Open Journal Systems

REVIEW ARTICLES

Received: 15/10/2015

Accepted: 23/11/2015

Hypertension during pregnancy: the challenge continues

Martín Rosas-Peralta,^a Gabriela Borrayo-Sánchez,^b Alejandra Madrid-Miller,^c Erick Ramírez-Arias,^d Gilberto Pérez-Rodríguez^e

^aDivisión de Investigación en Salud

^bDirección Médica

^cServicio de Terapia Posquirúrgica

^dServicio de Urgencias

^eDirección General

Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Gabriela Borrayo-Sánchez

Email: gabriela.borrayo@imss.gob.mx

Hypertensive disorders of pregnancy affect approximately from 5 to 10 % of all pregnant women, and are the main contributors of maternal and neonatal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, as well as the conditions that arise de novo in pregnancy: gestational hypertension and preeclampsia. This last group is believed to be part of the same continuum, but with arbitrary division. Research on the etiology of hypertension in pregnancy largely have focused on preeclampsia, with a majority of studies that explore any factor associated with pregnancy, e.g., the answers derived from the placenta or immunological reactions to tissue from the pregnancy or maternal constitutional factors, such as cardiovascular health and endothelial dysfunction. The basic foundations for the pathophysiology and progression of hypertensive pregnancy disorders, particularly preeclampsia, are reviewed in this paper. Therapeutic options for the treatment of preeclampsia are also explored.

Keywords: Pregnancy; Hypertension; Preeclampsia; Pregnancy-induced hypertension

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Hypertensive disorders are the most common medical complication in pregnancy affecting approximately between 5 and 10% of all pregnant women. Despite advances in obstetric medicine, it remains the second leading cause of maternal mortality worldwide,¹ as well as a major cause of morbidity for mother and child.^2,3 Hypertension can exist before (such as chronic hypertension) or develop de novo in pregnancy, subject to two distinct disorders: preeclampsia and gestational hypertension. Preeclampsia can often develop superimposed on pregnancy or in people with established chronic hypertension. The analysis of various national databases registers maternal outcomes and shows that poor quality care in the aspects of recognition and control of blood pressure can have devastating consequences for both the mother and the child.⁴  

Given the changing demographics of mothers around the world (towards a trend of older mothers with more chronic health conditions such as obesity and diabetes), the incidence of hypertensive disorders is expected to continue to rise. Obstetric services will have to be adapted to provide a proper diagnosis and timely intervention, ideally with interdisciplinary management by obstetricians, and cardiac and general medical services. Similarly, there are opportunities for further research in this area to better define the mechanisms of pathogenesis and treatment strategies to improve maternal and fetal outcomes.

Cardiovascular changes in pregnancy

Knowledge of the longitudinal physiological changes in pregnancy is crucial to recognize and manage hypertensive disorders that develop or worsen as pregnancy progresses. Pregnancy cohort studies have shown that early maternal hemodynamic adaptation occurs as early as five to six weeks after conception (Figure 1).^5-7 In uncomplicated pregnancies, brachial mean arterial pressure (MAP) decreases significantly after the middle of the follicular phase at six weeks gestation, reaching its lowest point between 16 and 20 weeks of gestation.⁵ It then slowly increases and approaches term in the stage prior to conception.^8,9 These results are reflected in central hemodynamic studies: aortic blood pressure and the rate of increase decrease significantly from the first trimester of pregnancy and reach a nadir in the middle of this cycle.¹⁰

By contrast, the values ​​of cardiac output (CO) increased significantly at six weeks gestation compared with preconception, with a simultaneous decrease in systemic vascular resistance (SVR). The CO increase plateaus in the second and third quarter with values ​​approaching 40% compared to the pre-pregnancy levels;⁵ the components of elevation are a 20% increase in systolic volume and heart rate, as well as an increase in left ventricular mass.¹¹ Mild and eccentric cardiac hypertrophy occurs during pregnancy as a result of volume overload and hormonal changes. Unlike pathological hypertrophy, observed in hypertension, changes in pregnancy are associated with the chamber dimension and wall thickness, which are reversible, although the reversal can take up to a year after childbirth.¹² Data from studies in animals and humans suggest that pregnancy is associated with and shares cardiac hypertrophy induced by exercise of similar characteristics, such as structural remodeling, reversibility, and common signaling pathways. Therefore, as in exercise, pregnancy can mimic the physiological changes observed during the second half (e.g. increased CO and decreased peripheral resistance).¹³

In the second trimester, the gravid uterus can affect the inferior vena cava in the supine position, which causes a decrease dependent on the preload position. In this position blood pressure is maintained by reflex vasoconstriction,¹⁴ which leads to narrowing of the pulse pressure. This can add additional stress on the cardiovascular system and maternal blood pressure control, causing symptoms of supine hypotension.

The plasma and blood volume increase significantly by 40% from the state of non-pregnancy, reaching peak levels at approximately 36 weeks of gestation.^5,8 The increased intravascular volume and neurohormonal changes lead to a reduction in vascular smooth muscle tone and widespread vasodilation in relation to the pre-pregnancy state. This probably facilitates placental perfusion with a low pressure system that requires a high flow to maintain the directional flow for the fetus.¹⁵

In addition, pregnancy is characterized by increased activity of the renin-angiotensin-aldosterone system (RAAS), which is activated by a reduction rather than because of the expansion of plasma volume. This is accompanied by early renal vasodilation and hyperfiltration.¹⁶ Meanwhile, alongside these increases, arterial distensibility and venous capacitance appear to be the basis of this unique physiological response, which has led to the description of pregnancy as a state of “decreased effective plasma volume".¹⁷ Interestingly, the reversal of this paradoxical response has been characterized by turning into preeclampsia.¹⁸

Blood pressure in pregnancy must be measured with the woman rested and upright for 10 minutes or more, or in left lateral decubitus with an appropriate size cuff at heart level using Korotkoff phases I and V.¹⁹ Korotkoff IV has been abandoned because phase V is detected more reliably and closer to the true diastolic blood pressure. The cuff should be inflated to 20 or 30 mmHg above palpated systolic blood pressure, then lowered slowly at 2 mm Hg per beat. Blood pressure should be read to the nearest 2 mm Hg.²⁰ Generally, mercury devices are preferred, since many oscillometric devices have not been validated in pregnancy. Ambulatory blood pressure monitors have been validated in pregnancy and reference ranges have been published;²¹ however, it has been observed that 24-hour ambulatory measurements are higher compared to clinical readings.²² Therefore, greater discretion may be needed to decide between normal and abnormal readings.

