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.
Studies also suggest that Y chromosomes with DNA deleted in particular regions may cause babies to be born with two X chromosomes in some cells of their bodies, but with only one X chromosome in others. While this only impacts the
sex chromosomes – the X and the Y – and does not, it should be said, create the situation seen in baby FD or in Jane from Boston, it does result in baby girls who have sexual ambiguities or Turner’s syndrome, which creates females without female sexual characteristics. People with Turner’s syndrome are noted for their short stature, and for a likelihood of other health problems, including difficulties with hearing, sight, thyroid and kidney function, high blood pressure, diabetes, and learning. Their ovaries also don’t work – so these children are nearly always, like their fathers before them, infertile. (They may also, like post-menopausal women, suffer from osteoporosis because of their failed ovaries.)
The bottom line is that, when making babies through ICSI, you are often working with screwed-up sperm. The more screwed up the sperm are, the more abnormalities you will see in them, and the more likely they are to carry damaged DNA. And because the Y chromosome is only ever passed from father to son, if a man is infertile because parts of his Y chromosome are missing, his ICSI son, by definition, will inherit that corrupted Y chromosome and his infertility too.
On the other hand, IVF and other forms of ART also now make it possible to diagnose genetic abnormalities very early – by the time the embryo is three days old – something that is not possible in natural pregnancies. As our techniques improve, screening an embryo to identify an abnormality before it is implanted in the mother’s womb could be utilized to reduce further and further the chances of the diseases that are made more likely by ART.
Today, there are two ways of approaching the process of screening. One, called pre-implantation genetic diagnosis, or PGD, looks for specific genetic disorders that a couple is known to be carrying, and which therefore they have a high risk of transmitting to their children. PGD takes three to four days, and is primarily used by fertile couples who are worried about a particular disease that runs in the family. The second is a less targeted technique, known as pre-implantation genetic screening, or PGS, which has a turnaround time of twenty-four hours. PGS looks for mistakes across all of an embryo’s chromosomes, using tests that can detect any abnormalities in an embryo’s chromosomes – for instance, if it gained extra chromosomes, or lost some of them. This technology is still new and evolving, but it is likely to improve in the next few years. As it does, the genetic weaknesses involved when IVF or ICSI is necessary will almost certainly become less of a problem. With better PGS, fertility doctors will gain the ability to pick the most normal embryos.
Of course, while genetic problems may be soon within the reach of science to resolve, IVF and ICSI also give birth to complex moral conundrums that would never arise in a world where every pregnancy happens through sex. When fertilization occurs outside of the womb, and the embryo is then placed there, a woman becomes able to carry a child to term who is not genetically her own. For a woman who does not have good quality eggs, this is a great advantage, because she can choose to use an egg donated from another woman.
The technology has also become a very efficient way for older women to have successful pregnancies – by freezing a number of eggs or early-stage embryos from which they can select, and then trying each one out. Some women choose to freeze their eggs at a young age, and use these healthier eggs later in life, when they are ready to have children. But mistakes do happen.
In 2009, Caroline Savage, a forty-year-old American mother of three, returned to the fertility clinic where she had previously received IVF – and got pregnant. The clinic had kept frozen five of her early-stage embryos, left over from her last cycle of treatments. Unfortunately, there was a mix-up, and the embryo implanted into her womb was not one of her own; it belonged to a completely different couple, who also had ‘leftover’ embryos stored at the clinic.
Ten days after the procedure, Savage received a call from her doctor, notifying her of the error – news she later described as the worst of her life. The clinic’s directors offered her a choice: an abortion (free of charge, one presumes) or a surrogate pregnancy (after which she would give the child to its rightful genetic parents). Savage opted for the latter, on religious grounds, and because she realized that if one of her embryos had been mistakenly inserted into another woman’s body, she would go to the ends of the earth to get back her child. And if that hypothetical surrogate had chosen the abortion, she would have been helpless to stop it. In the state of Ohio, where Savage lived, surrogacy agreements are open to interpretation, though genetic parents are considered natural and legal parents of a child that another woman has carried. This was no surrogacy case, however; there was no intention, let alone an agreement, to have someone else’s baby end up in Savage’s womb. Yet, in this case, Ohio law recognizes the woman whose womb the foetus is in to be the mother of the child, rather than the woman who is genetically related to it. As mere donors of genetic material used to create that embryo, the other couple have no parental rights or responsibilities with respect to the child being carried to term.
