Thirty Years of IVF

Happy birthday, Louise Brown!  As I write it is exactly 30 years ago that she was born.  25 July 1978 was a Tuesday.  And I am sure that in Oldham, a rather drab town in northern England, it seemed like an ordinary day, except it was not to be because, then and there, Louise Brown was born, the world’s first baby conceived by in vitro fertilisation (IVF).

The Louise Brown Story
Very few people make ground-breaking history during their lifetime.  Hardly anyone creates such history on the day of their birth.  Louise Joy Brown did just that.  She was born at Oldham and District General Hospital by Caesarean section just before midnight and weighed only 5 pounds and 12 ounces with blue eyes and blonde hair.  Popular newspapers called her ‘Superbabe’.

Her parents, John and Lesley Brown, had been trying to start a family for the previous nine years.  Medical examination had shown the cause of their infertility – Mrs Brown’s fallopian tubes were blocked.  It was recommended that she try a new, experimental technique.  During November 1977, a single mature ovum was collected from one of her ovaries and then fertilised by her husband’s sperm in a laboratory procedure devised by the consultant gynaecologist, Patrick Steptoe and the research physiologist, Robert Edwards.  On 10 November 1977, the resulting embryo was transferred to Mrs Brown’s womb.  And the rest, as they say, is history, albeit landmark history.

Louise Brown has apparently led a normal life.  She likes swimming, the pub and even darts.  She has been employed as a nursery nurse, a postal worker and currently as an administrative assistant for a shipping company in the Bristol area.  In 2004, she married and two years later, she produced a son, Cameron, who was conceived naturally.

How Did IVF Start?
Perhaps it all started with the Italian experimental scientist and priest, Lazzaro Spallanzani (1729-1799).  He mixed frogs’ eggs with frog’s seminal fluid in a container, and ecco là, he produced live tadpoles.  Pretty unimpressive, you might think, since the fertilisation of frogs’ ova naturally occurs outside the body anyway.

By contrast, such in vitro reproduction with mammals was to prove much more complex and intricate.  You need a ‘mature’ ovum, just released from the ovary, plus ‘capacitated’ sperm, capable of penetrating that ovum, plus precise in vitro incubation conditions, so that the zygote can develop, and finally, a ‘primed’ uterine environment in which the embryo can implant and grow.  These prerequisites took almost 100 years of experimentation before they were achieved by major players such as, Walter Heape, Gregory Pincus, John Rock and Miriam Menkin.  But it was not until 1959, when Min Cheuh Chang reported that rabbit ova could be fertilised in vitro and go on to produce living young.  He transferred a total of thirty-six IVF embryos into six female rabbits – four of them delivered a total of fifteen living, healthy bunnies.  Rabbit IVF had arrived.

Meanwhile, at the Institute for Medical Research in London, Robert Edwards, a mammalian reproductive physiologist, turned his attention from experimenting with mouse embryos to human embryos.  In 1962, after two years of painstaking research, incubating a total of seventy-six human ova for up to 20 hours, Edwards finally succeeded in maturing and fertilising a few human ova in a Petri dish.  The possibility of human IVF had shifted a big step closer.

A move to Cambridge in 1963 allowed Edwards to analyse the more detailed conditions required for the in vitro fertilisation of human ova.  Yet his work was constrained by the meagre supply of such ova.  This hurdle was cleared in 1968 when Edwards telephoned the obstetrician and gynaecologist Patrick Steptoe to discuss the latter’s innovative laparoscopic techniques.  They agreed to collaborate.  Steptoe would aspirate an ovum from a patient’s follicle via laparoscopy and Edwards, with his assistant Jean Purdy, would fertilise the ovum and culture the embryo, before Steptoe transferred it to the patient’s uterus.

The following years consisted of laborious experimenting with various types, dosages and delivery of fertility drugs, incubation media composition and conditions, plus their dogged inability to secure a pregnancy.  Nevertheless, Steptoe and Edwards did claim a few ‘biochemical pregnancies’ as defined by a rise in the hormone, human chorionic gonadotrophin (hCG), detected by a new immunoassay of patients’ blood.  But failure prevailed.  And it was not until 1976 that Steptoe and Edwards reported their first ‘clinical pregnancy’, but it turned out to be an ectopic pregnancy and had to be terminated at about 11 weeks.