The clinical spectrum of hypertension in pregnancy

By convention, the threshold for diagnosing hypertension in pregnancy is systolic blood pressure levels ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg, confirmed by two readings at rest four to six hours apart. The National High Blood Pressure Education Program in the United States (NHBPEP)²³ noted that patients with blood pressure readings (BP) below the threshold for diagnosis, but with an increase of 30 or 15 mm Hg in the systolic and diastolic pressure, respectively, are those with a higher risk of developing a hypertensive disorder in pregnancy. The UK National Institute for Clinical Excellence (NICE)²⁴ further divides pregnancy-associated hypertension risk levels as follows:

• Mild Hypertension: diastolic BP 90-99 mm Hg, systolic blood pressure 140-149 mm Hg.
• Moderate hypertension: diastolic BP 100-109 mm Hg, systolic blood pressure 150-159 mm Hg.
• Severe hypertension: diastolic BP 110 mm Hg or greater systolic blood pressure of 160 mm Hg or greater. 

A severe hypertensive crisis is usually indicated with a systolic reading > 169 mm Hg or diastolic > 109 mm Hg, and care must be taken to immediately reduce blood pressure in order to limit organ damage.²⁵ This differs from a hypertensive emergency situation, in which blood pressure should be reduced within a few hours. Readings in pregnancy are liable to change (especially in the context of preeclampsia, often characterized by changes in the behavior of fluids) and extremely sensitive to antihypertensive therapy. Therefore, high blood pressure measurements should be reduced rapidly, but gradually with continuous monitoring of maternal and fetal parameters; excess reduction leads to a decrease in the placental circulation and fetal distress. The recommendation is that diastolic blood pressure not be reduced by more than 30 mm Hg, and that mean arterial pressure (MAP) immediately be reduced by more than 25%. 

There are four categories of hypertensive disorders in pregnancy, as described below and in Figure 2. Using the terminology recommended by the NHBPEP working group,²³ these categories are classified as:

• Preeclampsia.
• Chronic hypertension of any cause.
• Preeclampsia superimposed on chronic hypertension.
• Gestational hypertension.

It should be noted that despite the above distinctions, it is believed that preeclampsia and gestational hypertension may be a continuum of the same condition, but with arbitrarily divided.

Preeclampsia

Preeclampsia, preeclampsia toxemia (PET) and hypertension induced by proteinuric pregnancy (HIPP) are almost synonymous terms that describe a syndrome characterized by newly appearing hypertension with significant proteinuria (300 mg or more of proteinuria in 24 hours or two urine samples collected more than four hours apart of ≥ 1 + proteinuria on dipstick test) diagnosed in the second half of pregnancy.²⁶ Incidence rates range between 3 and 7% of reports, which can be biased by the study population (number of primiparous women, body mass index- BMI- and age). The cause of preeclampsia is not known; however, it is observed that occurs most often in nulliparous women usually after 20 weeks of gestation and often at the end of the third trimester. There seems to be a genetic predisposition: the risk of preeclampsia is tripled in women with a first-degree relative affected.  

It is believed that preeclampsia develops from the interaction of two disease processes: 1) maternal disease (abnormal vasculature, kidney disease, or metabolic disease) or cardiovascular predisposition, and 2) fetal causes in the form of placental factors. The exact mechanisms of these interactions are unclear; however, it is postulated that the variation of the influence of both factors can produce two separate phenotypes of preeclampsia: a phenotype of early onset, which is associated with poor placentation and fetal growth restriction, and a phenotype of late onset, which is believed not to be related to placental causes.^27,28

In general, early onset preeclampsia (generally defined after 34 weeks) represents 20.5% of all cases, including the most severe manifestations.²⁹ This form is linked to a poor immune adaptation of the placenta and is characterized by early sympathetic dominance in the cardiovascular system, elevated markers of endothelial dysfunction, inadequate trophoblast invasion of the uterine spiral arteries, the early onset of fetal complications, and low birth weight.^30-32

In contrast, late onset preeclampsia is more common, with more than 80% of all cases;²⁹ it is commonly seen in the background of pre-existing maternal morbidities such as chronic hypertension, kidney disease, and obesity. Fetuses born of a pregnancy with late-onset preeclampsia have a proportionally higher birth weight compared with cases of early onset preeclampsia.³³

Subscapular hepatic hematoma

Subscapular hepatic hematoma (SHH) has been reported in less than 2% of pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). The incidence of SHH has been reported 1 in 40,000 to 1 in 250,000. This leads to an increase in the rate of maternal and perinatal morbidity and mortality. SHH symptoms may include epigastric pain, bloating, nausea, and vomiting. This hematoma can result in liver rupture and can therefore cause life-threatening problems such as disseminated intravascular coagulation (DIC) and renal failure.

Pathogenesis of preeclampsia: placental factors

For a long time there has been research regarding whether there is a defective placenta in preeclampsia. This approach has been taken because the natural resolution of the disease follows the birth of the child and the placenta. In a normal pregnancy, the maternal spiral arteries that supply blood to the placenta are remodeled: there is loss of smooth muscle tissue inside the terminal arteries. This is done to prevent neural humoral regulation of the vessels in reaction to an increased volume of blood flow in a pregnant uterus. It is thought that in preeclampsia this remodeling is incomplete, and smooth muscle tissue is found remaining, which in theory provides a regulatory control of vascular tone.³⁴ This could lead to spontaneous vasoconstriction and intermittent high speed perfusion in the intervillous space, causing ischemic injury, generating abnormal perfusion,³⁵ the release of several placental factors, maternal inflammatory response, and generalized vasoconstriction.

Several signaling pathways have been implicated in abnormal vascular remodeling of the placenta, such as the Notch signaling pathway, which serves to modulate vasculogenesis through cell to cell differentiation and function. By eliminating the Notch conditions² in mice, the size of the maternal blood vessels was reduced by 30-40% and placental perfusion by 23%.³⁶ In patients with preeclampsia, the expression of Notch ligand JAG1 was absent in peri- and endovascular placental trophoblasts, suggesting a defect in Notch signaling.³⁶ This finding has been reflected by other studies that detected a significant reduction in the immune reactivity of Notch proteins in the placentas of pregnancies with preeclampsia, compared with non-affected pregnancies.^37,38

Another characteristic histological finding (reported in 20 to 40% of preeclampsia placentas) is acute atherosis. This is characterized by aggregates of fibrin, platelets, and foam cells filled with subendothelial lipids that partially or totally clog spiral arteries.³⁹ Based on animal studies,⁴⁰ it has been postulated that acute atherosis develops after the unregulated calibration of arterial vascular tone and the diameter of the spiral leading to the tension of the vessel endothelial cells.³⁹ These lesion points become a target for lipid depositing within the arterial walls. Interestingly, in the postmortem examination of women who have died of preeclampsia, these atherosis lesions were not found, suggesting a quick resolution, possibly after delivery and the shedding of the decidua.⁴¹

