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ABSTRACT
INTRODUCTION
Hypertensive disorders of pregnancy complicate approximately 12-22 % of
all pregnancies. Gestational hypertension includes Preeclampsia, eclampsia
and chronic hypertension. Aggressive antihypertensive therapy is avoided to
maintain adequate uteroplacental circulation. Nitroglycerine can reduce
Blood Pressure, fetoplacental circulation resistance and inhibits platelet
aggregation. Transdermal nitroglycerine is safe to mother, fetus and is
promising new option for the treatment of pregnancy induced hypertension.
OBJECTIVE
To compare the effectiveness of transdermal nitroglycerine patch and oral
nifedipine in hypertension during pregnancy.
STUDY DESIGN
Quasi experimental.
DURATION
Study was conducted from 1st July 2007 to 31st Dec 2007.
1
SETTING
MCH Centre, Unit-II, Pakistan Institute of Medical Sciences, Islamabad
SUBJECTS AND METHODS
All patients admitted with raised blood pressure > 110mmHg diastolic
beyond 20 weeks of gestation diagnosed as having pre-eclampsia or
eclampsia were included in the study. Outcome measures included efficacy
of Transdermal nitroglycerine patch and oral Nifidipine, their dosage,
duration of use and side effects.
RESULTS
Total number of patients who fulfilled the inclusion criteria was 60.They were
further subdivided in two groups, each consisting of 30 patients. Mean age
of the patients was 27.5 years (SD+ 4.87). Among them, primigravidas were
32 (53%) and multigravidas were 28 (46.7%). In the Nitroglycerine group,
the mean values of systolic & diastolic Blood Pressure before using the drug
was 168.3mmHg (SD+ 20.3) and 108mmHg (SD+ 18.2) falling to
131.6mmHg (SD+ 5.9) and 87.1mmHg (SD+ 4.4) respectively. In the
Nifidipine group, the results were almost similar after using the drug. The
mean duration of action of Nitroglycerine was 9.47 hours (SD+ 8.9),
whereas, it was only 1.2 hours (SD+ 4.3) for Nifidipine which was statistically
significant (p= 0.00). The mean dose of Nitroglycerine used was 10mg,
2
while 24mg of Nifidipine was used on average (p= 0.00). No significant side
effects were reported.
CONCLUSION
Our study showed that Nitroglycerine was effective at reducing blood
pressure during pregnancy at a lower dosage. The efficacy of Nifidipine lies
in its shorter duration of action. Both the drugs can supplement each other.
Key words: Nitroglycerine Patch, Nifidipine, Hypertension
3
INTRODUCTION
Hypertensive disorders in pregnancy include Preeclampsia (formerly called
pregnancy-induced hypertension) which is the new onset of hypertension
and proteinuria after 20 weeks of gestation in a previously normotensive
woman and eclampsia (70%) describes the development of grand mal
seizures in a woman with preeclampsia. The seizures should not be
attributable to another cause. Where as chronic hypertension (30%) is
present before the 20th week of pregnancy, or persists longer than 12
weeks postpartum.1
Incidence of pregnancy induced hypertension is increased in patients older
than 35 yrs, twins or previous history of gestational hypertension in
pregnancy. Preeclampsia occurs in approximately 3 to 14 percent of all
pregnancies worldwide and about 5 to 8 percent in the United States. The
disease is mild in 75 percent of cases in the United States and severe in 25
percent. Ten percent of preeclampsia occurs in pregnancies less than 34
weeks of gestation. Chronic hypertension complicates 3 percent of
pregnancies and gestational hypertension occurs in 6 %.2
Risk factor includes pregestational diabetes, vascular or connective tissue
disease, nephropathy, Antiphospholipid antibody syndrome, obesity,
positive family history, African American race and socioeconomic status.3-6
Pathological deterioration of organs and systems due to vasospasm and
ischemia is seen in severe preclamsia and eclampsia. Aggressive
4
antihypertensive therapy is avoided to maintain adequate uteroplacental
circulation.7
Calcium channel blocker nifedipine in oral form is safe in pregnancy with no
significant side effects to mother and fetus.8
Glyceryl trinitrate improves fetoplacental circulation and is effective therapy
for controlling hypertension in pregnant patients.9
Nitroglycerine can reduce BP, fetoplacental circulation resistance and
inhibits platelet aggregation. Transdermal nitroglycerine is safe to mother,
fetus and is promising new option for the treatment of pregnancy induced
hypertension.10
The purpose to undertake this study will be to determine the role of
nitroglycerine transdermal patches in managing hypertensive disorders of
pregnancy and to see how helpful this management option would be in
reducing maternal morbidity and mortality.
5
REVIEW OF LITERATURE
There are four major hypertensive disorders in pregnancy:
PREECLAMPSIA (formerly called pregnancy-induced hypertension)
It refers to the new onset of hypertension and proteinuria after 20 weeks of
gestation in previously normotensive women. Eclampsia describes the
development of grand mal seizures in a woman with preeclampsia. The
seizures should not be attributable to another cause.
CHRONIC HYPERTENSION
Chronic hypertension is defined as systolic pressure > or =140 mmHg,
diastolic pressure > or =90 mmHg, or both that antedates pregnancy, is
present before the 20th week of pregnancy, or persists longer than 12
weeks postpartum.
PREECLAMPSIA SUPERIMPOSED ON CHRONIC HYPERTENSION
Superimposed preeclampsia is diagnosed when a woman with chronic
hypertension develops new onset proteinuria after 20 weeks of gestation.
Women with chronic hypertension and preexisting proteinuria (before 20
weeks) are considered preeclamptic if there is an exacerbation of blood
pressure to the severe range (systolic > or =180 mmHg or diastolic > or
=110 mmHg) in the last half of pregnancy, especially if accompanied by
symptoms or a sudden increase in proteinuria.
6
GESTATIONAL HYPERTENSION
Gestational hypertension refers to hypertension (usually mild) without
proteinuria (or other signs of preeclampsia) developing in the latter part of
pregnancy. If it resolves by 12 weeks postpartum, then in retrospect it is
classified as transient hypertension of pregnancy. If the hypertension
persists beyond 12 weeks postpartum, then the diagnosis is chronic
hypertension that was masked in early pregnancy by the physiologic
decrease in blood pressure. Some women who first present with
gestational hypertension will go on to develop preeclampsia as the
pregnancy progresses. This is most likely when gestational hypertension
develops before 30 weeks of gestation.
INCIDENCE
Preeclampsia occurs in approximately 3 to 14 percent of all pregnancies
worldwide and about 5 to 8 percent in the United States. The disease is
mild in 75 percent of cases in the United States, and severe in 25 percent.2
Ten percent of preeclampsia occurs in pregnancies less than 34 weeks of
gestation. Chronic hypertension complicates 3 percent of pregnancies and
gestational hypertension occurs in 6 %.7
7
RISK FACTORS
A woman under the age of 20 years who is undergoing her first pregnancy
is at particularly high risk for developing this disorder. It remains unclear
why the primigravid state is such an important predisposing factor.
Additional risk factors for the development of preeclampsia include
PAST OBSTETRIC HISTORY
It predicts preeclampsia risk in a future pregnancy. The incidence of
preeclampsia in a second pregnancy is less than 1 percent in women who
have had a normotensive first pregnancy (does not apply to abortions), as
compared to 5 to 7 percent in women who had uncomplicated
preeclampsia during the first pregnancy. Women with early, severe
preeclampsia (approximately 2 percent of cases in nulliparas) are at
greater risk for recurrence, as high as 60 to 80 percent.11
A HIGHER BLOOD PRESSURE AT THE INITIATION OF
PREGNANCY AND A LARGE BODY SIZE.
PIH is more common in young, obese, primigravidas with a family or past
history of PIH or hypertension and in those with poor socioeconomic status
and no regular dietary calcium supplementation.3, 5
FAMILY HISTORY OF PREECLAMPSIA
is associated with a two- to fivefold increase in risk, suggesting a heritable
mechanism in some cases.6 In one well-designed study, the incidence of
8
preeclampsia in primiparous sisters of women with preeclampsia was more
than twice that of primiparous women in the general obstetric population
(20 versus 8 percent; RR 2.6, 95 percent CI 1.8 to 3.6).12 The father of the
baby also may contribute to the increased risk, as the paternal contribution
to fetal genes may have a role in defective placentation and subsequent
preeclampsia.
MULTIPLE PREGNANCIES.
PREEXISTING (CHRONIC) MATERNAL HYPERTENSION.
PREGESTATIONAL DIABETES
It also increases risk, an effect that is probably related to a variety of
factors such as underlying renal disease, high plasma insulin levels, and
abnormal lipid metabolism
THE ANTIPHOSPHOLIPID ANTIBODY SYNDROME
It is associated with multiple pregnancy complications including
preeclampsia, fetal loss, and maternal thrombosis. Other coagulation
abnormalities such as protein C or S deficiency, factor V Leiden mutation,
and hyperhomocysteinemia also may be risk factors for the disease or may
alter the course of disease by accelerating the abnormal interaction
between endothelial cells and coagulation and fibrinolytic factors.13-16
.VASCULAR OR RHEUMATOLOGIC DISEASE
There has been association of rheumatologic disease and preeclampsia. 17
9
ADVANCED MATERNAL AGE
(>35 to 40 years) without other risk factors has been associated with
increased risk of preeclampsia.
