pih

Hypertensive Disorders in Pregnancy
Vol.2 No.6
back | home | register

Tanja Pejovic, M.D., Ph.D.
Department of Obstetrics & Gynecology
Yale University School of Medicine


INTRODUCTION

Hypertensive disorders are the most common medical complications of pregnancy, and the major cause of maternal and infant disease and death worldwide. They comprise two different entities: One (pregnancy-induced hypertension, PIH) appears for the first time during pregnancy and is reversed by delivery. The other (chronic hypertension), is a prexisting condition unrelated to but coinciding with pregnancy, which may be unmasked for the first time during pregnancy and which does not resolve with delivery.
Regardless of pregnant or non-pregnant state, hypertension is in many cases the result of small vessels' spasm (vasoconstriction). Therefore, the major risks to the fetus result from decreased placental perfusion leading to decreased supply of oxygen and nutrients necessary for fetal growth and well-being. Maternal risks include hypoperfusion of major organs such as kidney, liver, and brain. Hypertension may also lead to brain edema and hemorrhage, and to seizures.
Management of hypertensive disorders in pregnancy requires very careful maternal observation and measurement of fetal-placental function and fetal maturity, in order to balance maternal risks of continuing pregnancy against risk to the infant of premature extrauterine existance. Even mild hypertension may rapidly lead to catastophic complications such as placental abruption or seizures, that have no parallel in non-pregnant individual with mild hypertension. By timely recognition of the disease and treatment, these complications may be prevented. However, while therapeutic agents are useful, it is also essential to understand their pharmacokinetics and recognize possible side-effects to both mother and fetus.

CLASSIFICATION

The terminology used to classify hypertensive disorders of pregnancy has been inconsistent and confusing. More than 60 names in English and 40 in German have been applied to these conditions. In the past, hypertensive disorders of pregnancy were commonly called toxemia of the pregnancy, which reflected the opinion that these disorders resulted from circulating toxins. This theory is now known not to be true, and the term toxemia has been abandoned by the medical community. Therefore, the Committee on Terminology of the American College of Obstetricians and Gynecologists (ACOG; Hughes, 1972) prepared a classification system for hypertension in pregnancy which was approved by the National Institutes of Health (NIH) in 1990, and which is now in use all over the world.

Chronic hypertension

The ACOG Committeee defines hypertension as blood pressure higher than 140/90. Chronic hypertension is defined as hypertension present before pregnancy or diagnosed before the 20th week of gestation. Hypertension that persists beyond 42nd day postpartum is also classified as chronic hypertension.

PIH: preeclampsia and eclampsia

The definition/diagnosis of preeclampsia includes: elevated blood pressure, the abnormal presence of proteins in the urine (proteinuria), and leakage of blood plasma into the tissues (edema). The blood pressure in preeclampsia must either (a) exceed by 30mmHg systolic and 15 mmHg diastolic the blood pressure before 20 gestational weeks or (b) be more than 140/90 after 20 weeks. As it is sometimes difficult to define elevated blood pressure (e.g. when systolic pressure is elevated, but diastolic normal), Page and Christianson (1976) advocated the use of mean arterial pressure (AMP) as a criterion for elevated blood pressure in pregnancy: MAP= {Syst BP+ (2 x diastol BP)}/3.
Proteinuria is defined as excretion of 0.1g/l of proteins in a randomly sampled urine specimen or 0.3g/l in a 24hr specimen. Edema is diagnosed by tissue swelling and/or increase in body weight due to water retention.

Preeclampsa may be classified as mild or severe. One or more of the following may indicate severe preeclampsia:

(a) the blood pressure is > 160 systolic or >110 diastolic, registered on at least two occassions at least 6 hours apart in a patient at bed rest
(b) proteinuria is > 5g/24h
(c) Urine production is < 400 ml/24h (oliguria)
(d) Cerebral/visual disturbances
(e) Epigastric pain
(f) Pulmonary edema, cyanosis
(g) Impaired liver function
(h) Trombocytopenia

Criteria for mild preeclampsia include the following, documented on two occasions, 4 hr apart:

(a) blood pressure of 140/90 or MAP>105
(b) proteinuria > 0.3g/l in 24hr urine sample.

Eclampsia is preeclampsia accompanied by seizures: It has been known since Hippocrates' time as a convulsive disease occurring in pregnant women, but was not distinguished from epilepsy until the 19th century. However, the path from preeclampsia to eclampsia is highly variable: In some cases the preeclampsia is very mild, and seizures can occur even in a patient with only elevated blood pressure, or without proteinuria.

