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Antihypertensive Medications in Management of Gestational Hypertension-Preeclampsia Clinical Obstetrics and Gynecology vol 48(2) June 2005, pp441~459

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Indroduction International Guidelines (Severe Hypertension in pregnancy) Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension? Maternal Side Effects Adverse Effects on Fetal Heart Rate Perinatal Outcomes Discussion

Introduction:

Introduction Hypertension ( dBP ≥ 90mmHg ) : complicates 7~ 9% of pregnancies 1% : complicated by preexisting hypertension 5~6% : by gestational hypertension without proteinuria Preexisting hypertension : before pregnancy or before 20wks gestation 2 nd to diabetes or other maternal diseases Nonproteinuric gestational hypertension : ≥ 20 weeks’ gestation c proteinuria (-) Severe hypertension : dBP ≥ 110mmHg accounts for most of the increased maternal risk (such as death or stroke) associated with pregnancy hypertension ※ Most women with preexisting or gestational hypertension : mild~moderate elevation of BP(dBP 90~109mmHg) → associated with much lower maternal risk than that of severe hypertension

International Guidelines Severe Hypertension in Pregnancy:

International Guidelines Severe Hypertension in Pregnancy Maternal risk is decreased by antihypertensive treatment that acutely lowers very high blood pressure → meant that the control of acutely raise blood pressure has become central for women with severe hypertension, particularly that of preeclampsia Three short-acting antihypertensive agents hydralazine short-acting [sublingual or orally administered] nifedipine labetalol → commonly used control acute very high blood pressure in women with severe hypertension in pregnancy who may require emergency cesarean section and often receive magnesium sulfate

International Guidelines Severe Hyopertension in Pregnancy:

International Guidelines Severe Hyopertension in Pregnancy Hydralazine Short-acting nifedipine labetalol Choice of drug 1 st choice for severe pregnancy hypertension required by midwives or nurses in the absence of a doctor used extensively in pregnancy has a favorable side effect Side effect Headache Nausea Vomiting → mimic symptoms of deteriorating preeclampsia Maternal hypotension : associated with - an excess of c/sec - placental abruptions - low Apgar scores (<7) at 5min if coronary artery disease or diabetes (+) →associated with excess cardiovascular morbidity and mortality transient neuromuscular weakness (2 case reports) : nifedipine+magnesium sulfate risk of neonatal bradicardia ( ↑)

International Guidelines Severe Hyopertension in PregnancyM:

International Guidelines Severe Hyopertension in PregnancyM Hydralazine Short-acting nifedipine Labetalol Site of action Vasodilators - Vascular smooth muscle CCB (Calcium channel antagonists) - Vascular smooth m. Antiadrenergic agent – α ß receptors Indicat-ion moderate~severe HBP (oral) malignant hypertension (IV, IM) renal disease with hypertension Mild~moderate HBP Mild~moderate HBP Onset 10~20min (peak : 10~20min) Nicardipine : 5~10min (peak : 20~40min) 5min (peak : 20~30min) Duration 4~12h 1~4h 3~6h Dosage oral :10~75mg qid IV or IM:10~50mg every 6h (tolerance may develop) oral : 30~90mg qd oral:100~600mg bid IV : 2mg bid - Harrison’s15th edition p1423-1424 -

International Guidelines Severe Hyopertension in PregnancyM:

International Guidelines Severe Hyopertension in PregnancyM Hydralazine Short-acting nifedipine labetalol Contraindication /cautions Lupus erythematousus severe coronary aretery disease Heart failure, 2 nd or 3 rd degree heart block side effects Headache Tachycardia Anginal pectoris Anorexia Nausea/vomiting Diarrhea Lupuslike syndrome Rash Fluid retension tachycardia flushing gastrointestinal disturbance hyperkalemia edema headache Dizziness, depression bronchospasm nausea, vomiting, darrhea / constipation heart failure, fatigue Raynaud’s phenomenon hallucinations hypertriglyceridemia hypercholesterolemia psoriasis sudden withdrawal may - precipitate angina - myocardial injury in patients with heart disease. - Harrison’s15th edition p1423-1424 -

International Guidelines Severe Hyopertension in Pregnancy:

Recently performed and published a metaanalysis of randomized, controlled trials (RCTs) for treatment of moderate to severe hypertension in pregnancy comparing the effects of short-acting antihypertensive agents (in comparison to parenteral hydralazine) on perinatal, maternal and neonatal outcomes, particularly maternal hypotension International Guidelines Severe Hyopertension in Pregnancy

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?:

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ? Criteria of data : moderate ~ severe hypertension in pregnancy, randomized, controlled trial, hydralazine compaired with another short-acting antihypertensive and relevant clinical outcomes addressing maternal, perinatal or pediatric benefit or risk Severity of hypertension : according to mean dBP - mild : 90~99mmHg - moderate : 100~109mmHg - severe ≥ 110mmHg defined according to the National High Blood Pressure Education Program(NHBPEP) Mixed hypertension : mixed populations of women with either preexisting hypertension or gestational hypertension with or without proteinuria Pregnancy-induced hypertension : when women both with and without proteinuria were enrolled Preeclampsia : when all trial participants had pregnancy-induced hypertension with proteinuria at enrollment

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?:

Maternal outcomes persistent severe hypertension need for additional antihypertensive therapy maternal hypotension cesarean section placental abruption maternal mortality or morbidity : eclampsia, intracerebral hemorrhage, HELLP syndrome, pulmonary edema, oliguria, DIC maternal side effects - overall and those thought to indicate deteriorating maternal preeclampsia : headache, visual symptoms, epigastric pain and nausea or vomiting Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?:

Perinatal outcomes Adverse effects on fetal heart rate stillbirth apgar scores at 1and 5 minutes neonatal death, tachycardia hypotension hypethermia hypoglycemia admission to NICU (neonatal intensive care unit) respiratory distress syndrome, Intraventricular hemorrhage Necrotizing enterocolitis Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?:

Maternal outcome Persistent severe hypertension : dBP ≥ 90mmHg, 95mmHg, 100mmHg, 110mmHg : mean arterial blood pressure ≥120mmHg : failure to achieve a drop in systolic/diastolic blood pressure of 30/15mmHg Hydralazine < labetalol Hydralazine > nifedipine of isradipine Low –dose hydralazine infusion > Ketanserin(5mg iv bolus then 4mg/hr iv) ※ low-dose infusion : 1mg/hr intravenously increased by 1mg/hr/hr every hour~maximum of 10mg/hr High-dose bolus hydralazine < Ketanserin (10mg iv every 20min) ※ high-dose : 5mg intravenously every 20min Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ?:

Which Antihypertensive Agent Should Be Used for Severe Pregnancy Hypertension ? Maternal Hypotension Hydralazine : associated with more maternal hypotension than other antihypertensives (labetalol, nifedipine or isradipine, urpidil, ketanserin) Several maternal outcomes (cesarena section , placental abtuption , maternal oliguria) Hydralazine : more often than other antihypertensives In summary Persistent severe hypertension Maternal Hypotension Several maternal outcomes ( cesarena section , placental abtuption , maternal oliguria) Hydralazine < labetalol Hydralazine > nifedipine or isradipine Low –dose hydralazine infusion > Ketanserin High-dose bolus hydralazine < Ketanserin Hydralazine>other antihypertensives (labetalol, nifedipine or isradipine, urpidil, ketanserin) Hydralazine> other antihypertensives

Maternal Side Effects:

Maternal Side Effects Hydralazine associated with more maternal side effects than labetalol or ketanserin associated more headache, palpitations and maternal tachycardia than other antihypertensives whether hydralazine was associated with more side effects than nifedipine was unclear

Adverse Effects on Fetal Heart Rate:

Adverse Effects on Fetal Heart Rate Defined as acute fetal distress : need for cesarean section as a result of fetal distress or a decelerative fetal heart rate pattern : deterioration in the cardiotocographic tracings : abnormal fetal heart rate pattern in the 6hours after treatment : abnormal fetal heart rate in labor : fetal heart rate decelerations : late decelerations during continuous fetal heart rate monitoring or CTG abnormalities Hydralazine : associated with more adverse effects on fetal heart rate that other antihypertensives, with the significant heterogeneity isolated to the hydralazine vs labetalol subgroup.

Perinatal outcomes:

Perinatal outcomes Hydralazine associated with more low Apgar scores at 1minute than other antihypertnesives ※ but the incidence of low Apgar scores at 5min did not differ between groups associated with less neonatal bradycardia than labetalol more stillbirth than other antihypertensives

Discussion :

Discussion Hydralazine associated with some poorer maternal and perinatal outcomes than other antihypertensives, particularly labetalol and nifedipine less effective antihypertensive than nifedipine or isradipine ( not clearly differ from labetalol) - more several adverse outcomes : maternal hypotension, placental abruption, adverse effects on fetal heart rate cesarean section, maternal oliguria, stillbirth(statistical trend only) and low Apgar score at 1minute. : less neonatal bradycardia than labetalol - more poorly tolerated than other antihypertensives : more maternal side effects were seen than with labetalol or ketanserin ( more headaches, palpitations and maternal tachycardia were seen than with other antihypertensives, with the exception of nifedipine)