SERUM AND IMAGING MARKERS
A variety of placental peptides (eg, corticotropin-releasing hormone, inhibin
A, various androgens and other substances (eg, leptin, endothelin-I, sFlt-1)
have been investigated as possible markers for prediction of preeclampsia.
Elevated second trimester maternal serum alpha-fetoprotein and human
chorionic gonadotropin concentrations are also associated with adverse
pregnancy outcomes, such as preeclampsia. These abnormalities, in the
absence of congenital abnormalities, are thought to reflect early placental
pathology. None has been shown to be sufficiently sensitive and specific to
be clinically useful as a screening test.18-21 Evidence of abnormal uterine
and umbilical artery Doppler flow in the second trimester is another risk
factor for preeclampsia.22
CLINICAL MANIFESTATIONS
The gradual development of hypertension, proteinuria, and edema in
pregnancy is most often due to preeclampsia, particularly in a primigravida.
These findings typically become apparent in the latter part of the third
trimester and progress until delivery. In some women, however, symptoms
begin in the latter half of the second trimester, while others have an onset
10
that is delayed until delivery or even the early postpartum period. The
clinical manifestations develop weeks to months after pathogenic changes
in the placenta first occur.23 The clinical features of preeclampsia-eclampsia
described below are the result of generalized vasospasm, activation of the
coagulation system, and changes in several humoral and autoregulatory
systems related to volume and blood pressure control. The disease affects
multiple organ systems, sometimes with life-threatening results; as a result,
it is far more complicated than simple hypertension. Since poor perfusion is
a major component of the disease process, attempts to lower blood
pressure may exacerbate physiologic dysfunction even though the patient
may become normotensive.
HYPERTENSION
Pregnancy related hypertension is defined as a systolic blood pressure > or
=140 mmHg or diastolic blood pressure > or =90 mmHg in a woman who
was normotensive prior to 20 weeks of gestation. The blood pressure
should be taken with an appropriately sized cuff (ie, length 1.5 times the
upper arm circumference or cuff bladder able to encircle 80 percent or
more of the arm) placed on the right arm at the same level as the heart with
the woman sitting for at least 10 minutes; the disappearance of the fifth
Korotkoff sound indicates the diastolic pressure. The pressure should be
recorded to the nearest 2 mmHg. Hypertension is generally the earliest
clinical finding of preeclampsia and is the most common clinical clue to the
11
presence of the disease. The blood pressure (BP) may rise in the second
trimester, but usually does not reach the hypertensive range (> or =140/90)
until the third trimester, often after the 37th week of gestation. In some
cases, however, preeclampsia develops suddenly in a previously
normotensive woman or early in pregnancy. The typical gradual rise in
blood pressure has important implications for management during
pregnancy. As an example, a reading of 120/85 in the second trimester is
abnormal in a woman whose early pregnancy BP was 90/60. Such a
patient should be seen more frequently than the usual monthly visit,
especially if proteinuria and/or hyperuricemia are also present .24-25
PROTEINURIA
In addition to hypertension, most patients also have proteinuria (ie, > or
=0.3 g protein in a 24-hour urine specimen or 1+ on dipstick). Urinary
protein excretion increases gradually, may be a late finding, and is of
variable magnitude in preeclampsia, often reaching the nephrotic range
(>3.5 g/day). The approach to women with hypertension but no proteinuria
is uncertain, but close follow-up is prudent. Mild gestational hypertension
that occurs remote from term appears to be associated with the
subsequent development of preeclampsia and adverse neonatal outcome.
In the appropriate clinical setting it is necessary to monitor hypertensive
women without proteinuria very closely because they are at risk for adverse
outcomes.26
12
DIPSTICK
Urinary protein dipstick values do not correlate well with 24-hour urinary
collection protein excretion values in hypertensive pregnant women. In one
systematic review including six studies, the posttest probability for urine
dipstick of > or =1+ for predicting 24-hour urine protein excretion > or =300
mg ranged from 53 to 86 percent, and was 23 to 40 percent when the
dipstick was negative or trace. Thus, a negative dipstick does not
necessarily exclude significant proteinuria while many women with positive
tests do not have it.27
URINE PROTEIN TO CREATININE RATIO
Proteinuria can also be measured by calculating the protein-to creatinine
(P:C) ratio in a random urine sample. This minimizes collection and
laboratory errors, saves time in obtaining results, and is far more
convenient for the patient. However, there is no consensus on the best
threshold for identifying pregnant women with significant proteinuria.28-30 In
a report in which hospitalized patients were followed with serial tests, the
P:C ratio correlated with changes in 24-hour protein excretion over time.
Therefore, the test could be used to evaluate for progression of
preeclampsia, along with other clinical parameters.28
OTHER RENAL FINDINGS
The urine sediment is typically benign. The glomerular filtration rate (GFR)
13
and renal blood flow decrease. The plasma creatinine concentration is
generally normal or only slightly elevated (1.0 to 1.5 mg/dL [88 to 133
µmol/L]) because the preeclampsia-induced decrease in filtration fraction is
partially balanced by the normal pregnancy-induced increase in GFR.
Renal failure is an unusual complication that can occur in patients who
develop severe disease, frequently with features of the HELLP syndrome.31
Hyperuricemia and hypocalciuria also occur, although the mechanisms for
these changes are not clear.32-33
EDEMA AND INTRAVASCULAR VOLUME
Most pregnant women have edema, whether or not they have
preeclampsia. Therefore, the presence of edema is no longer part of the
diagnostic criteria. However, sudden and rapid weight gain and facial
edema often occur in women who develop preeclampsia. Intravascular
volume is lower than in normotensive pregnancy despite sometimes severe
edema. There is no evidence that there is underfilling of the arterial
circulation; rather, the reduced volume may be a consequence of
vasoconstriction. Nevertheless, this issue has not been conclusively
resolved, thus, diuretics should be avoided in the absence of pulmonary
edema.
HEMATOLOGIC CHANGES
Increased platelet turnover is a consistent feature of preeclampsia.33 The
most common coagulation abnormality in preeclampsia is
14
thrombocytopenia due to formation of microthrombi. The prothrombin time,
partial thromboplastin time, and fibrinogen concentration are not affected
unless there are additional complications such as abruptio placentae or
severe liver involvement. Microangiopathic hemolysis may also occur and
is detected by examination of a blood smear or elevation in the lactic
dehydrogenase concentration. Hemolysis is associated with a low
hematocrit, while hemoconcentration is associated with a high hematocrit.
The presence of both hemolysis and hemoconcentration may negate each
other, resulting in a normal hematocrit value.
LIVER
Factors involved in glomerular and hepatic injury may be similar, with
vasospasm and precipitation of fibrin affecting both organs. Periportal
hemorrhage, ischemic lesions, and microvesicular fat deposition are other
histologic findings observed in the livers of preeclamptic women. The
clinical manifestations of liver involvement are right upper quadrant or
epigastric pain, elevated liver enzymes and, in severe cases, subcapsular
hemorrhage or hepatic rupture.35-36
CENTRAL NERVOUS SYSTEM AND EYE
Central nervous system manifestations of preeclampsia include headache,
blurred vision, scotomata, and, rarely, cortical blindness; seizures in a
preeclamptic woman signify a change in diagnosis to eclampsia. One in
200 mildly preeclamptic and 2 percent of severely preeclamptic women will
15
develop eclamptic seizures.2 Histopathologic correlates include
hemorrhage, petechiae, vasculopathy, ischemic brain damage,
microinfarcts, and fibrinoid necrosis. Cerebral edema and
ischemic/hemorrhagic changes in the posterior hemispheres observed on
computed tomography and magnetic resonance imaging help to explain,
but do not fully account for, the clinicopathological findings. Cortical
blindness is typically transient. Blindness related to retinal pathology, such
as retinal artery or venous thrombosis, retinal detachment, optic nerve
damage, retinal artery spasm, and retinal ischemia, may be permanent.
HEART
Preeclampsia does not directly affect the myocardium. However,
decrements in left ventricular performance can occur and reflect a
physiologically appropriate response to increased afterload. Women who
develop preeclampsia have elevated cardiac outputs before clinical
diagnosis, with normal total peripheral resistance during the latent phase.
Severe preeclampsia can be associated with a highly variable
hemodynamic profile.
PULMONARY
The etiology of pulmonary edema in preeclampsia is multifactorial.
Excessive elevations in pulmonary vascular hydrostatic pressure (PCWP)
compared to plasma oncotic pressure may produce pulmonary edema in
some women, particularly in the postpartum period. However, not all
16
preeclamptic patients with pulmonary edema demonstrate this
phenomenon. Other causes of pulmonary edema are capillary leak, left
heart failure, and iatrogenic volume overload.
FETUS AND PLACENTA
The fetal consequences of chronic placental hypoperfusion are fetal growth
restriction and oligohydramnios. Severe or early onset preeclampsia results
in the greatest decrements in birth weight compared to normotensive
pregnancies, of 12 and 23 percent respectively. By comparison, late onset
preeclampsia can also be associated with higher than average birth weight,
possibly related to greater placental perfusion due to elevated cardiac
output and blood pressure.37 Abruptio placenta is infrequent (< 1 percent) in
women with mild preeclampsia, but occurs in 3 percent of those with
severe disease. Preeclampsia does not appear to accelerate fetal
maturation, as once believed. The frequency of neonatal morbidities such
as respiratory distress, intraventricular hemorrhage, and necrotizing
enterocolitis are similar in infants of preeclamptic women and age-matched
nonhypertensive controls. Iatrogenic preterm delivery is a secondary result
of fetal or maternal complications.
