IVF News

Following a two-year public consultation, the Human Fertilisation and Embryology Authority (HFEA) and the Human Genetics Commission have announced that there is wide support for embryo screening - otherwise known as preimplantation genetic diagnosis (PGD) - for couples where there is a family history of serious genetic disorders. The two organisations said the consultation showed that 70 per cent of respondents were in favour of the procedure, whilst only twenty per cent of respondents said that the licensing procedures should further limit the technique because it involved discarding human life. Some said that PGD procedures were eugenic.

Medical, consumer, religious and charity groups were involved in the consultation. Overwhelmingly, it was agreed that PGD should not be made available for the creation of so-called 'designer babies', and 81 per cent of the respondents believed that the technique should be limited to cases where there is a known family history of a serious genetic disorder.

As a result of the findings of the consultation, the joint working party of the two organisations recommended that PGD should only be available if there is 'serious risk of a serious genetic condition being present in the embryo'. It also said that human leukocyte antigen testing - where an embryo is selected on the basis that the resulting child can provide tissue for transplant to a family member - cannot be recommended 'without further discussion'.

The report also issues guidance upon which any decisions to provide PGD to a couple should be based. These include the likely degree of suffering that any resulting child might suffer, the availability of effective treatment now or in the future, the speed of degeneration in progressive diseases and the extent to which an affected individual would be intellectually impaired.
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Scientists at the Reproductive Genetics Institute in Chicago, US, say that they have developed a technique that could be used to allow two women to have a child together, without the need for sperm.

The technique involves manipulating cells taken from a woman and turning them into 'artificial sperm' which could then be used to fertilise another woman's egg, allowing two women to be the genetic parents of a child. The technique was developed to help men with no sperm have children.

The Chicago scientists say that they are already trialling the technique on human eggs, and it may be available within two years. Many other scientists, however, believe that the technique is dangerous. It involves a process known as 'haploidisation', where chromosomes within a cell are forced to separate in half. It is believed that this might cause illnesses that would not be apparent until the child was older. Professor Bill Ledger, from Sheffield University in the UK, said 'this technology has a high risk of creating damaged people and therefore I don't think it should be allowed to go ahead'.

But Mohammed Taranissi, a UK fertility specialist who has been working with the Chicago team, believes that the technique shows promise. He said 'it's being done in human eggs as we speak and the first results are going to be presented at a conference in April'.
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News this week that the Human Fertilisation and Embryology Authority (HFEA) has turned down an application for preimplantation genetic diagnosis (PGD) and tissue typing has bemused many people. Why has the HFEA denied the Whitakers access to the procedure when it was happy to let the Hashmi family go ahead under similar circumstances? The answer, it seems, lies in the reason for which the request was made. The Hashmis wanted PGD to avoid a genetic condition in their next child, as well as to ensure that it would be a compatible donor. The Whitakers want PGD solely to get a compatible donor.

The HFEA says that its decision was informed by the Human Fertilisation and Embryology (HFE) Act and the results of a consultation on PGD which it launched in November 1999. But these documents are by no means clear on the issue. The Act says that the HFEA can license procedures which determine whether embryos are 'in a suitable condition to be placed in a woman' - what 'suitable' means is open to interpretation. The result of the consultation on PGD, based upon 171 responses, is also unclear on this issue: the consultation paper makes no mention of PGD and tissue typing at all.

The HFEA was also concerned about the 'welfare of the child' provision in the Act. It is clearly in a child's best interests to be born healthy, but does that extend to being a tissue donor? It's worth remembering that in the Act, the welfare of the child not only requires consideration of the child born of treatment, but also of 'any other child who may be affected by the birth'. Furthermore, if PGD and tissue typing does not compromise the welfare of the Hashmi's next child, it's hard to see how it would have a deleterious effect upon the Whitaker's next child. Unfortunately, it isn't hard to see how denying access to PGD and tissue typing will have a deleterious effect upon Charlie Whitaker.
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The UK's Human Fertilisation and Embryology Authority (HFEA) will launch a consultation paper on sex selection this week. A leak has suggested that the document will ask whether choosing the sex of a baby for 'family balancing' or other purely social reasons should be allowed.

