Like a Virgin (22 page)

For couples with unexplained infertility, induced ovulation is sometimes accompanied with
intra uterine insemination
, or IUI, which can help to get underperforming sperm or eggs in the
same place, at the same time. In IUI, semen is first processed in the lab, so that only sperm that are moving can be selected. These ‘good’ – or, at least, somewhat mobile –
sperm are then delivered directly into the womb, near where the egg is preparing itself to be fertilized, bypassing the hazards that might assault them in the vagina and cervix, namely,
unfavourable pH environment and tricky-to-navigate mucus. The vast majority of sperm are normally killed somewhere en route. Among couples with no clear fertility dysfunction, there seems to be a
significantly higher chance of a successful pregnancy when IUI is used with ovarian stimulation rather than on its own, although simply having sex at the right time, which is much easier to
pinpoint with ovarian stimulation, might work just as well.

It may also be the case, as with Lesley Brown, that the reason a woman cannot get pregnant is because there is a blockage in her Fallopian tubes, the two passages that
connect the ovaries to the womb. If this is the problem, a woman might choose to have surgery to unblock the tubes. But if this fails, or if the woman is already in her mid- to late thirties, when
the biological clock is ticking away, IVF may indeed be the best bet.

In IVF, an egg is extracted from a woman and incubated with around fifty thousand sperm. The in vitro part of IVF literally means ‘within glass’, because it originally referred to
the fact that the experiments were performed in glassware, which was commonly used in labs instead of plastic. (This is in opposition to ‘in vivo’ fertilization, which comes from the
Latin for ‘within the living’.) Fertilization in vitro thus means that the egg and sperm are effectively left to mingle and ‘introduce themselves’ in a specially created,
artificial environment, something like a speed-dating night. With the plethora of obstacles in its way safely removed, a sperm can make a direct hit on the egg – as long as it can beat its
competitors to it. It follows from the particulars of the set-up that for men whose sperm cannot move properly to the egg or penetrate it to begin fertilization, IVF may simply not work.

By the late 1980s, fertility doctors had found a way to solve this matchmaking problem, without having to resort to donor sperm. Several techniques emerged that could improve an infertile
man’s chances of making a baby, with one frontrunner quickly establishing itself:
intra-cytoplasmic sperm injection
, or ICSI. Like IVF, ICSI does not correct defects in the sperm, but
it requires a much smaller number of sperm: instead of fifty thousand sperm, just one will do. ICSI does not leave fertilization to chance. This single sperm – possibly immobile, but
otherwise picked for its ‘good looks’ – is first stunned, for example by rubbing its tail. It is next sucked up, tail first, into
a sharp-tipped glass
pipette and injected directly into an egg. Or, instead of a whole sperm, the doctor can pluck just a single sperm head or nucleus, containing the DNA that provides all the necessary genetic
instructions for making a baby – the rest of the sperm is simply a vehicle to get the male DNA into an egg.

Neither IVF nor ICSI are without limitations – their success rates are, at best, only around thirty percent. These remain techniques for assisting natural reproduction, not for replacing
it.

But as the use of ART increases worldwide, it is certainly also important to consider some potential long-term consequences. For a start, in both IVF and ICSI, eggs need to be removed from a
woman in order to ensure sperm access to them. But eggs are tucked away in the ovaries, and released only infrequently following a biological programme, which makes them far trickier to acquire
than sperm. To harvest her eggs, the doctor places the patient under local anaesthetic, and then, guided by ultrasound, passes a long, thin needle through her vagina to the ovaries. The needle is
used to suck the fluid out of mature follicles, or egg-containing sacs. If an egg happens to be retrieved with this fluid, it is gingerly removed and tucked into an incubator. And then the process
is repeated, until several more eggs join it.

