Dr Lynda Verghese, pictured right, Consultant Obstetrician and Maternal Medicine Lead, and Dr Yee Ping Teoh, pictured left, Consultant Clinical Biochemist, based at Wrexham Maelor Hospital, along with Dawn Hannah, Clinical Educator at Quidel, discuss the results of a pilot study that showed the significant social, economic and health benefits of the timely management of pre-eclampsia.
Patients presenting with symptoms of pre-eclampsia are often sent for overnight observations to monitor changes in parameters, such as maternal blood pressure and urinary protein concentration. The Covid-19 pandemic put unprecedented strain on hospitals to optimise resources and prevent unnecessary inpatient admissions, giving Wrexham Maelor Hospital, North Wales, the impetus to assess the clinical use of point-of-care (POC) placental growth factor (PLGF) testing to evaluate pre-eclampsia in patients sooner and free up hospital beds. This sensitive and rapid quantitative fluorescence immunoassay measures PLGF levels in just 15 minutes, allowing doctors to quickly stratify patients by risk and identify those likely to progress to delivery in 14 days.
The significance of pre-eclampsia
Pre-eclampsia is one of the most common causes of maternal morbidity, affecting up to 6% of pregnancies in the UK, with some cases progressing to severe illness. Thankfully, most mothers with pre-eclampsia will only experience relatively mild complications from the disease, but it is still crucial to diagnose and monitor the condition before it develops into something much more sinister. If left untreated, it can lead to serious physical and psychological consequences for both mother and baby, including intra-uterine growth restriction, preterm birth and placental abruption, requiring urgent admission and an extended stay in a maternity ward or intensive care unit.
Challenges of the diagnostic pathway
Indicators of pre-eclampsia, including high blood pressure and proteinuria (leakage of protein into the urine), are usually identified first by community midwives. However, symptoms are highly variable between individuals and give very little indication of how this complex condition may progress. For example, some women with severe pre-eclampsia may be asymptomatic or present with very mild and subtle signs, while others with more conclusive symptoms may have a better prognosis. These uncertainties regarding the accuracy of predictive measures mean that maternity services tend to err on the side of caution when referring women for close observation.
The basic blood and urine tests that are currently used for assessing the severity of pre-eclampsia lack the sensitivity required to predict the outcome of the patient, so a significant number of cases are admitted to the unit for further observations. Once patients are admitted, midwives are tasked with frequently monitoring symptoms and blood pressure for any changes, which may be subject to observer error and ambiguity. In addition, laboratory-based tests have a longer turnaround time depending on the availability and proximity of the lab to the patient, which can cause delays of several hours, leaving the patient waiting anxiously, while midwives do their best to keep them comfortable. This has a knock-on effect on the efficiency of operations at the induction bay, creating issues for bed capacity and staffing resources, and hindering the smooth flow of patients onto the labour ward.
Prolonged stays and additional care put mounting economic strain on maternity wards, with it costing an estimated £500 a day for a hospital bed in the UK. A low threshold for admitting women with early signs of pre-eclampsia, as well as delays in obtaining results, could lead to potentially unnecessary costs to the hospital and an inefficient use of resources. However, the consequences of diagnosing pre-eclampsia too late can also incur far greater costs, with increased intensive care admissions, preterm neonatal morbidities, risk of stillbirth and maternal complications such as HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome, epileptic fits and intracranial haemorrhage.
Coping with a new challenge
The burden of extended overnight stays on healthcare institutions is challenging at the best of times, but it became increasingly unmanageable during the Covid-19 pandemic, with hospitals stretched beyond their capacity. Maternity units across the nation still had to monitor and observe mothers with suspected cases of pre-eclampsia alongside the mounting pressures of limited inpatient bed capacities and widespread staff shortages during the height of the crisis.
