Chapter 7 – Assisted Reproduction


Assisted reproduction technology (ART) encompasses fertility treatments which require manipulation of oocyte, sperm or both in vitro. This chapter aims to provide an overview of ART, including indications for treatment as well as the procedures involved. This will also include complications of ART as well as the evidence assessing the perinatal outcomes of children resulting from ART.

Chapter 7 Assisted Reproduction Role in the Management of Infertility

Kugajeevan Vigneswaran and Haitham Hamoda

7.1 Introduction

Assisted reproduction technology (ART) encompasses fertility treatments which require manipulation of oocyte, sperm or both in vitro. This chapter aims to provide an overview of ART, including indications for treatment as well as the procedures involved. This will also include complications of ART as well as the evidence assessing the perinatal outcomes of children resulting from ART.

Techniques uses in assisted reproduction include the following:

  • Intrauterine insemination

  • In vitro fertilization/intracytoplasmic sperm injection

  • Gamete intrafallopian transfer/zygote intrafallopian transfer

  • Oocyte donation

  • Surrogacy

7.2 Intrauterine Insemination (with or without Ovarian Stimulation)

Intrauterine insemination (IUI) describes the placement of prepared sperm into the uterine cavity around the time of ovulation. This can be done within a natural menstrual cycle or in combination with ovarian stimulation. The latter is used to induce ovulation in anovulatory women but can also be carried out in women with ovulatory cycles, with the rationale of increasing the number of eggs available for fertilisation.

John Hunter is credited with the first documented IUI procedure in the 1770s, when he advised a man with hypospadias to inject his seminal fluid using a syringe into his wife’s vagina, and this resulted in a pregnancy.

IUI is generally used when there are patent fallopian tubes and normal sperm parameters. The rationale for the use of IUI is to increase the density of motile sperm available for fertilisation of the oocyte. Preparation of the sperm removes dead and immotile sperms as well as debris, white cells and seminal plasma, which can interfere with fertilisation. IUI also bypasses the cervix, thus potentially avoiding cervical mucus problems.

7.2.1 Indications for IUI

The National Institute for Health and Care Excellence (NICE) fertility guidelines in 2013 [1] outlined several indications for which IUI could be considered. These included couples for whom vaginal sexual intercourse would be difficult, such as those where one partner has a physical disability or psychosexual problems. Other indications for IUI include the use of donor sperm in women in same-sex relationships and scenarios that require sperm washing such as HIV-positive men to minimise the risk of viral transmission.

The NICE fertility guidelines recommended that IUI should not be routinely offered in cases of unexplained infertility, mild endometriosis or mild male factor infertility, where regular unprotected intercourse was possible. This recommendation was based on randomised controlled trial (RCT) data from two studies comparing expectant management with both natural cycle IUI as well as stimulated cycle IUI (with gonadotropin therapy). One of these studies, by Bhattacharya et al. in 2008, was a three-arm study that included 580 women and concluded that there was no significant advantage to be gained with IUI over expectant management in relation to the primary outcome, namely live birth rates [2].

The NICE fertility guidelines 2013 literature review concluded that low-quality evidence comparing IUI with stimulation and IUI without stimulation did show a significantly higher live birth rate with stimulation. However, this was accompanied by a higher multiple pregnancy rate. The guideline group concluded that IVF provided greater control in regard to the number of embryos transferred and felt that several cycles of IUI with stimulation would be required to match the live birth rates achieved with a single cycle of IVF.

The NICE guideline recommendations led to a decline in the number of IUI cycles performed, with the Human Fertilisation & Embryology Authority (HFEA) data report in 2018 indicating a 50% decrease in the total number of procedures since 2013 [3].

In 2018, results from a pragmatic RCT were published designed to evaluate the use of IUI with ovarian stimulation for couples with unexplained infertility [4].

The trial randomised 201 women with unexplained infertility to either having three cycles of IUI with clomiphene citrate or letrozole or three cycles of expectant management. The former was associated with a three-fold greater live birth rate than the latter (31% vs. 9%), with a relatively low multiple pregnancy rate. The data were analysed on an intention to treat basis and it was of note that nearly 25% of the pregnancies in the IUI arm arose naturally, that is, independent of the intervention.

The group concluded that IUI with ovarian stimulation was a safe and effective treatment for couples with unexplained infertility and an unfavourable prognosis for natural conception.

Overall success rates with IUI will vary and are largely dependent on female age as well as the quality of injected sperm. Guidelines indicate that the concentration of progressively motile sperm is the most predictive factor for chance of success with IUI and generally recommend a cut-off of at least 5 million sperm being inseminated to optimise outcomes.

