Jon Hyett and Liona C. Poon
Preeclampsia is a relatively common disorder of pregnancy, affecting 2%–5% of women (1–3). It is potentially associated with severe and devastating complications that can lead to death or significant morbidity of both mother and child. Preeclampsia remains one of the major causes of maternal death, being associated with more than 76,000 deaths worldwide every year (4,5). Preeclampsia is also associated with significant maternal morbidity, fetal growth restriction, placental abruption, and stillbirth (Figure 7.1) (6,7).
Figure 7.1 Severe maternal and neonatal morbidities associated with preeclampsia.
Preeclampsia is a self-limiting disease insofar as while there is currently no treatment that will stop disease progression, delivery, specifically delivery of the placenta, effectively cures the disease. This frequently presents a conundrum for the obstetrician as the best management options for their two patients (mother and fetus) may be contradictory. Preeclampsia has been identified as leading to more than 500,000 preterm deliveries each year resulting in high mortality and morbidity for the infant (4,8,9).
The central characteristic of preeclampsia is the development of new-onset hypertension after 20 weeks’ gestation during pregnancy. This is typically defined through recurrent measurement of blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic (10). Preeclampsia is distinguished from gestation hypertension through the presence of one or more additional factors. Historically, this was based on observation of the presence of proteinuria (≥300 mg/day or ≥2+ on dipstick testing; indicative of some renal dysfunction) and the development of significant peripheral edema. More recent definitions include evidence of hematological, renal, or hepatic dysfunction; symptoms of neurological complication; or features of fetal growth restriction on a background of de novo hypertension at >20 weeks’ gestation as being diagnostic of preeclampsia (Table 7.1) (11).
Table 7.1 Diagnostic criteria for preeclampsia
Preeclampsia is a multisystem disorder that is related to pregnancy. It is typically characterized by the finding of hypertension with involvement of one or more of the following organ systems.
Significant proteinuria (protein/creatinine spot ratio ≥30 mg/mmol)
Serum creatinine >90 umol/L
Oliguria <20 mL/hour
Evidence of hemolysis through blood film
Evidence of disseminated intravascular coagulopathy
Severe epigastric/upper right quadrant pain
Raised serum transaminases
Fetal growth restriction
Source: Ref. 11.
Note: Hypertension in pregnancy is defined through repeated measures showing a systolic blood pressure >140 mm Hg and/or a diastolic blood pressure >90 mm Hg.
The definition of preeclampsia, which is based on the observations of symptoms, signs, and investigational findings associated with this disease, is quite broad and may in fact include a number of subtly different disease processes under one collective term. This is demonstrated by the spectrum of pregnancy outcomes that can be seen in women with preeclampsia (12). At one end of the spectrum, the disease may be identified early in the second trimester of pregnancy, hypertension may be difficult to control, and severe fetal growth restriction may also contribute to a decision to expedite delivery. Alternatively, the disease may not present until the latter part of the third trimester of pregnancy and may develop more slowly with no evidence of fetal compromise such that symptoms can be managed with relatively simple pharmacological interventions rather than necessitating early delivery. This range of presentations, with disease becoming apparent at a variety of gestational ages, developing at different rates, and requiring a number of different approaches to management, make prediction, diagnosis, and management of preeclampsia very difficult.
One approach to distinguishing between different subtypes of preeclampsia is to describe the disease according to the range of symptoms and signs that are identified and/or to the time point at which delivery needed to be expedited (13). This system allows clinicians and researchers to compare outcomes from various management strategies and interventions, but this can essentially only be done retrospectively as the course of disease is quite unpredictable making prospective classification difficult. Although the terms “mild” and “severe” preeclampsia are not synonymous with particular gestational age points, women who have early onset disease requiring delivery before 34 weeks’ gestation invariably had severe preeclampsia, as this is reflected in the balance of risks leading to the decision to expedite delivery.
Reports of prediction, prevention, diagnosis, and management of women with “early” preeclampsia (presenting with severe disease leading to delivery earlier than 34 weeks) have become increasingly common (14–17). Early onset preeclampsia (less than 34 weeks) is less prevalent, affecting approximately 1 in 200 to 1 in 250 pregnancies in most Western series and representing approximately 10% of all disease (3). Women who develop preeclampsia are known to have a higher risk of significant short- and long-term morbidity if they require early delivery, and this gestation also marks a transition in the ongoing needs/outcomes of the neonate. The mothers have higher risks of requiring admission to intensive care, eclamptic seizures, pulmonary edema, renal failure, retinal detachment, and thromboembolism (5). In later life, they also have significantly higher risks of cardiovascular disease such as ischemic heart disease and stroke (18). For the neonate, risks include cerebral palsy, cognitive delay, autism, and other neurodevelopmental, psychomotor, behavioral, and learning disorders (8). In later life, these infants are more likely to develop hypertension, diabetes, and obesity (9).