Wracked with this knowledge, Savage and her husband asked a lawyer to reach out to the genetic parents, and three months later the couples met. The pregnancy was a difficult one for Savage, and she was scheduled for a Caesarean section. She cannot now risk another pregnancy herself, but still wants to grant a chance of life to her remaining embryos. To do so, she will have to hire another woman to carry the embryos to term. Savage would never have given birth to someone else’s genetic child in a world without IVF, but nor would another woman have been able to give birth to hers.
Infertility is a complex problem with many causes, and its solutions present just as many ethical conundrums. A century ago, European doctors tried to allay the public’s fears by claiming that there was nothing truly ‘artificial’ about this new method of insemination. After all, the babies produced would be very real, the equal of any who had been naturally conceived. The field of reproductive medicine was simply a way of assisting nature.
Today, around one out of every fifty babies born in the UK, and one in a hundred babies in the US, starts life in a lab. What is more, starting life in vitro is no longer seen to be unnatural. In Europe, around one in four young men now have a sperm count that would render them subfertile or infertile; they will likely need to use ICSI if and when they decide to reproduce. An estimated sixty thousand women in Britain seek IVF every year. By the current medical definition of infertility – the failure to achieve a pregnancy within one year of regular, unprotected intercourse – some nine million people in the UK fall into this category.
There are many women with abnormally shaped wombs, unhealthy eggs, or no eggs; many men whose sperm are just not up to scratch; and men and women who have had, for example, treatments for cancer that have killed off their reproductive material before they have had a chance to become a parent. Some couples can’t have children because one of them is infertile, but if a couple cannot have a child because they are two men or two women, then technically, they are infertile too.
Bringing egg and sperm together cannot, by itself, resolve all of the issues that people may face when they want to have a child but cannot. So it makes sense that, one day, possibly soon, we will expand our means of reproduction to be far broader than our current repertoire. To get a glimpse at the future of reproduction, simply think about the problems that ART has not yet resolved. Who are the Lesley and John Brown of the next phase of human history?
Thirty years after the first test-tube baby, science is poised to add many new weapons to its armoury in the battle against infertility, including using your own stem cells to generate fresh sperm or eggs or both, when you don’t have any or have run out. There may perhaps be gene therapy to prevent miscarriages from corrupt chromosomes. There is even a body of research to prepare us for reproduction in space, where sperm seem to move faster (a fertility plus) but some hormones may not be activated (a developmental negative).
Since humans first evolved, men and women have needed each other to make babies. But the nature of human reproduction is about to change radically. Child
ren born this year will be able to make babies in ways their parents could barely dream of – when, that is, they decide to have children, at a time entirely of their own choosing.
7
OUT OF TIME
There will be nothing but time, don’t you understand?... If I can have a child at seventy-three, then why should you have one at forty-three, or forty-five?
Ann Patchett, State of Wonder, 2011
The Mosuo people live high in the Himalayas, in the Yunnan and Sichuan provinces, near the Tibetan border, in China. They live a primarily agrarian life, raising yak, water buffalo, sheep, and poultry. They are also one of the few peoples whose language appears to have no word for ‘father’ – perhaps the most exotic facet of their way of life, to an outsider.
The Mosuo are a matrilineal culture: it is the women who determine the family line and inherit the family property. Such practices have existed in Tibetan and northern Indian societies from Neolithic times, presumably motivated by a desire to keep wealth and resources within the kin group. These customs started to decline – or at least, to be hidden – after missionaries and colonists began to malign them in the nineteenth century. Among the Mosuo, however, maintaining a matrilineal culture grew into something of a necessity as more and more Mosuo men started to leave their villages to become monks or trade along the Silk Road.
With their men absent or unavailable, the Mosuo women took over the day-to-day administration of the community. They chose not to marry, opting instead to look after their own households, some populated with four generations of Mosuo women. At puberty, a girl would be given a private bedroom, in an otherwise open-plan home, and like a society debutante she would attend dances, looking for a suitable partner for courting. If a young man caught her fancy, the girl would be free to choose him as her lover – and not just as a lover, but as a father to one or more of her children. But their relationship was temporary; the man might be allowed to stay the night, but in the morning he would go back to his own dwelling, to live with his own mother’s line. There was no requirement – no expectation – that the father would stick around.
Like a Virgin Page 15