Fertility treatment is a rapidly evolving discipline. With changing dynamics of the patient population and rapid technological advances, there are few specialties that are challenged with medical and ethical dilemmas on the same scale as professionals working in the management of sub-fertility. Presented here are a few ‘hot topics’ that are causing intense debates and will continue to present new challenges in this exciting field.
Reducing multiple pregnancy
In the initial years of introduction of assisted reproduction technologies (ART), transferring multiple embryos was the norm. However with increasing experience and expertise with these treatments, the multiple pregnancy rates started to rise and the adverse effects of multiple pregnancies became all too evident. There was a move towards reducing the number of embryos transferred in each treatment cycle. The Human Fertilisation & Embryology Authority (HFEA) introduced the 2 embryo transfer policy in 2001 and currently this remains the practice in most treatment centres in the UK. However the incidence of twin pregnancy still appears to be rising (Fig. 1). The latest figures compiled by the HFEA show that with a two embryo transfer policy the chance of a twin pregnancy in In-Vitro Fertilisation (IVF) treatment cycles is approximately 1:4.
Around half of IVF twins are born too early and too small and this can potentially have long term health implications for these babies. Clearly this situation is not acceptable and there is a strong feeling among the fertility specialists, obstetricians, neonatologists and the wider community that steps need to be taken urgently to try and reduce the incidence of IVF related multiple births.
The only intervention that has been shown to reduce the incidence of IVF related twin pregnancy is to adopt an elective Single Embryo Transfer (eSET) policy. This needs to be accompanied by effective cryopreservation programmes. Some countries have adopted a policy of eSET and have shown that in properly selected cases, this policy can be implemented without compromising IVF success rates but significantly reducing the multiple birth rates1. An eSET policy may be particularly suitable in some groups of women for e.g. young women undergoing IVF treatment and women who have not had repeated IVF failures. Where blastocyst transfer is possible, an eSET policy can achieve high success rates.
The implementation of this policy is dependent on several factors. The HFEA has recommended that adequate support needs to be provided to the treatment centres by the way of clear guidance, additional NHS funding of IVF treatment cycles, including frozen embryo treatment cycles in NHS funding and a different approach to reporting success figures2. If we are to bring down the rate of IVF related multiple births, it is vital for a multi-disciplinary approach with involvement of patient groups, NHS commissioners, government agencies and fertility specialists. The HFEA is in the process of public consultations with the goal of setting a comprehensive policy to address this problem.
- eSET policy should be introduced to reduce the incidence of IVF related twin pregnancy
- Effective cryopreservation programmes need to accompany this policy
- Patient selection is crucial if IVF success rates are to be maintained
- Clear guidance from HFEA and likely some form of regulation is required for implementation of this policy
- Additional funding for IVF treatment cycles is essential to increase acceptability among patients
Intra-Uterine Insemination (IUI)
IUI is the process of depositing a small volume of concentrated motile sperm in the uterine cavity around the time of ovulation to maximise the chances of conception. IUI may be carried out after monitoring a natural cycle or after controlled ovulation stimulation with clomiphene citrate or gonadotrophins. The place for IUI has remained and continues to be controversial. In the absence of well designed trials with clear answers, it is not surprising that there is no agreement among the fertility specialists in relation to the indications, timing and protocols for IUI.
IUI is usually offered to couples suffering from sub-fertility due to male factor and in unexplained infertility. National Institute of Clinical Excellence (NICE) recommends that six cycles of IUI should be offered to couples suffering from mild male factor or unexplained infertility3. However a recent Cochrane review concluded that for male factor infertility effectiveness of stimulated or unstimulated IUI remains unproven4. For unexplained infertility, although IUI with controlled ovarian stimulation has been shown to increase pregnancy rates, this also leads to an increase in the risk of multiple pregnancies. The recently concluded Scottish Unexplained Infertility Trial has shown that for unexplained infertility, over a six month period, unstimulated IUI does not confer any additional benefit over regular intercourse (unpublished data).
