Abstract
This paper is a review of current techniques and best practice in reproductive medicine, including preimplantation genetic diagnosis and embryo freezing, and management of pregnancy after in vitro fertilization. It discusses medicolegal aspects that can arise from failure to follow best practice including ovarian hyperstimulation syndrome and mistakes occurring in the embryology laboratory.
Human in vitro fertilization (IVF) is just over 30 years old. Many will remember the furore surrounding the birth of Louise Brown after years of effort by Patrick Steptoe and Bob Edwards, a clinician from Oldham and a scientist from Cambridge. IVF was the first truly effective treatment for many forms of infertility and its use has blossomed over the past three decades. Variations on the theme, such as intracytoplasmic sperm injection (ICSI) for male infertility and preimplantation genetic diagnosis (PGD) to allow selection of healthy rather than affected embryos for couples who carry severe genetic disorders have widened the scope of IVF and there are now over 3 million IVF children in the world and over 40,000 IVF treatment cycles performed annually in UK.
Like all medical advances, the advent of the assisted reproductive technologies (ART) brought a downside. The techniques brought a plethora of unforeseen ethical and legal challenges that continue to vex professionals, the public and journalists to this day. In response to widespread anxiety about the potential for abuse of ART and its impacts on society, the UK Government passed the Human Fertilisation and Embryology (HF & E) Bill in 1990 which established the Human Fertilisation and Embryology Authority and created a legal framework within which medical practitioners and their colleagues were expected to practise. Despite setbacks, this system has stood the test of time and has been widely emulated around the world. The HF & E Act has now been updated and the revised Act is due to become law later this year.
Modern treatment of infertility is a complex, time-consuming, often expensive and frequently fruitless endeavour for patients. Even the best IVF clinics will fail to establish a healthy pregnancy for their clients in over 50% of cases leaving many with a deep sense of failure, unhappiness and, in a minority of cases, feeling let down by their doctors and the system. The NHS has consistently failed to support infertile patients, leaving many to pay for treatment with large sums from their own pockets. The new science of ART has many controversies and disagreements between professionals as to the best approach to take for different categories of patient are common. Intricate laboratory science is inevitably error prone even in the best laboratories, and these and other pitfalls can provoke dissatisfied patients to seek legal redress. Although difficult to quantify, there appear to be an increasing number of legal cases in this area of medicine, some of which involve allegation of serious harm to the woman or her child, or even premature death.
This article will discuss a number of IVF-related medicolegal issues derived from cases known to the authors. It will not cover the wider practice of medical or surgical treatment of infertility, although this is another area fraught with difficulty, and represents the personal opinion of the author and is not in any way the opinion or policy of the Human Fertilisation and Embryology Authority.
How does IVF work?
Louise Brown's conception followed the collection of a single human oocyte (egg) during the natural menstrual cycle of Louise' mother. However scientists rapidly learned that using drugs to stimulate the ovaries to produce multiple oocytes gave a much better chance of pregnancy. Human oocytes grow within small fluid filled structures within the ovaries, termed follicles. These will reach a diameter of about 2 cm before they rupture to release the egg, and can be both seen on a vaginal ultrasound scan and detected by their output of oestrogen hormones, particularly oestradiol. Early work used oral agents such as Clomifene citrate (Clomid) to stimulate multiple follicle development but research in the early 1960s led to use of human-derived gonadotropin hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) given by injection for 10–14 days to produce anything up to 50 eggs from a single stimulation cycle.
Modern IVF frequently begins with ‘pituitary desensitization’ with gonadotropin-releasing hormones (GnRH
FSH hormones can now be derived either from humans – isolated from the urine of postmenopausal women – from a bioreactor as a recombinant product of genetically modified hamster ovary cells. They are given by daily injection using an autoinjector device and are remarkably free of troublesome side-effects. The ovaries respond to this treatment by growing multiple follicles, each containing an oocyte. Follicle growth is monitored by blood tests for oestradiol, and vaginal ultrasound to count and measure the follicles.
Once the follicles are deemed mature, a final injection of a second hormone, human chorionic gonadotropin (hCG) is given. This injection is essential as it induces final oocyte maturation and prepares the oocyte to be fertilized. After hCG the woman will ovulate naturally about 40 hours later so oocyte collection has to be timed to allow sufficient time for the maturation process to complete but before ovulation occurs. In practice, injection of hCG is usually given late at night to allow egg collection in the morning about 36 hours later.
Eggs are almost universally collected by transvaginal ultrasound-guided needle aspiration of the ovarian follicles. This is done under a light general anaesthetic or using sedation, and involves insertion of a needle through the skin at the top of the vagina and into the ovary. Using ultrasound, the needle is guided into a follicle which is aspirated using a gentle suction apparatus. The fluid from the follicle is collected and the embryologist isolates the egg from the fluid using a microscope. The egg is placed into culture medium and incubated in a temperature- and atmosphere-controlled incubator. Each follicle is aspirated in turn and then the other ovary is aspirated in a process that takes 10–30 minutes and is usually done as a day case.
