|Year : 1999 | Volume
| Issue : 3 | Page : 298-312
|Hypertension in Pregnancy
Department of Obstetrics and Gynecology, Catholic University of Rome, Largo Gemelli, Rome, Italy
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|How to cite this article:|
Ferrazzani S. Hypertension in Pregnancy. Saudi J Kidney Dis Transpl 1999;10:298-312
| Introduction|| |
Hypertensive disorders may occur in about 3-10% of all pregnancies., These disorders remain a major cause of perinatal and maternal morbidity and mortality worldwide, because of complications such as preeclampsia, eclampsia, fetal growth retardation, premature birth or abruptio placentae. 
The incidence of hypertensive disorders in pregnancy varies among different hospitals and countries. There are several reasons for these differences, including the terminology used to classify the hypertensive disorders of pregnancy that has been often confusing and inconsistent, making comparison of studies difficult and sometimes impossible.
However, women with these disorders fall into four major categories: women with preeclampsia, chronic hypertension, chronic hypertension with superimposed preeclampsia, and gestational hypertension. ,, There is a difference in the outcome of these disorders.
It has been consistently noted that hypertension in the presence of proteinuria indicates more severe fetal and maternal consequences ,,, [Figure - 1].
| Definitions|| |
The most important criterion used to define hypertension in pregnancy is an increase by at least 30-mmHg systolic or 15 mmHg diastolic blood pressures above base line. Readings of 140/90 mmHg after 20 weeks gestation, if prior blood pressure is unknown, are considered sufficient for the diagnosis of preeclampsia. Diastolic blood pressure > 90 mmHg stable over four hours has the same value as only one measurement of 110 mmHg in the diagnosis of preeclampsia. Maternal posture and position of the arm used for measurement influence systolic and diastolic blood pressure. The blood pressure during pregnancy should be measured in a semirecurabent position with the arm roughly at heart level. The Joint (U.S.) National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure recommends using the fifth Korotkoff sound for determining diastolic blood pressure during pregnancy.  In contrast, most European and Australian physicians use phase IV (muffling of sound). The International Society for the Study of Hypertension in Pregnancy has recommended, until now, using phase V (disappearance of sound), based on the fact that it is more reproducible when measured in pregnancy. In general, most clinical trials of hypertension in pregnancy used phase IV for diastolic blood pressure measurements to avoid the problems of phase V recordings.14 A recent report by members of the Working Group on High Blood Pressure in Pregnancy recommended recording both phases throughout pregnancy.  Therefore, there has been considerable controversy over whether Korotkoff phase IV or phase V should be used to measure the diastolic blood pressure. More recently, it has been suggested that both phases should be measured but that phase V reading should be used for clinical trials and diagnosis. ,
Edema is defined as clinically evident diffuse subcutaneous, often generalized, fluid accumulation. However, fluid retention can also be manifest as a rapid increase in weight without evidence of edema.
Proteinuria is defined as a concentration of urinary proteins of 0.1 g/L or more in at least two random urine specimens collected 4 hours or more apart; or as 0.3 g/L in a 24hour collection in the absence of urine infection.
| Preeclampsia|| |
Preeclampsia is a form of hypertension that is unique to pregnancy. The incidence ranges between 10 and 15% in primigra vidas and between 5.7 and 7.3% in multiparas. ,, The incidence is further increased in patients with twin pregnancies and previous preeclampsia. , There are many reported predisposing factors related to preeclampsia: maternal age, familial aggregation, race, smoking, social economic level, diet, seasons and climate, and geographical area. 
The etiology of preeclampsia is unknown. Many theories have been suggested, but most of them did not withstand the test of time. Only the following theories are still under consideration: abnormal trophoblast invasion, coagulation abnormalities, vascular endothelial damage, cardiovascular maladaptation, immunologic phenomena, genetic predisposition, dietary deficiencies or excesses.
