Pre-eclampsia is defined as hypertension (systolic blood pressure≥140 mmHg and/or diastolic blood pressure≥90 mmHg) with proteinuria (≥300 mg/24 h or ≥2+ on urine dipstick testing) occurring after 20 weeks’ gestation 1,2. A leading cause of perinatal morbidity and mortality worldwide, it affects between 5 and 8% of pregnancies 3,4. It is estimated that hypertensive disorders are responsible for 16% of maternal deaths in the western world 5 and the incidence of these conditions is rising, potentially as a consequence of an increase in predisposing conditions including obesity and diabetes 3. Pre-eclampsia is not only associated with adverse short-term maternal outcomes including preterm labour, hepatic failure, renal dysfunction, coagulopathy and seizures 6,7 but also carries important long-term implications for future maternal health, in particular cardiovascular and renal disease 8,9. Despite such major implications for maternal and foetal well-being, the diverse range of affected organ systems has led to difficulty in defining the clinical syndrome, as well as in disentangling the complex pathophysiological mechanisms underlying the condition. This review article will focus on the endocrine mechanisms believed to contribute to this complex, multisystem disorder.
Pathophysiology of pre-eclampsia
The precise mechanisms underlying development of pre-eclampsia remain unclear but are almost certainly multifactorial. The pivotal role of the placenta has been well documented 10–12. It is hypothesized that pre-eclampsia develops as a result of immune maladaptation between mother and foetus in the very early stages of pregnancy, leading initially to abnormal placentation and later to overt clinical manifestations of the disease. Pathological examination of placental tissue from pre-eclamptic patients generally reveals changes including multiple infarcts and diminished cytotrophoblast endovascular invasion with impaired remodelling of the uterine spiral arteries 13. Not all pre-eclamptic placentae demonstrate such marked pathological changes, but abnormalities can be seen in uterine artery Doppler studies weeks in advance of the onset of the maternal clinical syndrome 14. A variety of proangiogenic and antiangiogenic factors are released by the developing placenta in order to establish adequate foetal nutrient and oxygen supply and it has been suggested that an imbalance between these factors is responsible for defective cytotrophoblast invasion and uterine spiral artery remodelling 15. This abnormal placentation and the hypoxic environment it causes are thought to lead to oxidative stress, systemic endothelial dysfunction and an exaggerated inflammatory response, culminating in the clinical syndrome of pre-eclampsia with end-organ hypoperfusion and damage 10,16,17.
More recently, the disorder has been further subcategorized into ‘early-onset’ and ‘late-onset’ subtypes, which are believed to originate from two distinct haemodynamic states with major differences in severity, placentation and pulsed Doppler findings 18,19. Although different diagnostic classifications exist, the early-onset syndrome is generally thought to occur before 34 weeks’ gestation, and is associated with foetal growth restriction, abnormal uterine artery Doppler and worse maternal and neonatal outcomes. Late-onset pre-eclampsia is diagnosed after 34 weeks’ gestation; foetal growth restriction is less common, there are generally less marked uterine arterial abnormalities and better perinatal outcomes 19.
The renin–angiotensin–aldosterone system
Changes in normal pregnancy
The renin–angiotensin–aldosterone system (RAAS) undergoes significant alterations in response to normal pregnancy. Renin levels are increased as a result of release by the ovaries and decidua, whereas excess circulating oestrogen stimulates hepatic angiotensinogen synthesis. As a result there is an overall increase in circulating angiotensin II and aldosterone levels even though angiotensin-converting enzyme levels decrease during pregnancy 20–22. In pregnancy, an elevated level of aldosterone relative to renin is commonly found 23,24, suggesting that factors other than renin and angiotensin II contribute to aldosterone synthesis. Despite an increase in angiotensin II, normotensive pregnant women are resistant to its vasopressor effects, possibly because of the effects of progesterone on angiotensin II sensitivity through altered agonistic angiotensin II type 1 (AT1) receptor gene expression 20,25,26. It is also thought that local prostaglandin production plays a role in development of vascular resistance to the pressor effects of angiotensin II 27.
