SMFM Special Report

smfm.org

Preeclampsia: a report and

recommendations of the workshop
of the Society for Maternal-Fetal Medicine
and the Preeclampsia Foundation
Society for Maternal-Fetal Medicine (SMFM); Judette M. Louis, MD, MPH; Jacqueline Parchem, MD; Arthur Vaught, MD;
Martha Tesfalul, MD; Anthony Kendle, MD; Eleni Tsigas, BA(Preeclampsia Foundation)

Preeclampsia is a substantial cause of perinatal and maternal morbidity and mortality. The prevalence of
this condition has increased over the past several decades. Additional opportunities are needed to foster
interdisciplinary collaborations and improve patient care in the setting of preeclampsia. In recognition of the
Preeclampsia Foundation’s 20th anniversary and its work to advance preeclampsia research and clinical
agendas, a 2-day virtual workshop on preeclampsia was cosponsored by the Society for Maternal-Fetal
Medicine and the Preeclampsia Foundation and held January 25-26, 2021 in conjunction with the 41st
annual pregnancy meeting. Leaders with expertise in preeclampsia research, obstetrical care, primary care
medicine, cardiology, endocrinology, global health, and patient advocacy gathered to discuss pre-
eclampsia prediction, prevention, management, and long-term impacts. The goals of the workshop were to
review the following issues and create consensus concerning research and clinical recommendations:

To present innovative opportunities for research on predicting, preventing, and managing

preeclampsia

To review the benefits and challenges associated with various strategies for preeclampsia prediction,
prevention, management, and postpartum follow-up

To identify research gaps for the prediction, prevention, management, and postpartum follow-up of
preeclampsia

To discuss needs and opportunities for research, increasing awareness, and risk mitigation of the
long-term effects of preeclampsia

This report, developed collaboratively between the SMFM and the Preeclampsia Foundation, presents
the key findings and consensus-based recommendations from the workshop participants.

Key words: maternal morbidity, maternal mortality, preeclampsia

Background cause of early severe forms has been attributed to

Evidence presented at the workshop demonstrates that abnormal placentation. Premature senescence or cellular
although preeclampsia is associated with substantial health aging has been proposed to underlie preeclampsia that
risks during and after pregnancy, there are opportunities to manifests later in gestation.1,2
improve the prediction, prevention, management, and
Preeclampsia is prevalent, occurring in 5% to 7% of
postpartum follow-up of patients with this disorder. pregnancies, representing approximately 10 million
Speakers highlighted the following: pregnancies per year worldwide.1

The incidence of preeclampsia increased by 25% between

Although much remains to be elucidated regarding the 1987 and 2004, potentially related to population-level in-
heterogeneity in the incidence and manifestations of creases in known risk factors for preeclampsia, such as
preeclampsia, this disorder is widely understood to be prepregnancy overweight and obese status, diabetes mel-
related to placental dysfunction and syncytiotrophoblast litus (DM), multiple pregnancy, and advanced maternal age.3
stress resulting from placental malperfusion. The root
Hypertensive disorders are responsible for 14% of
maternal deaths worldwide, representing the second
Corresponding author: The Society for Maternal-Fetal Medicine (SMFM). leading direct obstetrical cause globally,4 and 7.8% of
pubs@smfm.org maternal deaths in the United States.5

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American Indian or Alaskan Native, Black, and Hispanic patient safety bundles),40e43 addressing systemic and
birthing people in the United States are at increased risk community factors affecting health outcomes (eg, health
of maternal death in the context of hypertensive disorders insurance coverage),43,44 and investing in innovative care
of pregnancy compared with White birthing people sec- delivery models (eg, multidisciplinary clinics and
ondary to multiple factors, including disproportionate telemedicine).30,42,45
burden of comorbidities, racial bias, structural racism,
Concomitantly, support is needed for basic, translational,
and inequitable treatment.5 and clinical research efforts that aim to expand our

In low- and middle-income countries, a history of chronic fundamental knowledge of disease pathophysiology and
hypertension (HTN) is associated with an approximately phenotypes and to develop improved management
8-fold increased risk of preeclampsia, and preeclampsia strategies targeting those who are most likely to benefit
is associated with a 4.5-fold increased risk of maternal from existing or novel therapies.
death highlighting the importance of increased detection
and management of this comorbidity.6 Key findings and recommendations

Preeclampsia is associated with a 3-fold increased risk of The following key findings related to research and clinical
developing cardiovascular disease (CVD) later in life, care emerged from the workshop discussions:
which merits heightened awareness, risk mitigation, and
improved postpartum follow-up.7,8
Preeclampsia is a complex, heterogeneous disorder. The

Studies have found an association between sleep- clinical syndrome is composed of multiple overlapping
disordered breathing9,10 in pregnant patients and the clinical phenotypes that continue to complicate the
development of preeclampsia. diagnosis and management of the disease.

Higher rates of mental health disorders, including post-
Although multiple pathophysiological mechanisms have
traumatic stress disorder (PTSD), depression, and been associated with preeclampsia, placental dysfunc-
anxiety,11e13 are also observed among patients who had tion seems to be a unifying characteristic of the disease.
preeclampsia. Prioritization and assessments of targeted
Current research areas include preeclampsia risk
risk assessment and interventions could reduce this risk, assessment and risk stratification using molecular ana-
but more research is also needed to understand resil- lyses (eg, protein biomarkers and genetic variants) to
ience factors.14 identify high-risk patients and primary and secondary

Studies have reported associations of adverse neuro- prevention strategies using existing medications.
developmental and cardiovascular outcomes in offspring
Future research in the area of preeclampsia prevention and
in association with in utero exposure to preeclampsia.15e17 treatment should (1) use consistent and contemporary

Low-dose prenatal aspirin use has been found in many clinical definitions of preeclampsia; (2) incorporate molec-
studies to decrease the risk of preeclampsia18,19; how- ular biomarkers that reflect the risk of disease or subse-
ever, optimal strategy for implementation (eg, eligible quent disease severity to aid with objective recruitment of
pregnancies, dosing, or gestational age at initiation and patients and reporting of intervention outcomes, respec-
discontinuation) is still an area of ongoing debate and tively; and (3) recognize a spectrum of preeclampsia
study.20e26 severity that acknowledges several distinct pathways that

Remote home blood pressure (BP) monitoring, which has may result in the same pathologic endpoint.
increased in popularity during the COVID-19 pandemic, is
Several modifiable diseases that are implicated in pre-
feasible for the identification of subpopulations with BP eclampsia and adverse health outcomes—obesity,
elevations who benefit from greater monitoring and chronic HTN, DM, and sleep disorders—are potential
treatment, particularly those at higher risk of morbidity targets for reducing rates of preeclampsia during and
and mortality, such as Black birthing people.27e29 More after pregnancy.
work is needed to demonstrate the benefit of this inter-
Qualitative studies that incorporate patient experiences
vention and, if clinically beneficial, optimize and support with preeclampsia are needed.
access to its use both before and after delivery.30e34
As novel strategies for preeclampsia prevention, treat-

Guidelines, bundles, and collaboratives focused on ment, management, and postpartum follow-up are
optimizing the identification and management of hyper- developed, the appropriateness and feasibility of such
tensive disorders in pregnancy have been promoted to interventions must be considered in various settings,
decrease maternal morbidity and mortality.35e37 Further especially in low- and middle-income countries where
research is needed to determine the effectiveness of there is a disproportionate burden of disease and
these strategies on patient outcomes and potential un- resource limitations.
intended consequences.
Partnership with family medicine, internal medicine and

Improving outcomes related to preeclampsia domesti- their subspecialties, and emergency medicine should be
cally and globally will require listening to and engaging pursued in the development and implementation of HTN
patients and those close to them,38,39 ensuring access to care practices because of the important role these spe-
quality care (eg, respectful care, medical homes, and cialists play in caring for pregnant and postpartum people.

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Technologies, such as remote BP monitoring, telemedi- benefit pregnant patients, their families, and the scientific
cine, mobile and online health applications, and social community overall.
media, may be increasingly important interventions to
reach, educate, and empower patients and may be Preeclampsia prediction strategies and
crucial to improving access to some aspects of health- research needs
care.46 Larger, pragmatic studies are needed to deter- Role of predictive tools for preeclampsia
mine the impact of these technologies on patient Research efforts have focused largely on the early predic-
outcomes and potential unintended consequences. tion of preeclampsia or the development of adjunct diag-

Clinical interventions with the potential to improve pre- nostic tests. Early detection of heightened risk of
eclampsia outcomes that warrant further research preeclampsia through early risk assessment has the po-
include the use of diuretics, complement inhibition, sta- tential to improve outcomes by identifying candidates for
tins, more aggressive BP maintenance, postpartum and prophylaxis, such as acetylsalicylic acid and BP control, and
interpregnancy angiotensin-converting enzyme in- those who might benefit from increased surveillance.
hibitors, and optimal timing of delivery. Optimal delivery Furthermore, early risk assessment would ideally enable
timing also remains an important area of uncertainty researchers to detect disease earlier and define a target
worthy of ongoing discussion. population for treatment. This approach—akin to cancer

Patients with preeclampsia should have access to close screening, risk mitigation, and treatment—not only is more
clinical follow-up in the early postpartum period and care cost-effective than enrolling all patients but also increases
coordination with a primary care provider or cardiology the likelihood of identifying true treatment effects by limiting
for long-term risk assessment and mitigation. the enrollment of candidates (nonresponders) who are un-

