First trimester screening and preventative treatment for early-onset pre-eclampsia – new research offers interesting answers.

Pre-eclampsia is defined as hypertension (>=140mmHg systolic or >=90mmHg diastolic) usually developing after 20 weeks gestation with one or more co-existent conditions such as proteinuria, other maternal organ dysfunction or placental dysfunction.¹ It affects between two and five per cent of all pregnant women and is the leading cause of maternal and fetal morbidity and mortality.^2,3 Early onset pre-eclampsia resulting in delivery before 34 weeks gestation affects approximately one in 250 women.⁴

Pre-eclampsia is a multisystem disorder of unknown aetiology, but is associated with dysfunctional placentation (poor cytotrophoblast invasion and impaired spiral arteriole remodelling), leading to an abnormal maternal physiological response to the underlying vascular endothelial dysfunction and consequent imbalance in both local and circulating angiogenic factors. This is expressed as a second- or third-trimester syndrome of maternal hypertension associated with uteroplacental insufficiency and/or impairment of maternal end-organ function.⁵

It is an obstetric axiom that pre-eclampsia can only be cured by delivery of the fetus and placenta. Indeed, with deference to severity, this is the preferred management strategy when the gestational age is at term or close to term. The dilemma arises where pre-eclampsia is diagnosed before 35 weeks gestation, where the maternal and fetal morbidity and mortality are seen to increase owing not only to the presence of disease at an early gestation age (which may prompt preterm caesarean delivery), but also as a consequence of the maternal and fetal risks associated with the relentless progression of the disease if pregnancy is prolonged in an attempt to improve fetal maturity.

Table 1. Risk factors associated with pre-eclampsia (adapted from Lowe et al).⁷

There is another axiom in medicine: prevention is better than cure. However, effective prevention requires appropriate identification of the at-risk group, together with an intervention that will mitigate or eliminate development of the pathology.

With regard to identification of an at-risk group, over the last 30 years obstetricians have relied on obstetric, medical and family history to identify women at high risk of developing pre-eclampsia (see Table 1). Unfortunately, this screening method identifies only approximately 30 per cent of cases and has a high false-positive rate.⁶

A number of other factors are also associated with an increased risk of pre-eclampsia including maternal age (<20 years or ≥35 years), chronic hypertension, pre-existing renal disease, autoimmune disease, more than ten years since the previous pregnancy, short sexual relationship prior to conception and possibly periodontal disease.^8,9,10 More recently, as a result of experience with multi-parameter Bayesian risk assessment algorithms used in first trimester aneuploidy screening, it has become possible to identify pregnant women at increased risk of early-onset pre-eclampsia on the basis of a combination of maternal demographic and historical features, biophysical parameters (body mass index, mean arterial blood pressure [MAP], Doppler assessment of placental vascular resistance at 12–14 weeks gestation – uterine artery pulsatility index [UA PI]), and maternal serum analytes (principally pregnancy-associated plasma protein A [PAPP-A] and placental growth factor [PlGF]). On combining these parameters in a validated risk algorithm (Fetal Medicine Foundation, London) it is possible to identify in the first trimester approximately 90 per cent of those women destined to develop pre-eclampsia prior to 34 weeks with a false positive rate of ten per cent.^4,11 The contribution of each variable to the algorithm accuracy differs; being highest for biophysical factors (MAP, UA PI), moderate for angiogenic factors (PlGF), and lowest for placental proteins (hCG and PAPP-A). However, there is a summative increase in detection rate with the addition of each parameter.4,12 As early onset pre-eclampsia has a low prevalence, the positive predictive value of screening is low (approximately three to six per cent), but the negative predictive value is high (>99.5 per cent), allowing targeted intervention and improving confidence in the triaging of antenatal care.⁴ The Fetal Medicine Foundation first trimester screening algorithm for early-onset pre-eclampsia was developed in a high-risk population, but has been validated in low-risk groups.^4,12 There is little controversy that it performs better than historical approaches in identifying that subgroup of pregnant women at increased risk for pre-eclampsia of early-onset.

What controversy does exist surrounds the efficacy of low-dose aspirin in pregnancies identified at increased risk, as there is healthy scepticism surrounding the ability of aspirin to mitigate the onset or severity of the disease.

Aspirin is a logical therapeutic consideration. In pre-eclampsia there is a functional imbalance between vascular prostacyclin (which inhibits platelet activation and aggregation) and increased thromboxane A2 production (which promotes platelet activation and aggregation). Aspirin irreversibly inactivates the cyclo-oxygenase enzyme required for thromboxane synthesis. Low-dose aspirin therapy is known to be effective in reducing thromboxane A2 production.

