Draft Recommendation Statement

Preeclampsia: Screening

September 27, 2016

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Importance

Preeclampsia is a relatively common hypertension disorder in pregnancy, affecting approximately 4% of pregnancies in the United States,1 with multiple subtypes and potentially serious, even fatal outcomes.2, 3 Although other hypertension conditions overlap and can coexist with preeclampsia, preeclampsia is defined as new-onset hypertension (or in patients with existing hypertension, worsening hypertension) after 20 weeks of gestation combined with either new-onset proteinuria (excess protein in the urine) or other signs or symptoms involving multiple organ systems. The specific etiology is unclear.2-6 Preeclampsia can cause poor health outcomes in both the mother and infant. It is the second leading cause of maternal mortality worldwide7, 8 and may also lead to other serious maternal complications, including stroke, eclampsia, and organ failure. Adverse perinatal outcomes for the fetus and newborn include intrauterine growth restriction, low birth weight, and stillbirth. Many of the complications associated with preeclampsia lead to early induction of labor or cesarean delivery and subsequent preterm birth.

Detection

Obtaining blood pressure measurements to screen for preeclampsia could allow for early identification and diagnosis of the condition, resulting in close surveillance and effective treatment to prevent serious complications. The USPSTF has previously established that there is adequate evidence on the accuracy of blood pressure measurements.

The USPSTF found adequate evidence that testing for protein in the urine with a dipstick test has low diagnostic accuracy for proteinuria detection in pregnancy.

Benefits of Early Detection and Treatment

Preeclampsia is a complex syndrome. It can quickly evolve into a severe disease that can result in serious, even fatal health outcomes for the mother and infant. The ability to screen for preeclampsia using blood pressure measurements is important in order to identify and effectively treat a potentially unpredictable and fatal condition. The USPSTF found adequate evidence that the well-established treatments of preeclampsia result in a substantial benefit for the mother and infant by reducing maternal and perinatal morbidity and mortality.

The USPSTF found inadequate evidence on the effectiveness of risk prediction in identifying women who are at high risk for preeclampsia.

Harms of Early Detection and Treatment

The USPSTF found adequate evidence to bound the potential harms of screening for and treatment of preeclampsia as no greater than small. This assessment was based on the known harms of treatment with antihypertension medications, induced labor, and magnesium sulfate; the likely few harms from screening with blood pressure measurements; and the potential poor maternal and perinatal outcomes resulting from severe untreated preeclampsia and eclampsia. The USPSTF found inadequate evidence on the harms of risk prediction.

USPSTF Assessment

The USPSTF concludes with moderate certainty that there is a substantial net benefit of screening for preeclampsia in pregnant women with blood pressure measurements.

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Patient Population Under Consideration

This recommendation applies to pregnant women without a known diagnosis of preeclampsia or hypertension.

Assessment of Risk

All pregnant women are at risk for preeclampsia and should be screened. Important clinical conditions that put women at increased risk for preeclampsia include a history of eclampsia or preeclampsia (particularly early-onset preeclampsia in a prior pregnancy); a previous adverse pregnancy outcome; maternal comorbid conditions (including type 1 or 2 diabetes prior to pregnancy, gestational diabetes, chronic hypertension, renal disease, and autoimmune diseases); and multifetal gestation.4, 9 Other risk factors include nulliparity, obesity, African American race, low socioeconomic status, and advanced maternal age.4, 9

In the United States, preeclampsia is more prevalent among African American women. Differences in prevalence may be, in part, due to African American women being disproportionally affected by risk factors for preeclampsia. African American women also have case fatality rates from preeclampsia that are 3 times higher than those of white women.4, 10-12 Inequalities in access to adequate prenatal care may contribute to a more severe onset of preeclampsia in African American women.4, 12

Screening Tests

Blood pressure measurement has routinely served as a screening tool for preeclampsia. The accuracy of blood pressure measurement has been well established.13 Sphygmomanometry is the recommended method for blood pressure measurement during pregnancy. After 5 minutes has elapsed, the patient’s blood pressure should be measured while she is relaxed and in a sitting position, with her legs uncrossed and her back supported. The patient’s arm should be at the level of the right atrium of the heart. If the patient’s upper arm circumference is 33 cm or greater, a large blood pressure cuff should be used.5, 13-15 Clinicians should avoid measuring blood pressure in the upper arm in the left lateral position because this position falsely lowers blood pressure readings.13-15

Evidence does not support point-of-care urine testing to screen for preeclampsia, as evidence suggests that proteinuria may not be a good predictor of preeclampsia health outcomes.4, 5, 16-18 Proteinuria measurement is used in the diagnostic criteria for preeclampsia.

