Preeclampsia (PE) is a multisystem disorder of pregnancy classically characterized by hypertension with significant proteinuria after 20 weeks’ gestation.1–7 This disorder affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality. Worldwide, 76,000 women and 500,000 babies die yearly from this disorder.8 PE can be subdivided into preterm PE (with delivery at <37 weeks’ gestation) and term PE (with delivery at ≥37 weeks’ gestation). Preterm PE is associated with a higher risk of adverse maternal and perinatal outcomes than late-onset or term PE.9,10
The desire to predict PE effectively in the first trimester of pregnancy is driven by the need to identify pregnant women who are at high risk of developing the disorder, so that preventive measures can be initiated as early as possible in order to improve placentation and reduce the incidence as well as severity of the disorder.11,12 Despite the complex pathophysiology of PE, recent advances have made it possible to predict and prevent preterm PE in the first trimester of pregnancy.
First trimester screening for preterm preeclampsia
The traditional approach for the identification of high-risk women for PE follows the recommendations of professional organizations, such as National Institute for Health and Care Excellence (NICE) 13 and American College of Obstetricians and Gynecologists (ACOG).14–16 Risk factors include hypertensive disease in previous pregnancy, chronic hypertension, chronic renal disease, diabetes mellitus, autoimmune disease, nulliparity, advanced maternal age, obesity, family history of PE, and prolonged interpregnancy interval.13–16 This checklist-based approach essentially treats each risk factor as a separate screening test with additive detection rate (DR) and screen positive rate (SPR). Furthermore, evidence supporting these recommendations is mainly based on retrospective epidemiological studies on evaluating the relationship between individual risk factor and the development of PE; and most studies have not differentiated between preterm and term PE.
A large systematic review and meta-analysis of 92 studies, including 25,356,688 pregnancies, have determined the association between clinical risk factors identified before 16 weeks’ gestations and the risk of PE.17 Women with prior history of PE and chronic hypertension are the most significant risk factors and have relative risks (RR) of 8.4 (95% CI: 7.1–9.9) and 5.1 (95% CI: 4.0–6.5) for PE, respectively. Other clinical risk factors for PE include nulliparity (RR: 2.1; 95% CI: 1.9–2.4), maternal age >35 years (RR: 1.2; 95% CI: 1.1–1.3), chronic kidney disease (RR: 1.8; 95% CI: 1.5–2.1), conception by assisted reproductive technology (RR: 1.8; 95% CI: 1.6–2.1), prepregnancy body mass index (BMI) of >30 kg/m2 (RR: 2.8; 95% CI: 2.6–3.1), and preexisting diabetes mellitus (RR: 3.7; 95% CI: 3.1–4.3).17
An alternative approach to screening for PE, which allows estimation of individual patient-specific risks of PE with delivery before a specified gestation, is to use Bayes theorem to combine the a priori risk from maternal characteristics, medical and obstetric history with the results of various combinations of biophysical and biochemical measurements. Extensive research in the last decade has led to the identification of four potentially useful biomarkers at 11–13 weeks’ gestation: mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A), and serum placental growth factor (PlGF).
It has been well documented that women who are destined to develop PE have an elevated blood pressure (BP) in the first trimester of pregnancy.18–21 The measurements of BP should be undertaken using a standardized protocol; briefly, the BP is measured in both arms simultaneously using validated automated devices with correct positioning of women and the average of the four calculated MAP measurements is used for risk assessment.22 Abnormal uteroplacental circulation could be observed as abnormal Doppler in the uterine arteries by ultrasound (increased UtA-PI) from as early as the first trimester of pregnancy. In order to achieve reproducible, consistent, and accurate screening performance, standardization for the measurement of UtA-PI is required. Transabdominal ultrasound is used to obtain a sagittal section of the uterus and to locate the internal cervical os; then, ultrasound transducer is tilted to the lateral sides of the cervix, the uterine arteries are identified with the use of color Doppler flow mapping at the level of the internal cervical os. Pulsed wave Doppler is then performed with the sampling gate set at 2 mm to cover the vessel. The UtA-PI and peak systolic velocity are measured automatically by the ultrasound machine when three similar consecutive waveforms are obtained. The peak systolic velocity must be >60 cm/s to ensure measurement of the UtA-PI is performed at the level of the internal os.23 The average of the left and right UtA-PI is used for risk assessment. Maternal serum PAPP-A and PlGF have been investigated extensively, and have shown promising results in the early prediction of PE when values are observed to be reduced. These placental proteins have been implicated in the normal development of the placenta. Both PAPP-A and PlGF can be measured by several commercially available platforms of automated analyzers that provide reproducible results within 20–40 minutes of sampling. Certain maternal and pregnancy characteristics affect the crude values of these biomarkers and it is therefore necessary to express the measured values as multiple of medians, adjusting for these characteristics. It is also necessary to adjust for analyzer and reagents used for biochemical markers.24–26
