New clues to preventing miscarriage or pre-term births.

• 20 April 2011 by Hayley Crawford and Helen Thomson
• Magazine issue 2809.

MISCARRIAGE and pre-term birth are the two things all parents-to-be worry about. Two studies published this week could help establish why some pregnancies go wrong, and offer hope for new treatments to prevent pregnancies ending this way.

One in five pregnancies end in miscarriage, and the risk increases with the age of the mother. Patricia Hunt and colleagues at Washington State University in Pullman have now identified a surprising contributing factor: a lack of quality control during egg-making.

Hunt's team found that not all of the immature egg cells, or oocytes, produced by mice contain the correct number of chromosomes. Egg or sperm cells divide through a process called meiosis, rather than the mitosis that is typical of cell division elsewhere in the body. There are several checks in place to make sure that meiosis occurs correctly, but Hunt's team found that this process isn't as strictly controlled in eggs as it is in sperm.

Specifically, when the pairs of chromosomes line up at what is called the meiotic spindle at the centre of the parent cell, they should await a chemical signal called the spindle assembly checkpoint (SAC) before dividing into daughter cells. However, the team found that eggs bend this rule. When they observed eggs dividing in ovaries removed from mice, they noticed that the SAC trigger for cell division waits for most - but not all - of the chromosomes to be lined up correctly. The consequence is either too many or too few chromosomes in the resulting egg cells, which can lead to birth defects or miscarriage (Current Biology, DOI: 10.1016/j.cub.2011.03.003).

The cell division process "is highly conserved between mice and humans", says Hunt, suggesting that the same lack of quality control also applies to us. She reckons that we may be evolutionarily programmed to allow defective cells to divide because eggs are precious. "It is better to try and fail than to simply give up on an egg before it is even fertilised," she says.

As the absence of a control mechanism can only increase the risk of chromosomal abnormality, So Iha Nagaoka, co-author of the study, says that IVF could be adapted to include screening that sorts the bad eggs from the good in a way that the body does not, helping to reduce the risk of miscarriage.

Premature birth is also a distressing experience for parents, and it is this aspect of pregnancy that Justin Fay at Washington University School of Medicine in St Louis, Missouri, concentrates on. Some 12 per cent of babies are premature, and caring for them costs the UK £1 billion ($1.64 billion) a year.

Fay and colleagues think they have identified a contributing factor. "Humans have a shorter gestation period relative to their brain and body size than you would expect looking at other primate lineages," he says. This is a result of our large brains and the narrow female pelvis, which mean that in order to maximise the chance of both mother and baby surviving, our gestation period has had to shorten.

The researchers think that this shortening is encoded in the genes involved in birth timing, some of which must have evolved rapidly since we diverged from other apes, to keep up with the growth of our brains.

To find out, the team compared numerous genomes from humans and other primates and pinpointed around 150 likely candidates for genes involved in accelerated birth timing. When the researchers looked for these genes in 328 mothers in Finland they found that variations in a gene called FSHR were more frequent in mothers who gave birth before 37 weeks of gestation. The team says the gene could be a new target for therapeutic measures to prevent pre-term births (PLoS Genetics, DOI: 10.1371/journal.pgen.1001365).

"It was surprising to find that FSHR was involved," says Fay. The hormone it controls- follicle stimulating hormone (FSH)- has a well-known function in the establishment of pregnancy rather than the initiation of labour. "It suggests that we should start looking at risk factors for pre-term births much earlier than 25 to 35 weeks into gestation," he says.

David Haig at Harvard University says that it may be significant that the neighbouring gene to FSHR - called LHCGR - is responsible for producing a hormone that helps to maintain a thick uterus during pregnancy. Any variations to FSHR might have a knock-on effect on nearby genes, he suggests.

Chimp births are surprisingly like our own

The process of human birth is unique among primates because the infant emerges with its head facing in the opposite direction from its mother, or so the argument goes. Now, the first close-up videos of three chimpanzee births suggest that theory is wrong. In all three cases, the newborn emerged with its head facing away from the mother (Biology Letters, DOI: 10.1098/rsbl.2011.0214).

It has also been suggested that the orientation of human newborns accounts for another uniquely human aspect of birth- the need for a midwife. Indeed, midwives contacted by New Scientist say that the differences in birth-related mortality rates between countries with good and poor levels of medical care shows the difference their assistance makes.

But this idea may also now be up for revision. Satoshi Hirata at the Great Ape Research Institute of Hayashibara Biochemical Laboratories in Okayama, Japan, who led the study, says that chimps make nests so that they have a safe place to give birth, which could allow this style of birth to occur without assistance.