The underlying etiology of preeclampsia is not completely elucidated, but significant progress has been made in identifying the cascade of events that translate a primary pathological insult into clinical presentation of disease. A series of observations made by different research groups can be combined to describe two distinct series of pathological events—sometimes referred to as the two-hit hypothesis. The first event is focused on failure of normal placental implantation in early pregnancy, and the second is focused on the release of antiangiogenic factors and development of endothelial dysfunction that leads to multiorgan dysfunction (Figure 7.2) (19,20).
Figure 7.2 Abnormal shallow invasion of spiral arterioles leads to failure of implantation and placental hypoxia; a central defect that leads to early onset preeclampsia. (Source: Ref. 59. Under Creative Commons.)
There is evidence to show that at around 6–13 weeks’ gestation, the preeclamptic placenta fails to implant correctly. A variety of genetic and environmental factors contribute to poor trophoblast invasion with inadequate transformation of the spiral arteries in the myometrium (Figure 7.2) (21). Shallow placental implantation leads to chronic placental ischemia, hypoxia, and dysfunction throughout pregnancy. As a result of oxidative stress, the ischemic placenta releases a number of pro-inflammatory cytokines, chemokines, and trophoblast debris including the antiangiogenic factors sFlt-1 and sENG (Figure 7.3) (22,23).
Figure 7.3 Changes in pro- and antiangiogenic mediators impact endothelial function. (Source: Ref. 60, with permission.)
In normal pregnancies, there is a progressive increase in circulating sFlt-1 and sENG levels from 20 weeks’ gestation through to term. This increase is much more marked in pregnancies that develop preeclampsia, with sharp increases in sFlt-1 and sENG occurring in a 5-week window before delivery (24,25). sFlt-1, an extracellular splice variant of vascular endothelial growth factor (VEGF) receptor 1, binds circulating VEGF, antagonizing its angiogenic function. sFlt-1 also impairs phosphorylation of endothelial nitric oxide synthase (eNOS) and increases angiotensin II sensitivity, directly promoting hypertension. sENG antagonizes endothelial receptor signaling as well, but through a different pathway, competing with membrane-bound endoglin to prevent interaction with growth factor receptors that promote angiogenesis. Excessive secretion of these antiangiogenic factors results in widespread injury to maternal blood vessels, causing endothelial dysfunction (26). This also leads to vasoconstriction and hypertension and causes multiple organ injury that can lead to organ failure.
Although this mechanism describes an etiological pathway that fits the development and features of early onset preeclampsia quite well, it is harder to reconcile milder and later-onset forms of the disease. It is clear that an interaction between the placenta and maternal vasculature is still important in late-onset disease, and similar pathological processes are involved, but the emphasis is likely different with the primary insult being related to maternal endothelial dysfunction that, among other systemic effects, impacts placental function, leading to further release of antiangiogenic factors and maternal deterioration (27,28). This mechanism that describes the underlying etiological pathway associated with late-onset preeclampsia is not as clearly defined, and other processes have been advocated. As late-onset preeclampsia can also cause significant maternal pathology and lead to placental abruption and stillbirth, it is important to continue to identify the processes involved in the development of this disease, and research-based omics will be of value in this.
The two-hit hypothesis for the development of severe, early onset preeclampsia provides the rationale for predictive screening and prevention. There are essentially two points at which screening and intervention may be considered. The first involves identification of early failure of placental implantation and the prospect of therapeutic interventions that improve this process. This is most attractive as, if it were possible to improve placentation, then placental hypoxia may be prevented, removing the foundation for a secondary pathological “hit.” Once placental insufficiency is established, the clinical strategy changes. In this circumstance, early identification of the pregnancy that is likely to develop preeclampsia allows closer surveillance so that traditional interventions such as delivery can be better timed. It may also allow the introduction of interventions that slow disease progression that delay decisions for delivery and consequently reduce risks of prematurity.
An example of current success in developing a strategy for prediction and prevention of severe, early onset preeclampsia (leaving to delivery <34 weeks’ gestation) involves the combination of maternal demographic and medical characteristics with biophysical measurement of maternal blood pressure and uterine perfusion (by measurement of the uterine artery pulsatility index) and measurement of angiogenic placental biomarkers such as PaPP-A and PLGF (14). These measures have been successfully combined to create an algorithm that is able to predict more than 90% of cases of early onset preeclampsia that require delivery earlier than 34 weeks (14,29,30,31). The test is most effective in the prediction of early onset disease but will also identify 75% of cases requiring delivery less than 37 weeks and 40% of cases that develop preeclampsia at term (Figure 7.4). While there has frequently been concern about the performance of such algorithms when they are transferred to other populations (32), there are now a number of validation studies that have confirmed the performance of this screening test internationally (33–36). This approach is reinforced by the validated findings of others that have used a similar multivariate technique to improve screening efficacy (37,38). There is also a growing body of data, including a large prospective randomized controlled trial, that have shown that aspirin is an effective prophylactic therapy that prevents preterm delivery in up to 80% of women destined to deliver earlier than 34 weeks and 60% of those destined to deliver earlier than 37 weeks (Figure 7.4) (15,39). Interestingly, as the predictive algorithm performed more poorly with term pregnancies, so did the intervention with a nonsignificant 5% reduction in disease prevalence at or later than 37 weeks (15).