IVF children run increased risk of developing
retinoblastoma, claim Dutch researchers

By Dermot McGrath
in Amsterdam

CHILDREN conceived by in vitro fertilisation (IVF) may run an increased risk of developing retinoblastoma, according to a recent study by Dutch researchers.
A team, led by Annette Moll MD, PhD, of the Vrije Universiteit Medical Centre in Amsterdam, compared the incidence of the disease among the 1% to 1.5% of the population born after the introduction of IVF with its occurrence in the wider Dutch population.

Retinoblastoma tumour seen through the pupil.

Retinoblastoma tumour very close to the macula.

Between November 2000 and February 2002, five cases of retinoblastoma were diagnosed in children conceived by IVF in the Netherlands.
Their study, published in The Lancet, suggested that the risk of the cancer in children conceived by IVF might be between five to seven times higher than for children conceived in the usual way. Retinoblastoma typically occurs in around one in 17,000 births in the Netherlands and other western countries.

While one specialist referred to the report as “unprecedented and alarming”, other experts were quick to play down the significance of the Dutch team’s findings.
The European Society of Human Reproduction and Embryology (ESHRE), which represents more than 4,000 fertility experts worldwide, said the report "should be treated with caution".

Christina Bergh MD, an ESHRE member whose team in Gothenburg, Sweden, is reviewing the health of children born by IVF techniques, raised several concerns about the study. “It is small and it bases several figures — including the percentage of IVF births in the Netherlands — on assumptions rather than real observations. The five children identified with retinoblastoma in the study have all been successfully treated, yet the expected numbers of retinoblastomas were based on mortality rates rather than on cases recorded in the cancer registry, which would have been more appropriate since the register includes both fatal and non-fatal cases,” she said.

Professor Bergh added that three large cohort studies published between 1999 and 2001, which included almost 20,000 IVF children, found no increased cancer, nor was there a single case of retinoblastoma identified in 6,000 IVF children on the Scandinavian IVF database.
ESHRE Chairman, Hans Evers MD, said that the problem with studies involving small figures was that dividing a small figure by a second, even smaller figure could produce a very positive risk ratio.

“Of course, this does not exclude a connection between assisted reproductive techniques and childhood cancer and everyone involved in fertility treatment agrees that it is extremely important to follow ART children right through their childhood. But the present report should be treated cautiously for now,” Professor Bergh said.
A. Linn Murphree MD, Director of the Retinoblastoma Centre, Los Angeles Childrens Hospital, US expressed concern at the way the media had chosen to represent the Dutch report.

“It is inaccurate for news reports to state or imply that IVF is linked to the childhood eye cancer, retinoblastoma. The authors of The Lancet report clearly state that more studies need to be done before there can be any cause and effect demonstrated,” Professor Murphree said.
She added that it was regrettable that media reports had not taken more account of “the fine but critical distinction between observation and causation”.

“Unfortunately, the lack of that fine distinction in this case has caused parents of children with retinoblastoma, who may have had IVF, unnecessary emotional distress. It is critically important that media reports of medical observations be written with care, accuracy and humanity,” she said.
Annette Moll agreed that it was too early to draw any firm conclusions about possible links between IVF and retinoblastoma, but believed her group’s findings provided the basis for further investigation.

“We do need to conduct larger studies before these preliminary findings can be confirmed. Whether treatment with ovulation-inducing drugs increases the risk of childhood cancer is an important matter, especially with the rising numbers of women undergoing treatment for sub-fertility.

“Future investigators should consider the number of IVF treatments, other fertility drugs given before IVF, and the possibility that serious disorders in children conceived by IVF are diagnosed earlier than those in other children who do not have such close medical surveillance,” Ms Moll added.

In another commentary in The Lancet, David Ben Ezra, Hadassah Hebrew University Hospital in Jerusalem suggested that the increased risk as presented by the Dutch team was “unprecedented and alarming".
But he too urged caution in drawing hasty conclusions from the study.

“Whatever the true incidence of retinoblastoma is after IVF, there is little doubt that a heightened awareness and a multidisciplinary approach with a closer follow-up of children conceived with assisted reproductive technologies is needed,” he said.
With an estimated 16,000 cases worldwide each year, retinoblastoma accounts for about 3% of the cancers in children under 15 years, according to Retinoblastoma International, a not-for-profit charity based at the Childrens Hospital in Los Angeles.

The tumours, which are universally fatal if not detected early, were treated successfully in all five children cited in the Dutch report, who have since remained free of the disease. The tumour can be treated with enucleation, laser, cryotherapy, chemotherapy, external beam radiation, radioactive plaque therapy, or a combination of such treatments.

Annette Moll MD, PhD
Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
Email: a.moll@vumc.nl

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