ICSI: Is it really safe?

July 01, 2002

Vienna, Austria: The absolute risk of having a baby with a serious congenital malformation or chromosomal abnormality as a result of using ICSI* is small, Dr Ulla-Britt Wennerholm told a news briefing today (Monday 1 July) at the annual conference of the European Society of Human Reproduction and Embryology in Vienna.

"Intracytoplasmic sperm injection (ICSI) has made conception possible for many couples with male factor infertility and a previously bad prognosis, but, as for all other reproductive technologies ICSI must be safe as well as effective," she said.

Concern at findings this year in an Australian study of ICSI prompted ESHRE to examine the totality of the evidence. Dr Wennerholm and her colleague Professor Christina Bergh, both from the Department of Obstetrics and Gynaecology at the Institute for Health of Women and Children in Sahlgrenska University Hospital in Göteborg, Sweden, carried out the review.

"From the beginning ICSI has been considered a more risky procedure than conventional IVF, but so far the majority of later studies found no increase in congenital malformations in children born after conventional IVF or ICSI," said Dr Wennerholm.

An alarmingly high prevalence of major birth defects after ICSI and IVF was found in the Australian register study** with the figure being twice as high for ICSI and IVF children as for normally conceived children - 8.6% of 301 infants conceived with ICSI and 9% of IVF children compared with 4.2% of normally conceived babies. "However, a major problem with this study was that it contained only a small number of ICSI and IVF children," said Dr Wennerholm.

At the same time, a recent Belgian*** study comparing children born after ICSI and IVF concluded that the major malformations between the two groups were comparable. The study lacked a naturally conceived control group but the rates were comparable to the naturally born children in the Australian study.

In Sweden,**** a large controlled register study found a slight but significant increase in malformations in IVF and ICSI babies compared with the general population, but after adjusting for parental characteristics and the excess of preterm and multiple births the excess was no longer statistically significant. However, more ICSI children had hypospadias - a malformation of the penis, which may have be related to paternal subfertility.

"Chromosomal aberrations have been most extensively studied by the Belgium group. Their study, together with some other small studies, indicates that in absolute numbers there is a small but statistically significant increase in sex chromosomal aneuploidies (loss or gain of one or more chromosomes) and new aberrations in somatic (non-germ cell) chromosomes, among ICSI children compared with normally conceived controls."

Dr Wennerholm concluded: "What is most important for parents to know is that the absolute risk for a serious congenital malformation or chromosomal aberration associated with IVF or ICSI is small. For many couples who otherwise could not achieve a pregnancy the slight increase in risk associated with these techniques will be acceptable."

* ICSI - intracycloplasmic sperm injection: process by which an egg is fertilised by the injection of a single sperm

** Hansen et al, NEJM 346, 725-730.

*** Bonduelle et al, Human Reproduction 17, 671-694.

**** Wennerholm et al, Human Reproduction 15, 944-948.

New research shows ICSI children have normal development by the time they start school

New Australian research being presented to the ESHRE conference provides reassurance that the mental development of ICSI children is on a par with other IVF children and children born without recourse to fertility techniques.

A team from the University of Sydney and the Royal North Shore Hospital in St Leonards, New South Wales, carried out IQ tests on 97 ICSI children, 80 IVF children and 110 controls at the age of five.

The team had been concerned about possible long-term effects of ICSI after an earlier study found that one year old ICSI children appeared to be at increased risk for delayed mental development.

Researchers therefore reassessed these children, along with other ICSI and control children enrolled to provide the study with sufficient power to confirm the difference in risk they had seen at one year.

They found that by five years there was no significant difference between the groups for full-scale IQ, with the ICSI children scoring 110 ± 18, IVF children scoring 111 ± 13 and the control group scoring 114 ± 13. Nor was there any significant difference on verbal IQ or performance IQ tests.

Lead investigator Professor Garth Leslie, from the Sydney University Department of Obstetrics and Gynaecology at Royal Shore Hospital, said that the only significant risk factor for below average full-scale IQ at five years among the study children was lower maternal education level.

"When we found ICSI children were at increased risk for delayed mental development at one year concerns were raised about possible long-term adverse effects of this procedure," he said. "Because the findings were biologically plausible we considered it important to reassess child development at five years when a more accurate measure of long-term cognitive ability can be obtained.

