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

REFRENCES

1. Afifi Y, Churchill D. Pharmacological Treatment of Hypertension in

Pregnancy. Curr Pharm Des 2003; 9: 1745-53.

2. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons

learned from recent trials. Am J Obstet Gynecol 2004; 190:1520-6.

3.Lombardi DG,  Barton JR,  O'Brien JM,  Istwan NK, Sibai BM. Does an

obese prepregnancy body mass index influence outcome in pregnancies

complicated by mild gestational hypertension remote from term? Am J Obstet

Gynecol 2005 ; 192 :1472-4.

4. Xiong Xu, Fraser William D, Demianczuk, Nestor N. History of abortion,

preterm, term birth, and risk of preeclampsia: A population-based study. Am

J Obstet Gynecol 2002; 187:1013-8.

5. Akmal N, Raana G. Women with pregnancy induced hypertension;

epidemiological differences between normotensive pregnant women.

Professional Med J 2006;13:310-2.

6. Nilsson E, Ros HS, Cnattingius S, Lichtenstein P. The importance of

genetic and environmental effects for pre-eclampsia and gestational

hypertension: a family study. BJOG 2004; 111:200-6.

7. Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and

77

management of preeclampsia. JAMA 2002; 287:3183-6.

8. Munim TF. Management of Eclampsia by diazepam infusion and oral

nifedipine. J Surg Pak 2002;7:10-3.

9.Cetin A, Yurtcu N, Guvenal T, Imir AG, Duran B, Cetin M. The effect of

glyceryl trinitrate on hypertension in women with severe preeclampsia,

HELLP syndrome, and eclampsia. Hypertens Pregnancy 2004;23:37-46.

10.Schleussner E, Moller A, Gross W, Kahler C, Moller U, Richter S et al.

Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or

intravenous fenoterol combined with magnesium sulfate. Eur J Obstet

Gynecol Reprod Biol 2003; 106:14-9.

11. Xiong Xu, Fraser William D, Demianczuk, Nestor N. History of abortion,

preterm, term birth, and risk of preeclampsia: A population-based study. Am

J Obstet Gynecol 2002; 187:1013-8.

12. Dawson LM, Parfrey PS, Hefferton D, Dicks EL, Cooper MJ, Young D et

al. Familial risk of preeclampsia in newfoundland: a population-based study.

J Am Soc Nephrol 2002; 13:1901-6.

13. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT,

Jacobsen S et al. Antiphospholipid syndrome: clinical and immunologic

manifestations and patterns of disease expression in a cohort of 1,000

patients. Arthritis Rheum 2002; 46:1019-27.

14. Espinosa G, Bucciarelli S, Cervera R, Lozano M, Reverter JC, Red GD

78

et al. Thrombotic microangiopathic haemolytic anaemia and antiphospholipid

antibodies. Ann Rheum Dis 2004; 63:730-6.

15. Neville C, Rauch J, Kassis J, Chang ER, Joseph L, Comte ML et al.

Thromboembolic risk in patients with high titre anticardiolipin and multiple

antiphospholipid antibodies. Thromb Haemost 2003; 90:108-15.

16. Levine JS, Branch, DW, Rauch, J. The antiphospholipid syndrome. N

Engl J Med 2002; 346:752-63.

17. Wolfberg AJ, Lee-Parritz A, Peller AJ, Lieberman ES. Association of

Rheumatologic Disease With Preeclampsia. Obstet Gynecol 2004;

103:1190-3.

18. Zeeman GG, Alexander JM, McIntire DD, Byrd W, Leveno KJ. Inhibin-A

and superimposed preeclampsia in women with chronic hypertension.

Obstet Gynecol 2003; 101:232-6.

19.Salomon LJ , Benattar C , Audibert F , Fernan H, Duyme M , Taieb J. et

al. Severe preeclampsia is associated with high inhibin A levels and normal

leptin levels at 7 to 13 weeks into pregnancy. Am J Obstet Gynecol 2003;

189:1517-22.

20. Page NM. The endocrinology of pre-eclampsia. Clin Endocrinol 2002;

57:413-23.

21. Lepage N, Chitayat D, Kingdom J, Huang T, Association between

second-trimester isolated high maternal serum maternal serum human

79

chorionic gonadotropin levels and obstetric complications in singleton and

twin pregnancies. Am J Obstet Gynecol 2003;188 :1354-9.

22. Papageorghiou AT, Yu CK, Cicero S, Bower S, Nicolaides KH. Second-

trimester uterine artery Doppler screening in unselected populations: a

review. J Matern Fetal Neonatal Med 2002; 12:78-88.