In addition to the maternal circulation, there is evidence of local production of RAAS components as well as expression of AT1 receptors in foetal and placental tissues 20,28,29. Thus, the placenta appears to also contain a functioning RAAS in healthy pregnancy. The first systematic description of the presence and localization of RAAS components in the human placenta in early pregnancy was provided by Pringle et al. 30. The group localized the inactive renin precursor – prorenin, the prorenin receptor and AT1 receptor to extravillous trophoblasts. Their demonstration of high prorenin mRNA expression in early gestation, a critical period for placentation, suggests that prorenin may play a role in regulation of trophoblast migration and spiral artery remodelling. Interestingly, they also described high abundance of placental vascular endothelial growth factor (VEGF) mRNA in early pregnancy, and a strong correlation with AT1 receptor expression, pointing towards a role for the RAAS in early placental angiogenesis. High levels of AT1 receptor protein and mRNA were found throughout gestation, pointing towards a key role for the angiotensin II/AT1 receptor pathway in both early and late gestation 30.
Renin–angiotensin–aldosterone system in pre-eclampsia
In pregnancies complicated by pre-eclampsia, levels of renin, angiotensin I and aldosterone have been shown to be lower than in normotensive pregnancy 20,31. Prorenin, is also elevated in pre-eclampsia, and has been associated with risk of subsequent pre-eclampsia in type 1 diabetic populations 32,33, although its precise function remains unclear. Similarly, elevated circulating prorenin receptor levels appear to be associated with subsequent pre-eclampsia 34. Levels of angiotensin (1–7), a vasodilatory RAAS component, are also significantly decreased in pre-eclampsia 22, although its precise role in maintaining adequate uteroplacental blood flow requires clarification.
Angiotensinogen levels in pre-eclamptic pregnancy are similar to those seen in healthy normotensive pregnancy; however, an increase in abundance of ‘high-molecular mass’ angiotensinogen has been described in pre-eclampsia. This is a complex of angiotensinogen with proMBP (proform of eosinophil major basic protein) and its cleavage by renin is markedly altered, a fact that may explain the reduced plasma renin activity described in pre-eclampsia 35. In addition, Zhou and colleagues 36 have recently described two isoforms of angiotensinogen with either reduced or oxidized forms of a disulphide bridge in the molecule. The structural change resulting from oxidation leads to preferential interaction with renin that is bound to the prorenin receptor. The group also showed that oxidized angiotensinogen is more abundant in pre-eclampsia, a condition characterized by inflammation and oxidative stress 36. Broughton Pipkin and colleagues 37 described a strong association between first trimester angiotensinogen levels and birthweight centile, suggesting that inadequate angiotensinogen synthesis may contribute to the pathogenesis of conditions characterized by inadequate placentation.
In contrast to normotensive pregnancy, Gant et al.38 described increased sensitivity to angiotensin II in women with pre-eclampsia in comparison to normotensive pregnancy. It has since been suggested that this could be mediated by increased AT1 receptor sensitivity 29.
The tissue-based renin–angiotensin–aldosterone system
The effect of pre-eclampsia on the uteroplacental RAAS remain unclear. Herse et al.28 recently demonstrated that an increase in AT1 receptors in the maternal decidua was the only significant alteration in placental RAAS during pre-eclampsia, whereas others have shown increased renin expression in the maternal decidua and increased angiotensin II in the chorionic villi of pre-eclamptic placentae 20,39.
In 2009, Anton and colleagues 40 described significantly higher angiotensin II protein abundance and renin and angiotensin-converting enzyme mRNA in the uterine placental bed of pre-eclamptic women. This led the group to suggest that resultant increase in angiotensin II levels may lead to vasoconstriction within the uterine spiral arteries and contribute to the reduction in placental blood flow seen in pre-eclampsia 40. They also noted almost undetectable levels of all angiotensin receptors within the pre-eclamptic uterus, postulating that angiotensin II may play an endocrine role influencing the adjacent placental chorionic villi where it has been shown that AT1 receptors are more abundant in pre-eclampsia 40. Recent evidence also points to a role for shorter peptides produced by cleavage of angiotensin II in cardiovascular function. Angiotensin (3–8) (Ang IV) has been shown to influence blood flow through a mechanism mediated by its specific receptor (AT4 receptor) and nitric oxide. Ino et al.41 have previously described AT4 receptors in extravillous trophoblasts and suggested they may play a role in placentation. AT4 receptors are known to be upregulated in healthy placentae, possibly as a control mechanism to prevent Ang IV binding to the AT1 receptor. Recently, Williams et al.42 showed that these receptors are downregulated in pre-eclamptic placentae suggesting that this may be another key mediator of its pathogenesis. Last year the Broughton Pipkin group described for the first time a significant relationship between AT2 receptor and angiotensinogen expression in pre-eclamptic but not healthy placentae 43. The authors proposed that this may represent a compensatory mechanism that is not activated in healthy conditions, whereby angiotensin II binding to AT2 receptors causes apoptosis and vasodilation, supporting foetal tissue development 43.
