Hypertensive Disorders in Pregnancy Corrina Oxford, MD*

Educational Objectives:

After completing this seminar, the student should be better able to:

Understand the effects of pregnancy on the maternal cardiovascular system.

Devise a clear and rational plan for antepartum care in women with chronic

hypertension.

Understand the distinction between pregnancy-induced hypertension and

preeclampsia, and between “mild” and “severe” preeclampsia.

Discuss the risks and benefits of the various preventive strategies for women at high-

risk for developing preeclampsia.

Counsel patients with a diagnosis of preeclampsia about their management options.

Recognize and manage appropriately the complications of preeclampsia, including

eclampsia (seizures), uncontrolled hypertension and stroke.

I. Effects of pregnancy on the maternal cardiovascular system

Most physiologic changes of pregnancy are evolutionary protective mechanisms in preparation

for the blood loss associated with delivery.

The cardiac output in pregnancy increases by 30-50% of baseline with an average output of 6

L/min in term gravidas. This is associated with a 20-50% increase in blood volume which is

mainly due to a ~50% increase in plasma volume. The combination of a significant increase in

plasma volume, along with a 33% increase in red cell mass, results in an average blood volume

increase of ~1500 mL above the 5 L baseline average. This volume expansion begins as early as

7 weeks of pregnancy and is even higher in multiple gestations. An expanded blood volume to

this degree is an excellent way to prepare for the average 500 mL blood loss associated with

vaginal delivery (1000 mL in cesarean) without hemodynamic effects. Women can lose a

significant amount of blood before showing signs of hemodynamic compromise. 2

The systemic vascular resistance (SVR) decreases significantly in pregnancy as well. 2 The

formula for blood pressure is BP= CO x SVR. This reflects cardiovascular ability to perfuse-

organs (including fetus). BP decreases ~10% by the 7th week of pregnancy and is lowest at ~18-

24 weeks. Decreased BP due to lower SVR in pregnancy is because of progesterone mediated

vasoldilation. This leads to increased blood volume and a resultant increased C.O. However, the

increased C.O. cannot fully compensate for lower SVR and this explains the lower BP seen

during pregnancy. Blood pressure increases to near baseline levels in the late third trimester.

(figure 1)

Figure 1.

Blood pressure pattern in pregnancy

Measurement Normal value Change in pregnancy

(%)

Heart rate (beats/min)* 71 ± 10 +10-20

Stroke volume (mL)* 73 ± 9 +30

Cardiac output (L/min)* 4.3 ± 0.9 +30-50 (6 L/min)

Blood volume (L) 5 +20-50

Central venous pressure (mm Hg)* 4 ± 3 Not significant

Pulmonary capillary wedge pressure (mm Hg)* 6 ± 2 Not significant

Systemic vascular resistance (dyne/cm/sec)* 1530 ± 520 −20 (1210 dyne/cm/s)

Pulmonary vascular resistance (mm Hg)* 119 ± 47 −34

Mean arterial pressure (mm Hg)* 86 ± 8 Not significant

Oxygen consumption (mL/min) V02 250 +20-30

COP (mm Hg)* 20.8 ± 1.0 −14

COP - pulmonary capillary wedge pressure gradient (mm Hg)* 14.5 ± 2.5 −28

Left ventricular stroke work index (g/min/m2)* 41 ± 8 Not significant

As stated earlier, pregnancy is considered a state of “gestational hypervolemia” as it is

hallmarked by a vasodilatory state that leads to increased urinary Na+ and water retention.

Maternal plasma volume increases by 10% as early as 7 weeks of pregnancy and plateaus to ~45-

50% at ~32 weeks then remains stable until delivery. Hemodilution is maximal at 30-32 weeks. 2

(Table 1)

The massive blood volume expansion that occurs in pregnancy may be severely blunted by

pathologic conditions, in particular severe preeclampsia. The mean blood volume expansion in

women with preeclampsia has been reported to be ~200 mL as compared to the typical 1500 mL

in normal pregnancies. 2 This is particularly important as preeclampsia is a condition of relative

intravascular depletion with hyperdynamic cardiac output. All things considered, one must keep

in mind the limited ability for women with preeclampsia to tolerate hemorrhage.

Women with pre-eclampsia are also predisposed to pulmonary edema. The decrease in colloid

oncotic pressure (COP) in pregnancy may be exaggerated in preeclampsia, coupled with

increased hydrostatic pressure and vascular permeability is a recipe for pulmonary edema.

Of note, as magnesium sulfate is almost completely renally excreted, one should decrease the

dose of the infusion in women with preeclampsia (in particular) who have impaired renal function

to decrease likelihood of toxicity.

Placing women in the left lateral recumbent position augments cardiac output. 3 This position is

particularly important when surgical procedures are performed in pregnant patients. Supine

hypotension occurs secondary to diminished venous return from compression of the inferior vena

cava by a 20 week size or greater uterus. At 20 weeks, the uterus is at the umbilicus.

