Prediction of preterm PE

Extensive research in the past 20 years, mainly as a consequence of the shift in screening for aneuploidies from the second to the first trimester of pregnancy, has identified a series of early biophysical and biochemical markers of impaired placentation.5 A combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11–13 weeks' gestation can identify a high proportion of pregnancies at high risk for PE.6 A recent study involving 58 800 singleton pregnancies examined at 11–13 weeks’ gestation has further refined the prediction algorithm for PE. Using this algorithm, the estimated detection rate of preterm PE was 75%, at a false-positive rate of 10%.6

Prevention of preterm PE

The prophylactic use of low-dose aspirin for prevention of PE has been an important research question in obstetrics for the past three decades. In 1979, Crandon and Isherwood7 observed that nulliparous women who had taken aspirin regularly during pregnancy were less likely to have PE than those who did not. There have been two meta-analyses published reporting that the administration of low-dose aspirin in high-risk pregnancies is associated with a decrease in the rate of PE.8 ,9 However, there are also other possible pathways which lead to the development of PE among different risk groups, and it is not known which risk factors or pathological processes may be responsive to early initiation of low-dose aspirin.

Initiation of low-dose aspirin in early pregnancy

In most studies that evaluated aspirin for the prevention of PE, the initiation of treatment was at or after 16 weeks' gestation. Examination of a small number of randomised trials of low-dose aspirin in women at high risk for PE suggests that the effectiveness of therapy is related to the gestational age at the initiation of treatment. A meta-analysis by Bujold et al9 reported that low-dose aspirin started at 16 weeks or earlier was associated with a significant reduction in the relative risk (RR) for PE (0.47, 95% CI 0.34 to 0.65) and fetal growth restriction (FGR; 0.44, 95% CI 0.30 to 0.65). In contrast, aspirin started after 16 weeks did not have a significant benefit (PE: RR 0.81, 95% CI 0.63 to 1.03; FGR: RR 0.98, 95% CI 0.87 to 1.10). More detailed analyses of these data on PE demonstrated that low-dose aspirin started at or before 16 weeks' gestation was particularly effective in preventing preterm PE rather than term PE (RR: 0.11, 95% CI 0.04 to 0.33 vs RR: 0.98, 95% CI 0.42 to 2.33).10

The small number and small size of individual trials preclude definitive conclusions to be drawn regarding the effectiveness of aspirin starting before 16 weeks and the results need to be examined in a prospective major randomised trial.

Aspirin resistance

There is evidence that ∼30%, 10% and 5% of pregnant women are ‘aspirin resistant’ with dosage of 81, 121 and 162 mg, respectively.11 Furthermore, a retrospective cohort study reported that women who were identified by the PFA-100 test as being resistant to 81 mg of aspirin were less likely to develop severe PE when the dose of aspirin was increased from 81 to 162 mg, compared with those who continued with 81 mg.12 Consequently, a trial investigating the effectiveness of low-dose aspirin in the prevention of preterm PE should use a dose closer to 160 than 80 mg.

Safety of low-dose aspirin

The relative safety of first trimester use of low-dose aspirin has been demonstrated in large cohort and case–control studies, which reported that the drug is not associated with increase in risk of congenital heart defects or other structural or developmental anomalies.13–16

Randomised studies reported that ∼10% of women receiving low-dose aspirin presented with gastrointestinal symptoms; however, there was no evidence of increase in any type of maternal bleeding.17–19 Similarly, the best evidence suggests that low-dose aspirin started before 16 weeks' gestation does not increase the risk of placental abruption (RR 0.62, 95% CI 0.08 to 5.03).9 No additional adverse effects related to epidural anaesthesia have been reported in women taking low-dose aspirin compared with those taking placebo.20

Prospective and case–control studies did not find an association between daily consumption of 60–150 mg of aspirin during the third trimester and antenatal closure of the ductus arteriosus.21–23 A meta-analysis including more than 26 000 women randomised to low-dose (80–150 mg) aspirin or placebo/no treatment during pregnancy demonstrated that the use of aspirin was not associated with an increase in intraventricular haemorrhage or other neonatal bleeding.24 On the basis of currently available evidence, it would be reasonable to continue with low-dose aspirin well into the third trimester of pregnancy.

Primary objective

To determine the efficacy of low-dose aspirin (150 mg daily), given to high-risk women from 11–14 to 36 weeks' gestation, in reducing the incidence of preterm PE, requiring delivery before 37 weeks.

Secondary objectives

• To determine the effect of low-dose aspirin on adverse outcome of pregnancy at <37 weeks.