"Whilst we found ICSI was an independent predictor of delayed development at one year, this was no longer the case at five years when other demographic factors were more important. These results provide reassurance that the ICSI procedure does not produce children at increased risk for below normal long-term cognitive development."

Abstract no: O-009 (Monday 10.00hrs CET Hall D) URL: http://conf.eshre.com/PDF/O-009.pdf

Less chance of a boy with ICSI say French researchers

Couples who have a baby via ICSI seem to have less chance of having a boy, though the reasons are not yet clear, according to research being presented at ESHRE by a team from the French research institute INSERM and the FIVNAT centres*.

The team selected all the births in the French assisted reproductive technology register between 1995 and 1998, except those involving frozen semen. They compared the difference in sex ratio (number of boys divided by number of girls) for 5,782 IVF and 4,744 ICSI babies. Of the ICSI babies the vast majority of fertilisations were from normal ejaculated semen, but 204 babies were from semen taken directly from the epididymis and 130 from semen taken directly from the testes.

Overall, among IVF babies, 119 boys were born for every 100 girls, for ICSI with ejaculated semen 99 boys were born for every 100 girls, for ICSI with epididymal semen it was 73 boys for 100 girls and for testicular semen it was 91 boys for 100 girls - respective ratios of 1.19, 0.99, 0.73 and 0.91.

When divided into single and multiple births the respective ratios were:

single births: 1.10, 0.98, 0.83 and 0.71 multiple births: 1.14, 1.00, 0.65 and 0.90

The researchers also found that in the ejaculated semen group the sex ratio bore no relation to whether it was the man or the woman who had fertility problems.

Said lead investigator Dr Jacques de Mouzon: "There clearly seems to exist a decreased proportion of boys with ICSI, particularly if semen comes from the epididymis or testis. But, we still need to confirm these results as even with the large overall numbers of ICSI babies in the study the proportion conceived with surgically obtained semen remains low.

"However, if these result prove true, it remains to be demonstrated whether this decrease in boys comes totally from the father's characteristics or from the ICSI technique itself. And we have yet to elucidate any biological explanation, that is, whether it is due to higher early embryonic mortality among male foetuses or decreased fertility of the Y (male determining) sperm."

* Association FIVNAT was created in 1986 in France in order to evaluate IVF practice and results in France. It was one of the first and most significant epidemiological registers of IVF in the world and is a world reference for those working in reproductive medicine

Abstract no: O-011 (Monday 10.30hrs CET Hall D) URL: http://conf.eshre.com/PDF/O-011.pdf

Risk of faulty Y chromosome transmission with ICSI - consequences may be severe say researchers

Recent advances in male infertility treatment such as ICSI mean that men with very low sperm levels now have a chance to become fathers. It's known that the sperm of some of these men may contain small deletions in the Y (male) chromosome resulting in the male child itself being infertile.

Now, a research team led by Dr Philippos C. Patsalis from The Cyprus Institute of Neurology and Genetics in Nicosia has warned that infertility may not be the only consequence of passing on a Y chromosome with microdeletions.

In a study being presented at the ESHRE conference the researchers have linked these microdeletions to the risk of other serious conditions, including Turner's syndrome*, mixed gonadal dysgenesis**, male pseudohermaphroditism*** and, rarely, mental retardation or autism.

Recent data suggest that abnormalities in the sex chromosomes could arise when Y chromosome with a deleted AZFc gene is transmitted from one generation to another by ICSI. Dr Patsalis said that if this hypothesis was correct it raised the possibility that some patients in whom the X and Y (female and male) chromosomes were at odds with their outward physical make-up may in fact be harbouring Y chromosome microdeletions.

They tested the hypothesis by screening 12 patients with a particular karyotype (genetic make-up) - 45,X/46,XY. All the patients had sexual ambiguities because of a lack of Y chromosome-bearing cells in the sex organs or had non-germ cell anomalies characteristic of Turner's syndrome.

A third of the cases had a complete AZFc gene deletion. In two cases the DNA of the father was available for testing. The results revealed that the deletions were new or had been present at low levels in the father.

