Preeclampsia beyond pregnancy: long-term consequences for mother and child

Abstract

Preeclampsia is defined as new-onset hypertension after the 20th wk of gestation along with evidence of maternal organ failure. Rates of preeclampsia have steadily increased over the past 30 yr, affecting ∼4% of pregnancies in the United States and causing a high economic burden (22, 69). The pathogenesis is multifactorial, with acknowledged contributions by placental, vascular, renal, and immunological dysfunction. Treatment is limited, commonly using symptomatic management and/or early delivery of the fetus (6). Along with significant peripartum morbidity and mortality, current research continues to demonstrate that the consequences of preeclampsia extend far beyond preterm delivery. It has lasting effects for both mother and child, resulting in increased susceptibility to hypertension and chronic kidney disease (45, 54, 115, 116), yielding lifelong risk to both individuals. This review discusses recent guideline updates and recommendations along with current research on these long-term consequences of preeclampsia.

INTRODUCTION

Pregnancy results in temporary physiological adaptations that can have widespread effects. Diseases of pregnancy that further perturb the body’s physiology remain behind as an imprint of former disease and impact the health of affected women for the remainder of their lives. However, not until recently have parous history and history of pregnancy complications been included in recommended history taking for assessment of cardiovascular health risk. In 2011, the American Heart Association formally recognized history of preeclampsia as an independent risk factor for cardiovascular disease and followed with similar recommendations concerning stroke in 2014 (30, 105). Numerous studies and review articles have examined the relationship of preeclampsia with cardiovascular risk in postpartum years (56, 116, 130, 145), but the renal outcomes and risks have been less well explored. Although evidence suggests an association between preeclampsia and long-term renal disease, further study of the potential mechanisms is needed. Furthermore, the risk of preeclampsia should be isolated from the underlying risk intrinsic to the patient that may simply be exposed during the stress of preeclampsia (6). This information will assist in the development of novel therapies, interventions, and screening recommendations to improve the health of women worldwide.

WHAT IS PREECLAMPSIA?

In 2014, the International Society for the Study of Hypertension in Pregnancy (ISSHP) reevaluated their consensus statement and issued an update stating that preeclampsia is defined as the de novo appearance of hypertension after the 20th wk of gestation along with evidence of maternal organ failure, which includes the following: new-onset proteinuria of >300 mg/day or other indications of renal insufficiency, hematological complications such as thrombocytopenia and liver dysfunction, or neurological complications such as visual disturbance and/or evidence of uteroplacental dysfunction such as fetal growth restriction (28, 165). This definition has also been examined and confirmed by both the American College of Obstetricians and Gynecologists and the United States Preventive Services Task Force (6, 22). Notably, preeclampsia should be distinct from either history of chronic hypertension or gestational hypertension, the appearance of elevated blood pressure alone during pregnancy (28, 165). However, preeclampsia may be superimposed on a background of chronic hypertension, producing persistent hypertension in pregnancy with one of the aforementioned signs of maternal organ failure. Rates of preeclampsia have increased in the past 30 yr, affecting some 3.4% of 120 million deliveries in the United States from 1980 to 2010 (7). This trend was not associated with period-related population changes in behavior-related characteristics such as obesity and smoking.

In more recent years, it has become apparent that preeclampsia may consist of several distinct subtypes. In addition to the distinction between preeclampsia, gestational hypertension, and preeclampsia superimposed on chronic hypertension, preeclampsia may also be categorized as being with or without severe features. These severe features are more extreme and specifically defined manifestations of the signs and symptoms described in the aforementioned list, including blood pressure of >160/110 mmHg, platelet counts of <100,000 platelets/µL, liver enzymes elevated to twice normal concentrations, persistent right upper quadrant pain indicating severe liver involvement, serum creatinine of >1.1 mg/dL, or doubling of normal serum creatinine, pulmonary edema, and visual disturbances (6, 101). However, a statement by ISSHP in 2013 reports that these qualifications remain somewhat arbitrary (166). One specific combination of severe features has been further defined as hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome. HELLP syndrome is associated with increased perinatal risk (66) and accounts for 15.1% of those diagnosed with preeclampsia with severe features (82). This designation as a subtype of preeclampsia aids in diagnosis and distinguishing HELLP syndrome from thrombotic thrombocytopenic purpura by lactate measurement (6). A patient is diagnosed with eclampsia if she demonstrates new onset of seizures, up to and including 3 days postpartum (6). Another important distinction in preeclampsia diagnosis is between early and late onset (before or after 34 wk of gestation) (174b). It is thought that this may indeed define two distinct etiologies of preeclampsia based on segregation of specific data gathered from the two groups showing that early-onset preeclampsia tends to produce a more severe phenotype and late onset often produces mild or moderate disease (87, 94, 118).