The HFEA has not denied that the paper will look at this possibility. At present, sex selection can be done during preimplantation genetic diagnosis (PGD), but is only allowed for medical reasons, such as the avoidance of a sex-linked genetic disease. But it has been reported that six British couples have travelled to America to take advantage of the pre-conception sex selection techniques offered by the Genetics and IVF Institute in Virginia.

The American clinic uses a technique known as sperm sorting in order to allow couples to try for a child of the sex they desire. This works on the premise that the chromosome that determines a baby's gender comes from sperm, and whether the sperm carries an X (female) or Y (male) chromosome affects the amount of DNA carried. On this basis, 'male' and 'female' sperm can be separated. It would not be illegal for such a clinic to operate in the UK, but none do. Nine years ago, following reports of a clinic offering gender choice in London, the HFEA conducted its first public consultation, which found that there was little public support for the practice.

These days, there may be a little more support, if the treatments were seen to be safe and the circumstances in which they could be allowed to take place were carefully controlled. Dr Simon Fischel, director of Centres for Assisted Reproduction, said that he could see no objections to sex selection for a legitimate reason such as family balancing, provided that no one sex was being 'devalued', for example, by parents being allowed to choose to have all children of one sex.
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Abstract

The SCSA® test assesses DNA fragmentation using established methods that
are supported by 25 years of research published in peer reviewed journals. These
and ongoing studies indicate that sperm with elevated DNA fragmentation, as
measured by the SCSA® test, have a lower probability of supporting a successful
pregnancy.

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The severity of male factors should be assessed prior to determining the appropriate
treatment of couples presenting with infertility. The most common screening
for male factors in the infertility evaluation is conventional semen analysis,
which measures basic parameters including sperm concentration, motility and
morphology. Severe and irreversible male factors are often treated successfully
with intracytoplasmic sperm injection (ICSI) by injecting individual sperm into
the egg cytoplasm.

ICSI bypasses all requirements of normal sperm motility and sperm/oocyte oolemma
interaction. The only requirement for fertilization and early embryonic development
is oocyte activation and adequate DNA integrity. Thus, a test of DNA integrity
is very helpful in deciding which couple would most likely benefit from ICSI
and which might be advised to consider other options such as donor insemination
due to decreased odds for pregnancy with the male partner's sperm. Table I lists
conditions when DNA fragmentation testing could potentially benefit a couple.

The Sperm Chromatin Structure Assay (SCSA®) test measures the percent
of sperm in a semen sample that has fragmented DNA as well as the extent of
DNA fragmentation. In the SCSA® test, sperm with very low levels of fragmentation
fluoresce green, while sperm with moderate to high levels of fragmentation fluoresce
red. The flow cytometer measures the ratio of red to green fluorescence in each
of 5000 sperm. The percent of sperm with DNA fragmentation (red fluorescence)
is expressed as the DNA Fragmentation Index (DFI; Evenson et al 2002).

The SCSA® test is a rapid, consistent, statistically robust test providing
evidence for the relationship between sperm nuclear DNA fragmentation and function
(Evenson et al 1991). DFI statistically derived thresholds of 0-15%, 16-29%,
and >30% correlate with high, moderate, and low in vivo fertility potential,
respectively (Evenson et al 1999). Specifically, if the DFI is >30%, there
is a significantly greater risk for infertility (Evenson et al 1999, Evenson
et al 2002, Spano et al 2002).

A preliminary study of in vitro fertility found a similar DFI threshold (>27%)
to be predictive of a negative pregnancy outcome following ART (conventional
in vitro fertilization and ICSI; Larson et al 2000). Larger subsequent studies
including hundreds of infertile couples have validated that a man with >30%
DFI has a significantly greater risk for infertility even with ART. Although
this risk is influenced by a myriad of potential sources (maternal age, clinical
techniques, etc.), exceeding this DFI threshold appears to decrease pregnancy
rates by 50% upwards to 100% in some studies (Larson et al 2002a, Selah et al
2002, Virro et al, submitted).

