Associate Professor, Maternal Fetal Medicine, University of Colorado Departments of Obstetrics and Gynecology and Psychiatry, Wheat Ridge, CO
Dr. Hoffman reports no financial relationships relevant to this field of study.
SYNOPSIS: The use of 150 mg of daily aspirin from 11 to 14 weeks through 36 weeks of gestation reduces the rate of early preeclampsia (PE) in approximately 90% of at-risk pregnancies. In addition, aspirin also provides the benefit of reducing the risk of PE < 37 weeks by about 60% and the length of NICU stay by about 70%, primarily by reducing the number of neonates delivered before 32 weeks. What constitutes a high-risk patient and what quantifies patient-specific risks before PE develops remain to be answered.
SOURCES: Wright D, Tan MY, O’Gorman N, et al. Predictive performance of the competing risk model in screening for preeclampsia. Am J Obstet Gynecol 2019;200:199.e1-13.
Wright A, Wright D, Syngelaki A, et al. Two-stage screening for preterm preeclampsia at 11-13 weeks’ gestation. Am J Obstet Gynecol 2019;220:197.e1-11.
Preterm preeclampsia (PE) remains a large contributor to maternal and fetal/neonatal morbidity and mortality worldwide. Traditionally, women have been considered high risk for PE based on obstetric history and maternal medical risk factors,1 including a history of early severe PE, multiple gestation, chronic hypertension, systemic lupus erythematosus, underlying renal disease, and other maternal comorbidities. Based on the current categorization strategy, PE is predicted accurately less than 50% of the time.2 Using this traditional prediction approach, low-dose aspirin (81 mg) is recommended, starting prior to 16 weeks. When low-dose aspirin is given at ≥ 100 mg/day and taken consistently starting at < 16 weeks, the rates of very early and early-PE are reduced by 80% to 90% and the rate of preterm-PE is reduced by about 60%.3
Investigators from the United Kingdom completed three prospective studies evaluating the addition of the “triple test.” The triple test includes further assessment of women with preexisting risk factors for PE with a mean arterial blood pressure (MAP), uterine artery Dopplers (UtA-PI, average pulsatility index of both uterine arteries), and a placental growth factor (PLGF) maternal serum assessment between 11 weeks 0 days’ and 13 weeks 6 days’ gestation. The objective of the study by D. Wright et al (study 1) was “to examine the predictive performance of the competing risks model in screening for PE with delivery < 34 weeks (early-PE), < 37 weeks (preterm-PE), and delivery at any gestation (all-PE) by maternal factors alone and in combination of maternal factors, MAP, UtA-PI, and PLGF (the triple test).” This study included 61,174 singleton pregnancies with an overall rate of PE of 2.9% (n = 1,770). In this study, which used a set screen positive rate of 10% overall, the detection rates of early-PE, preterm-PE, and all-PE were 90%, 75%, and 50%, respectively. There was excellent agreement, close to 1.0 (100%) between overall predicted risk and observed incidence of early and preterm PE. On the other hand, prediction of all-PE was poor.
In study 2, using the same population, A. Wright et al looked more closely at a two-stage screening model in which the whole population (mostly low-risk women) was compared with a high-risk population selected based on traditional categorization to determine if triple testing can be reserved for a higher-risk group. In this analysis, the authors found that “if … first-stage screening is maternal factors, then measurements of MAP, UtA-PI, and PLGF can be reserved for only 70% of the population.” Detection rates for PE (and 10% screen positive rate) were similar to whole-population screening with the triple test, with an overall 85% detection rate for PE < 32 weeks. For the two-stage screening model (study 2), the ability to triage women who traditionally would have been high risk to undergo various combinations of the triple test remained highly predictive of actual development of early and preterm PE, while becoming more cost effective and less labor intensive by eliminating 30% of the overall population who were low risk. The ability of the triple test, in combination with preexisting maternal risk factors, to predict PE, especially the worst type (that which necessitates delivery prior to 32 weeks) was particularly high for black and South Asian women at 100% (95% confidence interval, 93.6-100 and 66.4-100, respectively).
A targeted attack on PE, and the suffering that it causes, is long overdue. After reviewing these studies, it is difficult to understand why we are not moving more eagerly toward this two-staged approach in the United States. A number of patients now have an automatic “preeclampsia risk score” included in their sequential screening. This is based on PLGF levels and reported out as a 1 in “x” risk, just as sequential or quad screen results are listed. Hopefully, clinicians at least will heed the preeclampsia risk score based on PLGF levels alone and recommend low-dose aspirin. In addition, it is easy and routine to collect a maternal blood pressure; therefore, MAP can be assessed and recorded easily. As for the uterine artery Dopplers, most perinatal sonographers and sonologists are familiar with these studies, and the fetal medicine foundation provides online instructions. They are certainly no more difficult than nuchal translucency measurements.
While we are missing cases of early and preterm PE with severe features with our current protocols — something that occurred in 0.36% and 0.81% of the 2.9% of overall diagnoses of PE in these studies — we continue to screen all patients for conditions (trisomy 21, open neural tube defects) that affect far fewer pregnancies overall. Why is this? Have we embraced the mantra for too long that preeclampsia is curable only by delivery and failed to recognize the risk reduction and prevention that the early advent of low-dose aspirin can accomplish?
Based on established research and supported by these studies, the following suggestions are offered to reduce the risk of early or preterm PE:
ACOG Committee Opinion no. 743 recommends that clinicians stratify patients by the following risks: a history of PE, multifetal gestation, renal disease, autoimmune disease, type 1 or type 2 diabetes, and chronic hypertension. If the patient has at least one risk factor, then the clinician should recommend a daily low-dose aspirin (81 to 150 mg/day).
- Bedtime dosing is best and women should start prior to 16 weeks’ gestation.
- U.S. aspirin formulations are 81 mg or 325 mg per tablet, but the U.K. studies suggest more significant benefit from a dose ≥ 100 mg/day. Women at particularly high risk could opt for two 81 mg tablets daily, one and one-half 81 mg tablets daily, or one-half 325 mg tablet daily. All approach this goal
If the patient has other known maternal risk factors, such as advanced maternal age, high body mass index, black and South Asian ethnicity, and the patient’s mother had PE, then checking a MAP and either doing UtA or adding a PLGF (or both) into your office’s sequential screen is worthy of consideration. If any of these are “positive,” proceed with the aspirin recommendations noted above.
- ACOG Committee opinion no. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018;132:254-256.
- Tan MY, Wright D, Syngelaki A, et al. Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: Results of SPREE. Ultrasound Obstet Gynecol 2018;51:743-760.
- Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613-622.