The 55 randomised trials involving more than 37 000 women over the past 30 years into the effects of low-dose aspirin in the prevention or amelioration of pre-eclampsia have provided mixed results. Most have shown a modest, but significant, reduction of pre-eclampsia in the treatment group, but the number needed to treat is very large, which has tempered enthusiasm for this intervention. Importantly, the majority of these studies have been hampered by small numbers, multiple study entry points (and therefore timing of intervention), definition changes and multiple study end points.

Recent meta-analyses have shown that in women at high risk for developing pre-eclampsia, daily low-dose aspirin (100–150mg) commenced before 16 weeks reduces the incidence of early and severe pre-eclampsia by between 50 and 90 per cent. The preventative effect is less apparent if aspirin therapy is commenced after 16 weeks.^13,14

Caution regarding subgroup analysis from meta-analyses has recently been urged, as these are subject to high false-positive and false-negative results.¹⁵ They should be used for hypothesis generation and then validity tested in separate studies. The systematic review of the effectiveness of low-dose aspirin before 16 weeks is encouraging, but not conclusive. There are small numbers in the trials, raising the possibility that the summary estimates would change significantly with the addition of new data. There is also a tendency to overestimate treatment effect owing to possible publication bias (where small negative trials are often missing).

There is an understandable concern that as aspirin is a ‘blood thinner’ and an ‘irritant to the stomach’ it should be used with caution. Benefits need to significantly outweigh risks. Aspirin is a weak acid absorbed from the stomach and small bowel, is metabolised by the liver and excreted mainly by the kidneys. Small doses have a half-life of approximately 2.0–4.5 hours. The current literature suggests that the use of low-dose aspirin during pregnancy is safe with regard to development of congenital anomalies and also to fetal, neonatal and maternal cardiovascular physiologic states and haemostasis. However, appropriate judgement does need to be exercised in prescribing aspirin prophylaxis to those with a history of bleeding, upper gastrointestinal tract ulcers or taking other medications with which aspirin may interact. It is best avoided in women with active vaginal bleeding and clearly should not be prescribed to women with aspirin allergy. Furthermore, in its recent review of this intervention, the United States Preventive Services Task Force considered there was adequate evidence that low-dose aspirin as preventive medication does not increase the risk for placental abruption, postpartum haemorrhage or fetal intracranial bleeding and does not increase the risk for perinatal mortality.¹⁷ Evidence on long-term outcomes in offspring exposed in-utero to low-dose aspirin is limited, but on first principles is unlikely to be adverse and no developmental harms were identified by 18 months of age in the one study reviewed.

Although some may consider first trimester screening for early-onset pre-eclampsia and aspirin prophylaxis controversial, with the exception of calcium supplementation in women with low calcium intake¹⁶, low dose aspirin is the only drug that can reduce the risk of pre-eclampsia. While there is argument about the magnitude of its effect, it can clearly mitigate the risks associated with the condition while exposing a pregnant woman and her fetus to a considered low risk from the introduction of aspirin. Where aspirin prophylaxis is considered appropriate then, on the basis of available literature, it is arguably preferable to start therapy in the first trimester of pregnancy, or at least before 16 completed weeks of gestation. Consideration of the dosing required to inhibit placental thromboxane, of diurnal rhythms and of other available published data, suggests a dose of 100–150mg per day taken at night is the most appropriate prophylactic regimen.

So, first trimester screening for early-onset pre-eclampsia and initiation of aspirin therapy in those considered at risk. Controversial? Possibly. But given available evidence, in an atmosphere of continuing legitimate academic argument, the judgement was made to offer screening programs in Australia, collect outcome data and publish the results. Women are currently screened in the first trimester of pregnancy using the Fetal Medicine Foundation algorithm for their risk of early-onset pre-eclampsia routinely at the High Risk Obstetric Unit at Royal Prince Alfred Hospital, in Sydney, and by request at Sydney Ultrasound for Women and Monash Ultrasound for Women (subspecialist obstetric imaging practices operating across greater Sydney and Melbourne). In all centres, it is recommended to referring doctors that consideration be given to commencing low-dose aspirin prophylaxis in women found to have a two per cent or greater risk of developing early-onset pre-eclampsia, and for this to be continued until 34 weeks gestation. The local experience is slowly emerging, with Prof Jon Hyett’s group at Royal Prince Alfred Hospital having recently published on the accuracy of screening in a low-risk population⁴ and on the therapeutic efficacy of low-dose aspirin in a local setting.¹⁸