During normal pregnancy impressive physiologic changes occur in the uteroplacental vasculature in general and in the cardiovascular system in particular. These changes are most likely induced by the interaction of the fetal allograft with maternal tissue. The development of mutual immunologic tolerance in the first trimester is thought to lead to important morphologic and biochemical changes in the systemic and uteroplacental maternal circulation. Pregnancies complicated by preeclampsia demonstrate inadequate maternal vascular response to placentation. In these pregnancies, the above vascular changes are usually restricted only to the decidual segments of the uteroplacental arteries. The myometrial segments of the spiral arterioles are left with their musculoelastic architecture, thereby rendering them unresponsive to hormonal influences. , This defective vascular response to placentation is due to inhibition of the second wave of endovascular trophoblast migration that normally occurs from 16 weeks of gestation. These pathologic changes may have the effect of curtailing the increased blood supply required by the fetoplacental unit in the later stages of pregnancy, and they may be responsible for the decreased uteroplacental blood flow seen in most cases of preclampsia. 
Preeclampsia is also associated with vaso-spasm, activation of the coagulation system, and abnormal hemostasis. There is good evidence from many studies that preeclampsia is accompanied by endothelial injury, increased platelet activation with platelet consumption in the microvasculature and excessive clotting activity. It has been found that preeclampsia is associated with high fibronectin and low antithrombin III.  Therefore, some authors suggest that endothelial cell injury plays a central role in the pathophysiology of preeclampsia. , The pathogenesis of preeclampsia may be related to abnormal prostaglandin production and metabolism in the uteroplacental and umbilical vasculature. However, it should be noted that the increased throm-boxane A2/ prostacyclin ratio, observed by various investigators in different materials and fetal tissues, may be an effect rather than a cause of preeclampsia. 
There is evidence that lipid peroxides and free radicals may be important in the pathogenesis of preeclampsia. ,, Some pauthors demonstrated that elevated plasma concentration of free radical oxidation roducts may precede the development of preeclampsia.  Several studies reported lower serum antioxidant activity in patients with preeclampsia compared to normotensive pregnant women. , The role of nitric oxide, a potent vasodilator released by endothelial cells, in the pathogenesis of preeclampsia has been recently studied. Many authors found that circulating levels of nitrite are decreased in patients with this disorder, supporting the concept that diminished nitric oxide synthesis may contribute to the pathophysiologic changes of preeclampsia. 
Inherited thrombophilia, in addition to thrombosis is associated with poor obstetric outcome, including recurrent miscarriage and preeclampsia. It has been found that 25% of women with history of severe early onset preeclampsia had protein S deficiency and 16% had activated protein C resistance (APCR) deficiency. More recently, molecular or protein anomalies of thrombophilia were found in 68% of women with severe preeclampsia. These findings suggest that women who develop severe preeclampsia should be tested for thrombophilia. 
Preeclampsia is a clinical syndrome that embraces a wide spectrum of signs and symptoms that may develop alone or in combination. Elevated blood pressure is the most important sign for diagnosis of the disease. However, recent evidence suggests that in some patients the disease may manifest itself in the form of either capillary leak (edema, proteinuria) or a spectrum of abnormal hemostasis with multiple organ dysfunction.
Diagnosis and severity of preeclampsia are generally based on maternal blood pressure measurements. It should be emphasized that the presence of pathologic edema, proteinuria, or other associated symptoms of preeclampsia such as persistent headache, visual symptoms, or epigastric are more important than the absolute level of blood pressure in establishing the diagnosis of preeclampsia.
The presence of proteinuria is usually determined by the use of either dipstick or protein-to-creatinine ratio in random urine samples. The diagnosis of severe preeclampsia based on dipstick measurements in urine sample (>3+) is not adequate for such a diagnosis. 
Detection of women at risk and prevention of preeclampsia
A review of the world literature reveals biochemical tests have been recommended to predict or identify the patient at risk for the future development of peeclampsia.  The value of mean arterial pressure in predicting preeclampsia was investigated by Chelsey and Sibai,  as well as by Villar and Sibai.  The same authors described the predictive value of substances that can be measured in maternal plasma, serum or urine. Some of the substances evaluated included cations, hormones, prostaglandin, metabolites, various parameters of coagulation and hemostasis, and uric acid.  The results of the pooled data for the various tests and the lack of agreement between them suggest that none of these clinical tests is sufficiently reliable for use as a screening test in clinical practice. 