It should be noted that atherosis and incomplete vascular remodeling are not specific to preeclampsia, and are also found in some isolated cases of intrauterine growth restriction, pregnancy-induced hypertension, diabetes mellitus, and even normal pregnancy.^39,42

It has also been hypothesized that the fragments arising from the placenta trigger an immune response and produce a greater state of inflammation compared to that commonly observed in normal pregnancy. It is believed that this abnormal immune response is manifested in preeclampsia.²⁶ Interactions between CD4 + regulatory T cells and natural killer uterine cells are involved in the recognition of fetal antigens, and facilitate placental growth. The absence of this leads to miscarriage, whereas partial failure is associated with worse placentation, dysfunctional uterine-placental perfusion, and chronic immune activation from the placenta. CD4 + regulatory T cells circulating decrease while T helper 17 cells (which are regulated even in several autoimmune diseases) are increased in women with preeclampsia.^43,44

Pathogenesis of preeclampsia: endothelial dysfunction

It is believed that in preeclampsia, the maternal endothelium is an important target for placental derived factors are released in response to placental ischemia or immunologic mechanisms.

The vascular endothelium is adapted to increased plasma volume from pregnancy, through the release of vasoconstriction and vasodilatation substances, but in preeclampsia endothelial disorders maintain a state of generalized vasoconstriction. Alterations in the circulating levels of many endothelial dysfunction factors and lesions have been reported in women who develop preeclampsia,^45-47 even several weeks before the onset of overt disease. Two of these factors are Fms tyrosine kinase 1 (sFlt-1) and soluble endoglin (SENG). Increased levels of sFlt-1 reduces the bioavailability of free VEGF and PlGF, factors that stimulate angiogenesis and maintain endothelial integrity. SFlt-1 levels are strongly correlated with the severity of the preeclampsia.^32,48,49 A pilot study that removed the sFlt-1 from the circulation of women with preeclampsia through apheresis was associated with lowered blood pressure and proteinuria and increased duration of gestation.⁵⁰

It is believed that sENG endangers the binding of transforming growth factor 1 with endothelial receptors, which decreases vasodilation derived from endothelial nitric oxide.² The simultaneous introduction of adenoviruses carrying both sFlt-1 and sENG in pregnant rats produces severe hypertension, proteinuria, and levels of elevated liver enzymes similar to the manifestation of preeclampsia in human beings.⁵¹ 

In pregnancy, physiological adaptation is accompanied by an increased production of nitric oxide (NO) and increased responsiveness of vascular smooth muscle cells to NO.^52,53 NO causes vasodilation to counteract vasoconstriction caused by activation of the sympathetic nervous system and RAAS, and it is also a potent inhibitor of platelet aggregation and the activation of both cyclic guanosine monophosphate (cGMP) -dependent and cGMP-independent mechanisms.^54,55 Balance between prooxidant and antioxidants forces in endothelial cells can be influenced by nitric oxide, and reduced bioavailability may contribute to the development of oxidative stress, as seen in preeclampsia. This endogenously produces competitive inhibitors of nitric oxide-synthase (NOS), which are not produced by enzymatic cleavage of L-arginine. Increased values ​​of these inhibitors have been found in patients with high resistance to placental circulation at risk of preeclampsia, intrauterine growth restriction, or both.⁵⁶

Pathogenesis of preeclampsia: maternal cardiovascular adaptation

The placenta as causal organ can convincingly explain some manifestations of preeclampsia, but it is not relatable to cases where hypertension and proteinuria develop late in pregnancy in association with normal or large babies. In some rare cases, preeclampsia has been reported after delivery, which does not fit with a "theory of the placenta". In such scenarios, it is believed that maternal predisposition to cardiovascular dysfunction is the etiology of preeclampsia, through interaction with the placenta and endothelial dysfunction.

A study of over 7,000 women found that in the first trimester (between 11 and 13 weeks) central systolic blood pressure, pulse wave velocity, and the rate of aortic increase (AIX) were significantly higher in women who subsequently developed preeclampsia, compared with normal controls.⁵⁷ Several weeks before the onset of clinical symptoms, of late onset for preeclampsia, cases can be characterized by a very low hyperdynamic state with peripheral resistance and high cardiac output, with large left ventricle diameters and increased systolic volume compared to normal pregnancies.^58,59 By contrast, early onset disease is denoted by a hypovolemic state with low cardiac output and high peripheral resistance with smaller left ventricular diameters, suggesting an insufficient state of output with pressure overload.^58,59

Cases of fetal growth restriction associated with preeclampsia have a lower cardiac index and increased peripheral resistance compared to non-affected pregnancies.⁵⁹ Moreover, longitudinal assessments in the first trimester (between 5 and 8 weeks) have found that pregnancies with growth restriction had a significantly lower cardiac output in early pregnancy, compared with control cases.⁶⁰ This suggests defective maternal adaptation: diminished response to the growing physiological demands of pregnancy. The timing is significant, as it comes weeks before functional uterine-placental circulation develops.

Maternal cardiovascular status may also be reflected by the appearance of the waveform in the uterine artery Doppler and increased impedance.^61,62 The increased pulsatility index of the uterine artery by Doppler in both the first and second trimester, and waveform notches in the second trimester, have poor positive predictive value for preeclampsia in any gestation, although these are more sensitive to early onset disease.^63-65 The refinement of predictive models to integrate maternal factors such as vascular parameters improves the prediction in all gestations. This is explained in part by the influence of non-placental factors in maternal cardiovascular adaptation and the emergence of the waveform.⁶² A high resistance of the uterine artery in mid-trimester has been seen to distinguish the different phenotypes of preeclampsia: arterial resistance index > 90th percentile for early onset, late onset, and controls were 63.6, 15.5, and 8.8%, respectively. With late onset preeclampsia, the less frequent was < 10^th percentile birth weight (p < 0.05).⁶⁶

In general, the occurrence of preeclampsia has detectable hemodynamic patterns, which may reflect poor physiological adaptation to pregnancy. Using this model, two distinctly different conditions can be identified:⁵⁸ 1) high peripheral resistance, a state of low cardiac output mainly associated with early onset preeclampsia (usually in relation to growth restriction); 2) low peripheral resistance, with high cardiac output mainly associated with late-onset preeclampsia, in which growth restriction is less common and distribution of birth weight may skew towards larger babies.

