coitus. Cervical cytology is obtained if she has not been tested within the preceding 3 years or if clinical examination suggests the presence of a suspicious lesion. Even then. dilatation and curenage semen analysis of 2-3 samples* Assessment of ovulation Normal ovulation is defined as rupture of the follicle with release of an oocyte8. Serum progesterone levels of>10 ng/ml a week after the LH surge or mid-cycle temperature change are indicative of adequate ovulation9. However. Fortuitous laparoscopic examination may demonstrate actual ovulation or the ovarian stigma. Routine high vaginal or cervical swab cultures are not usually taken unless there are symptoms or signs of infection. Home-testing of morning urine samples for the LH surge with one of the easily available proprietary kits may give more definite answers and more accurate timing9. The only true evidence of ovulation is a subsequent pregnancy and regrettably there is no established method to confirm completion of ovulation. the woman is tested for rubella immunity. alter the response to super-ovulation with gonadotropins. prolactin cycle day 21: progesterone* serial ultrasound scans of the ovaries cycle day 2-6: serum FSH. luteinizing hormone.

coincidentally with apparently regular cycles. The most common cause of POP in adults is probably autoimmune failure and investigations for autoimmune disorders should take place. polycystic ovaries. This loss accelerates around the age of 37 and precedes the menopause by 10—12 years17'18. menstruation. In normogonadotropic anovulation. and the cycles are cancelled. adrenal insufficiency. Patients Assessment of ovarian reserve A major factor in successful IVF treatment is the ability of the ovary to respond to gonadotropin stimulation and to develop several follicles. Hypergonadotropic hypogonadism is defined by raised FSH levels (> 20 mIU/ml) and indicates ovarian failure. We may take a blood sample at day 2-6 of the menstrual cycle for prolactin. besides the comparatively rare pituitary prolactinoma. rheumatoid arthritis. Other rare causes of high levels ofgonadotropins are summarized in Table 2. then a repeat estimation is made and a new sample is also sent for estimation of the level of thyroid stimulating hormone. Obviously. vitiligo. LH and escradiol to identify the four main causes ofovulatory failure: (1) Hyperprolactinemia. It may occur at any age.the follicle. This is common. often characterized by irregular oligomenorrhea. Whilst in younger women the cause is mostly genetic (e. she is classified as suffering from premature ovarian failure (POP). Although stress remains the commonest cause of a rise in prolactin level. the investigation and management of which are outside the scope of this chapter. myasthenia gravis. Some women fail to respond to gonadotropin stimulation. low estradiol level (<40pg/ml)13 along with a negative gestagen challenge test (no withdrawal bleeding). Hypogonadotropic hypogonadism is usually idiopathic and is a result of primary hypothalamic or pituitary failure.g. including thyroid autoanti-bodies. Anovulacory infertility is the commonest cause of female infertility. There is wide variation in the number and rate of depletion of follicles. a not uncommon finding of gynecologists used to laparoscopic oocytc recovery. Table 2 Causes of hypergonadotropic hypogonadism Idiopathic Concomitant autoimmune disease — thyroiditis. in older women near the end of their reproductive life a raised FSH level is due to aging of the ovary and therefore indicates imminent menopause. That response reflects the ovarian function or 'ovarian reserve'. The reduction of ovarian reserve is apparently due to reduced numbers of ovarian primordial follicles from about a million at birth to over 250 000 at menarche. idiopathic thrombocytopenic purpura. amenorrhea may or ovularory dysfunction occur Investigation of the infertile couple for assisted conception younger than 30 years of age should have a karyotype determination. (4) Normogonadotropic anovulation. particularly in older women. Turner's syndrome). malnutrition or underweight 12. pituitary adenoma 15 . to very few at the end of reproductive life. Other causes include excessive stress or exercise. psycho-therapeutic medication and the premenopausal state have to be considered. which occurs in 1% of women14. (2) Hypogonadotropic hypogonadism. autoimmune hemolytic anemia Resistant ovarian syndrome Previous surgery Chemotherapy and/or radiotherapy Infection Galactosemia 17-hydroxylase deficiency Tumors producing gonadotropins — lung cancer. If the woman is < 40 years old. The incidence of chromosomal abnormalities in POP patients with secondary amenorrhea is esrimatedto be 2-5%. however. Women who suffer from primary amenorrhea have usually been evaluated previously and not in the context of infertility. The presence ofaY chromosome requires surgical removal of the gonads as there is 25% risk of malignant tumor formation 15'16. Galacrorrhea may be present. This condition is best diagnosed by low LH and FSH levels (< 5 mIU/ml). thyroid function is further tested. the majority of patients are likely to have polycystic ovaries. If there is occult hypochyroidism. If the prolactin level is raised more than 800 mIU/ml". follicle stimulating hormone (FSH). (3) Hypergonadotropic hypogonadism. it would be clinically and economically helpful if we could predict a poor response before treatment. This condition is discussed in a separate chapter.