  • PE requiring delivery at <37 weeks;

  • Small for gestational age (<5th centile) requiring delivery at <37 weeks;

  • Miscarriage or stillbirth at <37 weeks;

  • Placental abruption (clinically or on placental examination) at <37 weeks;

  • Composite of any of the above.

• To determine the effect of low-dose aspirin on adverse outcome of pregnancy at <34 weeks.

  • PE requiring delivery at <34 weeks;

  • Small for gestational age (<5th centile) requiring delivery at <34 weeks;

  • Miscarriage or stillbirth at <34 weeks;

  • Placental abruption (clinically or on placental examination) at <34 weeks;

  • Composite of any of the above.

• To determine the effect of low-dose aspirin on adverse outcome of pregnancy at >37 weeks.

  • PE requiring delivery at >37 weeks;

  • Small for gestational age (<5th centile) requiring delivery at >37 weeks;

  • Miscarriage or stillbirth at >37 weeks;

  • Placental abruption (clinically or on placental examination) at >37 weeks;

  • Composite of any of the above.

• To determine the effect of low-dose aspirin on neonatal mortality and morbidity.

  • Neonatal intensive care unit admission;

  • Intraventricular haemorrhage (IVH) grade II or above—defined as bleeding into the ventricles

    • Grade II (moderate)—IVH occupies <50% of the lateral ventricle volume,

    • Grade III (severe)—IVH occupies >50% of the lateral ventricle volume,

    • Grade IV (severe)—haemorrhagic infarction in periventricular white matter ipsilateral to a large IVH;

  • Ventilation—defined as need of positive pressure (continuous positive airway pressure (CPAP) or nasal CPAP) or intubation;

  • Neonatal sepsis—confirmed bacteraemia in cultures;

  • Anaemia—defined as low haemoglobin and/or haematocrit requiring blood transfusion;

  • Respiratory distress syndrome—defined as need of surfactant and ventilation as a result of prematurity;

  • Necrotising enterocolitis (NEC) requiring surgical intervention;

  • NEC is defined by a combination of clinical, radiological and laboratory features:

    • Systemic signs—apnoea, bradycardia, temperature instability, hypotension.

    • Intestinal signs—abdominal distension, gastric residuals, bloody stools, absent bowel sounds, abdominal tenderness, peritonitis.

    • Radiological signs—pneumatosis intestinalis or portal venous air, pneumoperitoneum.

    • Laboratory changes—metabolic and or respiratory acidosis, thrombocytopaenia, disseminated intravascular coagulation.

  • Composite of any of the above.

• To determine the effect of low-dose aspirin on the incidence of neonatal birth weight below the 3rd, 5th and 10th centiles.

  • Birth weight will be recorded in the participants' medical notes, and birthweight percentile for gestational age at delivery is calculated using a normal range derived from our population.25

• To determine the effect of low-dose aspirin on the incidence of stillbirth or neonatal death.

  • Owing to any cause;

  • Ascribed to PE or FGR;

  • In association with maternal or neonatal bleeding.

• To determine the effect of low-dose aspirin on the incidence of spontaneous preterm delivery at <34 and <37 weeks.

  • Spontaneous delivery at <34 weeks (early preterm) and at <37 weeks (total preterm) includes those with spontaneous onset of labour and those with preterm prelabour rupture of membranes.

Internal pilot study

The main study has been preceded by a 2-month pilot study, undertaken at King's College Hospital. In total, 1106 participants have been consented into the screening study and 56 participants to the randomised controlled trial (RCT). This pilot study has been used to assess the feasibility of recruitment to the screening study and RCT, and the ability of the centre to ensure successful compliance. A review by the ASpirin for evidence-based PREeclampsia prevention (ASPRE) Independent Data Monitoring Committee (IDMC) and Trial Steering Committee (TSC) of the internal pilot study has demonstrated the study has been successful with respect to recruitment to the screening study and RCT; however, it has also highlighted the complexity of the main ASPRE trial and confirmed the need for enhanced quality systems to be in place in advance of starting the main ASPRE trial in order to ensure the quality of pivotal data.

Screening quality study

A screening quality study, with a minimum recruitment period of 1–3 months (dependent on sites' performance) at each site, has been introduced to precede the main ASPRE trial. The aim of this study is to establish systems that will monitor quality of the measurement of uterine artery PI, MAP, PAPP-A and PlGF in a more detailed, formalised manner at sites and use these systems to assess quality, identify areas for improvement and, where required, implement strategies to improve quality, for example, retraining. This is based on the Down's syndrome screening quality assurance support service (DQASS) system that has been successful for improving the quality of the ultrasound and biochemical measurements in the National Health Service (NHS) fetal anomaly screening programme.