There are several reports and clinical trials describing the use of various methods to prevent or reduce the incidence of preeclampsia. Since the etiology of the disease is unknown, these methods were used in attempts to correct theoretical abnormalities in preeclampsia. 
Laboratory findings in preeclampsia
Women with preeclampsia may exhibit a variety of signs and symptoms ranging from minimal blood pressure elevation to derangement of multiple organ systems. The renal, hematologic, and hepatic systems are most likely to be involved. Renal plasma flow and glomerular filtration rate increase during normal pregnancy. These changes are responsible for the fall in serum creatinine, urea and uric acid concentrations. In preeclampsia, vasospasm and glomerular capillary endothelial swelling lead to an average reduction in glomerular filtration rate of 25% below the level in normal pregnancy. 
Serum creatinine is somewhat elevated in preeclampsia, but uric acid is commonly increased.  The clinical significance of elevated uric acid levels in preeclampsia has been confusing.
The liver is not primarily involved in preeclampsia, and hepatic involvement is seen in only 10% of women with severe preeclampsia.  When liver dysfunction occurs, mild elevation of serum transaminase is common.  Bilirubin is rarely increased in preeclampsia but, when elevated, the indirect fraction predominates.
There are numerous studies evaluating the hematologic abnormalities in women with preeclampsia. Plasma fibrinopeptide A and D-dimer level, and circulating thrombin-antithrombin complexes are higher in preeclamptic than in pregnant normotensives. In contrast, plasma antithrombin III activity is decreased in women with preeclampsia. , Plasma fibrinogen levels are rarely reduced in women with preeclampsia in the absence of abruptio placentae.  Thrombo-cytopenia is the most common hematologic abnormality in women with preeclampsia. Its incidence depends on the definition and severity of the disease process, and the presence or absence of abruptio placentae. , Recently, Leduc et al concluded that fibrinogen levels, prothrombin time, and partial thromboplastin time should be obtained only in women with a platelet count of less than 100,000/µL. 
The HELLP syndrome
This syndrome consists of elevated liver enzymes and low platelets in the context of severe preeclampsia. Thrombocytopenia (platelet count < 100,000/µL) has been the most consistent finding among the various reports. In addition, there are considerable differences regarding what constitutes an abnormal level of serum glutamicoxaloacetic transaminase or bilirubin.  Lactic dehydrogenase is increased (>600 IU/L) and an abnormal peripheral blood smear is present. The incidence of HELLP syndrome in preeclampsia has ranged from 2 to 12 percent.  The true incidence is unknown, because there are some differences in diagnostic criteria. Usually patients present with epigastric pain (65%), some have nausea or vomiting (50%) and others have non-specific symptoms.  It is important to indicate that severe hypertension is not a constant or even a frequent finding in HELLP syndrome. Sibai et al  studied a group of 112 patient, and they found that 66 percent of them had a diastolic blood pressure of at least 110 mmHg, 14.5% percent had a diastolic blood pressure of less than 90 mmHg. The HELLP syndrome may develop antepartum or postpartum. In the postpartum period, the time of onset of the manifestations ranged from a few hours to seven days, with the majority developing within 48 hours postpartum. The optimal management of this syndrome is controversial. Some European authors, in contrast to American, suggest a conservative therapy in order to delay the time of delivery.  In a large series of patients, they did not find an increased incidence of maternal complications.
Mangement of preeclampsia
The most effective therapy for preeclampsia is delivery. In pregnancies at or near term (after 37 weeks of gestation), labor should be induced, under intravenous magnesium sulfate to reduce the risk of convulsions. In pregnancies with preeclampsia far from term, the decision of whether to deliver a preterm infant or to temporize (expectant management) is based on the disease severity and the fetal gestational age. 