At the same time, the male partner produces a sperm sample, either by masturbation or through use of a needle biopsy of the testis or epididymis for men who are severely infertile and need ICSI. The embryologist will strip the oocyte from its surrounding cumulus cells and either expose the egg to about 50,000 sperm to allow natural fertilization, or perform ICSI with a single sperm being injected into each egg. The fertilized egg will then be incubated for 2–5 days before replacement into the uterus using a transfer catheter passed through the cervix into the uterine cavity. This is no more painful than a cervical smear, takes a few minutes and is followed by two weeks of waiting to see if pregnancy will ensue.
Where can it go wrong?
The above 700 words describe a process that many women and men find both physically and psychologically taxing. Things can go wrong at every stage and the HFEA database (see
Ovarian hyperstimulation syndrome
The most serious threat to the health of the woman during and after IVF treatment is that of ovarian hyperstimulation syndrome (OHSS). This occurs when the ovaries are overstimulated by gonadotropin drugs. Many follicles develop and oestradiol levels exceed 10 times those ever seen normally. OHSS is a complex multisystem disorder that leads to accumulation of fluid in the abdomen and chest along with dehydration of the vascular compartment. Complications include arterial and venous thrombosis, respiratory and cardiac failure and stroke. Several recent well-publicized cases have resulted in permanent handicap or death of previously healthy young women after severe OHSS. Clinics can adopt several strategies to reduce risk of OHSS, although the condition is not completely avoidable even in expert hands. The dilemma is that strategies to minimize risk of OHSS may reduce the chances of a live birth from this expensive and stressful treatment, leading to pressure from patients that can lead an unwary clinician to over-stimulate, fail to cancel a cycle or freeze all embryos when clinically prudent. Recently the concept of ‘mild’ stimulation has been introduced into ART practice. This uses low doses of gonadotropin drugs with a GnRH antagonist instead of an agonist. GnRH antagonists act more directly and hence much more quickly to suppress hormone levels, and have improved IVF safety and acceptibility over the older generation of agonists. ‘Mild’ IVF is quicker and less stressful than conventional treatment, with a 50% reduction in incidence of OHSS. It is likely that this will become a more widely used approach in the future, particularly for women at particular risk of OHSS. Further details of OHSS and its management can be found at
Provided that OHSS is avoided, the process of IVF carries low risk of physical harm to patients. Gonadotropin injection can lead to local skin reaction or bruising although this is mild and self-limiting, and the blood tests and vaginal scans are undeniably unpleasant but not dangerous. Transvaginal egg collection is surprisingly free of frequent complications although the proximity of the ovaries to the major iliac vessels can rarely lead to significant haemorrhage after collection that may require abdominal surgery. There are the usual hazards of anaesthesia and some patients treated under sedation only may find the process unacceptably painful.
Equally, production of sperm is usually straightforward although needle aspiration to obtain sperm may be followed by extensive bruising, pain and swelling of the scrotum.
Embryology
The major area of potential hazard is in the embryology laboratory. Cases in which the ‘wrong’ sperm and eggs were mixed, or in which the ‘wrong’ embryos were transferred led to the HFEA requiring that a second person ‘witness’ all parts of gamete and embryo handling and labelling. This has been followed by systems for automatic labelling of specimens using bar coding or radiofrequency tagging which should minimize such incidents. Embryology is a tightly regulated profession with a well-run system of training and qualification which produces reliable and conscientious practitioners. However a laboratory suffering staff shortage or poor staff relations may still produce errors, the consequences of which are long-lasting and profound. There are many other potential problems in embryology, ranging from unexpected failure of any eggs to fertilize to incubator infection necessitating disposal of embryos before transfer, or loss of frozen embryos. While scientifically justifiable, patients may see their investment, and more importantly their chances of a child, disappear when such accidents happen and poor explanation by the clinic can lead to complaint.
As IVF science has progressed, the need to transfer several embryos in a single treatment cycle in order to have a reasonable chance of a pregnancy has diminished. At the same time, the hazards of twin and triplet pregnancy have become clear as the number of multiple births has increased because of the contribution of ART. The burden of iatrogenic multiple pregnancy has clear economic consequences for the NHS, particularly since private clinics do not provide antenatal, intrapartum or neonatal intensive care and instead pass these problems back to the State to fund. More importantly, the chance of long-term handicap to a child born from a multiple gestation is significantly raised compared with that of a singleton and hence HFEA and the majority of responsible fertility practitioners have recently promoted the concept of single embryo transfer (SET). The HFEA website (
Embryo freezing
The corollary to widespread use of SET is that more embryos are available for cryopreservation (freezing). Embryo freezing technology is well-developed and the health of children born from cryopreserved embryos seems equivalent to their naturally conceived counterparts. However, freezing offers another possibility for disaster – none of the embryos may survive freeze-thawing, embryo quality after thawing may be significantly and surprisingly impaired or the embryos may be transferred in repeated cycles and pregnancy not result. Recently, the novel technology of vitrification, ultra-rapid freezing, has been applied to both embryo and egg freezing. While the benefits of vitrification in embryo freezing are unclear, there is definite benefit when eggs are frozen with this technique. Conventional slow freezing has not been particularly successful when applied to eggs – they are very large cells and ice crystals form which later disrupt the delicate architecture of the cell when thawing occurs. In contrast, vitrification avoids this problem, and pregnancy rates when frozen eggs are thawed and fertilized with ICSI are relatively high. The use of ‘relative’ in this context is important. Vitrification is a new process and still has to establish its place in routine practice. Its benefits are obvious when used to freeze the oocytes of young women who are about to undergo sterilizing treatment for cancer – after cure they have at least a chance of having children later in life. The benefits are less clear, at least to this author, when this technology is offered to healthy young women who wish to defer their childbearing until after the natural reproductive lifespan has passed. This may offer false hope – the ‘customer’ may return years later to use her frozen eggs but fail to conceive, only to find that natural pregnancy is no longer possible and that she and her partner will not be able to have their family. The consequences if careful, well-documented counselling about this risk has not been carried out are obvious.