if the level is above that Dynamic tests 3 32 Basal inhibin-B level Inhibin-B is a heterodimeric glycoprotein released by the granulosa cells of the follicle.In Vitro Fertilization and Assisted Reproduction Age of the female partner is an important factor in fertility. As more couples delay the commencement of child rearing. However. problems in the uterus and embryo loss . huge variations between different laboratories and monthly variations in FSH secretion means that FSH measurement is of only limited value in assessing the prognosis ofIVF treatment27'33. In the aging process. around 15% of our treatment cycles were performed on women of 40 years or older. This simple rest 16 . Small ovaries are associated with poor response to superovulation and a high cancellation rate in IVF38'39. It is important for each fertility center to define their cut-off point. We inform patients at the end of their reproductive life about their slim chance of conceiving. until they are totally refractory at the time of the menopause. including the decline in the frequency of intercourse25. as a woman gets older her fertility diminishes19'23. there is already a decreased ovarian reserve and it is not clear whether starting stimulation in a later month with 'normal' FSH levels will give a better result34. The biological age is more important than the chronological age . Age and regularity of menses alone are unreliable ways of predicting ovarian reserve. Our cut-off point is 12 IU/1 or 12 mIU/ml. Once the FSH levels start to fluctuate. In developed countries. while the average age of our patients is 36.5 years. decreasing numbers of primordial follicles17. Although many women are fertile nto their late forties. an estradiol level of less than 80 pg/ml with a normal FSH level in women of 3S-42 years gives a good prognosis of successful treatment35. Currently. On cycle day 3. Basal serum FSH levels Once the ovary is more or less exhausted. Ovarian reserve may be evaluated by the following assessments. depending on their experience and results. Transvaginal measurement of ovarian volume is quick. Ovarian volume Increased age is associated with decreased ovarian volume. Decreased ovarian volume is a sign of ovarian aging that may be observed earlier than a rise in FSH levels. We check the day 2 FSH level in the treatment cycle of all patients of 38 years or older and women with previously reduced response to superovulation. This event takes place a few years before the actual menopause. Recently. At Bourn Hall we do not limit the upper age for treatment for women as long as they are not menopausal. the ovaries cease to respond to stimulation even though some follicles still remain in the srroma. but the precise reason for this loss of fertility is not understood. accurate and cosc-effective. Oddly. There are thought to be a number of factors. more women are now choosing to delay starting a family 24 for various social reasons. the ovaries become progressively less responsive to exogenous gonadotropins. poorer oocyte quality ' . A recent study has shown that women with low day-3 inhibin B level (< 45 pg/ml) had a poorer response to superovulation for IVF and were less likely to conceive a clinical pregnancy. most are not. Basal estradiol level Measurement of basal estradiol in addition to FSH might improve the ability to predict fertility potential compared with basal FSH and chronological age alone35"37. increased pituitary production of FSH follows. 30 26 27 28 threshold we postpone treatment and check the PSH level again in the next cycle. Other tests that are not widely used clinically and are performed only in special circumstances in our clinic include the following. the FSH level is the best marker for assessing ovarian reserve and for predicting the response to superovularion. with a good correlation with pregnancy rates '• . sometimes due to chromosomal abnormalities29. lack of a clear cut-off point. the age of those attending for infertility treatments will increase25. The clomiphene challenge test (GCT) was first described in 1987 by Navot and colleagues41. It also showed that a decrease in inhibin-B probably precedes the increase in FSH levels40.