Patients and their loved ones are at higher risk of mental likely to manifest preeclampsia or its severe sequelae.
health sequelae (eg, anxiety and PTSD) after experi- The ideal early risk assessment strategy would be safe,
encing preeclampsia and merit related screening and valid, reliable, easy to perform, and cost-effective.49 The
trauma-informed care accordingly. disease should be medically important and clearly defined,

Optimization of long-term cardiovascular risk stratifica- and an intervention must be available; the burden of pre-
tion and mitigation for patients who experience pre- eclampsia worldwide and the effectiveness of low-dose
eclampsia is needed given the underestimation of risk by aspirin prophylaxis satisfy these criteria. Historically, na-
many existing tools. tional guidelines have endorsed the assessment for pre-

The immediate postpartum period is an important time for eclampsia risk based on maternal factors, such as a history
clinicians to target interventions for people with pre- of preeclampsia, multifetal pregnancy, chronic HTN, or
eclampsia. The rates of maternal morbidity and mortality autoimmune disease.50e53 No combined risk assessment
are the highest during this time frame, and safe, effective strategy (ie, which uses molecular biomarker or imaging
interventions exist. modality in addition to clinical risk factors) has been uni-
versally endorsed because of unclear cost-effectiveness
Preeclampsia: “imitator” or “originator”? and the need for more evidence demonstrating robust
Preeclampsia is often referred to as the “great imitator.” This performance, including validation studies with adequate
description arises from the phenotypic similarities between sample size and diversity. In addition, the potential harms of
preeclampsia and other diseases.47 However, we argue that high false-positive rates after combined early risk assess-
this label is flawed and that preeclampsia does not merely ment require examination.54
mimic other conditions. Alternatively, perhaps the mecha- Several caveats regarding the use of early risk assess-
nisms underlying its progression are shared or common to ment for preeclampsia were discussed during the work-
other diseases. We propose that reconceptualizing the shop. Although screening that identifies individuals who will
framework for preeclampsia will be an important step for- develop early, severe forms of preeclampsia could avert the
ward towards its mechanistic origin. most severe adverse outcomes, a minority of preeclampsia
Preeclampsia is associated with an increased risk of cases fall into this category.54 Another important discussion
adverse health outcomes for pregnant people and their point regarding equity was that screening requires the early
children later in life.7,8,15e17 Because of the potential impli- establishment of prenatal care. This approach may dispro-
cations for lifelong health, more fervor in understanding the portionately preclude populations that have historically
mechanistic pathways and nidus of disease is needed. experienced barriers to healthcare, such as lack of insur-
Clinicians and researchers are encouraged to disentangle ance coverage and distance from a provider, but are
and examine the various manifestations of preeclampsia nevertheless at high risk of developing preeclampsia.
instead of merging the diverse array of phenotypes into 1 Furthermore, although there is general agreement that
category.48 Approaching the mechanistic pathways under- identification of appropriate candidates for low-dose aspirin
lying preeclampsia as “originators” of other conditions or a prophylaxis is an important goal, in the United States, many
disease process with its origin, will generate findings that patients will already meet the criteria for treatment based on

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the US Preventative Services Task Force (USPSTF) disease, and poor positive predictive value remains a
criteria.18,55 Thus, despite some geotargeted analyses,56 concern (ie, the maternal phenotype does not manifest in all
the added value and cost-effectiveness of universal cases of placental dysfunction). Fetoplacental-maternal in-
screening beyond clinical risk factors in the United States teractions are complex, and disease phenotype depends on
remains undetermined, until other interventions are multiple factors, including maternal susceptibility (preex-
identified. isting chronic disease and genetic predisposition) and the
In addition, objective tests may have a role later in preg- adequacy of compensatory responses. The National Insti-
nancy during the evaluation for suspected preeclampsia as tute for Health and Care Excellence (NICE) is the only or-
diagnostic and prognostic tools. When an individual pre- ganization that currently recommends incorporating
sents to a clinic or labor and delivery triage with new-onset biomarkers into standard clinical assessment and subse-
HTN or symptoms, prompt and accurate diagnosis and risk quent clinical follow-up to assist with ruling out pre-
stratification are key. Biomarker tests have been studied eclampsia.62 Guidance from the American College of
extensively for their potential to improve clinical decision- Obstetricians and Gynecologists (ACOG) in 2020, the So-
making in this context by (1) increasing the confidence in ciety of Obstetricians and Gynaecologists of Canada
and shortening the time to diagnosis of preeclampsia57 and (SOGC) in 2014, and the International Society for the Study
(2) identifying individuals at risk of disease progression and of Hypertension in Pregnancy (ISSHP) in 2018 states that
adverse outcomes.58 These tests have the potential to help the use of biomarkers and ultrasonography in the prediction
ensure appropriate surveillance (eg, high-risk patients are of preeclampsia should remain investigational and cannot
not inappropriately discharged from the hospital) and to aid be recommended routinely until such screening has been
in the decision to transfer to a higher-level center if needed. shown to improve pregnancy outcome.50e52
Moreover, there has been interest in their use as rule-out Novel tests and prediction models are being developed
tests given their high negative predictive value. A test that using data from transcriptomic and proteomic studies.63e65
reliably rules out development of severe disease or need for Recent work has identified maternal cell-free RNA signa-
delivery within the next week could allow for safe outpatient tures associated with preeclampsia.64,66 Another example is
monitoring of appropriately lower-risk patients and also the Congo red dot paper test based on proteomic studies
provide reassurance to patients and clinicians. showing that misfolded proteins are present in the urine of
patients with preeclampsia.67,68 Although workshop par-
Use of biomarkers for early risk assessment ticipants agreed that basic science efforts and exploratory
and prediction omics studies are important for the discovery of novel bio-
Biomarkers have been studied alone and as part of com- markers, participants also expressed the desire to see in-
bined strategies, such as the Fetal Medicine Foundation depth study and validation of existing biomarkers given
approach for preeclampsia screening.59 Although several the substantial amount of effort it takes to bring any one
placenta-derived proteins have been evaluated, the best- candidate to clinical use. A major challenge arising from the
studied and most robust predictive biomarkers for pre- complexity of preeclampsia and its heterogeneity and
eclampsia are the angiogenic factors placental growth subphenotypes is the lack of validation of predictive algo-
factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt- rithms. A recent study showed that protein-based predic-
1).60 Consistent alterations in levels of these circulating tion models derived from 2 cohorts from different
factors in preeclampsia and other diseases of placental geographic regions with disparate sociodemographic
dysfunction (eg, fetal growth restriction [FGR], stillbirth, and characteristics did not perform well when cross-validation
placental abruption) occur before the manifestation of clin- was attempted.69 Thus, multicenter studies that include
ical disease and reflect shared underlying pathophysiology diverse participants are necessary to develop prediction
involving placental hypoperfusion and oxidative stress.54 models that perform well for different populations and can
PlGF and sFlt-1 currently seem to be the best clinically be implemented beyond a local setting. In addition, the
available markers of placental reserve and are used in most identification and separate investigation of disease sub-
commercial preeclampsia tests for both screening and types will likely improve the accuracy of predictive tests.48
diagnostic aids during the evaluation for suspected pre-
eclampsia; however, no biomarker test for preeclampsia is Prediction research strategies
currently available for commercial use in the United States. Various research strategies are being used to better predict
Despite their potential and use in some countries (eg, the who is most at risk of developing preeclampsia and subse-
United Kingdom), some challenges have limited the wide- quent adverse outcomes once a diagnosis has been estab-
spread adoption of biomarker tests. Reference ranges are lished.67,70 Experimental studies in patients and animal
dependent on gestational age; thus, accurate gestational models during the last decade have led to a better under-
dating is essential. Different assays for the same protein standing of the pathophysiology of this disorder and thera-
may not be comparable because of differences in assay peutic targets for treatment.1 Placental ischemia caused by
performance and specifications.61 Importantly, the pres- impaired placental spiral artery remodeling and reduced
ence of placental dysfunction is not sufficient to cause perfusion is thought to play a central role in the