Recently revised criteria for the diagnosis of preeclampsia include high blood pressure (≥140 mm Hg systolic or ≥90 mm Hg diastolic on two occasions, 4 hours apart, after 20 weeks of gestation) and either proteinuria (≥300 mg/dL on a 24-hour urine protein test, a protein:creatinine ratio of ≥0.3 mg/mmol, or a protein dipstick reading of >1 if quantitative analysis is not available) or, in the absence of proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms.5

Screening Interval

Blood pressure measurements should be obtained during each prenatal care visit throughout pregnancy. If a patient has an elevated blood pressure reading, it should be confirmed with repeated measurements. Further diagnostic evaluation and clinical monitoring are indicated for patients with elevated blood pressure on multiple measurements.

Treatment of Preeclampsia

Management strategies for diagnosed preeclampsia include close fetal and maternal monitoring, antihypertension medications, and magnesium sulfate.4, 5

Additional Approaches to Prevention

The USPSTF recommends the use of low-dose aspirin (81 mg/day) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia.9

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Research Needs and Gaps

The USPSTF has identified several research gaps. More research on the complex pathophysiology of preeclampsia is needed to better understand and define its subtypes and their risks to maternal and perinatal health. Once preeclampsia is more clearly defined, screening tools targeting its various subtypes and different study populations may be necessary. Descriptive studies that characterize variations in current preeclampsia screening practices in various types of health care settings would be helpful for identifying alternative screening approaches to evaluate in clinical studies. Research examining screening algorithms and new markers for screening are needed. Studies are needed to further develop and validate tools for risk prediction using rigorous methodology, including appropriate calibration statistics and validated models that use parameters (e.g., clinical history, clinical testing) available in routine care. Large studies are needed to compare different approaches to screening and effects on maternal and perinatal health outcomes, as well as long-term health outcomes.

Further evaluation of the accuracy of the protein:creatinine ratio in point-of-care urine testing in general populations and repeat testing could better determine its optimal role for detecting proteinuria. Research to evaluate the effects of changing diagnostic criteria on screening practices is also needed.

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Burden of Disease

Preeclampsia is a complex syndrome defined by new-onset hypertension after 20 weeks of gestation. Proteinuria is often but not always present. Recent guidance indicates that a preeclampsia diagnosis can be made without proteinuria when other clinical signs or symptoms are present.5

Preeclampsia is a multisystem inflammatory syndrome with an unclear etiology and natural history. Some have theorized that it may be comprised of multiple subtypes.2-4 Preeclampsia is thought to involve the abnormal formation of uterine arteries during placental development, possibly resulting in increased oxidative stress and a maternal inflammatory response.2-4 However, these two processes of preeclampsia may occur alone or in combination.

Preeclampsia is a relatively common condition in pregnancy, with an estimated 2% to 8% of pregnancies affected worldwide.4, 7, 8 Approximately 9% of maternal deaths in the United States are directly attributed to preeclampsia and eclampsia4, 19 and more than one third of severe obstetric complications are associated with preeclampsia.4, 20 Maternal complications include cerebrovascular bleeding, retinal detachment, and complications from HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). Approximately 1% to 2% of preeclampsia cases lead to eclampsia, a severe manifestation of the syndrome characterized by seizures and complications such as brain damage, aspiration pneumonia, pulmonary edema, placental abruption, disseminated coagulopathy, acute renal failure, cardiopulmonary arrest, and coma.4, 8

Fetal and neonatal complications of preeclampsia include restricted growth, oligohydramnios, placental abruption, neonatal intensive care unit admission, stillbirth, and neonatal death. Delivery of the fetus is the definitive treatment of preeclampsia and, as a result, preeclampsia is a leading cause of medically-indicated induced preterm birth and low birth weight in the United States.4, 21 Infants born to mothers with preeclampsia account for 6% of preterm births and 19% of medically-indicated preterm births.4, 21 Most cases of preeclampsia occur after 34 weeks of gestation. Preterm infants (born before 37 weeks of gestation) are at increased risk of morbidity and mortality; the risk of poor outcomes increases with earlier delivery.4, 22

Scope of Review

In 1996, the USPSTF recommended screening for preeclampsia using office-based blood pressure measurement for all pregnant women at the first prenatal visit and periodically throughout the remainder of the pregnancy (B recommendation).18 The USPSTF commissioned an evidence review to systematically appraise and update the evidence on screening for preeclampsia.