The increased GFR in pregnancy results in a reduced upper limit of normal serum creatinine of

0.8 mg/dL in normal pregnancies. 3 This means when faced with what would otherwise be a

normal creatinine of 1.0 mg/dL in a pregnant patient, one should consider renal compromise and

investigate the cause. Medications infused via femoral central catheters may not circulate well

Adapted from Clark S, Cotton D, Lee W, Bishop C, Hill T, Southwick J, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989;161:1439-42; and Elkayam U, Gleicher N. Hemodynamics and cardiac function during normal pregnancy and the puerperium. In: Elkayam U, Gleicher N, editors. Cardiac problems in pregnancy. 3rd ed. New York: Wiley-Liss; 1998. p. 3-19.

with compression from the gravid uterus on the iliac vessels and this may be critical when

resuscitating a patient.

Pregnancy is also a hypercoagulable state designed to attenuate the bleeding with childbirth.

Unfortunately this evolutionary adaptation also increases the risk for venous-thromboembolism in

pregnancy.

Renal plasma flow and glomerular filtration rate (GFR) both increase in pregnancy. The GFR

may increase up to 50% in pregnancy. 3

II. Hypertensive disorders of pregnancy

The hypertensive diseases that are encountered most commonly during pregnancy include:

gestational hypertension (HTN), chronic hypertension, and chronic hypertension with

superimposed pre-eclampsia, mild or severe preeclampsia and HELLP Syndrome.

Development of hypertensive disorders is the most common medical complication during

pregnancy, affecting 10% to 20% of all pregnancies worldwide. Elevated blood pressure (BP) is a

common denominator in a number of clinical entities that complicate pregnancy, including

pregnancy-induced hypertension (PIH), preeclampsia, eclampsia, and hemolysis, elevated liver

enzyme levels, low platelet count (HELLP) syndrome. Preeclampsia complicates 5% to 14% of

pregnancies worldwide and 5% to 8% in the United States. 4

Criteria established by the National High Blood Pressure Working Group, in pregnant women,

gestational hypertension is defined as: SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg that occurs after

20 weeks of gestation in a woman with previously normal blood pressure. 5 If blood pressure

elevations described above occur before 20 weeks of gestation, this is a patient with chronic

hypertension. If a woman with chronic HTN develops preeclampsia during pregnancy, the

nomenclature to describe this is: chronic hypertension with superimposed preeclampsia. One

does not have to qualify if it is mild or severe when described in patients with chronic HTN.

The hallmark of preeclampsia is hypertension and proteinuria. This is in comparison to the

patient with elevated blood pressure without proteinuria who may have gestational hypertension.

Preeclampsia is defined as: SBP >140mm Hg or DBP >90 mm Hg on 2 occasions 6 h apart with

an onset after 20 weeks and urine protein +1 on dipstick on 2 occasions 6 h apart or urine protein

>300 mg/24 h. 5 A screening spot urine protein/creatinine ratio>0.19 is suspicious and depending

on other maternal clinical signs and symptoms will help solidify a diagnosis of preeclampsia.

Severe preeclampsia is defined by severely elevated BPs (SBP >160, DBP >110), proteinuria and

evidence of end organ effects described in the table below. Eclampsia is the development of a

tonic-clonic seizure and this can occur in 1-2% of women with severe preeclampsia. 6

III. Management of women with chronic hypertension

In pregnancy, chronic hypertension is defined by hypertension prior to pregnancy or before the

20th week of gestation. Hypertension is defined as systolic blood pressure of 140 mm Hg or

greater, or diastolic blood pressure of 90 mm Hg or greater, or both (Box 1). Young women who

develop severe hypertension (>180/110 mm Hg) early in pregnancy may require evaluation for

secondary causes of their hypertension.

Ideally, a blood pressure measurement before 12 weeks of gestation is obtained because the

normal decrease in blood pressure in the midtrimester, may mask previously undiagnosed chronic

hypertension. When this occurs, hypertension may only become apparent when blood pressure

increases back near baseline later in pregnancy. In the office, blood pressure readings should be

taken with an appropriate-sized cuff (length 1.5 times the upper arm circumference or a cuff with

a bladder that encircles 80% or more of the arm) to ensure accurate readings. Blood pressure

should be measured only after the patient has rested (preferably 10 minutes or more) and is seated

with the cuff positioned at the level of her heart.

When hypertension develops during pregnancy, typically in the third trimester, in the absence of

signs or symptoms of preeclampsia, the diagnosis of gestational hypertension is appropriate.

However, up to 25-30% of women with chronic hypertension or gestational hypertension also can

develop preeclampsia. Chronic hypertension is associated with several adverse pregnancy

outcomes, including premature birth, fetal growth restriction, fetal demise, placental abruption,

and cesarean delivery. The incidence of these adverse effects appears related to the duration of

the disease, the severity of the hypertension, and the presence or absence of superimposed

preeclampsia.

End-organ testing before pregnancy or early in pregnancy includes assessment of renal function,

electrocardiography, echocardiography, and ophthalmologic evaluation. Baseline laboratory tests

to assess renal function include serum creatinine, blood urea nitrogen, 24-hour urinary protein

excretion or spot urine for protein/creatinine ratio and creatinine clearance. Most providers will

collect an early 24-hour urine protein excretion to have a comparison sample later in pregnancy

as a significant increase in proteinuria may be indicative of preeclampsia in women with baseline

proteinuria.