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pathophysiology of many, but not all, instances of pre- Future omics studies will require large, well-phenotyped
eclampsia.71,72 The release of antiangiogenic and proin- cohorts with genetic data to examine relationships among
flammatory placental factors from the ischemic placenta individual data points. Thus far, research in this area has
results in an up-regulation of the endothelin system, impaired been limited by cohorts without paired maternal-fetal or
production of nitric oxide, and vasoconstriction that contrib- placental samples and studies of small sample sizes or with
utes to disruptions in cardiac, cerebrovascular, renal, and different methodologies. Sharing data and biosamples is
hepatic function and, subsequently, the development of necessary to acquire sufficient data and materials for omics
HTN.71 Workshop participants concluded that translational studies. This sharing would be facilitated by common defi-
research incorporating findings from animal models, in vitro nitions and endpoints77e79 and the use of harmonized
studies, and clinical studies is necessary to develop suc- databases.80
cessful preeclampsia treatment and prediction strategies.
The application of machine learning for early detection of Future research
preeclampsia and identification of subtypes of the disorder Exciting advances in preeclampsia research have revealed
and molecular targets for intervention is a relatively recent insights into the complex biology and mechanisms under-
and new approach. By identifying patterns within large lying the syndrome. However, our knowledge of disease
datasets, such as ultrasound imaging data, machine biology and the optimal approach to clinical management
learning may be a useful strategy for predicting or classi- remains incomplete. Improving our primitive understanding
fying preeclampsia subtypes. Workshop participants of preeclampsia requires the integration of basic science
emphasized that such an approach has been successful in and clinical research through multidisciplinary collabora-
cancer research, where the focus has shifted to classifying tions between physicians and scientists. Advanced ap-
disease subtypes based on tumor genotype. proaches in the laboratory, including comprehensive
However, there is a potential for unintended conse- assessments of circulating placental factors during preg-
quences of machine learning. Because models are built by nancy, and the application of sophisticated analytical
humans, they can be trained to reinforce existing biases techniques, such as machine learning, are generating novel
related to race and ethnicity, age, or other variables. A reli- hypotheses and big data ripe for discovery. Simultaneous
ance on machine learning or artificial intelligence has the investigation of protein function and fundamental disease
potential to result in overtesting during pregnancy and mechanisms using in vivo and in vitro model systems will
removing the “human element” from clinical practice. continue to be important to validate and interpret findings
Workshop participants cautioned that although a global, big from exploratory studies.
data approach may help identify new mechanisms under- The identification of preeclampsia subtypes based on
lying the pathophysiology of preeclampsia, basic science mechanism is crucial if we are to develop a classification
approaches will still be necessary to test hypotheses scheme that is useful for clinical research. The recognition
generated through machine learning and from any explor- and subtyping of disease-based molecular phenotypes
atory experiments or datasets. similar to the approach that has been taken in oncology
As noted previously, omics, including genomics, tran- would enable the move away from the suboptimal one-size-
scriptomics, proteomics, and metabolomics, have uncov- fits-all approach toward the ultimate goal of precision
ered insights into disease pathophysiology and further medicine—the right treatment for the right patient at the
highlighted the heterogeneity of preeclampsia. Preeclamp- right time.81 In clinical research, the grouping of heteroge-
sia is a complex genetic trait with heritability that has been neous patients under the umbrella of “preeclampsia” has
estimated at 55% to 60%.73 Genome-wide association likely diluted effect sizes and undermined efforts to identify
studies (GWASs) have been used to identify variations in the interventions effective for certain subtypes of preeclampsia.
maternal and fetal genome associated with an increased International consensus regarding a framework for pre-
risk of preeclampsia.74e76 For example, results from a eclampsia diagnosis and classification is an important goal
GWAS of 4380 offspring from pregnancies with pre- so that study results can be compared and for cross-
eclampsia compared with that of 310,238 controls suggest validation efforts.
that multiple causal variants near the fetal FLT1 locus may
contribute to disease risk. This association is biologically Preeclampsia prevention strategies and
plausible as FLT1 encodes fms-like tyrosine kinase 1, which research needs
has been implicated in the pathology of preeclampsia.74,75 A Aspirin
meta-analysis of 8 GWASs comparing 9515 women with Aspirin has been studied extensively for its role in modifi-
preeclampsia with 157,719 controls found 1 locus near the cation of cardiovascular health. Initial investigation of aspi-
fat mass and obesity-associated gene with genome-wide rin’s role in preventing preeclampsia began in the 1980s.
importance in the risk of preeclampsia.75 Moreover, this Since that time, it has emerged as a recommended medical
locus has been found to be important in the development of treatment in the prevention of preeclampsia.
HTN and increased body mass index (BMI), supporting In 2013, the ACOG published the Hypertension in Preg-
overlap among preeclampsia genetics with other traits.75 nancy Task Force Report, which supported the use of

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low-dose aspirin in people with a previous history of early- mg of aspirin showed a greater relative risk (RR) reduction with
onset preeclampsia or multiple pregnancies complicated by higher doses (RR, 0.88 vs 0.64).19 In the same year, the
preeclampsia. In 2021, the ACOG and the SMFM recom- Perinatal Antiplatelet Review of International Studies Collab-
mended the use of low-dose aspirin (81 mg/day) between 12 oration—an individual patient data meta-analysis of 31 ran-
and 28 weeks of gestation in people at high risk of pre- domized trials—found an RR of 0.9 (95% confidence interval
eclampsia and those with multiple moderate risk factors.82,83 [CI], 0.84e0.97) for preeclampsia with doses of aspirin
Many other large healthcare organizations have adopted ranging from 50 to 150 mg daily.93 The effects of a similar
recommendations regarding the use of antiplatelet agents for aspirin dose range (60e150 mg daily) were the subject of a
the prevention of preeclampsia, including the USPSTF, NICE, systematic review by the USPSTF in 2021 that pooled data
and World Health Organization (WHO).18,53,84 These recom- from 23 good- and fair-quality randomized trials. This review
mendations are summarized in Table 1. reported a 15% reduction in preeclampsia among patients
Antiplatelet therapy has some of the most robust evi- administered aspirin compared with controls (16 randomized
dence as a prevention strategy for preeclampsia. However, controlled trials [RCTs], n¼14903; RR, 0.85; 95% CI,
interpretation of the data has resulted in varying opinions 0.75e0.95).18 The Aspirin for Evidence-Based Preeclampsia
regarding the optimal dose, timing, and target population, Prevention (ASPRE) trial—a recent multicenter randomized
as reflected by the differing recommendations by national trial of 1776 at-risk patients—showed a decreased odds of
organizations, suggesting more research is needed to refine developing preterm preeclampsia in the 150 mg per day
and standardize treatment guidelines. The earliest trials aspirin group compared with the placebo group (odds ratio
exploring the use of low-dose aspirin demonstrated a [OR], 0.38; 95% CI, 0.2e0.74; P¼.004).94 Conversely, a 2021
reduction in preeclampsia with doses between 60 and 100 multicenter randomized trial of 898 at-risk patients in China
mg daily; however, these trials were limited by small sample failed to show a statistically significant reduction in the inci-
size.85e88 Initial randomized trials, such as the 1994 dence of preeclampsia (RR, 1.220; 95% CI, 0.720e2.066;
Collaborative Low-Dose Aspirin Study in Pregnancy trial P¼.459) among a high-risk pregnant population.95
and the 1998 National Institute of Child Health and Human Most studies of low-dose aspirin for preeclampsia pro-
Development (NICHD) Network of Maternal-Fetal Medicine phylaxis start intervention between 12 and 28 weeks of
Units trial called into question the efficacy of aspirin in gestation. Large studies evaluating the timing of low-dose
preventing preeclampsia among women at risk of the con- aspirin have consistently used 16 weeks of gestation to
dition.89,90 Other randomized trials of aspirin for the pre- distinguish comparative groups. Several large aggregate
vention of preeclampsia among healthy, nulliparous women meta-analyses have shown the greatest reduction of severe
demonstrated a very small or no effect on the incidence of preeclampsia when low-dose aspirin is started before 16
preeclampsia in this population.91,92 weeks of gestation.96,97 However, a recent individual patient
Since this time, however, several large studies have data meta-analysis showed consistent benefit regardless of
demonstrated a modest risk reduction with variable doses of the timing of low-dose aspirin, concluding that high-risk
aspirin. A 2007 Cochrane review of 59 trials noted an overall people should be offered prophylaxis even if their entry to
17% reduction in preeclampsia with antiplatelet therapies. prenatal care is beyond 16 weeks of gestation.98 No study
Subgroup analysis comparing those trials using 75 and >75 has demonstrated apparent benefit to discontinuing aspirin

TABLE 1
Recommendations for low-dose aspirin for prevention of preeclampsia
Organization Dose recommendation
18
USPSTF (2021) 81 mg daily after 12 weeks of gestation with any high-risk condition or more than 1 moderate-risk condition
83
ACOG or SMFM (2021) 81 mg daily between 12 and 28 weeks of gestation (ideally by 16 weeks) with any high-risk conditiona or more than
1 moderate-risk conditionb
WHO84 75 mg daily before 20 weeks of gestation with any high-risk condition
53
NICE (2019) 75e150 mg daily after 12 weeks of gestation with any high-risk condition
ACOG, American College of Obstetricians and Gynecologists; NICE, National Institute for Health and Care Excellence; SMFM, Society for Maternal-Fetal Medicine; USPSTF, United States Preventative
Services Task Force; WHO, World Health Organization.
a
High-risk factors: history of preeclampsia, especially when accompanied by an adverse outcome, multifetal pregnancy, chronic hypertension, pregestational type 1 or 2 diabetes mellitus, kidney
disease, autoimmune disease (ie, systemic lupus erythematous or antiphospholipid syndrome), or combinations of multiple moderate-risk factors.; b Moderate-risk factors: nulliparity, obesity (ie,
body mass index of >30), family history of preeclampsia (ie, mother or sister), age of 35 years, personal history factors (eg, low birthweight or small for gestational age, previous adverse
pregnancy outcome, and >10-year pregnancy interval), and in vitro pregnancy. The moderate-risk factors Black race (as a proxy for underlying racism) and lower income are associated with
increased risk of preeclampsia because of environmental, social, structural, and historic inequities shaping health exposures, access to healthcare, and the unequal distribution of resources, not
biologic propensities, and low-dose aspirin can be considered if the patient has one of these moderate-risk factors.
Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet
Gynecol 2022.