Accuracy of Screening Tests

The USPSTF has previously assessed the accuracy of blood pressure measurements to identify hypertension in adults as adequate.13

Accuracy of Diagnostic Tests

There are several tests for proteinuria, including the protein:creatinine ratio urine test, albumin:creatinine ratio urine test, urine protein dipstick test, and the 24-hour urine protein test. Although the 24-hour urine protein test is the gold standard, it is not practical for use in primary care. The USPSTF found variable and limited evidence on the accuracy of these various tests.

Fourteen studies (n=1,888; four good-quality and 10 fair-quality) assessed the diagnostic accuracy of urine tests in detecting proteinuria compared with 24-hour urine collection (gold standard). Twelve studies assessed the protein:creatinine ratio urine test, two studies assessed the albumin:creatinine ratio urine test, and four studies assessed the urine protein dipstick test. Evidence on the accuracy of repeated testing was not found.4 All studies of urine protein test performance were conducted among pregnant women with suspected preeclampsia. Six studies took place in the United States, four in the United Kingdom, one in New Zealand, one in Canada, one in Chile, and one in the Netherlands.4 Meta-analysis was not performed due to clinical and statistical heterogeneity across the studies.4

For the protein:creatinine ratio urine test (12 studies), sensitivity ranged from 0.65 to 0.96 (I2=80.5%; 11 studies), with most studies reporting sensitivity greater than 0.81; specificity ranged from 0.49 to 1.00 (I2=91.8%; 11 studies). The albumin:creatinine ratio urine test (two studies) had high sensitivity (0.94 and 1.00) and dissimilar specificity (0.94 and 0.68).4 The automated protein urine dipstick test (four studies) had sensitivity ranging from 0.22 to 1.00 and specificity ranging from 0.36 to 1.00.4 One automated protein urine dipstick test had both specificity and sensitivity near 80%. The remaining studies found either high sensitivity and low specificity or vice versa.4

Performance of protein urine tests varied widely. Issues such as limited information on the diversity of index tests used, study eligibility criteria, prevalence of proteinuria, spectrum bias, and heterogeneity limit the conclusions that can be made about the accuracy of protein urine tests in routine clinical care. In addition, the studies were conducted among pregnant women with suspected preeclampsia and not in the general pregnant population typically found in primary care.4

Evidence suggests that automated tests have better test performance than manually read tests. The time of day of testing is not predictive of performance for the protein:creatinine ratio test, and test sensitivity depends on the 24-hour test assay used.4

Effectiveness of Risk Prediction

The USPSTF identified 16 multivariable risk prediction models that were evaluated in four validation studies. The risk models were primarily developed for the purpose of targeting aspirin as a preventive medication for preeclampsia.4 Five of the 16 externally-validated multivariable risk prediction models had good or better discrimination, but all had low positive predictive value. There was insufficient information on discrimination and no information on calibration from validation studies to comprehensively evaluate model performance.4 In addition, the models used serum markers and Doppler ultrasonography, which are not always available in primary care and are not generally used in the first trimester of routine prenatal care.4

Effectiveness of Early Detection and Treatment

No studies directly compared the effectiveness of screening for preeclampsia on health outcomes in a screened versus unscreened population. One randomized, controlled trial examined the benefits and harms of a reduced prenatal visit schedule. This trial was an opportunity to evaluate a specific screening approach compared with the standard of care. This fair-quality trial (n=2,764) among low-risk pregnant women showed that fewer prenatal care visits (9 vs. 14 visits) did not result in worse maternal or neonatal health outcomes. However, the difference in the number of visits between groups was smaller than intended and the study was underpowered to detect difference for some health outcomes. In addition, the trial was published nearly 20 years ago, and there have since been changes to clinical practice in the United States.4, 23

Although the USPSTF found no recent studies on the direct effectiveness of screening for preeclampsia in improving health outcomes, trial evidence and extensive clinical experience provide evidence of effective treatments for preeclampsia. Antihypertension medications, when indicated, and administration of magnesium sulfate reduce the risk of adverse events. The Magpie Trial (n=10,141), an international randomized, controlled trial of treatment with magnesium sulfate, showed a benefit for preventing eclampsia. Pregnant women diagnosed with severe preeclampsia who were given magnesium sulfate had a 58% lower risk of eclampsia (95% confidence interval [CI], 40 to 71) than women who received placebo.4, 24 Incidence of placental abruption was significantly lower in the treatment group, and there was no evidence of short- or longer-term (up to 2 years) harms from treatment for the mother or infant.4, 24 A Cochrane review of anticonvulsant management of preeclampsia found that treatment with magnesium sulfate reduced the risk of eclampsia by more than half and also likely reduced maternal death.4, 25