Women with significant left ventricular hypertrophy and abnormal function secondary to

hypertension are more prone to experience cardiac decompensation and heart failure as pregnancy

progresses because of the increased intravascular volume and cardiac demand. Renal dysfunction

increases the risk of adverse pregnancy outcome.

It is often difficult to distinguish worsening chronic hypertension from superimposed

preeclampsia when the patient presents with elevated blood pressure late in pregnancy. In the

woman with chronic hypertension and renal disease, it may not be possible to distinguish between

the two entities. However, most young, nulliparous women who present with hypertension for the

first time during late pregnancy will have preeclampsia.

Antihypertensive therapy has been shown to reduce the risk of a severe maternal hypertensive

crisis but has not been shown to improve the overall perinatal outcome.

Experts in the United States have recommended that pregnant women with hypertension in the

blood pressure range of 150–160/100–110 mm Hg should be treated with antihypertensive

therapy, and that their blood pressure should be kept lower than 150/100 mm Hg. Guidelines

from Canada and the United Kingdom suggest considering treatment at lower values by main-

taining a blood pressure of 140–159/90–109 mm Hg. In women with evidence of end-organ

damage, such as left ventricular hypertrophy or renal insufficiency, antihypertensive treatment is

recommended to maintain blood pressure in the normal range, thereby reducing the risk of further

end-organ damage. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor

blockers are contraindicated during all trimesters of pregnancy.

The most appropriate management of mild hypertension in women who received antihypertensive

medications at conception is unclear. For women with mild hypertension, antihypertensive

therapy offers long-term maternal benefits, but there have been few if any short-term benefits

noted in pregnancy. 7

Evaluation of fetal growth by ultrasound in women with chronic hypertension is warranted.

Monitoring may include weekly nonstress testing or biophysical profile testing in the late third

trimester, and the use of umbilical artery Doppler is appropriate.

Pregnant women with uncomplicated mild chronic hypertension generally are candidates for a

vaginal delivery at term because most of them have good maternal and neonatal outcomes.

Cesarean delivery should be reserved for obstetric indications. Women with hypertension during

pregnancy and a prior adverse pregnancy outcome (eg, stillbirth) may be candidates for earlier

delivery after documentation of fetal lung maturity. Although there are no randomized trials that

evaluate best time of delivery, a recent consensus panel recommended that women with chronic

hypertension who are not taking medications, give birth at 38–39 weeks of gestation, women

whose hypertension is controlled with medications should give birth at 37–39 weeks of gestation,

and women with severe hypertension that is difficult to control should give birth at 36–37 weeks

of gestation. 7

In women with chronic hypertension, documentation of discussion of risks of chronic

hypertension in pregnancy, documentation of baseline proteinuria, and documentation of plan for

evaluation for fetal growth should be part of the record. 7

IV. Various prevention strategies for women at high risk of preeclampsia

There are no interventions that can reliably prevent preeclampsia. However, there have been

recent studies to suggest possible interventions to modify the risk in women at increased risk for

developing preeclampsia. Risk factors are listed on Table 1

Several studies have looked at prevention of preeclampsia and the three interventions

with some promising data are: low-dose aspirin, heparinoids and calcium

supplementation.

One systematic review and meta-analysis of randomized controlled trials was performed

where studies in which women were randomized at or before 16 weeks' gestation to low-

dose aspirin versus placebo or no treatment were included. The outcomes of interest were

severe preeclampsia and mild preeclampsia. Pooled relative risks with their 95%

confidence intervals (CIs) were calculated. Results Among 7941 citations retrieved, 352

were completely reviewed and four studies (392 women) fulfilled the inclusion criteria

and were analyzed. When compared with controls, aspirin started at ≤16 weeks was

associated with a significant reduction in severe (relative risk: 0.22, 95% CI: 0.08 to 0.57)

but not mild (relative risk: 0.81, 95% CI: 0.33 to 1.96) preeclampsia. The author’s

conclusion was that low-dose aspirin (ASA 81 mg by mouth daily) initiated at or before

16 weeks reduces the risk of severe, but not mild preeclampsia.8

Another study recognizing the link between early-onset hypertensive disorders (HD) of

pregnancy, small-for-gestational age infants (SGA) associated with placental vascular

thrombosis, and inheritable thrombophilia showed that aspirin reduced the recurrence risk. They

theorized that adding low-molecular-weight heparin (LMWH) to aspirin at < 12 weeks gestation

reduces the recurrence of HD in women with previous early-onset HD (pre-eclampsia, HELLP

syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without

antiphospholipid antibodies. They performed a multicenter randomized control trial (RCT) where

139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery< 34 weeks

gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S

deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene

G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention:

either daily LMWH (dalteparin, 5000 IU weight-adjusted dosage) with aspirin 80 mg or aspirin

80 mg alone. Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective

of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal

hospitalization, spontaneous abortion and individual HD. Analysis by intention-to-treat. The

results showed low-molecular-weight heparin with aspirin reduced recurrent HD onset < 34

weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P =

0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not

different between the arms. No women withdrew as a result of adverse effects. They concluded

that adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks

gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks.