The anxiety about staying overnight in a hospital for fear of contracting Covid-19 has also deterred many mothers from seeking additional care during pregnancy. 86% of maternity units in the UK reported a significant reduction in antenatal emergency presentations, despite advice to mothers to continue attending hospital in these incidences. Two-thirds of units also reported a significant decrease in the frequency of routine antenatal care appointments in 2020, and almost all units replaced some face-to-face reviews with phone calls or online sessions. Despite the best efforts of healthcare institutions to reassure mothers, the prospect of attending hospital as an outpatient during the pandemic was daunting enough, let alone the thought of an overnight stay.
Reading the signals
Never before has tightening up diagnostic pathways been more important and, for pre-eclampsia, changes were already tentatively underway since 2016, when testing for placental growth factor (PLGF) was first recommended for use by NICE and later, evaluated as a potential biomarker by the PARROT study. This study measured PLGF values in over 1,000 women with suspected pre-eclampsia over 16 months, and reported that it was effective in guiding decision-making for patient treatment and subsequently reducing poor patient outcomes.
PLGF is a protein that mediates the remodelling of placental spiral arteries for placental development. The concentration of PLGF in the blood naturally rises during gestation, reaching a peak at 26-30 weeks before falling towards term in healthy pregnancies. Aberrant PLGF levels can therefore signal placental dysfunction, which causes straight and narrow arteries to develop, restricting the flow of blood and nutrients to the fetus and potentially resulting in fetal growth restriction. Abnormally low concentrations of PLGF seem to precede the clinical onset of pre-eclampsia and may even pre-date symptoms by up to 10 weeks, making it an effective biomarker.
Bringing testing closer to the patient
A rapid, quantitative fluorescence immunoassay can be used as a point-of-care test (POCT) to quantify PLGF levels in the diagnosis of pre-eclampsia in women presenting with symptoms after 20 weeks and prior to 35 weeks gestation. The test has a high negative predictive value so can be used by clinicians in combination with other diagnostic measures to evaluate pre-eclampsia earlier, and stratify patients into risk categories based on their prognosis. Crucially, as a POCT, it can be performed in close proximity to the patients on the maternity ward, removing any potential delays in logistics.
Testing the clinical use of POCT
- During the Covid-19 pandemic, the Royal College of Obstetricians and Gynaecologists issued updated guidance for maternal medicine services to use PLGF and reduce the contact time of vulnerable pregnant women within secondary care. This gave the maternity department at Wrexham Maelor Hospital, North Wales, the impetus to embark on a pilot project to test the clinical utility of PLGF POCT as an adjunct in the management of pre-eclampsia. The department intended to use this rapid and accurate method to help make prompt decisions about the urgency of cases and reduce unnecessary hospital stays under the strain of the pandemic. Senior midwives in the department were trained to use the PLGF POCT so that it could be operated as a bedside test. The clinical utility of this POCT was assessed prospectively and presented by Obstetric Clinical Fellow, Dr Ashwin Ahuja. Over six months, 32 patients presenting with suspected pre-eclampsia were given a PLGF POCT upon admission, along with standard blood pressure and proteinuria monitoring, and stratified into three groups based on their recordings (table 1):
- normal PLGF ≥ 100 pg/mL (green)
- low PLGF 12-99 pg/mL (amber)
- very low PLGF <12 pg/mL (red)
- The need for a solution
Getting help to those who need it
Each of the three risk-based groupings were assigned to a different patient care pathway, determined by their need for further surveillance and risk of preterm delivery. Four women with PLGF <12 pg/mL were characterised as high risk for preterm delivery, and assessed as having pre-eclampsia – regardless of proteinuria levels – and given heightened inpatient surveillance and fetal growth ultrasounds. All of these women delivered in the same week as diagnosis, with pre-eclamptic toxaemia and HELLP syndrome was diagnosed in two of the four pregnancies. Importantly, all babies were delivered without a single case of maternal or fetal mortality.
