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What's Wrong with Assisted Reproductive Technologies?

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The Institute of Science in Society

Science Society Sustainability

http://www.i-sis.org.uk

 

General Enquiries sam

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ISIS Director m.w.ho

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ISIS Press Release 03/11/03

What's Wrong with Assisted Reproductive Technologies?

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Assisted reproductive technologies are associated with a range of birth defects

at least partly due to stresses experienced by germ cell and embryo during

culture and storage. Dr. Mae-Wan Ho (m.w.ho) reports

 

A longer, fully referenced version of this report has been posted on ISIS

members’ website (http://www.i-sis.org.uk/full/wwwARTFull.php). Full details

here (http://www.i-sis.org.uk/membership.php).

 

Since the birth of Louise Brown in 1978, more than a million babies have been

delivered worldwide with assisted reproductive technologies or ARTs. An

estimated one in ten people of reproductive age are infertile in the

industrialized countries, and ARTs are now involved in 1% to 3% of annual

births.

 

ARTs include in vitro fertilization (IVF), induced ovulation (IV) and

intracytoplasmic sperm injection (ICSI), which, in turn, form the basis of all

newer reproductive and related technologies such as cloning, somatic cell

nuclear transplant, genetic modification of germ cells, and recently,

transformation of stem cells into germ cells.

 

Simultaneously as the new reproductive technologies are enthusiastically

developed and exploited by biotech companies, however, evidence is emerging that

ARTs themselves carry risks to the unborn (see Box 1).

 

Birth defects associated with ARTs identified between 2002 and 2003

 

A study in the United States reported a 7.3-fold relative increase in incidence

of an extremely rare urogenital system birth defect during the first trimester

of gestation.

IVF was reported to increase risk of retinoblastoma (malignant tumour of the

retina) in the Netherlands 4.9 to 7.2 fold compared to non-IVF controls.

A study funded by the US National Institutes of Health found three (5%) out of

65 children with Beckwith-Wiedemann syndrome - characterized by enlarged tongue

and predisposition to rare cancers - were conceived via IVF. Overall, only 0.8%

of births in the US occur after IVF.

In Brazil, four children aged from 6 months to 3 years with several types of

cancer were born and diagnosed between 1996 and 2000, whose IVF took place in

Sao Paulo. These are out of approx 2000 live births during the five-year period

as the result of IVF. The annual incidence rate for cancer for children aged 0-4

years in Brazil was 117.5 cases per 1 000 000. Thus, only one case of cancer

would be expected among the IVF children.

A large study in Sweden compared the development of neurological problems in

5680 children born after IVF with 11 360 matched controls. Researchers found

that children born after IVF are more likely to need habilitation services than

controls, the overall risk (OR) was 1.7. For singletons (single births), the

relative risk was 1.4. The most common neurological diagnosis was cerebral

palsy, with increase overall risk of 3.7 after IVF, and 2.8 for IVF singletons.

Suspected developmental delay was increased four-fold in children born after

IVF.

In Western Australia, the rates of major congenital birth defects in children

conceived by IVF, ICSI and control cohorts were found to be 8.6%, 9% and 4.2%

respectively.

In Northern Finland, 304 IVF children born in 1990-1995 were compared with 569

randomly chosen matched controls. The overall IVF risks for incidences of

preterm birth was 5.6, very low birth weight, 6.2, low birth weight, 9.8,

neonatal morbidity, 2.4, hospitalization, 3.2. The prevalence of heart

malformations was four-fold in the IVF compared to controls. With the exception

of heart malformations, most of the risks were attributed to multiple births

after IVF.

 

 

Multiple pregnancy emerged as the most important, albeit not the only risk

factor. The European Society of Human reproduction and Embryology (ESHRE)

reviewed its guidelines on good practices in IVF laboratories in 2002, and

recommended aiming for singleton pregnancies. It is claimed that methods of

single embryo transfer have been refined to result in acceptable pregnancy

rates, made feasible by improved in vitro techniques in identifying good quality

embryos.

 

However, a review in the Lancet points to in vitro germ cell and embryo culture

techniques as the cause of certain birth defects.

 

Three studies in 2003 all report an unexpectedly high incidence of Beckwith

Wiedemann syndrome (BWS) in children conceived with ARTs. Patients with BWS have

abnormalities at chromosome 11p15 associated with organ overgrowth and abdominal

wall defects as well as increased risk of embryonal tumours. Six of 149 cases

were reported from a British BWS registry, the same numbers in a French registry

and a further 7 in the USA. These frequencies are extraordinarily high for such

a rare congenital condition, representing a significant 4.2-fold increase

associated with ARTs.

 

These findings are reminiscent of reports of sporadic cases of the ‘genetic

imprinting’ disorder, Angelman Syndrome, which has also been linked with ARTs.

Angelman Syndrome is characterized by severe mental retardation, motor defects,

lack of speech and a happy disposition, and is linked with a loss of function of

the maternal allele (copy of gene inherited from the mother) of UBE3A on

chromsome 15.