0 ml or more. The highest sperm concentration commonly presents in the first part of the ejaculate. As described in later chapters. However. (7) Immunobead test < 20% spermatozoa with adherent particles. A few studies have shown that. (A5. (4) Motility > 50% with forward progression. Armour Pharmaceutical Company Limited. At Bourn Hall we recommend that the ejaculate produced by masturbation be split into two (linked with adhesive tape) dry plastic pots. In this test changes in estradiol levels from cycle day 2 to 3 after subcutaneous administration of leuprolide acetate45 or FSH increase 2 h after buserelin injection46 are measured. problems tend to arise with fertilization should the score be less than 2. it may be suggested that ovarian biopsy could have a place in the evaluation of unexplained infertility and in women in the later part of reproductive life.Investigation of the infertile couple for assisted conception consists of measuring the serum FSH level on cycle day 3 and again on day 10 after administration of 100 mg of clomiphenc from days 5 to 9. This is not only an aid to prognosis. (5) Morphology > 30% with normal forms. if these findings are confirmed in studies of more patients. it is not yet clear whether they are more useful than measurement of basal FSH in predicting IVF outcome. These include: (1) Volume of ejaculate 2. the pregnancy rate and the chance of having a child are the same as for women with two intact ovaries. or > 25% with rapid linear progression. Eastbourne. The mixed antiglobulin reaction (MAR) rest will distinguish IgG antibodies attached to the motile spermatozoa and therefore present in the seminal plasma. This provocative test unmasks patients who might not be detected by basal FSH screening alone. but is also helpful to the laboratory in any subsequent sperm preparation procedure (see Chapter 13). An abnormal test is defined by elevated FSH levels on cycle day 10. addition of50%Albuminar-5. Women older than 35 years have only one-third of the concentration of follicles of younger women. UK) to the pots may alleviate sperm agglutination or diminish the effect of proven antibodies. the addition of culture medium to the specimen pots before semen collection results in improved sperm motilicy if there has been marked viscosity of previous semen samples. (2) Sperm concentration > 20 X 106 spermatozoa/ml. 17 . An abnormal test is highly predictive of diminished ovarian reserve in natural cycles. but there are some points worth emphasizing here. during ovulation induction and in IVF42"44. Although this was a preliminary study in a relatively small group of patients. although the response to superovulation is slightly reduced. Semen analysis This topic is reviewed in greater length elsewhere. Follicular density decreases significantly with increasing age. Fewer primordial follicles are found in women with unexplained infertility than in women with tubal disease. The grading of sperm activity on an arbitrary scale of 0-4 is useful for comparing samples from the same man. It is superior to early follicular FSH screening. then Ovarian biopsy A method of quantifying the number of small follicles in ovarian biopsies from infertile patients was established recently47. although the dynamic tests are strongly predictive of stimulation outcome. within 60 min of ejaculation. Likewise. (6) White blood cells < 1 x lO^ml. (3) Total sperm count S40X 106 spermatozoa per ejaculate. The gonadotropin releasing hormone agonist (GnRH-a) challenge test has been proposed recently 45'46. providing they reach the stage of embryo transfer47"51. The World Health Organization (WHO) laboratory manual for the examination of human semen and semen—cervical mucus interaction 52 contains a wealth of practical information and outlines the criteria of fertility commonly used for semen samples. Should the MAR test be positive. A unique group of patients with some concern about their adequate ovarian reserve are those with only one ovary. but has poor predictive value in women over 40 in terms of response to superovulation and pregnancy rate in assisted reproduction technology cycles42'43.

