Preeclampsia, a serious, potentially life-threatening hypertensive and inflammatory disorder of pregnancy, occurs in only 5%–8% of pregnant women but poses severe consequences for affected mothers and infants. In the U.S., an estimated 9% of maternal deaths and at least one-third of severe obstetric complications result from preeclampsia or its most severe manifestation, eclampsia. Adverse fetal and neonatal outcomes include intrauterine growth restriction, placental abruption, preterm delivery, respiratory distress syndrome, and necrotizing enterocolitis. Preeclampsia also puts women at risk for cardiovascular disease later in life.
The diagnostic mainstays of preeclampsia are hypertension ≥140 mmHg systolic or ≥90 mmHg diastolic and new-onset proteinuria, defined as ≥300 mg/dL in a 24-h urine collection or protein:creatinine ratio of 0.3—usually developing after 20 weeks of pregnancy. However, not all women with preeclampsia develop proteinuria, so the American College of Obstetricians and Gynecologists in 2013 updated its definition to reflect the syndrome’s complexity. In the presence of hypertension and other clinical signs as well as the absence of proteinuria, diagnostic test results indicative of preeclampsia include: thrombocytopenia, defined as a platelet count <100,000/µL; impaired liver function with enzymes “twice normal concentration”; and progressive renal insufficiency with serum creatinine concentration >1.1 mg/dL or in the absence of other renal disease.
Even with these diagnostic guideposts, clinicians would like better ways to identify preeclampsia earlier and to distinguish patients most at risk of severe complications. Diagnostic challenges arise particularly in women who have borderline symptoms, symptoms consonant with other conditions, or pre-existing diseases that mask preeclampsia until it blooms in full.
“For patients with pre-existing high blood pressure or diabetes, what’s new and what’s superimposed? It’s basically guesswork,” said Belinda Jim, MD, attending physician in the division of nephrology at Albert Einstein Medical College’s Jacobi Medical Center in the Bronx, New York.
A Complex Syndrome
The search for better preeclampsia diagnostic tools has been constrained by clinicians’ murky understanding of the disorder’s underlying causes, despite decades of research. Current models posit that maternal, fetal, and placental factors yield different manifestations of the syndrome. Abnormal vascular formation in the developing placenta, maternal endothelial dysfunction, and vascular inflammation appear to play varying roles.
Even with an imperfect understanding of preeclampsia’s pathogenesis, considerable research efforts are underway to identify biomarkers that could help clarify which women are truly at risk for progressing to full-blown preeclampsia and require early delivery, versus those unlikely to get worse.
“If these tests were positive, we could refer women to a tertiary care hospital with the potential for early detection of complications and delivery down the line,” said Ananth Karumanchi, MD, professor of medicine at Harvard Medical School and senior scientist with the department of obstetrics and gynecology at Beth Israel Deaconess Medical Center in Boston. Doctors could prescribe steroids, a common practice to help fetal lungs to prepare for early delivery. “If [tests are] negative, you could expect to prolong pregnancies by expectant management and perhaps not require mothers to remain in the hospital until they deliver,” he added.
A Promising Duo
Researchers have explored a laundry list of candidate biomarkers capturing different aspects of preeclampsia’s suspected pathophysiology, from human chorionic gonadotropin and α-fetoprotein to kallikrein and endothelin. Of these contenders, a particularly promising duo is the antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt1) and the proangiogenic placental growth factor (PlGf).
In 2003, Karumanchi and his colleagues reported sFlt1 was more abundant in the serum of women with preeclampsia. Karumanchi noted that sFlt1 seems to be expressed by the struggling placenta.
Subsequent studies showed the potential diagnostic significance of high circulating concentrations of sFlt1 in combination with low concentrations of PlGF. Automated tests for sFlt1 and PlGF have made large-scale diagnostics a realistic option. The sFlt1:PlGF ratio has been used to diagnose and predict preeclampsia in Europe since 2009, in countries such as the U.K., Germany, Italy, and Spain.
“The sFlt1:PlGF ratio helps us to better predict and diagnose preeclampsia. It is actually the first biomarker for the disease that has been proven to be helpful in the clinical setting,” said Stefan Verlohren, MD, PhD, a consultant in obstetrics and gynecology and head of the preeclampsia research group at Charité University Medicine in Berlin, which recently formed a research alliance with LifeCodexx to accelerate development of a novel genetics-based assay to detect preeclampsia in its early stages.