The algorithm of a combination of maternal risk factors, MAP, UtA-PI, PAPP-A, and PlGF, was developed from a study of 35,948 singleton pregnancies, including 1058 pregnancies (2.9%) that experienced PE; the DR of preterm PE and term PE were 75% and 47%, respectively, at false positive rate (FPR) of 10%.27 Subsequently, data from three reported prospective nonintervention screening studies at 11–13 weeks’ gestation in a combined total of 61,174 singleton pregnancies, including 1770 (2.9%) that developed PE, have demonstrated that screening by a combination of maternal risk factors, MAP, UtA-PI, and PlGF and using a risk cutoff of 1 in 100 for preterm PE in Caucasian women, the SPR was 10% and DR for preterm and term PE were 69% and 40%, respectively. With the same method of screening and risk cutoff in women of Afro-Caribbean racial origin, the SPR was 34% and DR for preterm and term PE were 92% and 75%, respectively.26
In the latest National Institute for Health Research (UK) commissioned prospective validation study of the Bayes-based model in 16,747 pregnancies, including 473 (2.8%) women that developed PE, the SPR by the NICE method was 10.3% and the DR for all PE was 30% and for preterm PE it was 41%. The DR of the mini-combined test (maternal factors, MAP, and PAPP-A) for all PE was 43%, which was superior to that of the NICE method by 12.1% (95% CI: 7.9%–16.2%). In screening for preterm PE by a combination of maternal factors, MAP, UtA-PI, and PlGF, the DR was 82%, which was higher than that of the NICE method by 41.6% (95% CI:33.2%–49.9%).28 The addition of PAPP-A to this combined model did not improve the overall screening performance.
A secondary analysis of data from the ASPRE (Aspirin for Evidence-Based Preeclampsia Prevention) trial of a total of 34,573 women with singleton pregnancies who underwent prospective screening for preterm PE, including 239 (0.7%) cases of preterm PE, showed that in ACOG or NICE screen positive women who were screen negative by the Bayes-based method, the risk of preterm PE was reduced to within or below background levels.29 The study demonstrated that at least one of the ACOG criteria was fulfilled in 22,287 (64.5%) pregnancies and the incidence of preterm PE was 0.97% (95% CI: 0.85%–1.11%); in the subgroup that was Bayes method screen positive, the incidence was 4.8% (95% CI: 4.14%–5.55%), in those who were screen negative, it was 0.25% (95% CI: 0.18%-0.33%) and the relative incidence in Bayes method negative to Bayes method positive, the incidence was 5.1% (95% CI: 3.7%–7.1%). In 1392 (4%) pregnancies, at least one of the NICE high-risk criteria was fulfilled and in this group the incidence of preterm PE was 5.17% (95% CI: 4.13%–6.46%); in the subgroups of screen positive and screen negative by the Bayes method, the incidence of preterm PE was 8.71% (95% CI: 6.93%–10.89%) and 0.65% (95% CI: 0.25%–1.67%), respectively, and the relative incidence was 7.5% (95% CI: 2.8%–20.5%). In 2360 (6.8%) pregnancies with at least two of the NICE moderate-risk criteria, the incidence of preterm PE was 1.74% (95% CI: 1.28%–2.35%); in the subgroups of screen positive and screen negative by the Bayes method, the incidence was 4.91% (95% CI: 3.54%–6.79%) and 0.42% (95% CI: 0.2%–0.86%), respectively, and the relative incidence was 8.5% (95% CI:3.8%–19.2%).29 These results provide further evidence to support risk-based screening using biomarkers.
Previous studies have demonstrated that biomarker values derived from Chinese populations are different from those derived from non-Chinese populations.30–33 These variations or changes in biomarkers can affect the screening performance. A case-control study including 3000 normotensive and 30 preeclamptic pregnant women evaluated the first-trimester PE prediction test in a South Chinese population.30 Biomarker values were adjusted for maternal and pregnancy characteristics with the use of published expected values based on European data.31 The study demonstrated that the predictive performance based on European algorithms in the South Chinese population was lower than those obtained from the original studies. The investigators postulated that the poor performance of screening was due to the lower rate of PE in the South Chinese population and the under-measurement of MAP and UtA-PI.30 An Asia-wide prospective validation study of the Bayes-based model is underway and results are expected in mid-2019 (ClinicalTrials.gov Identifier: NCT03554681).