Discussion :

→ these results are biologically plausible. : rapid or excessive falls in maternal blood pressure may decrease placental perfusion (reflected by abnormal fetal heart rate pattern) and lead to placental abruption, cesarean section and low Apgar scores at 1min (with recovery by 5min with resuscitation) The unpredictability of the timing and magnitude of the blood pressure-lowering effect of hydralazine may make its use in pregnancy problematic → The results of this metaanalysis do not support recent recommendations favoring initial use of hydralazine over other antihypertensives (including keranserin) Discussion

Discussion :

Nifedipine : reasonable alternative to hydralazine - profound m. weakness and respiratory arrest were associated with concomitant use of nifedipine and magnesium sulfate (in 2case reports) ※ Hydralazine : no neuromuscular blockade was describe in any of the trials comparing hydralazine with nifedipine or isradipine, even though magnesium sulfate was given to all or some woman and no such blockade was reported in the Magpie trial, in which 29% of women allocated to receive magnesium sulfate also received nifedipine ☞ any risk of neuromuscular blockade is likely to be low Discussion

Discussion :

Labetalol : reasonable alternative to hydralazine less effective in preventing recurrent severe hypertension , but controlled severe hypertension in 87% of women and was similar to other antihypertensive agents in the need to prescribe further antihypertensives association between parenteral labetalol and neonatal bradycardia Ketanserin : an agent investigated most widely in The Netherlands and South Africa, compared favorably with hydralazine Discussion

Discussion :

The most recent Cochrane review found no good evidence that 1 short-acting antihypertensive is better than another, with the exception of ketanserin, which is associated with more persistent hypertension Discussion

Discussion :

Conclusion The result of this review should generate uncertainty about the agent of first choice for treating severe hypertension in pregnancy Definitive data from adequately powered clinical trials are needed, with the most promising comparison being that of nifedipine with labetalol The result of this review support the use of antihypertensive agents other than hydralazine for the acute management of severe hypertension in pregnancy Discussion

Discussion :

Discussion Interaction Between Nifedipine And MgSo 4 Table 2 . Summary : Neuromuscular Blockade Among the Calcium Channel Blocker Arms of Nifedipine/Nicardipine vs. Other Antihypertensive Trials in Which Magnesium Sulfate Was Given, This Study and the Magpie Trial

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Discussion Interaction Between Nifedipine And MgSo 4 : concluded that using nifedipine and magnesium sulfate together does not appear to be associated with an excess of serious Mg-related effects

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Mild-to-Moderate Hypertension in Pregnancy The Effect of Blood Pressure control on Maternal and Perinatal Outcomes The nature of Risks to the Mother - Typically, elevated BP among nonpregnant women is monitored over months before initiating antihypertensive medication - In hypertensive pregnant women, BP is typically elevated only over months, given the midtrimester nadir in BP Discussion

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Mild-to-Moderate Hypertension in Pregnancy The Nature of Risks to the Baby Both preexisting hypertension and nonproteinuric gestational hypertension have been associated with a high risk of adverse perinatal outcome. Preexisting hypertension : the perinatal mortality rate - 40/1000 SGA(small-for-gestational-age)infant(<10 th percentile) : approximately 15% 20% of preexisting hypertension and 40% of nonproteinuric gestational hypertension (<34wks) → develop superimposed preeclampsia → the risks of adverse perinatal outcome : even higher → risk of SGA : ~ 40%(increasing) Discussion

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Relevant Systematic Reviews 27 RCTs examined the impact of differential BP control for mild~moderate pregnancy hypertension on maternal and perinatal outcomes. 26 trials compared between “tight” control – aiming for a dBP <90mmHg- “less tight” control – aiming for a dBP : 100~110mmg 1trial : compared “tight” to “very tight” control → although the RCTs did not report outcome by type of hypertension and were too small to examine the risk of BP control in terms of perinatal complications or SGA infants, these trials provide the least biased information on treatment effectiveness 35 trials compared 1 antihypertensive with another, applying the same dBP treatment goals to women in both treatment group “less tight” control : associated with a lower risk of SGA infants compared with “tight”control Discussion

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Relevant Systematic Reviews These was a significant and linear correlation between the decrease in mean arterial pressure and both an increase in the incidence of SGA infants and a reduction in birthweight “less tight” control associated with an increased risk of respiratory distress syndrome (RDS) ← little confidence can be placed in this finding because only 6/22 trials reported on RDS and the incidence of RDS was unusually high in the “less tight” group(6.4) considering that most infants were delivered at term increased the risk of severe hypertension , hospitalization and proteinuria at delivery The increase in the risk of severe hypertension and proteinuria was not associated with an increase in the incidence of preterm birth and thus may not have been clinically important Discussion