However, close monitoring of the mother and fetus remains important throughout pregnancy. 9

The Cochrane Group conducted a meta-analysis to assess the effects of calcium

supplementation during pregnancy on hypertensive disorders of pregnancy and related

maternal and child outcomes. The randomized trials compared at least 1 g daily of

calcium during pregnancy with placebo. They included 13 studies of good quality

(involving 15,730 women). The average risk of high blood pressure was reduced with

calcium supplementation rather than placebo (12 trials, 15,470 women: risk ratio (RR)

0.65, 95% confidence interval (CI) 0.53 to 0.81). There was also a reduction in the

average risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730

women: RR 0.45, 95% CI 0.31 to 0.65). The effect was greatest for high-risk women

(five trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and those with low baseline

calcium intake (eight trials, 10,678 women: RR 0.36, 95% CI 0.20 to 0.65).The average

risk of preterm birth was reduced in the calcium group overall (11 trials, 15,275 women:

RR 0.76, 95% CI 0.60 to 0.97) and amongst women at high risk of developing pre-

eclampsia recruited to four small trials (568 women: RR 0.45, 95% CI 0.24 to

0.83).There was no overall effect on the risk of stillbirth or death before discharge from

hospital (11 trials 15,665 babies; RR 0.90, 95% CI 0.74 to 1.09). The composite outcome

maternal death or serious morbidity was reduced (four trials, 9732 women; RR 0.80, 95%

CI 0.65 to 0.97). Most of the women in these trials were low risk and had a low calcium

diet. Maternal deaths were reported in only one trial. One death occurred in the calcium

group and six in the placebo group, a difference which was not statistically significant

(RR 0.17, 95% CI 0.02 to 1.39). Blood pressure in childhood has been assessed in two

studies, only one of which is currently included: childhood systolic blood pressure greater

than 95th percentile was reduced (514 children: RR 0.59, 95% CI 0.39 to 0.91). The

authors concluded that calcium supplementation appears to approximately halve the risk

of pre-eclampsia, reduce the risk of preterm birth and reduce the rare occurrence of the

composite outcome 'death or serious morbidity'. There were no other clear benefits, or

harms.10

V. Management of mild and severe preeclampsia

The rate of seizures in women with mild preeclampsia not receiving magnesium sulfate is very

low. Based on data from observational studies and 2 randomized placebo trials (Table V), this

rate is estimated to be about 1 in 200 women. Magnesium sulfate prophylaxis has been shown to

reduce the risk of seizure by 50% therefore 400 women need to be treated to prevent a single

seizure without possible additional benefit to either mother or fetus. In this group, magnesium

sulfate may potentially be associated with a higher number of adverse maternal effects due to

treatment than the seizure itself. Therefore, the benefit-to-risk ratio does not support routine use

of magnesium sulfate prophylaxis in mild preeclampsia. The rate of seizures in women with

severe preeclampsia not receiving magnesium sulfate is 2.0%, while it is 0.6% in those receiving

such therapy (Table I). Thus, 71 women with severe preeclampsia need to be treated to prevent 1

case of eclampsia that is not associated with untoward adverse effects on the mother, fetus, or

neonate. Women with severe preeclampsia are a heterogeneous group with substantially different

risks for seizure.

Based on results of observational studies, randomized trials, and anecdotal experience, it is

recommended that magnesium to be used intravenously as a 6 g loading dose over 20 to 30

minutes, and followed by a maintenance dose of 2 g/hour. The infusion should be started at the

beginning of labor and continued for at least 24 hours’ postpartum. For women requiring cesarean

delivery, the infusion should begin at least 1 hour before surgery and continued during the

surgery. The drip rate should be reduced or stopped in women with renal dysfunction. 11

There is evidence-based data from the HYPITAT trial that suggests delivery is indicated in

pregnancies complicated by mild gestational hypertension or mild pre-eclampsia occurring at

37 or more weeks’ gestation. This is the first multicenter trial designed to compare the risks and

benefits of induction of labor versus expectant monitoring for women with mild gestational

hypertension/pre-eclampsia at >36-0/7 weeks’ gestation. The trial included 756 women with a

singleton pregnancy at 36-0/7 to 41-6/7 weeks who had mild gestational hypertension (n = 496)

or mild pre-eclampsia (n = 246); 377 were allocated to induction and 379 to expectant

monitoring. Women randomized to the induction group had a significant reduction in primary

outcome (Table 3). This reduction was mainly attributable to differences in the rates of

progression to severe hypertension. There were no differences in adverse neonatal outcomes. In

addition, the overall rates of cesarean delivery were not different in both groups; however, in the

induction group, the rate of cesarean delivery was lower in nulliparous women and in those with a

cervical Bishop score <2. This latter finding refutes the belief that induction of labor in these

women increases the rate of cesarean delivery. Therefore, induction of labor and/or delivery at

>37 weeks’ gestation should be offered to all such women provided that gestational age is well

documented and the induction period is not prolonged beyond 48 hours.