The optimal management of mild preeclampsia remote from term (<37 weeks' gestation) is controversial about the need of hospitalization and the use of antihvpertensive drues. Sibai et al.  limit out patient management to women with less than 1 g/day of proteinuria and found that perinatal outcome was not improved by using antihypertensive therapy. In the past, diuretics were used to treat hypertension in pregnancy; however, they have no proven beneficial effect. 
In severe preeclampsia there are increased rates of perinatal mortality and increased risks of maternal morbidity and mortality. The therapeutic objective for treatment of severe hypertension is to prevent maternal cerebrovascular accidents and congestive heart failure with maintenance of cerebral autoregulation and to prevent jeopardizing uteroplacental blood flow.  There is a universal agreement that all patients with preeclampsia diagnosed after 34 weeks' gestation should be delivered. In this situation, appropriate management consists of preventing convulsions, control of maternal blood pressure (systolic blood pressure below 160 mmHg or diastolic blood pressure below 110 mmHg) followed by delivery.  In the presence of a preterm" infant (<36 weeks' gestation) the mother should be delivered in a tertiary care center with a neonatal intensive care unit.
There is disagreement about management of patients with severe preeclampsia prior to 34 weeks of gestation. Antihypertensive agents, diuretics, sedatives and chronic parenteral magnesium sulfate can be used as temporizing measures.  However, prompt delivery is indicated for the presence of imminent eclampsia, multiorgan dysfunction or fetal distress.  Magnesium sulfate is the drug of choice for therapy and prophylaxis of convulsions. It does not cause significant maternal or neonatal central nervous system depression when used properly.  Guidelines for management of severe preeclampsia are described in [Figure - 2].
Studies concerning preeclampsia in the puerperium are generally limited to single case reports. Ferrazzani et al found that normalization time of preeclampsia was longer than in gestational hypertension [Table - 1]. In preeclampsia, the longer time to normalization of blood pressure might reflect the recovery time of the endothelial damage. ,
| Chronic Hypertension|| |
Maternal risks associated with chronic hypertension include superimposed preeclampsia or eclampsia, deterioration of renal function, cerebrovascular accidents, congestive heart failure and hemorrhage secondary to placental abruption. These events are very unusual in pregnant women with mild chronic hypertension,,, and are seen most often in patients with more severe degrees of hypertension. , Nevertheless, the patients should be aware of the increased risk of superimposed preeclampsia and associated complications as well possible exacerbation of preexisting renal disease or systemic illnesses. On the other hand, they should be also informed of the high likelihood of a favorable outcome in most cases of mild to moderate essential hypertension.
Fetal and neonatal effects of chronic hypertension include increased prevalence of intrauterine growth retardation, prematurity and perinatal mortality. It is helpful to inform women before pregnancy of possible adjustments in life-style that may be necessary during pregnancy, i.e. the possibility that restricted activity, bed rest, or even hospitalization may be needed.
In case of elevated blood pressure before pregnancy, it is important to perform a careful diagnosis of essential or secondary hypertension. This is also true for women who develop hypertension before 20 weeks of gestation. Most of them have, or will have, essential hypertension. Although the majority of pregnant patients with elevated blood pressure will have uncomplicated essential hypertension, some will have secondary causes including renovascular hypertension, parenchymal renal disease, pheochromocytoma, Cushing's syndrome, primary hyperaldosteronism, hyperthyroidism and coarctation of the aorta. The presence of renal insufficiency (serum creatinine >200 µmol/L or >180 µmol/L according to various authors), especially if accompanied by pregestational hypertension, tends to be complicated by marked exacerbation of blood pressure during pregnancy, premature delivery and deterioration of maternal renal function.,,, Pheochromocytoma, although rare, has a propensity to manifest, or be activated, by pregnancy. It is associated with a maternal mortality which approaches 50% when undiagnosed prior to the onset of labor. ,,
Renal, cardiac and/or cerebrovascular disease is unusual in women of childbearing age with chronic hypertension, but these complications do occur and must be identified, as they are associated with increased risk for both mother and fetus. This may be especially true in pregnant women over 40 years of age in whom hypertension may have been present for more than a decade.
