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Abstract
Hypertensive disorders of pregnancy are common and require special care to prevent maternal and fetal morbidity and mortality. Hypertension during pregnancy may result from several distinct processes. While the clinical presentations of these conditions often overlap, their pathophysiology and management differ. Since the symptoms of preeclampsia, the most dangerous disorder, are variable, overdiagnosis is appropriate. Chronic hypertension complicates 5% of all pregnancies and is becoming more common due to delayed child bearing. The exact cause of hypertensive vascular disease remains elusive so far, despite intensive research, and thus requires special attention. In the present review, some of the major aspects of the disease in relation to diagnosis and possible treatment will be discussed.

Introduction
Hypertension during pregnancy has always been a fascinating subject of study. Hypertensive disorders complicating pregnancy are common and form one of the great triad along with hemorrhage and infection that continues to be responsible for large number maternal deaths.

The incidence of hypertension occurs in well over 6% to 8% of all pregnancies,^1-3 and hypertensive disorders of pregnancy are the leading causes of maternal and perinatal mortality in developed countries.^2,4,5 As many as 20% of primigravidas (women for the first time) may develop hypertension, and it was observed by Duennoelter et al. that young teenaged primigravidas are at high risk for preeclampsia.⁶ The literature regarding the classification is controversial, because often it is difficult to differentiate clinically among preeclampsia, essential or secondary hypertension, renal diseases, and a combination of these separate entities. There have been observations of 58%, when a nephrologist and obstetrician participated in the study, and the diagnosis could be confirmed only in 25% of primigravidas when kidney biopsies were performed. More often than not, the clinical diagnosis was wrong in multiparous patients when edema and proteinuria were taken into consideration, and surprisingly large number of patients had unsuspected primary parenchymal renal disease.

How pregnancy per se incites or aggravates hypertensive vascular disease remains elusive, despite decades of intensive research; and these disorders remain among the most important unsolved problems in obstetrics.

Definition
Since arterial pressure falls in the second half of the first trimester, by 12 to 20 weeks of gestation, 2% women represents blood-pressure (BP) levels of 140/90 or higher and 0.1% of 170/110 mm Hg. The relationship between prepregnancy and early pregnancy has not been defined, but the gestational fall in pressure may be exaggerated, so that severe chronic hypertension ceases to be apparent by 12 weeks. Later in pregnancy, the arterial pressure tends to rise towards its nonpregnancy level. Many chronically hypertensive women may normally cross this threshold simply because they are close to it. Henceforth the pregnancy-induced hypertension may be defined as:

1. Detection at a time beyond 20 weeks of pregnancy.
2. Multiple reading of BP >140/90 mm Hg. Rise in systolic B.P. >30 mm Hg. Rise in diastolic BP 15 mmHg.

During pregnancy, the diastolic BP is generally included in the diagnostic criteria, and if above 84 mmHg at any gestational age then the possibility of fetal mortality may increase. Lindheimer has recommended the classifications used by the American College of Obstetricians and Gynecologists as the most practical and concise, and these are of four types:

1. (a) preeclampsia: increased blood pressure beyond 20 weeks of pregnancy usually associated with proteinuria and edema
Today, most authorities believe that edema is such a common finding in pregnancy, its presence should not validate the diagnosis of preeclampsia any more than its absence should preclude the diagnosis (National High Blood Pressure Education Program 1990).

1. (b) eclampsia: condition associated with occurrence of seizures not accountable by any coincidental neurological disease such as epilepsy in a patient of preeclampsia

2. chronic hypertension of all causes: when hypertension presents or is diagnosed before 20 weeks of gestation, or persists beyond 6 weeks postpartum

3. chronic hypertension with super imposed preeclampsia or eclampsia: defined as preeclampsia or eclampsia in women with chronic hypertension, vascular, or renal disease

In this condition proteinuria appears in the patient who is known to be hypertensive before pregnancy.