Following a diagnosis of preeclampsia, some women may be admitted to the hospital, especially if severe features such as HELLP syndrome are identified. Alternatively, they may also be followed on an outpatient basis with increased frequency of appointments and laboratory measurements (6, 165). While current therapies may assist with lowering of blood pressure to allow time for further fetal development (6, 101, 118), these serve only as a stopgap against premature delivery until fetal viability. Delivery of the placenta has been thought to be the only “cure” for many years; however, recent evidence shows that although the immediately fatal risks fade after birth, both mother and child experience increased risk for various insults to their health for the entirety of their postpartum lives (13, 45, 56, 72, 97, 116, 129).

Although the etiology of preeclampsia is clearly multifactorial, the most prominently accepted theory is that inadequate invasion of fetal cytotrophoblasts results in lack of vascular remodeling in the maternal spiral arteries (79, 80, 99). This results in a high-pressure, low-flow uteroplacental unit that is opposite of the low-pressure, high-flow status seen in normal pregnancy. The resulting cycle of repeated placental ischemia-reperfusion leads to increases in oxidative stress and release of inflammatory cytokines (177), antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) (60, 91), and maternal immune cell imbalance (141, 161), which propagate the maternal phenotype defined as preeclampsia (85). This theory is referred to by some as the modified two-stage model (132). However, it should be noted that there are many variations in the preeclampsia syndrome and various subtypes of this complex pathophysiology (22), and there are likely many causes of the disease aside from defects in vascular remodeling. These mechanisms, particularly the activation of immune cells, may result in a lasting physiological memory that contributes to the long-lasting consequences in women with a history of preeclampsia (75, 167).

PRECLINICAL MODELS OF PREECLAMPSIA

For many years, research in preeclampsia was limited by the lack of appropriate preclinical models due to the infrequency of spontaneous preeclampsia in animals. However, at this time, several animal models have been developed that recapitulate many characteristics of the human phenotype (51, 121). Although the vast majority of these models tend to be derived from rodents, there are also documented models in sheep (190), apes (188), rabbits (88), and guinea pigs (26).

Surgically induced models of preeclampsia have proven very useful for studying the latter half of the maternal phenotype of preeclampsia and are usually referred to as reduced uterine perfusion pressure (RUPP) models. Typically involving occlusion of the uterine arteries or abdominal aorta with metal clips (104), this procedure has been used in mice (74), rats (64), baboons (91), sheep (164), rabbits (88), guinea pigs (26), and dogs (183). It has been most widely used in rodents and has been validated to show several markers consistent with the human phenotype, including hypertension, oxidative stress, and antiangiogenic profile (104). It has also been used to test potential therapeutic options, including N-acetylcysteine (33), β-hydroxy β-methylglutaryl-CoA reductase inhibitors (16), and sildenafil (57). Although an excellent model for studying maternal consequences of hypertension during pregnancy and offspring effects of intrauterine growth restriction (IUGR), the rodent RUPP model is limited due to its restricted window into pathogenesis (clips are placed on gestational day 14, with a typical pregnancy lasting only 21–22 days) and potential to affect systemic hemodynamics of the animal via the sympathetic nervous system and cardiac output (151).