 

About 50 genes are differentially expressed according to their origin in either

the oocyte (egg cell) or spermatozoon (sperm cell). These ‘imprinted’ genes have

roles in growth and development and in tumour suppression (for example,

retinoblastoma has been reported by Dutch investigators to be more frequent

among ARTs children than normal). At the imprinted genes, only one allele is

active (maternal or paternal) and the inactive allele is epigenetically

(developmentally) marked, by chemical modification of the histone protein bound

to DNA, or by adding a methyl group (-CH3) to the base cytosine on the DNA, or

both.

 

Early in development of the fetal germ cells in both sexes, the germ-cell

genomes are erased of methylation marks on the imprinted genes. During

maturation of sperm and egg cell, however, re-methylation of the imprinting

alleles takes place. DNA methylation, almost invariably associated with

repression of transcription, targets one of the two parental alleles to silence

it. After fertilization, there are further changes in overall genomic

methylation in specific cellular lineages of the embryo but importantly,

imprinted alleles are protected from these waves of demethylation and

remethylation to maintain their proper dosage effects.

 

Thus, major epigenetic events take place during both germ-cell development and

pre-implantation stages when ART procedures are performed, possibly interfering

with the proper establishment (in gamete culture) and maintenance (in embryo

culture) of genomic imprints.

 

Both BWS and AS are associated with imprinted gene clusters. In about 50 to 60%

of sporadic cases of BWS, and 5 – 10% of the cases of AS, an epigenetic defect

is involved rather than a mutation in the gene. In contrast, all cases of AS and

13 of 19 cases of BWS linked to ARTs were due to epigenetic defects, involving

loss of methylation in the maternal allele.

 

Gene expression - and methylation status - in animal embryos is known to be

affected by culture conditions. Notable changes in expression of other genes

take place in embryos in culture, but effects on imprinted genes are different

in character and are unlikely to be reversible adaptations to altered

environmental conditions. In some farm animals, embryo culture and cloning

technologies carry high risks of neonatal overgrowth, morbidity and mortality,

which, in sheep are associated with loss of imprinting at the Igf2r locus. The

so-called large offspring syndrome in animals is reminiscent of BWS in man.

 

Some researchers have made connections between the effects of the manipulation

of gametes and embryos in IVF and those resulting from the manipulation of the

maternal diet, even briefly, during early pregnancy. Diets both high and low in

protein content can have detrimental effects on embryonic and neo-natal

development. High protein diets in sheep during the peri-conceptual period have

been linked with low embryo survival and high birth weights similar to the large

offspring syndrome. Low protein diets during early pregnancy in rats were found

to significantly reduce birth weight of pups. Experimental studies in animal

models have clearly established links between poor maternal nutrition to altered

prenatal growth and adverse outcomes in terms of cardiovascular and metabolic

function in adult offspring.

 

Intriguingly, similar results following embryo culture are now reported: lighter

fetal weight in mice and increased post-natal adiposity, together with body

weight gain and abnormal organs in adults. Compared with in vivo derived

embryos, culture reduced total cell number and inner cell mass (which eventually

gives rise to the fetus). Adding granulocyte-macrophage colony stimulating

factor appeared to mostly to overcome those effects.

 

In vitro culture in ruminants is linked with defective placenta formation. In

cow, in vitro embryo production can yield fetuses with abnormal allantoic

development and failed blood vessel supply to the developing placenta at day 35

of pregnancy. Similar effects were observed in sheep. But oversized fetuses or

placentas have also been reported in cows.

 

Epigenetic modification in ART embryos is thus a component of a broader causal

model linking environmental stress factors with disturbances to development

though both transcriptional and epigenetic modification of gene expression (see

" Diet trumping genes (http://www.i-sis.org.uk/DTG.php) " , this series).

 

In yet another setback to ARTs, scientists at Brown University, Providence,

Rhode Island in the United States reported in October 2003 that using frozen

embryos in fertility treatments raises the risk of ectopic pregnancy 17 times.

They compared 2452 cycles of IVF using fresh embryos with 392 using frozen

transfers. Ectopic pregnancies were 1.8% in the former group and 31.8% in the

latter.

 

Ectopic pregnancies are potentially fatal to the embryo, which gets stuck in the

fallopian tube. It causes agonizing pain and can be fatal for the woman if not

detected early enough and the embryo removed.

 

When a woman first has IVF, one to three fresh embryos are usually transferred

into the uterus. Within the past decade, as increasing numbers of couples are

choosing to freeze some of the spare embryos, giving them a chance to try again

if the first attempt fails, thus avoiding the painful process of hormone

treatment to induce ovulation.

 

Storage of frozen embryos also allows patients who have to undergo chemotherapy

treatment and other women to create fertilized embryos and delay motherhood.

 

Dr. David Keefe, the lead researcher, expressed surprise at the finding, " We did

not expect it to be so high and we obviously need more research. " He said. He

thought it could be the thawing process that may disrupt the development of the

embryo, making it more prone to stick to the fallopian tube.

 

A total of 250 000 babies have been born through frozen embryo transfer.

 

 

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This article can be found on the I-SIS website at

http://www.i-sis.org.uk/wwwART.php

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General Enquiries sam

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ISIS Director m.w.ho

 

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