Ever since Louise Brown, the first ever test-tube baby, came into the world in 1978, in-vitro fertilisation (IVF) has become the first port of call for people having trouble conceiving. Since Louise's birth, approximately one million IVF children have been born - accounting for 1 per cent of all births in the developed countries.
According to the World Health Organization, some 10 per cent of couples in the West experience difficulty conceiving and, among those who undergo infertility treatment, some 1.6 per cent now participate in IVF.
Judging by some of the media headlines, you'd think the early low success rates have finally been sorted, and that women using IVF can have babies virtually at will. However, the reality is a far different scenario. The rates of success remain low - only 22 per cent of couples undergoing IVF end up with a live baby - while issues concerning its safety continue to multiply.
These questions surfaced again recently, with publicity about TV personality Paul Merton's wife, Sarah Parkinson, who this year died of breast cancer, and Liz Tilberis, former editor-in-chief of Harper's Bazaar, who died of ovarian cancer in 1999. Both women were convinced their disease was caused by their efforts to conceive by IVF. Both had gone through several treatment cycles, involving high levels of female hormones.
Although the media brushed such concerns aside, the fact remains that IVF is still one vast clinical experiment. All the various varieties of IVF have been unleashed upon millions of men and women with virtually no proper studies conducted and little understanding of the risks it places on either mother or child. Indeed, every fresh discovery - and now genetically modified hormones are the latest wrinkle (see box, p 3) - is rushed into the clinic without sufficient experimental studies to back it up.
No less a figure than Lord Robert Winston himself, one of the pioneers of IVF and a member of the team that produced the test-tube 'miracle' in 1978, has recently spoken out publicly on the potential risks of the procedure, calling for better child follow-up and a fresh approach to IVF regulation.
So, 25 years on, we still have to ask: how safe is IVF to either mother or child?
How it works
In the most basic type of IVF procedure - where eggs from the mother and sperm from her partner are used - doctors give the woman drugs to stimulate her ovaries to produce multiple eggs. These eggs are then removed through some guided technique such as ultrasound. A sample of semen is gathered from the partner, and used to fertilise the eggs in a laboratory dish. Up to three of the resultant healthy embryos are then placed in the woman's womb, on the (unproven) grounds that the more that are allowed to develop, the greater the likelihood that one will make it to term.
Pharmaceutical stimulation of the ovary is now the central plank of assisted reproduction. The technique essentially depends on giving multiple, powerful drugs that cause the ovaries to pump out as many mature eggs as possible.
The most dangerous potential complication is something known as 'ovarian hyperstimulation syndrome' (OHSS), which affects nearly 1500 women a year in the UK, or 6 per cent, of the nearly 24,000 a year who undergo IVF. Even MIMS, the UK doctors' drugs 'Bible', warns that OHSS is a potentially fatal side-effect of fertility drugs, and that all patients undergoing ovulation induction are at risk. The syndrome can lead to life-threatening dehydration, massive fluid accumulation in the chest and abdomen, blood-clotting disorders and damage to the kidneys.
Clomiphene citrate (Clomid), one of the oldest and most basic of the fertility drugs, is supposed to be indicated only for those women with ovulatory dysfunction. Its manufacturer, Aventis Pharma, does not recommend its use in more than three cycles (Medicines Compendium, Pharmaceutical Press, 2003). Despite this guidance, it is common practice to prescribe it as a first-line therapy, regardless of whether a woman is ovulating regularly, and to extend its use to six cycles.
Taken orally, clomiphene works by blocking oestrogen, which tricks the pituitary gland into producing follicle-stimulating hormone (FSH) and luteinising hormone (LH), boosting follicle growth and the release of the egg. Side-effects include a reduced amount and quality of cervical mucus, and thinning of the womb lining, in which case, yet more hormonal agents may be given to restore thickness. Women may also develop ovarian cysts, hot flushes, nausea, weight gain and fatigue.