Pharmacological models of preeclampsia provide a somewhat less invasive approach. One of the earliest approaches was infusion of N-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthase (NOS) (102, 187). l-NAME infusion produces both maternal hypertension and renal injury as well as reduction in pup growth, appropriately mimicking the human phenotype. Although the effects of sildenafil have also been examined in the l-NAME model (124), it is to be expected that most results would be positive, as both the etiology of insult and mechanism of treatment target the same pathway. An antiangiogenic drug, suramin, has also been shown to at least partly recapitulate the maternal phenotype of preeclampsia when administered to rats (110). A single dose of endotoxin has also been shown to initiate blood pressure (BP) increase and albuminuria in pregnant rats, but it is difficult to assess the contribution of the preeclampsia phenotype to systemic and renal inflammation in the context of the inflammatory effects of endotoxin itself (52). Additionally, the infusion models, similarly to the RUPP models, reflect a limited window into the pathogenesis of preeclampsia, as they are restricted to only the latter half or third of rodent gestation.

In contrast to the predominance of the rat in surgical and pharmacological models of preeclampsia, the majority of transgenic models have been developed in mice. Knockouts of indoleamine 2,3-dioxygenase (140) and IL-4 (35) allow for study of the latter stages of preeclampsia much like RUPP and pharmacological models, whereas those such as high-temperature requirement A1 (70) actually allow earlier study that is more focused on abnormal placentation. One transgenic rat model that has been developed involves the expression of the human genes for renin or angiotensinogen and uses the same genetic background as the model presented in current studies, the Sprague-Dawley rat (58). A methodology that blends the infusion model and the genetic approach is overexpression of the antiangiogenic factor sFlt-1 through an adenoviral vector. sFlt-1 is known to contribute significantly to the pathogenesis of preeclampsia and produces a similar phenotype in both rats and mice, although it occurs regardless of pregnancy status (96).

An ideal model to study preeclampsia is one that is spontaneous, is noninvasive, and exhibits all features of the human phenotype. The first report of such a model was by Davisson et al. (46) in the BPH/5 inbred mouse strain. Our laboratory has determined that the Dahl salt-sensitive rat (Dahl SS/jr) is a spontaneous model of superimposed preeclampsia, exhibiting a similar state of hypertension, renal injury, oxidative stress, and antiangiogenesis to human preeclampsia even in the absence of a high-salt diet (62, 160). The Dahl SS/jr rat is a model of salt-sensitive hypertension, which is commonly seen in African American women who also have a higher prevalence of preeclampsia with worse outcome measures (191). Because of this and the noninvasive and cost-effective nature of the rodent model, the Dahl SS/Jr rat is an ideal model to study preeclampsia from its pathogenesis to its developmental programming effects. We have also shown data testing the efficacy of sildenafil citrate in this model and have demonstrated its attenuation of the maternal phenotype along with improvements in fetal growth (61). Weaver and colleagues (180, 180a) have also developed a promising spontaneous model in African green monkeys, and we look forward to the contribution of their findings in nonhuman primates.

MATERNAL CONSEQUENCES

Rates of maternal morbidity and mortality have increased since the 1980s, topping out at 18 pregnancy-related deaths per 100,000 live births per year in 2014, with 6.8% of those from 2011 to 2014 attributable to hypertensive disorders of pregnancy (32). Other short-term maternal complications include cerebrovascular bleeding, retinal detachment, HELLP syndrome, and eclampsia (22). However, as previously mentioned, preeclampsia is becoming recognized for its long-term consequences that may manifest up to 15 yr postpartum.

Numerous studies, including prospective (181), retrospective (149), and meta-analysis (19), have shown that preeclampsia is associated with increased risk of chronic hypertension, ischemic heart disease (56, 92), stroke, and death from cardiovascular events (9), even after adjustment for confounding risk factors. It is important to note that not only does preeclampsia seem to predispose women to develop hypertension, but these women also develop hypertension at an earlier age, allowing the condition to add years to its impact on their bodies (56). Selvaggi et al. (149) showed that half of women with a history of preeclampsia were hypertensive at 10 yr following delivery. Ambulatory BP measurement in this population has also revealed that in addition to increased prevalence, there is variability among the type of hypertension observed (diurnal, nocturnal, or masked) as well as significantly increased variability throughout a 24-h period per patient in women with a history of preeclampsia as compared with their peers (48). However, many factors may influence the interpretation of these studies, including reliance on diagnostic coding or patient questionnaires for data and the changing threshold for the diagnosis of hypertension.