There is also the hypothesis that rather than maladaptation, a subgroup of women have a predetermined risk for cardiovascular disease, and the continuity of this risk is manifested as preeclampsia or gestational hypertension in response to the growing demands of pregnancy. This idea is supported by studies showing significant associations between cardiovascular risk factors, pre-eclampsia, and pre-pregnancy, for example, high triglycerides, low density lipoprotein, cholesterol, and essential hypertension.⁶⁷ In addition, epidemiological follow-up studies show that women who had preeclampsia have a significantly higher risk of heart disease and stroke, extrapolated from 10 and 30 years,^68,69 and this risk is even higher if the preeclampsia was serious or early onset.⁷⁰ A large retrospective cohort study has shown that women who develop preeclampsia during pregnancy have an doubly increased risk of ischemic heart disease in the next 15 to 19 years.⁷¹

Manifestation and complications of the disease

Women with preeclampsia are usually asymptomatic when the disease begins. The absence of the "classic" signs of hypertension, proteinuria and edema, do not rule out diagnosis; and in practice, preeclampsia is diagnosed when there is a constellation of recognized features. It is the association of hypertension with these features that makes it possible to distinguish preeclampsia from chronic and gestational hypertension.

A sudden rise in blood pressure above a critical threshold (which may commonly be a mean arterial pressure > 150 mm Hg) can cause acute arterial damage, especially in the central nervous system, which is particularly sensitive to hypertensive disease. The most common cause of death in preeclampsia is the loss of cerebral autoregulation, which leads to a brain hemorrhage. A serious and rare complication of preeclampsia is eclampsia, a form of hypertensive encephalopathy defined as tonic-clonic (grand mal) seizures that occur in association with the characteristics of preeclampsia. Eclampsia can be associated with ischemic or hemorrhagic stroke with cerebral vasospasm or edema. Cortical blindness (usually reversible) is well described, although its association with preeclampsia/eclampsia is not uncommon. Acute hypertension during pregnancy or after childbirth can affect cerebral autoregulation, which leaves permanent damage and may cause death. 

Other systemic complications include impaired renal function in the form of reduced uric acid clearance and glomerular hypofiltration. Increased plasma uric acid is an early sign of preeclampsia, but is not always seen, reflecting the heterogeneity of the disease.

Hypoalbuminemia causes low colloid osmotic pressure, disrupting fluid transport through the capillaries, so the vascular system in preeclampsia turns to poor liquid distribution in the interstitial spaces, or "leakage" from the vascular compartment, leading to intravascular depletion and possibly vasoconstriction. Extravascular fluid leads to rare complications such as ascites and pulmonary edema. About 10 to 15% of cases of preeclampsia can occur without edema (“dry preeclampsia"), and are associated with increased perinatal mortality.²⁶

Liver dysfunction, as a characteristic of preeclampsia, may initially cause epigastric pain and vomiting, and may progress to jaundice and liver failure. The coagulation system normally activated during pregnancy (a "hypercoagulable" state) is exaggerated in preeclampsia. There is increased platelet activation, size, and decreased life. There is the accentuated hypercoagulability of normal pregnancy (e.g. reduction of antithrombin III, and proteins S and C), which can in some cases decompensation in CID. CID is particularly serious if there is concomitant liver involvement. If both are present with hemolysis, the acronym HELLP has been used to identify the presence of hemolysis, elevated liver enzymes, and low platelet count. HELLP syndrome is a dangerous complication characterized by epigastric pain, and it has a maternal mortality rate ranging between 4 and 15%.⁷²

A diagnosis of pre-eclampsia requires hospitalization, given the potential for the disorder to quickly worsen the health of the patient, and the increased risk of placental abruption, especially when superimposed chronic hypertension develops.⁷³ The birth of the child remains the known "cure". At the end, induction of labor or cesarean section is indicated.²⁴ Attempts to prolong pregnancy to reduce the risk of neonatal morbidity with optimal blood pressure management should be made if the pregnancy is over 34 weeks and there a good clinical response to treatment. The pregnancy is allowed to continue if blood pressure is controlled enough, if there are no signs of maternal life-threatening complications (such as CID, HELLP, eclampsia), and if fetal monitoring is reassuring.

After diagnosis, women should have a normal blood pressure record and monitoring of urea and serum creatinine, uric acid, hemoglobin, platelet count, liver function, and coagulation if thrombocytopenia is present. Doppler blood flow monitoring should be conducted in the uterine artery, looking especially for waveforms of high resistance in the uterine arteries; these waveforms predict associated intrauterine growth restriction and placenta detachment.

Excessive fluid replacement should be avoided, as this can aggravate interstitial edema. Urine production as low as 10 mL per hour may be acceptable. In order to prevent venous thromboembolic disease (TED), thromboprophylaxis will be done with compression stockings, and low molecular weight heparin should be given.

There is no pharmacological cure for preeclampsia. Treatment is aimed at addressing hypertension. The choice of pharmacological agents for the treatment of preeclampsia and other hypertensive disorders in pregnancy are similar, and are therefore elaborated in a separate section and summarized in Tables I and II.

Specifically for preeclampsia, the goal should be to use oral therapy to reduce blood pressure slowly to a target of 140-150/80-100 mm Hg.²⁴ There is no evidence that stricter control (< 140/90 mm Hg) gives better results, and the rapid reduction in mean arterial pressure by 25% could lead to maternal end hypoperfusion (e.g. stroke, myocardial infarction) or may affect the placenta, perfusion, and fetal growth.

Chronic hypertension in pregnancy

Chronic hypertension is diagnosed either by the existing medical history or a reading of high blood pressure (> 140/90 mm Hg) in the first half of pregnancy. It complicates about 3% of all pregnancies, most of which correspond to essential hypertension. Occasionally, secondary hypertension can be diagnosed de novo in pregnancy, and it is the most common cause of intrinsic renal disease. Other causes, such as pheochromocytoma, primary hyperaldosteronism, Cushing's syndrome, and aortic coarctation should be investigated and excluded.

The physiological decrease in blood pressure in early pregnancy and increased blood pressure after pregnancy are exaggerated in women with chronic hypertension. Therefore, they may present with normal tension in early pregnancy visits and be misdiagnosed with gestational hypertension later.

The increased risk of chronic hypertension in pregnancy is the development of superimposed preeclampsia, since risk increases fivefold compared with a normotensive person. Meanwhile, chronic hypertension is also associated with adverse morbidity for mother and fetus: the overall risk of developing eclampsia increases 10 times, and there is a threefold increase in fetal death and 2.5 times in the possibility of preterm birth.⁷⁴

The signs of preeclampsia superimposed on chronic hypertension are the same as in isolated preeclampsia, except that blood pressure levels begin to rise from a higher baseline. In the differentiation of both conditions, generally with chronic hypertension, there is no change in blood pressure from baseline, no increase in levels of maternal plasma urate (values ​​below 0.30 mmol/L unlikely in preeclampsia), and no significant proteinuria.

