Study sheds light on major killer of pregnant women

Downton Abbey fans will be familiar with the tragedy of preeclampsia. In series three, at a late stage of her pregnancy, things do not go well for Sybil Crawley. Her local doctor finds her disoriented, with swollen ankles, and there’s protein in her urine.

His diagnosis is preeclampsia. He advises that Sybil be taken to hospital for an immediate caesarean section. But the specialist obstetrician overrules that decision. Sybil delivers her baby naturally, has a brief moment of joy with her beloved husband and child, then convulses and dies.

Though that episode was set in 1920, the state of knowledge about the cause of this dire condition has barely changed until today. Nor is there much more that doctors can do when the condition becomes severe. Then as now, the only answer is to deliver the baby immediately.

That’s because the placenta – the baby’s life support system – is the problem: it produces factors that raise the mother’s blood pressure to dangerously high levels, causing kidney and liver failure, and the risk of stroke and convulsions.

While we know the placenta is the problem, researchers have long struggled to find out why. Now, by studying the DNA of more than 300,000 individuals, Linda Morgan at Nottingham University and colleagues from across Europe, Central Asia and Australia have finally zeroed in on a genetic variant in the DNA of the foetus that is linked to the condition. The finding, published in Nature Genetics, shines the first light into the long-standing fog surrounding preeclampsia.

Eclampsia means convulsions. Preeclampsia is the dangerously high blood pressure that builds up during a pregnancy – usually detectable after the 20th week. About one in 20 women will experience the condition. It is the most common danger to mothers and their unborn babies. Worldwide, about 76,000 pregnant women and 500,000 babies die from the condition each year, mostly in underdeveloped countries. Most cases can be managed by treating the mother with drugs to lower her blood pressure; but when the condition becomes extreme, as it does in 1-2% of cases, the only remedy is to deliver the baby.

Preeclampsia remains a mysterious disease. It’s more common in a first pregnancy, runs in families and is less common in smokers!

What we do know is that the source of the trouble lies with the placenta. As the embryo develops, the first cells it produces are trophoblasts; their job is to burrow into the walls of the uterus to tap into the mother’s blood supply. They secrete “angiogenic” factors (VEGF, vascular endothelial growth factor; and PlGF, placental growth factor) to stimulate the growth of new interconnecting blood vessels. It is these vessels together with their supporting tissues that become the placenta.

In one in 20 pregnancies, the process goes awry. The growing foetus fails to get enough blood, and the placenta starts secreting vasoactive factors that raise the mother’s blood pressure, perhaps to increase the supply to the foetus.

One of the mysteries of the disease is that, even though it affects the mother so severely, it’s not necessarily the mother’s blood line that confers the risk. It may be passed on from the father. That’s why scans of the mother’s DNA have failed to find parts of the genetic code that predispose her to preeclampsia.

So in the current study Morgan and her colleagues scoured the DNA of “offspring” whose mothers had experienced preeclampsia – 4,380 such offspring to be precise, sourced from families in Britain, Iceland, Norway and Finland. Their DNA was compared to the DNA of more than 300,000 offspring whose pregnancy proceeded normally. The comparison revealed a small but significant link to the disease: two tiny DNA code changes near a gene called FLT.

Not only was it a statistically significant association, the gene had long been considered a smoking gun. It was known to make a protein (sFlt-1) that clogged up the VEGF and PlGF proteins, interfering with their ability to stimulate blood vessel growth.

Furthermore, abnormally high levels of sFlt-1 had been found in the blood of women with preeclampsia. Until now, however, researchers could not be sure whether the sFlt-1 protein was a cause or consequence of the disease. Finding that a change in the DNA that codes for this protein can raise the risk of the disease nails it as the culprit.

Nevertheless it is only one of many genetic culprits. If a foetus has this faulty version of the FLT gene, it raises the mother’s risk only by 20% (or by 40% if the foetus has inherited two copies). So the mother’s overall risk of developing preeclampsia increases from 5% to 6% or 7%.

That’s not yet enough for meaningful risk prediction. As Morgan says: “The importance of these findings lies in the insights which they give to the underlying mechanisms that lead to pre-eclampsia.”

John Kemp, a statistical geneticist at the University of Queensland and co-author of the study, also points out that the technique of comparing the DNA of affected and unaffected offspring should, with an increased number of subjects, aid the identification of more disease genes and provide new insights into the biological mechanisms that cause pre-eclampsia.