The main aim of expectant treatment is to improve perinatal outcome by prolonging gestation and

reducing neonatal morbidities (acute and long-term). There are potential perinatal complications

during expectant treatment; consequently, all reported studies recommended intensive fetal

surveillance for early detection of fetal compromise. The most common indication for delivery in

most studies was deterioration in fetal status. Expectant treatment improves perinatal outcome in

a select group of women with severe preeclampsia at <32 6/7 weeks of gestation. It must be

emphasized that these recommendations are based on only 2 randomized trials (a total of 133

women) and several observational studies on the subject.

The presence of severe preeclampsia at >34 0/7 weeks of gestation mandates immediate

hospitalization in the labor and delivery unit. Intravenous magnesium sulfate therapy should be

started to prevent convulsions and antihypertensive medications to lower severe hypertension

(systolic pressure SBP >160 mm Hg and/or diastolic pressure DBP >110 mm Hg). The goal is to

keep SBP between 140 -155 mm Hg and DBP between 90- 105 mm Hg.

In addition, corticosteroids are administered for fetal lung maturation. During the observation

period, maternal and fetal conditions are assessed, and a decision is made regarding the need for

delivery. After initial clinical and laboratory evaluation, a decision must be made for immediate

delivery vs expectant treatment. Patients with eclampsia, neurologic deficit (blindness, confusion,

motor deficit), pulmonary edema, disseminated intravascular coagulation, suspected abruptio

placentae, or nonreassuring fetal heart rate testing are delivered regardless of the benefit of

corticosteroids after maternal stabilization. Patients with a gestational age of <23 0/7 weeks

should be offered termination of pregnancy because no babies have survived in reported studies

during the expectant treatment of severe preeclampsia at this gestational age. In addition,

expectant treatment in patients with gestational age between 23 0/7 and 23 6/7 results in

extremely high maternal and perinatal morbidity and mortality rates. Therefore, expectant

treatment in these patients should be considered only as an option after extensive counseling.

Maternal evaluation includes monitoring of blood pressure, urine output, cerebral status, and the

presence of epigastric pain, tenderness, labor, or vaginal bleeding. Laboratory evaluation

includes a platelet count, liver enzyme and serum creatinine testing, and a type and screen. Fetal

evaluation includes continuous fetal heart rate monitoring, a biophysical profile, and

ultrasonographic assessment of fetal growth, amniotic fluid status, and umbilical artery Doppler

velocimetry. Patients with resistant severe hypertension despite maximum doses of intravenous

labetalol (220-240 mg) plus either intravenous hydralazine (25 mg), oral nifedipine (50 mg), or

persistent cerebral symptoms while on magnesium sulfate should be delivered within 24-48

hours, irrespective of gestational age. In addition, patients with thrombocytopenia (platelet count

<100,000) or elevated liver enzymes with epigastric pain and tenderness (HELLP syndrome) or

serum creatinine of >1.5 mg/dL4,7,14 also are delivered within 48 hours. Moreover, patients

with gestational age of 33 0/7-34 6/7 with labor and/or rupture of membranes, severe FGR (<5th

percentile for gestational age), persistent severe oligohydramnios (amniotic fluid index of <5 cm

on at least 2 occasions that were >24 hours apart), or umbilical artery doppler studies with

persistent reverse blood flow, also are delivered within 48 hours. 12

During observation on the antepartum ward, blood pressure is measured every 4-6 hours. Patients

receive antihypertensive drugs as needed, usually oral nifedipine 10-20 mg every 4-6 hours (40-

120 mg per day) and/or labetalol 200-800 mg every 8-12 hours (600-2400 mg per day), to keep

SBP between 140 and 155 mm Hg and DBP between 90 and 105 mm Hg. Alternatively, a long

acting (XL) version of nifedipine (30 mg every 12 hours) can be used for BP control. During

titration of oral antihypertensive agents, if the patient has a persistent severe hypertensive

episode, blood pressure is assessed every 15 minutes. If the blood pressure remains in the severe

range after 30-60 minutes, the patient should be transferred to the labor and delivery unit for more

intensive monitoring and treatment. The patient should then receive an acute dose of either oral

nifedipine 10mg or labetalol 20 mg intravenously or hydralazine 5-10 mg intravenously, as

needed.

Patients with resistant severe hypertension after maximum doses of IV labetalol should receive

magnesium sulfate and delivered. The patients receive frequent assessment of maternal and fetal

well-being. Maternal assessment includes: frequent evaluation of symptoms (headache, blurred or

double vision, confusion, nausea, vomiting, epigastric or right upper abdominal pain, shortness of

breath, uterine activity, and vaginal bleeding), volume intake and output, and laboratory testing.

Laboratory testing includes complete blood count with platelet count and transaminase, lactate

dehydrogenase, and serum creatinine levels. Fetal assessment includes daily fetal kick counts, at

least daily nonstress test (NST) with uterine activity monitoring with biophysical profile (BPP) if

the NST is nonreactive and twice weekly amniotic fluid assessment. Severe oligohydramnios is

defined as an amniotic fluid index of <5 cm on at least 2 occasions that are at least 24 hours apart.