National UK data from 2016 showed an overall birth rate of 12% per treatment cycle of IUI. The highest success rates were observed in women less than 38 years of age (14% in women less than 35 years of age and 12% for women 35–37 years old). Beyond the age of 42 years, the live birth rates were low. The multiple pregnancy rates were recorded as 8%.

In summary, IUI is an effective and safe treatment option for patients who are unable to have regular vaginal sexual intercourse. The evidence suggests that in the context of unexplained infertility, IUI without ovarian stimulation does not appear to offer a significant advantage over expectant management. However, when combined with ovarian stimulation, there may be an improvement in live birth rates compared to expectant management alone.

IUI with ovarian stimulation provides a less invasive treatment option when compared with IVF, although the latter is likely to be more successful. Further research is required to compare the efficacy of cumulative cycles of IUI compared to IVF. IUI combined with ovarian stimulation may therefore offer an option in unexplained infertility, particularly for younger women who are not yet ready to proceed with IVF.

7.2.2 Monitoring

To ascertain the optimal timing of the insemination procedure as well as to ensure safety where stimulation has been carried out, monitoring of folliculogenesis by transvaginal pelvic ultrasound is utilised. Typically, serial ultrasound scans from day 10 of the menstrual cycle are performed to allow assessment of the number and size of dominant follicles. In cycles where more than two stimulated follicles have been detected on tracking, cancellation of the IUI cycle should be advised because of the higher risk of multiple pregnancies. The couple should be advised in this situation to avoid unprotected intercourse.

Monitoring of a luteinising hormone (LH) surge is also undertaken to determine the optimal time for insemination. IUIs are typically carried out within 24 hours of the LH surge as assessed by urinary ovulation prediction kits. Alternatively, ovulation can be triggered by the administration of human chorionic gonadotropin (hCG) once the leading follicle is 16–18 mm diameter followed by insemination approximately 36 hours later.

7.2.3 Procedure

Fresh semen is produced by masturbation after approximately 2–7 days of abstinence. The sperm is then prepared and drawn up in a catheter, passed gently through the cervical canal and injected into the uterine cavity.

7.2.4 Complications

The main complication of IUI is multiple pregnancy associated with ovarian stimulation. There is a small risk of developing ovarian hyperstimulation syndrome (OHSS) in cycles stimulated with gonadotropins. The risk of ectopic pregnancy or miscarriage has not been shown to increase in IUI cycles compared with natural conceptions. The reported risk of pelvic inflammatory disease after IUI has been estimated at 0.01%–0.2%.

7.3 In Vitro Fertilisation

The development of IVF has revolutionised the management of infertile couples and since the birth of Louise Brown in 1978, it is estimated that more than 8 million children have been born from IVF. Live birth rates with IVF have steadily increased over the years largely as a result of clinical improvements and advances in laboratory technology and expertise.

7.3.1 Ovarian Stimulation

Early cycles of IVF performed by Edwards and Steptoe required the retrieval of a mature oocyte during a natural cycle for patients with fallopian tube defects. IVF has since found a wider application in the management of other causes of infertility including male factor, anovulation as well as unexplained infertility. Ovarian stimulation prior to oocyte retrieval became standard practice with the objective of increasing the number of oocytes collected and consequently increasing the pool of embryos available to select from for transfer.

Ovarian reserve tests serve to counsel IVF patients and guide clinicians in predicting the likely ovarian response to stimulation. Using a combination of antral follicle count and anti-mullerian hormone assessment along with female age, it is possible to estimate oocyte numbers at retrieval thereby optimising ovarian stimulation in IVF. Pituitary Control

In the early years following its introduction, IVF was carried out using gonadotropins for controlled ovarian stimulation, but without pituitary suppression. This resulted in less flexibility with both the scheduling of IVF cycles and the timing of oocyte retrievals, which resulted in collections being performed at night and throughout weekends. This also resulted in higher cycle cancellation rates owing to the frequent occurrence of a premature endogenous LH surge prior to oocyte retrieval.

The introduction of gonadotropin-releasing hormone (GnRH) agonists for pituitary suppression in the mid-1980s to be used alongside gonadotropin ovarian stimulation enabled greater planning of controlled ovarian stimulation. Once downregulation had been achieved, oocyte retrieval could be timed to precisely 34–38 hours following administration of hCG, which serves as a surrogate for the mid-cycle LH surge and causes resumption of meiosis within an oocyte, in preparation for fertilisation.