Down-regulating your cycle
If this approach fails, the woman is then moved onto even more potent fertility drugs. These are the 'superovulation' drugs that force a woman's body to pump out multiple eggs. Many of these are either hormones taken from natural sources, such as the urine of pregnant or postmenopausal women, or are recombinant - genetically developed - versions (see box, p 3).
In February this year, the Committee on Safety of Medicines advised that Metrodin, one of the older superovulation drugs, should no longer be used in the UK. This is a precautionary measure following a case of confirmed variant Creutzfeldt-Jakob disease (vCJD) in Italy from where the human urine used to make the drug is sourced.
Most women undergoing fertility treatment are likely to be bombarded with three types of drugs: a GnRHa (gonadotropin-releasing hormone agonist) to suppress the release of LH from the pituitary gland (the LH surge) and to prevent ovulation until the follicles are mature; an FSH product to stimulate production of multiple follicles; and hCG (human chorionic gonadotropin) to bring about final maturation of the eggs in the follicles.
In addition, gonadotropins such as LH and FSH are given directly every day for four to eight days of the treatment.
During 'pituitary down-regulation' - as this phase of the treatment is known - when ovulation is postponed, one GnRHa drug given is goserelin acetate, which can be 100 times more potent than the natural hormone for ovarian stimulation. This and other GnRHa drugs are usually given together with human menopausal gonadotropin (hMG) during the superovulation stage of IVF, and there have been reports of potentially life-threatening ovarian hyperstimulation in women given the two drugs in combination (Medicines Compendium, Pharmaceutical Press, 2003).
The hCG stage is a delicate balancing act, in which at least three follicles have to be of a particular size and blood levels of oestradiol, an oestrogen, have to be at a certain level, before hCG can be given, warns Organon, one of the manufacturers. About 36 hours later, the eggs are then ready to be harvested.
If ovarian hyperstimulation does arise, the hMG must be stopped immediately and the hCG held back (Medicines Compendium, Pharmaceutical Press, 2003).
Throughout this entire procedure, where science and chemistry have basically taken over - and drastically altered - the entire female cycle, oestrogen levels and ovary size must be carefully monitored, preferably by ultrasound, to avoid the risk of high dosages causing oestrogen levels to rise too rapidly.
Is there a cancer risk?
The short answer is, we still don't know. The ovaries produce the female sex hormones oestrogen and progesterone, and artificially raising their levels in the body could enhance the risk of developing hormone-related cancers such as breast or uterine (womb) cancer (BMJ, 1989; 299: 309-11).
There is no doubt that excess exogenous oestrogen (not made in the body naturally) causes cancer. There is substantial evidence that sex hormones are implicated in a number of women's cancers, as they are the hormones that stimulate cell division in organs such as the breast, ovaries and lining of the womb.
In the US, it is now accepted that hormones account for more than 30 per cent of all cancers seen in American women (At Risk: Health, Safety & Environ-ment, 1998; 9 [Summer]: 201-27).
During IVF, hormone levels are sent sky high. In some instances, levels of these hormones more than double for up to three consecutive days.
There is an analogy here with the use of hormone replacement therapy, where large-scale studies like the Women's Health Initiative in the US and the Million Women Study in the UK have now indisputably shown an increased risk of breast and ovarian cancer after a single year of HRT use (JAMA, 2002; 288: 321-33; Lancet, 2003; 362: 419-27).
Another possible reason for an increased risk of ovarian cancer in IVF is that ovarian stimulation results in a high number of eggs. One stimulated IVF cycle results in the equivalent number of eggs in a single month that would ordinarily take a woman's body a year or even two to produce. Women can have as many as 20 goes with IVF, thereby producing between 200-500 eggs - equal to 20 years' worth - in less than two years.
However, the research into the risks is, to say the least, conflicting. In one of the latest studies, researchers at La Trobe University in Carlton, Australia, carried out a series of observational studies on one of the largest sample sizes to date. They followed-up 29,700 women, treated at 10 Australian IVF centres before January 1994, for a period ranging from one to 22 years, with most followed-up for five to 10 years. Of these women, 20,656 had received fertility drugs during IVF (the 'treated' group) and 9044 had not (the 'untreated' group).