Prevention of preeclampsia
Evidence from the aforementioned studies indicates that there is an effective screening tool for the identification of women at risk of developing preterm PE. This allows early introduction of prophylactic treatment and therapeutic intervention. Several approaches have been proposed to prevent PE, including the administration of low-dose aspirin, heparin, antioxidants, calcium supplementation, proton pump inhibitor, or metformin. The only proven effective preventive strategy is the administration of low-dose aspirin to high-risk women for preterm PE at <16 weeks’ gestation.33–50
In 1978, Goodlin et al. described a patient with recurrent PE and thrombocytopenia who seemed to have benefited from aspirin prophylaxis.37 Crandon and Isherwood demonstrated that nulliparous pregnant women who had taken aspirin or aspirin-containing compounds for more than once a fortnight throughout pregnancy had a lower risk of PE than those who had no reported history of aspirin consumption.51 In 1985, a randomized, open-labeled trial showed that women at risk for PE or fetal growth restriction (FGR), based on obstetric history, who received 300 mg of dipyridamole and 150 mg of aspirin since 12 weeks of gestation until delivery, were not complicated by PE, fetal loss, or severe FGR, compared to those in the nonintervention group.52
A landmark individual patient data meta-analysis, including 31 randomized trials of PE prevention (n = 32,217 women), showed that patients who received antiplatelet agents especially aspirin, for the prevention of PE, had a 10% reduction in the rate of PE (RR: 0.90; 95% CI: 0.84–0.97), irrespective of aspirin dosage, starting time, and indications.53 Bujold et al. demonstrated that low-dose aspirin started at 16 weeks or earlier in patients at risk of PE had a substantial reduction in the rate of PE (RR: 0.47; 95% CI: 0.34–0.65). However, aspirin started after 16 weeks of gestation did not decrease the rate of PE (RR: 0.81; 95% CI: 0.87–1.10).54
There is now substantial evidence from the ASPRE trial that the rate of preterm PE can be reduced by >60% by low-dose aspirin started at 11–14 weeks of gestation in high-risk women identified by the Bayes-based prediction model.35 In this multicenter, double-blind, placebo-controlled trial, 1776 women with singleton pregnancies at high risk of preterm PE were randomly assigned to receive aspirin, at a dose of 150 mg per night, or placebo from 11 to 14 weeks of gestation until 36 weeks.35 The primary outcome was delivery with PE before 37 weeks of gestation (preterm PE). Preterm PE occurred in 13 (1.6%) participants in the aspirin group and in 35 (4.3%) in the placebo group (odds ratio [OR] in the aspirin group 0.38; 95% CI: 0.20–0.74; P = 0.004). Adherence was good with a reported intake of 85% or more of the required number of tablets in 80% of the participants.35 There were no significant between-group differences in adverse events and serious adverse events, concluding that low-dose aspirin was considered safe.35 Furthermore, a secondary analysis of data of 1620 participants with 1571 live-born neonates showed that the total length of stay in neonatal intensive care (NICU) was substantially longer in the placebo group than in the aspirin group (1696 vs. 531 days). This was a reflection of significantly shorter mean lengths of stay in babies admitted to the NICU in the aspirin group compared to the placebo group (11.1 vs. 31.4 days; a reduction of 20.3 days).55 Overall, in the whole trial population, including zero lengths of stay for those who were not admitted to the NICU, the mean length of stay was longer in the placebo group than in the aspirin group (2.06 vs. 0.66 days; reduction of 1.4 days). This corresponded to a reduction in length of stay of 68%.55
The latest systematic review and meta-analysis, including 16 randomized controlled trials with a total of 18,907 participants, has demonstrated that the administration of aspirin is associated with a reduction in the rate of preterm PE (RR: 0.62; 95% CI: 0.45–0.87).36 However, there is no significant effect on term PE (RR: 0.92; 95% CI: 0.70–1.21). Only the subgroup in which aspirin is started at ≤16 weeks of gestation at a dose of ≥100 mg/day is associated with a reduction in the frequency of preterm PE (RR: 0.33; 95% CI: 0.19–0.57, P = 0.0001). Either the initiation of aspirin at >16 weeks or the daily dose of <100 mg is not associated with a reduction in preterm or term PE.36
Benefit and harm
The ASPRE approach that screens for preterm PE followed by a simple intervention of daily aspirin can be assessed in terms of “benefits” and “harms.” Benefits and harms are simple concepts, readily understood by most individuals and frequently applied to medicine and health care, as every intervention, no matter how innocuous it may appear, carries both benefits and harms. Any prediction and intervention study has to balance the benefits and harms in the context of the condition being screened for and the impact, if any, of the treatment intervention being offered in order to practice “good” evidence-based medicine. Ideally, a screening and treatment protocol should offer all the benefits and none of the harms; the reality, however, is that there is always some compromise.