laparoscopy is probably not required56. via a semen sample report. but also a urethral swab taken after prostatic massage. although the administration of a non-steroidal anti-inflammatory agent prior to the procedure can reduce the occurrence of spasm. A rigid tube. probably do not need investigation of the Fallopian tubes. It is still not uncommon to find that the only previous medical contact with the male partner of an infertile couple has been indirect. where there is any history of pelvic inflammation or surgery. locates tubal occlusion and identifies pathologies such as hydro-salpinx. Sperm progression and motility may appear unexpectedly poor on assessment if a long time has elapsed between the production and testing of the sample. The effect is stronger with oil-soluble rather than in water-soluble media54'55. Tubal patency on HSG does not necessarily indicate normal tubal function and. with or without superovularion. The MAR/immunobead test is regarded as positive when more than 10% of the motile spermatozoa have adherent particles/beads. distinguish between genuine occlusion and tubal spasm. In cases with a normal HSG. HSG has therapeutic value. The flow of the media in the tubes and the spillage in the pelvis is detected by ultrasound63'64. Laparoscopic evaluation of the Fallopian tubes. Tubal-peritoneal factor Knowledge about tubal patency and function is crucial for deciding which treatment is the best for the couple. The role of salpingoscopy in tubal infertility is discussed in depth by Brosens62. the falloposcope. is hysterosalpingo-constrast-sonography (Hy-Co-Sy). women with severe tubal damage need IVF and cannot be treated by other methods such as intrauterine insemination. The reader is recommended to refer to Chapter 4 for a fuller exposition of the investigation and management ot the infertile male and to Chapter 17 for details concerning the newer techniques of assisted reproduction when male infertility factors predominate. laparoscopy is recommended to confirm the normality of the tubo-ovarian relationships. HSG cannot. especially tubal motility. A combination of air and saline or contrast medium (Echovist-200) is introduced to the tubes through the cervix. adnexae and pelvic peritoneum in patients with radiolog-ically damaged tubes permits decisions to be made about 18 . without any relevant • medical history. To achieve this. however. A reported normal' result may thus exonerate a man who in fact has a sperm motility problem. concurrent medications and a history of any recent (within the last 2-3 months) debilitating disease. a new endoscope. It is not now our usual clinic practice to culture the seminal fluid. A history of previous sexually transmitted disease would make it wise to culture not only the urine. couples whose only chance of conceiving using their own gametes is by IVF. Another option to assess the patency of the Fallopian tube. even with free flow of dye on laparoscopy. although it does not give much information about its function. but also IgA antibodies. which can be introduced into the tube via a laparoscope5'"59 or transcervically60'61 has been developed. If any abnormality is present in the semen analysis. provides a measure of tubal diameter. Periadnexal adhesive disease and cubal occlu-sive disease can be identified and staged. especially in the first few months following the procedure. possibly by removing mucus plugs and debris.In Vitro Fertilization and Assisted Reproduction an indirect test with immunobeads will distinguish the presence of not only IgG. HSG is not reliable for the evaluation ofperitubal adhesions53. It is a relatively easy procedure. Many non-specialized laboratories quote onl'7 a percentage of sperm motility and fail to assess the grade of sperm progression. Hov/ever. The significance of abnormal results must always be measured against the length of abstinence before production of the semen sample and ought also to take into account tobacco and alcohol consumption. Laparoscopy is a patency test rather than a functional one because it does not provide information about the mucosa and the lumen of the tube. The first-line diagnostic tool for assessing tubal status is hysterosalpingography (HSG). and the state of the fimbriae. unless there is excessive leukocytosis or genitourinary symptoms. such as influenza. a full history should be taken from the male and an examination of at least his external genitalia and prostate gland performed. Clearly. Laparoscopy is the only accurate means of detecting and staging endo-metriosis. salpingitis isthmica nodosa or tubal polyps. for example those with severe oligospermia. is unlikely to be functional. Moreover.