Severe oligohydramnios is considered an indication for delivery in all patients with a gestational

age of >30 weeks, irrespective of other fetal testing results. In those <30 weeks of gestation,

pregnancy may be continued with reassuring NST and umbilical artery Doppler findings. 12

Umbilical artery Doppler studies are performed weekly, or more often if IUGR is suspected

and/or testing reveals abnormal diastolic flow. Umbilical artery doppler studies with reverse

diastolic blood flow after initial maternal/fetal stabilization is considered an indication for

delivery. Ultrasonographic assessment of fetal growth is performed every 2 weeks. If a patient

experiences headache that does not resolve with oral analgesics within 6 hours and the headache

continues to be severe, they should be transferred to the labor and delivery unit and receive

intravenous magnesium sulfate and antihypertensives as needed. If the headache persists,

preparations should be made for delivery. Patients with new onset epigastric or right upper

abdominal pain, retrosternal pain or pressure, and recurrent heart burn, particularly in association

with nausea and vomiting, are also transferred to the labor and delivery unit for further

assessment. If the symptoms persist and/or the liver enzymes are abnormal, preparations are made

for delivery. In addition, the onset of uterine contractions and/or vaginal bleeding requires

immediate transfer to the labor and delivery unit because it could signify the development of

abruption placentae. At any time during expectant treatment, the development of any of the

findings in the table below is an indication for delivery. 12

The cesarean section rates among reported studies range from 66%-96%, with the higher rates for

patients with severe preeclampsia at <28 weeks of gestation. On the basis of the available data, a

plan for vaginal delivery be attempted in patients with a gestational age of >32 0/7 weeks with

vertex presentation. In addition, vaginal delivery may be attempted in those women between 27

0/7 and 31 6/7 weeks of gestation in the absence of severe IUGR and/or reverse UA doppler

findings. The goal is for delivery within 24 hours of the induction. Serial induction days are not

appropriate in these cases. Elective cesarean section is recommended for all patients with

gestational age below 27 weeks of and for all those with severe FGR and/or reverse umbilical

artery Doppler (UAD) at <32 weeks of gestation because successful vaginal delivery is less likely

in these groups. Once the decision is made for delivery, the patients should receive intravenous

magnesium sulfate in labor and for at least 24 hours after delivery. The figure below shows an

approach to the management of severe preeclampsia at <34 weeks. 12

VI. Complications of preeclampsia and management

Hypertensive emergency

Hypertensive disorders are the third most common cause of pregnancy-related maternal death

(17.6% all outcomes; pregnancy-related mortality ratio, 1.6 deaths/100,000 live births). The

objective of treating severe hypertension is to prevent intracerebral hemorrhage and cardiac

failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow, which

is already reduced in many women with preeclampsia. Table 2 below outlines different

manifestations of hypertensive emergency.

Studies of women with mild preeclampsia have shown no benefit to antihypertensive therapy

(labetalol or calcium-channel blockers) and suggested that antihypertensive therapy may increase

the risk of IUGR. Antihypertensive therapy is therefore administered primarily to prevent

complications in the mother.

The Working Group Report on High Blood Pressure in Pregnancy recommends initiation of

antihypertensive therapy for a DBP > 105 mm Hg. Furthermore, most authorities and the current

guidelines from the American College of Obstetricians and Gynecologists, recommend keeping

SBP from 140-160 mm Hg and DBP from 90-105 mm Hg. This recommendation is supported by

a study demonstrating that SBP > 160 mm Hg was the most important factor associated with a

cerebrovascular accident in patients with severe preeclampsia and eclampsia. This would suggest

that SBP from 155-160 mm Hg should be the primary trigger to initiate antihypertensive therapy

in a patient with severe preeclampsia or eclampsia. It should be noted that patients with

preeclampsia/eclampsia may have a very labile BP because of intravascular depletion; this fact

together with the narrow target BP range dictate that these patients be closely monitored in a high

acuity setting, preferably with an arterial catheter. Intracerebral hemorrhage is a devastating

complication in these patients that can be avoided by scrupulous attention to BP control.

Intravenous labetalol or nicardipine, are easier to titrate and have a more predictable dose

response than hydralazine. Both agents appear to be safe and effective in hypertensive pregnant

patients. Nitroprusside can be given for a limited amount of time and risks cyanide toxicity to the

mother and fetus. ACE inhibitors are contraindicated in pregnant patients. 17

Pulmonary Edema

Pulmonary edema is the most common cardiopulmonary complication of pre-eclampsia and

refers to an excessive accumulation of fluid in the pulmonary interstitial and alveolar spaces. The

development of pulmonary edema is usually multifactorial. According to the Starling equation,

any factor that results in a reduction in colloid osmotic pressure, an increase in capillary

permeability, or an increase in intravascular hydrostatic pressure will lead to extravasation of

fluid from the vasculature and predispose to the development of pulmonary edema. The

underlying physiological changes in the maternal cardiovascular system, including increased

plasma blood volume, cardiac output, heart rate, and capillary permeability, and a decrease in

plasma colloid osmotic pressure, are exaggerated in pre-eclampsia along with increased

hydrostatic pressure and predispose women to develop pulmonary edema.

Medical therapies to treat pulmonary edema should be optimized to expedite treatment results.