17
DIAGNOSIS
The diagnosis of preeclampsia is largely based upon the characteristic
clinical features described above developing after 20 weeks of gestation in
a woman who was previously normotensive. The elevated blood pressure
should be documented on two occasions at least 6 hours, but no more than
7 days, apart. The clinical diagnosis of preeclampsia is more likely to be
correct in primiparous women.23 The limited sensitivity of clinical
impression, particularly in multigravidas and in mild disease has led to an
investigation of markers of disease to help discriminate between
preeclampsia and other hypertensive disorders. The clinical utility of the
following markers is under investigation and must be confirmed in larger
studies: serum concentrations of inhibin A and total activin A are believed
to be of placental origin, and elevated levels in the blood of preeclamptic
women may be further evidence of placental/trophoblast dysfunction.
DIFFERENTIAL DIAGNOSIS
PREECLAMPSIA VS ESSENTIAL HYPERTENSION
In the absence of a documented past history of hypertension,
distinguishing between preeclampsia and essential hypertension may be
difficult due to the reduction in blood pressure that typically occurs during
the first two trimesters. Thus, a patient with preexistent hypertension may
be normotensive when first seen by the obstetrician. In this setting, a
variety of factors may be helpful in establishing the likely diagnosis:
18
ONSET
Hypertension occurring before the 20th week is usually due to an
underlying tendency to hypertension rather than to preeclampsia.
PARITY
Preeclampsia is far more common in primiparas than in multiparas.
AGE
Preeclampsia is somewhat more common in both young (<20 years) and
older (>35 years) primigravidas, although the latter are more likely to have
essential hypertension, as are older multiparous women.Thus age is of
diagnostic utility primarily in young primigravidas.
PROTEINURIA
Proteinuria is present and increases with time in preeclampsia,
occasionally reaching the nephrotic range; by comparison, protein
excretion is usually less than 1 g/day in hypertensive nephrosclerosis.
PLASMA URIC ACID CONCENTRATION
Preeclampsia is typically associated with a rise in the plasma urate level to
above 5.5 to 6 mg/dL (327 µmol/L); this alteration is thought to reflect
increased proximal sodium and secondarily urate reabsorption induced by
renal ischemia. The plasma urate concentration remains below this level in
essential hypertension unless the patient is treated with diuretics or has
superimposed preeclampsia.38
19
PATHOGENESIS OF PREECLAMPSIA
Preeclampsia is a syndrome characterized by the new onset of
hypertension and proteinuria after 20 weeks of gestation. Additional signs
and symptoms that can occur include edema, visual disturbances,
headache, epigastric pain, thrombocytopenia, and abnormal liver function.23
These clinical manifestations are the result of mild to severe
microangiopathy of target organs, such as brain, liver, kidney, and
placenta.7
IMPAIRED TROPHOBLAST INVASION
The earliest pathologic change in preeclampsia occurs in the
uteroplacental circulation. In normal pregnancies, the cytotrophoblast
invades the endothelium and highly muscular tunica media of the maternal
spiral arteries (branches of the uterine artery that supply blood to the
placenta). As a result, these vessels undergo transformation from small
muscular arterioles to large capacitance vessels of low resistance. This
allows increased blood flow (ie, oxygen, nutrients) to the fetus. Remodeling
of the spiral arteries probably begins in the late first trimester and is
completed by 18 to 20 weeks of gestation, although the exact gestational
age at which trophoblast invasion of these arteries ceases is unclear.
By comparison, in preeclampsia the cytotrophoblast infiltrates the decidual
portion of the spiral arteries, but fails to penetrate the myometrial portion.
Thus the large, tortuous vascular channels created by replacement of the
20
musculoelastic wall with fibrinoid material do not develop; instead the
vessels remain narrow.39
ABNORMAL TROPHOBLAST DIFFERENTIATION
The primary event that contributes to failed trophoblast differentiation is
unknown but placental ischemia, immunologic factors, and genetic factors
are thought to play a role.
Placental ischemia appears to be an important factor in the pathogenesis
of preeclampsia. This is consistent with the observation that maternal risk
factors for preeclampsia include medical conditions that predispose to
vascular insufficiency such as hypertension, diabetes, systemic lupus
erythematosus, and acquired and inherited thrombophilias.
Obstetrical conditions that increase placental mass with a relative
decrease in placental blood flow such as hydatiform mole, also increase
the risk of preeclampsia. Placental hypoperfusion becomes more
pronounced as pregnancy progresses because the abnormal uterine
vasculature is unable to accommodate the normal rise in blood flow to the
fetus/placenta with increasing gestational age. Late placental changes
consistent with ischemia include atherosis (lipid-laden cells in the wall of
the arteriole), fibrinoid necrosis, thrombosis, sclerotic narrowing of
arterioles, and placental infarction. Although all of these lesions are not
uniformly found in patients with preeclampsia there appears to be a
correlation between the severity of the disease and the extent of the
21
lesions. It is unclear at the present time if the ischemic placenta is the
cause or the consequence of abnormal placental cytotrophoblast
differentiation and invasion. The ischemic placenta may elaborate soluble
factors into the maternal bloodstream such as sFlt-1 (described below) and
proinflammatory cytokines that further alter maternal vascular endothelial
cell function and lead to the characteristic signs and symptoms of
preeclampsia.40
Immunologic factors The focus on immunologic factors as a possible
cause of placental abnormality is based upon the observation that prior
exposure to paternal/fetal antigens appears to protect against
preeclampsia. This is illustrated by the following examples: The length of
sexual cohabitation before conception is inversely related to the risk of
preeclampsia, suggesting that prolonged exposure to paternal sperm
antigens may be protective.41-42
Genetic factors Although most cases of preeclampsia are sporadic,
genetic factors are thought to play a role in disease susceptibility. A genetic
predisposition to preeclampsia is suggested by the following observations.
Primigravid women with a family history of preeclampsia (eg, affected
mother or sister) have a two to five fold higher risk of the disease than
primigravid women with no such history. The spouses of men who were the
product of a pregnancy complicated by preeclampsia are more likely to
develop preeclampsia than spouses of men without this history. A woman
22
who becomes pregnant by a man whose previous partner had
preeclampsia is at higher risk of developing the disorder than if the
pregnancy with the previous partner was normotensive. These data
suggest that both maternal and paternal contributions to fetal genes may
have a role in defective placentation and subsequent preeclampsia.
Several candidate genes such as the angiotensinogen gene variant (T235),
endothelial nitric oxide synthase (eNOS), and genes causing thrombophilia
have been linked with preeclampsia but large studies have not shown them
to be important for susceptibility to the disease.43 In spite of these genetic
studies the causative gene products responsible for the placental defects in
preeclampsia remain elusive.
SYSTEMIC ENDOTHELIAL DYSFUNCTION
All of the clinical features of preeclampsia can be explained as maternal
responses to generalized endothelial dysfunction. Disturbed endothelial
control of vascular tone causes hypertension, increased vascular
permeability results in edema and proteinuria, and abnormal endothelial
expression of procoagulants leads to coagulopathy. These changes also
cause ischemia of target organs such as the brain, liver, kidney, and
placenta. Laboratory evidence supporting generalized endothelial
dysfunction in preeclamptic women includes: Increased concentrations of
circulating cellular fibronectin, factor VIII antigen, and thrombomodulin.
Impaired flow-mediated vasodilation and impaired acetylcholine mediated
23
vasorelaxation. Decreased production of endothelial-derived vasodilators
such as nitric oxide and prostacyclin and increased production of
vasoconstrictors such as endothelins and thromboxanes. Enhanced
vascular reactivity to angiotensin II
VEGF and sFlt-1
Increased placental expression and secretion of soluble fms-like tyrosine
kinase 1 (sFlt-1 or sVEGFR-1) a naturally occurring circulating vascular
endothelial growth factor (VEGF) antagonist, appears to play a central role
in the pathogenesis of preeclampsia.45 VEGF is an endothelial specific
mitogen that plays a key role in promoting angiogenesis.46 Mammalian
placentation requires extensive angiogenesis for the establishment of a
suitable vascular network to supply oxygen and nutrients to the fetus. A
variety of proangiogenic (VEGF, PlGF) and antiangiogenic factors (sFlt-1)
are elaborated by the developing placenta and the balance among these
factors is important for adequate placental development. The importance of
VEGF for maintenance of normal glomerular capillary function was
illustrated by a study in mice in which a 50 percent reduction in renal
podocyte VEGF expression resulted in glomerular capillary endotheliosis
the pathognomonic lesion of preeclampsia.47 In preeclampsia, increased
production of sFlt-1 appears to shift this balance toward antiangiogenic
factors.48-49 Excess sFlt-1 production may be secondary to the placental
ischemia. In vitro studies have shown that placental cytotrophoblasts
24
possess a unique property to enhance sFlt-1 production when oxygen
availability is reduced.50 Thus placental ischemia could lead to increased
sFlt-1 production, which then antagonizes the angiogenic activity of VEGF
and PlGF. In the aggregate these observations suggest a major role for
sFlt-1 in the pathogenesis of at least some features of preeclampsia.