Screening benefits would be early awareness, by both the physicians and patients, that the pregnancy is at increased risk of developing preterm PE, clinical interventions to increase pregnancy duration by preventing or delaying PE, thus reducing NICU admission duration, and ultimately preventing reduction in maternal life expectancy as well as future risk of cardiovascular disease.55–57 Women with a history of PE, relative to those without, have a twofold increased risk of major coronary events, with risks being even higher if the pregnancy was also complicated by FGR (threefold) or preterm delivery (fivefold). Screening and treatment harms would include unnecessary induced anxiety and potential indirect side effects associated with aspirin and overtreatment. A recent registry analysis of Danish and Norwegian mother–child pairs has reported that children exposed to aspirin and paracetamol during pregnancy have an elevated risk of cerebral palsy.58 However, this Scandinavian-based retrospective registry has major limitations. First, the aspirin dosage effect has not been assessed. Second, whether cerebral palsy is a result of the delivery process or other potential antenatal event has not been evaluated. A meta-analysis review on behalf of the US Preventive Services Task Force in 2015 concluded that daily aspirin at dosages of up to 160 mg per day was not associated with an increased risk of maternal postpartum hemorrhage (RR: 1.02; 95% CI: 0.96–1.09) and perinatal mortality (RR: 0.92; 95% CI: 0.76–1.11), but was associated with a risk reduction in preterm birth (RR: 0.86; 95% CI: 0.76–0.98), FGR (RR: 0.80; 95% CI: 0.65–0.99), and PE (RR: 0.76; 95% CI: 0.62–0.95).59
Cost-benefit or cost-utility decision analysis modeling is frequently used to determine both the optimum strategy and incremental cost of one strategy over another to decide whether a new strategy or approach is an improvement over alternatives. The impact or potential benefits versus that of potential harms, provided they can be represented either monetarily or by their impact on quality of life, is reported. This approach has been used to assess the cost-effectiveness of Down syndrome screening and more recently has been reported for first-trimester PE screening and treatment.60,61
An alternative and increasingly adopted approach is to perform decision analysis based on assessment of net benefit relative to harm as “exchange rates”/“threshold probabilities” (pt) between potential strategies change.62,63 Decision curve analysis (DCA) has an advantage over traditional diagnostic/screening performance assessment because DCA assesses clinical utility, whereas the latter are measures of diagnostic/screening accuracy. A clinical judgment of the relative value of benefits (treating a true positive [TP] case) and harms (treating a false positive [FP] case) associated with screening prediction models can then be assessed on a common scale. To compare strategies at a given threshold probability, the net benefit (for the screening) can be determined as (TP − FP (pt/(1 − pt))/n), where n is the number of cases screened and pt is the threshold probability at which an individual is screened “high risk” as opposed to “low risk.” The DCA could, therefore, be used to assess the potential benefit/harm of preterm PE prediction performance within the ASPRE trial. After correcting for the effect of aspirin use in those randomized to aspirin, it was estimated that the DR of the first-trimester screening was 77% for preterm PE, at 10% FPR, using a risk cutoff of 1%,35,64 a figure consistent with the 75% DR reported in an earlier nonintervention study.29
For a threshold of 1% (1:99), the Bayes-based screening model using maternal risk factors in combination with biomarkers correctly predicted 138 of the 180 women who developed preterm PE and identified 2375 of the 25,167 unaffected women as FPs. The net benefit is therefore (138–2375 × (1/99))/25,347 = 0.45%. The net benefit of “no screen” and offering all aspirin would be (180–25,167 × (1/99))/25,347 = −0.29%, an absolute difference of 0.74%. Offering no screening and prescribing aspirin would be considered harmful. Overall, offering screening implies that for every 1000 patients screened, ≈8 true positives are identified without increasing FPR. The net benefit however will change. Had ASPRE used a lower threshold and adopted a FPR of 30%, a threshold probability would be 0.27% (1:370), assuming that TP rate of the screening test increased to 90% and then net benefit of screening increases to 0.58% ((162–7550 × 0.2/99.8)/25,347), whereas no screening would be 0.51% ((180–25,167 × 0.2/99.8)/25,347) and thus still beneficial, although it would detect only ≈1 additional TP case.
Traditional method of screening as recommended by professional guidelines has limited predictive performance and therefore should be updated to reflect recent scientific evidence that the target of screening should be preterm PE, the best way to identify the high-risk group is the Bayes-based method that combines maternal risk factors and biomarkers, the threshold should be set at SPR of 10%, aspirin should be started before 16 weeks’ gestation, and the daily dose should be higher than 100 mg.
Conflicts of Interest
Liona C. Poon has received speaker fees and consultancy payments from Roche Diagnostics. In addition, she has received in-kind contributions from Roche Diagnostics, PerkinElmer, Thermo Fisher Scientific and GE Healthcare.
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