Furosemide (Lasix) can be administered intravenously as a single dose of 10-40 mg over 2

minutes to promote diuresis. Bladder catheterization allows for accurate measurement of urine

output. Most patients will respond to initial diuresis therapy. If adequate response is not seen

within 30-60 minutes, the dose should be increased to 40-60 mg administered by slow

intravenous injection to a maximum of 120 mg in 1 hour. Electrolytes should be monitored

closely and repleted as indicated. Morphine sulfate can be administered intravenously as needed

both for pain as well as in an attempt to reduce the adrenergic vasoconstrictor stimuli to the

pulmonary arteriolar and venous beds. As with the management of all parturients with pre-

eclampsia, sodium and water should be modestly restricted, and maternal fluid balance should be

strictly monitored.

Oxygen saturation should be monitored using a pulse oximeter, and oxygen supplementation

using a nonrebreather facemask can be used to treat maternal hypoxemia. Intubation is rarely

required. In addition to these standard measures, it is appropriate to follow the patient’s blood

pressure, electrocardiogram, and fetal heart rate tracing. Afterload reduction using vasodilators

may be necessary, especially in parturients with chronic hypertension and superimposed pre-

eclampsia. 16

ARDS

Pre-eclampsia complicated by HELLP syndrome, pulmonary edema, and/or cardiopulmonary

disease can advance to pregnancy-related ARDS in rare instances. In a series of 83 obstetrical

patients with ARDS from all causes, the antepartum mortality rate was 23% and the postpartum

mortality rate was 50%. 16

Cerebrovascular Accidents

The vast majority of patients with cerebral ischemia present with acutely elevated BP regardless

of the subtype of infarct or preexisting hypertension. The BP elevation decreases spontaneously

over time. The elevated BP is not a manifestation of a hypertensive emergency but rather a

protective physiologic response to maintain cerebral perfusion pressure to the vascular territory

affected by ischemia. Lowering the BP in patients with ischemic strokes may reduce cerebral

blood flow, which because of impaired autoregulation, may result in further ischemic injury. The

common practice of “normalizing” the BP following a cerebrovascular accident is potentially

dangerous.

The American Stroke Association and the European Stroke Initiative guidelines recommend

withholding antihypertensive therapy for acute ischemic stroke unless there is planned

thrombolysis, evidence of concomitant noncerebral acute organ damage, or if the BP is

excessively high, arbitrarily chosen as a SBP > 220 mm Hg or a DBP > 120 mm Hg based on the

upper limit of normal autoregulation. In these patients, the aim is to reduce the mean arterial

pressure by not more than 10 to 15% in the first 24 h. Semplicini and colleagues demonstrated

that a high initial BP was associated with a better neurologic outcome following an acute

ischemic stroke. These authors suggest that hypertension may be protective during an acute

ischemic stroke and that lowering the BP may be potentially harmful. Hypertensive therapy is

required for SBP > 185 mm Hg or DBP >110 mm Hg, with a targeted SBP of 180 mm Hg and a

DBP of 105 mm Hg. The current American Heart Association guidelines recommend the use of

labetalol or nicardipine if the SBP is > 220 mm Hg or the DBP is from 121- 140 mm Hg, and

nitroprusside for a DBP > 140 mm Hg. For the reasons outlined above, we believe nitroprusside

to be a poor choice in patients with intracranial pathology. These parameters are in place for non-

pregnant patients and are applied to the gravid population, however, no well done studies define

appropriate parameters in pregnancy.

In patients with intracerebral hematomas, there is almost always a rise in intracranial pressure

with reflex systemic hypertension. There is no evidence that hypertension provokes further

bleeding in patients with intracranial hemorrhage. However, a precipitous fall in systemic BP will

compromise cerebral perfusion. The controlled lowering of the BP is currently recommended

only when the SBP is >200 mm Hg, the DBP is > 110 mm Hg, or the MAP is > 130 mm Hg.

One study demonstrated that the rapid decline of BP within the first 24 h after presentation of an

intracranial hemorrhage was associated with increased mortality; the rate of decline in BP was

independently associated with increased mortality. Nicardipine has been demonstrated to be an

effective agent for the control of BP in patients with intracerebral hemorrhage. 17

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) affects patients late in pregnancy or in the early postpartum

period. It is an infrequent complication of pre-eclampsia, but a history of preeclampsia can be

found in up to 70% of those who develop PPCM. The 4 following criteria are needed to meet the

definition of peripartum cardiomyopathy: (1) development of cardiac failure in the last month of

pregnancy or within 5 months of delivery; (2) absence of an identifiable cause for the cardiac

failure; (3) absence of recognizable heart disease before the last month of pregnancy; (4) left

ventricular systolic dysfunction (for example, left ventricular ejection fraction (EF) below 45%).

The etiology remains unclear, but risks factors include multiple pregnancy, pre-eclampsia,

multiparity, and advanced maternal age. Pre-eclampsia is associated with peripartum

cardiomyopathy as a risk factor; however, peripartum cardiomyopathy is an infrequent

complication of pre-eclampsia. Women with residual cardiac dysfunction postpartum should be

counseled against future pregnancy given associated risk for worsening left ventricular function

and mortality. 16

Myocardial Ischemia and Infarction

Myocardial infarction associated with pregnancy is a rare event, usually related to maternal risk

factors for ischemic heart disease, such as hypertension, diabetes mellitus, and coronary

atherosclerosis. However, a mechanism of coronary spasm has been suggested to be a cause of

myocardial infarction in patients with normal coronary arteries or in those with minimal

nonobstructive coronary artery disease, especially infarction related to pre-eclampsia, after

administration of ergot alkaloids, bromocriptine, oxytocin, and prostaglandin.