Although there was no significant difference in breast and ovarian cancer in the two groups during the study, more women than predicted in the treated group had a breast cancer diagnosed in the first year after treatment with fertility drugs - nearly double the predictions (Lancet, 1999; 354: 1586-90).
Nevertheless, another recent study arrived at a different conclusion. In this report, where investigators from the US and other countries collected data on infertility and fertility-drug use from eight case-control studies, women who had used fertility drugs were no more likely to develop ovarian cancer than those who had never used them. Every successful pregnancy reduced the risk of developing it later. Women who had spent more than five years unsuccessfully trying to conceive were at a 2.7-fold higher risk for ovarian cancer than those who tried for less than a year.
It may well be that infertility itself predisposes to ovarian or breast cancer, as all the women with unexplained infertility had more cancers of the ovary and uterus than predicted - whether or not they had treatment with fertility drugs. Endometriosis also appeared to be a risk factor (Lancet, 1999; 354: 1586-90; Am J Epidemiol, 2002; 155: 217-24).
This accords with other research into breast and ovarian cancers suggesting that the constant triggering of hormones for ovulation without a rest period - such as during pregnancy - eventually sets the cancer in motion. Certainly, the American study found that pregnancy and breastfeeding had a protective effect against ovarian cancer.
Nevertheless, a number of earlier observational studies have shown a threefold risk of ovarian cancer with IVF. For instance, 12 studies analysed by the American Collaborative Ovarian Cancer Group at Stan-ford University in California discovered that the risk of invasive ovarian cancer among infertile women who'd taken fertility drugs was almost three times that of fertile women and higher than that of infertile women who had not taken the drugs (Am J Epidemiol, 1992; 136: 1175-83).
Studies of clomiphene citrate have shown that women who take the drug are increasing their chances of developing an invasive ovarian tumour by two and a half times. Those who'd taken the drug for 12 or more cycles were at an even higher risk (N Engl J Med, 1994; 331: 771-6).
There is also evidence that follicle-stimulating hormone activates a certain enzyme that has a growth-stimulatory effect on the surface cells of the ovaries (J Clin Endocrinol Metabol, 2002; 87: 2245-53).
However, the problem with the studies thus far is that they are 'observational' - that is, they assemble a group of women who'd taken fertility drugs, and another group who hadn't, and then compare the rates of cancer. This kind of study doesn't control for other factors, such as healthy lifestyle or other hormone use, known to affect cancer risk.
So, we could be comparing two groups of women who have used hormones - one with IVF and the other from the Pill. Furthermore, we could be comparing IVF cancers against the normal breast and ovarian cancer statistics - which, of course, are inflated because of the cancers caused by other hormone use in the general population. In the case of HRT, earlier case-control studies were ultimately proved false when a prospective, randomised, double-blind placebo-controlled study (where a group of similar women are randomly put into groups, with one group given infertility drugs and the other, a placebo) was finally carried out.
Children at risk
Cancer is not the only concern about IVF. For a long time now, there have been worries over the possible risks of rare birth defects or other health problems in the children themselves, particularly those that develop over the longer term.
This led the Johns Hopkins University in Baltimore, Maryland, to join forces with the American Society for Reproductive Medicine and the American Academy of Pediatrics earlier this year to convene a panel of experts, who are currently analysing the available research. In the UK, the Human Fertilisation and Embryology Authority is working along the same lines.
The key risks involve multiple births, which are 27 times more likely among IVF babies than non-IVF babies, with a 5.4 per cent chance of abnormality. Babies are also five times more likely to be born prematurely and to be underweight at birth (Lancet, 1999; 354: 1579-85).
IVF babies also have three times the rate of cerebral palsy compared with children in the general population, and this applies whether they are twins, triplets or singletons of normal birthweight, according to a Swedish study (Clin Dev Med, 2000; 151: 67-83; Lancet, 2002; 359: 459-60, 461-5).