GnRH agonists can be administered using intranasal, subcutaneous or intramuscular preparations. There are several proposed regimens when using GnRH agonist therapy for pituitary downregulation. In the long GnRH agonist protocol, the agonist is commenced in the mid-luteal phase of the preceding cycle before commencing ovarian stimulation, resulting in a 10–14-day lead-in to treatment. The objective of this is to allow time for the initial ‘flare effect’ that GnRH agonist administration will have on the pituitary gland to wear off before pituitary desensitisation is achieved 8–10 days later. Once pituitary downregulation has been achieved, stimulation with gonadotropins can begin. Downregulation can be confirmed by ultrasound (thin endometrium and quiescent ovaries), and this will be associated with low serum follicle stimulating hormone FSH, LH and oestradiol levels. The short GnRH agonist protocol involves commencing the agonist in the early follicular phase of the IVF cycle to take advantage of the initial flare effect on the pituitary gland before desensitisation is achieved. The ultrashort protocol, on the other hand, involves administering GnRH agonist for only 2–3 days in the early follicular phase using only the flare-up effect, with some studies reporting its use in poor responders.

The literature suggests comparable efficacy between the long and short GnRH agonist protocols for pituitary suppression with IVF, although there is limited evidence assessing the role of the ultrashort GnRH agonist protocol in this context. In practice, the long protocol remains the most commonly used GnRH agonist regimen.

In 1994, GnRH antagonists were introduced as an additional option to GnRH agonists in preventing premature LH surges in controlled ovarian stimulation. The GnRH antagonist acts immediately on the pituitary and prevents pituitary secretion of both FSH and LH, without the need for desensitisation. Ovarian stimulation could begin on day 2 of the menstrual cycle and daily administration of the antagonist would typically begin on day 5 or 6 of stimulation or once the leading follicle had reached 14 mm (usually by day 6–7). A fixed start (beginning on day 5 or 6 of stimulation) protocol seems to be comparable in regard to clinical outcomes when compared with a flexible start (once the leading follicle had reached 14 mm) protocol.

By eliminating the need for pituitary desensitisation, antagonist cycles are much shorter and more convenient for patients and have been shown to require lower total gonadotropin doses. Furthermore, there appears to be a reduced risk of OHSS. In antagonist cycles this risk reducing advantage is furthered by the discovery that the final maturation of oocytes can be initiated by using a single dose of GnRH agonist instead of hCG. The LH rise induced with an agonist trigger has a shorter half-life than that of hCG and this reduces the OHSS risk significantly.

A recently updated meta-analysis including all RCTs to date comparing GnRH agonist versus antagonist regimes revealed similar IVF success rates, with a lower overall consumption of gonadotropins and a reduced risk of OHSS with antagonist cycles [5].

The combined contraceptive pill (COCP) has been commonly used as pretreatment with IVF. This allows greater control with the scheduling of IVF cycles and may prevent the development of ovarian cysts which can occur with the flare effect of starting treatment with a GnRH agonist. A recent meta-analysis, however, showed a slight reduction in clinical pregnancy rates with the COCP (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.66–0.97). Gonadotropins

Human pituitary gonadotropins were first extracted in 1958, from cadaveric human pituitaries. In 1954, it had also been discovered that FSH and LH could be extracted from the urine of post-menopausal women. Human menopausal gonadotropin (hMG) was proposed for therapy in humans in 1957. The initial products required very large volumes of urine (3.5 L required per 75 IU of FSH) and contained several other unwanted urinary proteins. In the absence of an alternative, hMG was used to induce ovulation in hypogonadotropic patients as well as anovulatory normogonadotrophic patients.

In the early 1980s hMG/hCG protocols became standard practice for assisted reproduction cycles, shifting from monofollicular development to superovulation with multiple follicles (Figure 7.1).

Figure 7.1 Ultrasound image of a stimulated ovary showing multiple follicles.

Highly purified hMG followed in 2004, which was produced through an eight-step purification process of menopausal urine. Part of this process incorporated immunological techniques and utilised specific monoclonal antibodies to FSH and LH. Following these steps, hypersensitivity was minimised and consequently it was possible to produce a subcutaneous preparation for injection.

Recombinant human FSH (rFSH) was developed to eliminate the inherent variation found with urinary FSH products as well as ensuring greater availability of a product not reliant on urinary donation. The increased purity of rFSH reduced the possibility of oxidation and led to the production of liquid gonadotropin formulations, dispensed in prefilled injection devices.

Systematic review and meta-analysis data suggested that adding recombinant human LH (rLH) to rFSH for ovarian stimulation may improve pregnancy outcomes in poor responders compared with rFSH alone. Subsequently, however, an RCT (ESPART 2016) assessed this question in poor responders and included 462 women randomised to IVF with rFSH/rLH and 477 to IVF with rFSH alone. The study found no significant difference in the number of oocytes retrieved between the two groups.