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before delivery, and current guidelines recommend contin- shown a lack of teratogenicity in observational and ran-
uation until delivery.82,83 domized trials. Safety profiles have been well established in
Maternal risk stratification is common in most profes- the nonpregnant adult population.101 A 2016 pilot random-
sional organization recommendations for determining the ized trial conducted by the Eunice Kennedy Shriver NICHD
target population for low-dose aspirin prophylaxis.18,84 In a Obstetric-Fetal Pharmacology Research Units Network
2019 Cochrane review, the administration of aspirin led to a found a reduction in the rates of preeclampsia in the small
substantially greater reduction in the development of pre- group of patients with a previous history of preterm pre-
eclampsia in high-risk pregnancies than in moderate-risk eclampsia who received 10 mg pravastatin initiated be-
pregnancies, 25% vs 14%, respectively.19 Similarly, the tween 12 and 16 weeks of gestation compared with placebo
analysis of risk group disease prevalence and treatment (40 vs 0%).102 The data are promising and signal a possible
effect by the USPSTF suggests that a risk of preeclampsia effective intervention but the small size of 10 patients per
of at least 8% be used to identify high-risk patients likely to arm precludes definitive judgment. A 2021 double-blind
benefit from low-dose aspirin.18 Because aspirin is inex- placebo-control trial randomized 1120 high-risk patients
pensive, is widely available, and has favorable maternal and between 35 and 36 weeks of gestation to pravastatin 20 mg
fetal safety profiles, some experts have advocated for the vs placebo. Pravastatin in these patients did not reduce the
universal administration of aspirin during pregnancy for the incidence of delivery with preeclampsia in this study.103
reduction of preeclampsia and other adverse perinatal Although further trials will help define the role of pravas-
outcomes.20,21,55,99 tatin as an effective prophylactic treatment in the develop-
Workshop participants emphasized that the potential ment of preeclampsia, other studies have examined its role
benefits of aspirin therapy in the prevention of preeclampsia as a therapeutic agent in pregnancies after the diagnosis of
cannot be achieved without patient awareness and support. preeclampsia. The Statins to Ameliorate Early Onset Pre-
Discussion of the risks and benefits of low-dose aspirin Eclampsia randomized trial did not find a difference in
therapy in pregnancy should be a component of the initial maternal sFlt-1 levels, latency to delivery, or other preg-
prenatal visit, especially for people at high risk of developing nancy outcomes.104 Conversely, in a prospective study of
preeclampsia during their pregnancy. Educational resources women with antiphospholipid antibody syndrome, those
for patients are available through organizations, such as who received pravastatin 20 mg in addition to standard of
MotherToBaby (https://mothertobaby.org/fact-sheets/low- care at the time of preeclampsia diagnosis were found to
dose-aspirin), the Preeclampsia Foundation (https://www. have lower BPs, longer pregnancy latency, and higher infant
preeclampsia.org/aspirin), and the SMFM (https://www. birthweights.105 Given the current body of literature, the use
highriskpregnancyinfo.org/preeclampsia). Moreover, pro- of statins for the prevention or treatment of preeclampsia is
viders should be aware of additional opportunities for promising, but it remains investigational.
delivering information and resources to at-risk individuals.
Programs, such as Aetna Maternity Program—a collabora- Novel therapeutics
tion between CVS Health and Aetna—use insurance claims Preeclampsia therapeutics is a burgeoning field within
data to identify people at high risk of preeclampsia. The maternal care. There is insufficient evidence to recommend
Aetna program sends a kit containing educational materials many of the proposed prevention modalities, including
and a bottle of 81 mg aspirin to patients to promote aware- vitamin C, vitamin E, vitamin D, folic acid, fish oil, garlic
ness of preeclampsia and encourage patient-initiated supplements, and sodium restriction.50 Metformin has
engagement with their prenatal providers on this topic.100 been studied as a potential medical therapy with promising
findings.106 Similar to statins, metformin has been
Statins shown to alter angiogenic imbalance by reducing sFlt-1
Statins are another class of commonly used drugs that have and soluble endoglin.107 A meta-analysis of studies in
become a focus for preeclampsia prevention research. high-risk women with insulin resistance did not show a
Statins are classically known as cholesterol-lowering reduction in preeclampsia compared with placebo or con-
agents; however, their use in overall endothelial health is trol; however, there was a reduction noted among 8 ran-
becoming more evident. Beyond their antiatherogenic domized trials comparing metformin with insulin (RR, 0.68;
properties, statins have also been implicated in the stabili- 95% CI, 0.48e0.95; P¼.02; I2¼0%).108 Moreover, non-
zation of atherosclerotic plaques, endothelial protection, pharmaceutical interventions are being explored as a
and decreased inflammation.101 These characteristics strategy for preeclampsia treatment. In 2011, Thadhani
contribute to the biologic plausibility of statins as agents to et al109 investigated single dextran sulfate cellulose apher-
prevent the development of preeclampsia. esis treatment in women with very preterm preeclampsia
Pravastatin, a first-generation statin, was discussed dur- and showed a reduction in circulating sFlt-1, proteinuria,
ing the workshop as a potential candidate for treatment in and BP. Current use of metformin and plasma apheresis for
both animal and human trials. As a low-potency statin with the prevention and treatment of preeclampsia is limited to
limited transplacental transfer, pravastatin has consistently clinical trials.

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Future research and clinical issues pregnancy, it is prudent to follow long-term infant neuro-
Compelling evidence for any 1 prevention strategy for developmental outcomes because of the intimate role of
people at risk of preeclampsia has not yet been found, and cholesterol in fetal brain development.
given the heterogeneity in disease subtypes and pheno- Abundant opportunity exists to study preeclampsia pre-
types, it is unlikely that a single intervention will be beneficial vention strategies concerning population health and health-
in all cases. Even the best candidates for treatment regi- care disparities. Several modifiable diseases that are
mens, including aspirin and statins, are met with conflicting implicated in preeclampsia and adverse health outcomes—
results from trials often limited by small sample size or obesity, chronic HTN, DM, and sleep disorders—are poten-
inconsistent definitions of disease. Future research in the tial targets for reducing rates of preeclampsia. Weight
area of preeclampsia prevention depends on establishing reduction and bariatric surgery have been associated with
an objective framework for stratifying patients into trials reduced rates of hypertensive disorders of pregnancy.111
(potentially using biomarkers) and selecting appropriate in- Similarly, the use of continuous positive airway pressure
terventions based on risk factors and preeclampsia sub- therapy in people with sleep-related breathing disorders may
types. In the past 30 years, our understanding of be an avenue to reduce preeclampsia and modify future
preeclampsia has evolved from a hypertensive disorder with cardiovascular risk long term.112 Additional studies that reli-
renal dysfunction to a complex cascade of angiogenic and ably include race and ethnicity and address healthcare dis-
inflammatory dysfunctions resulting in a multisystemic parities, effects of systemic racism, and the role of
syndrome. This evolution has seen multiple iterations of the psychosocial stressors not only contribute to data on pre-
definitions and clinical diagnostic criteria of preeclampsia. eclampsia prevention but also help ensure equity in popula-
This fact alone confounds the interpretation of noncon- tion trials.113 Moreover, qualitative studies incorporating
temporary randomized trials and large meta-analyses and patient voices and their experiences with provider counseling
brings into question the actual disease and severity being on preeclampsia prevention are important to evaluate how
assessed. evidence-based recommendations for prevention are per-
As such, future research in the area of preeclampsia formed on a practical level. Programs, such as the Pre-
prevention should (1) use strict, consistent, and contem- eclampsia Foundation’s Cuff Kit Program, Aetna’s Maternity
porary clinical criteria for defining preeclampsia; (2) incor- Program, and various remote BP monitoring programs, can
porate molecular biomarkers that reflect the risk of disease be leveraged to study ways to reduce disparities in patient
or subsequent disease severity to aid with objective education and intervention in high-risk populations. Lastly, it
recruitment of patients and reporting of intervention out- is crucial to continue to study efforts of preeclampsia pre-
comes, respectively; and (3) recognize a spectrum of pre- vention globally. Multinational data from the WHO have
eclampsia severity that acknowledges several distinct shown that an increased number of antenatal visits was
pathways that may result in the same pathologic endpoint. protective for preeclampsia.6 As novel strategies for
Filling gaps in knowledge is a priority not only for preeclampsia prevention arise, consideration of
improving the efficacy of current well-investigated prophy- intervention cost and disease effect in low- and middle-
lactic strategies but also for identifying potential innovations income countries must be considered when formulating
in preeclampsia prevention. Although low-dose aspirin is recommendations.6
currently endorsed by the ACOG and the SMFM, additional
large RCTs are needed, such as the ASPRE trial,110 that Preeclampsia management strategies and
incorporate serum markers into maternal risk stratification. research needs
Head-to-head trials comparing different doses of aspirin will Telehealth in preeclampsia
aid in determining optimal dosing and adjust for variations in Telehealth and patient monitoring range from patient input
dosing based on regional availability of drug formulations. of blood sugars and BP in the settings of DM and hyper-
Translational research of thromboxane and prostacyclin tensive disorders of pregnancy to face-to-face consultation
imbalance in preeclampsia not only will improve under- using camera services.114e116 The COVID-19 pandemic
standing of aspirin’s mechanistic role in preeclampsia pre- necessitated the expansion of telehealth and showed its
vention but also may offer novel assays that can be used for potential to provide a mechanism for improved provider-
risk stratification. Lastly, there is a paucity of data regarding patient relationships and care continuation, including in
the use of low-dose aspirin in the prevention of postpartum the setting of preeclampsia. Research from before the
preeclampsia. pandemic showed that telehealth is useful.114e116 Tele-
As studies continue to investigate the role of statins in the health may even provide equitable access to care by
prevention of preeclampsia, a need for additional large, reducing geographic or social barriers posed by in-person
randomized trials will also be warranted to define the optimal visits. Patients can consult with clinical teams and seek
statin drug, dose, timing, and target population. In addition, expert opinion in other geographic regions. Moreover, it
future studies comparing the effects of low-dose aspirin vs adds active patient participation and accountability via
statin vs combination should be explored. Although safety recording data points, such as BP and maternal weight.
data for pravastatin have been established during Therefore, it is not surprising that telehealth may be a