SCSA® test parameters are weakly correlated with conventional examinations
of sperm concentration, motility, and morphology (Evenson et al 1991, 1999).
Semen samples with normal conventional parameters may have very poor DNA quality
that contributes to infertility. Therefore, the SCSA® test offers additional
clinical information not provided by conventional semen analysis alone.

Twelve couples with multiple failed ART cycles and no known male factors progressed
to therapeutic donor insemination following discussion of their abnormal SCSA®
test results (>30%). Nine of these couples conceived within 3 cycles of donor
insemination after years of infertility (Virro et al, submitted). Insight into
DNA integrity provided by the SCSA® test appears to offer an explanation
for these previous failures.

Age (Evenson et al 2002a, Spano et al, 1998), long periods of abstinence (Spano
et al, 1998), high fever (Evenson et al, 2000), and leukocytospermia (Alvarez
et al, 2002) appear to be related to a significant increase in sperm DNA fragmentation.
Data also show that exposure to environmental stresses, some prescription drugs
(Evenson et al, 1999), pollutants (Selevan et al, 2000) or cigarette smoking
(Spano et al, 1998; Potts et al, 1999) may have a detrimental effect on sperm
DNA.

DNA fragmentation by the SCSA® test reflects the quality of sperm that
have just undergone maturation in the male reproductive tract. While an excellent-quality
sample is likely reflective of previous and future quality, poor DNA quality
may be transient due to high fever, medications, physical or mental stress,
or other unidentified conditions. Therefore, if SCSA® test results are poor,
it is necessary to question the patient as to whether he has been exposed to
conditions that may negatively affect sperm quality, correct these conditions
if possible, and repeat the SCSA® test in 2 to 3 months.

The SCSA® test is a rapid, sensitive, unbiased, quantitative assessment
of sperm DNA fragmentation that independently predicts natural and in vitro
infertility. This prognostic information provides a significant medical, emotional,
and financial benefit to couples considering ART, donor sperm or adoption.

Table I. Conditions Indicating SCSA® Testing

• Unexplained Infertility


• Persistent Infertility after Treatment of Female


• Recurrent Miscarriage


• Prior to Assisted Reproductive Technologies


• Cancer in Male: Before and after Treatment


• Abnormal Semen Analysis


• Advancing Male Age (> 50 years)

References

Alvarez, JG, Sharma RK, Ollero M, Saleh RA, Lopez MC, Thomas AJ, Evenson
DP, Agarwal AA. (2002) Increased DNA damage in sperm from leukocytospermic
semen samples as determined by the sperm chromatin structure assay. Fertility
and Sterility 78;319-329.

Evenson DP, Larson KL, Jost LK. (2002) The sperm chromatin
structure assay (SCSA®): clinical use for detecting sperm DNA fragmentation
related to male infertility and comparisons with other techniques. Andrology
Lab Corner. Journal of Andrology 23;25-43.

Evenson D, Larson K, Jost L, Virro M, DeJonge C, Brannian J. (2002a)
Relationship between age of man, sperm DNA fragmentation and infertility. April
2002, Seattle Washington. American Society of Andrology.

Evenson DP, Jost LK, Corzett M, Balhorn R. (2000) Effect of
elevated body temperature on human sperm chromatin structure. Journal of
Andrology 21;739-46.

Evenson DP, Jost LK, Marshall D, Zinaman MJ, Clegg E, Purvis K, De
Angelis P, Claussen, OP. (1999) Utility of the sperm chromatin structure
assay as a diagnostic tool in the human fertility clinic. Human Reproduction
14;1039-49.

Evenson, DP, Jost LK, Baer RK, Turner T, Schrader S. (1991)
Individuality of DNA denaturation patterns in human sperm as measured by the
sperm chromatin structure assay. Reproductive Toxicology 5;115-125.