He and his colleagues recently reported in the New England Journal of Medicine the results of an international multi-center study involving more than 1,000 women in which they found that the sFlt1:PlGF ratio was useful in ruling out preeclampsia in women suspected of having the condition (N Engl J Med 2016;374:13–22). Among women who presented with signs and symptoms of preeclampsia after 24 weeks of pregnancy, those with a sFlt1:PlGF ratio ≤38 were not likely to develop the syndrome within the subsequent week. sFlt1:PlGF had a high negative predictive value of 99.3%. If women with suspected preeclampsia had an sFlt1:PlGF-ratio >38, the positive predictive value was 36.7% for them to develop preeclampsia in the subsequent 4 weeks.
“With this test we now are able to better decide whom to hospitalize and whom to send home. In Germany, we use this test in our routine clinical work-up for preeclampsia,” said Verlohren, who pointed out that fewer days of hospitalization translate to cost savings as well.
Karumanchi compared the current state of preeclampsia biomarkers to that of cardiac care before the development of assays for creatinine kinase and troponin. The introduction of those blood tests enabled clinicians to better understand what happens in myocardial infarction and, over time, to develop better interventions, he noted.
“That’s a big reason we need better diagnostic tests,” Karumanchi said. “We could then study those patients with interventions. Preeclampsia could become a lot like cardiology. We could treat patients early and avoid long-term damage.”
Karumanchi and Verlohren hope that Food and Drug Administration-approved tests for sFlt1:PlGF in preeclampsia will become available in the U.S. in as little as 2 years, but acknowledged that licensing a new diagnostic test can be unpredictable. “I hope it is closer to two years than 10 years,” Verlohren said.
Balancing Sensitivity and Specificity
Other researchers are not as enamored with the sFlt1:PlGF ratio. “What’s really needed for a rare condition like preeclampsia is a test with high positive predictive value,” said Ann Gronowski, PhD, DABCC, FACB, professor of pathology and immunology and medical co-director of clinical chemistry at Washington University School of Medicine in St. Louis. In cases of suspected preeclampsia, the chances that a woman referred for biomarker testing will be negative is already fairly high—even in a population of women with high blood pressure. So a biomarker with a high negative predictive value, like sFlt1:PlGF ratio, isn’t a useful tool, she added.
Gronowski is eager for a biomarker with a high positive predictive value that picks up the few patients who will go on to have preeclampsia from the many pregnant women with high blood pressure and proteinuria. In a recent post on The Pregnancy Lab, a blog about laboratory tests during pregnancy, she noted that the sFlt1:PlGF negative predictive value is not much better than a coin flip.
Gronowski conceded, however, that there may be some subpopulations for which this biomarker may be better at identifying women with preeclampsia. This would make sFlt1:PlGF more valuable in those subgroups, but those subgroups have yet to be identified.
Karumanchi concurred with Gronowski about the benefits of having a preeclampsia test with a high negative predictive value. “In the absence of a specific therapy for preeclampsia, the clinical need today in the population of suspected preeclampsia is for a negative predictive test that would enable physicians to safely prolong pregnancy for several weeks in those patients who have a negative test,” he explained.
That said, he still believes sFlt1:PlGF ratio, with its relatively low positive predictive value, has a place in identifying and managing women with preeclampsia. “The natural course of the disease is interrupted by early iatrogenic delivery in this population, and so [many] don’t have time to develop full-blown preeclampsia. If we use indicated delivery as a surrogate outcome then the positive predictive values are greater than 90 percent,” said Karumanchi.
For now, testing in the U.S. will continue to rely on blood pressure readings and proteinuria tests, practices endorsed in April 2017 by the United States Preventive Services Task Force in its first review of preeclampsia screening since 1996. Although this influential group noted the need for new markers to screen for the disorder, it also underscored that an incomplete understanding of preeclampsia’s complex pathophysiology limits researchers’ ability to assess screening tools.
Once that understanding sharpens, the promise of making the best use of current biomarkers and of developing even more informative tests may be realized.
Rina Shaikh-Lesko is a freelance science writer in San Jose, California. +Email: [email protected]