The kidney is unique in expressing every component of the RAAS, with compartmentalization in tubules and interstitium as well as intracellular accumulation; yet, relatively little is known of the role of the renal RAAS in pre-eclampsia. Recent evidence points towards a role for the renal RAAS in the pathogenesis of hypertension and renal disease. Yilmaz and colleagues recently explored the relationship between urinary angiotensinogen and clinical phenotype in pre-eclamptic pregnancies. They confirmed that renal RAAS activity, reflected by urinary angiotensinogen levels, was increased in pre-eclampsia and this appeared to be correlated with both systolic and diastolic blood pressure, as well as urinary protein excretion. In addition, they showed that augmentation of urinary angiotensinogen levels in normotensive pregnancy was not associated with any change in blood pressure, suggesting that in healthy pregnancy, women are resistant to the vasopressive effects of renal RAAS components 44.
Angiotensin II type 1 receptor agonistic antibodies
A landmark study in 1999 demonstrated that agonistic autoantobodies to the AT1 receptor (AT1-AA) were present in women with pre-eclampsia and not in normal pregnancy 45. Subsequently, many others have shown that a number of the features of pre-eclampsia may be explained by the effects of AT1-AA on a variety of cell types. For example, Zhou et al.46 reported that injecting pregnant mice with AT1-AA from pre-eclamptic women resulted in the development of characteristic features of pre-eclampsia including hypertension, proteinuria, placental abnormalities and foetal growth restriction.
There is also evidence supporting a role for AT1-AA in disseminated intravascular coagulation that can complicate severe pre-eclampsia. Dechend et al. 47 demonstrated that AT1-AA IgG from women with pre-eclampsia induced a cascade of events resulting in increased tissue factor expression in vascular smooth muscle cells and this effect was blocked by the AT1 receptor antagonist losartan. Tissue factor initiates the extrinsic coagulation pathway and increased expression has been reported in pre-eclamptic placentae 47. It has since been shown that AT1-AA also stimulate tissue factor production and endothelial cell adherence in monocytes 48. In addition, plasminogen activator inhibitor 1 (PAI-1) plays a key role in prevention of clot dissolution by the fibrinolytic system 49 and is known to be upregulated in pre-eclamptic placentae 50. A potential procoagulant role for AT1-AA has been suggested by evidence that these antibodies can stimulate PAI-1 synthesis through activating trophoblast AT1 receptors 51.
It is accepted that pre-eclampsia is associated with an exaggerated underlying inflammatory response. Reactive oxygen species production is known to be increased in pre-eclampsia and contributes to the characteristic inflammatory picture 52. AT1-AA are thought to increase reactive oxygen species production and nuclear factor κB in vascular smooth muscle cells and placental tissue 53. In addition, it has been reported that AT1-AA can induce secretion of inflammatory mediators such as interleukin-6 (IL-6) and tumour necrosis factor α 51,54 and the vasoconstrictor endothelin-1 55, whereas blockade of these factors attenuates features of pre-eclampsia in animal models 56. In addition, recent evidence points to a role for IL-17 and IL-17-producing CD4+T cells (TH17 cells) in modulating AT1-AA activity 57,58. TH17 cells have been shown to play an important role in other inflammatory conditions including autoimmune arthritis, multiple sclerosis and psoriasis and Dhillion et al. 58 recently showed that infusion of IL-17 into pregnant rats led to increased oxidative stress and production of AT1-AA.
Levels of soluble vascular endothelial growth factor receptor-1 (sFlt-1) are elevated in pre-eclampsia 59. sFlt-1 inhibits VEGF and placental growth factor signalling, preventing their interaction with proangiogenic receptors 47 and its administration has been shown to produce typical features of pre-eclampsia in animal models 59. The mechanism underlying increased sFlt-1 production in pre-eclampsia is unclear; however, it was demonstrated by Zhou et al. 60 that this was in part dependent on angiotensin II. Subsequent studies have shown that AT1-AA have an additive effect on this process through increased AT1 receptor activation 50,60 and that AT1-AA-mediated sFlt-1 induction may contribute to the reduced aldosterone production seen in pre-eclampsia, possibly through deleterious effects on adrenal vasculature 61.