4. late transient or gestational hypertension: may be recognized by elevation of blood pressure near term without other sign of preeclampsia or coincidental hypertension and may disappear after delivery

This usually recurs during subsequent pregnancy.⁷

Maternal complications with hypertension in pregnancy:
There are several risks associated with hypertension in pregnancy that affect both mother and fetus. The majority of women with chronic hypertension have essential hypertension, and their pregnancies are usually uncomplicated and successful. However, secondary hypertension due to such factors as endocrine and renal causes has a poor prognosis. High maternal deaths have been documented with scleroderma and polyarteritis nodosa. Preeclampsia and eclampsia are syndromes that affect virtually all maternal organ systems. According to Robert, the widespread presence of hemorrhage and necrosis suggests reduced perfusion rather than the gross vascular disruption that would be expected with mechanical damage from high blood pressure.⁸ In the brain, the most frequent lesion is petechial hemorrhage, and the subendocardial necrosis found in this disorder is identical to that seen in hypovoluemic shock. The primary pathological changes in the kidneys take place in the glomerular capillary endothelial cells, which enlarge greatly, leading to glomeruloendotheliosis. These changes support the idea that preeclampsia/eclampsia are unique to pregnancy, and special attention is needed to protect from vascular endothelial cell damage in these disorders. During eclampsia/preeclampsia, the mother may suffer from accelerated hypertension, left ventricular dysfunction cerebral haemorrhage, hypertensive encephalopathy, and disseminated intravascular coagulation. The fetus is at the risk of preterm delivery, intrauterine growth retardation, asphyxia, and abruptio placentae.

Preeclampsia
Several risk factors for preeclampsia have been identified viz. twin pregnancy, hydatiform mole, and gestational diabetes. Placental ischemia, excessive uterine stretch, damage to chronic villi, and deciduas have been known to secrete extra renin, with fibrinoid necrosis of glomerular tuft and endotheliosis. All of these have been identified as possible causes for hypertension. The condition may advance towards eclampsia once renal damage leads to significant damage of the endothelial basement membrane, resulting in proteinuria.

Hemodynamic adaptation
Circulatory changes are profound during normal pregnancy. Normally, pregnancy represents a low–blood pressure state with marked vasodilation that reduces peripheral vascular resistance, but expanded fluid volume increases cardiac output.⁹ Renal blood flow also increases with marked elevation of the renin-angiotensin system. In preeclampsia, the basic abnormality appears due to vasoconstriction that reduces the intravascular capacity even more than the blood volume. Thus, the resulting hypoxia due to vasospasm may be responsible for changes in tissue structure and function.

Pathogenesis
Though the exact mechanism of action continues to be elusive, the following factors may contribute to pregnancy induced-hypertension:

1. Abnormal trophoblast invasion: Normally, trophoblastic tissues invade spiral arteries and convert them into deltas, which is known to improve fetoplacental circulation. But deficient trophoblastic migration and expression of adhesion molecules form trophoblastic cells that may affect curtail the increased blood supply required by the fetoplacental unit in the later stages of pregnancy.¹⁰

2. Uteroplacental hypoperfusion: The decreased uteroplacental blood flow and the clearance of steroid precursors for the synthesis of estrogens by the placenta, used as an indicator of placental perfusion, supports uteroplacental hypoperfusion.

3. Prostaglandin imbalance due to defective production of vasoconstricting and vasodilating prostaglandin: Vasoconstriction and vasodilation may affect the pathophysiology of preeclampsia as well as eclampsia. Vascular constriction causes resistance to blood flow and accounts for the development of arterial hypertension. Goodman et al. reported elevated concentration of vasodilating prostaglandins during normal pregnancy.¹¹ Elevated concentration of thromboxane along with decreased concentration of prostacyclin and PGE2 were observed in preeclamptic women, which resulted in vasoconstriction, platelet aggregation, and sensitivity to infused angiotensin II.¹²

4. Endothelial dysfunction: The deficiency in the trophoblast invasion of the placental-bed spiral arteries leads to a poorly perfused fetoplacental unit, causing the secretion of a factor or factors into maternal circulation. These may lead to activation of the vascular endothelium with the clinical syndrome resulting in widespread changes in endothelial cell function.^10,13,14

5. Inappropriate intravascular coagulation: Platelets play a crucial role in the pathophysiology of preeclampsia by promoting vascular damage and obstruction, leading to tissue ischemia. Redman concluded that preeclampsia is a trophoblast-dependent process that is obviously mediated by platelet dysfunction.¹⁵

6. Unexplained immunologic injury probably due to exposure to a foreign antigen: Immunologic factors may play an important role in the development of preeclampsia,¹⁶ as a marked reduction in C3 and C4 components in preeclampsia have been found, suggesting increased complement use in the acute phase of the disease.¹⁷ Hofmeyr et al. reported that C4 concentration decreased only in hypertensive pregnant women with proteinuria, whereas other findings showed the occurrence of neutrophil activation in preeclampsia localized in part of the placental bed.¹⁸

Perhaps the most popular concept in the pathophysiology of preeclampsia is suboptimal unteroplacental perfusion leading to decreased fetoplacental prostacyclin. On one hand, this leads to decreased renal rennin, resulting in decreased aldosterone with a consequent reduction in plasma volume. On the other hand, an elevated maternal thromboxane/prostacyclin ratio brings about increased angiotensin II sensitivity, arterial vasoconstriction with subsequent elevation of blood pressure, and endothelial cell injury, leading to activation of intravascular coagulation and venous vasoconstriction resulting in edema.