23. Sibai BM. Diagnosis and Management of Gestational Hypertension and

Preeclampsia. Obstet Gynecol 2003; 102:181-192.

24. Milne F, Redman C, Walker J ,Baker P, Bradley J, Cooper C et al. The

pre-eclampsia community guideline (PRECOG): how to screen for and

detect onset of pre-eclampsia in the community. BMJ 2005;330: 576–80.

25. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal

booking: systematic review of controlled studies BMJ 2005;330:565. 

26. Buchbinder A, Sibai BM, Caritis S, MacPherson C, Hauth J, Lindheimer

M et al. Adverse perinatal outcomes are significantly higher in severe

gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol

2002; 186:66-71.

27. Waugh JJS, Clark TJ, Divakaran TG, Khan KS, Kilby MD. Accuracy of

Urinalysis Dipstick Techniques in Predicting Significant Proteinuria in

Pregnancy. Obstet Gynecol 2004; 103:769-77.

28. Neithardt AB, Dooley SL, Borensztajn J. Prediction of 24-hour protein

excretion in pregnancy with a single voided urine protein-to-creatinine ratio.

80

Am J Obstet Gynecol 2002;86:883-6.

29. Durnwald C, Mercer B. A prospective comparison of total

protein/creatinine ratio versus 24-hour urine protein in women with

suspected preeclampsia. Am J Obstet Gynecol 2003;189:848-52.

30. Al RA. Baykal C, Karacay O, Geyik PO, Altun S, Dolen I. Random urine

protein-creatinine ratio to predict proteinuria in new-onset mild hypertension

in late pregnancy. Obstet Gynecol 2004; 104:367-71.

31. Abraham KA, Kennelly M, Dorinan AM, Walshe JJ.Pathogenesis of

acute renal failure associated with the HELLP syndrome: a case report and

review of the literature. Eur J Obstet Gynecol Reprod Biol 2003;108:99-102.

32. Ingec M, Nazik H, Kadanali S. Urinary calcium excretion in severe

preeclampsia and eclampsia. Clin Chem Lab Med 2006; 44:51-3.

33. Powers RW, Bodnar LM, Ness RB,  Cooper KM, Gallaher MJ, Frank

MP et al. Uric acid concentrations in early pregnancy among preeclamptic

women with gestational hyperuricemia at delivery. Am J Obstet Gynecol

2006; 194:160-6.

34. Ihsan I, Akram M. A study of Platelet Activation in Pre-Eclampsia. Ann

King Edward Med Coll 2003;9:7-9

35. Bayraktaroglu Z, Demirci F, Balat O, Kutlar I, Okan V, Ugur G. Plasma

exchange therapy in HELLP syndrome: A single-center experience. Turk J

Gastroenterol 2006; 17: 99-102.

81

36. Dessole S,  Capobianco G , Virdis P, Rubattu G, Cosmi E, Porcu A.

Hepatic rupture after cesarean section in a patient with HELLP syndrome: a

case report and review of the literature. Arch Gynecol Obstet 2007;189-92.

37. Rasmussen S, Irgens LM. Fetal growth and body proportion in

preeclampsia. Obstet Gynecol 2003; 101:575-83.

38. Saeed GA, Hamid R, Khattak NB. Serum Uric Acid level as a marker for

predicting progression of gestational hypertension to pre-eclampsia and fetal

morbidity. Pak Armed Forces Med J 2003;53:136-41.

39. Naicker T, Khedun SM, Moodley J, Pijnenborg R. Quantitative analysis of

trophoblast invasion in preeclampsia. Acta Obstet Gynecol Scand

2003;82:722-9.

40. Wang X, Athayde N, Trudinger B. A proinflammatory cytokine response

is present in the fetal placental vasculature in placental insufficiency. Am J

Obstet Gynecol 2003; 189:1445-51.

41. Wang JX, Knottnerus AM, Schuit G, Norman RJ. Chan A. Dekker GA.

Surgically obtained sperm, and risk of gestational hypertension and pre-

eclampsia. Lancet 2002; 359:673-4.

42. Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Sperm exposure and

development of preeclampsia. Am J Obstet Gynecol 2003; 188:1241-3.

43. Lachmeijer AMA, Dekker GA, Pals G, Aarnoudse JG, Kate LPT,

Arngrimsson R. Searching for preeclampsia genes: the current position. Eur

82

J Obstet Gynecol Reprod Biol 2002; 105:94-113.