Early diagnosis of acute myocardial infarction in pregnancy is often hindered by the normal

changes of pregnancy and low level of suspicion.

Pre-eclampsia and coronary artery disease share common risk factors for endothelial dysfunction

and damage, such as hypertension, diabetes, and obesity. The associated maternal physiological

changes from pre-eclampsia include increased inflammatory markers, dyslipidemia, insulin

resistance, endothelial dysfunction, and oxidative stress and are associated with an increased risk

for cardiovascular disease in later life. A history of pre-eclampsia has been reported to be a risk

factor for several distinct cardiovascular conditions later in life. 16

Cortical Blindness and PRESS (aka PLES)

Blindness in pre-eclampsia could be due to ocular pathologies such as retinal detachment or

vascular occlusion, or more frequently cortical origin (Table 1). It can be seen in 1–15% of all

preeclamptic patients and the rates are higher in underdeveloped countries. Visual disturbances

are a well-known clinical entity seen in patients with hypertensive disorders of pregnancy. Exact

central defects of this finding were not known until Hinchey et al. described PLES as a clinical

syndrome in 1996. Although they describe this condition as a puerperal entity, the exact

frequency of cerebral involvement is not known as cranial imaging is not routine in the absence

of obvious neurological symptoms. Therefore, most cases of posterior cerebral edema might go

unnoticed in pre-eclamptic women, even with visual disturbances (figure 1). Acute cortical

blindness is one of the most dramatic presentations of pre-eclampsia and is historically known to

be reversible. However, blindness, especially when secondary to ocular pathologies, may be

irreversible. 15

Summary

The diagnosis and management of hypertensive disorders of pregnancy can be quite challenging.

One needs to be mindful of pregnancy physiology, gestational age at presentation and maternal

co-morbidities. Severe complications of preeclampsia often involve a multi-disciplinary

approach with blood pressure control and delivery.

References:

1. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control

and Prevention National Center for Health Statistics Hyattsville, Maryland February 2007 DHHS

Publication No. (PHS) 2007-1417

2. Dildy, Gary. Critical Care Obstetrics. 4th ed. Blackwell Science 2004

3. Yeomans, E, Gilstrap, L. Physiologic changes in pregnancy and their impact on critical care.

Critical Care Medicine. Volume 33(10) Supplement. pp S256-S258. October 2005

4. Henry, CS, Biedermann, S, Campbell, M, Guntupalli, JS. Spectrum of hypertensive

emergencies in pregnancy. Critical Care Clinics 20. p 697-719. 2004

5. American College of Obstetricians and Gynecologists (ACOG) practice bulletin. Diagnosis

and management of preeclampsia and eclampsia. Number 33, January 2002.

6. Eric A P Steegers, Peter von Dadelszen, Johannes J Duvekot, Robert Pijnenborg. Pre-

eclampsia. Lancet 2010; 376: 631–44

7. ACOG practice Bulletin 125: Chronic Hypertension in Pregnancy. Vol 119 (2) part I.

February 2012. p396-402

8. Roberge S, Giguère Y, Villa P, Nicolaides K, Vainio M, Forest JC, von Dadelzen P, Vaiman

D, Tapp S, Bujold E. Early Administration of Low-Dose Aspirin for the Prevention of Severe

and Mild Preeclampsia: A Systematic Review and Meta-Analysis. Am J Perinatol. 2012 Apr 11.

[Epub ahead of print]

9. de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH; FRUIT Investigators.

Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-

eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. Thromb Haemost. 2012

Jan;10(1):64-72.

10. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy

for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2010

Aug 4;(8):CD001059.

11. Sibai BM. Management of late preterm and early-term pregnancies complicated by mild

gestational hypertension/pre-eclampsia. Semin Perinatol. 2011 Oct;35(5):292-6.

12. Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term:

patient selection, treatment, and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-

514.e9.

13. Sibai, BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent

trials. American Journal of Obstetrics and Gynecology (2004) 190, 1520e6

14. Bauer, ST, Cleary, KL. Cardiopulmonary Complications of Pre-eclampsia. Semin Perinatol

33:158-165. 2009

15. Lutfu S. Onderoglu, Polat Dursun, Murat Gultekin and Nilufer Y. Celik Posterior

leukoencephalopathy syndrome as a cause of reversible blindness during pregnancy J. Obstet.

Gynaecol. Res. Vol. 33, No. 4: 539–542, August 2007

16. Charles S. Henry, MD, Scott A. Biedermann, MD, Michel F. Campbell, MD, Jayarama S.

Guntupalli, MD Spectrum of hypertensive emergencies in pregnancy. Crit Care Clin 20 (2004)

697– 712

17. Paul E. Marik, MD, FCCP; and Joseph Varon, MD, FCCP Hypertensive Crises Challenges

and Management CHEST 2007; 131:1949–1962