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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 highrisk 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 perfuseorgans (including fetus). BP decreases ~10% by the 7th week of pregnancy and is lowest at ~1824 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 Heart rate (beats/min)* Stroke volume (mL)* Cardiac output (L/min)* Blood volume (L) Central venous pressure (mm Hg)* 71 ± 10 73 ± 9 4.3 ± 0.9 5 4±3 Change in pregnancy (%) +10-20 +30 +30-50 (6 L/min) +20-50 Not significant Pulmonary capillary wedge pressure (mm Hg)* Systemic vascular resistance (dyne/cm/sec)* Pulmonary vascular resistance (mm Hg)* Mean arterial pressure (mm Hg)* Oxygen consumption (mL/min) V02 COP (mm Hg)* 6±2 1530 ± 520 119 ± 47 86 ± 8 250 20.8 ± 1.0 Not significant −20 (1210 dyne/cm/s) −34 Not significant +20-30 −14 COP - pulmonary capillary wedge pressure gradient (mm Hg)* 14.5 ± 2.5 −28 Left ventricular stroke work index (g/min/m2)* Not significant 41 ± 8 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. 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 ~4550% 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 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 maintaining 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 lowdose 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 preeclampsia 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 (40120 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 preeclampsia, 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 preeclampsia. 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 nonpregnant 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. 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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.e1514.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. 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