This process of extracting eggs is not just invasive; it carries very real health risks as well. To persuade the ovaries to release multiple eggs from their grip, these organs must be stimulated
with a suite of hormones that the body itself uses for that purpose, but often at higher than normal doses. These include a drug to stop eggs from being released until they are mature (a
gonadotropin-releasing hormone
, or GnRH, agonist or antagonist; a
follicle-stimulating hormone
, or FSH, that kick-starts the development of multiple eggs; and
human chorionic
gonatotropin hormone
, or HCG, which forces the eggs to mature properly
(and is the hormone that causes over-the-counter tests to test positive for pregnancy). Without
stimulating medications, the ovaries generally produce one egg a month. With them, they churn out anywhere from five to twenty-five eggs that might be harvested, and some young women have been
reported to produce fifty to seventy eggs from one high-dose stimulation. This sounds like good news, but this stimulation can cause severe
ovarian hyperstimulation syndrome
, or OHSS –
most likely as a result of too high a dose of HCG. When OHSS sets in, the woman’s blood vessels become much more permeable than they should be. This leads to a drop in blood volume, so that
her blood thickens. It can lead to organ failure, and is a life-threatening condition.

The cocktail of medications served up in IVF and ICSI can also cause developmental problems in the babies they beget. FSH, if given in high doses, may lead to the production of eggs with too
many or too few chromosomes or of eggs with chromosomal abnormalities. Having the right number of chromosomes is incredibly important; for example, in Down syndrome three copies of some genes are
carried on chromosome number 21, rather than the usual two copies (an issue we will look at in more detail in the next chapter). High levels of FSH might also have a detrimental effect on the
lining of the womb, which could compromise the growth and health of the baby growing in it. Children conceived in vitro, and even those conceived merely with the assistance of ovary-stimulating
drugs, may also be more likely to be born with several syndromes. Babies with Beckwith-Wiedemann syndrome grow too large – both in the womb and outside it. This overgrowth can affect all
systems of the body and cause diabetes, abdominal wall defects, kidney problems, and embryonal tumours. Another condition, Angelman syndrome, may express itself through severe mental retardation or
delayed motor development, which means
poor balance, jerky movements, and difficulties with speech. The growth disorder Silver-Russell syndrome leads to dwarfism.
Fortunately, all of these conditions are rare in the general population, so an elevated risk after IVF or ICSI does not translate into an epidemic among scientifically fertilized offspring. Indeed,
the absolute risk for a serious congenital malformation or chromosomal abnormality after IVF and ICSI appears to be small.

What is interesting from a medical perspective is that the last three syndromes are model ‘imprinting’ disorders – they result from changes in genes that work selectively
depending on which parent provided them. Typically, of course, we inherit two complete sets of chromosomes, one from our mother and one from our father, and most genes are an expression of both of
these sets. Imprinted genes, however, are expressed from only one of the pair of genes, the mother’s or the father’s, and as we saw earlier, many imprinted genes are critical in normal
growth and development – hence the problems here with overgrowth and mental retardation.

Around half of all children diagnosed with Beckwith-Wiedemann syndrome have lost the key to a gene inherited from their mothers, and this change has been detected in almost one hundred percent
of children with the syndrome who were conceived after any brand of ART. Experiments with laboratory animals indicate that imprinting disorders that occur as a result of IVF may be triggered by a
few specific techniques – and so the risk might vary from clinic to clinic.

Remember that genetic imprinting was only discovered in 1984 – and the first child was born using IVF in 1978. For that reason alone, imprinting defects in IVF babies could not have been
predicted from the start. Since then, reams of research have been compiled to compare the genetics of naturally- and laboratory-conceived children. But why should children born
through ART be more susceptible to imprinting disorders? What is it about manipulating egg and sperm that leaves genes unable to ‘tell’ which parent they hail from, and
whether and how they are supposed to go to work on developing the foetus?