44. Wang Y, Gu Y, Zhang Y,  Lewis DF. Evidence of endothelial dysfunction

in preeclampsia: decreased endothelial nitric oxide synthase expression is

associated with increased cell permeability in endothelial cells from

preeclampsia.2004; 190: 817-24.

45. Maynard SE, Min JY, Merchan J, Lim KH, Li j, Mondal S et al. Excess

placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to

endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin

Invest 2003; 111:649-58.

46. Dvorak HF. Vascular permeability factor/vascular endothelial growth

factor: a critical cytokine in tumor angiogenesis and a potential target for

diagnosis and therapy. J Clin Oncol 2002; 20:4368-80.

47. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N et al.

Glomerular-specific alterations of VEGF-A expression lead to distinct

congenital and acquired renal diseases. J Clin Invest 2003; 111:707- 16.

48. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF et al.

Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med

2004; 350:672-83.

83

49. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A et al.

Overexpression of the soluble vascular endothelial growth factor receptor in

preeclamptic patients: pathophysiological consequences. J Clin Endocrinol

Metab 2003; 88:5555-63.

50. Nagamatsu T, Fujii T, Kusumi M, Zu L, Yamashita T, Osuga Y et al.

Cytotrophoblasts up-regulate Soluble Fms-like Tyrosine Kinase-1 (sFlt-1)

Expression under Reduced Oxygen: An Implication for the Placental Vascular

Development and the Pathophysiology of Preeclampsia. Endocrinology 2004;

145:4838-45.

51. Papageorghiou AT, Yu CK, Nicolaides KH. The role of uterine artery

Doppler in predicting adverse pregnancy outcome. Best Pract Res Clin

Obstet Gynaecol 2004; 18:383-96.

52. Becker R, Vonk R, Vollert W, Entezami M. Doppler sonography of

uterine arteries at 20-23 weeks: risk assessment of adverse pregnancy

outcome by quantification of impedance and notch. J Perinat Med 2002;

30:388-94.

53. Harrington K, Fayyad A, Thakur V, Aquilina J. The value of uterine artery

Doppler in the prediction of uteroplacental complications in multiparous

women. Ultrasound Obstet Gynecol 2004; 23:50-5.

84

54. Xu B, Thornton C, Makris A, Ogle R, Hennessy A. Anti-hypertensive

drugs alter cytokine production from preeclamptic placentas and peripheral

blood mononuclear cells. Hypertens Pregnancy. 2007;26:343-56.

55. von Dadelszen P, Magee LA. Fall in mean arterial pressure and fetal

growth restriction in pregnancy hypertension: an updated metaregression

analysis. J Obstet Gynaecol Can 2002; 24:941-5.

56. Magee LA, Cham C, Waterman EJ, Ohsson A, von Dadelszen P.

Hydralazine for treatment of severe hypertension in pregnancy: meta-

analysis. BMJ 2003; 327:955-60.

57. Umans JG. Medications during pregnancy: antihypertensives and

immunosuppressives. Adv Chronic Kidney Dis 2007; 14: 191–8.

58. Waterman EJ, Magee LA, Lim KI, Skoll A, Rurak D, von Dadelszen P. Do

commonly used oral antihypertensives alter fetal or neonatal heart rate

characteristics? A systematic review. Hypertens Pregnancy. 2004; 23: 155–

69.

59. Bartels PA, Hanff LM, Mathot RA, Steegers EA, Vulto AG, Visser W.

Nicardipine in pre-eclamptic patients: placental transfer and disposition in

breast milk. BJOG. 2007; 114: 230–3.

85

60. Brown MA, Buddle ML, Farrell T, Davis GK. Efficacy and safety of

nifedipine tablets for the acute treatment of severe hypertension in

pregnancy. Am J Obstet Gynecol. 2002; 187: 1046–50.

61. Magee LA, Miremadi S, Li J, Cheng C, Ensom MH, Carleton B, Cote AM,

von Dadelszen P. Therapy with both magnesium sulfate and nifedipine does

not increase the risk of serious magnesium-related maternal side effects in

women with preeclampsia. Am J Obstet Gynecol. 2005; 193: 153–63.

62. Nevo O, Thaler I, Shik V, Vortman T, Soustiel JF. The effect of isosorbide

dinitrate, a donor of nitric oxide, on maternal cerebral blood flow in gestational

hypertension and preeclampsia. Am J Obstet Gynecol. 2003; 188: 1360–5.

63. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon

PS, Hall K, Ray WA. Major congenital malformations after first-trimester

exposure to ACE inhibitors. N Engl J Med. 2006; 354: 2443–51.

64. Zia RA, Bashir A, Gul A, Tajammal A. Fetal and maternal out come in

Eclampsia. Ann King Edward Med Coll 2006;12:140-1.