However it is not known if sFlt-1 is responsible for the early impairments in
placental development and what triggers increased sFlt-1 production by the
placenta including whether sFlt-1 release is a secondary response to initial
placental ischemia caused by some other factor. In the future it is possible
that drugs binding to sFlt-1 might prevent and treat preeclampsia.
Other mediators
In addition to sFlt-1 it is likely that additional synergistic factors (yet to be
identified) elaborated by the placenta play a role in the pathogenesis of the
generalized endothelial dysfunction noted in preeclampsia. Consistent with
this hypothesis is the observation that the plasma concentration of sFlt-1
protein needed to produce the preeclampsia phenotype in rats was several
fold higher than the levels typically seen in patients with preeclampsia and
no coagulation or liver function abnormalities were reported in the sFlt-1
treated animals.45 The following mediators are among those that have been
evaluated: Several investigators have reported preeclamptic women have
elevated levels of cytokines (eg, tumor necrosis factor-alpha, interleukin-6,
interleukin-1-alpha, interleukin-1-beta), Fas ligand, and markers of
25
oxidative stress (eg, oxidized thiols, lipid peroxidases, isoprostane)
released by the placenta; however there is no evidence that any of these
molecules are etiologic.
SCREENING
Pregnant women are routinely screened for signs and symptoms of
preeclampsia at each prenatal visit. Women at high risk of developing
preeclampsia should be seen in early pregnancy to assess blood pressure,
establish accurate pregnancy dating, and perform baseline laboratory tests
such as platelet count, creatinine concentration, and urine protein
determination. In addition to the historical risk factors discussed above a
variety of tests have been proposed to detect subgroups of women at high
risk of developing preeclampsia. None of these tests performs well enough
to use for screening.
UTERINE ARTERY DOPPLER
Impedance to uteroplacental blood flow is another early feature of
preeclampsia. Sonographic evidence of diastolic notching in the arcuate
vessels of the uterus in the second trimester has been used to predict
preeclampsia and other disorders associated with impaired placentation
(eg, fetal growth restriction). These studies are difficult to compare because
the investigators have used different Doppler sampling techniques,
definitions of abnormal flow velocity waveform, populations, gestational age
at examination, and criteria for the diagnosis of preeclampsia.22 In general
26
the positive predictive value of an abnormal test is poor in low risk
populations. An abnormal doppler study increased the likelihood of
preeclampsia approximately six-fold in otherwise low risk women; this
result was not considered adequate to recommend the test for screening
purposes. The test performs somewhat better in high risk women, and
appears to be reassuring when it is negative.51-53 However it is not
sufficiently accurate to alter clinical management of high risk women and is
not recommended.
MATERNAL ANALYTES
Abnormal second trimester maternal serum analyte concentrations are also
predictive of preeclampsia. The association is not sufficiently strong to
warrant deviation from routine prenatal care. Maternal analyte testing
should only be offered to screen for Down syndrome.
SECOND TRIMESTER BLOOD PRESSURE
Second trimester ambulatory blood pressures are slightly higher in women
who go on to develop preeclampsia than in those who do not. Although
blood pressure should be measured at each prenatal visit to establish a
baseline and detect subsequent changes, a single mild second trimester
elevation is not useful as a screening test.
LATE PREGNANCY SCREENING
Measurement of blood pressure and urine protein at regular intervals in the
27
late second and third trimesters is critical for timely diagnosis of
preeclampsia. A rising blood pressure is usually the first sign of developing
disease, although not specific as many women with increases in blood
pressure do not go on to develop preeclampsia. A repeat examination in
one to three days is recommended for women who do not meet criteria for
establishing the diagnosis. Woman should also be educated to immediately
report possible signs of preeclampsia that may occur between office visits
such as persistent or severe headache, visual changes, right upper
quadrant or epigastric pain, sudden large weight gain, or facial edema.
MATERNAL ASSESSMENT OF WOMEN WITH
HYPERTENSION AFTER MID PREGENANCY
The initial goal is to distinguish women with preeclampsia from those with
other disorders. The secondary goal is to assess the severity of disease
whether mild or severe. Mild preeclampsia includes those women who
satisfy the criteria for preeclampsia but do not have any features of severe
disease. It is important to remember that severe preeclampsia can be
present with only a mild elevation in blood pressure and lack of significant
symptoms. Hypertension should be confirmed by at least two
measurements at least several six hours apart. Laboratory evaluation
typically includes Hematocrit, Platelet count, Quantification of protein
excretion, Serum creatinine concentration, Serumuricacid concentration,
Serum alanine and aspartate aminotransferase concentrations Lactic acid
28
dehydrogenase concentration (LDH): this test and review of the red blood
cell smear may indicate the presence of microangiopathic hemolysis.
GENERAL PRINCIPLES OF MANAGEMENT
The definitive treatment of preeclampsia is delivery to prevent potential
maternal complications. Delivery is recommended for women with mild
preeclampsia at or near term and for most women with severe
preeclampsia or severe gestational hypertension regardless of gestational
age.26 However preterm delivery is not always in the best interests of the
fetus; therefore exceptions to this recommendation may be made for
women remote from term (less than 32 to 34 weeks of gestation) who
improve after hospitalization and do not have significant end-organ
dysfunction or fetal deterioration.
MANAGEMENT STRATEGIES
A number of management strategies have been developed to prevent
maternal and fetal complications during the peripartum period.
TREATMENT OF HYPERTENSION
The use of antihypertensive agents to control mildly elevated blood
pressure in the setting of preeclampsia has not been shown to alter the
course of the disease nor to diminish perinatal morbidity or mortality.
Indeed, such therapy may reduce birthweight. However antihypertensive
agents are administered to prevent a maternal cerebrovascular accident
29
from severe hypertension. The risk of hemorrhagic stroke correlates
directly with the degree of elevation in systolic blood pressure (and is less
related to diastolic pressure) but it is not clear whether there is a threshold
systolic pressure above which emergent therapy should be instituted.
Antihypertensive drugs may alter Th1/Th2 cytokine balance in preeclamptic
tissues in vitro.54
INDICATIONS FOR ANTIHYPERTENSIVE THERAPY
The indications for antihypertensive therapy in preeclampsia are based on
practice patterns established over the years rather than clinical trials with
clearly defined outcomes. Thus many physicians withhold treatment in
asymptomatic adult women with preeclampsia unless the diastolic pressure
is > or =105 to 110 mmHg or the systolic pressure is > or =160 to 180
mmHg, a level at which the risk of cerebral hemorrhage becomes
appreciable. However some feel that these thresholds may be too high
particularly in younger women whose baseline diastolic pressures are
below 75 mmHg. The concern with lowering blood pressure in women with
preeclampsia is that treating less severe hypertension may further reduce
placental perfusion and may not improve perinatal outcome.55 Severe
hypertension should be treated to prevent maternal vascular complications.
There is no consensus on the exact blood pressure threshold to initiate
therapy. In adult women diastolic blood pressures > or =105 to 110 mmHg
or systolic pressures > or =160 to 180 mmHg have been suggested. The
30
threshold may be lower in adolescents whose baseline diastolic pressure is
less than 75 mmHg; in such patients treatment is initiated at diastolic
pressures of > or =100 mmHg.56
CHOICE OF DRUG
The Food and Drug Administration reviews human and animal data to
assign letter grades corresponding with risk of fetal exposure in pregnancy.
Most antihypertensive agents used in pregnancy are designated as
"category C," which states that human studies are lacking, animal studies
are either positive for fetal risk or are lacking, and the drug should be given
only if potential benefits justify potential risks to the fetus. This category
cannot be interpreted as no evidence of risk and is so broad to preclude
usefulness in practice, leading some groups to suggest that the Food and
Drug Administration classification be abandoned.57 Information is thus
based on clinical cases, small studies, and meta-analyses.
SYMPATHETIC NERVOUS SYSTEM INHIBITION
Methyldopa remains one of the most widely used drugs for the treatment of
hypertension in pregnancy. It is a centrally acting 2-adrenergic agonist
prodrug, which is metabolized to -methyl norepinephrine and then replaces
norepinephrine in the neurosecretory vesicles of adrenergic nerve terminals.
BP control is gradual over 6 to 8 hours because of the indirect mechanism of
action. It is not thought to be teratogenic based on limited data and a 40-year
31
history of use in pregnancy. It has been assessed in a number of
prospective trials in pregnant women compared with placebo or with
alternative antihypertensive agents. Treatment with methyldopa has been
reported to prevent subsequent progression to severe hypertension in
pregnancy and does not seem to have adverse effects on uteroplacental or
fetal hemodynamics or on fetal well being. Adverse effects are
consequences of central 2-agonism or decreased peripheral sympathetic
tone. These drugs act at sites in the brain stem to decrease mental alertness
and impair sleep leading to a sense of fatigue or depression in some
patients. Frequently decreased salivation leading to xerostomia is
experienced. Methyldopa can also cause elevated liver enzymes in 5%;
hepatitis and hepatic necrosis have also been reported. Some patients will
develop a positive antinuclear antigen or antiglobulin (Coombs’) test with
chronic use and this is occasionally associated with clinical hemolytic
anemia. In these cases medications from other classes are substituted.58
Clonidine a selective 2-agonist acts similarly and is comparable to
methyldopa with respect to safety and efficacy, In pregnancy it is mainly
used as a third-line agent for multidrug control of refractory hypertension.