Clinical approach

Before conception, there is widespread unawareness that a majority of commonly used antihypertensive drugs are teratogenic, and therefore continue to be used. However, angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) should be avoided because they are associated with fetal abnormalities, renal agenesis, and particularly with miscarriage in the first trimester.^75-77 By the 12^th week of pregnancy, decreased blood pressure in normal pregnancy usually means that antihypertensive treatment may be temporarily suspended until blood pressure rises again, usually in the third trimester.  

Although no placebo-controlled studies are available, historical data suggest that treatment of severe chronic hypertension in pregnancy reduces maternal and fetal risks. However, there is no clear evidence that lowering blood pressure reduces the risk of developing preeclampsia.⁷⁸ The threshold consensus level for treatment is split between recommending treatment above 160/100 or 140/90 mmHg. Given the potential concerns about excessive BP reduction, individual cases should be carefully considered. In general, therapy should be initiated if the readings are close to 160/100 mm Hg. The target blood pressure is less clear, but a reasonable guide would aim for a blood pressure 130/150/80/100 mm Hg. The choice of drugs is dictated by fetal considerations. Methyldopa may be preferred, as its fetal effects are more clearly defined; subsequently, other antihypertensive therapies are used. 

Unlike preeclampsia, women do not have to be hospitalized in an obstetric unit for diagnosis, since there is no conclusive evidence that preeclampsia predisposes to placenta detachment.⁷⁹ Admission and intravenous therapy for severe uncontrolled hypertension (without superimposed preeclampsia) is rare, and blood pressure can be reasonably controlled with oral drugs. 

Pregnancy-induced hypertension  

The pregnancy-induced hypertension (PIH) is significant hypertension "without proteinuria" that develops after 20 weeks of pregnancy. It is sometimes seen in the context of chronic hypertension solution in the first and second trimesters due to normal physiological changes in pregnancy, followed by exposure in the third trimester, leading to a presumptive diagnosis of preeclampsia. In general, the blood pressure of women with preeclampsia is expected to return to normal after childbirth or in the postpartum period.

There is much about the etiology of PIH that remains unknown. This hypertension may be within the spectrum of hypertensive disorders of pregnancy and, therefore, it may be a continuation of preeclampsia, or a separate entity with its own pathology, or we may also be facing an exaggerated form of adaptation to cardiovascular changes in pregnancy to maintain placental perfusion as pregnancy progresses.

Most women with preeclampsia have good maternal and fetal outcomes. However, PIH can become preeclampsia (diagnosed with significant proteinuria) in 15-20% of pregnancies.⁸⁰ There are suggestions in the literature that when PIH is diagnosed before 35 weeks, it is more predictive for diagnosing later development of preeclampsia as pregnancy progresses.⁸¹ The identification of this subgroup is significant, because these pregnancies are at increased risk of stillbirth, premature delivery, and low birth weight compared with PIH itself or non-affected pregnancies.⁸²

Severe PIH (defined as blood pressure > 160/110 mm Hg in two separate measurements) is associated with increased adverse perinatal outcomes (children small for gestational age at birth and prematurity), compared with pre-eclampsia with lower blood pressure readings.⁸³ This is supported by a previous study, in which high diastolic blood pressure is associated with high perinatal mortality.⁸⁴

Therapeutic approach

The NICE guidelines recommend the treatment threshold for PIH >150/100 mm Hg (moderate hypertension); this is similar to the threshold for preeclampsia.²⁴ However, the approach to well controlled PIH is made frequently on an outpatient basis, compared to the latter.

Pharmacological treatment of hypertensive disorders in pregnancy

When choosing an antihypertensive drug for use in pregnancy, the main consideration in addition to the efficacy and adverse effects on the mother, is the risk of teratogenicity. In women with chronic hypertension, the time until 13 weeks of gestation is considered to be the window of greatest risk, while organogenesis is occurring. For this reason, agents that were widely used in older patients before there were concerns of teratogenicity were proposed, and tend to be the mainstay agents with records of being tested as "safe". The most antihypertensive agents are not licensed for use in pregnancy, since they have no safety and efficacy studies. However, drugs administered in the late stages of pregnancy can still affect fetal growth and well-being, while drugs administered near the time of delivery may have prolonged effects in the newborn. Considerations to initiate or continue the use of a pharmacological agent in pregnancy, therefore, must take into account an agent that can be used to prolong pregnancy safely for as long as possible, with minimal fetal exposure in the uterus and with minimal vertical transfer during lactation.

Several national and international guidelines have been published to guide the choice of antihypertensive agents during pregnancy.⁸⁵

Oral treatment for hypertensive disorders in pregnancy

For less severe levels of hypertension, alpha-methyldopa, calcium channel blockers, and beta-blockers are used universally and routinely as first- and second-line drugs.⁸⁵

There is an extensive database on the use of methyldopa, a false transmitter and alpha-2-agonist, and there seems to be no fetal or neonatal risk from treatment. Birthweight, neonatal complications, and development during the first year were similar in children exposed to methyldopa and those in the placebo group.⁸⁶ The same happened with intelligence and neurocognitive development at 7.5 years of age in children whose mothers were treated with methyldopa.⁸⁷ Blood pressure control is gradual over a period of six to eight hours due to the mechanism of indirect action. Compared with methyldopa, labetalol was faster and more efficient in controlling blood pressure in PIH, with a trend toward a lower rate of intervention (cesarean section or induced labor), reducing the appearance of proteinuria, plus it was better tolerated.⁸⁸ Adverse effects of the central alpha-2-agonist include a decrease in mental alertness and sleep disturbances, leading to a feeling of fatigue or depression in some patients. This is particularly relevant in patients at risk for postpartum depression. Clonidine, a selective alpha-2 agonist, acts similarly and is comparable with methyldopa in terms of safety and efficacy, but sleep disorders are reported in infants who were exposed in utero.⁸⁹

The aforementioned labetalol is a common first- or second-line drug with beta-1 and beta-2 blocking actions, properties of alpha-1 adrenergic receptor blocking, and a direct action on vasodilation. Maximum concentrations in the blood are produced in an hour in pregnant patients, and the half-life in plasma in the third trimester ranges 1.7-5.8 hours. When administered in the early stages of PIH, labetalol can slow the progression of preeclampsia. The use of atenolol is controversial because some early studies showed a significant association with lower birth weight and a considerably higher proportion of babies for gestational age.^90-92 A meta-analysis of 13 population-based case-control or cohort studies on the use of beta-blockers in the first trimester of pregnancy showed no increased odds of all or major birth defects (odds ratio [OR] = 1.00, 95% confidence interval [CI] 0.91-1.10; five studies). However, in analyses examining specific organ malformations, there was an increase in the odds of cardiovascular defects (OR = 2.01, 95% CI 1.18-3.42; four studies), cleft lip/palate (OR = 3.11, 95% CI 1.79-5.43; two studies) and neural tube defects (OR = 3.56, 95% CI 1.19-10.67).⁹³ The causality is difficult to establish, given the small number of heterogeneous studies.   