even in the best units. fibroids. with the advent of specific new and reliable sperm antibody tests for both partners. complicated forceps delivery). (3) Failure of implantation of reasonable embryos after three consecutive IVF cycles. such as ovulation induction. (3) Microtubal surgery. the maximum conception rate. post-Cesarean section. in women with a previously normal hysteroscopy followed by three or more consecutive failed cycles of IVF-embryo transfer (IVFET). they can cause pregnancy loss and early delivery. Cervical mucus hostile to spermatozoa was usually diagnosed by the post-coital test (PCT). magnetic resonance imaging (MRI)66'67. The indications.2% demonstrated abnormalities on repeat hysteroscopy74. the presence of a good number of motile spermatozoa 4—lOh after intercourse provides direct. Recent studies have shown that this test has a very low predictive power for achieving a pregnancy77'78 and therefore the PCT has become less fashionable and. Uterine factor In spite of much progress in the earlier days of IVF. intrauterine synechiae and endometria! polyps are commonly considered to be closely associated with spontaneous and recurrent miscarriages. Although these lesions. with the exception of intrauterine adhesions. with possible referral to specialized centers. severe pelvic inflammatory disease. We believe that diagnostic hysteroscopy Immunological infertility Immunological factors account for up to 10% of the causes of infertility. oocyte retrieval and culture media. Uterine anomalies. Moreover. the 'gold standard' for uterine cavity assessment is diagnostic hysteroscopy. are not a cause of infertility. However. If a lesion causes a significant distortion of the uterine cavity and is therefore estimated to jeopardize the chances to conceive or to carry the pregnancy to term. (4) IVF. Caution must be exercised in interpreting an 19 . and at least 90% of apparently normal embryos fail to implant4. It is a tragedy to establish a pregnancy by IVF only to lose it because of a preventable miscarriage. There are few accurate methods for investigating the uterine cavity: HSG. The abdominal approach is required for large intramural fibroids. Numerous studies have demonstrated that the incidence of intrauterine pathology (mainly adhesions) before IVF treatment is up to 50% of the patients68"71 with a similar frequency in women who failed to conceive in one72 or two IVF cycles73. The options that may be offered include: (1) Transcervical tubal recanalization. effectiveness. termination of pregnancy. (c) Congenital uterine anomaly. evidence that cervical mucus hostility is not a cause of' infertility. (c) Recurrent miscarriage. still does not exceed 30% per embryo transfer.g. Every woman should ideally have her uterine cavity investigated by HSG and/or hysteroscopy before starting IVF treatment. Nevertheless. (b) History of endometritis: post-delivery. it is now possibly outmoded. hydrosonography and. it can be corrected successfully by surgical hysteroscopy in the majority of cases. ultrasound. were satisfactory72'75'76. (2) Laparoscopic tubal surgery. or after surgical correction of intrauterine anomalies. complications and costs of these different options should be fully discussed with the patients. is mandatory in the investigation of the subfertile woman in the following situations: (1) An intrauterine lesion suspected on HSG or on transvaginal scan (a) Fibroid. Pregnancy rates following myomectomy in women whose fibroids were the unique cause of infertility. 18. dilatation and curettage (D & C). recently. classification and role in reproductive failure65 and especially in IVF treatment. although there is still controversy about their incidence. (b) Endometrial polyp. (2) Relatively high risk of intrauterine adhesions (a) Instrumental interventions in the past (e.Investigation of the infertile couple for assisted conception che optimum treatment.

some women react adversely to this drug and any pelvic pain warrants at least a pelvic examination and more helpfully an ultrasound scan to exclude multifollicular development and ovarian hyperstimulation syndrome (OHSS). (4) IVF. (2) Ovulation induction. Indeed. as detailed above. After completion of all investigations the results are discussed with the couples and the optimum treatment modalities decided for each couple. the cost.In Vitro Fertilization and Assisted Reproduction apparent 'shaking phenomenon' of the spermatozoa within the mucus. (6) Use of donated gametes or embryos. they are usually an anxious group of patients who find it difficult to come to terms with the inability of advanced scientific investigation to give them a logical explanation for their longstanding infertility. led some authors to investigate the correlation of these antibodies with infertility and repeated IVF failure79'80. Female age of > 30 years. steroids or immunoglobulins have been suggested81"84. mainly anticardio-lipin and lupus anticoagulant. Various combinations of mini-dose aspirin. not least. heparin. The sperm-mucus contact test makes it easier to ascertain that the cervical mucus itself is responsible for the 'shaking'.6 20 . The dose may be increased to 50 mg twice or even three times daily. the couple's own preferences. These options are described in detail elsewhere in this book. Although couples with unexplained infertility have a 40-89% chance of conceiving spontaneously in the 3 years following investigation'. The indications for proceeding to IVF treatment at Bourn Hall Clinic during the period 1995-96 are shown in Figure 1.