Pre-eclampsia was considered a possibility in 14 women identified as having low PLGF levels between 12-99 pg/mL, with a perceived increased risk of preterm delivery. These mothers were given weekly outpatient surveillance, regular monitoring and a fetal ultrasound if deemed necessary. Only six received inpatient management due to experiencing further complications, such as a small-for-gestational age (SGA) fetus.
14 women were in the normal category with PLGF levels ≥ 100 pg/mL, providing reassurance to doctors and patients. Nine were deemed as highly unlikely to need preterm delivery due to pre-eclampsia within 14 days, so could return to routine outpatient antenatal care, while five were admitted for other clinical indicators.
Changing the outcome for patients
The introduction of POC PLGF triage testing helped to streamline the turnover of patients in the maternity unit and led to efficient use of midwifery staff. This POC immunoassay test demonstrated an excellent diagnostic value as an adjunct for the timely management of pre-eclampsia, returning results in approximately 15 minutes of starting the assay, so that those most at risk could be treated promptly to prevent further complications such as eclampsia, stroke or maternal morbidity. In instances of normal PLGF levels, testing provided much-needed reassurance to both the medical team and the patient, alleviating maternal anxiety and allowing mothers to return home safely for outpatient surveillance, or to continue to receive only routine antenatal care. This improved the overall patient experience for these women, reducing the impact on their mental health and avoiding the stress of having their lives turned upside down – potentially requiring additional childcare, time out of work, and unexpected costs from travel and parking.
There was also a measurable positive financial impact on the maternity ward and the trust as a whole. Safely evaluating the condition earlier for many women reduced the need for overnight observations, freeing up hospital beds and resources, amounting to a cost-saving of bed space equivalent to £37,296 over six months. A report by the Oxford Sustainable Coalition also suggested that the introduction of PLGF triaging testing across England could potentially save 1,000 tonnes of CO2 by subsequently cutting patient journeys and hospital stays. This was based on a study at the Oxford University Trust where evaluating pre-eclampsia sooner with PLGF testing reduced emissions by 35 tonnes of CO2, saved 37 cubic metres of water and produced almost two tonnes less waste per year.
There were also significant benefits to cases where pre-eclampsia could not be ruled out by PLGF testing, by streamlining these patients for further treatments or observations sooner. Of course, the physical and psychological implications of a healthy birth on mother and baby is the highest priority to any hospital, but the trust can also benefit financially from a safe delivery, which it can then put back into caring for more mothers. The hospital saved £1,118 per day by minimising the need to care for an iatrogenic preterm baby in intensive care, as well as avoiding the potential medicolegal costs of litigation that may ensue following a misdiagnosis.
Implementing POC PLGF triage testing as an adjunct in the decision-making for pre-eclampsia at Wrexham Maelor Hospital proved to have social, clinical and economic benefits for the NHS. Performing this assessment near to the patient helped provide a timely conclusion in under 30 minutes, allowing low-risk patients to promptly return home and back to normality. In the height of the pandemic, the pressure for rapid triaging solutions was critical, but the need to optimise resources and provide urgent reassurance to expectant mothers will always be there. Introducing POC PLGF testing can provide a quantitative method to streamline the maternal care pathway and improve patient experiences.
PLGF – Placental growth factor
POCT – Point-of-care testing
HELLP – Haemolysis, Elevated Liver enzymes, Low Platelets
Dr Verghese is a Consultant Obstetrician and Gynaecologist, and Labour Ward Lead at Wrexham Maelor Hospital. She runs the Maternal Medicine Clinic, which sees pregnant women with complex medical comorbidities, and the Preconception Women’s Clinic. She is also the principal investigator in the PARROT 2 research trial at Wrexham.
Dr Yee Ping Teoh has been a Consultant Chemical Pathologist at the Wrexham Maelor Hospital, North Wales, since 2008. Dr Teoh is also the Current Clinical Lead for Pathology services in Betsi Cadwaladr University Health Board, and a principal investigator for a significant number of cardiovascular and metabolic clinical trials.
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