Calcium channel blockers (CCB) in pregnant rats have shown increased prevalence of digital and limb defects; however, a review of case-control studies in humans have not shown an association with an increased prevalence of congenital abnormalities in children exposed to CCB in the uterus.^94-96 Short-acting (immediate release) and long-acting formulations of nifedipine are commonly used to treat severe hypertension episodes as well as for long-term control of non-severe hypertension in pregnancy, although it is reported that short-acting nifedipine is associated with episodes of maternal hypotension and fetal distress.^97,98 Maternal side effects of CCB include tachycardia, palpitations, peripheral edema, headache, and facial redness.⁹⁹ One concern with the use of CCB in preeclampsia refers to the concomitant use of magnesium sulfate to prevent seizures. Additive effects have been observed between nifedipine and magnesium sulfate in a few cases, which resulted in neuromuscular blockade, myocardial depression, or circulatory collapse.^100,101 However, a recent evaluation has suggested that they can be used together without increased risk in to mother.¹⁰²

Unlike the above classes of drugs, ACE inhibitors and ARBs are the two class-D drugs according to the classifications of the US Food Drug Administration (FDA), although these are generally treated as absolute contraindications throughout pregnancy because of related fetal toxicity. The use of these agents has been reported associated with miscarriage, stillbirth, and congenital malformations, as well as fetal kidney failure in particular.^103-105 It is believed that the cause of the associated defects is related to fetal hypotension that develops, as well as reduction in renal blood flow in the fetus and disruption of prenatal fetal development of the uropoietic system as a result of suppression in the fetal renin-angiotensin system.^105,106 The risk of use in the first trimester is unclear and it is believed to be similar to other antihypertensive agents,⁷⁵ although a relative risk of 2.71 for congenital malformation is reported when fetuses were exposed in the first trimester.¹⁰⁴ As such, it is best to avoid them, and women attending prenatal visits should be given an alternate agent.  

In patients with chronic hypertension, diuretics administered before pregnancy can be continued during this process, with an attempt to decrease the dose; they can also be used in combination with other agents, especially for women with salt-sensitive hypertension. Gentle contraction of volume with diuretic therapy may cause hyperuricemia and in so doing may invalidate the levels of serum uric acid as a marker for the diagnosis of preeclampsia. Spironolactone is not recommended due to its anti-androgenic effects observed in an animal models (embryogenesis), although this was not repeated in a clinical case report.¹⁰⁷

 

Intravenous antihypertensive drugs for acute crisis

Hydralazine remains a popular first-line option for hypertensive crisis in pregnancy and for maintenance treatment. It is a potent arteriolar vasodilator and venous dilator whose mechanism is not known although it relaxes arteriolar vascular smooth muscle, which causes a reduction in peripheral vascular resistance and vasodilation. 30 minutes is sufficient for maximum plasma concentration; this vasodilator also offers hypotensive effects lasting up to eight hours. With parenteral administration, the onset of action occurs within 10 to 20 minutes and can last up to four hours. Hydralazine crosses the placenta freely and also appears in small quantities in breast milk. Plasma renin activity is increased, which can lead to edema. Vasodilation is not widespread, with minimal venous dilatation and, therefore, less frequent incidence of postural hypotension. Patients given intravenous hydralazine often experience shortness of breath, headache, palpitations, and sleep disturbances.

To date, there are no reports of teratogenic effects of this drug; however, there is minimal data of use in the first trimester. The hemodynamic effects of hydralazine are more pronounced in patients with preeclampsia, leading to more cases of fetal distress, compared to administration in patients with PIH. Similarly, hydralazine has a more dramatic effect when used in PIH compared to patients with chronic hypertension in pregnancy. Therefore, lower doses and gradual control of blood pressure reduction should be used depending on the diagnosis.

A small study of 24 patients receiving hydralazine showed that it is associated with more cases of fetal distress requiring delivery by cesarean.¹⁰⁸ However, a broader study found that hydralazine bolus up to 5 mg repeated every 15 minutes achieved an ambulatory blood pressure monitoring (ABPM) of 125 mm Hg. Hydralazine was administered without significant differences in the condition of the fetus in the treatment group and the non-treatment group,¹⁰⁹ and with good control of maternal blood pressure; the administrative protocol provided was respected.

Labetalol is another drug commonly used in acute hypertensive crisis pregnancy. However, the use of intravenous labetalol near delivery has been associated with some cases of neonatal bradycardia, hypotonia, respiratory distress, hypoglycemia, circulatory collapse, and feeding problems.^110,111 For severe hypertension, it has been observed that intravenous labetalol produces less maternal symptoms (hypotension, palpitations, or tachycardia) than intravenous hydralazine, but is more associated with fetal bradycardia.^112,113 A meta-analysis of 24 trials found no significant differences between parenteral labetalol and hydralazine, whether in the efficacy or safety profile, in the context of its use in severe hypertension.¹¹⁴ Similarly, a systematic review of 15 randomized controlled trials for the treatment of severe hypertension in pregnancy and postpartum reported that nifedipine, labetalol, and hydralazine achieved similar success in treatment in most women, with no differences in adverse maternal or fetal outcomes.¹¹⁵

 

Magnesium sulfate

It would be feasible to implement the intervention to treat women with preeclampsia with magnesium sulfate. The difficulty lies in finding ways to define the severity of preeclampsia. Low-risk cases, taking into account the high number needed to treat, may not be suitable candidates for treatment with magnesium sulfate; however, at present there are no clear definitions. What is a fact is that it is still indicated in patients with high risk of convulsive preeclampsia.

Possible new therapies

Most clinical trials of new drugs for the prevention and treatment of hypertensive disorders in pregnancy have focused on preeclampsia, based on what is thought to relate to the pathophysiology of the disease (deficiency of bioavailability of nitric oxide, oxidative stress, endothelial dysfunction, and maternal cardiovascular risk factors).

The regulatory role of oxidative stress in preeclampsia, together with the promotion of in vivo data, presented the hypothesis that antioxidant vitamins may have therapeutic potential. However, clinical trials of vitamins C and E showed no reduction in the incidence of preeclampsia in women with risk.^116,117 This has been confirmed by systematic reviews and meta-analyzes of trials evaluating a combination of these vitamins.^118,119 Importantly, questions have been raised concerning the safety of the administration of vitamins C and E.

