18 April 2016
Professor of Cytogenetics, King's College LondonAppeared in BioNews 847
Professor Magda Zernicka-Goetz and her colleagues recently published an elegant study (1) of early events in mouse embryo and fetal development (see BioNews 845). The authors fused normal mouse embryos with embryos that had been treated to create abnormal cells with the wrong number of chromosomes (aneuploidy). They found that, as development proceeded, the abnormal cells in the fused embryos gradually disappeared, by a process called apoptosis (programmed cell death). Some of these embryos developed into apparently normal pups, as long as there were sufficient numbers of normal cells at the start.
It is already known that, in humans, many early embryos produced via IVF have the wrong number of chromosomes in some or all of their cells (the phenomenon is called mosaicism when only some cells are affected). Identifying and discarding these embryos has therefore been suggested, and many centres follow this approach with the aim of improving IVF success.
However, recent studies have shown that at this very early stage of human development the abnormal cells may be lost, and mosaic aneuploid embryos can indeed give rise to normal babies (2,3). The Zernicka-Goetz mouse study models this very early stage aneuploidy, and gives some insights into the mechanisms by which these embryos may be 'rescued'. Screening human IVF embryos for aneuploidy at this very early stage may therefore result in the destruction of potentially viable embryos and may not be in the best interests of the patients.
Press coverage of the Zernicka-Goetz paper speculated that termination of human pregnancies diagnosed with aneuploidy at prenatal diagnosis could therefore be unnecessary because of the ability of the fetus to 'heal itself'. In fact, this mouse paper tells us very little that we didn't already know about human fetal development in relation to aneuploidy, and its findings are certainly not relevant to aneuploidy detected at prenatal diagnosis, which is carried out when fetal development is already quite advanced.
Approximately half of all miscarriages are found to have aneuploidy, usually involving one extra chromosome. These pregnancies miscarry because the genetic burden of the extra material is not compatible with further fetal development. An extra copy of a smaller chromosome can sometimes allow development to term, resulting in a baby with congenital problems such as Down's syndrome. Prenatal diagnosis by sampling the placenta (chorionic villus sampling, or CVS) at around 11 to 13 weeks' gestation is the earliest point in an ongoing pregnancy at which aneuploidy can be definitively diagnosed.
We know that in mosaic aneuploid pregnancies, the normal cells allow the pregnancy to proceed further than when all the cells are abnormal. In addition, the abnormal cells may be confined to the placenta (confined placental mosaicism, or CPM), or may be lost by preferential growth of the normal cells or by apoptosis, resulting in a normal baby. However, the outcome of any pregnancy with mosaic aneuploidy will depend on the proportion of the abnormal cells, the genetic content of the extra chromosome, and the presence or absence of the abnormal cells in different fetal tissues.
Laboratories finding mosaicism after CVS will recommend a follow-up amniocentesis test, which looks directly at fetal cells. However, there can be no generalisations as to the outcome – at amniocentesis low-grade mosaicism can be benign, depending on the chromosome involved and, similarly, the absence of abnormal cells in amniotic fluid does not exclude the possibility that mosaicism is present in some other fetal tissues.
It would certainly be dangerously wrong to tell a woman that her fetus will 'heal itself' and that she will have a normal baby. Many of the fetal structures that could be affected by the abnormal cells will already have been formed by the time the CVS is taken, and even if the abnormal cells decrease in number as the pregnancy progresses, the damage may already have been done.
The press coverage of the Zernicka-Goetz paper is therefore mostly misinformed and irresponsible and could lead to distress and confusion for women regarding their prenatal testing results. Detailed and expert ultrasound assessment, further testing and genetic counselling is offered to any woman with a mosaic finding at CVS. But in the end it is her decision as to how to manage the pregnancy – for some, any risk of fetal abnormality may be unacceptable.