They then changed tactics.  They abandoned the use of fertility drugs and decided to collect a single ovum during a natural menstrual cycle.  In addition, they transferred the resulting embryo at the earlier eight-cell stage of development in order to circumvent the inadequacies of their in vitro culture conditions.  Their second attempt with this new regimen, though the 104th overall, resulted in the birth of Louise Brown in 1978.

Human IVF had arrived.  It was a UK first, but it was about to become a global phenomenon.  The second IVF baby was Kanupriya Agarwal, born in Calcutta, India on 3 October 1978.  The third was Candice Reed, born on 23 June 1980 in Melbourne, Australia.  The first American ‘test-tube’ baby was Elizabeth Jordan Carr, born on 28 December 1981 at Norfolk, Virginia.  During the following year, IVF births occurred in Sweden and France.

Thirty years on, it is estimated that as many as 4 million babies have been born after being conceived by IVF.  In several countries this accounts for approximately 1% of all births.

The Bioethical Problems of IVF
IVF has become THE mainstream technique of all the assisted reproductive technologies (ARTs), which includes such variants as, gamete intra-fallopian transfer (GIFT), intracytoplasmic sperm injection (ICSI) and subzonal intra-fallopian transfer (ZIFT), as well as artificial insemination by husband (AIH) and by donor (AID).

But the establishment of IVF has also opened up a vast raft of novel science –human embryo experimentation.  This is always destructive because UK law forbids such experimentation after 14 days.  Such research is possible only because IVF has provided us with access to the human embryo.  What had previously always been internal, IVF had made external.  Now we can see it, manipulate it, store it, and destroy it.

Not surprisingly, bioethical problems have continued to dog IVF and its associated activities.  For some people such concerns are entirely incomprehensible.  Since the outcomes of successful IVF are bouncing, cuddly babies for infertile couples, who could possibly object?  Similarly, since the promises of human embryo experimentation are cures for degenerative and genetic diseases, who would complain?  Well, many do.  And the problems are medical, financial, bioethical, psychological and social.  And they are not trivial.  Indeed, they strike at the heart of what it means to be human.

For instance, some consider that the whole of IVF is artificial and that this technological ‘making’ of children is morally unacceptable.  Children as laboratory products is an uncomfortable concept.  It must certainly be conceded that IVF is very different from normative parenthood, where a child is the result of life expressed in the procreative act of married union and therefore has much to do with deep human integrity and profound human relationships.  The laboratory environment of IVF, with its white-coated technicians, is undoubtedly different.

That notwithstanding, the greatest bioethical controversies surround the very practice of IVF.  The success rates of IVF procedures are terribly poor.  Even now, after thirty years of IVF, the likelihood of a ‘take home’ baby, or as the HFEA defines it, a ‘live birth event’, are less than 30 per cent.  Put the other way, IVF generally has an 70+ per cent failure rate.

In order to achieve even this meagre success rate, women undergoing IVF are typically ‘super-ovulated’.  That is, they undergo hormonal treatment so that their ovaries are stimulated to produce not one, but many, perhaps 10 or even 20, ova each month.  These are subsequently mixed with sperm in the hope of producing numerous human embryos.  Herein lies the root of many bioethical dilemmas.

First, such super-ovulation treatment can cause a serious, even rarely fatal, condition in a few women known as ovarian hyperstimulation syndrome (OHSS).  More commonly, it produces poor quality ova that often do not fertilise, and also a uterine environment that is unfavourable for embryo implantation.  This latter problem can be circumvented by freezing the embryos and transferring them to a menstrual cycle or two later, when the woman’s hormonal balance is more favourable.

Second, this leads to the problem of scrutiny, assessment, selection, and replacement of only the ‘best’ embryos.  This is nothing other than QC (quality control) for human beings. It is simply old-fashioned eugenics.  Embryos are therefore discarded from IVF procedures because there are too many, or because, for some other reason, they are deemed unsuitable.  After all, what doctor would dare transfer a less than seemingly ‘perfect’ human embryo to a woman’s womb?