Data from the Stroke Prevention in Young Women Study showed that women with a history of preeclampsia are 60% more likely to experience ischemic stroke after multivariable adjustment (27). Studies from the World Health Organization also showed an increased risk of hemorrhagic stroke (192) and venous thromboembolism (193) with history of hypertension in pregnancy. In addition to this increased risk of thrombosis, there is also increased morbidity and mortality associated specifically with stroke in these women (181).

Preeclampsia is associated with an increased relative risk for the development of end-stage kidney disease (ESKD) in the mother. This progression to ESKD could be proportional to the timing and severity of the disease during gestation and increases with each preeclamptic pregnancy experienced (173). Because standardized followup care for women after preeclamptic pregnancy is not well established, long-term postpartum studies of these women are sparse. One study showed a reduction in glomerular filtration rate (GFR) maintained up to 12 mo postpartum (78). Population-based studies based on insurance claims in Taiwan showed significantly increased hazard ratios of ESKD development in women with a history of preeclampsia (176, 186). Meta-analysis of existing studies in 2013 showed a fourfold increase in microalbuminuria (a predictor of subclinical kidney damage and increased cardiovascular risk) at a mean of 7.1 yr postpartum, and severe preeclampsia was associated with an eightfold increase in microalbuminuria at this interval (10, 97, 106). While data on microalbuminuria and GFR were fairly consistent across most studies, other expected sequelae of preeclampsia were more heterogeneous in the postpartum period, including the presence of postpartum hypertension (97). Later in same year of this publication, conflicting results emerged via additional meta-analysis, showing that history of preeclampsia was not associated with persistent microalbuminuria or decreased estimated GFR (138). There are several possibilities for the discrepancy in these results. The earlier meta-analysis represented relatively small individual studies that included women with a history of more severe disease, whereas the latter mainly included women with a history of milder preeclampsia (138). The previously analyzed studies also did not differentiate between preeclampsia in an initial pregnancy and preeclampsia in multiparous women.

There is some debate as to whether the renal disease following preeclampsia is a result of the condition itself or whether preeclampsia merely unveils underlying disease (170), especially since cardiorenal diseases and preeclampsia share many risk factors, and hypertension itself is a key contributor to renal fibrosis (100, 134). Preeclampsia increases the risk of developing the indications for kidney biopsy (172), and while the relative risk for ESKD as indicated by kidney transplantation or dialysis is significantly increased for women with a history of preeclampsia (173), a later study by the same group showed no relationship between biopsy-diagnosed ESKD and preeclampsia (171). However, it is likely that some degree of risk exists due to a significant correlation between biopsy diagnosed ESKD and preterm birth, which is common in preeclampsia (especially early onset/severe preeclampsia). Those with a history of preeclampsia were also diagnosed with kidney disease at an earlier age than those without such history, mirroring the previously mentioned effect seen with hypertension (171). Some of these women may in fact have had underlying renal disease, but the proposed threshold for further workup based on these studies could be delayed as much as 2 yr due to extended recovery from preeclampsia-induced changes, avoiding undue diagnostic confusion and distress from false diagnosis (21). Related work completed in animal models of preeclampsia with and without co-existing renal disease suggests that preeclampsia exerts a blood pressure-independent exacerbation of kidney injury (116, 167).

One explanation in the heterogeneity of postpartum renal injury data may be the heterogeneity of the renal injury itself, including sclerotic changes in glomeruli, varying degrees of glomerular expansion and immune cell infiltration, and/or adhesions and vacuolation of glomeruli (67). It also appears that while many women experience severe kidney injury and recover in as little as 3 mo, as current medical advice suggests, others may require up to 2 yr (21) and some even more (11, 111, 150, 172). This variation among studies indicates that further study is required to reveal the mechanism or mechanisms responsible for these postpartum changes.

PROPOSED MECHANISMS UNDERLYING POSTPARTUM MATERNAL RISK

As previously mentioned, a percentage of the risk for these postpartum consequences may reside in the shared risk factors between preeclampsia and cardiovascular disease. However, several disease-specific mechanisms may explain the postpartum risk that persists as a result of a preeclamptic pregnancy beyond the damage that is simply exposed by the stress of pregnancy. These proposed mechanisms are also supported by studies showing postpartum perturbations of physiological pathways, including sodium and angiotensin II (ANG II) sensitivity, sympathetic activation, and endothelial function.

