Pre-eclampsia: The deadly mystery scientists can’t solve

Instead, researchers have had to try and pick up abnormal levels of certain molecules in the blood, as a way of detecting that something might be going wrong. In particular, studies have shown that in women with high levels of inflammation in the uterus, placental cells respond to the impaired blood supply by releasing a protein known as soluble fms-like tyrosine kinase 1 (sFlt-1). Once in the bloodstream, excess levels of this protein have a toxic impact, increasing the sensitivity of the fragile barrier between the mother and foetus to inflammation.

“That protein accumulates to about 100 times normal levels in patients who are developing pre-eclampsia,” says Craig Mello, a biologist at the University of Massachusetts Medical School who was a co-recipient of the 2006 Nobel Prize for Physiology or Medicine. “So it can be used as a diagnostic prior to the dangers of organ failure that you can get with pre-eclampsia.”

Last year, the life science and clinical research company Thermo Fisher Scientific received approval from the US Food and Drug Administration (FDA) regulator for a new diagnostic for pre-eclampsia. The process helps to fast-track the development of medical technologies that treat or diagnose serious conditions. In this case, the diagnostic tool involves looking for high sFlt-1 levels in comparison to low levels of another protein, placental growth factor, which represents normal placental development.

Clinically, the test will be used to quickly predict whether a pregnant woman hospitalised with signs of hypertension will develop severe pre-eclampsia within the next two weeks. Its efficacy was provisionally demonstrated in a 2022 study examining more than 700 pregnant women across 18 different hospitals, in which patients who tested positive were able to receive enhanced surveillance and accelerated care before their symptoms could worsen. 

While it’s thought that the new diagnostic technique will save lives, Cindy Anderson, professor of maternal infant health at the Ohio State University College of Nursing, feels that there remains a need for more advanced diagnostics which can detect warning signs of pre-eclampsia at a much earlier stage in pregnancy. If the tentative hints of pre-eclampsia could be identified at a point where the placenta is not fully developed, and it might still be possible to prevent the condition. 

“After nine weeks the placenta has developed,” says Anderson. “So can we see these signals earlier, and could we then intervene with a treatment to either halt it or even cure it?”

To try and enable this, a group of scientists are turning to a new technology, one which has evolved at a rapid pace within the last few years.

Placenta on-a-chip

In a lab in Sydney, McClements and her team are painstakingly assembling layers of living placental cells, connected with supporting gels, to create natural tissue-like structures. Their idea is to model some of the processes which might take place in the earliest stages of pre-eclampsia, outside of the human body, something which has never been done before. The team have affectionally dubbed the technology “placenta on-a-chip”.

“We’ve been trying to develop these models that can mimic what’s happening in the human placenta in pre-eclampsia conditions,” says McClements. “For example, we’ve used trophoblasts, the layers of cells which direct the formation of the placenta, from the first trimester. We’re trying to understand what’s happening to them under the conditions of inflammation, oxidative stress, lack of oxygen and restricted blood vessel development, which precede pre-eclampsia early in pregnancy,” she says.

According to McClements, the hope is that one day this research could yield new biomarkers which could form the basis of future blood tests for newly pregnant mothers. But having a more realistic model of pre-eclampsia could also make it easier for researchers to test potential therapies, ones which might actually alter the course of the disease.

“Two-out-of-three women who have gone through pre-eclampsia in pregnancy will die prematurely from heart attacks and cardiovascular disease,” says McClements. “So there’s a real need to find new treatments to prevent both pregnancy and post-pregnancy disease.”

To date, the only recommended therapy for pregnant women deemed to be at high risk of pre-eclampsia is low dose aspirin from 12 weeks until birth. Studies have shown that an estimated 60% of women who begin aspirin therapy before week 16, do not develop any symptoms of pre-eclampsia.

But this still leaves 40% of patients who remain vulnerable, along with many who do not receive it at all because their doctors did not suspect them to be vulnerable to pre-eclampsia. “There are many who don’t get it, and it’s not even discussed with them,” says Andrew Shennan, professor of obstetrics at King’s College London.