Pregnancy after IVF
IVF pregnancies are high-risk pregnancies. Women pregnant after IVF are often older than average and may have co-existant medical disorders that contribute to their infertility. The care of these patients provided by the IVF clinic should not cease on the day of a positive pregnancy test. The possibility of miscarriage or, more medically worrying, ectopic pregnancy, are increased compared with spontaneous pregnancy and hence a responsible clinic should at least offer a ultrasound scan a few weeks after conception to rule this out. Failure to diagnose ectopic pregnancy can lead to catastrophic intraperitoneal bleeding, and rupture of an ectopic pregnancy remains the leading cause of death in the first trimester of pregnancy. Women who conceive after ART should be regarded as ‘high risk’ obstetrically as there is good evidence of a higher than average obstetric complication rate and of Caesarean delivery.
Preimplantation genetic diagnosis
One of the new growth areas for ART involves the use of IVF to allow access to embryonic DNA. Although the media have characterized techniques of preimplantation genetic diagnosis (PGD) as leading to designer babies, the reality in 2009 is that this technology is being used to prevent conception of pregnancies affected by serious genetic disorders that would lead to premature death and/ or severe disability in the child. PGD avoids the alternative of prenatal diagnosis by amniocentesis or chorionic villus sampling. The latter approach provides a diagnosis only after a pregnancy is established, leading in many cases to late first trimester or second trimester abortion. Although PGD has obvious advantage over prenatal diagnosis, techniques for analysing the single cell collected by embryo biopsy remain at the cutting edge of science, and a misdiagnosis can produce disastrous consequences. Responsible laboratories take great care to minimize this risk but as in other areas of clinical embryology, the processes used are complex, involving many intricate steps and demanding considerable skill from the operator.
IVF has come a long way since the almost miraculous conception of Louise Brown. Clinics can now offer effective treatment to couples suffering from most of the common causes of subfertility. However it is not a universal panacea and should not be used where there is little or no chance of success. The National Institute for Health and Clinical Excellence (NICE) Guidelines on the management of the infertile couple highlight the position of IVF as one aspect of the holistic care of infertile patients. Some couples should be advised to try naturally for a longer period before entering treatment, others can be offered reproductive surgery or simpler techniques such as intrauterine insemination (IUI) with good results, avoiding the cost and stress of IVF. However, again, conflict may sometimes occur in a clinic that cannot offer surgical approaches or IUI, or where the profit per case is significantly greater after IVF. Additionally, IVF techniques do not work well in women aged over 40 years. For example, the United States SART registry gives live birth rates for women aged 43 and 44 years at time of treatment as 5.1% and 3.0%, respectively, and live birth after IVF in women over 44 years is vanishingly rare. The profound demographic changes that have occurred over the last three decades have resulted in an increasing number of women in their 40s wishing to conceive a child. Many find this impossible naturally and consult a fertility specialist – while most will be pessimistic, advise consideration of alternative approaches such as oocyte donation from a younger woman or adoption. A minority will offer repeated IVF cycles, often with multiple adjuvant treatments in an attempt to achieve implantation. Even in the rare cases where embryo implantation occurs, miscarriage rates in this group are approximately 50% and hence chance of live birth is low and potential for later dissatisfaction high. Despite considerable effort, techniques such as co-treatment with steroids, Sildenafil, heparin, immunoglobulins or growth hormone, or attempts to select the ‘best’ embryo using preimplantation genetic selection (PGS) have consistently failed to show evidence of benefit when subjected to randomized controlled trials and such treatments should not be offered without research studies.
The image of IVF treatment purveyed by the media invariably involves pictures of babies. In my view this entirely misses the point of the process. IVF is about helping infertile couples start or complete their family, allowing them to raise, educate and enjoy children, giving them the likelihood of support in old age and continuance of their family line. These are among the most important reasons for existence and drive the most powerful of all human emotions. It is not surprising that the enormous reward that ‘success’ brings to many couples is mirrored by the huge disappointment of ‘failure’. A good quality IVF clinic will spend far more time managing expectations, injecting realism and supporting those who have a negative pregnancy test at the end of an arduous treatment programme than on the happy minority who conceive after treatment. Given the complexity of the science and the profundity of the emotional burden of infertility it is hardly surprising that litigation in this area of medicine is on the increase.