Postpartum ambulatory blood pressure monitoring of women with and without preeclamptic pregnancy has not only shown increased hypertension in those with a history of preeclampsia, but based on the data collected, these women also have a significantly higher index of salt sensitivity (48). Significantly increased pressor responses to high-salt diet have been recorded in women as late as 10 yr after a preeclamptic pregnancy (93). Work in animal models of preeclampsia, such as the reduced uterine perfusion pressure (RUPP) model, has demonstrated similar results, including increased salt sensitivity at 3 wk postpartum, which is ostensibly related to an increase in vasopressin production and circulation (95).

Preeclampsia is accompanied by significantly lower levels of ANG II compared with normal pregnancy, and women with a history of preeclampsia have exhibited exacerbated vascular responses to ANG II (86, 144, 158). Additionally, levels of ANG II differ significantly between patients with preeclampsia with and without severe features (86). This correlates with the increases in ANG II sensitivity that have been reported in both the sFlt-1 overexpression and l-NAME (inhibitor of NOS) infusion animal models of preeclampsia (29). Similarly, studies in postpartum women have shown continued increases in ANG II sensitivity with concurrent reductions in endothelium-dependent and NO-dependent vasodilation (158). One study demonstrated an increased pressor response to both high-salt diet and ANG II infusion in postpartum women with a history of hypertensive pregnancy compared with their peers with normotensive pregnancies (144).

Other proposed mechanisms linking preeclampsia with postpartum disease risk include increased sympathetic activity, persistent inflammation, endothelial dysfunction, and angiogenic imbalance. Two groups have shown maladaptive baroreceptor responses related to persistently reduced plasma volume in women after preeclamptic pregnancy (39, 83), although in those who return to euvolemia, sympathetic activity has also been shown to normalize (53, 148). Continued increases in proinflammatory cytokines and exacerbated increases in components of the acute phase reaction have been demonstrated in animal models and human studies (129, 167). Endothelial dysfunction has been demonstrated in human subjects up to 5–8 yr following preeclamptic pregnancy (3, 84), with abnormalities in circulating endothelial and antiangiogenic factors persisting much longer, up to 10 yr postpartum (139).

OFFSPRING CONSEQUENCES

In addition to the postpartum risks experienced by women with a history of preeclampsia, the offspring exposed to the intrauterine consequences of the disease also experience increased disease risk in their postnatal lives. Preeclampsia is known to be a leading cause of IUGR and preterm birth (73, 98). IUGR itself has been shown to be an isolated risk factor for the development of hypertension and other cardiovascular diseases (13). However, even infants born from preeclamptic pregnancies weighing >2.5 kg show significant increases in systolic blood pressure as children and adolescents (45). These data are in line with later followup studies showing relative risks of 1.8 and 2.2 for the development of stroke in offspring of nonsevere preeclampsia and severe preeclampsia, respectively (77). The central hypothesis this area of research was pioneered by Dr. David Barker and is known as the Developmental Origins of Health and Disease theory. It states that a fetus that is exposed to a particularly adverse uterine environment, including insufficient nutrition or blood flow, responds by altering patterns of gene expression, causing results such as changes in metabolism and stress response mechanisms (12–15).

Vascular dysfunction is known to contribute to the development of hypertension and cardiovascular disease and is also present in preeclamptic women (24, 47). One study of vascular function in offspring of preeclamptic pregnancies restricted its subject population to those born full term (born at 37–42 wk of gestation) compared with age-matched offspring of normotensive pregnancies, adjusted for socioeconomic status, and compared 10 of the preeclamptic subjects with their siblings born to normotensive pregnancies in the same mother (76). This study found that not only do offspring of preeclamptic pregnancies exhibit impaired vascular function as measured by flow-mediated dilation compared with those of unrelated normotensive pregnancies but a similar level of dysfunction was not present in siblings of those children born to the same mother after a normotensive pregnancy (76). This indicates that although the genetics of preeclampsia likely contribute to the risk conveyed to the offspring (175), other factors related to the specific experience of preeclampsia also play a role. Furthermore, systemic vascular dysfunction or malformation may lead to other consequences of preeclamptic pregnancy, such as cognitive impairment (126, 127).