Recruitment rates have also been monitored. Furthermore, an assessment of data quality was made by the trial team at University College London Comprehensive Clinical Trials Unit (UCL CCTU) and any site-specific operational issues, which could not have been foreseen by the site assessment process, were identified, and addressed in advance of starting the main ASPRE trial.

Screening study and RCT

Following receipt of the results of the screening study, eligible high-risk women will be invited to take part in the RCT designated by the trial teams. It is anticipated that 10% of the population will screen positive for preterm PE and be invited to participate in the trial (figure 1).

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Figure 1

Flow chart of participants in the screening study and the randomised controlled trial. *Clinical visits at 19–24 and 30–37 weeks will only be performed on screen-negative participants at sites where a scan is performed by the fetal medicine unit as part of the routine clinical care pathway at either of these times. FGR, fetal growth restriction; PE, pre-eclampsia.

Screening phase inclusion criteria

• Age >18 years;

• Singleton pregnancy;

• Live fetus at 11–13 weeks of gestation;

• English, Italian, Spanish, French, Dutch or Greek speaking (otherwise interpreters will be used);

• Informed and written consent.

Screening phase exclusion criteria

• Multiple pregnancy;

• Pregnancies complicated by major fetal abnormality identified at the 11–13 weeks assessment;

• Women who are unconscious or severely ill, those with learning difficulties, or serious mental illness;

• Age <18 years.

Randomisation inclusion criteria following screening

• Screening phase inclusion criteria fulfilment;

• High risk for preterm PE at 11–13 weeks by the algorithm combining maternal history and characteristics, biophysical findings (MAP and uterine artery PI) and biochemical factors (PAPP-A and PlGF);

Randomisation exclusion criteria following screening

• Women taking low-dose aspirin regularly;

• Bleeding disorders such as Von Willebrand's disease;

• Peptic ulceration;

• Hypersensitivity to aspirin or already on long-term non-steroidal anti-inflammatory medication;

• Concurrent participation in another drug trial or at any time within the previous 28 days;

• Any other reason the clinical investigators think will prevent the potential participant from complying with the trial protocol.

Laboratory tests

At the time of the 11–13 weeks scan, 20 mL of maternal blood will be taken for the measurement of PAPP-A and PlGF using automated machines that provide reproducible results (DELFIA Xpress system, PerkinElmer Life and Analytical Sciences, Waltham, Massachusetts, USA). The remaining serum and plasma will be stored at −80°C for future studies of potential biochemical markers for adverse pregnancy outcomes.

Primary outcome

• Incidence of preterm PE (delivery at <37 weeks).

PE will be defined as per the International Society for the Study of Hypertension in Pregnancy.29 The systolic blood pressure should be 140 mm Hg or more and/or the diastolic blood pressure should be 90 mm Hg or more on at least two occasions 4 hours apart developing after 20 weeks of gestation in previously normotensive women (blood pressure <140/90 mm Hg) and there should be proteinuria of 300 mg or more in 24 hours or urinary protein creatinine ratio of 30 mg/mmol or more or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-hour collection is available. The efficacy will be assessed by the development of PE at any gestation after 20 weeks of pregnancy as defined above.

Secondary outcomes

• As defined above in the Secondary objectives section.

Type of analysis and statistical tests

The primary analysis will be a mixed-effects logistic regression analysis of the incidence of preterm PE with fixed effects for treatment and risk, and random effects for centre. A choice of transformation of risk (eg, logit transform) or grouping into levels will be made on the basis of a blinded review of the data. The treatment effect will be tested at the two-sided 5% level. Ninety-five per cent CIs will be produced for the proportions developing preterm PE in each of the two groups and for the treatment effect (active–placebo).

Planned secondary analysis of the primary outcome will include a survival analysis of the time to delivery with PE treating births for other causes as censoring. Prespecified baseline variables considered to be predictive will be included as appropriate. Their interactions with the treatment effect will be investigated. Gestational age at randomisation and its interaction with treatment will also be investigated. This analysis of treatment interactions will be considered as exploratory.

Descriptive statistics

A full set of descriptive statistics for all variables, overall and by treatment group, will be produced. Graphical displays will be produced as appropriate.

Secondary analysis

Secondary outcomes will be compared across treatment groups using appropriate tests. p Values and 99% CIs will be produced for treatment effects. No corrections will be made for multiplicity.

Safety

The incidence rates of AEs and SAEs and their relationship to trial drugs will be summarised by treatment group. The proportion of women discontinuing treatment will be summarised by reason and by treatment group.