32
PERIPHERALLY ACTING ADRENERGIC RECEPTOR
ANTAGONISTS
β-Blockers have been used extensively in pregnancy.Given differences in β-
blockers with respect to lipid solubility and receptor specificity, the potential
for clinically relevant differences between agents exists but has not been
investigated in pregnancy. Oral β-blockade had been associated with
nonclinically significant neonatal bradycardia although in a systematic review
of trials labetalol does not (along with oral methyldopa, nifedipine, or
hydralazine) seem to cause neonatal heart rate effects. Maternal outcomes
are improved with the use of β-blockers with effective control of maternal BP
decreased incidence of severe hypertension and decreased rate of preterm
admission to hospital. Labetalol a nonselective β-blocker with vascular 1-
receptor blocking capabilities has gained wide acceptance in pregnancy.
When administered orally to women with chronic hypertension it seems as
safe and effective as methyldopa although neonatal hypoglycemia with
higher doses has been reported Of some concern, 1 placebo controlled
study reported an association with fetal growth restriction in the
management of preeclampsia remote from term. Parenterally it is used to
treat severe hypertension and because of a lower incidence of maternal
hypotension and other adverse effects its use now supplants that of
hydralazine. Adverse effects may be predicted as consequences of β-
receptor blockade. Fatigue, lethargy, exercise intolerance (because of β2-
33
blocking effects in skeletal muscle vasculature), peripheral vasoconstriction,
sleep disturbance (with use of more lipid-soluble drugs), and
bronchoconstriction may be seen; however discontinuation because of
adverse effects is uncommon. Peripherally acting -adrenergic antagonists
are second-line antihypertensive drugs in nonpregnant adults. These are
indicated during pregnancy in the management of hypertension because of
suspected pheochromocytoma and both prazosin and phenoxybenzamine
have been used with β-blockers used as adjunctive agents after -blockade
is accomplished. Because there is but limited experience with these agents
in pregnancy, their routine use cannot be advocated.
CALCIUM CHANNEL ANTAGONISTS
Calcium channel antagonists have been used to treat chronic hypertension,
mild preeclampsia presenting late in gestation and urgent hypertension
associated with preeclampsia. Orally administered nifedipine and verapamil
do not seem to pose teratogenic risks to fetuses exposed in the first
trimester. Most investigators have focused on the use of nifedipine although
there are reports of nicardipine, isradipine, felodipine and verapamil.59
Although used in pregnancy the dihydropyridine amlodipine is yet unstudied
in this population. Maternal adverse effects of the calcium channel blockers
include tachycardia, palpitations, peripheral edema, headaches, and facial
flushing. Nifedipine does not seem to cause a detectable decrease in uterine
34
blood flow. Short-acting dihydropyridine calcium antagonists particularly
when administered sublingually are now not recommended for the treatment
of hypertension in nonpregnant patients because of reports of myocardial
infarction and death in hypertensive patients with coronary artery disease.
Administration of short-acting nifedipine capsules has been in case reports
associated with maternal hypotension and fetal distress. If rapid BP control
is desired then we recommend using parenteral labetalol or hydralazine until
the desired target is achieved. One study has shown efficacy and safety of
long-acting oral nifedipine in pregnant patients with severe hypertension in
pregnancy and given possible untoward fetal effects of short-acting
sublingual nifedipine also advocate use of the long-acting preparation.60 A
concern with the use of calcium antagonists for BP control in preeclampsia
has been the concomitant use of magnesium sulfate to prevent seizures;
drug interactions between nifedipine and magnesium sulfate were reported
to cause neuromuscular blockade, myocardial depression, or circulatory
collapse in some cases. In practice and in a recent evaluation these
medications are commonly used together without increased risk.61
DIURETICS
Diuretics are commonly prescribed in essential hypertension before
conception and given their apparent safety, the National High Blood
Pressure Education Program Working Group on High Blood Pressure in
35
Pregnancy concluded that they may be continued through gestation (with an
attempt made to lower the dose) or used in combination with other agents,
especially for women deemed likely to have salt-sensitive hypertension.
However mild volume contraction with diuretic therapy may lead to
hyperuricemia and in so doing invalidate serum uric acid levels as a
laboratory marker in the diagnosis of superimposed preeclampsia.
Hydrochlorothiazide may be continued during pregnancy; the use of low
doses (12.5 to 25 mg daily) may minimize untoward metabolic effects such
as impaired glucose tolerance and hypokalemia. Triamterene and amiloride
are not teratogenic based on small numbers of case reports. Spironolactone
is not recommended because of its antiandrogenic effects during fetal
development.
SEROTONIN2 RECEPTOR BLOCKERS
Serotonin-induced vasodilation is mediated by S1 receptors and subsequent
release of prostacyclin and NO. Endothelial dysfunction and loss of
endothelial S1 receptors allows serotonin, of which the levels are greatly
increased in pregnancy, to react only with S2 receptors resulting in
vasoconstriction and platelet aggregation. Ketanserin is a selective S2
receptor-blocking drug that decreases systolic and diastolic BP in
nonpregnant patients with acute or chronic hypertension. Ketanserin has not
been found to be teratogenic in animals or humans and has been studied
36
primarily in Australia and South Africa in small trials, which suggest that it
may be safe and useful in the treatment of chronic hypertension in
pregnancy, preeclampsia, and hemolysis elevation of liver enzymes, low
platelets syndrome. Ketanserin has not been Food and Drug Administration
approved in the United States.
DIRECT VASODILATORS
Hydralazine selectively relaxes arteriolar smooth muscle by an as-yet-
unknown mechanism. Its greatest use is in the urgent control of severe
hypertension or as a third-line agent for multidrug control of refractory
hypertension. It is effective orally, intramuscularly, or intravenously;
parenteral administration is useful for rapid control of severe hypertension.
Adverse effects are mostly those due to excessive vasodilation or
sympathetic activation and include headache, nausea, flushing, or
palpitations. Chronic use can lead in rare cases to a pyridoxine-responsive
polyneuropathy or to immunologic reactions including a drug-induced lupus
syndrome. Hydralazine has been used in all trimesters of pregnancy and
data have not shown an association with teratogenicity, although neonatal
thrombocytopenia and lupus have been reported. It has been widely used for
chronic hypertension in the second and third trimesters but its use has been
supplanted by agents with more favorable adverse effect profiles. For acute
severe hypertension later in pregnancy, intravenous hydralazine has been
37
associated with more maternal and perinatal adverse effects than
intravenous labetalol or oral nifedipine such as maternal hypotension,
cesarean sections, placental abruptions, Apgar scores <7, and oliguria.
Furthermore the common adverse effects such as headache, nausea, and
vomiting, mimic the symptoms of deteriorating preeclampsia. Effects on
uteroplacental blood flow are unclear likely because of variation in the
degree of reflex sympathetic activation and fetal distress may result via a
precipitous drop in maternal pressure. A recent meta-analysis of the use of
intravenous hydralazine in severe hypertension in pregnancy concluded that
parenteral labetalol or oral nifedipine were preferable first-line agents, with
hydralazine as a suitable second-line agent.56 Isosorbide dinitrate, an NO
donor has been investigated in a small study of gestational hypertensive and
preeclamptic pregnant patients. It was found that cerebral perfusion
pressure is unaltered by isosorbide dinitrate despite significant changes in
maternal BP thus decreasing the risk for ischemia and infarction when BP is
lowered.62 Nitroglycerine is now being tried because it can reduce BP,
fetoplacental circulation resistance and inhibits platelet aggregation. It has
got few side effects and is promising new option for the treatment of
hypertension in pregnancy.9-10 Sodium nitroprusside is a direct NO donor,
which nonselectively relaxes both arteriolar and venular vascular smooth
muscle. Administered only by continuous intravenous infusion it is easily
titrated because it has a near-immediate onset of action and duration of
38
effect of 3 minutes. Nitroprusside metabolism releases cyanide which can
reach toxic levels with high infusion rates; cyanide is metabolized to
thiocyanate and this toxicity usually occurs after 24 to 48 hours of infusion
unless its excretion is delayed due to renal insufficiency. It is seldom used in
pregnancy, usually only in cases of life-threatening refractory hypertension in
the moments before delivery. Adverse effects include excessive vasodilation
and cardioneurogenic (ie, paradoxical bradycardia) syncope in volume-
depleted preeclamptic women.The risk of fetal cyanide intoxication remains
unknown. Given the long experience with hydralazine and alternative use of
parenteral labetalol or oral calcium channel blockers, this drug is considered
as a last resort.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND
ANGIOTENSIN RECEPTOR ANTAGONISTS
Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor
blocking agents are contraindicated in the second or third trimesters
because of toxicity associated with reduced perfusion of the fetal kidneys;
use is associated with a fetopathy similar to that observed in Potter’s
syndrome (ie, bilateral renal agenesis) including renal dysgenesis,
oligohydramnios as a result of fetal oliguria, calvarial and pulmonary
hypoplasia, intrauterine growth restriction, and neonatal anuric renal failure,
leading to death of the fetus. Angiotensin receptor blocker use in pregnancy
has also caused fetal demise, attributed primarily to renal failure. First-
trimester exposure to ACE-I has been associated recently with a greater
incidence of malformations of the cardiovascular and central nervous
39
systems. Of 29096 pregnancies analyzed, 209 were exposed to ACE-I in the
first trimester alone, associated with a risk ratio of congenital malformation of
2.71 when compared with no antihypertensive medication or other types of
antihypertensive medication.63 Whether adverse outcomes are because of a
hemodynamic effect in the fetus or specific (nonhemodynamic) requirements
for angiotensin II as a fetal growth factor is unknown. As such, first-trimester
use of ACE-I and angiotensin receptor blocking agent medications should be
avoided. Because exposure to ACE inhibitors during the first trimester
cannot be considered safe, it may be best to counsel women to switch to
alternate agents while attempting to conceive. However, in those who
inadvertently become pregnant while taking ACE-I or angiotensin receptor
blocking agents, the risk of birth defects rises from 3% to 7%.63
RECOMMENDATION
There are two settings in which antihypertensives are considered: for the
acute management of severe hypertension, which may require parenteral
therapy and oral drugs for more chronic blood pressure control. Options for
acute therapy include Intravenous labetalol is both effective and safe
(beginning with 20 mg intravenously followed at 10 to 15 minute intervals by
40 mg then 80 mg up to a maximum total cumulative dose of 220 mg).