In summary, current evidence which includes an updated Cochrane review shows similar efficacy between urinary and recombinant gonadotropins including the use of FSH alone or combined FSH/LH preparations with respect to implantation rates, live births and multiple pregnancy rates. FSH Dose

The starting dose of gonadotropins used in IVF is typically between 150 and 300 IU of FSH, with the treatment dose often based on the patient’s age and her ovarian reserve. Patients at risk of developing OHSS can be started on relatively low doses of 100–150 IU per day. Lower doses of 75 IU per day do not appear to be sufficient for most women.

An RCT (OPTIMIST) reported no clinically significant difference in cumulative live birth rates when using individualised FSH dosing regimens (100–450 IU) compared to a standard dose regimen (150 IU). The study, however, noted significantly higher cancellation rates and significantly higher rates of OHSS in the standard dose arm compared to the individualised arm. Several limitations need to be considered when interpreting the data reported in the OPTIMIST trial including that adjustments in FSH doses were allowed in the standard dose arm after the first cycle and cumulative outcomes were assessed only up to 18 months.

A Cochrane review published in 2018 concluded that tailoring the FSH dose in any particular population (low, normal, high ovarian reserve), did not appear to influence the rates of live birth/ongoing pregnancy. The review, however, concluded that individualisation of FSH doses reduced the overall incidence of moderate and severe OHSS. The authors noted that there were sample size limitations in the studies included that need to be considered when interpreting these data [6].

In summary, evidence from recent randomised studies suggests that the concept of individualised FSH dosing in IVF may not necessarily offer a significant advantage in terms of live births with IVF but does appear to reduce the risk of OHSS and lowers the risk of cycle cancellation. There are limitations to the methodology and study sample size of these reports which suggest one should exercise caution in the interpretation of these findings. More research is needed to evaluate this further. Poor Responders

A description of poor response to fertility treatment was first defined by Garcia in 1983 as peak oestradiol levels of less than 300 pg/mL following controlled ovarian stimulation with 150 IU of hMG.

The European Society of Human Reproduction (ESHRE) provided a more recent definition of poor ovarian response (Bologna criteria 2011) as having at least two of the following three features:

  • Advanced maternal age >40 or other factors for diminished ovarian reserve

  • Previous history of poor ovarian response (fewer than three oocytes retrieved with conventional ovarian stimulation)

  • An abnormal ovarian reserve test (AFC <5–7 follicles or AMH <5.4 pmol/L)

IVF treatment for patients with diminished ovarian reserve can be challenging and is often associated with poor clinical outcomes, namely high risk of cycle cancellation and low pregnancy rates.

There is no consensus on what constitutes the optimal stimulation protocol for poor responders, although it is common practice to use high-dose FSH in such cycles. Some studies have reported on using low doses of FSH for ovarian stimulation or no FSH (natural cycle IVF) in such cases, instead of using high-dose FSH for ovarian stimulation. There is limited published evidence to guide practice and further research is required to assess the optimal treatment regimen in this context. Monitoring During IVF

Monitoring ovarian response to superovulation is usually performed using vaginal ultrasound tracking of the follicular response to stimulation. Approximately from day 8–10 of stimulation, measurement of the number and average diameter of each follicle within the ovaries is calculated, typically on alternate days, with stimulated follicles expected to grow by 2 mm a day. Endometrial thickness is also noted during these scans. The pre-ovulatory hCG trigger can be administered once a set number of leading follicles reaches at least 17 mm (many clinical protocols aim for at least 3) and a satisfactory cohort of intermediate follicles has been achieved.

The use of biochemical indicators of follicular activity, namely serum oestradiol concentrations, may aid clinical decision-making in women at risk of OHSS although they appear of limited clinical value in women with normal or low ovarian reserve. A Cochrane review (2014) concluded that there was no evidence to suggest that combined monitoring by transvaginal pelvic ultrasound scan and serum oestradiol is more efficacious than monitoring by transvaginal pelvic ultrasound scan alone in respect of clinical pregnancy rates or the incidence of OHSS. However, the quality of the evidence assessing this was noted to be low. The authors concluded that a combined monitoring protocol including both transvaginal pelvic ultrasound scan and serum oestradiol would be precautionary good clinical practice in a subset of women considered at high risk of OHSS.

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Feb 26, 2021 | Posted by in GYNECOLOGY | Comments Off on Chapter 7 – Assisted Reproduction
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