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Conclusion “ Less tight” control : may be beneficial by decreasing the risk of SGA infants : may be harmful by increasing the risk of RDS , the risk of severe hypertension, antenatal hospitalization and proteinuria at delivery → The reviews do not provide sufficient evidence on which to base clinical decisions because of reporting bias and uncertainty about the clinical importance of the outcomes. → A large RCT needs to be conducted now Discussion

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Which antihypertensive Agent(s) should be used for pregnancy hypertension ? All antihypertensive agents have been shown or should be assumed to cross the placenta and reach the fetal circulation . None of the commonly used classes of antihypertensive drugs has been shown to be teratogenic when taken in early pregnancy ACEi(Angiotensin-converting enzyme inhibitors) and presumably, angiotensin-receptor antagonists, when taken later in pregnancy, → associated with a characteristic fetopathy, the only antihypertensive agents contraindicated in pregnancy. Any antihypertensive agent : may increase the risk of SGA infants by lowering BP and, presumably, placental perfusion However as a result of a lack of sufficient information , no reliable conclusions can be made about the impact of antihypertensive agents (even methyldopa) on long-term child development Discussion

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Which antihypertensive Agent(s) should be used for pregnancy hypertension ? As such. “ no evidence of harm ” cannot be regarded as equivalent to “ evidence of no harm ” and the clinician must have clear therapeutic goals in mind when initiating treatment in pregnancy. Given that BP falls in early pregnancy and most young women have no other major cardiovascular risk factors, hypertension-related target organ damage or other relevant disease, clinicians should consider discontinuing antihypertensive therapy early in pregnancy. Use of oral agents later in pregnancy is of uncertain benefit and may have a negative impact intrauterine fetal growth Discussion

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Orally administered antihypertensive agents should be used in standard doses in pregnancy. Agents used for the acute severe hypertension of preeclampsia should be initiated at lower doses, given that women with preeclampsia are intravascularly volume-depleted and at increased risk of hypotension All commonly used antihypertensive agents, ( including labetalol, methyldopa, nifedipine,and captopril ) : considered to be compatible with breast feeding, based on their pharmacology and low detectable drug levels in breast milk. Discussion

Maternal and perinatal outcomes in trials comparing hydralazine with other Antihypertensives for Severe Hypertension of pregnancy - table 1:

Maternal and perinatal outcomes in trials comparing hydralazine with other Antihypertensives for Severe Hypertension of pregnancy - table 1

Maternal and perinatal outcomes in trials comparing hydralazine with other Antihypertensivesfor Severe Hypertension of pregnancy - table 1:

Maternal and perinatal outcomes in trials comparing hydralazine with other Antihypertensivesfor Severe Hypertension of pregnancy - table 1

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Persistent severe maternal hypertension in trials that compared hydralazine with other antihypertensives – Figure 1

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FIGURE 2. Maternal hypotension in trials that compared hydralazine with other antihypertensives (Reprinted from Figure 3 of Magee et al. BMJ . 2003.) 15

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FIGURE 3. Any maternal side effect reported in trials that compared hydralazine with other antihypertensives. (Reprinted from Magee et al. BMJ . 2003.) 15

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FIGURE 4. Adverse effects on fetal heart rate (FHR) in trials that compared hydralazine with other antihypertensives. (Reprinted from Magee et al. BMJ . 2003.) 15

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FIGURE 5. Stillbirth in trials that compared hydralazine with other antihypertensives. (Reprinted from Magee et al. BMJ . 2003.) 15

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FIGURE 6. Relation between fall in mean arterial pressure and proportion of small-for-gestational-age infants. Spearman's r = 0.69 ( P = 0.007) without Butters and colleagues' trial, r = 0.64 ( P = 0.01) with that trial. (Reprinted from von Dadelszen et al. Lancet . 2000.) 77

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FIGURE 7. Relationship between fall in mean arterial pressure and low birthweight. MAP, mean arterial pressure (diastolic blood pressure + pulse pressure/3). Excluding Butters et al and Jannet et al, treatment-induced mean difference in MAP was associated with lower mean birth weight (slope: -17.55 [standard deviation 6.67], r 2 = 0.19, Spearman's nonparametric P = 0.031, Pearson's parametric P = 0.013). (Reprinted from von Dadelszen, Magee. J Obstet Gynaecol Can . 2002.) 78