Intravenous hydralazine (beginning with 5 mg intravenously, followed by 5 to
10 mg boluses as necessary every 20 minutes, maximum dose 30 mg) has
been the drug of choice. However, a meta-analysis of 11 trials in 570
women found that parenteral hydralazine was associated with significantly
more maternal hypotension than other antihypertensive drugs. A
40
subsequent meta-analysis by the same group also did not support the use of
hydralazine as a first-line drug for treatment of severe hypertension in
pregnant women.56 Occasionally preeclamptic women with severe
hypertension are stabilized and not delivered. In these patients oral
antihypertensive therapy is often indicated. The only oral drugs that have
been proven to be safe in pregnant women are methyldopa (250 mg twice
daily orally, maximum dose 4 g/day), hydralazine, and beta blockers such as
labetalol (100 mg twice daily orally, maximum dose 2400 mg/day).
Methyldopa and labetalol should be considered first line oral drugs and
atenolol should be avoided early in pregnancy. Long-acting nifedipine is also
acceptable.23
BLOOD PRESSURE GOAL
The goal of therapy is a systolic pressure of 140 to 155 mmHg and diastolic
pressure of 90 to 105 mm of Hg.23 Sodium restriction and diuretics have no
role in therapy. Restricted physical activity can lower blood pressure,
although its efficacy for improving perinatal outcome has not been proven.
FETAL ASSESSMENT
Components of fetal evaluation in preeclamptic pregnancy include daily fetal
movement counts and nonstress testing and/or biophysical profiles at
periodic intervals, depending upon clinical status.. A sonographic estimation
of fetal weight should be performed to look for growth restriction and
41
oligohydramnios and repeated serially. Doppler velocimetry is useful if there
is fetal growth restriction.
LUNG MATURITY
Antenatal corticosteroids to promote fetal lung maturation should be
administered to women less than 34 weeks of gestation who are at high risk
for delivery within the next seven days.
MATERNAL MONITORING
Women with mild gestational hypertension are monitored for signs of
progression to severe hypertension or preeclampsia. Women with mild
preeclampsia are monitored for signs of development of severe
preeclampsia and those with severe disease if not delivered are monitored
for evidence of significant end-organ dysfunction, which places the gravida
and/or fetus at risk of death or serious morbidity.64-66
SYMPTOMS
Patients should be told to call their health care provider immediately if they
develop severe or persistent headache, visual changes, right upper
quadrant or epigastric pain, nausea or vomiting, shortness of breath, or
decreased urine output. As with any pregnancy, decreased fetal movement,
42
vaginal bleeding, abdominal pain, rupture of membranes, or uterine
contractions should be reported immediately, as well.
LABORATORY EVALUATION
Laboratory evaluation including platelet count, creatinine, urine protein, and
liver enzymes should be repeated once or twice weekly in women with mild
stable preeclampsia, but more often if clinical signs and symptoms suggest
worsening disease. Quantification of protein excretion can be performed
using a 24 hour collection or protein-to creatinine ratio. A rising hematocrit
can be useful to look for hemoconcentration, which suggests contraction of
intravascular volume and progression to more severe disease, while a falling
hematocrit may be a sign of hemolysis. An elevated lactic acid
dehydrogenase (LDH) concentration is a better sign of hemolysis, and a
marker of severe disease or HELLP syndrome (ie, Hemolysis, Elevated
Liver enzymes, Low Platelets). Hemolysis can be confirmed by observation
of schistocytes on a blood smear. Coagulation function tests (eg,
prothrombin time, activated partial thromboplastin time, fibrinogen
concentration) are usually normal if there is no thrombocytopenia or liver
dysfunction, and therefore do not need to be monitored
43
INPATIENT VERSUS OUTPATIENT
Close maternal monitoring upon diagnosis is important to establish disease
severity and rate of progression. Hospitalization is useful for making these
assessments and facilitates rapid intervention in the event of fulminant
progression to eclampsia, hypertensive crisis, abruptio placentae or HELLP
syndrome. However these complications are rare in women with mild
hypertension, minimal proteinuria (eg, less than 1 g in 24 hours), and no
other abnormalities therefore carefully selected patients with these findings
may be managed on an ambulatory basis after initial in-patient evaluation.
Such women should be able to comply with frequent maternal and fetal
evaluations (every one to three days) and have ready access to medical
care. Restricted activity is typically recommended; there is no evidence that
complete bedrest improves pregnancy outcome. Hospitalization is indicated
if there are signs or symptoms of disease progression.
SEVERE PREECLAMPSIA
Severe preeclampsia is generally regarded as an indication for delivery
regardless of gestational age to minimize maternal complications. However
prolonged antepartum management may be considered in selected women
under 32 to 34 weeks of gestation who have:
44
1. Severe preelampsia by proteinuria (greater than 5 g in 24 hours) alone,
since this finding alone is not associated with serious maternal or fetal
sequelae, while preterm delivery may be hazardous for the neonate.67-68
2. Severe preeclampsia by mild intrauterine fetal growth restriction (fifth to
tenth percentile) alone, as long as antepartum fetal testing remains
reassuring, oligohydramnios is not severe, umbilical artery diastolic flow is
not reversed on Doppler velocimetry, and there is progressive fetal growth.
3. Severe preeclampsia by blood pressure criteria alone, hypertension with
blood pressure reduction after hospitalization.67-68
4. Asymptomatic laboratory abnormalities that quickly resolve after
hospitalization 67-68
The rationale for delaying delivery in these pregnancies is to reduce
perinatal morbidity and mortality by delivery of a more mature fetus and, to
a lesser degree, to achieve a more favorable cervix for vaginal birth. The
risk of prolonging pregnancy is continued poor perfusion of major organs
with the potential for severe end organ damage to the brain, liver, kidneys,
placenta/fetus, and hematologic and vascular systems. Decisions
regarding continuation of pregnancy in these women depend upon daily
maternal and fetal assessment with continual review of the ongoing risks of
conservative management versus the benefit of further fetal maturation.
They should be cared for in a hospitalized setting and in consultation with a
maternal-fetal medicine specialist. Attempts to delay delivery should be
45
abandoned after a course of antenatal corticosteroid therapy if possible, if
any of the following features develop:
Symptoms of persistent severe headache or visual aberrations
Poorly controlled severe hypertension
Eclampsia
Thrombocytopenia (absolute platelet count less than 100,000
platelets/microL) or a rapid drop in platelet count. Although there is no clear
definition for what constitutes a rapid drop in platelet count, Several studies
have suggested using high-dose antenatal corticosteroid (dexamethasone)
therapy in patients with HELLP syndrome to increase platelet counts, but
this is not generally recommended.34
Elevated liver function test results(greater than two times normal) with
epigastric or right upper quadrant pain.
Pulmonary edema
Rise in serum creatinine concentration by 1 mg/dL over baseline.
Placental abruption
Worsening fetal testing including severe oligohydramnios, severe fetal
growth restriction (less than the 5th percentile), or persistent, absent or
reversed end-diastolic flow of the umbilical artery.
OUTCOME
The major adverse outcomes associated with preeclampsia are maternal
organ dysfunction (brain, liver, kidney), thrombocytopenia, preterm
delivery, fetal growth restriction, abruptio placentae, and perinatal death.
46
Factors that influence outcome include gestational age at onset and
delivery, severity of disease, and whether there are coexisting conditions
present, such as multiple gestation, diabetes mellitus, renal disease, or
thrombophilia.69
MILD PREECLAMPSIA
Neonatal outcomes are generally good and comparable to those of
normotensive women except for a significantly higher frequency of labor
induction.
SEVERE PREECLAMPSIA
The highest risk of maternal and neonatal morbidity was in pregnancies
complicated by severe second trimester preeclampsia.