In addition to contributing to the humoral features of pre-eclampsia, it has been demonstrated that binding of AT1 receptors by AT1-AA leads to reduced trophoblast invasion, an early pathological features of pre-eclampsia 62. As shallow trophoblast invasion precedes the overt clinical syndrome, it would seem intuitive that AT1-AA may serve as an early risk marker for pre-eclampsia. Certainly one study detected AT1-AA early in the second trimester in pregnant women with abnormal uterine perfusion, 80% of whom went on to develop pre-eclampsia. However, in this study AT1-AA were also found in women who developed intrauterine growth restriction and even in normal healthy pregnancies. This suggests that AT1-AA is an early but nonspecific marker for later pre-eclampsia and appears to be associated with a number of pregnancy disorders relating to abnormal placentation 63 (Fig. 1).
Although the symptoms of pre-eclampsia typically abate soon after delivery, affected women remain at increased long-term cardiovascular risk 64. Whether the AT1-AA contributes to this sustained risk remains to be fully elucidated. It has previously documented that AT1-AA titres fall by 50% in the week following delivery 45 but their levels may not regress completely in women with a history of pre-eclampsia, remaining detectable at least 1 year following delivery 65. AT1-AA levels after delivery have also been shown to correlate with other factors, which may contribute to cardiovascular risk after pre-eclampsia such as insulin resistance, sFlt-1 and VEGF levels 65, although their significance in the longer term following pre-eclampsia remains unclear.
Aldosterone is one of the key mediators of the increased plasma volume that is characteristic of normal pregnancy, allowing adequate perfusion of the uteroplacental unit, as well as supporting renal blood flow, glomerular filtration and the required increase in cardiac output 66. It has been well documented that aldosterone levels are suppressed in pregnancies complicated by pre-eclampsia despite reduced plasma volume 66,67. This volume-contracted state and underlying defects in the ability to maintain the plasma volume required for normal gestation are thought to be key to the development of pre-eclampsia, and indeed these changes in plasma volume can be observed before the clinical presentation of disease 67.
In 2009, Mohaupt and colleagues 68 reported their observations of the close interrelationship between aldosterone availability, gestational maternal blood pressure status and infant birthweight. They confirmed reduced urinary tetrahydroaldosterone (the principal urinary metabolite of aldosterone) excretion in pre-eclamptic individuals compared with healthy pregnant controls. In addition, they illustrated that mutations within the aldosterone synthase gene (CYP11B2) previously shown to associate with increased aldosterone bioavailability, were associated with better pregnancy outcomes 68. In support of the hypothesis that genetically determined variations in aldosterone synthase activity could contribute to the pathophysiology of pre-eclampsia, the group reported that individuals with pre-eclampsia had altered corticosteroid metabolic profiles suggestive of reduced aldosterone synthase activity 69. However, this was suggested only on the basis of an increased precursor (deoxycorticosterone+corticosterone/tetrahydroaldosterone) to product ratio with no direct assessment of enzyme activity nor expression within the placenta.
In addition to its effect on maternal plasma volume, aldosterone may also play a role in other key pathological aspects of the development of pre-eclampsia. For example, there are data to suggest that human trophoblast growth, a key determinant of maternal and foetal outcome, is time-dependently and dose-dependently increased with aldosterone 70. This growth pattern can be reversed by addition of the mineralocorticoid receptor (MR) antagonist, spironolactone, supporting the hypothesis that aldosterone, through MR signalling, plays a key role in the development of a healthy placenta 70. Placental size has also been shown to correlate with aldosterone availability 70.
Until recently it has been debated whether the inappropriately low aldosterone levels seen in pre-eclampsia are a cause or consequence of the disease process Gennari-Moser and colleagues 71 have recently shown that blood pressure in pregnancy appears to be aldosterone-independent and that increased salt intake in pregnancy does not affect aldosterone level, suggesting that the two become somehow uncoupled in pregnancy. A subsequent seminal paper by the same authors 72 has provided a key link between the impaired angiogenesis seen in pre-eclampsia and reduced aldosterone availability, demonstrating that VEGF could stimulate aldosterone production in adrenal cell and that overexpression of sFlt-1 in rats correlated inversely with adrenal capillary density and aldosterone levels. These studies provide a plausible mechanism linking reduced VEGF and increased sFlt-1 levels (i.e. antiangiogenic factors) with reduced aldosterone levels in preeclampsia.