Larson-Cook K, Brannian J, Hansen K, Jost L, Evenson D. (2002a)
Relationship between assisted reproductive techniques (ART) outcomes and DNA
fragmentation (DFI) as measured by the Sperm Chromatin Structure Assay (SCSA).
American Society for Reproductive Medicine. Seattle Oct 12-17. #100777.

Larson KL, DeJonge CJ, Barnes AM, Jost LK, Evenson DP. (2000)
Relationship of assisted reproductive technique (ART) outcomes with sperm chromatin
integrity and maturity as measures by the sperm chromatin structure assay (SCSA).
Human Reproduction 15;1717-1722.

Potts RJ, Newbury CJ, Smith G, Notarianni LJ, Jefferies TM. (1999)
Sperm chromatin changes associated with male smoking. Mutation Research
423;103-11.

Saleh RA, Agarwal A, Nelson DR, Nada EA, El-Tonsy MH, Alvarez JG, Thomas
AJ Jr, Sharma RK. (2002) Increased sperm nuclear DNA damage in normozoospermic
infertile men: a prospective study. Fertility and Sterility 78(2):313-8.

Selevan SG, Borkovec L, Slott VL, Zudova Z, Rubes J, Evenson DP, Perreault
SD. (2000) Semen quality and reproductive health of young Czech men
exposed to seasonal air pollution. Environmental Health Perspectives 108;887-94.

Spano M, Bonde JP, Hjollund HI, Kolstad HA, Cordelli E, Leter G. (2002)
Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner
Study Team. Fertility and Sterility 73;43-50.

Spano M, Kolstad AH, Larson SB, Cordelli E, Leter G, Giwercman A, Bonde
JP. (1998) The applicability of the flow cytometric sperm chromatin
structure assay in epidemiological studies. Human Reproduction 1998;2495-505.

Virro MR, Evenson DP. (submitted) Sperm Chromatin Structure
Assay (SCSA®) related to blastocyst rate, pregnancy rate and spontaneous
abortion in IVF and ICSI cycles. Fertility and Sterility.

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In case you hadn't already noticed, a public consultation has been taking place in the UK over the past few months. Your views are being sought as to whether couples should be able to choose the sex of their prospective children.

When a woman is expecting a baby, someone is sure to ask her whether she wants a boy or a girl. Some people genuinely don't mind which sex their baby is, whilst others have a clear preference. That preference might be motivated by vague notions of what boys and girls are like; it might be borne of a desire to balance up a family dominated by one sex; or it might be caused by real social and economic pressures. It's clear that some people really do care what sex their child is going to be. But is it right to act on that preference?

The organisation carrying out the public consultation, the Human Fertilisation and Embryology Authority (HFEA), decided to launch an enquiry into social sex selection after news from the United States that American couples are now able to determine the sex of their baby before conception, by using a technique that sorts sperm according to the sex determining chromosome they carry. The technique isn't currently available in the United Kingdom. But if and when it is, how should we react?

Is it always wrong to choose the sex of one's child for reasons other than avoiding a serious genetic condition? What happens if a couple has two or more children of the same sex: should they be given special permission to sex select? And what about the effect of sex selection upon society; would it skew the sex ratios or lead to discrimination? Or might it offer a harmless option to those couples who feel strongly enough to act? To take part in the consultation, go to http://www.hfea.gov.uk/forPatients/Consultations/ where you can complete the online questionnaire or download the full consultation document.

If you miss the deadline to respond to the HFEA public consultation, you could come along to Progress Educational Trust's conference next week in London to take part in a public discussion on sex selection. We have a wide range of speakers and delegates, and it promises to be an interesting and lively discussion. You can visit http://www.progress.org.uk/events for the full programme. Please email Laura Riley at [email protected] if you would like to attend. Delegates can pay on the door as long as they register in advance.
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This week's BioNews reports on the recent High Court ruling that the biological father in the case of the IVF embryo mix-up is also the legal father. This might sound like common sense until the facts of the case are made clear.