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reasonable option for monitoring patients for preeclampsia, Although the benefits of maternal safety bundles seem
specifically in the postpartum period.27,31 promising, gaps in success in protocolized hospitals could
Similar to many areas of medicine, the use of telehealth be the result of inequitable use of such safety bundles
must continue to be evaluated for overt and underlying across hospital systems and within hospital systems with
disparities. For example, although institutions may report patients. Current data show that unconscious bias and
that telehealth visits are available to everyone, there may systemic racism in medicine contribute to healthcare dis-
be disparities in access to mobile devices, wireless parities, particularly for Black women.129e131 A research
Internet and cell phone coverage, technology literacy, opportunity for collaborative hospitals and organizations
home BP monitors, and safe and private spaces to discuss should be to identify if these disparities exist internally in the
medical care. Social media and electronic health records ability or willingness of staff to implement a HTN safety
may be useful mechanisms for providing information to bundle consistently. Finally, because pregnant and post-
patients. However, clinicians should be aware that ease of partum patients may be seen in the emergency department,
use for patients with 1 technology may not translate to labor and delivery triage, urgent outpatient care, or other
another. It is important for patients to receive information community healthcare settings, partnership with primary
through methods and language that they can easily care, internal medicine and their subspecialties and emer-
understand. gency medicine should be pursued in the development and
implementation of HTN care bundles.
Bundles
Approximately 50% to 60% of pregnancy-related deaths Preeclampsia criteria, hypertension
are preventable.117,118 In a study of pregnancy-related management, and delivery timing
deaths in California, 60% of preeclampsia deaths were One of the challenges identified by workshop participants in
preventable.119 Similar preventability has been observed for implementing preeclampsia guidelines and protocols from
severe maternal morbidity (SMM), particularly in cases of other countries was the inconsistency in terminology, such
preeclampsia and severe HTN.120e122 Provider factors, as the criteria and management of severe disease (Table 2).
such as knowledge and referral, and system of care factors, For example, in the US classification system, the ACOG
such as communication, have been identified as key con- delineates 4 different classifications of preeclampsia.132 In
tributors to preeclampsia and eclampsia deaths.123 contrast, the ISSHP does not have a specific classification
Maternal safety “bundles” are 1 intervention aimed at for people with preeclampsia. The ISSHP states that the
reducing such preventable adverse outcomes.41,124 Bun- “severity” of preeclampsia is arbitrary, and it does not
dles are developed from evidence-based guidelines and advocate for a clinical distinction between “mild” and “se-
expert opinion and provide standardized approaches to vere” diseases.52,133 The subtle differences in the ISSHP
managing obstetrical emergencies and complications. system could allow a person who once had severe-range
Bundles include patient information, provider information, HTN (preeclampsia with severe features [SFs]) to continue
and algorithms that include risk assessment tables and a pregnancy beyond 34 weeks of gestation as long as their
medication dosages. The national and international in- BPs were controlled or allow a person with downtrending or
vestments in maternal safety bundles, such as the severe improving laboratory parameters (eg, hemolysis, elevated
HTN bundle, stem from the preventable nature of maternal liver enzymes, and low platelet count [HELLP] syndrome) to
morbidity and severe maternal mortality and the relatively remain pregnant past betamethasone completion. More-
simple measures for treating HTN. over, NICE does not recommend that all people with pre-
The use of care bundles in obstetrics does show promise. eclampsia be admitted, and they delineate features
Care bundles seem to be most effective in settings, such as consistent with more severe disease that requires admis-
intensive care units or trauma wards during sion.53 Finally, similar to NICE and the ISSHP, the SOGC
procedures.125e127 Clark et al124 showed a decrease in agrees that there is no international consensus on what
hypertension-related deaths in a large national database defines “severe” preeclampsia. The SOGC characterizes
reviewing maternal mortality before and after safety bundle the end-organ dysfunction of preeclampsia as either
and protocol implementation (15 vs 3 deaths; P¼.02). In Il- “adverse conditions” or “severe complications” and rec-
linois, the implementation of a severe maternal HTN initia- ommends timing of delivery based on maternal and fetal
tive between 2016 and 2017 led to an increase in the well-being (Figure 1).52
percentage of new-onset severe HTN cases treated within Recommendations for the management of BP also differ
60 minutes (41.5%e78.9%) across 98 hospitals.128 In Cal- by society and within institutions (Figure 1). The ISSHP,
ifornia, Nevada, and Arizona, the implementation of a toolkit ACOG, NICE, and SOGC all agree that antihypertensive
aimed at reducing the incidence of eclampsia and SMM treatment should be initiated expeditiously for severe acute
across 23 hospitals between 2015 and 2016 led to a HTN (systolic BP of 160 mm Hg, diastolic BP of 110 mm
decrease in the incidence of eclampsia by 42.6% Hg, or both) that is confirmed and persistent.50,51,53,134
(1.150.15/1000 to 0.620.09/1000 births) and a decrease Intravenous labetalol, hydralazine, and immediate-release
in SMM by 16.7% (2.400.10 to 2.000.15; P<.01).37 oral nifedipine are all reasonable first-line agents in the

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TABLE 2
Preeclampsia classification, definition, and management by academic society (as of January 2021)
Preeclampsia for expectant management to Preeclampsia for expectant management Preeclampsia requiring delivery at betamethasone
Variable 37 weeks of gestation to 34 0/7 to 36 6/7 weeks of gestation completion or immediate delivery
ACOG50 Preeclampsia without SFs Preeclampsia with SFs
Uncontrolled severe-range BPs (persistent SBP of 160 mm Hg
BP:
SBP of 160 mm Hg or DBP of 110 mm or DBP of 110 mm Hg not responsive to antihypertensive

SBP of 140 mm Hg or DBP of 90 mm Hg on 2 occasions at least 4 h apart (unless medication)
Hg on 2 occasions at least 4 h apart after antihypertensive therapy is initiated before
Persistent headaches or refractory to treatment
20 weeks of gestation in a woman with a this time)
Epigastric pain or RUQ pain unresponsive to repeat analgesics
previously normal BP
Thrombocytopenia
Visual disturbances, motor deficit, or altered sensorium

SBP of 160 mm Hg or DBP of 110
Impaired liver function that is not accounted
Stroke
mm Hg Proteinuria: for by alternative diagnoses and as indicated
Myocardial infarction

300 mg per 24 h urine collection (or this by abnormally elevated blood concentrations
HELLP syndrome
amount extrapolated from a timed collection) of liver enzymes (to more than twice the upper
New or worsening renal dysfunction (serum creatinine

Protein or creatinine ratio of 0.3 limit normal concentrations) or by severe of >1.1 mg/dL or twice the baseline)

Dipstick reading of 2þ (used only if other quantitative persistent RUQ or epigastric pain unresponsive
Pulmonary edema
methods not available) to medications
Eclampsia
In the absence of proteinuria
Renal insufficiency
Suspected acute placental abruption or vaginal bleeding
or new-onset HTN with the new onset of any of
Pulmonary edema in the absence of placenta previa
the following:
New-onset headache unresponsive to
Abnormal fetal testing

Thrombocytopenia: platelet count <100  109/L medication and not accounted for by
Fetal death

Renal insufficiency: serum creatinine concentrations alternative diagnoses
Fetus without expectation for survival at the time
of >1.1 mg/dL or a doubling of the serum creatinine
Visual disturbances of maternal diagnosis
concentration in the absence of other renal disease
Persistent reversed end-diastolic flow in the

Impaired liver function: elevated blood concentrations umbilical artery
of liver transaminases to twice normal concentration

Pulmonary edema

New-onset headache unresponsive to medication
and not accounted for by alternative diagnoses
or visual symptoms
ISSHP51 No specific title other than preeclampsia: No specific management strategy No specific title other than preeclampsia:

All preeclampsia cases not requiring immediate
Gestation at 37 weeks of gestation
delivery or delivery at betamethasone completion
Ongoing neurologic features, such as severe intractable
headache, repeated visual scotomata, or eclampsia

SMFM Special Report

Uncontrollable HTN despite using 3 classes of
antihypertensives in appropriate doses

Maternal pulse oximetry of <90 %

Progressive deterioration in liver function, renal function,
hemolysis, or platelet count