There have been case reports suggesting that IVF children may also be more prone to developing cancer. A letter to the Lancet (22 December, 1990) spoke of five children born between 1985 and 1987 in Australia who developed brain tumours. The researchers believed that the common factor among them was the use of Clomid (clomiphene) to stimulate ovulation. Another study from La Trobe University in Australia looked at all live births (5249) following IVF at two clinics in Victoria, and checked these with a cancer registry. What they found was a slight increase in cancer incidence over that expected (Hum Reprod, 2000; 15: 604-7).
Early reports of assisted conceptions found that 7 per cent of the infants were born with major congenital malformations - ranging from heart abnormalities to clubfoot (Lancet, 1991; 337: 762-3). This compares with a 2-per-cent rate in the general population. Heart malformations were the greatest problem, accounting for almost 4 per cent of cases, compared with the usual rate of around 0.4-0.5 per cent.
IVF babies have also been linked to a cluster of rare genitourinary birth defects called cloacal-bladder exstrophy-epispadias complex. The Johns Hopkins Children's Center has evaluated 12-14 per cent of all such cases in the US. Of 78 children treated at the Center during 1998-2001, four were IVF births. The expected incidence for all IVF children born during the study period (112,137) was five, indicating that the defects could be seven times more widespread in IVF children than in the general population (J Urol, 2003; 169: 1512-5).
Another problem coming to the surface are rare genetic imprinting defects. Imprinting 'marks' certain genes - notably, those associated with the development of the baby in the womb - to distinguish whether they have come from the mother's egg or the father's sperm. This reveals how active a gene is. Fathers' genes tend to make babies grow faster while those from mothers tend to slow growth down. Disruption of imprinting means a loss of control.
One example of such a disruption is the Beckwith-Wiedemann syndrome (BWS), a collection of defects characterised by excessive growth of various tissues. Its incidence is about 1 in 15,000 births overall. US scientists studying the national registry of BWS patients found six times more IVF-initiated conceptions registered than expected (Am J Hum Genet, 2003; 72: 156-60).
Imprinting problems may also arise through a procedure called ICSI (intracytoplasmic sperm injection), which involves injecting a single sperm directly into the egg. In two cases of Angelman's syndrome (also known as happy puppet syndrome, a condition akin to autism), the researchers concluded that ICSI may interfere with the maternal imprint in the pre-embryo cell (Am J Hum Genet, 2002; 71: 162-4).
ICSI is also suspected of causing mild genetic abnormalities, including passing the father's infertility to the child as, ordinarily, only the strongest sperm succeeds in getting through to the egg. ICSI may also play a role in brain defects. One study found that, at age one, 17 per cent of ISCI children showed mild-to-significant delayed development compared with 2 per cent of those conceived by ordinary IVF and 1 per cent of those conceived naturally (Lancet, 1998; 351: 1524-5).
Lord Winston himself is especially concerned about the safety of using frozen embryos and the procedure of blastocyst transfer, where embryos are not placed back into the body for up to five days, instead of the usual two, after fertilisation. This delay may be the cause of potential genetic abnormalities (Nat Cell Biol, 2002; 4 [Suppl 1]: S14-8; Nat Med, 2002; 8 [Suppl 1]: S14-8).
His words appear to have been confirmed by a study, from the Dexeus Institute and the Autonomous University of Barcelona, which showed that the structure of frozen eggs becomes disordered during the thawing process, resulting in the embryo having too few or too many chromosomes. There is also a high incidence of miscarriage (Eur J Hum Genet, 2003; 11: 325-36).
Elsewhere, doctors have cautioned against the unseemly haste that now prevails in rushing couples into IVF - usually only a year after trying in vain for a baby. But, unless you have clinical indications of infertility, such as blocked fallopian tubes, waiting for two years may mean that you don't need IVF at all, according to a joint study by the National Institute of Environmental Health Sciences in Washington, DC, and the University of Padua.
Deanna Wilson and Lynne McTaggart