Preeclampsia Testing

Medical Experts

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Nelson H

Heather Nelson, PhD, DABCC

Assistant Professor (Clinical), University of Utah

Medical Director, Clinical Chemistry, ARUP Laboratories

Preeclampsia is a pregnancy-related multisystem progressive disorder characterized by hypertension (systolic blood pressure [BP] ≥140 mmHg and/or diastolic BP ≥90 mmHg) and one or more additional signs of physiologic dysfunction. Preeclampsia typically occurs after 20 weeks of gestation, usually near term, although it can develop earlier in pregnancy or postpartum. Laboratory testing for preeclampsia includes markers of maternal organ and uteroplacental function. Test selection may differ depending on the indication for testing (eg, risk assessment versus diagnosis) and stage of pregnancy.^, Because multiple organs are involved and presentation can vary greatly from case to case, a range of tests may be needed to diagnose preeclampsia.

Quick Answers for Clinicians

What are the recommended use cases for serum sFlt-1:PlGF ratio testing?

Soluble fms-like tyrosine kinase 1 and placental growth factor (sFlt-1:PlGF) ratio testing is useful in appropriate populations to assess for angiogenic imbalance, which is indicative of uteroplacental dysfunction.

When used in the context of suspected preeclampsia, sFlt-1:PlGF testing has a negative predictive value of approximately 96%. As such, a normal result (sFlt-1:PlGF <40) in the absence of other preeclamptic findings indicates a substantially reduced likelihood of progression to preeclampsia with severe features within 2 weeks.^,^, The sFlt-1:PlGF ratio has a positive predictive value of approximately 65%; thus, an abnormal result (sFlt-1:PlGF ≥40) alone is insufficient to diagnose preeclampsia with severe features.

Is sFlt-1:PlGF ratio testing appropriate in all patients with suspected preeclampsia?

The American College of Obstetricians and Gynecologists (ACOG) strongly recommends limiting the use of soluble fms-like tyrosine kinase I and placental growth factor (sFlt-1:PlGF) ratio testing to the populations in which it was evaluated as part of the Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification (PRAECIS) trial, which assessed the performance characteristics of the BRAHMS sFlt-1/PlGF KRYPTOR test. Participants in the study were adult women carrying singleton pregnancies between 23 weeks and 0 days and 34 weeks and 6 days of gestation who were hospitalized with a hypertensive disorder (but not yet diagnosed with preeclampsia with severe features) and were not receiving intravenous heparin.

What are the recommended use cases for serum placental growth factor testing?

Testing of serum placental growth factor (PlGF), an angiogenic protein, may be performed at various stages of pregnancy to assess risk for preeclampsia or to provisionally rule out the condition.

As part of preeclampsia risk assessment, serum PlGF should be measured in conjunction with other markers to determine the risk of preterm preeclampsia. Risk assessment is recommended for all pregnant individuals to inform patient management.^, For more information, refer to the Risk Assessment section.

When serum PlGF testing is performed in the context of suspected preeclampsia, a normal result points to typical uteroplacental function and, in the absence of other preeclamptic findings, essentially rules out the condition for 7-14 days.^, Conversely, an abnormal PlGF result can be used to support a diagnosis of preeclampsia.

Currently, serum PlGF as an individual marker is not widely used or available in the United States, and testing for this marker is not offered by ARUP Laboratories.

Does laboratory testing for preeclampsia differ in patients with chronic kidney disease?

No, the recommended testing for preeclampsia is the same for individuals with or without chronic kidney disease (CKD). Similarly, guidelines do not expressly account for preexisting kidney dysfunction in classification criteria or diagnostic thresholds, except to indicate that increases in urinary protein alone are insufficient to diagnose superimposed preeclampsia in patients with proteinuric renal disease.

However, data are limited as to the performance of angiogenic marker testing (ie, soluble fms-like tyrosine kinase-1 and placental growth factor [sFlt-1:PlGF] ratio and serum PlGF alone) in those with preexisting kidney disease or proteinuria. Notably, it remains unclear whether PlGF, which is cleared by the kidneys, is impacted by preexisting kidney dysfunction.

For additional discussion, including provisional criteria for preeclampsia in those with CKD, refer to Updates in Diagnosis and Management of Preeclampsia in Women with CKD.

What laboratory testing is used to diagnose hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome?

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is considered to be a severe complication of preeclampsia, although hypertension and proteinuria may be absent in up to 20% of HELLP cases.^, Laboratory tests to confirm HELLP syndrome include a CBC, peripheral blood smear, and liver enzyme, bilirubin, and lactate dehydrogenase (LDH) tests. Additional testing for other conditions (eg, disseminated intravascular coagulation [DIC], antiphospholipid syndrome [APS], acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, etc.) may be considered if clinically indicated.

Consensus has not been achieved with respect to diagnostic criteria for HELLP syndrome; however, the following thresholds are in common use:

LDH ≥600 IU/L
Liver enzymes >2 times the upper limit of normal
Platelet count <100,000/μL

Indications for Testing

Initial risk assessment for preeclampsia is indicated in all pregnant individuals, regardless of preeclampsia risk status.

Baseline testing is recommended in pregnant individuals at first diagnosis of chronic hypertension.

Diagnostic testing should be performed in patients newly diagnosed with gestational hypertension and in individuals with hypertension and possible manifestations of preeclampsia, including during the postpartum period.

Unless a specific cause of hypertension is clinically suspected, routine etiologic testing is not recommended.