In studies of timing of delivery, trial evidence supports delivery of the fetus to reduce the risk of adverse maternal outcomes for women with preeclampsia after 37 weeks of gestation. The large multicenter HYPITAT (Hypertension and Preeclampsia Intervention Trial at Term) found that immediate delivery of the fetus reduced the risk of composite adverse maternal outcomes for women with preeclampsia after 37 weeks of gestation (relative risk, 0.71 [95% CI, 0.59 to 0.86]; p<0.0001), with no difference in the rate of cesarean delivery or neonatal outcomes.4, 26

Potential Harms of Screening and Treatment

Previous evidence reviews commissioned by the USPSTF found good-quality evidence that measuring blood pressure has few major harms.13 The USPSTF found limited evidence on the harms of screening for and risk prediction of preeclampsia.

The USPSTF identified two fair-quality studies that reported on potential harms of alternative approaches to screening for preeclampsia. Neither study found evidence of harms, but both were underpowered to provide evidence on rare clinical outcomes. One was a fair-quality trial (n=2,764) that found no difference in birth outcomes (e.g., low birth weight, preterm birth, cesarean delivery) when the number of prenatal care visits were reduced from 14 to nine visits.4, 23 As noted earlier, this trial was not sufficiently powered to detect differences for rare outcomes related to preeclampsia such as progression to eclampsia, organ failure, stroke, and death.

The second study was a fair-quality, retrospective, before-after comparison cohort (n=1,952) of low-income pregnant Hispanic women, which did not identify any harms related to preeclampsia diagnosis and birth outcomes when targeted urine protein screening was only used for specific indications compared with use on a routine basis in prenatal care.4, 27

One fair-quality prospective cohort study (n=255) conducted in Spain found no differences in anxiety before and after counseling on preeclampsia risk and categorization as high or low risk based on results of a multivariable risk prediction model. High-risk women were subject to changes in their clinical care, with usual care for the low-risk group. Measures of anxiety over time did not change but were collected from less than half of the study participants.4, 28

The potential harms of treating preeclampsia are well established and include preterm delivery, neonatal complications, cesarean delivery, and side effects from magnesium sulfate (e.g., nausea, headache, blurry vision, floppy infant) and antihypertension medications (e.g., fatigue, headache, nausea).29

Estimate of Magnitude of Net Benefit

Given the evidence that treatment can reduce poor maternal and perinatal health outcomes and the well-established accuracy of blood pressure measurements, the USPSTF found adequate evidence that screening for preeclampsia results in a substantial benefit for the mother and infant. In addition, there is adequate evidence to bound the harms of screening for and treatment of preeclampsia as no greater than small. Therefore, the USPSTF concludes with moderate certainty that there is a substantial net benefit of screening for preeclampsia in pregnant women.

How Does Evidence Fit With Biological Understanding?

Preeclampsia is a complex syndrome that occurs among a range of hypertension disorders of pregnancy. Preeclampsia may involve abnormal formation of uterine arteries during placental development or increased oxidative stress and a maternal inflammatory response (or both).2-4 Although preeclampsia may remain stable until delivery, it can rapidly and unpredictably result in serious, even fatal health outcomes for the mother and infant.4

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This recommendation updates the 1996 USPSTF recommendation statement on screening for preeclampsia with blood pressure measurements throughout pregnancy (B recommendation).18

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The Society of Obstetricians and Gynaecologists of Canada recommends that the diagnosis of hypertension be based on office or in-hospital blood pressure measurements and that all pregnant women should be assessed for proteinuria. It does not recommend screening with biomarkers or Doppler ultrasonography.30 The National Institute for Health and Care Excellence recommends screening for preeclampsia by obtaining a blood pressure measurement and urinalysis for proteinuria at each antenatal visit.31 The Royal College of Obstetricians and Gynaecologists recommends that all pregnant women with an elevated blood pressure measurement, with or without proteinuria, be referred for assessment. It does not recommend screening for preeclampsia with Doppler ultrasonography.32 The American College of Obstetricians and Gynecologists recommends using medical history to evaluate for risk factors for predicting preeclampsia.5, 33

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