Two new biomarkers can be used to diagnose preeclampsia early

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Preeclampsia is a devastating disorder that occurs very suddenly in the second half of pregnancy and causes severe health problems for both mother and baby.

Preeclampsia also increases the risk of developing life-long chronic diseases such as diabetes and heart disease.

The discovery of two novel biomarkers, called FKBPL and CD44, has the potential to change the way the condition is managed according to research published in the Journal of Clinical Endocrinology and Metabolism.

Preeclampsia can cause high blood pressure and organ failure in mothers and lead to preterm births and even stillbirth.

Senior author, Dr. Lana McClements from the University of Technology Sydney, said the biomarkers can be used to diagnose and assess the risk of getting preeclampsia in both early and late pregnancy, “in women who otherwise appear healthy”.

“There are two main types of preeclampsia: early-onset preeclampsia diagnosed before 34 weeks of a pregnancy and late-onset preeclampsia diagnosed from 34 weeks onwards,” Dr. McClements said.

“The vast majority of the current screening and monitoring strategies are focused on early-onset preeclampsia, which comprises only 10-15% of all preeclampsia cases, whereas late preeclampsia has been largely neglected,” she said.

The researchers say the two biomarkers are particularly useful for diagnosing cases of late-onset preeclampsia, between the second and third trimester, a period that currently lacks reliable biomarkers.

Summary of changes FKBPL and CD44 changes throughout gestation in pregnancies complicated by pre-eclampsia. Credit: Oxford Press

” The biomarkers allow the prediction of irregular placenta or maternal vascular function, which are key underlying causes of preeclampsia.

“This could lead to the early diagnosis and prevention of severe preeclampsia and associated complications including death, therefore also giving insight into disease mechanisms and possible treatment targets,” Dr. McClements said.

The research also has potential to enhance the development of therapeutics to treat preeclampsia because the increase in one of the biomarkers, FKBPL, can be inhibited by mesenchymal stem cells potentially stopping the development of preeclampsia.

” This is why we are so excited by the discovery. In addition to their use in diagnosis, FKBPL and CD44 also show potential as drug and cell therapy targets of emerging treatments for preeclampsia, which offers hope for a future cure to this terrible disorder,” Dr. McClements said.


Pre-eclampsia is an increase in blood pressure associated with a proteinuria (≥ 300 mg/day) occurring after 20 weeks gestation in women previously known to be normotensive [1].

It is a multisystemic disorder of unknown etiology and unclear pathogenesis [2]. It is frequent among primigravid, women with diabetes, chronic hypertension, multiple pregnancy etc., [3].

Pre-eclampsia and its most deadly complication, eclampsia constitute two major components of the large clinical entity known as hypertensive disorders in pregnancy [1].

A pregnant woman is considered hypertensive if her blood pressure is greater than or equal to 140/90 mmHg on two consecutive measurements [4].

Worldwide, 10% – 15% of maternal deaths that occur every year are associated with hypertensive disorders of pregnancy (eclampsia/pre-eclampsia accounting for about 1 in 7 maternal deaths) [5,6].

It is the most prevalent maternal complication worldwide affecting about 5% – 10% of all pregnancies [1]. Pre-eclampsia and eclampsia stands out as two major causes of maternal and perinatal morbidity and mortality, affecting between 5% and 8% of all pregnancies and accounting for about 50.000 to 60.000 maternal and 500,000 fetal deaths per year worldwide [2,7].

In Africa, hypertensive disorders of pregnancy accounts for 9.1% maternal deaths and a woman’s lifetime risk of dying from pregnancy-related complications in developing countries is 14 times higher than in developed countries [8].

In sub-Saharan Africa, 1 of every 1,500 pregnancies ends in a maternal death attributable to eclampsia/pre-eclampsia [9]. In Cameroon, a prevalence of 8.2% of hypertensive disorders of pregnancy was recorded by Mboudou, et al. in 2009 (pre-eclampsia accounting for up to 77% proportion of the 4 disorders constituting this disease) [10].