Said Dr Patsalis: "These results highlight a potential risk for children born to fathers carrying Y chromosome microdeletions and treated by ICSI. The risk is the development of sex chromosome aneuploidy (the loss or gain of one or two chromosomes) during foetal and embryonic development. The clinical consequences of transmitting these Y chromosome deletions can be severe."

* Turner's Syndrome: congenital disorder affecting about 1 in 3,000 females, who have one absent or abnormal X chromosome. Characteristics may include a lack of ovarian function, short stature, cardiovascular problems, and a range of physical abnormalities.

** Gonodal dysgenesis: genetically determined failure of the testes or ovaries to produce germ cells. The most common manifestation of the condition in women is Turner's Syndrome. In men it is Klinefelter's Syndrome, which occurs in about 1 in 1,000 men, who are born with an extra X chromosome. They tend to be tall, thin and have female physical characteristics. They have normal sexual function but are sterile.

*** Pseudohermaphrodites have a physical appearance that is at variance with their gonadal sex. Females have a normal 46XX chromosome but varying degrees of male bodily features while males have a normal 46XY chromosome but female bodily features.

Abstract no: 0-077 (Monday 15.45hrs CET Hall F2) URL: http://conf.eshre.com/PDF/O-077.pdf

ICSI safety - innovative US technique eliminates sperm with chromosome abnormalities

A groundbreaking invention by a team from Yale University should eliminate a major concern about ICSI safety - chromosome abnormalities in the children born by this technique.

Scientists from the university's School of Medicine will present to the ESHRE conference (Tuesday 2 July) the concept and first results of a method they have developed for selecting individual mature sperm with very low frequencies of chromosomal aberrations and a high degree of DNA integrity.

Previous research by the team showed a close correlation between the proportion of immature sperm (which are often used in ICSI) and the frequency of aneuploidy (i.e. sperm that possess more or less than the usual one copy of each chromosome). This correlation was linked to low levels of a sperm protein called HspA2.

HspA2 is synthesised at two points of sperm development - firstly as a component of the molecular 'scaffold' that allows chromosomes to cross over in the process of cell division, and secondly at the final stages of sperm formation whereby immature spermatids assume the shape of recognisable spermatozoa with heads and tails. At this final stage there is also a remodelling of the cell membrane in the maturing spermatids and formation of a new feature of the outer 'shell' of the mature sperm - the binding site for hyaluronic acid (HA). Thus, the Yale team has identified a crucial relationship between the genetic content and surface properties of sperm. It is by using the HA binding site on mature sperm that ICSI sperm pre-selection has been facilitated - similar to the principle of a 'mature sperm magnet'.

The research team led by Professor Gabor Huszar,* whose work is supported by the National Institutes of Health, tested the incidence of chromosomal aberrations (with probes for the X and Y sex and 17 autosomal chromosomes) in the initial semen fraction and in the HA selected fractions. Chromosomal abnormalities were reduced 4-5-fold in the HA-bound sperm fraction (a rate comparable to the increase of sex chromosome aberration in ICSI children), whether the men had diminished or normal sperm concentrations. HA is a normal component of a woman's reproductive tract, so the method should not cause safety concerns.

Said Professor Huszar: "HA selection eliminated sperm with the inappropriate number of chromosomes and yielded a sperm in the normal range of aneuploidy rate between 0.04 and 0.13%, no matter how high the frequency of the aberrant sperm was in the initial sperm fractions. The HA method represents a major breakthrough in ICSI sperm selection, and it is safe and efficient. We are testing the hypothesis that the HA selected sperm is equivalent to those sperm that cause fertilisation in the natural conception process."
* The presenting author to the conference of this research is Dr Huszar's colleague, Dr. Attila Jakab.

Abstract no: 0-102 (Tuesday 10.00hrs CET Hall D) URL: http://conf.eshre.com/PDF/O-102.pdf

Further information:

Press Office: (Sunday 30 June -Wednesday 3 July)
Margaret Willson, Emma Mason, Janet Blümli
Tel: +43 (0) 1 260 69 2010 or +43 (0) 1 260 69 2011
Fax: +43 (0) 1 260 69 2012

European Society of Human Reproduction and Embryology

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