The blood pressure of chronically hypertensive women is variably altered by pregnancy.,,,, Nearly half of them experience a decrease of blood pressure during the midtrimester with a risk of later exacerbation in less than 10%. Often the decrease is to levels well into the normal range. This fact is of importance for two reasons: a) the presence of chronic hypertension may be masked in the pregnant women seen for the first time in the second trimester, b) anticipation of this decrement may obviate the need for antihypertensive drugs during early pregnancy in the woman with mild to moderate essential hypertension. The other half of the hypertensive women will fail to decrease blood pressure in the second trimester; blood pressure actually increases in one third of them. These last two groups are at the greatest risk of severe exacerbation of hypertension during the third trimester. ,,
The reported incidence of abruptio placentae ranges between 0.45 to 10%, depending on the duration and the severity of the hypertension, 0.45-2% for mild uncomplicated hypertension and 2.3-10% for patients with complicated severe hypertension.  ' Deterioration of renal function, cerebrovascular accidents and congestive heart failure are very unusual in pregnant women with mild chronic hypertension. These complications are seen most often in patients with severe degrees of chronic hypertension and are often associated with increased maternal mortality and morbidity. Most of the complications have been reported in elderly multiparous patients with severe hypertension early in pregnancy and in those with associated medical and obstetric complications.,,,,,,,,,,
Fetal and neonatal effects of chronic hypertension in pregnancy include increased incidence of intrauterine growth restriction (10-15%), prematurity (25-30%), and perinatal mortality (10-25%). As is the case for the mother, fetal jeopardy is greatest in those women with the most marked elevation of blood pressure and especially in those who develop superimposed preeclampsia.,
The severity of chronic hypertension seems to correlate with the risk of superimposed preeclampsia, ranging from 10% in pregnant women with mild chronic hypertension to nearly 50% in those with severe hypertension. ,
The hazards of years of chronically elevated blood pressure in non-pregnant patients differ substantially from those incurred over a period of nine months during pregnancy, and thus the rationale used to treat hypertension in non-pregnant populations cannot be applied during gestation.
The majority of women with chronic hypertension in pregnancy have mild to moderate elevations of blood pressure (about 95%), and therefore the risk of acute cardiovascular complications is extremely low. Some studies on chronic hypertension demonstrated that treatment of diastolic blood pressures 105 to 114 mmHg in elderly men decreased cardiovascular morbidity in just 10 months. Patients with diastolic pressures 95 to 104 mm Hg showed benefits of therapy only after five years had elapsed. , Therefore, if results from men could be applied to pregnant women, no maternal benefits from antihypertensive therapy for mild chronic hypertension could be expected during the nine months of pregnancy.
For the small number of women who have severe hypertension, the increased risk of cerebral hemorrhage, cardiac failure, and myocardial infarction needs close monitorring and aggressive treatment during pregnancy. The objective in treating a pregnant woman with chronic hypertension is to reduce the short-term risks to the mother of elevated blood pressure while avoiding therapeutic maneuvers that compromise fetal well being. The fetal and maternal benefits of antihypertensive medications are well documented in the treatment of severe chronic hypertension. ,,,,,,,,,,,,
Although there is increased risk of perinatal morbidity and death when the mother has chronic hypertension, most pregnancies in these women result in healthy, full term infants. Women with chronic hypertension are at increased risk of development of superimposed preeclampsia, and there is evidence that most of the increased perinatal morbidity and death associated with chronic hypertension is attributed to this complication. , However, some studies showed that chronic hypertension without super-imposed preeclampsia have the same perinatal outcome of normotensive pregnancy. , Other studies reported a higher perinatal loss in uncomplicated pregnancies with chronic hypertension, especially with higher levels of blood pressure. ,
There are few adequate studies concerning teratogenicity, direct fetal toxicity, effects on uteroplacental blood flow, influences on the ability of the fetus to respond to hypoxic stress and long-term impact on neurobehavioral development, consequent to the administration of antihypertensive medications to mothers with chronic hypertension. Therefore, the use of those agents that have been studied thoroughly and/or have been in use in pregnant patients for long time is recommended. Physicians should never be pioneers in using new drugs in pregnancy.