Other mineralocorticoid receptor agonists
As previously mentioned, cortisol has similar affinity to aldosterone for MR binding in vitro but is far more abundant in plasma. Under normal circumstances, the enzyme 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone, thus protecting the MR from activation by high levels of glucocorticoid exposure 73. The relevance of this protective mechanism in pre-eclampsia will be discussed later in this review. Another hormone with affinity for the MR is progesterone, which has a low level of MR agonistic activity 74. Progesterone is converted by 21α-hydroxylase into deoxycorticosterone, a potent mineralocorticoid that also binds to activate the MR. Concentrations of progesterone and of deoxycorticosterone 75, rise significantly during pregnancy to levels that could theoretically be expected to cause hypertension 76 but their relevance to the development of pre-eclampsia remains poorly understood.
Cortisol in normal pregnancy
Plasma concentrations of cortisol and cortisol-binding globulin are markedly elevated in pregnancy; total plasma cortisol, cortisol-binding globulin and 24 h urinary free cortisol excretion appear to rise progressively throughout pregnancy and peak in the third trimester. Despite elevated cortisol levels its circadian rhythm is preserved 77. It has been suggested that these changes can be explained by upregulation of the maternal hypothalamic–pituitary–adrenal axis in pregnancy 78.
Effects of cortisol on the trophoblast
In utero, the endometrium, placenta and foetus are exposed to cortisol from both maternal and foetal adrenal glands. While glucocorticoids exert a range of positive effects in establishing early pregnancy such as stimulation of human chorionic gonadotropin (hCG) secretion and suppression of uterine natural killer cells 79, they can also adversely influence the progression of a healthy pregnancy. For example, it has been reported that glucocorticoids stimulate growth of the early trophoblast – now known to be a key factor in the development of pre-eclampsia 80,81. These effects, however, are not consistent and it has also been demonstrated that dexamethasone impairs the ability of human trophoblasts to invade a matrigel matrix in vitro82. In addition, dexamethasone has been shown to induce apoptosis and necrosis in cultured human trophoblasts 83. Furthermore, cortisol has been shown to increase expression of PAI-1 in trophoblasts that could theoretically prevent tissue plasminogen activator from inducing the fibrinolysis required for adequate trophoblast invasion and subsequent placental nutrient transfer 79,84.
Role of 11β-hydroxysteroid dehydrogenase 2 in pre-eclampsia
Given the apparent detrimental effects of cortisol on the trophoblast, and therefore later placental function, it is perhaps not surprising that excessive glucocorticoid exposure in utero has been associated with intrauterine growth restriction and prematurity 79,85,86. Ordinarily, the placenta and foetus are protected from excessive glucocorticoid exposure by placental expression of the enzyme 11β-HSD2 that converts cortisol to its inactive metabolite, cortisone, preventing activation of both the glucocorticoid receptor and MR 87,88. In normal pregnancy, placental 11β-HSD2 is upregulated during differentiation of trophoblast to syncytiotrophoblast 87,88 and placental cortisol levels are low. However, in pre-eclamptic pregnancy, placental 11β-HSD2 mRNA expression and consequent enzyme activity have been found to be significantly lower than in normotensive individuals 89,90, meaning that placental cortisol levels are increased in up to 80% of pre-eclamptic pregnancies 86. These changes are detectable in the first trimester, before clinical symptoms of pre-eclampsia evolve 85.
A number of factors have been proposed to play a regulatory role in 11β-HSD2 activity in pre-eclampsia. For instance, altered oxygen tension has been shown to affect enzyme expression and activity in the placenta, leading to the hypothesis that reduced placental oxygenation may in turn impair 11β-HSD2 activity, propagating the cycle of inadequate placental function 91. In addition, several other pathophysiological conditions known to be associated with pre-eclamptic pregnancy have been shown to compromise 11β-HSD2 activity, including increased levels of circulating inflammatory cytokines such as IL-6 and tumour necrosis factor α 87.