There is a serious paucity of well designed trials analysing IUI success, risks of multiple pregnancies and the cost involved in this form of treatment. Hence many fertility experts believe that the whole question of IUI needs to be re-evaluated on the basis of urgently needed well designed trials to address the various aspects of this treatment.
- IUI continues to be a controversial form of treatment
- IUI for male factor infertility remains unproven
- In unexplained infertility, stimulated IUI increases pregnancy rates but there are concerns of multiple pregnancies
- In unexplained infertility, unstimulated IUI is no better than regular intercourse
Pre-Implantation Genetic Diagnosis (PGD)/ Pre-Implantation Genetic Screening (PGS)
Pre-Implantation Genetic Testing is a new technique that allows a diagnosis of a genetic or a chromosomal abnormality through the biopsy of a single cell from an embryo prior to implantation. PGD is carried out for patients at risk of transmitting a genetic or chromosomal abnormality to their children. Initially this technique was introduced to prevent sex linked diseases but now the indications have broadened to include single gene defects (autosomal recessive, autosomal dominant and X-linked disorders) and chromosomal abnormalities (translocations, structural aberrations, etc.). Cystic Fibrosis, Huntington’s Disease and Duchenne Muscular Dystrophy are examples of conditions that can be diagnosed using PGD. Although the place for PGD seems to be well established in a selected group of patients, PGS is more controversial.
The aim of PGS is to screen the embryos for presence of anueploidy or other karyotype abnormality and to transfer only those embryo(s) that have a normal karyotype in the hope of improving pregnancy rates. PGS is carried out for patients undergoing IVF with the aim of increasing the IVF pregnancy rates. Current examples of indications for PGS include women of advanced maternal age, couples with repeated IVF failure and couples with normal karyotypes who have experienced repeated miscarriages5. In women over the age of 37 years, due to poor quality oocytes, over 60-70% of embryos have numerical chromosomal abnormalities.
Currently, in the practice of PGS, there are several inconsistencies. There is no consensus on the age group in which PGS should be offered. There is no consensus on the number of cells that should be biopsied from each embryo. There are concerns of misdiagnosis due to mosaicism and there are concerns of costs and the emotional impact of these complex procedures. A recent Cochrane review failed to show any benefit in terms of improved live birth rates when PGS was used for anueploidy screening6. Hence at the present time PGS cannot be recommended in women with advanced age undergoing IVF. Furthermore it has not been shown to improve live birth rates in cases of repeated IVF failures and recurrent miscarriages7 and hence the place for PGS in the current IVF practice is very uncertain.
Other concerns of PGS relate to sex selection of the embryos purely for balancing the family. Currently HFEA does not license PGS for this purpose.
- In selected cases, the place for PGD is well established
- PGS has not been shown to improve birth rates in women with advanced age, repeated IVF failures or recurrent miscarriages with normal karyotype of both partners
- HFEA currently does not license PGS for sex selection of embryos purely for family balancing
Obesity and Fertility
Obesity in the UK is now labelled a modern epidemic with over 33% women considered overweight (Body Mass Index (BMI) > 25) and 23% women considered obese (BMI > 30). Obesity is very frequently associated with sub-fertility and it has a major impact on maternal and fetal health. Although BMI is an easy measure, it is being increasingly recognised that truncal obesity is a better determinant of cardiovascular and metabolic risk8. In relation to sub-fertility, obesity has a significant association with anovulation and polycystic ovarian syndrome (PCOS). PCOS is the predominant cause of anovulation and upto 60% of women with PCOS are known to be obese. The causes of anovulation in this group of women are complex but are thought to be due to an interplay of androgen excess, insulin resistance and other unknown factors.