Transient hypertension is an elevated blood pressure after 20 weeks of pregnancy or in the first 24 hours postpartum, that is not associated with other signs of preeclampsia or chronic hypertension and which disappears 10 days after delivery.

Preeclampsia Superimposed upon Chronic Hypertension

This diagnosis is made in a pregnant patient with known hypertension when the baseline blood pressure increases by 30mmHg systolic and 15 mm Hg diastolic, or 20mmHg MAP, together with edema and proteinuria.

Pathophysiology of Preeclampsia-Eclampsia

The major pathophysiologic feature of preeclamsia-eclampsia is vasospasm. This concept, first introduced 1918 by Volhard, is based upon direct observation of small vessels in the retina, nail beds and bulbar conjuctiva, and histologic examination of various organs during preeclampsia. Vasospasm causes increased resistance to blood flow, leading to arterial hypertension and damage to the endothelium of blood vessels. The areas of damaged endothelium become sites of platelet and fibrinogen deposition and thrombus formation, which, together with hypoxia caused by vasospasm, weaken the vessel wall and lead to hemorrhage, necrosis and organ dysfunction.

One of the explanations for the generalized vasospasm in preeclampsia is increased vascular responsivity to normal concentrations of endogenous pressors (angiotensin II, norepinephrine, vasopressin)(Talledo et al., 1968). Similarly, women with chronic hypertension, who are refractory to angiotensin II between 21-25 gestational weeks, start to loose this refractoriness after 27 weeks (Gant et al., 1973). The blunted response to angiotensin II in normal pregnancy is probably caused by endothelial synthesis of prostaglandins (Cunningham and Lindheimer, 1992). Prostacyclin, one of the prostaglandins, is a very potent vasodilatator produced by the endothelium. Vessels of preeclamptic women and umbilical veins of their fetuses produce far less prostacyclin as compared with normal pregnancy (Dadak et al., 1982). Nitric oxide is another vasodilator produced by endothelium (EDRF, endothelium-releasing factor) which acts synergistically with prostacyclin (Moncada et al., 1991). Nitric oxide production is also decreased because of endothelial cell injury. Therefore it seems clear that endothelial injury and decreased production of vasodilatators play a major role in pathogenesis of pregnancy induced hypertension.

Maternal and fetal consequences of preeclampsia-eclampsia

Deterioration of maternal organs secondary to vasospasm and hypoperfusion is a direct consequence of pregnancy induced hypertension. Similarly, deterioration of fetal staus is caused by vasoconstriction and placental hypoperfusion.

Cardiovascular system

Blood pressure elevation in severe pregnancy induced hypertension constitues an acute threat to the mother. Pressures as high as 200/120 are sometimes encountered. Cerebral hemorrhage and cardiac decompensation are potential complications of such blood pressure increases, and heart failure is one of the most common causes of maternal death due to preeclampsia; it is rarely encountered in young women who are otherwise healthy. Circulatory collapse (sudden decrease in systolic blood pressure to less than 70mmHg) may occur few hours after delivery. Another serious complication is pulmonary edema as a part of generalized edema. However, pulmonary edema is far more frequently a consequence of treatment and not of PIH itself; typical causes of iatrogenic fluid overload are agressive replacement of fluids after cesarian section, and prolonged administration of oxytocin.

Cerebral involvement
Vascular resistance in cerebral vessels is unaltered in normal pregnancy, but is increased in 50% of women with PIH. This leads in some patients to cerebral hemorrhage, one of the common causes of death in women with PIH. Some patients with severe preeclampsia may have cerebral edema, which occurs by the same mechanisms as generalized or pulmonary edema. Headache, altered consciousness, and blurred vision are common symptoms of cerebral edema. They also typically precede eclamptic seizures.

Liver function

Liver involvement is seen in about 10% of women with severe preeclampsia: A variety of liver functions may be deranged (Chesley, 1978). Most commonly transaminases are mildly elevated, as are bilirubin levels. Liver functions usually return to normal once preeclampsia is treated by delivery of the fetus.

Renal function

Glomerular filtration rate increases in normal pregnancy and therefore the serum concentration of creatinine, urea, and uric acid decrease. In preeclampsia, vasospasm and glomerular endothelial swelling lead to a reduction of glomerular filtration rate of 25% below that of normal pregnancy. Serum creatinine is however rarely elevated in preeclampsia, but uric acid is commonly increased. In some studies, uric acid levels of more than 5mg/dl have been associated with poor fetal outcome (Redman et al, 1976).