Third, the production of supernumerary embryos, perhaps as many as 6 or 8 or 10 from a single IVF treatment cycle, creates the problem of ‘spare’ embryos.  Nowadays, typically only the ‘best’ two embryos are transferred to the woman’s womb, though in the recent past, many more were transferred.  This leads to the problem of multiple pregnancies.  About a quarter of all current IVF babies come from multiple pregnancies, though the proportion used to be much higher when triplets and even quads were not uncommon.  These multiple births are associated with maternal health problems, such as, an increased danger of pre-eclampsia, haemorrhage, even death.  For the unborn IVF children, they are more likely to be born prematurely, have a significantly higher risk of stillbirth, low birth weights, neonatal deaths, and long-term disabilities like cerebral palsy.  Moreover, these risks from multiple pregnancies have sometimes been dealt with by the horrors of ‘selective reduction’, whereby a number of the siblings are killed by piercing their hearts, in utero.

Fourth, the problems of these ‘surplus’ embryos are highlighted by the fact that IVF clinics are destroying thousands and thousands each year.  ‘Surplus’ embryos have five fates.  They may be transferred to the patient, donated to another woman, frozen for later use, donated to research for up to 14 days, or simply squashed

The numbers in each category can be determined from the latest figures published by the HFEA, which relate to the 120 or so IVF clinics in the UK during 2005.  In that year, 32,626 women underwent 41,932 IVF treatment cycles – obviously some had more than one treatment cycle.  As a result of the administration of fertility drugs, a colossal 306,883 ova were collected from these women – an average of between 7 and 8 ova per treatment cycle.

Only 8 of these ova were donated to other women, only 179 were stored for later use and only 667 were donated for research.  The vast majority (278,948 or 90.9%) were mixed with sperm.  Of course, not all of these ova were fertilised.  Nevertheless, 186,602 human embryos were created in these laboratories – this is a key datum.

During 2005, an additional 28,385 frozen embryos were thawed.  Some of these would have been frozen, stored and then thawed in 2005, and some would have been embryos stored during previous years.  Furthermore, there were some donated as ‘fresh’ embryos.  The HFEA statistics do not allow a full analysis of this dynamic situation.  However, helpfully, the HFEA records that during 2005 a grand total of 214,177 embryos were ‘used’.

Yet of this almost one-quarter of a million embryos, only 68,083 were transferred to women.  That is just one-third.  What happened to the other two-thirds?  The HFEA states that 43,892 were frozen and stored, 230 were donated to other women, 4,338 were donated for research, but 97,634 were euphemistically ‘discarded’.

So there we have it.  Transferred, 31.8%; frozen, 20.5%; donated, 0.1%; for research, 2.0%; discarded, 45.6%.  The latter two categories constitute those destined for deliberate and imminent destruction – a total of 101,972 human embryos, or almost half of those created by IVF, destroyed, in just one year.

Then there are the financial costs of IVF.  Currently, one treatment cycle in a private clinic (where the vast majority of IVF occurs) costs between £4,000 and £8,000.  Those sums of money, plus the inherent failure rate of IVF, have, after three or four cycles, financially crippled many infertile couples.

Finally, there are the psychological costs.  IVF creates its own stresses.  There is already the stigma of infertility to cope with and IVF treatment serves to heighten the reality and fear of its own additional failure.  The strict IVF regime with its sequence of hormonal injections, repeated monitoring and series of clinic visits can cause rollercoaster reactions.  It strains most couple’s relationships and for some, especially with the intervention of third-party gamete donations, it can prove to be too much.

So what has IVF achieved?  Of course, some lovely bouncing babies.  But more importantly it has reintroduced the era of ‘the end justifies the means’, especially with human embryos.  It has produced a view of human life that is pretty cold, if not chilling, where human ova, sperm, embryos are little more than laboratory materials.  Human sexuality has become simply a biological phenomenon, controlled by technicians.  It is a prescription for a clinical, dehumanized world, where there is not much awe, little reverence, and virtually no dignity.  In short, IVF has further encouraged the trivialization of human life.

What of the Next 30 Years?
Over these last 30 years we have constructed an uneasy world of reproductive medicine.  Its two most newsworthy achievements are paradoxically contradictory.  The one branch, called assisted reproductive technology, has tried to give children to those who cannot have them.  And the other branch, known as a reproductive healthcare, a euphemism for abortion, has removed children from those who do not want them.