Classification of Preeclampsia

Preeclampsia is defined as the presence of hypertension plus one or more new-onset manifestations of physiologic dysfunction associated with the condition. In pregnant individuals, hypertension is defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg on at least two occasions at 4 or more hours apart.

The classification criteria for preeclampsia are the same, regardless of whether hypertension is gestational or chronic, although recommended testing varies based on the hypertensive subtype. Chronic hypertension is classified as occurring before 20 weeks of gestation (including before pregnancy). Gestational hypertension is classified as occurring de novo at or after 20 weeks of gestation in the absence of other preeclamptic findings.

Guidance on classification in light of other overlapping preexisting conditions (eg, chronic kidney disease [CKD]) is currently limited.^,

Physiologic Dysfunction	Examples
Renal dysfunction	Proteinuria,^a acute kidney injury
Neurologic dysfunction	Eclampsia, stroke, clonus, blindness, visual disturbances, altered mental status, severe headache
Hematologic dysfunction	Disseminated intravascular coagulation, thrombocytopenia, hemolysis
Hepatic dysfunction	Elevated liver enzymes, epigastric or upper right quadrant pain
Cardiopulmonary dysfunction	Pulmonary edema
Uteroplacental dysfunction^b	Angiogenic imbalance, fetal growth restriction, placental abruption, intrauterine fetal death
^aProteinuria is present in up to 75% of preeclampsia cases. Quantitative measurement is recommended. ^bUteroplacental dysfunction is not included as a criterion amongst guidelines from ACOG. ACOG, American College of Obstetricians and Gynecologists Sources: Magee, 2022; ACOG, 2020

Laboratory Testing

Risk Assessment

According to guidelines from the International Society for the Study of Hypertension in Pregnancy (ISSHP) and the International Federation of Gynecology and Obstetrics (FIGO), all pregnant individuals should undergo a full preeclampsia risk assessment at their first prenatal care visit (ideally, at 11 to 14 weeks of gestation), regardless of current risk status. A combination of maternal risk factors, BP values, uterine artery pulsatility index, and serum placental growth factor (PlGF) should be used to calculate preeclampsia risk.^, If serum pregnancy-associated plasma protein A (PAPP-A) values are available from a fetal aneuploidy screen, they can also be included. The Fetal Medicine Foundation offers a preeclampsia risk assessment calculator that includes all of the above measures.

This initial screening is useful to inform patient management and predict the development of preterm preeclampsia. Notably, although there are many risk factors associated with preeclampsia (eg, autoimmune disease, diabetes mellitus, CKD, obesity, history of preeclampsia, etc.), none of these factors alone is strongly predictive, and screening performs poorly in predicting whether patients will develop term preeclampsia. Previous risk assessment does not preclude the possibility of preeclampsia, including during the intrapartum or postpartum period, given that preeclampsia can develop or manifest even after delivery.

ARUP Laboratories does not currently offer a test option for serum PlGF as an individual marker.

Baseline Testing

In pregnant individuals with chronic hypertension, baseline testing is recommended to establish initial renal, hepatic, and hematologic values for later comparison, should symptoms of preeclampsia develop. The ISSHP does not currently recommend baseline testing in other populations.

The following laboratory tests should be performed:

Urine microscopy
Serum creatinine
Urinary albumin-creatinine ratio, urinary protein-creatinine ratio, or 24-hour urine total protein
Liver enzymes
Platelet count

Additional testing may be indicated to follow up on abnormal results. In those with chronic hypertension, routine monitoring for the development of preeclampsia should be based on individual risk.

Diagnostic Testing

Patients With Gestational Hypertension

In patients newly diagnosed with gestational hypertension, the ISSHP recommends performing the following laboratory tests to rule out current preeclampsia:

Serum creatinine
Urinary albumin-creatinine ratio, urinary protein-creatinine ratio, or 24-hour urine total protein
Liver enzymes
Platelet count
Serum PlGF or (in appropriate populations) sFlt-1:PlGF ratio (refer to Quick Answers for Clinicians)

Urinary protein testing is recommended on a weekly basis for those with gestational hypertension. Reevaluation for preeclampsia should be performed as needed based on future clinical suspicion for the condition.

Patients With Symptoms of Preeclampsia

Testing for preeclampsia should be performed in any individual with symptoms suggestive of the condition, both pre- and postdelivery. If preeclampsia is suspected before 20 weeks of gestation, other possible diagnoses should also be considered.

The same laboratory tests are recommended regardless of a patient’s hypertensive history:

Serum creatinine
Urinary albumin-creatinine ratio, urinary protein-creatinine ratio, or 24-hour urine total protein
Liver enzymes
Platelet count
Serum PlGF or (in appropriate populations) sFlt-1:PlGF ratio (refer to Quick Answers for Clinicians)

Additional testing may be required to investigate severe manifestations of preeclampsia, such as hemolysis, elevated liver enzymes, and low platelet count (HELPP syndrome).

Because preeclampsia can develop in the intrapartum and postpartum periods, evaluation for preeclampsia should be performed if clinical suspicion for the condition arises. Guidelines stop short of providing a specific time frame within which continued vigilance is needed.

Following a diagnosis of preeclampsia, serum creatinine, liver enzymes, and platelet count should be retested at least twice weekly.

Postpartum Monitoring

Although data and expert consensus are lacking with respect to postpartum monitoring, it is recognized that preeclampsia, including preeclampsia with severe features (eg, HELLP syndrome), can develop postpartum and that vigilance is warranted.^, ISSHP guidelines recommend that all individuals be tested at 3 months and 6 months postpartum to ensure any previously abnormal lab values have normalized. Urinalysis should be included.