Management
The objectives of management of hypertension in pregnancy are:

· measures to ensure maternal and fetal safety
· improvement of uteroplacental blood flow
· prevention of eclampsia.

The principle includes careful antenatal monitoring; assessment of biophysical severity; safe and effective use of antihypertensive drugs; fetal monitoring; and, in extreme situations, termination of pregnancy. It has been documented that even a modest increase in blood pressure during pregnancy is clearly associated with greater risk for the fetus, and whether it can be reduced by pharmacological intervention remains to be established. Data analysis of randomized trials of various drugs versus no treatment showed a lower risk of fetal or neonatal death in the treated group. These potential benefits must be weighed carefully against the possible immediate and long-term effects of therapy on the offspring. Antihypertensive therapy in the acute inpatient setting should be initiated when diastolic pressure is greater than 105 mmHg, with the goal of lowering it between 90 and 100 mmHg, at which point the risk of placental hyperfusion is extremely low.

Controversies surround the question of whether to give antihypertensive drugs to patients with mild uncomplicated hypertension, when it seems likely that such treatment may reduce the number of hospital admissions and emergency deliveries. There is no clear evidence that antihypertensive treatment with any of the drugs available may defer or prevent the occurrence of preeclampsia or fetal growth retardation and perinatal death. The majority of workers agree that unless diastolic pressure is more than 15mmHg above borderline (75 to 80 mmHg and 85 to 90 mmHg, in the second and the third trimester, respectively), pharmacological treatment may not be necessary. Bed rest and diet modification may reduce the need for antihypertensive drugs; however, sodium restriction during pregnancy may induce severe volume depletion, azotemia, and electrolyte imbalance. Calcium supplements have been found to reduce preeclampsia in populations with low calcium, but there is no evidence that they are useful in the treatment of established hypertension.¹⁹

Drugs
The a-2 agonist methyldopa is the drug of choice and has established its safety over decades. The b-adrenergic blockers or combined a-b blocking agent labetalol have been found to be equally effective without serious side effects to the mother and fetus.

Now, it is known that b-blockers cross the placental barrier and may cause fetal bradycardia. Experimental evidence also suggests that b-blocking agents reduce fetal tolerance to hypoxic stress. Further, prospective randomized trials on atenolol and metaprolol versus no drug therapy showed no adverse maternal or fetal effects of this class of drugs in pregnancy. Five randomized trials comparing the effects of the b-blockers (oxprenolol, atenolol and labelatol) with methyldopa did not show significant difference in blood pressure control or the incidence of preeclampsia.²⁰ These trials failed to demonstrate untoward effects of b-blockers on the fetus. However, the safety of b-blockers is not yet fully established, and these agents should be used only if methyldopa is ineffective. Labetalol should be the drug of choice in chronic hypertension in pregnancy when methyldopa has failed to attain therapeutic response. Long-term studies have shown that labetalol causes a relatively higher incidence of intrauterine growth retardation. Among the calcium channel blockers, sublingual nifedipine has been used during hypertensive crisis. Since calcium channel blockers cross the placenta, their use has been suggested for the treatment of intrauterine fetal bradycardia. Angiotensin-converting enzyme inhibitors are contraindicated throughout pregnancy, and cause intrauterine fetal death and acute renal failure. Though hydralazine is safe, its use is not very popular and often-therapeutic range of doses are not very effective. It may cause a lupuslike syndrome. In a hypertensive emergency, intravenous magnesium sulphate, diazoxide, or nitroprusside can also be used, which may cause profound hypotension.

During a hypertensive crisis, the following are recommended:

· sublingual nifedipine
· intravenous (IV) hydralazine: 5 mg to 10 mg 4 to 6 hourly slowly. Dihydralazine 6.25 to 12.5 mg IV slowly, followed by an IV infusion of 0.1 mg/mt total dose of 25 mg. Tachycardia may be counteracted by b-blockers
· IV labetalol 2 mg/mt infusion to a dose of 1.2 mg/kg body weight
· IV verapamil 5 mg bolus or infusion 2.5 mg/mt to a total dose of 1.5 to 2.0 mg. Maternal and fetal bradycardia may occur, which it may be counteracted by simultaneous therapy with oral hydralazine. IV verapamil should not be used if sublingual nifedipine has failed to control blood pressure.