Changes in normal pregnancy
Normal pregnancy is characterized by reduced fasting blood glucose levels, higher postprandial readings and higher insulin levels as gestation progresses. Pregnant women demonstrate prolonged hyperinsulinaemia and hyperglycaemia along with greater glucagon suppression following an oral glucose challenge 92. This phenomenon is explained by increased insulin resistance in pregnancy, probably an adaptation to ensure adequate postprandial glucose supply to the developing foetus 92. Overall, insulin sensitivity is thought to be reduced by up to 70% in the latter stages of pregnancy 93.
Insulin sensitivity in pre-eclampsia
Insulin resistance is implicated in the pathogenesis of pre-eclampsia, given that related conditions such as type 2 diabetes, polycystic ovarian syndrome and gestational diabetes are all known risk factors for the condition 94. In addition, a number of characteristics associated with insulin resistance have also been reported in pre-eclampsia, such as systemic inflammation, endothelial dysfunction and altered fibrinolysis. For example, a case–control study by Solomon et al. 95 reported that early third trimester fasting insulin levels were significantly higher among a subgroup of pregnant women who went on to develop pre-eclampsia, but not among the group who developed gestational hypertension. Furthermore, others have reported low placental insulin receptor affinity in pre-eclampsia. Both systolic and diastolic blood pressure values correlated significantly with placental insulin receptor affinity, as did placental weight 96.
Insulin resistance has also been proposed as an early, preclinical marker of subsequent pre-eclampsia. In a nested case–control study of 572 normotensive pregnant women recruited at less than 30 weeks’ gestation, women who subsequently developed pre-eclampsia were found to have higher insulin resistance as measured by homeostatic model assessment (HOMA-IR) compared to matched normotensive pregnancies 97. Parretti et al.98 assessed insulin sensitivity in 829 pregnant women and found that at 16–20 weeks’ gestation HOMA results had sensitivity of 79–85% and specificity of 97% for prediction of subsequent pre-eclampsia. Hauth et al. 92 reported similar findings in the secondary analysis of a study of over 10 000 pregnant women and reported that midtrimester insulin resistance was associated known risk factors for pre-eclampsia including obesity and ethnicity.
Insulin sensitivity following pre-eclamptic pregnancy
Pre-eclampsia and cardiovascular diseases share a number of risk factors including insulin resistance. Certainly a previous pregnancy complicated by pre-eclampsia appears to be a risk factor for later development of diabetes mellitus. Feig et al.99 recently reported that women with pre-eclampsia have a two-fold increased risk of later development of type 2 diabetes when followed up to 16 years postdelivery. In addition, a registry-based study of 230 000 Norwegian pregnancies reported that women with pre-eclamptic pregnancy were three times more likely to be prescribed blood glucose lowering therapies in the first 5 years following delivery 100.
In a study using hyperinsulinaemic euglycaemic clamp to compare insulin sensitivity at 6 months postpartum between pre-eclamptic and control pregnancies, it was shown that women with a history of pre-eclampsia had characteristics consistent with the metabolic syndrome, including impaired glucose tolerance and lower insulin sensitivity 101. Similar results have been described using the HOMA-IS index of insulin sensitivity at 18 months and 2.5 years postpartum 102,103. In longer-term follow-up studies of women with pre-eclampsia, Girouard et al.104 reported increased insulin resistance measured by HOMA at 7.8 years follow-up, whereas Sattar and colleagues 105 demonstrated a tendency towards increased fasting insulin and glycosylated haemoglobin (HbA1c) levels up to 25 years after delivery. They also found markedly increased levels of the endothelial inflammatory marker intracellular adhesion molecule-1, suggesting that inflammation and endothelial dysfunction may underpin the insulin resistance and cardiovascular risk associated with previous pre-eclampsia 105.
Changes in normal pregnancy
Pregnancy is characterized by a number of alterations in thyroid biochemistry. Serum thyroid-binding globulin (TBG) is responsible for transport of the majority of thyroxine (T4) and tri-iodothyronine (T3) 106. During pregnancy its concentration is markedly elevated in comparison to the nonpregnant state, this is evident from a few weeks after conception and is thought to result from increased hepatic synthesis of TBG and oestrogen-related alterations in sialylation that increases its half-life 107. As a consequence of this plasma, concentrations of the total T4 and T3 also increase in early pregnancy and can often reach concentrations double the prepregnancy value 108. This increase is, however, less than would be expected for the change in TBG and has previously been described as ‘relative hypothyroxinaemia’ 109. Free thyroid hormone levels are often 10–15% lower in pregnancy compared to nonpregnant levels, although in most women they still fall within the nonpregnant reference range 110. hCG is also known to have thyrotropic activity 111 and studies have confirmed an inverse relationship between hCG and thyroid-stimulating hormone in early pregnancy, when hCG levels are at their peak 109. Taken together, the above alterations in thyroid status highlight the importance of referring to trimester-specific reference ranges when evaluating thyroid function in pregnancy.