Mr and Mrs A have two children, twin babies, who were conceived after Mrs A's eggs were mistakenly mixed with the sperm of another man, Mr B. Mr B has never met the twins in question; he has no desire to be their father, to have custody of them or parental responsibility for them. Mr A, meanwhile, has been father to the twins since their birth; he wants to carry on being their father, to have custody of them and parental responsibility for them. He is also, as the court confirmed, the person whom the twins regard as their father. Yet, according to the High Court, he is not their legal father.

Why was this judgement made? Reading the court judgement, it is difficult to get inside the head of Dame Elizabeth Butler-Sloss, the judge presiding over the case. But on the legal points, Mr A was unable to establish himself as the legal father of the twins under the Human Fertilisation and Embryology Act because he did not consent to the use of another man's sperm in his wife's treatment. According to the court, because Mr A could not be regarded as the legal father, Mr B should be regarded as such, even though, as Dame Elizabeth Butler-Sloss said, it is 'only the use of his sperm that connects him with the twins'.

Does it matter that Mr B is the legal father? Since Mr B does not seek any kind of fatherly role in the twins' lives, what are the real implications of the court's finding him to be their legal father? The main practical effect of the judgement is that Mr and Mrs A will have to adopt their own children. This is, at the very least, a peculiar situation for parents to find themselves in. Apart from this serious issue, the judgement will have few practical implications. But its declaratory impact should not be underestimated. If someone is a legal father, that sounds important. And in this case, where legal paternity is placed next to biological paternity, the genetic connection seems to be regarded as more important than the social one. Indeed, Dame Elizabeth stated that one advantage of her judgement is that the twins 'retain the great advantage of preserving the reality of their paternal identity'.

But what is the reality of their paternal identity? The twins' biological father is Mr B - this much is indisputable. But declaring him to be the legal father too begins to make him look like the 'real father'. But Mr A intended to be their father. He was there at conception (even though he wasn't responsible for it), during the pregnancy, at the birth and, more importantly, he has been their father every day since their birth and intends to be their father until the day he dies. Shouldn't that be regarded as the 'reality of their paternal identity'?
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Over the weekend, a misleading and inflammatory story appeared in the Sunday Times newspaper concerning the number of selective terminations performed in the UK. Entitled 'IVF mothers abort 'spare' babies', the article told us that 'women who find they are expecting twins or triplets after receiving treatment for infertility are choosing to have one or more babies aborted'. Further, the article told us that babies are destroyed 'usually to spare the mothers the additional burden of raising them'. The article gave the impression that hundreds of women are destroying their unwanted multiple babies on a whim to suit their lifestyles. But the reality of selective terminations is rather different.

Selective terminations are offered to women who are carrying twins, triplets or quads; most, though not all, of which are the result of fertility treatment. Those who decide to reduce the number of fetuses that they are carrying do not do so for their own convenience, but because of the health risks to their prospective children. Babies in multiple pregnancies are more likely to be born early, thereby increasing the chance of low birth weights and increasing the chance of disability. Although the selective termination itself is not without risk to the whole pregnancy, some couples feel that such a risk is worth taking in order to promote the health of the remaining fetuses.

What provoked the publication of this story? Are selective terminations on the rise or more frequently offered to women with multiple pregnancies? It seems that the story was written after new statistics on the number of abortions performed in England and Wales were released by the Office of National Statistics. The statistics show that the total number of abortions performed in 2001 was 187,402. Of these, 40 were selective terminations, 20 of which were carried out because of fetal abnormality. This very small number of selective terminations has hovered around 40 for the past decade and, if anything, is likely to fall from now on, as the number of multiple conceptions starts to come down.

Contrary to the impression given by the Sunday Times article, selective terminations are not common, nor are they on the increase. They are performed in rare circumstances in which, for an individual couple, reducing the number of fetuses in a pregnancy, as undesirable as it might seem, is the best way to protect the health and wellbeing of their future children.
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This week's BioNews reports on the latest news about the Hashmi family, who were recently given leave to continue with an embryo screening which might provide life-saving treatment for their son, Zain. A Court of Appeal ruling in April gave them the go-ahead, but details of the three judges' decision has only just been made public. The overriding message from the appeal court was: there will be no 'free-for-all'. But what exactly do they mean by this?