Placental abruption

Reverse end-diastolic flow of the umbilical artery Doppler,
NOVEMBER 2022

a nonreassuring CTG, or stillbirth

Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet Gynecol 2022. (continued)
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TABLE 2
Preeclampsia classification, definition, and management by academic society (as of January 2021) (continued)
Preeclampsia for expectant management to Preeclampsia for expectant management Preeclampsia requiring delivery at betamethasone
Variable 37 weeks of gestation to 34 0/7 to 36 6/7 weeks of gestation completion or immediate delivery
SOGC134 Preeclampsia with adverse conditions: There is no formal recommendation outside the Severe complications

Headache or visual symptoms, RUQ pain, or guidance for delivery for severe complications
Eclampsia, PRES, cortical blindness, retinal detachment
epigastric pain
GCS of <13, stroke, TIA, or RIND

Chest pain or dyspnea
Uncontrolled severe HTN (over a period of 12 h despite

Oxygen saturation of <97% the use of 3 antihypertensive agents)

Elevated WBC, INR, or aPTT
Oxygen saturation of <90%, need for 50% oxygen

Elevated serum creatinine or serum uric acid for >1 h, intubation (other than for cesarean delivery),

Elevated serum AST, ALT, LDH, or bilirubin or pulmonary edema

Low plasma albumin
Positive inotropic support

Low platelet count
Myocardial ischemia or infarction

Nausea or vomiting
Platelet count of <50  109/L

Fetal growth restriction, oligohydramnios
Transfusion of any blood product

Absent or reversed end-diastolic flow
Serum creatinine of >150 micrometer with no previous
by Doppler velocimetry renal disease

Abnormal fetal heart rate
New indication for dialysis

INR of >2 in the absence of DIC or warfarin

Hepatic hematoma or rupture

Abruption with maternal or fetal compromise

Reverse ductus venosus A wave

Stillbirth
NICE53 No specific title other than preeclampsia: There is no formal recommendation outside the Planned early birth before 37 weeks of gestation

Any form of preeclampsia that does not meet guidance for delivery for severe complications
Uncontrolled HTN despite using 3 classes of
the criteria for early birth antihypertensives in appropriate doses

Maternal pulse oximetry of <90%

Progressive deterioration in liver function, renal function,
hemolysis, or platelet count

Ongoing neurologic features, such as severe intractable
headache, repeated visual scotomata, or eclampsia

Placental abruption

Reverse end-diastolic flow in the UA, nonreassuring
CTG, or stillbirth
Adapted from the American College of Obstetricians and Gynecologists,50 Brown et al,51 the National Institute for Health and Care Excellence,53 and Magee et al.134
ACOG, American College of Obstetricians and Gynecologists; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BP, blood pressure; CTG, cardiotocograph; DBP, diastolic blood pressure; DIC, disseminated
intravascular coagulation; GCS, Glasgow Coma Scale; GFR, glomerular filtration rate; HELLP, hemolysis, elevated liver enzymes, and low platelet count; HTN, hypertension; INR, international normalized ratio; ISSHP, International Society for the Study of Hypertension
in Pregnancy; LDH, lactate dehydrogenase; NICE, National Institute for Health and Care Excellence; PT, prothrombin; PRES, posterior reversible encephalopathy syndrome; RIND, reversible ischemic neurological disability; RUQ, right upper quadrant; SBP, systolic
blood pressure; SF, severe features; SOGC, Society of Obstetricians and Gynaecologists of Canada; TIA, transient ischemic attack; UA, urinalysis; WBC, white blood cells.
Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet Gynecol 2022.

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FIGURE 1
Comparisons of severity criteria and management for preeclampsia by various organizations

The asterisk indicates the inability to control BPs on 3 classes of antihypertensive agents in appropriate doses; maternal pulse oximetry of <90%;
progressive deterioration in liver function, renal function, hemolysis, or platelet count; ongoing neurologic features, such as severe intractable headache,
repeated visual scotomata, or eclampsia; placenta abruption; or reversed end-diastolic flow. The double asterisk indicates headache, visual symptoms,
chest pain or dyspnea, oxygen saturation of <97%, elevated white blood cells, elevated INR or activated partial thromboplastin clotting time, low platelet
count, elevated serum creatinine, elevated serum uric acid, nausea or vomiting, right upper quadrant pain, elevated aspartate aminotransferase, alanine
aminotransferase, lactate dehydrogenase, or bilirubin, low plasma albumin, abnormal fetal heart rate, fetal growth restriction, oligohydramnios, or absent
or reverse end-diastolic flow by Doppler velocimetry. The triple asterisk indicates eclampsia, posterior reversible encephalopathy syndrome, cortical
blindness or retinal detachment, Glasgow Coma Scale of <13, stroke, transient ischemic attack, reversible ischemic neurologic deficit, uncontrolled
severe hypertension in 12 hours, oxygen saturation of <90%, intubation, pulmonary edema, need for positive ionotropic support, myocardia ischemia or
infarction, platelet count of <50,000, transfusion of any blood product, acute kidney injury, creatinine level of >150 mm with no previous renal disease,
new indication for dialysis, hepatic dysfunction, INR of >2 in absence of disseminated intravascular coagulation or warfarin, hepatic hematoma or
rupture, abruption with evidence of maternal or fetal compromise, reverse ductus A wave, or stillbirth. The plus indicates the inability to control BP despite
using 3 or more classes of antihypertensives; maternal pulse oximetry of <90%; progressive deterioration in liver function, renal function, hemolysis,
or platelet count; ongoing neurologic features (headache, repeated visual, scotomata, or eclampsia); placental abruption, reverse end-diastolic flow in the
umbilical artery, nonreassuring cardiotocography, or stillbirth. American College of Obstetricians and Gynecologists,50 Brown et al,51 the National
Institute for Health and Care Excellence,53 and Magee et al.134
ACOG, American College of Obstetricians and Gynecologists; BP, blood pressure; DBP, diastolic blood pressure; INR, international normalized ratio; ISSHP, International Society for the Study of Hypertension in
Pregnancy; NICE, National Institute for Health and Care Excellence; SBP, systolic blood pressure; SF, sever feature; SOGC, Society of Obstetricians and Gynaecologists of Canada.
Society for Maternal-Fetal Medicine. Special Report: Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet
Gynecol 2022.

treatment of severe HTN in the setting of preeclampsia.52 will prolong latency or decrease maternal or neonatal
Although guidelines are clear to aggressively treat severe- morbidity.
range HTN, BP maintenance with antihypertensive medi- Regarding HELLP syndrome, the ISSHP does not
cation is more nuanced. There is no current international recognize it as a separate disorder but rather within the
agreement regarding the optimal BP ranges while under- spectrum of preeclampsia.133 Although ISSHP recognizes
going expectant management or what BP management there are inconsistencies in the definition of HELLP syn-
may be required to prevent reaching severe range pres- drome, they agree that platelet values of <100,000/dL,
sures. Tighter BP control has been shown to reduce severe- aspartate aminotransferase (AST) and alanine aminotrans-
range maternal HTN but not maternal or neonatal morbidity ferase (ALT) 2-fold the upper limit of normal, and elevated
in preexisting HTN and gestational HTN.135,136 Data on lactate dehydrogenase (LDH) 2-fold the upper reference
aggressively managed BP control are lacking in active limit are reasonable to define the illness.133 Although it is
preeclampsia with SFs; thus, it is unclear if tight BP control clear that patients with HELLP syndrome can have a worse