Thyroid function in pre-eclampsia
Thyroid disease can affect up to 4% of pregnancies, with hypothyroidism being the most common disorder 112. It has been shown that thyroid dysfunction represents a risk to maternal and foetal health during pregnancy, although not all studies are in agreement 112–114. Thyroid disease has been associated with pregnancy-specific complications including placental abruption 114 and gestational diabetes 112, although this has not been consistently shown in all studies 113,115.
Abnormalities in thyroid function tests have been described in patients with pre-eclampsia. Most studies agree that pre-eclamptic women show elevated levels of thyroid-stimulating hormone with reduced T3 and T4116,117. In a large prospective population-based study of 24 883 pregnancies, Wilson et al. 118 found a significant association between subclinical hypothyroidism in pregnancy and severe pre-eclampsia, a relationship that remained significant after adjustment for confounders including age, parity, race and weight. This is in agreement with a number of other published studies 119,120. In a large retrospective analysis of a US cohort of 223 512 singleton pregnancies, Mannisto et al.112 again described an association between hypothyroidism, both primary and iatrogenic, and pre-eclampsia. In this cohort they also observed increased risk of pre-eclampsia among hyperthyroid women; however, this is at odds with a 2010 study by the same group where no association was seen 121. To date there are little data available on the risk of pregnancy complications in mothers with treated thyroid disease. Interestingly, in 2009 an association was described between the elevated sFlt-1 levels seen in pre-eclamptic pregnancy and later subclinical hypothyroidism. This may in part be attributable to sequestration of VEGF and a subsequent negative effect on the fenestrated endothelium of thyroid capillaries 122.
In terms of a mechanistic link between thyroid disease and pre-eclampsia, a number of studies have linked thyroid dysfunction with cardiovascular disease in nonpregnant populations 123,124. Studies have shown an association between thyroid disease and carotid artery intima–media thickness 125 and abnormal lipid metabolism 126. In addition, a causal relationship has been suggested between thyroid disease and endothelial dysfunction, a key clinical feature of pre-eclampsia, as evidenced by impaired vascular reactivity in patients with subclinical hypothyroidism that was subsequently alleviated by levothyroxine treatment 127. Furthermore, in 2005, Barber et al.128 described a synergistic relationship between epidermal growth factor and T3 in the regulation of human trophoblast proliferation and differentiation, another feature that is known to be impaired in pre-eclamptic pregnancy.
The pathogenesis of pre-eclampsia is complex and despite years of research is not yet fully understood. Current theories suggest that an abnormal maternal immune response to the developing trophoblast triggers oxidative stress and placental hypoperfusion with subsequent release of placental factors causing widespread endothelial dysfunction even in the early stages of pregnancy, long before the onset of clinical manifestations of disease. Interplay between a number of biochemical mechanisms including dysfunction of numerous hormonal axes appear to underpin this process.
The RAAS has long been appreciated as a key player in placentation and the pathophysiology of pre-eclampsia but how all its various components interact to maintain healthy and hypertensive pregnancies remains unclear. The emerging role of AT1-AA and aldosterone in the induction of placental factors such as sFlt-1 and placental growth factor has stimulated a great deal of interest in recent years. Similarly, the 11β-HSD2 pathway appears to be critically important in the maintenance of a healthy normotensive pregnancy and appropriate foetal environment. Given that these pathways contribute to the early pathogenesis of the disease it seems intuitive that they may provide useful markers for early detection of ‘at-risk’ pregnancies but at the time of writing this does not appear to be the case. Pre-eclampsia can be considered as a vascular ‘stress test’ predicting future maternal cardiovascular health 129; moreover, the pivotal role of endocrine mechanisms in both conditions cannot be underestimated.
The work is supported by grants from the Chief Scientist Office (project reference ETM/196) and the European Union (‘PRIORITY’, project reference 279277; and ‘EU-MASCARA’, project reference 278249).
Conflicts of interest
There are no conflicts of interest.
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