Thus far, geneticists have learned that these imprints are erased in the cells that are specifically programmed to become eggs or sperm – a tantalizing piece towards
solving the puzzle. While eggs and sperm are being made, the imprint is reset accordingly – in sperm, a certain subset of genes will be rendered non-functional; in eggs, a different set.
It’s a reversible process that depends on the parent of origin, and determines the different functions of the eggs and sperm as they are developing. This means that the very process of making
eggs and sperm is critical for the ‘right’ genetic imprinting, and ART procedures affect these developmental periods when genomic imprints are so vulnerable.

Genes are imprinted much earlier during the production of sperm than they are for eggs. For this reason, if you were to induce an egg to mature artificially, as happens in induced ovulation, you
might disturb the genetic imprints that should be taking place in the egg, but are unlikely to affect the sperm. In fact, for growing eggs, the genetic imprints are not completed for some genes
until just prior to ovulation. If this vital process is vulnerable to the hormones used, then it’s not surprising that in these developmental syndromes, the fault always lies with the egg.
But even after fertilization has occurred, there is another critical period for getting the embryo’s genetic imprints right. In ART, it happens that embryos are usually still in vitro during
this second, vital window, making them vulnerable once again.

Further, infertility is often linked to genetics, and these genetic problems may be inherited by a child produced through ART. This raises the provocative question of
whether generations of babies created with IVF or ICSI might ‘naturally’ pass along genetic defects that will lead to a significantly more infertile population. In December 2006, Louise
Joy Brown, our first test-tube baby, gave birth to a healthy son; seven years earlier, Louise’s little sister Natalie, who herself was the fortieth child born by IVF, became the first child
of ART to have a baby of her own. Neither of the Brown sisters had required fertility treatment. Of course, Lesley and John Brown had turned to IVF because of a blockage in Lesley’s Fallopian
tubes, a condition that can often be corrected with surgery. If it had been John whose fertility had been the main issue, and if Louise and Natalie had been a Louis and a Nathan instead, then the
next generation might have been more complicated to conceive.

This is especially true for patients of ICSI, which is used when sperm is abnormal. Although ICSI takes longer and is more invasive than artificial insemination using donor sperm, couples trying
to conceive still tend to prefer using their own abnormal sperm; a child who is genetically ‘their own’ outweighs all other considerations. Chromosome anomalies are seen in about seven
percent of men who fail to produce sufficient sperm – and among this seven percent, more than ninety-nine percent of whatever sperm they do make will exhibit abnormalities.

There are concerns about the effect of using abnormal sperm for ICSI, because abnormal sperm are associated with increased chromosome defects in the babies produced. The chance of having a baby
with major malformations through ICSI is twice as high as in the general population – nine percent, versus three to four percent. This may be because abnormal sperm also tend to carry the
wrong number of chromosomes. In men with very
low sperm counts, seventy percent or more of their sperm will carry too many or too few chromosomes. Moreover, the most commonly
recognized genetic cause of infertility in men is the appearance of Y chromosomes with corrupt or missing genes. The genes on the Y chromosome are essential for sperm production – this is,
after all, the chromosome that makes males male. But these missing genes could hint that there are abnormalities on other chromosomes too. Indeed, there is evidence that ICSI children have an
increased number of abnormalities, mostly inherited from the father’s side, and that ICSI sons are more likely to be affected than daughters.

The missing genetic material could make many of these sons infertile. Already, adult men whose mothers received fertility treatment are reported to have lower sperm concentration and count, more
abnormal spermatozoa, smaller testes, and lower testosterone levels. Boys conceived by ICSI sometimes have reduced levels of testosterone. And ART has been associated with hypospadias and another
condition, cryptorchidism, where one or both testicles fail to move down into the scrotum before birth. Most of these cases do resolve on their own, but sometimes surgery is required.
Unfortunately, as incidents of hypospadias and cryptorchidism increase, poor semen quality and the rate of testicular cancer rise too. So boys diagnosed with hypospadias or cryptorchidism will need
to be monitored for testicular cancer throughout life. IVF and ICSI also increase the chance of pre-term birth, low birth weight, and multiple births. And in premature boys, an undescended testicle
is more common.