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overall prognosis, the use of these diagnostic parameters is conditions and prolongation of pregnancy for this patient
questionable.137 Hemolysis in preeclampsia and HELLP population.152
syndrome is associated with adverse outcomes but is rarely Finally, the international consolidation of diagnostic
severe enough to destabilize a patient to necessitate de- criteria may provide an advantage in the collection of large
livery and be the sole driver of clinical care.138 Clinically, global datasets that examine clinical outcomes, disparities
LDH levels rarely drive patient care and are more an indi- in practice, and therapeutics and facilitate translation of
cation of end-organ damage. Moreover, AST and ALT can research and clinical practices.
persist without clinical deterioration, as can low platelet
levels that do not meet transfusion thresholds or cause Long-term impacts of preeclampsia
disseminated intravascular coagulation. Lastly, some co- Discussions during the workshop focused on the potential
horts observed 30% of participants showing improvement to affect the lives of those with the diagnosis of pre-
or even normalization of laboratory values when expectantly eclampsia, their children, and the individuals who support
managed; however, these patients still experienced preterm them far beyond delivery. However, patients and their
birth for worsening preeclampsia symptoms or BP families and clinicians are often unaware of these risks and
control.139e142 how to mitigate them.45,153 There is a need for scalable,
evidence-based strategies and interventions to address the
Future clinical management research unique challenges faced by patients with preeclampsia and
To move forward in both clinical management and research their families.44,45,154,155
of preeclampsia, the criteria definition and classification
must be reexamined. Workshop participants emphasized Cardiovascular health
that the reliance on merging all clinical phenotypes into one Heart disease is the leading cause of death among women
definition of preeclampsia has led to uniform treatment and in the United States, awareness of which has declined in
management strategies that either show no clinical differ- recent years to <50% among women.156,157 Birthing people
ence or lead to early preterm birth and increased maternal who develop preeclampsia, particularly those with preterm,
morbidity and may lead to masking of effective therapeutics severe, and recurrent preeclampsia, are at a 2- to 3-fold
in a precision medicine approach. Better classification of higher risk of developing CVD, including coronary artery
phenotypic and biologic pathways may lead to advances in disease, myocardial infarcts, heart failure, and
therapeutics targeted to specific populations that can stroke.7,8,44,158 This increased risk of CVD is mediated at
improve both short- and long-term outcomes for the preg- least in part through increased risk of comorbidities,
nant person and neonate. including chronic HTN, hyperlipidemia (HLD), and DM,
Future research should focus on matching clinical phe- which are more common among those with a history of
notypes to available and emerging biomarkers. Although preeclampsia.
placental ischemia and the imbalance of sFlt to PlGF in the Although racial disparities in the prevalence of pre-
first trimester of pregnancy is the nidus of disease, other eclampsia and chronic HTN are widely known, recent data
pathways may predominate later in pregnancy.2,74,143 For have shown racial differences in early postpartum BP tra-
example, people with persistent, intractable HTN and signs jectories among patients with hypertensive disorders of
of diastolic dysfunction on echocardiography may have pregnancy. These data highlight that Black patients have a
abnormal angiotensin receptor autoantibody levels.144e146 heightened burden in both the immediate and long-term
Furthermore, patients with HELLP syndrome may have a postpartum windows.159,160 Moreover, disparities exist in
preponderance of germline variants associated with other rates of maternal mortality through 1 year after delivery, with
diseases of complement.147e150 Multiple studies have American Indian or Alaskan Native, Black, and Hispanic
suggested that the complement system may be involved in birthing people in the United States being at increased risk
the pathophysiology of preeclampsia and HELLP syn- of maternal death in the context of hypertensive disorders of
drome through excess complement activation, decreased pregnancy compared with White women.5 These disparities
complement regulation, or both.151 Unlike other bio- necessitate greater emphasis on equity in postpartum care
markers, the complement system may give biologic and and outcomes by centering the distinct needs of these
mechanistic information via increases or decreases of subpopulations.
certain regulator protein pathways. However, additional
research is needed to determine the clinical use of com- Mental health
plement protein biomarkers and complement genetic var- Increased rates of adverse mental health outcomes,
iants in the prediction, diagnosis, and management of including depression and PTSD, have been reported among
preeclampsia. As with the other biomarkers discussed those who develop hypertensive disorders in preg-
earlier in this report, a more in-depth understanding of how nancy.12,161 Unpublished data shared during the workshop
dysregulation of complement pathways contributes to the from the Heart Health 4 Moms lifestyle intervention trial of
progression of preeclampsia and HELLP syndrome will 151 people with a history of preeclampsia revealed that 23%
allow for more accurate, tailored management of these of participants had probable PTSD, which is higher than the

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1.5% to 5.0% reported among a general population of symptoms or vital signs, effectively controlling HTN,
birthing people and the 15% to 18% among those with educating staff and patients regarding BP management
severe complications, including stillbirth and emergency postpartum, and ensuring continuity of care.119 Table 3
cesarean delivery.162e164 Increasing severity of disorders, highlights select national professional societies’ key rec-
from gestational HTN to eclampsia, has been associated ommendations for care after delivery.
with increased positive screening for PTSD and the preva- Workshop participants emphasized the need to
lence of postpartum depression, suggesting increased empower patients and their families by providing infor-
mental health risk among those with the highest medical mation about their risks and how to mitigate them. Per-
risk.11,12 sonal accounts shared by individuals who had
preeclampsia highlighted the need to engage patient per-
Offspring health spectives in disseminating data about long-term impacts
Evidence is growing regarding the associations between of preeclampsia for those affected by this disease. Patients
exposure to preeclampsia in utero and adverse health out- can benefit from being activated not only to engage in
comes. The exact mechanisms for these associations have strategies to lower their risk but also to advocate for
yet to be completely elucidated. Theories that in utero ex- themselves. Workshop participants stressed that ongoing
posures have a causal relationship with ex utero diseases, collaboration between professional medical societies and
such as the Barker hypothesis that FGR and prematurity patient advocacy groups is necessary to facilitate such
have a causal relationship with the development of HTN and crucial awareness and capacity building.
DM, are widely accepted.165,166 Potential differences in The postpartum period is a crucial time to assess future
gene expression (eg, epigenetics), cell biology (eg, differ- pregnancy intention and family planning goals. Patients who
entiation, proliferation, and programming), and other factors have preeclampsia should be made aware of the risk of
(eg, cytokine exposure) are thought to play a role. recurrence and advised of risk reduction strategies. In
Notable associations between in utero exposure to pre- addition to highlighting the role of low-dose aspirin in their
eclampsia and offspring health reviewed during the work- future pregnancies,82 patients should also be made aware
shop included adverse cardiovascular and neurologic that optimal control of certain comorbidities, such as
outcomes. Findings from multiple studies have shown chronic HTN, DM, and systemic lupus erythematous, and
increased risks of elevated BP, higher BMI, and even distinct achieving a healthy weight before their next pregnancy
echocardiographic findings in children whose mothers had lower their risk of developing preeclampsia again. The ideal
preeclampsia during their pregnancy compared with those interpregnancy interval for patients with preeclampsia is not
whose mothers did not have preeclampsia during their well defined, and some patients with very severe disease
pregnancy.15,167,168 Similarly, increased risks of neuro- (eg, associated with cardiac compromise) may be cautioned
developmental disorders, including attention deficit hyper- against future pregnancy given concern for severe morbidity
activity disorder, autism spectrum disorder, epilepsy, and and mortality. However, a recommendation for avoiding
intellectual disability, have been associated with exposure interpregnancy intervals shorter than 6 months is reason-
to preeclampsia.16,17,169 However, emphasis was placed on able given the association with adverse outcomes among
the need for more evidence to understand the role of con- the general birthing population.40
founders, effect modifiers, and mechanisms of these as- Prioritization of CVD risk prevention among those with a
sociations to better determine the degree of causation and history of preeclampsia is necessary because of the
how to address it. increased risk of disease progression in this population and
the high mortality rates of first cardiovascular events in
Opportunities and challenges to improving women.8,30,44 Fortunately, the progressive nature of CVD
outcomes risk accrual affords patients and their providers time to
The postpartum period provides unique opportunities to address modifiable risk factors, including, but not limited to,
engage in counseling and risk reduction, given the greater cigarette smoking and secondhand smoke exposure,
access to care and the increased motivation to optimize detection and management of comorbidities (eg, DM, HLD,
one’s own and family’s health during this window. Work- and HTN), salt reduction, physical activity, and weight.
shop participants emphasized that the immediate post- Unfortunately, CVD risk models, such as the 10-Year
partum period is an optimal time for clinicians to target Modified Framingham Risk Score and the Cardiometabolic
interventions for people with preeclampsia, with most Model, seem to underestimate the morbidity and early
maternal deaths occurring in the first week after delivery.170 mortality associated with hypertensive disorders of preg-
Immediately after delivery, fetal health concerns are no nancy.174 Large, long-term studies demonstrating effective
longer included in the risk-benefit calculus for intervention, strategies to decrease long-term morbidity and mortality
and most candidate drugs are compatible with breast- specifically associated with preeclampsia are needed.
feeding. Actions clinicians and healthcare systems can take However, extrapolation from other at-risk populations and
to reduce preventable maternal deaths because of pre- expert opinion reveals postpartum care strategies with
eclampsia include a timely response to changes in promise for improving long-term outcomes. Ongoing

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TABLE 3
Recommendations for long-term postpartum care of patients with preeclampsia
Variable ACOG (2019e2021)40,50,171,172 AHA (2021)44 FIGO (2016)173 ISSHP (2018)51
Visits
Maternal care visit 1e3 wk after delivery; comprehensive visit 4 0e12 wk after delivery Within 24 h after delivery, postpartum Within 1 wk after delivery if requiring
e12 wk after delivery day 3, postpartum weeks 2 and 6 antihypertensive medication on
discharge; 3 mo after delivery
Primary care visit Annually 8e12 wk after delivery Referral to internal medicine or Annual or regular
nephrology if difficult to control BP or
3e6 mo of proteinuria, decreased
eGFR (<60 mL/min) or other
indications of renal disease
Assessments
Initial BP check 3e10 d after delivery — 3e6 d after delivery Within 1 wk after delivery if requiring
antihypertensive medication on
discharge; 3 mo after delivery
CVD risk assessment Within 3 mo and annually or At 6 wk, 8e12 wk, 6 mo, No earlier than 3e6 mo after delivery Annual or regular
Frequency sooner if there is an abnormality and 12 mo after delivery Screening using national guidelines; BP and periodic fasting lipids and
Evaluation Medical history (smoking, BP, lipids, fasting glucose, evaluation of BP, BMI, lipid panel, or blood sugar
components physical activity, breastfeeding, and BMI glucose intolerance screening
comorbidities, and family history), resting BP
and HR, BMI, WC, cholesterol or lipid profile,
fasting glucose, urine protein, nutrition, or
social determinants of health
Other laboratory — — Confirmation that end-organ Repeat abnormal laboratory tests the
testing dysfunction resolution or facilitate day after delivery and daily until
further workup stable; repeat any laboratory tests that
were abnormal at 3 mo to determine if
they have normalized or if further
workup is needed
Mental health Screen for postpartum depression and anxiety — Evaluation and referral for postpartum Assessment for depression, anxiety,
with a validated instrument psychological care or PTSD symptoms
Substance use Screen for tobacco and other substances; Encourage smoking cessation Encourage smoking cessation —
screening and encourage smoking cessation
intervention
Counseling
Lifestyle modification Actionable guidance on physical activity, diet, Heart-healthy diet and Heart-healthy diet, regular Aim to achieve prepregnancy weight
and weight increasing physical activity physical activity, reduce alcohol by 12 mo after delivery, maintenance
consumption, ideal body weight and of healthy weight, and regular