POSTPARTUM COURSE
Hypertension due to preeclampsia resolves postpartum, often within a few
days, but sometimes taking a few weeks. Severe hypertension should be
treated; some patients will have to be discharged on antihypertensive
medications that can be discontinued when blood pressure returns to
normal levels. Elevated blood pressures that remain 12 weeks postpartum
are unlikely to be related to preeclampsia and may require longterm
treatment. Risk of recurrence in subsequent pregnancy depends upon
gestational age at onset, maternal race, fetal paternity, parity, and
presence of other medical complications.70
47
PREVENTION
The lack of awareness about prophylaxis among care givers may be
responsible for high maternal and perinatal mortality.71
ROLE OF ASPIRIN
The observation that preeclampsia was associated with disturbances in
prostanoid and platelet function led to randomized trials evaluating low-
dose aspirin therapy in women thought to be at increased risk for the
disease. Low-dose aspirin (60 to 150 mg per day) was chosen in an
attempt to diminish platelet thromboxane synthesis while maintaining
vascular wall prostacyclin synthesis. In a systematic review of 14 trials
including over 12,000 women with historical risk factors for preeclampsia
(eg, previous history of preeclampsia, chronic hypertension, diabetes, renal
disease), low-dose aspirin prophylaxis was found to be modestly and
significantly effective. Aspirin reduced the risk of preeclampsia (odds ratio
[OR] 0.86, 95 percent CI 0.76 to 0.96), perinatal death (OR 0.79, 95
percent CI 0.64 to 0.96) and preterm birth (OR 0.86, 95 percent CI 0.79 to
0.94), but did not significantly affect birth weight or the risk of abruption.72
The above studies primarily including women with moderate or high risk
factors for preeclampsia and suggested benefit from aspirin therapy.In
contrast, two major trials in unselected nulliparous women, a group still at
48
increased risk, have shown little or no benefit from prophylactic aspirin
therapy. A multicenter French trial randomly assigned 3294 nulliparous
women to receive either 100 mg aspirin or placebo from inclusion at 14 to
20 weeks of gestation until 34 weeks. Women with chronic hypertension
were excluded. The incidence of preeclampsia (defined as blood pressure
> or =140/90 mmHg and proteinuria of at least 2+ or 0.5 g/L) was very low
and similar in both groups: 1.6 and 1.7 percent. There was no significant
difference in the incidence of placental abruption or fetal growth restriction
(less than the 10 percentile). Minor maternal bleeding was more common in
the aspirin group (11.6 versus 9.3 percent).73 The risk of preeclampsia in
unselected nulliparous women (2 to 6 percent) is higher than in multiparas
(1 percent), but is still relatively low compared to women with risk factors
such as chronic hypertension or renal disease (10 and 20 percent,
respectively). Aspirin therapy in nulliparas has not been shown to effect
birth weight, the incidence of fetal growth restriction or length of gestation,
but may modestly decrease the risk of preeclampsia.
ABNORMAL UTERINE ARTERY DOPPLER
Abnormal uterine artery Doppler ultrasonography may be the best clinically
available test for selecting women at high risk for developing preeclampsia,
but it is not clear on whom it should be performed. Aspirin prophylaxis
reduces the incidence of subsequent preeclampsia. Evidence of benefit
was demonstrated in a trial of 90 women with abnormal Doppler
49
velocimetry who began aspirin therapy at 12 to 14 weeks of gestation. 74
The value of routine Doppler surveillance for selecting patients to be
treated with aspirin was evaluated in a French trial which confirmed the
predictive value of uterine artery Doppler, but failed to demonstrate the
value of routine screening followed by aspirin therapy for a positive test
compared to routine prenatal care. 75
SUMMARY AND RECOMMENDATIONS
At present there is no easily identifiable group of pregnant women that will
predictably derive a clinically significant benefit from low-dose aspirin
therapy. Treatment should begin at 12 to 14 weeks of gestation. Early
therapy is probably important since the pathophysiologic features of
preeclampsia develop at this time, weeks before clinical disease is
apparent. Some observers recommend discontinuing aspirin five days
before expected delivery to diminish the risk of bleeding during delivery;
however, no adverse maternal or fetal effects related to aspirin have been
proven. The safety of aspirin use in the second and third trimesters is well-
established.76
CALCIUM SUPPLEMENTATION
Calcium supplementation (1.5 to 2 g of calcium carbonate per day) is
another modality that has been used in an attempt to prevent hypertensive
complications in pregnancy. The rationale for this regimen is based, in part,
upon the potential hypotensive action of calcium. In a study a 1.5-g
50
calcium/day supplement did not prevent preeclampsia but did reduce its
severity, maternal morbidity, and neonatal mortality, albeit these were
secondary outcomes.77
VITAMINS C AND E
The pathogenesis of preeclampsia has been described as a two-stage
process: reduced placental perfusion followed by the release of placental
factors that trigger maternal endothelial cell dysfunction. Oxidative stress
has been proposed as one cause of this endothelial cell dysfunction. In a
report looking at multiple markers of oxidative stress, vitamin
supplementation in women at high risk of developing preeclampsia was
associated with levels comparable to those in low risk women. 78
FISH OIL
It has been proposed that fish oil supplements may have a variety of
protective vascular effects, including reductions in systemic blood
pressure and in the incidence of preeclampsia and pregnancy-induced
hypertension. Fish oil supplementation had no effect on the incidence or
development of hypertension in either study but may increase the length
of gestation.79-80
51
OBJECTIVE OF STUDY
The objective of the study is:
To compare the effectiveness of transdermal
nitroglycerine patch and oral nifedipine in
hypertension during pregnancy.
52
OPERATIONAL DEFINITION
EFFECTIVENESS:-
Effectiveness will be measured in terms of
decrease in BP < 100 mm of Hg diastolic
HYPERTENSION IN PREGNANCY:-
Hypertension in pregnancy is defined as diastolic
BP > 110 mmHg on any one occasion or diastolic
BP of > 90 mm of Hg on 2 or more consecutive
occasions 4hrs apart.
HYPOTHESIS
Transdermal nitroglycerine is significantly effective
in the treatment of pregnancy induced
hypertension as compared to oral nifedipine.
53
MATERIAL AND METHODS
SETTING
Department of Gynae & Obstetrics, Maternal and
Child Health CenterPakistan Institute of Medical
Sciences Islamabad.
DURATION
Study was conducted from 1st July 2007 to 31st
Dec 2007
SAMPLE SIZE
30 patients in each group of study
SAMPLING TECHNIQUE
Non-probability convenience sampling.
SAMPLE SELECTION
54
INCLUSION CRITERIA
All Patients with raised BP.> 110 mmHg diastolic
reporting in OPD or in the casualty beyond 20wks
of gestation.
Patients of Pre eclampsia
Patients of Eclampsia
EXCLUSION CRITERIA
Patients with history of heart failure.
Patients receiving treatment during course of
current pregnancy.
STUDY DESIGN
Quasi experimental.
DATA COLLECTION PROCEDURE
55
The data was collected from admitted patients having
acute rise in diastolic BP> 90 mm of Hg with or
without Proteinuria and edema. Informed consent was
taken for participation in the study. Detailed history
and clinical examination was performed on all
patients. Patients were randomized in 2 groups and
were assigned specific number e.g. for trasdarmal
patch group A and for oral nifidipine group B. All
patients were allocated to these groups by using
random numbers table. Complete blood picture,
serum uric acid, ALT, PT/APTT, urine R/E, 24 hr.
urinary proteins were sent to laboratory for analysis.
Patient’s vital signs were monitored hourly and effect
of these drugs were recorded on a pre-designed
Performa (Annexed). In transdermal group 10 mg
patch was applied for 24 hours and blood pressure
was measured hourly. Decrease in blood pressure
equal to or <100 mm of Hg diastolic was considered
56
significant at which patch was removed. In oral
nefidipine group 20 mg nefidipine was given to the
patients repeated after 30 minutes if blood pressure
wouldn’t fall and the dose was adjusted accordingly.
57
DATA ANALYSIS
The data was entered into SPSS version
11. Descriptive statistics like mean+SD, frequencies,
and percentages were calculated. Chi-square test
was applied for categorical data (presenting
complaint, parity, side effects).Student T test was
used to determine statistical significance of numerical
data (age , duration of drug , dosage required )
RESULTS
58
Total number of patients who fulfilled the inclusion
criteria was 60.They were further subdivided in two
groups, each consisting of 30 patients. Mean age of
the patients was 27.5 years (SD+ 4.87). Among them,
primigravidas were 32 (53%) and multigravidas were
28 (46.7%). In the Nitroglycerine group, the mean
values of systolic & diastolic B.P. before using the
drug was 168.3mmHg (SD+ 20.3) and 108mmHg
(SD+ 18.2) falling to 131.6mmHg (SD+ 5.9) and
87.1mmHg (SD+ 4.4) respectively. In the Nifidipine
group, the results were almost similar after using the
drug. The mean duration of action of Nitroglycerine
was 9.47 hours (SD+ 8.9), whereas, it was only 1.2
hours (SD+ 4.3) for Nifidipine which was statistically
significant (p= 0.00). The mean dose of Nitroglycerine
used was 10mg, while 24mg of Nifidipine was used
on average (p= 0.00). No significant side effects were
reported.
59
60
TABLE I
FREQUENCY OF PARITY AMONG STUDY POPULATION (n=60)
Gravida Frequency Percent (%)
Primigravida 32 53.3
Multigravida 28 46.7
61
TABLE II
EFFECTS OF ANTIHYPERTENSIVES ON BP(mm of Hg)
Blood pressure
drug group
MeanStd.