Acknowledgement: The authors are thankful to the vice chancellor at SASTRA University for providing the necessary facilities to process the material in this article.

Upadhyay L¹, Mishra M¹, Tripathi R², and Tripathi K³
1) Centre for Advanced Research in Indian System of Medicine, SASTRA University,Tamil Nadu, India; 2) Department of Home Science, AKAPG College, Varanasi, India; 3) Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Lokesh Upadhyay, PhD
assistant professor
Centre for Advanced Research in Indian System of Medicine
SASTRA University
Thanjavur – 613 402
Tamil Nadu
India
(91)09994511860
lokeshbhu@rediffmail.com
lokeshbhu@yahoo.co.uk

Notes
1. Mudaliar Al, Menon MK. Clinical Obstetrics. 7th ed. Orient Longman; 1972.
2. Devi PK, Sultana S, Sautpur SR. Review of eclampsia cases. J Obstet Gynaecol India. 1976:26-53.
3. Chesley LC. Superimposed pre-eclampsia or eclampsia. In: Chesley LC, ed.: Hypertensive Disorders in Pregnancy. New York: Appleton-Century-Crofts; 1978.
4. Pnitchard JA. Management of severe pre-eclampsia and eclampsia. Semin Perinatol. 1978:2:82.
5. Walker JJ. Advances in the management of severe pre-eclampsia and anti-hypertensive therapy. In : Bonnar J, Dunlop W, eds. Recent Advances in Obstetrics & Gynaecology. Vol 23. London, England: Royal Society of Medicine Press Ltd.;1999.
6. Duennoether JH, Jimenez JM, Baumann G. Pregnancy performance in patients under 15 years of age. Obstet Gynaecol. 1975;46:49.
7. Lindheimer MD. Diagnosis and management of hypertension complicating pregnancy. Am J Kid Dis. 1989 Jun;13(6 Suppl 1):17-27.
8. Roberts JM, Taylor RN, Musci TJ et al. Pre-eclampsia an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200.
9. Howie PW, Prentice CRM, McNicol GP. Coagulation, fibrinolysis and platelet function in pre-eclampsia, essential hypertension and placental insufficiency. J Obstet Gynaecol Br Common. 1971;78(11):992-1003.
10. Friedman SA, Schiff E, Emeis JJ, Dekker GA, Sibai BM. Biochemical corroboration of endothelial involvement in severe preeclampsia. Am J Obstet Gynecol.1995;172 :2002.
11. Goodman RP, Killam AP, Brush AR, Branch RA. Prostacyclin production during pregnancy: Comparison of production during normal pregnancy and pregnancy complicated by hypertension. Am J Obstet Gynecol. 1982;142:817.
12. Walsh SW. Pre-eclampsia : An imbalance placental prostacyclin and thromboxane production. Am J Obstet Gynecol. 1985;152: 335.
13. DeGvoot CJM, Davidge ST, Friedman SA et al. Plasma from pre-eclampsia women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass. Am J Obstet Gynecol. 1995;172:976.
14. Smarson AK, Sargent IL, Redman CWG. Endothelial cell proliferation is suppressed by plasma but not serum from women with preeclampsia. Am J Obstet Gynecol. 1996;174;787.
15. Redman CWG. Platelets and the beginning of pre-eclampsia. N Engl J Med. 1990;323,478.
16. Sibai BM. Immunological aspects of pre-eclampsia. Clin Obstet Gynaecol. 1991;34:27.
17. Petrucchio O. Etiology of pre-eclampsia. In: Studd J, ed. Progress in Obstetrics and Gynaecologyl. Vol. I. Edinburgh: Longman Group; 1981.
18. Hofmeyer GJ, Wilkins T, Redman CWG. The C4 and plasma protein in hypertension during pregnancy with and without the proteinuria. Brit Med J. 1991;302:218.
19. Tripathi K, Prakash J. Kidney diseases in pregnancy. In: Mandal AK, ed. Textbook of Nephrology. New Delhi: JP Brothers; 1993.
20. Mukherjee S, Hazara B. Hypertension in pregnancy. J Intern Med India. 1996;7:64-67.