The number of stillbirths over 24 weeks, the need for magnesium sulfate or intravenous antihypertensive therapy, and the incidence of gestational hypertension have been observed in women receiving vitamins C and E compared to placebo,¹¹⁷ although the combined daily doses of vitamins were below the maximum recommended by the US Institute of Medicine.¹²⁰ It is thought that vitamin E supplements may favor a proinflammatory response (Th1) in the maternal-fetal interface, therefore causing adverse results in pregnancy.¹²¹ Therefore, vitamins C and E cannot be recommended in the prophylaxis or treatment of preeclampsia. 

A deficient bioavailability of NO or an abnormal sensitivity to endothelial NO have been described in vivo and ex vivo in preeclampsia; several nitric agents have been tested for the prevention and treatment of this pathological condition. These include organic nitrates, S-nitrosothiols, precursors such as l-arginine, and cGMP degradation inhibitors. Nitroglycerin (NTG) is an organic nitrate widely used in clinical practice for angina. The evidence for the use of NTG in pregnancy is limited by the small number of women in trials; however, it has potential as a therapeutic agent in the context of hypertensive disease of pregnancy. Use in women at risk of developing preeclampsia was first reported in 1994; on that occasion a reduction in the dependent dose on the resistance of the uterine artery was demonstrated with intravenous infusion of NTG with no effect on maternal cardiovascular parameters.¹²²

However, other studies have shown a significant reduction in maternal blood pressure without significant adverse events.^123,124 A randomized placebo-controlled trial with low-dose NTG transdermal patches in women with abnormal Doppler velocimetry of the uterine artery at 24-26 weeks showed that although there was no change in the incidence of preeclampsia, NTG increased the likelihood of a pregnancy without complications.¹²⁵ 

A donor compound similar to NTG, but without the effect of drug tolerance, is pentaerythritol tetranitrate (PETN), which enhances the expression of heme-oxygenase-1 antioxidant genes (HO-1) and ferritin heavy chain (FEHC) in human endothelial cells. In a randomized double-blind placebo trial, it has been shown that PETN significantly reduces the risk of perinatal death (adjusted relative risk [RR] = 0.410, 95% CI 0.184-0.914), but not the incidence of preeclampsia in women at risk.

Note that placental detachment did not occur in the PETN treatment arm, compared to the five cases in the placebo group. These results suggest that secondary prophylaxis of adverse outcomes of pregnancy may be possible in pregnancies with abnormal placentation using PETN.¹²⁶

S-nitrosothiols have an NO group attached to the thiol moiety (RSH); the first of them can be transferred effectively to endogenous thiols that act as a biological deposit of NO. The S-nitrosothiol that has been investigated in women with preeclampsia is S-nitrosoglutathione (SNOG). The first case of use of SNOG was a woman with severe preeclampsia, HELLP syndrome. A rapid improvement in the clinical parameters of the patient and the platelet count was observed following infusion with SNOG.¹²⁷

A study of SNOG infusion in ten women with severe preeclampsia showed a reduction dependent on the significant dose of blood pressure, without any significant effect on fetal circulation.¹²⁸ It was recently found that SNOG infusion administered in women with early onset preeclampsia serves to reduce the rate of increase, a marker of long-term cardiovascular health that has been observed in association with preeclampsia,⁵⁷ and improved proteinuria and platelet function.¹²⁹ SNOG may be a promising therapeutic agent for cases of severe preeclampsia; however, larger studies are needed to investigate the safety, efficacy, and clinical endpoints for both mother and baby. SNOG is metabolized in vivo via SNOG reductase, and it has been shown that N6022, a reversible SNOG reductase compound inhibitor, improves endothelial function in vivo and has potential to be studied in the context of preeclampsia.   

A large trial based in Mexico investigating the use of L-arginine (a precursor of NO) showed that supplementation of a combination of L-arginine and antioxidants reduced the incidence of preeclampsia compared with placebo (30.2 versus 12.7%). However, these results should be interpreted with caution. Moreover, the study population reported an exceptionally high rate of recurrence of preeclampsia (30%), compared to approximately 5 to 16% risk of recurrence observed in other countries.^130-133 Therefore, the results they may not be generalizable or applicable to other obstetric populations. Note that a small study of intravenous infusion of L-arginine in pregnant women showed a significant reduction in blood pressure, and this effect was more pronounced in patients with preeclampsia.¹³⁴

Preeclampsia has many pathophysiological similarities as well as risk factors shared with cardiovascular disease in adults. This includes dyslipidemia. Given the encouraging evidence of the beneficial effects of statins in preventing cardiovascular events in humans, several trials have tested the effect of pravastatin in rodent models of preeclampsia. Treatment with pravastatin significantly reduced sFlt-1, lowered blood pressure, and prevented kidney damage in rats.^135-138

In addition, pravastatin also exerts protective effects on the endothelium and improves preeclampsia symptoms by increasing the release of NO.^137,139 Pravastatin has now been tested in the first randomized placebo-controlled human trial in the UK, for which the multi-center recruitment was completed in 2014.

Several other compounds have been tested on animals (and have been shown in early clinical studies), but none has proven to be of therapeutic efficacy. These include phosphodiesterase inhibitors (designed to improve the NO signaling pathway), such as sildenafil, and hormones that are thought to contribute to vasodilator actions in pregnancy, such as relaxin. 

Postpartum considerations

Postpartum hypertension is often preceded by pre-pregnancy (chronic) hypertension, by prenatal hypertension (PIH/PE) or intrapartum hypertension. However, it could also occur de novo in the postpartum period like preeclampsia. One particular difficulty in the postpartum period is the ability to accurately quantify proteinuria due to contamination of lochia. It is also important to consider other relevant factors that may have contributed to high blood pressure; these include pain, anxiety, and drug use.

The NICE guidelines recommend blood pressure control within six hours after birth in all normotensive women without underlying medical problems and who have had a pregnancy and childbirth without complications.¹⁴⁰ One more blood pressure check is recommended on the fifth day postpartum to detect people with late-onset postpartum hypertension. The proper identification and treatment of hypertension is important because adverse complications (eclampsia, intracranial hemorrhage, aortic dissection, reversible cerebral vasoconstriction syndrome) are closely associated with inadequate treatment of systolic hypertension. This is reflected in the first 10 recommendations published in "The Confidential Enquiry into Maternal and Child Death in the UK", a consensus report stating that systolic blood pressure above 150/160 mmxHg requires urgent and effective treatment.¹⁴¹  

In postpartum women with known hypertension, NICE recommends blood pressure checks every two days after discharge.²⁴ In addition, close monitoring (at least weekly blood pressure controls) allows drugs to be properly titrated according to blood pressure readings. In women with chronic hypertension, one should consider restarting treatment after pregnancy if this is appropriate.

