A human oocyte is held by a glass holding pipette (left). A beveled glass pipette containing an immobilized ejaculated spermatozoon is inserted through the zona pellucida and deep into the oolemma, creating a deep furrow. Once the membrane of the oocyte is penetrated, the sperm is deposited therein. Photo credit: Eugene Ermolovich (CRMI)/Wikipedia Commons

EXPERT REACTION: Fertility techniques linked to intellectual disability

Embargoed until: Publicly released:

A Telethon Kids Institute study showing a link between intellectual disability and some forms of Assisted Reproductive Technology (ART) has reinforced the need for coordinated long-term monitoring of outcomes of children conceived using these techniques. The study found 1 in 48 ART children were diagnosed with intellectual disability, compared to 1 in 59 for non-ART children. ICSI-conceived children showed a higher risk of intellectual disability: 1 in 32. However, lead author Dr Michele Hansen said it was important to note the findings related to births from 1994 to 2002 and that there had been major shifts in ART clinical practice in Australia since that time.

Journal/conference: Pediatrics

Organisation/s: Telethon Kids Institute

Funder: National Health and Medical Research Council

Media Release

From: Telethon Kids Institute

A Telethon Kids Institute study showing a link between intellectual disability and some forms of Assisted Reproductive Technology has reinforced the need for co-ordinated long-term monitoring of outcomes of children conceived using these techniques.

The research, published in the journal Pediatrics, found children conceived using Assisted Reproductive Technology (ART) between 1994 to 2002 had only a small increased risk of intellectual disability overall.

However, the risk more than doubled for those born very preterm or using a technique where a single sperm is injected directly into the egg – known as intracytoplasmic sperm injection (ICSI).

Lead researcher Dr Michele Hansen said while the results were important, they needed to be interpreted with caution due to the age of the data available for the study and the fact that technology and procedures in Western Australia had advanced since the study was performed.

“During the study period, the transfer of multiple embryos in a single treatment cycle was the norm in Australia. This practice led to high rates of multiple pregnancies and preterm birth – which are both known to increase the risk of intellectual disability,” Dr Hansen said.

“However, this practice has changed dramatically in Australia over time. As of 2016, 88 per cent of treatment cycles saw only a single embryo transferred, resulting in much lower proportions of multiple and preterm births.”

Dr Hansen said the findings did have important implications for many regions in the world – such as parts of North America, Latin America and the Middle East – where the transfer of multiple embryos in an individual cycle was still the norm.

She said her study also reinforced concerns about ICSI, which was restricted to couples with severe male factor subfertility during the study period, but is now used more broadly.

“Genetic abnormalities occur more frequently in men who are infertile, so ICSI – which bypasses natural selection barriers by injecting a sperm directly into an egg – may allow for the transmission of anomalies to the offspring,” Dr Hansen said.

“ICSI fathers in our study were also older on average and we know that advanced paternal age is associated with a small increased risk of genetic mutations in sperm and genetic disorders in offspring.”

Dr Hansen said her study showed an urgent need for more recent data to try to establish whether the increased risks of intellectual disability are solely related to male subfertility and older paternal age, or if there are other risks associated with the technique itself.

“Until we know more, clinics may consider restricting the use of ICSI to those couples that are unlikely to be able to conceive without it – that is, those with severe male factor subfertility,” Dr Hansen said.

The study included 210,627 live births, of which 1.4% were conceived using ART (1,939 IVF and 937 ICSI births).

Key findings:

·       Children conceived using ART had a small increased risk of intellectual disability overall (1 in 48 ART children were diagnosed vs 1 in 59 for non-ART children)

·       ICSI-conceived children showed a higher risk of intellectual disability: 1 in 32

·       The risk of intellectual disability in very preterm births is much greater regardless of method of conception (but within preterm singleton births the risk was doubled for those that were ART-conceived). 1 in 8 ART singletons vs 1 in 14 non-ART singletons born before 32 weeks were diagnosed with intellectual disability.

·       The risk of severe intellectual disability (IQ<40) is more than doubled for ART births: 1 in 353 ART-conceived children vs 1 in 889 non-ART children were diagnosed with severe intellectual disability.

The research, published as Intellectual Disability in Children Conceived Using Assisted Reproductive Technology, was supported by the National Health and Medical Research Council.

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Michele Hansen from the Telethon Kids Institute is the lead author on this study

Our study confirms there are increased risks of intellectual disability in children conceived using Assisted Reproductive Technology who are born very preterm and those conceived using intracytoplasmic sperm injection (ICSI) – a technique where a single sperm is injected directly into the egg. However, it is important to note our findings relate to births from 1994 to 2002 and there have been major shifts in ART clinical practice in Australia since that time.

Most notably, there has been a strong move towards single embryo transfer in Australia, leading to major improvements in perinatal health outcomes after ART (reduced rates of preterm birth and of low birth weight and perinatal mortality) and fewer multiple births – all of which may contribute to lower risks of intellectual disability. 88 per cent of treatment cycles in 2016 involved the transfer of a single embryo. The results of our study do however have important implications for many regions in the world where the transfer of multiple embryos in an individual cycle is still the norm.

ICSI use on the other hand has increased over time in Australia since our study and is currently used in
63 per cent of treatment cycles. Our findings show an urgent need for more recent data to establish whether the increased risks of intellectual disability seen in children conceived using ICSI are solely related to severe male subfertility and older paternal age, or if there are other risks associated with the technique itself.

Last updated: 15 Nov 2018 3:44pm
Declared conflicts of interest:
None declared.
Dr Genia Rozen is an obstetrician and gynaecologist actively involved in fertility preservation services and research.