-ing comprehensive investigation of the infertile couple. The characteristics ofovulatory cervical mucus are clearly and helpfully detailed in the WHO manual 52. risks and side-effects of each method and. The effect of treatment on improving pregnancy races and decreasing miscarriage rates is still under evaluation and is discussed in Chapter 20. to which reference should be made. The final decision on which treatment options to select depends on the infertility diagnosis. nor has the best treatment yet been established. The association between recurrent miscarriage and antiphospholipid antibodies (APA). (3) Inrrauterine insemination. (5) IVF plus intracytoplasmic sperm injection (ICSI). rather than an antagonistic factor derived from the female. there are some patients for whom a dose of only Unexplained infertility Follov. The prevalence of APA in infertile patients is yet not clear. Today our treatment 'arsenal' is quite wide and Includes: More than one cause 17% Tubal disease 24% Unexplained infertility ^ale factor 12% 24% Figure I Indications for proceeding to in vitro fertilization treatment at Bourn Hall Clinic during 1995-9. increasing duration of infertility and primary infertility are factors which adversely affect their chances of conceiving without treatment. the female patient's age. Antiestroecns such as clomiphene citrate 50 mg daily from cycle days 2 to 6 inclusive provide a good initial starting therapy. Whilst luceal phase progesterone levels may be used to confirm ovula-tion (with the limitations previously described). (1) "Wait and see'. (7) IVF surrogacy. their estimated chance of success. Performing the test at other times than that ofovulation can produce grossly misleading results. Ovulation induction may be all that is required for the anovulatory woman of normal body weight85 with normal Fallopian tubes and whose husband has normal sperm. as this may represent preliminary coating with antibody from the male genital tract. but false-positive reactions do occur 52. some 10—15% of couples will have no apparent reason for their infertility and will therefore be classified as suffering from 'unexplained infertility'.

The effect of increasing age on the reduction in fertility has been discussed previously in this chapter. At Bourn Hall. serial ultrasound scanning with hormone monitoring (estradiol. for women having timed intercourse following this sort of induction regimen. Female age emerges as the single most important factor influencing the outcome of IVF90"93.6 21. alternate-day regimens commencing with 1 or 2 ampoules daily are used.0% per cycle4. Should the antiesrrogens fail to induce ovulation and hyperprolactinemia. of which the most used has been human'menopausal gonadotropin (hMG) or FSH. decide to embark on demanding and expensive IVF treatment. especially for ovulation induction in intrauterine insemination cycles. However. LH and progesterone) is employed. Rossing and co-workers86 established an increased risk of ovarian cancer after the use of clomiphene (but not tamoxifen) for more than 12 months. For a small percentage of women. then recourse may be made to the use ofgonadotropins. or the number of previous unsuccessful cycles) or from the fact that some tertiary referral centers with very good records are treating the most resistant cases. is tamoxifen in an initial dose of 20 mg daily from days 2 to 5 inclusive. estrogen monitoring (urinary or blood) is regarded as insufficient by itself ro exclude the possibility of hypersiimulation and multiple pregnancy. their main concern is usually what their real chance of succeeding is. In the UK live birth races range from 9 to 26% while the national live birth rate is 15. injection of human chori-onic gonadotropin may be required to induce ovulation. The most comprehensive study was conducted on more than 50 000 cycles registered on the Human Fertilization and Embryology Authority (HFEA) database90.1 17. The biological age is more important than the chronological age. and the Policy and Practice Subcommittee of the British Fertility Society (BFS) has recommended that the use of clomiphene be limited to 6 months87. At Bourn Hall. (1) The success rate of the individual clinic. by limiting the upper female age.1 18. Nowadays.5 12:5 1.Investigation of the infertile couple for assisted conception 25 mg of clomiphene citrate daily is sufficient. Alternate-day or daily doses of FSH or hMG may be employed. and 40% will conceive. beginning on day 9 or 10 of the menstrual cycle. Although no definite answer can be given before treatment is started. Pregnancy rates vary enormously in different countries and in clinics in the same country and region4'88'89. and ultrasound scan monitoring is considered essential. as older women with a good response to superovulation and satisfactory cycles have very reasonable chances of conceiving.1 9.5 3. Our results at Bourn Hall confirm this finding (Table 3). after proper investigation and careful counselling.g. In spite of increased Table 3 Correlation between maternal age and delivery rate in 1943 IVF cycles performed at Bourn Hall Clinic in 1995 and 1996 Age (years) C n <30 30-34 35-39 40-44 S45 Total 269 748 651 243 32 1943 'yclcs % 13. The lower pregnancy races seen in older women seem to be due partly to a worsening response to superovulation. as is most convenient to the patient and the medical attendant. the two major factors influencing success are: 21 . Another alternative. (2) The characteristics of the couple.1 PREGNANCY RATES IN IVF TREATMENT Where a couple.8 38. This difference may result partly from different entry criteria (e. variations in success rates reflect genuine differences in quality of care and experience between clinics and each clinic should therefore present couples with accurate recent pregnancy rates from their clinic. especially for women who experience some sideeffects with clomiphene. Clomiphene is successful in inducing ovulation in 80% of the women after 6 months of treatment.6 Number of deliveries 58 158 111 23 I* 351 Delivery rate (%) 21.5 33. and whether they will become parents. and hypergonadotropic states have been excluded as previously described. Numerous studies have investigated the factors that affect the outcome of IVF treatment. rather than quoting national or international figures.

