1

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.

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,

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

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

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.

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.

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

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

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

10

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

11

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

12

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

13

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)

14

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 mol/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

15

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

16

develop

eclamptic

seizures.2

Histopathologic

correlates brain

include damage, and

hemorrhage, microinfarcts,

petechiae, and

vasculopathy, necrosis.

ischemic Cerebral

fibrinoid

edema

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

17

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.

18

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:

19

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 mol/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

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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

21

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

22

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

23

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

24

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

25

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

26

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

27

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

28

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

29

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

30

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

31

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

32

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.

33

PERIPHERALLY ANTAGONISTS

ACTING

ADRENERGIC

RECEPTOR

-Blockers have been used extensively in pregnancy.Given differences in 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 -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 -blockers with effective control of maternal BP decreased incidence of severe hypertension and decreased rate of preterm admission to hospital. Labetalol a nonselective -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 receptor blockade. Fatigue, lethargy, exercise intolerance (because of 2-

34

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 -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

35

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

36

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 S 1 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 S 2 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

37

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-yetunknown 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

38

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

39

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 volumedepleted 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 ANGIOTENSIN RECEPTOR

ENZYME INHIBITORS ANTAGONISTS

AND

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 Potters 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. Firsttrimester exposure to ACE-I has been associated recently with a greater incidence of malformations of the cardiovascular and central nervous

40

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

41

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

42

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,

43

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

44

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:

45

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

46

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.

47

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

48

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 lowdose 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

49

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

50

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 wellestablished.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

51

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

52

OBJECTIVE OF STUDY
The objective of the study is: To compare the effectiveness and oral of transdermal in

nitroglycerine

patch

nifedipine

hypertension during pregnancy.

53

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.

MATERIAL AND METHODS

SETTING

54

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
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

55

EXCLUSION CRITERIA
Patients with history of heart failure. Patients receiving treatment during course of current pregnancy.

STUDY DESIGN
Quasi experimental.

DATA COLLECTION PROCEDURE

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,

56

serum uric acid, ALT, PT/APTT, urine R/E, 24 hr. urinary proteins were sent to laboratory for analysis. Patients 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 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 wouldnt 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.

TABLE I

FREQUENCY OF PARITY AMONG STUDY POPULATION (n=60)

Gravida Primigravida Multigravida

Frequency 32 28

Percent (%) 53.3 46.7

TABLE II

EFFECTS OF ANTIHYPERTENSIVES ON BP (mm of Hg)

Blood drug Mean pressure group systolic blood TDP 168.33 pressure before drug Nifidipine 158.33 systolic blood pressure after drug TDP 131.67

Std. Deviation 20.36 15.55 5.92 17.39 18.27 7.18 4.49 3.07

Nifidipine 129.30

diastolic blood TDP 108.00 pressure before drug Nifidipine 110.33 diastolic blood pressure after drug TDP Nifidipine 87.17 88.17

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

TABLE III

DURATION OF ACTION OF DRUGS (HOURS)

drug group TDP Nifidipine

Mean 9.47 1.23

Std. Deviation 8.90 0.43

p-value =0.000 n=30 for each drug

TABLE IV

EFFECTIVE DOSE OF DRUGS(mg)

drug group TDP NIFIDIPINE p-value =0.000 n=30 for each drug

Mean 10.00 24.67

Std. Deviation .00 8.60

FIG - I

60

50 48

no of patients

40

30

20

10 0

12

yes

no

symptoms of headache
yes=20% no=80%

FREQUENCY OF HEADACHE AMONG STUDY POPULATION n=60

FIG - II

60

50

51

no of patients

40

30

20

10 9 0 yes no

symptoms of syncope
yes=15% no=85%

FREQUENCY OF SYNCOPE AMONG STUDY POPULATION n=60

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 is a subsides completely with delivery since disease

preeclampsia process.1

reversible

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 are for antihypertensive based on therapy in

preeclampsia

practice

patterns

established over the years, rather than clinical trials with

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

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 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+ 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 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 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.

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.

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Pregnancy1999;18:107-13.

PROFORMA
Name: Phone no: Antenatal Visit Husband name: Gestational age Age: Address:

Presenting complaint; headache, Visual disturbance, Epigastric pain, vomiting. Obstetric history: Past history: Menstrual History: Physical Examination: BP... ..reflexes..edema..clonus. INVESTIGATIONS

S. No. 1. 2. 3. 4.

Test Blood CP(Hb , PLT count) Urine For Albumin 24 Hr urine proteins S. Uric Acid 1ST hr

Value S. No. Test 6. 7. 8. PT/ APTT SGOT USG

Value

FALL IN BP:

2nd hr

3rd hr

(transdermal patch).

1ST hr 2nd hr 3rd hr (nifidipine group). MAINTANANCE DOSE MINIMUM DOSE .. MAXIMUM DOSE. Pts.COMPLAINTS.