The authors are to be congratulated for this well conducted, local population study with high numbers of participants and a lengthy follow up period (of over 8 years).

In agreement with similar studies it shows a higher rate (though absolute risk is still low) of intellectual disability in the ART population, even when comparing similar groups such as singleton births. As fertility specialists this is something we must be counselling our patients about.

Due to its retrospective design causality (that ART causes higher risk of ID) cannot be inferred. The population using ART (who are often older, with underlying fertility and/or other medical issues and higher rate of genetic abnormalities) is a confounding factor and confers higher rates of intellectual disability.

However, the technology may play a role and long term follow up studies are essential, especially as techniques used are rapidly changing. For example, Cleavage-stage (day 2 or 3 after fertilisation) embryos were used during the period of the study, while most clinics now use extended culture with blastocyst (day 5) transfer.

Also, there are much higher rates of ICSI use, compared to the study, even as high as 90-98% in some parts of the world. To uphold ‘primum non nocere’ (first do no harm) studies such as this one, are imperative.

Last updated: 15 Nov 2018 3:40pm
Declared conflicts of interest:
None declared.
Professor Jane Halliday is a group leader in Public Health Genetics, from the Murdoch Children's Research Institute

This record linkage study comprising 1291 IVF and 618 ICSI singletons and 648 IVF and 319 ICSI twins, aged up to 8 years, is important because of the databases available in WA to provide novel and population-based data on intellectual disability (ID).

The sample size limitations are spelled out with quite small numbers of children with ID (10% with Down Syndrome) amongst the ART groups. Specific issues related to multiple births exist and they are recognised to be at greater risk than singletons of adverse outcomes, so their findings of more with ID are not surprising and neither is the association with pre-term birth.

The data related to ICSI are more controversial. We have recently published a review of outcomes for ICSI-conceived children compared with spontaneously conceived children and the section on neurodevelopment summarised 24 studies of mostly good quality showing these children are comparable in neurodevelopment.(1) Seven studies did report some clinically insignificant differences while others had methodological limitations. We also reviewed ICSI-conceived compared with IVF-conceived offspring and only five of 24 studies reported ICSI children faring worse in terms of neurodevelopment.

The 19 other studies found no differences. (2) Our reviews highlight the difficulty in obtaining a definitive result on this topic. This new record linkage study adds weight to the negative side, but it is good that they themselves emphasise the importance of other research and that times have changed in regard to singleton versus multiple embryo transfer. They rightly also note that ICSI has become the ART method of choice and that a degree of caution should be present in this regard.
 

  1. Sarah Catford Robert I. McLachlan, Moira K. O’Bryan and Jane L. Halliday. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring: A systematic review of health outcomes beyond the neonatal period. Andrology: doi 10.1111/andr.12526 (2018)
     
  2. Sarah Catford Robert I. McLachlan, Moira K. O’Bryan and Jane L. Halliday.  Long-term follow-up of ICSI-conceived offspring compared with IVF-conceived offspring: A systematic review of health outcomes beyond the neonatal period. Andrology doi: 10.1111/andr.12369 (2017) 
Last updated: 15 Nov 2018 3:40pm
Declared conflicts of interest:
None declared.
Gino Pecoraro is Associate Professor of obstetrics and gynaecology at the University of Queensland, a Federal Councillor for the National Association of Specialist Obstetricians and Gynaecologists (NASOG) and a Federal member of the Australian Medical Association (AMA) Board

IVF remains one of the greatest scientific  advances of our time giving hope to previously childless couples.
 
New research looking at over 210, 000 children born between 1994 and 2002 has suggested however that children conceived through ART ( Assisted Reproductive Technology) had a higher rate of intellectual disability.
 
One form in particular (ICSI –intracytoplasmic sperm injection) used to treat couples where the male had poor quality semen and individual sperm were directly injected into an egg, had an almost doubling of the rate of intellectual impairment  - from 1 in 59 normally conceived children to 1 in 32 in ICSI conceived children.
 
There may be a number of reasons for this finding though and caution used be used interpreting the results.
 
Prematurity is still one of the greatest risk factors for intellectual impairment no matter how the babies are conceived but it appears that ART babies have a doubling of this risk when compared to others.
 
It may be related to the technique of puncturing the egg to insert the sperm directly inside or it might be that the sperm itself is of a low quality which was why the technique was needed in the first place. Also older fathers are more likely to need ICSI to help have a family and age is also a factor associated with increased risk of sperm having  genetic mutations.
 
More research needs to be done but until the answer is clear, it is worthwhile for couples undergoing fertility treatment to be aware, ask their specialist what type of ART they will be receiving and whether ICSI is the only option or if an alternative available.

Last updated: 15 Nov 2018 3:38pm
Declared conflicts of interest:
None declared.
Associate Professor Peter Illingworth is Medical Director at IVF Australia

This interesting study suggests a small increase in intellectual disability in children conceived after IVF carried out in Western Australia in the late 1990s.  The results of this study are at odds with several other studies that have found the later development of IVF-conceived children to be no different from naturally-conceived children. 
 
One critical factor in this study is that almost all the transfers in the 1990s were multiple embryo transfers.  It is now well-known that following multiple embryo transfer, even singleton pregnancies are at higher risk of complications.  This study identifies the importance of good IVF practice, particularly transferring one embryo at a time in modern IVF but should not be regarded as a major source of concern for patients considering IVF.

Last updated: 15 Nov 2018 3:35pm
Declared conflicts of interest:
None declared.

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