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.
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
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
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
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.
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.
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.
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.
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
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
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
· 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.
The authors are thankful to the vice chancellor at SASTRA University
for providing the necessary facilities to process the material in
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
Centre for Advanced Research in Indian System of Medicine
Thanjavur – 613 402
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