The IVF and the abortion industries can be unnervingly similar.  Ethically, both say, ‘It’s OK for human beings to be deliberately destroyed.’  Economically, both say, ‘There’s money to be made from desperate people.’  Medically, both say, ‘The tiny are of little consequence.’  Philosophically, both say, ’These are complex, unfathomable matters.’  Statistically, both say, ‘Abortion destroys 200,000 lives each year, IVF destroys only 100,000.’

But what of the next 30 years?  Let’s speculate!  I have already had a go.  In my 2001 book, Responding to the Culture of Death – A Primer of Bioethical Issues, I wrote:

“The closing years of the twentieth century recorded some bizarre cases of assisted reproductive techniques and parenthood.  The early years of this century will do the same, but even more extreme.  I challenge you to spot the future winners.  How about castrating all pre-pubescent boys, freezing their gamete-producing cells, and letting them reproduce by IVF at the behest of the State?  That would solve the teenage pregnancy problem.  Ah, but the catch is that older men would then impregnate teenage girls.  So, better still, now that we have the technology to freeze and thaw ova successfully, why not remove and freeze all ova from teenage girls and return them only if and when ‘breeding’ is allowed?  Or what about a lesbian couple (Jean and Ovida), who, rather than using donated sperm, use reproductive cloning techniques to transfer Jean’s genetic material to one of Ovida’s denucleated ova?  If Ovida carries the baby, who must be a girl because she is derived from Jean’s genes, the child would have two biological mothers.  Or, what about using cell nuclear replacement (CNR) to produce a cloned embryo from a woman, harvest the embryo’s stem cells, reprogramme them to become sperm-producing cells and use the sperm to inseminate her?  The mother would then also be the father – one person, both parents.  Or again, what about two men having a baby, without a mother?  Cloning procedures could introduce a sperm nucleus, from one man, into a donor ovum to produce a ‘male egg’.  This could be fertilised with sperm from the other man by IVF techniques, the embryo could be transferred to a surrogate, and bingo, a baby with two fathers?  You think this is wacky?  Then let me tell you that scientists have already discussed its feasibility.  Or, what about having embryos implanted in men and letting them carry babies to term? Right, that’s enough of that!”

This 30-year anniversary of IVF has encouraged others to speculate too.  High on the list is the possibility that sperm and ova will be derived from induced pluripotent stem (iPS) cells.  If so, then skin cells would be used to make iPS cells, to make gametes, to make human embryos.  In other words, we could not only extend the fertile years for women, but everyone – newborns and centenarians – could have their own genetic children.  Infertility would be eradicated.  Maybe.

If huge numbers of human embryos could be produced and grown relatively easily in culture then genetic modification, correcting defects and engineering improvements, will be attempted.  Similarly, a more widespread use of pre-implantation genetic diagnosis (PGD), in conjunction with IVF, will sift out more so-called ‘defective’ embryos and herald the age of the true designer baby – not just avoiding Parkinson’s disease or cystic fibrosis, or choosing mere hair or eye colour, but also selecting for ambition or intelligence.

The health of IVF children will need to be studied more carefully.  Will they, and their offspring, suffer for example from epigenetic effects, namely, the way a person’s genes are switched on.  For instance, there are preliminary reports that Beckwith-Wiedemann syndrome and retinoblastoma are more common among IVF children – currently the jury is still out on such crucial topics.

Will artificial wombs move from science fiction to reality?  As well as assisting infertile couples, could they perhaps end the practice of abortion by the transfer of a threatened fetus to such an artificial womb?  Maybe not.  Or will human reproductive cloning finally succeed?  There is no doubt that scientists are attempting such a feat in countries that have not yet banned the practice.

Indeed, will IVF itself still be prospering 30 years on?  Probably, yes.  Yet it is currently too cumbersome, too high-tech and too expensive to have a major impact on human reproduction worldwide.  Minor modifications will improve its success rate, but its impact will remain on the thousands of people rather than the millions each year.  The old-fashioned way is certainly easier, cheaper and more fun – that will not change in the next 30 years!