Other differences have also been shown, including delayed physical development and sensorimotor reflex maturation (169), increased body mass index (45), changes in neuroanatomy and reductions in cognitive function (126, 127), and hormonal changes. In early adolescence, both male and female offspring of preeclamptic pregnancies were shown to have increases in testosterone, whereas male offspring showed decreases in dehydroepiandrosterone sulfate, testicular volume, and circulating aldosterone (5, 179). These differences could translate into differences in the onset and progression of puberty and contribute to development of hypertension and cardiovascular risk.

PROPOSED MECHANISMS UNDERLYING OFFSPRING RISK

As previously mentioned, genetic transmission likely contributes to the link between IUGR and offspring hypertension (175) due to the overlap in risk factors between cardiovascular disease and IUGR. Heritable traits such as hypertension likely confer their own level of risk (13). Vascular dysfunction likely serves as a mediator between the fetal environment and later disease (76). However, there are additional perturbations to the fetal physiological responses that may result in increased risk of hypertension and cardiovascular and renal disease.

Many of the proposed mechanisms for the increases in BP seen in these offspring stem from renal function and development (116). Because human nephrogenesis occurs mainly in the third trimester of pregnancy, when preeclampsia is often the most fulminant, it stands to reason that the resulting changes in blood flow and circulating factors could adversely affect the fetal kidneys. Indeed, fetal growth restriction induced by uteroplacental insufficiency yields a nephron deficit and glomerular hypertrophy in both male and female rats (103, 182). Human studies seem to support these data, as small for gestational age (often caused by placental insufficiency) infants have an increased risk of ESKD compared with either controls or low-birth weight (often associated with gestational age at birth) infants (135).

Human studies have shown an inverse relationship between birth weight and salt sensitivity of BP and a direct relationship between birth weight and creatinine clearance (46a, 136, 154). More specifically, this has been shown in multiple animal models of uteroplacental insufficiency, including rodents and baboons (55, 188). Yeung et al. (188) specified that their baboon model of preeclampsia results in a phenotype similar to that of humans but without the typically concurrent IUGR, allowing further isolation of the programming effects of preeclampsia itself. This group found both higher systolic BPs and higher circulating aldosterone concentration in their offspring of preeclamptic pregnancies despite equivalent sodium administration and excretion throughout the study. This suggests a link between preeclampsia, sodium handling, and the renin-angiotensin-aldosterone system (RAS) (188). The impact on sodium handling could also be a consequence of the aforementioned nephron deficit known to occur in uteroplacental insufficiency leading to overloaded excretory capacity (103, 182) or alterations in sodium transporter expression (155).

Models of IUGR and maternal protein restriction have shown alterations of the RAS in offspring subjected to these insults in utero. Woods et al. (184) used the maternal protein restriction model to show that the intrarenal RAS is suppressed in the male offspring of these pregnancies and suggested a link between the reduction of developed glomeruli and later hypertension. They also later showed a relative protection for female offspring subjected to the same gestational insult (185). BP hypersensitivity to ANG II has also been demonstrated in offspring of the RUPP-IUGR model in a similar sex-specific fashion (112, 113). However, limited data exist on the status of the RAS in offspring of preeclampsia-specific models, and especially those that are spontaneous in origin. Additional research should be focused on this area, particularly due to the well-known interplay between ANG II and NO, a potent vasodilator in normal pregnancy that is also known to be affected by preeclampsia (89, 174).

THERAPEUTIC POTENTIAL

Despite the clearly demonstrated risks, both peri- and postpartum, screening tools and treatment options for preeclampsia are severely limited. In the recently revised screening recommendations by the United States Preventive Services Task Force, the only recommended detection method is regular blood pressure measurements at each prenatal visit. After elevated measurements are recorded at the specified intervals (≥140/90 mmHg on two occasions, 4 h apart, after 20 wk of gestation), ancillary confirmatory tests are performed, such as urine protein measurement (22). Although newer angiogenesis-related biomarkers such as placental growth factor (PlGF) and the PlGF-to-sFlt-1 ratio are gaining both predictive and diagnostic utility, they have yet to achieve widespread clinical use (34, 49, 189). It is important to note that studies indicate that PlGF and s-Flt-1-to-PlGF ratio may also be helpful in distinguishing preeclampsia from other causes of hypertension in pregnancy (34, 49, 189).