Deviationsystolic blood
pressure before drug
TDP 168.33 20.36
Nifidipine 158.33 15.55
systolic blood pressure after
drug
TDP 131.67 5.92
Nifidipine 129.30 17.39
diastolic blood pressure before
drug
TDP 108.00 18.27
Nifidipine 110.33 7.18
diastolic blood pressure after
drug
TDP 87.17 4.49
Nifidipine 88.17 3.07
p-value for systolic Blood pressure before drug =0.037 p-value for systolic Blood pressure after drug =0.483 p-value for diastolic Blood pressure before drug =0.518 p-value for diastolic Blood pressure after drug =0.318 n=30 for each drug
62
TABLE III
DURATION OF ACTION OF DRUGS (HOURS)
drug group MeanStd.
Deviation
TDP 9.47 8.90
Nifidipine 1.23 0.43
p-value =0.000 n=30 for each drug
63
TABLE IV
EFFECTIVE DOSE OF DRUGS(mg)
drug group Mean Std. Deviation
TDP 10.00 .00
NIFIDIPINE 24.67 8.60
p-value =0.000 n=30 for each drug
64
FIG - I
FREQUENCY OF HEADACHE AMONG STUDY POPULATION n=60
65
FIG - II
FREQUENCY OF SYNCOPE AMONG STUDY POPULATION n=60
66
DISCUSSION
The definitive treatment of preeclampsia is delivery,
which is always beneficial for the mother. As long as the
gravida remains undelivered, she is at increased risk of
complications such as seizures, abruption,
thrombocytopenia, cerebral hemorrhage, pulmonary
edema, liver hemorrhage, and renal failure. The risk of
these complications subsides with delivery since
preeclampsia is a completely reversible disease
process.1
However, delivery may not be beneficial for the fetus if it
is born preterm. Although the fetus is at increased risk of
intrauterine growth restriction and stillbirth in the
preeclamptic environment, conservative management
may be entertained in selected cases to gain fetal
maturity.4
The indications for antihypertensive therapy in
preeclampsia are based on practice patterns
established over the years, rather than clinical trials with
67
clearly defined outcomes.
Severe hypertension should be treated to prevent
maternal vascular complications. There is no consensus
on the exact blood pressure threshold to initiate therapy.
In adult women, diastolic blood pressures > or =105 to
110 mmHg or systolic pressures > or =160 to 180
mmHg have been suggested. The threshold may be
lower in adolescents whose baseline diastolic pressure
is less than 75 mmHg; in such patients, treatment is
initiated at diastolic pressures of > or =100 mmHg.23
Occasionally preeclamptic women with severe
hypertension are stabilized and not delivered. In these
patients, oral antihypertensive therapy is often indicated.
In a study in Australia Sixty-four women in the second
half of pregnancy who were not in labor randomly
received 10 mg nifedipine tablets (n = 55 studies) or 10
mg nifedipine capsules (n = 74 studies) if blood
pressure was > or =170/110 mm Hg. Blood pressure,
heart rate, and cardiotocography were monitored over
the subsequent 90 minutes. Successful treatment was a
target blood pressure of 110 to 169/80 to 109 mm Hg
68
after 90 minutes; unsuccessful treatment included fetal
distress at any stage, the requirement for additional
treatment (intravenous hydralazine), or the development
of hypotension by 90 minutes after treatment. Nifedipine
capsules lowered blood pressure further (28/19 vs 21/13
mm Hg; P =.03) than nifedipine tablets, but more than
three quarters of each group had a successful
treatment. Twice as many women (28%) who received
nifedipine tablets required a second dose to achieve
successful treatment (P =.05), but fewer women had
hypotensive episodes (P =.001). Fetal distress was
uncommon in both groups (3%-4%), and both groups
were delivered an average of 4 days after the study.This
study showed Nifedipine tablets although of slower
onset were as effective as nifedipine capsules for the
rapid treatment of severe hypertension in pregnancy. In
our study oral nifedipine was used to control Blood
Pressure acutely in comparison with transdermal
nitroglycerine and it was found to be safe and
effective.81
69
In a study done in Poland Transdermal nitroglycerine
patches when used in pregnancy induced hypertension
Blood Pressure was easily controlled without any
serious side effects besides transient headaches
eliminated by oral analgesics with no long term side
effects comparable with our study. Mean blood pressure
value in this Polish study ranged in 135/85 mmHg was
received after 8 to 48 hours of treatment. The time of
therapy was three to thirteen weeks. Twenty four new
borns were delivered in Apgar score 8-9. No side effects
of long-term therapy with patches releasing GTN were
observed among the newborns.This study showed that
the long-term transdermal treatment affords possibilities
for pregnancy prolongation until the term of delivery and
improves the foetal development conditions. The side
effects of treatment are transient and affected only
mothers. In our study the mean duration of action of
Nitroglycerine was 9.47 hours (SD+ 8.9) and the mean
values of systolic & diastolic Blood Pressure. before
using the drug was 168.3 mm of Hg (SD+ 20.3) and 108
mm of Hg (SD+ 18.2) falling to 131.6 mm of Hg (SD+
70
5.9) and 87.1 mm of Hg (SD+ 4.4) respectively. We only
monitored Blood Pressure for acute control not the long
term control as done in this study. But both studies show
that Transdermal nitroglycerine is safer option in
pregnancy related hypertensive disorders. 82
In another study done in Germany Transdermal
nitroglycerine when used in tocolysis appeared to be
safe to mother and fetus with fewer maternal side
effects like headaches 71 percent with four drop out
cases. While in our study Our study was of only for short
term effects of transdermal nitroglycerine for
hypertension which was effectively controlled with fewer
maternal side effects like headache which was observed
in 13.3 percent cases.10
A study done in Italy the researchers compared the
effectiveness of transdermal glyceryl-trinitrate versus
oral nifedipine in lowering blood pressure in patients
affected by pregnancy-induced hypertension. Thirty-six
consecutive pregnant women were evaluated at
different gestational ages after the diagnosis of PIH or
preeclampsia. After a 24-h ambulatory blood pressure
71
monitoring, patients were allocated to three groups:
those receiving oral nifedipine and those receiving
transdermal glyceryl-trinitrate in a continuous (24 h/day)
or intermittent (16 h/day) administration. A second blood
pressure monitoring was performed after 2 weeks of
treatment. Systolic and diastolic blood pressures were
compared by using the Cosinor method looking at
mesor, amplitude, and acrophase. Baseline systolic and
diastolic blood pressures were similar among the three
groups. Neither the transdermal glyceryl-trinitrate
administered for 24 or 16 h nor oral nifedipine affected
systolic and diastolic blood pressure. Analysis of
variance showed that the posttreatment values were
similar among the groups.83 Our study showed that both
drugs Nitroglycerine and Nifedipine were effective at
reducing blood pressure in short term period with no
significant side effects. In our study we did not follow the
patients for long term effects of the drugs.
A prospective study of three years duration was carried
out at Abbasi Shaheed Hospital Karachi to assess the
response of oral nifedipine and diazepam infusion in the
72
management of eclampsia, There were 121 eclamptics
whereas there were 4,936 deliveries giving an incidence
of 1:40.79 or 24.51 per 1000 deliveries .The fits were
controlled with diazepam infusion in 117 patients(96.7%)
while blood pressure was controlled with oral nifedipine
in all the patients. There was a neonatal mortality of 7.3
per 1000 and maternal mortality of 1.4 per 1000. None
of these were related to the treatment. 8 As compared to
this study we studied effects of drugs only in PIH not in
eclamptics.
In our study we compared nitroglycerine transdermal
and oral nifedipine. Our study showed that
Nitroglycerine was effective at reducing blood pressure
during pregnancy at a lower dosage. The efficacy of
Nifidipine lies in its shorter duration of action. Both the
drugs can supplement each other. We did not follow the
patients for longer effects of the drugs on mother and
further outcome of the pregnancy.
73
74
CONCLUSION
From our study we concluded that both the drugs
transdermal nitroglycerine and oral nifedipine were
effective in reducing Blood Pressure with no significant
side effects. Only difference was in the dose and duration
of action. Dose was more in oral nifedipine and duration
of action was prolonged in transdermal nitroglycerine with
similar outcome. Further studies are recommended in our
population to establish the effect of nitroglycerine in
pregnancy induced hypertension because of its safer
profile.
75
76
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PROFORMA
Name: Husband name: Age: Address: Phone no:
Antenatal Visit Gestational age
Presenting complaint; headache, Visual disturbance, Epigastric pain, vomiting.
Obstetric history:
Past history:
Menstrual History:
Physical Examination: BP... …..reflexes……..edema……..clonus.
INVESTIGATIONS
S. No.
Test Value S. No. Test Value
1. Blood CP(Hb , PLT count)
6. PT/ APTT
2. Urine For Albumin 7. SGOT
3. 24 Hr urine proteins 8. USG
4. S. Uric Acid
FALL IN BP: 1ST hr 2nd hr 3rd hr (transdermal patch)………….
1ST hr 2nd hr 3rd hr (nifidipine group)………….MAINTANANCE DOSE……………………MINIMUM DOSE ……………………………..MAXIMUM DOSE……………………….Pts.COMPLAINTS……………………….
90