Preeclampsia Prevention: Key to the Reduction of Maternal Mortality

Obstetricians, politicians, and pundits have been discussing the problem of maternal mortality on a multitude of academic, media, and government platforms. Hypertensive disorders of pregnancy—specifically preeclampsia—remain prime targets since these disorders continue to constitute the leading causes of morbidity and mortality worldwide. Within the past few years, an array of new screening tests has come to the fore with a goal of combining pharmacological prophylaxis (low-dose aspirin), better stratification of care, and closer prenatal surveillance intent on preventing adverse outcomes.

The inception of serologic screening for preeclampsia has its roots in the mid-1970s, when U.S. screening programs for spina bifida utilizing maternal serum alpha-fetoprotein (AFP) were launched. Soon thereafter, note was made of the association of low circulating levels of AFP with fetal aneuploidy and of high ambient levels of AFP with adverse pregnancy outcomes including fetal demise, growth restriction, placenta accreta, and preeclampsia. ¹ An explosion in research efforts followed, with an eye toward uncovering serologic and sonographic markers for various fetal and maternal diseases with manifold practical and commercial applications. It is the purpose of this Brief Communication to discuss the newest frontier in assessing the risk of adverse maternal outcomes through the use of maternal serologic data and noninvasive testing with particular attention to preeclampsia.

Traditionally, a patient’s risk of preeclampsia drew on a variety of historical factors, including the patient’s pregnancy, medical, and even family history. While important for understanding the etiology and epidemiology of this disease, the relative risks so derived proved modest and certainly carried low positive predictive values for those who had proven screen-positive. While many substances and interventions have been studied in the prevention of preeclampsia (magnesium, zinc, antihypertensive medications, statins, vitamins), none has proven to be effective with the exception of aspirin. Thanks to a series of aspirin intervention studies in the late 20th and early 21st centuries, several meta-analyses affirmed a protective effect of aspirin in the prevention of preeclampsia. Moreover, the number of patients needed to treat seemed to be reasonable when only high-risk women were treated. By 2014, the United States Preventive Services Task Force (USPSTF) published guidelines as to which pregnant patients should be offered baby aspirin for the prevention of preeclampsia. These recommendations were reiterated and strengthened by the USPSTF in 2021.

The next iteration of screening for preeclampsia coincided with the arrival of noninvasive assessment of maternal risk with ultrasound and serologic markers. Rolnik et al. reported in 2017 on the impact of baby aspirin on reducing the incidence of preeclampsia in women at high risk for preterm disease. ² Although there had been a number of aspirin trials that preceded this trial dating back to the 20th century, the Rolnik trial was one of the first trials to base its inclusion criteria on a screening algorithm that included maternal history and noninvasively-derived characteristics from gestational ultrasound (uterine artery pulsatility index) plus maternal serum measurements (pregnancy-associated plasma protein A and placental growth factor [PIGF]). Several commercial labs have since entered this field to provide the requisite platforms to test patient sera in the first trimester of pregnancy so as to yield a risk assessment for preeclampsia.

To this crowded field of preeclampsia predication models, one can now add cell-open-access RNA (cfRNA). Circulating placentally derived RNA is just one subset of a larger category of circulating nucleic acids in maternal plasma and serum that are being investigated for their ability to predict maternal and fetal disease. Rasmussen et al. published data on cell-open-access RNA signatures that were associated with an increased risk of preeclampsia. ³ Their model yielded a sensitivity of 75% and a positive predictive value of 32.3%. Moreover, clinical variables such as BMI, age, and race proved immaterial, that is, they did not add to the accuracy of the model, which seems to lead us one step further towards generating a personalized risk profile early in pregnancy, one that can be acted upon to prevent morbidity and mortality. These cfRNA-based technologies are presently being offered by commercial laboratories.

Two other screening tests are worth mentioning as well. In May 2023, the U.S. Food and Drug Administration approved a screen that uses the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PIGF ⁴ to predict the progression of disease in women who present with preeclampsia in the late 2nd trimester and beyond. Moreover, in September 2023, De Borre et al. published preliminary data on the utility of cell-open-access DNA methylation patterns in the first trimester to predict preeclampsia. ⁵

So where are we heading? We now have noninvasive predictors early in pregnancy for a variety of fetal and maternal diseases, with more such prospects on the horizon. The literature is already being peppered with studies on predicting preterm birth, gestational diabetes, and the placenta accreta spectrum. The indications for and the utility of cfDNA in screening for fetal disease are expanding as well to chromosomal deletion syndromes (e.g., DiGeorge) and dominant diseases. Screening for monogenic disorders and whole exome sequencing of the fetus from maternal serum samples is likely not far off. Last but not least is a growing body of research that will allow one to design better screening programs for preeclampsia.

The challenge for clinicians and their professional organizations will be to sift through this body of data and establish screening algorithms that can be easily, broadly, and equitably implemented. The experience had in the early 21st century with the advent of prenatal cfDNA screening for aneuploidy is that, not surprisingly, much of the implementational thrust came from industry intent on popularizing and expanding the scope and indications for these tests. And, of course, one would have to figure out how to explain these screening algorithms to patients in ways that are efficient while fulfilling the ethical prescripts of informed consent.

Modern obstetrics is certainly up to this challenge. The discipline is in possession of many tools that professional organizations could use to analyze data and derive screening protocols that are both cost-effective and not burdensome for patients. The ability to predict maternal disease will benefit society by empowering the medical discipline to design prevention, treatments, and care pathways to further reduce maternal morbidity and mortality. And last, but certainly not least, in so doing, neonatal outcomes are bound to improve as well.

Precis

New serologic and sonographic screening tools are useful adjuncts in the predication and prevention of preeclampsia and, thus, maternal morbidity and mortality.

Authors’ Contributions

S.J.R. and E.Y.A. were involved in the conceptualization and the writing/editing of this article. S.J.R. wrote the original draft.