As previously mentioned, the exact etiology of preeclampsia has yet to be identified. However, central concepts of all theories include endothelial dysfunction and reduced placental blood flow (24, 80, 99, 142). The vasodilatory response of normal pregnancy is highly dependent upon NO (8), with levels of both NO and NOS shown to be consistently increased in both animals and humans with normal pregnancy (23, 36, 63). In healthy pregnancy, this has been shown to originate from an increase in neuronal NOS (NOS1) (157). NO functions by diffusing into vascular smooth muscle, binding guanylyl cyclase, and producing the second messenger molecule cGMP, which activates protein kinase G to reduce calcium concentration and cause vasodilation (123, 125). The endothelium is also a major source of NO from the NOS isoform called endothelial NOS (NOS3) (122). NO production as measured by its metabolic end products (NO_x) and NOS3 expression seem to be reduced systemically in animal models of preeclampsia (29, 40), whereas in humans, NO production is likely reduced only in the kidney (18, 37, 44, 146). There are discrepancies in the literature on NO bioavailability in preeclampsia (44, 153, 156), likely due in part to the difficulty of generalizing quantification of NO_x to endogenous production of NO in the whole body (17). In animal models, inhibition of NOS using l-NAME produces a preeclampsia-like phenotype (187). Polymorphisms in the NOS3 gene have been identified in whole blood samples of women with preeclampsia that may correlate to the reduction in NO bioavailability as well as to their degree of hypertension (4). More recently, a microRNA (miR-31-5p) targeting NOS3 was found to be upregulated in sera from preeclamptic women, which inhibits NOS3 expression and activity, recapitulating several features characteristic of the endothelial dysfunction seen in preeclampsia in an ex vivo model system (81).

Phosphodiesterase-5 (PDE5) is the enzyme that degrades cGMP, halting the NO-cGMP signaling cascade (107). In fact, both NO and cGMP have been shown to activate PDE5 (108), and thus the NO-driven vasodilation in pregnancy may lead to an increase in PDE5 expression. Increased intrarenal PDE5 has been shown to contribute to the volume expansion in normal pregnancy by attenuating the response to NO and causing sodium retention, thus filling the NO-relaxed vessels (143). Increased PDE5 activity has been shown in women with preeclampsia (119), but additional studies of this pathway have been more equivocal, failing to show a reduction in NO biosynthesis and even demonstrating increased cGMP during preeclampsia (37, 147).

Sildenafil citrate, a PDE5 inhibitor, was first studied for its potential efficacy in the treatment of heart failure. Due to a noted side effect, it was later targeted for the treatment of erectile dysfunction and later still for pulmonary hypertension (59). However, sildenafil also gained popularity as a potential therapeutic for preeclampsia due to its potential to cause maternal endothelial relaxation and decreased BP (178). Because PDE5 is expressed in the uterine arteries (38), a more targeted vasorelaxation could be achieved, improving circulation to the fetoplacental unit and reducing the hypoxic conditions of preeclampsia without a significant decrease in blood flow. Beneficial effects of PDE5 inhibition were shown in in vitro studies and in several animal models, with many showing attenuation of the maternal phenotype and some going further to show increased fetal growth (61, 71, 114, 117, 159, 168, 178). Specifically, sildenafil has been shown to increase endothelium-dependent vasodilation of myometrial arteries (178), attenuate maternal hypertension in several models (29, 61, 71, 117, 168), reduce contractility to ANG II (29), reduce the uterine artery resistance index (61, 71, 159), attenuate renal injury (61, 71), and attenuate levels of oxidative stress (29, 61). These developments were very exciting, especially due to sildenafil’s previous approval for treatment of pulmonary hypertension during pregnancy, indicating an acknowledged degree of safety. However, most clinical trials showed modest benefit to uteroplacental blood flow and fetal growth, which was likely due to low sample size and drug dosage, although they did demonstrate safety and tolerability (43, 50, 137, 174a). The most recent trial, Sildenafil Therapy in Dismal Prognosis Early-Onset Intrauterine Growth Restriction, was the largest to date, with the most inclusive criteria conducted in several countries concurrently. The Dutch arm of the trial was halted when the independent safety monitoring committee concluded that there were signs of potential harm and that the trial was unlikely to show beneficial effects on interim analysis, although final data and analyses have not yet been released (65). Additionally, a recent study in an animal model of fetal growth restriction showed that in utero exposure to sildenafil may actually increase BP in later life for offspring (128). Although sildenafil is unlikely to make a return to the clinic as treatment during pregnancy, its utility in studying the contributions of the NO pathway to preeclampsia and other potential therapeutic targets cannot be understated.

