The first antenatal diagnosis of Down's syndrome was made in 1968. Initially there was amniocentesis for older mothers (Penrose noted association with maternal age in 1933; rates of Down's are 1:1500 babies if mother aged 20, 1:800 if aged 30, 1:270 if aged 35, 1:100 if aged 40, 1:50 if aged 45 or older.) Then screening by blood test was introduced, and nuchal screening (p 11). By 2007 the UK plans nationwide screening with tests giving detection rates of 75% with a false positive rate of <3% (and aims for 60% detection with <5% false positive from 2005). Tests aim to estimate the risk of Down's taking into consideration information from nuchal scanning, blood tests and the woman's age. Where risk of Down's is >1:250 (high risk-estimated to be 5% of pregnancies) she will be offered further tests such a chorionic villus sampling (p 46) and amniocentesis (p 10). Early ultrasound is vital for dating pregnancies for these tests.
The combined test
This combines nuchal translucency (NT)+ free Î-human chorionic gonadotrophin (ÎHCG) + pregnancy associated plasma protein PrAP-A + the woman's age. Used between 10 weeks 3 days and 13 weeks 6 days. It can achieve detection rates of 95% of all aneuploides, 86% trisomy-21, and 100% of trisomy-18 and trisomy-13. In one study (n=4190), 97.6% took up screening; false positive screening occurred in 6.7%: 7 cases had neural tube defects, and 2 ventral wall defects were picked up on scan. 200 accepted chorionic villus sampling: there was fetal demise in 2 in next 28 days 1 of which had Down's.1
The integrated test
This is better than the combined test if there are good facilities for nuchal translucency measurements available and the woman is prepared to wait for 2nd trimester results. It involves NT+ PrAP-A in the first trimester + the quadruple test in the 2nd trimester.
The quadruple test
This combines maternal α-fetoprotein (AFP) + unconjugated estriol + free ÎHCG or total ÎHCG + inhibin-A + the woman's age in the second trimester. This test is useful for women presenting in the second trimester.
The emotional cost to the mother is impossible to calculate
From the parents' point of view, a telling statistic is that 56 out of every 57 women under 37yrs old who had a +ve test, proved, after amniocentesis, not to have an affected fetus. Amniocentesis causes fetal loss, and these losses will usually be of normal babies. New screening regimens in the 1st trimester go some way to mitigating distress and anxiety.
We have no idea of the best way of counselling parents before the test. If you just hand out a leaflet, few will read it, and then when it comes to amniocentesis and termination, many will refuse”and the screening test wastes money, as well as laying health authorities open to litigation: I never understood that I might lose a normal baby The alternative is to provide full details at the time of the initial blood test. The irony is that gaining informed consent is then the most expensive part of the test, and one which itself could cause much distress. Imagine an overjoyed expectant mother arriving in the clinic serenely happy in fulfilling her reproductive potential: the quintessence of health. She leaves only after being handed ethical conundrums of quite staggering proportions, involving death, disease, and human sacrifices, and a timetable for their resolution that would leave even the most fast-moving philosopher breathless and disorientated, and which may leave her forever bereft of one of Nature's most generous gifts: the fundamental belief in one's own wholeness.
Preimplantation genetic diagnosis1
Preimplantation genetic diagnosis (PGD) is an early form of prenatal diagnosis in which embryos created in vitro are analysed for well-defined genetic defects. Defect free embryos are then used for implantation.
It is used in those with high risk of genetic disease eg carriers of monogenic disease or chromosome structural abnormalities (eg translocations) who have repeatedly terminated pregnancies due to prenatal tests showing abnormality, who have concurrent infertility, who have had recurrent miscarriage (as occurs with translocation carriers), and for those with moral or religious objections to termination.
It may also be used to screen for aneuploidy (PDG-AS) in those undergoing in vitro fertilization to enhance chance of ongoing pregnancy (sometimes the case for women >37“40 years old).
Pioneered in the early 1990s, by mid 2001, 3000 PGD cycles had been performed resulting in 700 pregnancies (pregnancy rate 24%), of which 5% of babies had some kind of abnormality. PGD selection of embryos by HLA type so that a child born after using this technology can be used as a stem cell donor to save a sibling from certain conditions is controversial but possible.
Genetic analysis at the single cell level occurs using 1st polar body of an egg, or 2nd polar body (extruded after fertilization and completion of second meiotic division), or using blastomeres from cleavage-stage embryos. The blastocyst is the latest stage from which cells can be used but is little used as it leaves little time for analysis as embryos must be transferred before day 5 or 6. Biopsied surplus embryos can be cryopreserved but implantation rate for these is only 12%.
Fluorescence in situ hybridisation (FISH) is used for analysis of chromosomes and polymerase chain reaction (PCR) for analysis of genes in monogenic diseases. PGD can currently be applied for detecting 33 monogenic diseases. Gene analysis for X-linked conditions has the advantage that healthy male embryos and non-carrier female embryos can be transferred. Sexing embryos for X-linked conditions remains useful for conditions where the single gene is not known (eg non-fragile-X X-linked mental retardation), has been judged too difficult a search, and for women eg over 37 who do not wish to wait for specific tests to be developed.
Pregnancy rates are 17% after testing for structural chromosome abnormality (including translocations), 16% after sexing, 21% after testing for monogenic diseases. This is lower than the expected rate of 20“25% expected for regular IVF. For PGD-AS 25% pregnancy rates are achieved overall for women of previously poor prognosis due to advanced maternal age, repeated IVF failure (but only 8% do get pregnant) and recurrent miscarriage (28% pregnancy rate achieved).
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