older women generally yield fewer oocyrcs and have a higher cancellation rare. or decreased chance with each consecutive cycle90 (Figure 4). cycles99. followed by a significantly reduced chance93. we now expect similar pregnancy races in infertility from all causes (Figure 2). regardless of the pregnancy outcome90'96. Therefore.-1 4 the next cycle than women who did not become pregnant in their first attempt90'93'96. are reported to have a ^4: better prognosis98. ovarian response from reference 90) and fertilization rates of those who returned ag.ainsi those 0 3 0 per cycle 0 per OCR 0 per ET Figure 3 who did not. Women who suffer from secondary infertility (i. in a large study of more than 9000 by duration of infertility (HFEA data. ^ Croucher and colleagues93. others. age. 6-9 >10 While earlier studies reported the probability of pregnancy Number of previous IVF attempts Figure 4 Live remaining constant throughout successive birth rates by number of previous unsuccessfu IVF attempts (HFEA data. even if two or more f ctors are involved. found little evidence for this view. male infertility was associated with lower pregnancy races in IVF95'96. Women who had unsuccessful pregnancies in •s 12 their first cycle (e. adapted from reference. studying larger numbers of patients. treatment cycles cannot be realistically D per cycle a per OCR o per ET considered in isolation. miscarriage.e. 22 . 25 20 15 '1 5-1 0 Tubal Male Unexplained Others Male and female CUMULATIVE PREGNANCY RATES Figure 2 Delivery rates in 1943 treatment cycles at Bourn Hall Clinic during 1995-96 related to the causes of infertility (not significant) Because the chance of conception with a single IVF treatment is still relatively low.g. found an equal chance in the first three cycles. ectopic pregnancy or c 10 biochemical pregnancy). even after adjustment for age90 (Figure 3). have a better chance for a live birth in •° 8 ^ 0 . cycles in a single tertiary center. It is 'widely believed that couples who discontinue IVF 0 llo 3 4 loti 7 to 9 10 to 12 >12 Duration of infertility (Y) Live birth rate after a failed attempt do so because they have a poor prognosis. In ihe past. Calculations of cumulative pregnancy 20-i 18-16-14 -12 -14 -12-10-8 -6 rates are needed. The HFEA database showed a significant reduction in the success rates with increasing duration of infertility. fertile population. they found no difference in outcome. This suggests adapted that poorer responders were not dissuaded from returning.90^.In Vitro Fertilization rind Assisted Reproduction dosages of hMG. having delivered a live infant after an IVF cycle. those who have had a previous pregnancy) are more likely to have a live birch after IVF treatment. does not affect IVF outcome90'93. but since the introduction ofICSI97. Roest and colleagues94 suggested recently that ovarian response was a more useful predictor of pregnancy than age alone. When they compared the etiology. 20-i 18Those women returning for a repeat IVF attempt. The cause of infertility. The overall cumulative pregnancy rates after six cycles of IVF range from 56%100 to 72%93 compared with 55% cumulative probability of pregnancy after 6 months of intercourse in a normally cohabiting. as are trends in success rates with repeated cycles.