Hematological changes

Most prominent hematologic changes involve plasma volume and hematocrit, clotting factors, and platelets. In severe preeclampsia there is a reduction in plasma volume which may be indicated by rise in hematocrit. In 20% of patients with severe preeclampsia there is evidence of increased consumption of coagulation factors (Pritchard et al., 1976).The best indicators of the activation of the clotting system are decreased concentrations of plasma antithrombin III (a subtance which inhibits coagulation by preventing reaction between thrombin and fibrinogen) and a decrease in the ratio of clotting factor VIII activity to factor VIII antigen. Low platelet count (< 150,000/mm ) is also a common finding in preeclamptic patients. Repeated platelet-count testing is an important aid in the management of established hypertensive disease in pregnancy.

The HELLP Syndrome

Recent reports have described a syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) in severe preeclampsia (Weinstein, 1982). Criteria for the diagnosis of this syndrome include: 1) hemolysis, defined by abnormal peripheral blood smear and increased bilirubin (>1.2mg/dl); 2) elevated liver enzymes, defined as increased alanine liver transferase (ALT>70U/L) and increased lactate dehydrogenase (LDH>600U/L); and as platelet count less than 100 000/ml. Not all women have all of these findings. It is essential to understand that this syndrome may develop even in women with mild preeclampsia , i.e. in women with no severe hypertension (Sibai et al., 1986). Patients may present with the syndrome either before the delivery or shortly thereafter. Usually patients present before term complaining of malaise, epigastric pain or pain under the right diaphragm, nausea and vomiting, and some symptoms similar to those of viral infection, and are often misdiagnosed as having some other medical condition. Pregnancies complicated by HELLP syndrome are associated with poor maternal and fetal outcome. Most HELPP patients require blood product transfusions and are at increased risk of developing acure renal failure, pulmonary edema, pleural effusions, and hepatic rupture. Moreover these patients are at increase risk for abruptio placentae and disseminated intravascular coagulopathy. During the course of the disease it is essential to establish fetal wellbeing by continuous fetal heart monitoring and ultrasound examinations. In the postpartum period, the majority of patients with HELLP syndrome manifest symptoms within 48 hours. Eighty percent of these patient were diagnosed with preeclampsia prior to delivery, while 20% have no such evidence before delivery or intrapartum. Patients with this syndrome should be treated at specialized obstetrical care centers. The first priority is to assess and stabilize the maternal condition, particulary to control bleeding and coagulation abnormalities. The next step is to evaluate fetal well-being using fetal heart monitoring and ultrasound examination. Then, a decision must be made whether immediate delivery is indicated. Amniocentesis may be recommended in patients at less than 34 weeks of gestation, but must be balanced against risks of bleeding complications. The presence of this syndrome is NOT an indication for cesarian delivery, which may be actually detrimental to both mother and the fetus. Patients with delayed resolution of HELLP syndrome after delivery are typically treated with fresh frozen plasma transfusions.


Placenta

In pregnancies complicated by preeclampsia there is an inadequate maternal response to placentation i.e. a fraction of spiral uterine arterioles fail to dilate in the same way as in normal pregnancy, thus decreasing the blood supply to fetus (Khong et al, 1986). Electron microscopic studies have shown characteristic damage to endothelial cells that is somewhat similar to that of vessels in transplanted but rejected kidney. This observation has led to suggestion that immunological mechanisms i.e., rejection of the fetus by maternal immune system, may be operative in preeclampsia (Kitzmiller and Benirschke, 1973).

Management of Preeclampsia

Delivery is the only cure for preeclampsia. The ultimate goal of treatment is always maternal safety first, then the delivery of a live, mature newborn. Beyond hospitalization for preeclampsia and the monitoring of blood pressure, biochemical tests, and fetal well-being, the major goal is prevention of eclampsia. The majority of eclamptic episodes occur in labor or early postpartum period. The agent of choice for seizure prevention is magnesium sulfate, which typically prevents seizures without sedating the mother. Magnesium sulfate is given intravenously. Normal magnesium concentration in serum is 1.8-2.0mEq/l; therapeutic concentrations for anticonvulsive purposes are 4-7mEq/l. At magnesium levels above 7mEq/L signs of toxicity appear (loss of patellar reflex). Excessive accumulation of magnesium can be fatal: Respiratory depression/arrest occur at levels of 10-15mEq/l, and cardiac arrest ensues when magnesium concentration reaches 30mEq/l. The major advantage of magnesium-sulfate is that it is very safe for the fetus and neonate (Pritchard and Stone, 1967).