Several studies suggest but not conclusively demonstrate fetal benefits of treating mild to moderate hypertension during pregnancy.  Although, given the potential hazards of antihypertensive medications, treatment of mild-moderate hypertension must be undertaken cautiously, weighing the risks and benefits of treatment for both mother and child at all times. Excessive reduction of blood pressure is to be avoided, and conservative approach is recommended.
The U.S. National Institute of Health Working Group ,,,,,,,,,, has recently advised initiating drug treatment of uncomplicated chronic hypertension during pregnancy when phase V diastolic levels are >100 mmHg (a value similar to phase IV levels of 110 mmHg suggested by others ,), a recommendation that is believed reasonable by most authors.
According to some authors, if a patient receiving antihypertensive agents is counseled prior to pregnancy or in the first trimester, it should be better to make an attempt to stop all drugs, since little is known about the teratogenicity of hypotensive agents. In addition, the hypotensive effect of early gestation will often lower blood pressure below levels requiring drug treatment. In the patient in whom continued drug therapy is deemed necessary (baseline moderate to severe hypertension or the presence of renal disease or diabetes mellitus) it is preferable to replace current medication with alfamethyldopa. The antihypertensive drugs mainly used in the treatment of chronic hypertension in pregnancy are shown in [Table - 2].
| Chronic Hypertension with Superimposed Preeclampsia|| |
There is considerable disagreement regarding the incidence of superimposed preeclampsia in patients with chronic hypertension. The reported incidence has ranged from 4.7-52%,,,, with differences related to the population studied, the severity of hypertension at the time of pregnancy, and the diagnostic criteria used for superimposed preeclampsia. In addition, some pregnant chronic hypertensive women may have silent, undiagnosed chronic renal disease and may experience an increased urinary protein excretion with advancing gestation, particularly in the third trimester. 
For patient with severe hypertension in the first trimester, the reported incidence of superimposed preeclampsia ranged from 28-52% and was unaffected by the use of antihypertensive medications.  For patients with mild hypertension early in pregnancy, the reported incidence was as low as 4.7%. 
| Gestational Hypertension|| |
Late or transient or gestational hypertension is defined as the development of elevated blood pressure occurring antepartum, in labor, or in the first 24 hours postpartum without other signs of preeclampsia or preexisting hypertension. The blood pressure must return normal within 10 days after delivery. Generalized edema is common in normal pregnancy, although it does not occur as frequently and is not as marked as when associated with preeclampsia.
Gestational hypertension may often become chronic hypertension, a disease that requires one or two decades before its manifests. It might be the first symptom of preeclampsia or develop within days or weeks. Therefore, if a diagnosis of preeclampsia cannot be excluded, it is most appropriate to manage the patient as if she had preeclampsia. 
The causes of gestational hypertension and the risk factors associated with it are unknown. Except of nulliparity and previous history of preeclampsia in multiparas, few other risk factors are agreed upon.
The pattern of the normalization time in gestational hypertension has been investigated in rare studies.  When compared with preeclampsia, the interval between delivery and the return to normal blood pressure is quite shorter. The explanation for this pattern might be that gestational hypertension probably includes a sample of mixed disorders having in common the symptom of hypertension.  Furthermore, gestational or transient hypertension can be a predictor of essential (genetic) hypertension.
| Conclusions|| |
In the present state of knowledge, the most important problems associated with hypertensive disease in pregnancy are the fetal and maternal morbidity and mortality respectively associated with severe preeclampsia and premature delivery, eclampsia and the HELLP syndrome. Our objective is to identify the factors that distinguish between women at low risk and those at high risk of developing hypertensive complications, and to detect the disease as early as possible in order to plan a rational antenatal care and maternalfetal monitoring.
| Acknowledgement|| |
The author thanks Dr. Carmen Trivellini and Dr. Giorgia Soreca for their precious contribution, without which it would have been impossible to write this manuscript.
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Department of Obstetrics & Gynecology, Catholic University of Rome, Largo Gemelli 8, 00168, Rome
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