There are limited data on the use of antihypertensive drugs in the post-natal period, since there are no studies on neonatal effects of antihypertensive drugs administered through the mother. Safety in breastfeeding remains one of the main considerations. Pharmacological factors that increase drug levels in breast milk include high lipid solubility and low binding capacity to maternal plasma proteins. Still, the newborn’s level of exposure to these drugs will be affected by the dose, frequency of administration, and bioavailability of the medication.¹⁴²

In the UK none of the commonly used antihypertensive drugs are licensed for use in breastfeeding. However, most doctors prescribe according to the general consensus among the NICE guideline development group.²⁴ Labetalol, atenolol, amlodipine, and nifedipine are widely used in the postpartum period, with the formulation of "once a day" which is preferred by some doctors to improve compliance. Postpartum use of methyldopa is not encouraged, as it has been associated with sedation and depression. By contrast, although ACE inhibitors and angiotensin receptor blockers are contraindicated in pregnancy, enalapril can be considered for use in breastfeeding with evidence suggesting minimal detectable levels in the child.¹⁴³ Labetalol is one of the antihypertensives most used after delivery. It is excreted in breast milk with peak concentration in milk three hours after the dose.¹⁴⁴

It is generally accepted that any hypertension and proteinuria should be resolved six weeks after birth.²³ In the long term, a proportion of women with postpartum hypertension will need drug treatment beyond this period if they are affected by risk factors such as BMI, age, ethnicity, and some pre-existing medical conditions. Women under 40 years with blood pressure > 140/90 mm Hg should be checked for secondary causes, including kidney disease (chronic renal disease, renal arterial stenosis), some endocrine disorders (Conn’s syndrome, Cushing's syndrome), and neurological disorders.¹⁴⁵

Proteinuria persists after six weeks postpartum in some women, which could be due to previously undiagnosed underlying kidney disease.

Women who develop hypertension in pregnancy and the postpartum period have a higher risk of complications in future pregnancies. This includes preeclampsia, fetal growth restriction, and preterm birth. Women with previous PIH have a recurrence rate ranging between 16 and 47% for developing PIH in pregnancy, and a subsequent risk of developing preeclampsia ranging from 2 to 7%. In women with preeclampsia, a recurrence rate of preeclampsia and preeclampsia in a subsequent pregnancy has been cited between 13 and 53% and 16%, respectively.²⁴ The risk factors for recurrence include the appearance of preeclampsia during early pregnancy, persistent hypertension in the fifth week after delivery, and the presence of chronic hypertension before pregnancy.²³

The use of low-dose aspirin in women with increased risk of preeclampsia has been extensively investigated as a preventive therapy. Low-dose aspirin reduces the risk of preeclampsia by 17%, the risk of fetal or neonatal death by 14%, and the relative risk of preterm birth by 8%.¹⁴⁶ The NICE guidelines recommend 75 mg of aspirin daily, every day from week 12 until delivery in women who had at least two moderate risk factors (first pregnancy, more than 40 years old, a period of over 10 years between pregnancies, BMI > 35 kg/m², family history of preeclampsia, and multiple pregnancies) or at least one high-risk factor (hypertensive disorder in a previous pregnancy, chronic kidney disease, autoimmune disease, antiphospholipid syndrome, diabetes mellitus, or chronic hypertension).²⁴

Long-term implications

Pregnancy disorders previously considered self-limiting, as well as a short duration after childbirth, are a disturbing pattern of increased risk of future fatal and nonfatal cardiovascular disease for women with a hypertensive disorder in pregnancy.^147,148 Although there may be a determination of hypertension and proteinuria after birth, there seems to be no increased risk of chronic hypertension, heart disease and cerebrovascular disease, and thromboembolism at adult ages.^149,150

The retrospective analysis of data from a study with a mean follow-up of 26 years found that women with a history of preeclampsia were twice as likely to develop hypertensive disease, taking into account age and tobacco use.¹⁵¹ In assessing the risk of hospitalization for cardiovascular events, a retrospective link from a cohort of more than 800,000 pregnancies with discharge summaries found that women affected by gestational hypertension or preeclampsia were significantly more likely to be hospitalized compared to control cases.

Recently, a well-designed prospective study significantly reported that more women with early onset preeclampsia had signs of heart failure in asymptomatic stage B until 1 year after delivery, and up to 25% of them developed chronic hypertension two years after birth, compared with 1.3% of unaffected controls.¹⁴⁹

Some small prospective preconception cohorts have not reported examining pregnancies affected by prior pre-eclampsia.^5-7,152 There is scope for a prospective longitudinal cohort to undergo cardiovascular assessment before conception, with a number large enough to detect differences between results of pregnancy. A useful adjunct in this group before pregnancy could be a stress test, which can mimic the hemodynamic status of pregnancy after and provide information on whether there is a maladaptive response (measured by parameters such as cardiac output or left ventricle mechanics), which can predict the development of hypertension during pregnancy.¹⁵³ In fact, the American Heart Association guidelines on cardiovascular disease in women now consider preeclampsia equal with a failed stress test in assessing risk factors for future heart disease.¹⁵⁴  

While causality is not yet clear, the appearance of hypertensive disorders in pregnancy should guarantee health interventions after birth, such as smoking cessation and weight loss tips, in order to reduce future cardiovascular risk. It was previously thought that exercise during pregnancy made women fall into a higher risk of premature delivery or miscarriage. However, in most low-risk pregnancies (with absolute contraindications, such as restrictive lung disease, incompetent cervix), most medical bodies now recognize that moderate activity (30 minutes a day) carries minimal risk and has benefits such as improved maternal posture and a better ability to cope with labor.^155,156

There is currently no clear consensus on the impact of exercise on preventing hypertensive disorders in pregnancy, with studies showing a significant and insignificant decrease in risk,^157-159 or no protective role.¹⁶⁰ However, since physiological responses are similar between exercise and pregnancy, exercise before conception and in the prenatal stage could play a key role in the prevention or correction of poor early cardiovascular adaptation, which may be associated with poor pregnancy outcomes. Future randomized studies of larger cohorts are needed to investigate the impact of exercise and the type of exercise that provides the most benefit, as well as different modalities (low, moderate, high intensity), which may produce different adaptations.

Conclusions

There is an association between long-term pre-eclampsia, especially the early onset variant, and cardiovascular risk factors and cardiovascular events.^145,146 Most women with preeclampsia who give birth before term have signs of heart failure in asymptomatic stage B until one year after delivery.¹⁴⁷ Even if hypertension and proteinuria were resolved after birth, it seems that there is a greater risk of chronic hypertension, cardiovascular disease, cerebrovascular disease, and thromboembolism.^147,148 Health interventions have been proposed, for example, advice to stop smoking or lose weight (or avoid weight gain), and regular exercise, with a view to reducing future cardiovascular risk, but so far this is not based on evidence.

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