65. Ashraf M, Sheikh NH, Sheikh AH. Feto maternal outcome in Eclampsia.

Biomedica 2003;19:68-73.

66. Jamil SN, Akhtar S. Maternal outcome in Eclampsia. J Med Sci Jul

2005;13:161-4.

86

67. Newman MG, Robichaux AG, Stedman CM, Jaekle RK, Fontenot MT,

Dotson T, Lewis DF. Perinatal outcomes in preeclampsia that is complicated

by massive proteinuria. Am J Obstet Gynecol 2003; 188:264-8.

68. Hall DR, Odendaal HJ, Steyn DW, Grove D. Urinary protein excretion

and expectant management of early onset, severe pre-eclampsia. Int J

Gynaecol Obstet 2002; 77:1-6.

69. Hnat MD, Sibai BM, Caritis S, Hauth J, Lindheimer MD, MacPherson C

et al. Perinatal outcome in women with recurrent preeclampsia compared

with women who develop preeclampsia as nulliparas. Am J Obstet Gynecol

2002;186:422-6.

70. Tabassum R, Naureen S, Ahmed M, Khan NH. Pre-Eclampsia /

Eclampsia: the time taken to become normotensive. a prospective study.

Med Channel 2006;12:22-4.

71. Sikandar R, Memon A, Shaikh F. Pre-eclampsia: prevention strategies. J

Surg Pakistan 2003;8:30-1.

72. Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin

for prevention of preeclampsia in women with historical risk factors: A

systematic review. Obstet Gynecol 2003; 101:1319.

73. Subtil, D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G et al.

Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women:

the Essai Regional Aspirine Mere-Enfant study (Part 1). BJOG 2003;

87

110:475-84.

74. Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J. Low dose

acetylsalicylic acid in prevention of pregnancy-induced hypertension and

intrauterine growth retardation in women with bilateral uterine artery notches.

BJOG 2002; 109:161-7.

75. Subtil D, Goeusse P, Houfflin-Debarge V, Puech F, Lequien P, Breart G

et al. Randomised comparison of uterine artery Doppler and aspirin (100 mg)

with placebo in nulliparous women: the Essai Regional Aspirine Mere-Enfant

study (Part 2). BJOG 2003; 110:485-91.

76. Kozer E, Costei AM, Boskovic R, Nulman I, Nikfar S, Koren G. Effects of

aspirin consumption during pregnancy on pregnancy outcomes: meta-

analysis. Birth Defects Res Part B Dev Reprod Toxicol 2003; 68:70-84.

 77. Villar J, Abdel-Aleem H, ,  Merialdi M,  Mathai M, Ali MM,  Zavaleta N et

al. World Health Organization randomized trial of calcium supplementation

among low calcium intake pregnant women. Am J Obstet Gynecol 2006;194:

639-49

78. Chappell LC, Seed PT, Kelly FJ, Briley  A, Hunt BJ, Charnock-Jones D

et al. Vitamin C and E supplementation in women at risk of preeclampsia is

associated with changes in indices of oxidative stress and placental function.

Am J Obstet Gynecol 2002; 187:777-84.

88

79. Khoury J, Henriksen T,  Christophersen B, , Tonstad S. Effect of a

cholesterol-lowering diet on maternal, cord, and neonatal lipids, and

pregnancy outcome: A randomized clinical trial. Am J Obstet Gynecol

2005;193:1292-301.

80. Smuts CM, Huang M, Mundy D, Plasse T, Major S, Carlson SE. A

randomized trial of docosahexaenoic acid supplementation during the third

trimester of pregnancy. Obstet Gynecol 2003; 101:469-79.

81. Brown MA, Buddle ML, Farrell T, Davis GK. Efficacy and safety of

nifedipine tablets for the acute treatment of severe hypertension in

pregnancy. Am J Obstet Gynecol 2002;187:1046-50.

82. Brozozowska M, Kowalska-Koprek U, Karowicz-Bilinska A, Pajszczyk-

Kieszkiewicz T. [Effect of long-term therapy with transdermal patches

releasing glyceryl trinitrate (GTN) used in pregnant hypertensive women on

stabilisation of blood pressure and on the condition of the newborn infant].

Ginekol Pol 2004;75:134-8.

83. Neri I, Valensise H, Facchinetti F, Menghini S, Romanini C, Volpe A. 24-

hour ambulatory blood pressure monitoring: a comparison between

transdermal glyceryl-trinitrate and oral nifedipine. Hypertens

Pregnancy1999;18:107-13.

89

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