Although at present there is no proven method to prevent preeclampsia, several studies have indicated a beneficial effect of low-dose (60-80mg) aspirin prophylaxis to prevent growth retardation (Imperiale and Petrulis, 1991). Aspirin reduces generation of platelet derived vasoconstrictors and thus alleviates the basic pathologic changes in pregnancy induced hypertension. However, the long term effects of aspirin induced inhibition of prostaglandin synthesis on fetal homeostasis are not known, and this type of therapy is reserved for women at high risk for development of preeclampsia.

Antihypertensive agents are not routinely given to women with preeclampsia, as there is no evidence that it improves fetal well-being or risk of seizures in the mother. Therapy is reserved for women with severe hypertension (blood pressures elevated to more than 160/110) to decrease risks of intracranial bleeding. Ideally, blood pressure should be lowered to mildly elevated levels to keep good placental perfusion. Alpha-methyldopa (Aldomet) is the preferred agent.

Labor is usually uneventful in preeclamptic women. Pain control by epidural anesthesia may be provided. The feared complications of this type of anesthesia are sympathetic blockade, pooling of blood and hypotension with compromise of placental perfusion and fetal stress.

Prognoses (mother and child)

The perinatal mortality rate is higher for infants of preeclamptic women (Plouin et al., 1986). Causes of infant death are placental insufficiency and placental abruption, leading to intrauterine death or prematurity (Naeye and Friedman, 1979). The perinatal mortality rate is highest in preeclampsia superimposed on already preexisting hypertensive disease. Growth restriction is also very common in infants of preeclamptic mothers and increases in severity with increasing maternal blood pressure (Tervila et al., 1973). However, by careful observation of intrauterine well-being, perinatal infant mortality rate has decresed in recent years.

Preeclampsia usually resolves promptly and completely after delivery. Proteinuria resolves within one week, and hypertension within two weeks. The risk of recurrent preeclampsia in subsequent pregnancies is 10-25% if the disease was diagnosed in the third trimester and as high as 60-70% if the disease was diagnosed in the second trimester.


REFERENCES

Chesley LC (1978): Hypertensive Disorders in Pregnancy. New York, Appleton-Century-Crofts.

Cunningham FG, Lindeheimer MD (1992): Hypertension in pregnancy. N Enlg J Med 326:927
Dadak C, Kefalides A, Sinzinger H, Weber G (1982): Reduced umbilical artery prostacyclin formation in complicated pregnancies. Am J Obstet Gynecol 144:792

Gant NF, Daley GL, Chand S et al (1973): A study of angiotensin II Pressor response throughout primigravid pregnancy. J Clin Invest 52:2682

Hughes EC (ed): Obstetric-Gynecologic Terminology. Philadelphia, FA Davis, 1972.

Imperiale TF, Petrulis AS (1991): A meta-analysis of low-dose aspirin for the prevention of pregnancy-induced hypertensive disease. JAMA 266:261

Khong TY, De Wolf F, Robertson WB, Brosens I (1986): Inadequate maternal response to placentation in pregnancies complicated by pre-eclampsia and by small-gestational age infants. Br J Obste Gynecol 93:1049

Kitzmiller JL, Benirschke K (1973): Immunofluorescent study of placental bed vessels in pre-eclampsia. Am J Obstet Gynecol 115:248

Moncada S, Palmer RMI, Higgs EA (1991): Nitic oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109

Naeye RL, Friedman EA (1979): Causes of perinatal death associated with gestational hypertension and proteinuria. Am J Obstet Gynecol 133:8

Page EW, Christianson R (1976) The impact of mean arterial blood pressure in the middle trimester upon outcome of pregnancy. Am J Obstet Gynecol 125:740

Plouin PF, Chatqllier G, Breart G et al (1986) Frequency and perinatal consequences of hypertensive disease of pregnancy. Adv Nephrol 57:69

Pritchard JA, Stone SR (1967) Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol 99:754

Pritchard JA, Cunningham FG, Mason RA (1976): Coagulation changes in eclampsia: their frequency and pathogenesis. Am J Obstet Gynecol 124:855

Redman CWG, Beilin LJ, Bonnar J (1976): Plasma urate measurement in predicting fetal death in hypertensive pregnancies. Lancer 1:1370

Sibai BM, Taslimi MM, El-Nazar A et al (1986) Maternal-perinatal outcome associated wuth the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155:501

Talledo Oe, Chesley LC, Zuspan FP (1968) Renin-angiotesin system in normal and toxemic pregnancies. III. Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. Am J Obstet Gynecol 100:218

Tervila L, Goecke C, Timonen S (1973) Estimation of gestosis of pregnancy (ERH-gestosis). Acta Obstet Scand 52:235

Weinstein L (1982): Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142:159