smfm.org
WC, reduce salt intake, and smoking exercise
cessation
Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet Gynecol 2022. (continued)
 smfm.org
TABLE 3
Recommendations for long-term postpartum care of patients with preeclampsia (continued)
Variable ACOG (2019e2021)40,50,171,172 AHA (2021)44 FIGO (2016)173 ISSHP (2018)51
Infant feeding Association of breastfeeding with decreased Association of lactation and Compatibility of breastfeeding Compatibility of breastfeeding with
rates of HTN, HLD, T2DM, and CVD; breastfeeding with lower with select antihypertensive regimens select antihypertensive regimens
compatibility of breastfeeding with select cardiometabolic risk;
antihypertensive regimens compatibility of breastfeeding
with select antihypertensive
regimens
Family planning Avoid interpregnancy intervals of <6 mo and — — —
consider risks and benefits for intervals of
<18 mo; shared decision-making regarding
contraceptive options
Future CVD and other Counseling regarding: CVD risk Counseling regarding: CVD Counseling regarding: CVD, renal Counseling regarding: CVD, DM, VTE,
disease risk risk disease, and mental health risks CKD, and mortality risk
Future pregnancy risk Counseling regarding: recurrence risk; aspirin Counseling regarding: Counseling regarding: risk of recurrent Counseling regarding: risk of
and prevention use in future pregnancy for prevention recurrence risk; aspirin use in preeclampsia or gestational HTN; recurrent preeclampsia and SGA;
future pregnancy for aspirin use and calcium use if intake is aspirin use and calcium use if intake is
prevention low in future pregnancy for prevention low in future pregnancy for prevention
Future risk to newborn — — Counseling regarding: potential long- —
term neurodevelopment, CVD, and
pregnancy complications
Adapted from the American College of Obstetricians and Gynecologists,40,50,171,172 Parikh et al,44 Brown et al,51 and Magee et al.173
BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HR, heart rate; HLD, hyperlipidemia; HTN, hypertension; PTSD, posttraumatic stress disorder;
SGA, small for gestational age; T2DM, type 2 diabetes mellitus; VTE, venous thromboembolism; WC, waist circumference.
Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet Gynecol 2022.

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FIGURE 2
Interactions among preeclampsia, mental health conditions, and CVD

Reproduced with permission from Stuart JJ. The impact of preeclampsia on long-term mental health. Oral presentation at: Preeclampsia Workshop; 41st
Annual Pregnancy Meeting; January 25, 2021; Virtual.
CVD, cardiovascular disease; PTSD, posttraumatic stress disorder.
Society for Maternal-Fetal Medicine. Report and recommendations of the Society for Maternal-Fetal Medicine and the Preeclampsia Foundation on preeclampsia. Am J Obstet Gynecol 2022.

advocacy is needed to drive awareness of these recom- Participants stressed that structural changes to the
mended strategies among providers and patients. healthcare system are also needed. In the United States,
Screening for postpartum depression and anxiety is health insurance coverage beyond 60 days after delivery
widely accepted,40 but the increased risk of PTSD seen was highlighted at multiple points as being crucial to miti-
among patients with preeclampsia and other pregnancy gating some of the long-term risks that patients with pre-
complications highlights the potential role of explicitly eclampsia and other pregnancy complications have by
screening for PTSD.161,163 Patients with symptoms of these affording them the ability to engage in primary care.155
mental health disorders should be promptly referred for Workshop participants recognized that insurance
evaluation and treatment by a trained professional. coverage does not equate to healthcare access. There is a
Collaborative care models, such as the medical home need for more equitable infrastructure to enable patients to
model and postpartum transition clinics, have demon- access diverse provider types and interventions, particularly
strated success in connecting patients to care, early risk around specialty care (eg, cardiology and psychiatry) and
assessment for CVD, and initiating prevention measures for treatments (eg, mental healthcare). Financing and staffing of
patients at increased risk of later disease.8,45,175,176 The innovative care models were raised as potential barriers,
opportunity to leverage technology to facilitate care coor- particularly in areas with limited resources (eg, rural areas,
dination both between the patient and the healthcare sys- public hospitals, and countries with limited resources).
tem and within the healthcare system was highlighted During the workshop, the importance of challenging long-
through examples, such as the Heart Health 4 Moms online term health disparities was also emphasized, both domes-
lifestyle intervention.177 tically and internationally, through targeted interventions
Workshop participants emphasized the importance of and stratification of data to understand how disparities are
engaging providers across specialties, particularly emer- being narrowed or exacerbated over time.
gency medicine, primary care, and pediatrics. Given their Workshop participants called for improved dissemination
frequent interactions with patients with a history of pre- of best practices from research and clinics, hospitals, health
eclampsia, specialists in these areas can provide risk systems, and larger collaborations. In response to this call
assessment, care coordination, and patient education. to action, a small group of expert workshop participants is
Moreover, there was an emphasis on the opportunity to developing a toolkit compiling examples of clinical guide-
increase awareness and engagement of primary care and lines and tools (eg, CVD risk models), care models (eg,
gynecologic providers in identifying patients with a history Kingston General Hospital Maternal Health Clinic’s clinical
of hypertensive disorders of pregnancy as part of their workflow and select materials), and patient education ma-
standard medical history, even when individuals are terials (eg, Preeclampsia Foundation’s video on how to take
beyond reproductive age. This identification is one step in one’s BP).
ensuring that such patients receive appropriate cardio-
vascular health assessments and interventions (eg, modi- Areas for future research
fication of their 10-year atherosclerotic CVD risk estimate). Improving long-term health outcomes for people who
In addition, the role of subspecialists, such as preventative experienced preeclampsia and their children will require
cardiologists, was highlighted with the recognition that additional research to guide practice improvements.
primary care providers are well positioned to triage patients Greater insights into which patients with a history of pre-
to these experts. eclampsia are at the highest risk of long-term adverse

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outcomes (eg, stroke and PTSD) and thus would benefit the understand confounders (eg, maternal and paternal
most from tailored interventions in the postpartum period comorbidities), effect modifiers (eg, exposure to magnesium
are needed. sulfate in utero and prematurity), and the mechanism un-
Regarding the risk of CVD, one challenge that was high- derlying the pathophysiology to improve outcomes in
lighted was the limitation of many models used to predict offspring.
CVD risk, which often underestimates the risk for young Workshop participants highlighted the importance of
women.8,178 Work to create improved models, particularly multidisciplinary teams to advance research to improve
within populations with high rates of hypertensive disorders long-term outcomes for patients and families affected by
in pregnancy, is promising but has notable limitations (eg, preeclampsia. The importance of training programs and
reliance on administrative data and missing clinical vari- funding opportunities that promote such collaboration was
ables, such as BP and echocardiogram parameters).178 emphasized. Moreover, participants highlighted the impor-
Given the heterogeneity in clinical presentation of pre- tance of advancing the systematic and widespread uptake
eclampsia (eg, preterm vs term, with vs without SFs), it is of evidence-based practices to move the needle on popu-
likely that models that account for nuances of the diagnosis lation health, thus emphasizing the importance of imple-
might have better discernment for who has greater long- mentation sciences research alongside basic science,
term risks. In addition, research is needed to understand clinical, and epidemiologic research.
how to optimally integrate more sensitive prediction models
into clinical care and how they can guide the provision of Conclusion
interventions. It is not yet clear whether preeclampsia Workshop participants proposed many recommendations
management during pregnancy, particularly around delivery for preeclampsia prediction, prevention, and management
timing after diagnosis, affects long-term CVD risk.179e182 If and identified several opportunities to improve postpartum
preeclampsia management decisions do have long-term and long-term follow-up care. It is hoped that this workshop
health effects, how to incorporate that information into pa- serves as a catalyst for developing clinical guidelines and
tient counseling about whether to prolong pregnancy is an patient education strategies, generates new research
opportunity for further investigation.181 questions, and strengthens relationships between re-
The mechanisms through which racism (eg, interpersonal searchers and clinicians to increase collaboration and
and structural) and related stressors (eg, socioeconomic support for patients with preeclampsia. n
and environmental) contribute to disparate hypertensive
disease burdens inside and outside pregnancy need greater ACKNOWLEDGMENTS
elucidation and targeted interventions. Exploration of the The authors would like to acknowledge the contributions of Sarah J
potential effect of promising efforts in other patient pop- Kilpatrick, MD, PhD, Heather S Lipkind, MD, and George R Saade,
MD for their work as breakout session co-leaders for the workshop.
ulations, including access to culturally appropriate and
community-based interventions, may offer ways to mitigate
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183. Hutchinson RN, Shin S. Systematic review of health disparities for The SMFM has neither solicited nor accepted any commercial
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and Alaska Native populations. PLoS One 2014;9:e80973.
184. Kaholokula JK, Ing CT, Look MA, Delafield R, Sinclair K. Culturally
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Document Review Committees and final approval by the SMFM Ex-
Americans: implementations for controlling hypertension. Curr Hypertens
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188. Schobinger E, Stuijfzand S, Horsch A. Acute and post-traumatic
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