Baltimore: Williams &Wilkins.43:137-42 10. Liege. Glass RH. Dakar. WHO Technical Report Series.58:194-7 6. Morrola J. Attention to detail throughout the whole process is necessary and yet a flexible approach to investigation and treatment must be maintained. The ESHRE Capri Workshop. Pasquali R. Schoemaker J. Characterization of idiopachic premature ovarian failure. Unexplained infertility. Lenton EA. FSH.1. November 1988. Belsey FH.48:605-7 12. 1989. Hum Reprod 1997.68:173-9 7. Kalcass G. eds. Hum Reprod 1996:11: 1779-807 2. Cooke ID. Cooke ID. / Clin Endocrinol Metab 1987. CONCLUSIONS In summary. Gosden RG. Nutrition and Hormonal Events in Women.30 4. Conway GS. Infertility revisited: the siare of the an today and tomorrow. Rowc PJ. Thompson IE. laboratory scientists. with equal chances of pregnancy in each. A mathematical model of follicle dynamics in (he human ovary. Clinical Gynecologic Endocrinohgy and Infertility. and the chances are still good enough to encourage those with sufficient resources and commitment to try three more attempts. Only in this way can one give them soundly based advice about future therapy. et al. 6th Annual Report 1997. Sulaiman R. References 1. Belgium: International Union for the Scientific Study of Population. eds. / Reprod Fertil 1982. The selection criteria on an IVF program can remove the 23 . Anrenucci D. Hum Reprod 1995. Arthur ID. LH. Hargrave TB. 1988. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. Adamson SC. Masson GM. The prevalence and etiology of infertility. Hum Reprod 1993. 1997 5. Fertil Steril 1995. Richardson SJ. PadillaSL. In Basdevant A. eds.15-2. 4th edn. 1992 3. BringerJ. Sobowale E. oescradiol and progesterone in conceiving and non-conceiving women. World Health Organization. Bopp BL. 1993 14.(Suppl 12):26-32 8. Proceedings of the African Population Conference. Speroff L. FertilSteril 1996. Failures of treatment. Beyond three cycles. et al. 173-9 17. Voorhorst FJ. GarciaJE.65: 337-il 16. EurJ Obstet Gynecol Reprod Biol 1992. a clinic offering IVP and associated treatment methods must pay attention at the initial consultation to the past investigations of an infertile couple.65:1231-7 18. Cassimiri F. Kase GN. In Biological Components of Fertility. Hum Reprod 1995. conception IVF treatment should not be seen as an isolated event. Collins J. Cambridge: Cambridge University Press. Fertil Steril 1989. In no field of medicine is there a closer relationship between clinicians. 1:2. Eicon RA.8:977-80 11. BrJ Urol 1986. Coulam CB. albeit at a slower rate. Bray AG. counsellors and patients. which sadly always exceed the successes. Reliability of urinary LH testing for planning of endomecrial biopsies. Annegers JF. Incidence of premature ovarian failure. Faddy MJ. Crosignani PC. Spcroff L. Parley TM. analysis of the cumulative pregnancy rates from an IVF center provides useful information to help couples make decisions about their treatment. success rates per cycle do fall.Investigation of the infertile couple for assisted. Geneva: World Health Organization Publications. Obesity and reproduction. Alper MM. Hargrave TB.67:604—6 15. Patel A. Glass RH. Recent Advances in Medically Assisted Conception. and biochemical and failed clinical pregnancies should be viewed with a degree of cautious optimism. The human menstrual cycle: plasma concentrations of prolactin. Kase GN. Mellows HJ. Martinez AR. Camhairc FH. Baltimore: Williams &Wilkins. Nelson JF. 4th edn. The ESHRE Capri Workshop. Human Fertilisation and Embryology Authority (HFEA). Fecundability races from an infertile male population. Senegal. 1989:213-32 13. et al. 10:1549-53 9.63:1278-83 20. WHO Manual for the Standardised Investigation of the Infertile Couple. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. Scnikas V.52:270-3 21. Success rates with gamete intrafallopian transfer and in vitro fertilization in women of advanced maternal age. Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. / Clin Endocrinol Metab 1989.1. Anovulatory infertility. Lefebvre P. Anthony FW. Clinical Gynecologic Endocrinology and Infertility. must be discussed with couples in the light of information drawn from both the medical and the scientific records of previous treatment cycles. London: HFEA. All couples undergoing IVF treatment should consider that this implies a course of at least three treatments. 820. Whilst accurate prediction of those who are likely to have a child is impossible. although cumulative pregnancy rates continue to rise. their previous obstetric and gynecological history and the need for further special investigations. Thomas EJ. Weight. Obstet Gynecol 1986.10: 770-5 19.

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