The maternal mortality ratio in Cameroon has gradually been on a rise for a couple of years, from 430/100 000 live births in 1991, 669/100000 live births in 2004 to 782/100000 live births (LBs) in 2011 [11]. Nevertheless, a recent decrease was observed and recorded by the Demographic and Health Survey board in 2015 (596/100 000LBs) [12].

Several preventive measures have been proposed to decrease morbidity and mortality among pregnant women at risk of pre-eclampsia. The proposed prophylactic measures are antiplatelet therapy, magnesium sulfate and calcium supplementation [13].

Several studies in different countries, have been undertaken to study the effect of calcium supplementation on reducing the incidence of pre-eclampsia among pregnant women but conflicting results have been reported [14–20]. To the best of our knowledge, no study up to date in central Africa has evaluated this therapeutic modality.

Discussion
The effect of calcium supplementation on prevention of pre-eclampsia has been a controversial issue highly debated on in several clinical trials in recent years. Majority of these trials have proven to have favorable effects for calcium supplementation during pregnancy.

Calcium acts by influencing the action of calcitrophic hormones on intracellular calcium. Calcium influx in a variety of cells, including vascular smooth muscle cells (stimulated by 1,25-dihydroxyvitamin D) leads to blood pressure increase.

Accordingly, low calcium diets, which elicit a 1,25-dihydroxyvitamin D response, would be expected to increase blood pressure, whereas a high diet, by virtue of suppressing 1,25-dihydroxyvitamin D levels, would be expected to reduce vascular smooth muscle cell intracellular calcium, peripheral vascular resistance and blood pressure [21].

It has as well been suggested the inhibiting role of calcium intake on parathyroid hormone release, thereby reducing renin secretion by the kidneys [14].

This study demonstrated that a daily dose of 1.5 g of calcium can reduce the occurrence of preeclampsia up to sevenfold among primigravid women. The overall incidence in pre-eclampsia was observed to be 11.4%.

The difference in gestational age at supplementation and in calcium doses administered to the participants probably explains the greater incidence obtained in this study compared to that of Kumar, et al. in 2009 (7.8%) [15].

Effectively, Kumar in their study enrolled and supplemented primigravid women at 12 weeks gestation, earlier than ours (20 weeks). Also, these primigravid women in 2009 were placed on 2 g calcium, a dose higher than ours and more susceptible of having a greater protective effect on the incidence of pre-eclampsia.

The black race, the average poor nutritional state and the sub-Saharan climatic condition characterizing our study population and site of study, might be contributing factors to the differences in incidences observed.

As time goes by, better management attitudes are adopted towards cases of pre-eclampsia. This might explain the absence of cases of eclampsia in this current study. To note that, even a larger sample-sized study carried over a 36 months period in recent years recorded no case as well [15].

The risk factor of eclampsia being the poor management and follow-up of participants with preeclampsia, no case of eclampsia was recorded since diagnosed pre-eclampsia cases were immediately managed.

No statistically significant difference was observed in the diastolic blood pressure at delivery (p = 0.126). A recent study carried out in Colombia by Herrera et al recorded a significant difference [22]. The inclusion of women less than 19 or greater than 35 years with a family history of preeclampsia and a daily dietary calcium intake less than 600mg might have been determining factors responsible for the significant difference observed with our recent study.

Participants in the calcium group developed pre-eclampsia 3 weeks later than the control group. The mean duration of pregnancy was 2 weeks longer in the calcium group (40.0 ± 1.3 weeks) compared to the control group (38.0 ± 2.2 weeks), findings similar to that recorded by Kumar, et al. in 2009 (39.5 ± 0.8 weeks and 37.7 ± 2.5 weeks in the calcium and control groups respectively). The observed effect could be mediated by a reduction in uterine smooth muscle contractibility induced by calcium [15].

In the light of our observation, calcium supplementation during pregnancy has proven to be effective in reducing the risk of occurrence of pre-eclampsia among primigravid pregnant women.

References

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More information: Journal of Clinical Endocrinology and Metabolism (2020). DOI: 10.1210/clinem/dgaa403

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