It is well recognised that obese women do not respond well to fertility treatments. Ovulation induction is less effective, the requirement of clomiphene and gonadotrophins is increased and the chances of successful conception after ovulation induction or assisted conception are significantly reduced. Furthermore, after conception, maternal obesity is associated with numerous maternal and neonatal complications9. As a result of these problems fertility treatment is sometimes withheld from obese women with a BMI over 32-34 until they reduce weight or show evidence of falling weight. However there is no consensus on what constitutes an acceptable weight for commencement of fertility treatment.
Since insulin resistance is thought to be a significant factor in the underlying cause for anovulation, metformin was one of the strategies employed. However in a recent trial clomiphene was found to be superior than metformin in achieving a live birth in women with PCOS10. Hence the place for metformin in fertility treatment remains controversial. Weight reduction appears to be an effective strategy that can have a significant impact on ovulation rates in obese women with infertility. Even a 5-10% reduction of body weight can reduce truncal adiposity by 30% thereby improving the metabolic profile and ovulation rates.
- Truncal obesity is a better determinant of cardiovascular or metabolic risk
- Up to 60% of women with PCOS are obese
- Obese women do not respond well to fertility treatment
- Clomiphene is superior than metformin in achieving a live birth in women with PCOS
Immunological treatment of Fertility problems
Recently there has been a lot of debate surrounding the immunological factors affecting fertility and several treatments have been advocated to improve pregnancy rates. Antiphospholipid antibodies, Thyroid antibodies, Ovarian antibodies, Antinuclear antibodies, Antisperm antibodies, Natural Killer cells are just some of the factors thought to adversely affect fertility11. Various agents have been proposed to treat this array of conditions but apart from the treatment of Antiphospolipid syndrome (APS), none of the other treatments are thought to be supported by strong evidence. Hence at the present time no special tests or treatments for most of these immunological conditions are recommended in routine clinical practice.
- There is good evidence for the treatment of APS related fertility problems
- No tests or treatments are currently recommended for Immunological infertility
Funding in the NHS
Although not a medical problem, this needs a mention since it is one factor that has the greatest impact on the nature and the quantum of the services delivered. With the devolution of NHS finances in the hands of the regional health boards and primary care trusts, there is great disparity between different regions regarding the type, quality and the timing of the services offered. Despite some guidance from the NICE, across the country, there is no universal agreement on the criteria for patient selection, number of treatment cycles to be offered and waiting time limits for patients in need of fertility treatment. Inevitably these vary widely leading to a great deal of discontent, frustration and anger among patient groups and health care providers. This is arguably the biggest challenge facing the service at the present time.
- Karlstrom PO, Bergh C. Reducing the number of embryos transferred in Sweden-impact on delivery and multiple birth rates. Hum Reprod. 2007; 22: 2202-7. Epub 2007 Jun 11.
- Report of the Expert Group on Multiple Births after IVF. HFEA publication. 2006.
- National Institute of Clinical Excellence – Fertility: assessment and treatment for people with fertility problems. Clinical Guideline 11. 2004.
- Bensdorp A, Cohlen B, Heineman M, Vandekerckhove P. Intra-uterine insemination for male subfertility. Cochrane Database Syst Rev. 2007; 18:CD000360.
- Thornhill AR, deDie-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN, Sermon KD, Wilton L; ESHRE PGD Consortium. ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preim plantation genetic screening (PGS)’. Hum Reprod. 2005; 20:35-48.
- Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006; 25:CD005291.
- Donoso P, Devroey P. PGD for aneuploidy screening: an expensive hoax? Best Pract Res Clin Obstet Gynaecol. 2007; 21: 157-68.
- Nelson SM, Fleming R. Obesity and reproduction: impact and interventions. Curr Opin Obstet Gynecol. 2007; 19: 384-9.
- Farquhar CM, Gillett WR. Prioritising for fertility treatments– should a high BMI exclude treatment? BJOG. 2006; 113:1107-9.
- Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.N Engl J Med. 2007; 356: 551-66.
- Royal College of Obstetricians and Gynaecologists – Scientific Advisory Committee Opinion Paper 5. 2003.