The legal case turned on the matter of whether the Human Fertilisation and Embryology Authority (HFEA) had the powers to grant a license for the procedure to take place in the first place. Although embryo screening (or preimplantation genetic diagnosis, PGD) for serious genetic conditions has been available to UK couples for some years, the Hashmi's request for treatment went one step further. They want not only to make sure that their next child is free from the inherited condition which affects their son, but also to ensure that that child would be a matched tissue donor for him. The HFEA considered this to be a reasonable request and, ultimately, the Court of Appeal agreed. So why all the talk of preventing a free-for-all?

The judges were keen to stress that Parliament did not intend for the HFEA to license PGD for any reason. And so, according to Lord Justice Schiemann, `If the decision of the Authority is upheld in the present case it does not mean that parents have a right to in vitro fertilisation for social selection purposes'. What the court did not want to sanction was the use of PGD for non-medical reasons such as sex selection, although this is not something the HFEA [has shown any desire to] necessarily wants to license.

However, the ruling must surely mean that couples in the same position as the Hashmis, who want PGD for their prospective child as well as to help an existing child, will also be given permission to go ahead with treatment. The HFEA might treat applications on a case by case basis, but it nonetheless has to be consistent and fair. This is good news for other couples who want to maximise the health and well-being of their current and future children.
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This week, the British media has gone crazy about a newborn baby. His name is James Whitaker and he was conceived in order to provide stem cells for his older brother, Charlie. In the reams of commentary which followed James' arrival into the world, two main ethical issues emerged. The first question is whether it is wrong to create a child in the hope that it will be of some use to another child. The second issue, which follows from the first, is whether it is psychologically harmful to a child to know that it has been born for this purpose.

These questions raise what seem like new dilemmas brought on by the new age of genetics. But, in reality, they are rather old quandaries which many parents have faced before. Couples with a sick child whose health depends upon a matched tissue donation have been known to have another child in the hope that they will be a suitable donor. Whilst this might not be considered the most noble reason for having a child, it is usually regarded as a private family decision. And indeed it was in the case of the Whitakers, whose second child, Emily, was conceived naturally, but who sadly turned out not to be a compatible donor for Charlie. To answer the second question, whether psychological harm will be done to the so-called saviour child, one need only look at Emily, who shows no signs of being neglected or psychologically scarred in any way, despite the fact that her stem cells could not be used to treat her older brother.

If parents have been left to make such judgements privately up until now, why were the Whitakers forced to have their wishes scrutinised by the nation? Because the technique they sought to use is one normally carried in order to avoid the birth of a child with an inherited disease. In the case of the Whitakers, the government regulator, the HFEA, did not consider the reason for having embryo screening to be sufficiently immediate to warrant its use. As chairman, Suzy Leather, told a number of newspapers, 'No one can say for certain what the long-term risks of embryo biopsy are. If there are benefits for the child to be created from the biopsied embryo... the balance of potential harm and potential good falls in a different place than if you're simply biopsying an embryo for the benefit of another person.'

This sounds reasonable enough. But it is important that we do not get safety and morals mixed up in a case like this. If people have difficulty accepting what the Whitakers did, they have to find a way of explaining why they think that. Perhaps people who object to this case really are concerned about the slim chance that the procedure will have damaged James Whitaker in some way. But sometimes safety concerns can be an easy route out of a moral maze. Mere mention of a 'precautionary approach' is often enough to trump all other concerns.

The fact that James did not himself benefit from the embryo screening procedure does make the issue slightly different, but only in the sense that it might have made it a more difficult decision for his parents. Decisions that parents make in relation to their children are often about weighing up risks and benefits and making a judgement which seeks to maximise their health and well-being. The difference with Jayson and Michelle Whitaker is that, because of their unfortunate situation, the stakes were higher.
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