Current treatment of preeclampsia is limited to close monitoring, limited use of antihypertensive medications, magnesium sulfate for prevention of eclamptic seizures, and early delivery of the fetus (6). Antihypertensive therapy is recommended at BPs at or above 160 mmHg systolic and 105 mmHg diastolic (6). The most recommended antihypertensive medications for chronic hypertension in pregnancy and superimposed preeclampsia are labetalol, nifedipine, or methyldopa both for urgent lowering of BP and for chronic treatment (6). However, more recent review indicates that β-blockers (such as labetalol) and calcium channel blockers (nifedipine) are superior to any other antihypertensive currently used (2). Of these two, labetalol has been more thoroughly studied in pregnancy, although most studies include women with chronic hypertension in addition to those with superimposed preeclampsia (6). Labetalol is a nonselective β-blocker that also has vascular α-blocking activity. Overall, results have been positive or equivocal, showing a reduction of BP and no difference in perinatal outcomes compared with placebo or methyldopa (1, 120, 152). However, one study suggested a slight increase in small for gestational age infants with a relative risk of 1.34 compared with placebo or no treatment (90).

Current experimental therapeutic alternatives include antioxidant molecules (e.g., aspirin, NO donors, and vitamins C and E), drugs potentiating the vasodilatory NO signaling pathway, drugs reducing sFlt-1 production and/or inhibiting its action, therapies to remove sFlt-1 from the circulation, and drugs that act to restore the balance of growth factors involved in pathogenesis (VEGF and PlGF) (16, 20, 61, 68, 109, 131, 133, 162, 163). These therapies are often limited by their potential for toxic effects on the fetus by crossing the placental barrier, which presents hurdles to conducting human trials. Substantial preclinical work through methods such as cell or organ cultures and in animal models should be performed before expansion into the human population.

PERSPECTIVES

Upon review, it is clear that preeclampsia presents a salient and multifaceted problem for scientists and clinicians worldwide. The lack of specific prevention, screening, and treatment tools indicates that the pathogenesis must be more fully understood before steps can be taken to reduce morbidity and mortality. Further understanding of the pathogenesis and mechanisms of postpartum consequences may lead to as-yet undiscovered therapeutic targets that will not only ameliorate the gestational phenotype but reduce long-term health risks to both mother and fetus.

One important contribution to this process is the addition of more long-term followup studies of mothers and their children after preeclampsia. It is important to note that among the difficulties of the long-term studies described in this review (especially those that are retrospective), medical coding differences stand out as particularly variable across health records in different regions. Therefore, it would be beneficial moving forward for codes for preeclampsia/hypertension in pregnancy to be standardized and to place more focus on longitudinal prospective studies. Although such studies admittedly pose many difficulties of their own, they would allow for more accurate patient-to-patient comparison and thus stronger conclusions and associations between preeclampsia and postpartum consequences.

A multifaceted problem demands a multifaceted approach. Open communication between groups addressing pathogenesis, disease progression, and treatments, from cell culture to animal models to human studies, is key to the advancement of the field. The ultimate goals remain united: improved detection, treatment, and follow-up of preeclampsia, leading to better lives for women and children worldwide.

GRANTS

This work was supported by National Institutes of Health Grants R01-HL-134711 (to J. M. Sasser) and F30-DK-118864 (to H. R. Turbeville).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

H.R.T. conceived and designed research; H.R.T. performed experiments; H.R.T. and J.M.S. analyzed data; H.R.T. and J.M.S. interpreted results of experiments; H.R.T. drafted manuscript; H.R.T. and J.M.S. edited and revised manuscript; H.R.T. and J.M.S. approved final version of manuscript.