UOG Journal Club: January 2017 Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy D. Stott, M. Bolten, D. Paraschiv, I. Papastefanou, J.B. Chambers and N.A. Kametas Volume 49, Issue 1, Date: January (pages 85–94) Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension D. Stott, I. Papastefanou, D. Paraschiv, K. Clark and N.A. Kametas Volume 49, Issue 1, Date: January (pages 95–103) Journal Club slides prepared by Dr Katherine Goetzinger (UOG Editor for Trainees)

UOG Journal Club: January 2017 Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy D. Stott, M. Bolten, D. Paraschiv, I. Papastefanou, J.B. Chambers and N.A. Kametas Volume 49, Issue 1, Date: January (pages 85–94)

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Effective treatment of hypertension decreases the risk of developing severe hypertension and associated pregnancy complications However, there remain uncertainties regarding the most appropriate first-line antihypertensive agent in pregnancy Outside of pregnancy, treatment for hypertension has been shown to be more effective when it is individualized according to the patient’s hemodynamic profile Hemodynamic monitoring in pregnancy may assist in selecting appropriate first-line pharmacologic therapy whilst allowing prompt adjustment to treatment in order to preserve maternal cardiac output and avoid placental hypoperfusion

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Objective To examine maternal hemodynamics at presentation of hypertension and during acute phase of treatment with labetalol in order to: Determine which hemodynamic changes are more likely to be associated with lack of response AND 2. Determine whether these changes could be used to guide antihypertensive treatment effectively

Prospective Observational Cohort Study Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Methodology Prospective Observational Cohort Study Study Population 134 consecutive pregnant women with hypertension requiring treatment Oral labetalol was initiated when maternal blood pressure was >150/100mmHg or >140/90mmHg, with evidence of end-organ damage Measures Assessed using a non-invasive cardiac output monitor at enrollment, 1 hour and 24 hours following treatment with labetalol Blood pressure, stroke volume, heart rate, cardiac output, peripheral vascular resistance

Methodology Primary Outcome Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Methodology Primary Outcome Need for additional vasodilatory therapy, despite maximal labetalol (2400mg daily), to maintain blood pressure around 135/85mmHg Secondary Outcomes Maternal: Pre-eclampsia, pregnancy-induced hypertension, severe hypertension requiring admission to high dependency unit Fetal: Birth weight and birth-weight centiles Analysis Logistic regression using maternal demographics and longitudinal hemodynamic profile data to generate prediction models

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Results Compared to women who required labetalol monotherapy, women who required additional vasodilatory therapy with nifedipine for blood pressure control were - 10x more likely to be admitted with severe hypertension - 2x more likely to be diagnosed with pre-eclampsia - More likely to present and deliver earlier in gestation There was no significant difference in birth-weight centiles between the two groups Black women were twice as likely to need additional therapy

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Results Patients who required additional vasodilatory therapy (grey bars) demonstrated significantly increased MAP (a), SBP (b) and DBP (c) at all time points

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Results Patients who required additional vasodilatory therapy (grey bars) demonstrated significantly lower cardiac output only at time of presentation Patients who required additional vasodilatory therapy (grey bars) demonstrated significantly higher PVR at all time points

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Results Patients who required additional vasodilatory therapy (grey bars) demonstrated significantly lower HR all time points There was no difference in stroke volume between the two groups at any time point

Results: Final prediction model for need for vasodilatory therapy Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Results: Final prediction model for need for vasodilatory therapy Independent predictors: maternal heart rate ethnicity mean arterial pressure Detection rate: 100% False-positive rate: 20% AUC = 0.975

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Conclusions Ethnicity and longitudinal changes in heart rate and mean arterial pressure during the first 24 hours of labetalol treatment for hypertension provide a powerful tool to predict the likelihood of a lack of sustained response and consequent need for additioanl vasodilatory therapy Cardiac output remained stable in those patients who remained on labetalol monotherapy with no significant observed decrease in neonatal birth weight, suggesting that uterine perfusion is not adversely affected with judicious use of labetalol Given the strong association between need for vasodilatory therapy and adverse pregnancy outcome, this prediction model provides a cost- effective method of triage, identifying those patients who require both additional pharmacologic therapy and increased antenatal surveillance

Strengths Limitations Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy Stott et al., UOG 2017 Strengths Limitations Longitudinal measurement of hemodynamic parameters All patients recruited from dedicated hypertension clinic Use of rigorous statistical modeling Able to further investigate the pharmacologic properties of labetalol in pregnancy Hemodynamics not recorded beyond 24 hours of treatment Numbers too small to assess effect of labetalol on birth weight Lack of follow-up data in postpartum period Non-invasive measurement of maternal hemodynamics

UOG Journal Club: January 2017 Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension D. Stott, I. Papastefanou, D. Paraschiv, K. Clark and N.A. Kametas Volume 49, Issue 1, Date: January (pages 95–103)

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Effective blood pressure control in pregnancy reduces the rate of severe hypertension, abnormal liver function and thrombocytopenia Although individualization of blood pressure treatment based on maternal hemodynamic status is well-established outside of pregnancy, little research exists on its feasibility in pregnancy In the previous study, these same authors created a prediction model using maternal demographics and hemodynamic parameters to anticipate a response or non-response to labetalol

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Objective To use the previously derived prediction model to guide antihypertensive treatment throughout pregnancies complicated by hypertension, with the aim of reducing the rate of non-response to treatment and thereby lowering the rate of severe hypertension

Prospective Observational Cohort Study Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Methodology Prospective Observational Cohort Study Study Population 52 consecutive pregnant women not already on antihypertensive medication who were referred for hypertension treatment Oral treatment was initiated when maternal blood pressure was >150/100mmHg or >140/90mmHg with evidence of end-organ damage Choice of agent based on previously derived prediction model Measures Maternal demographics Maternal hemodynamics assessed using a non-invasive cardiac output monitor at enrollment and serially throughout pregnancy

Methodology Primary Outcome Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Methodology Primary Outcome Reduction in rate of severe hypertension (≥160/110mmHg) using serial maternal hemodynamic data to guide treatment Secondary Outcomes Comparison of serial maternal hemodynamic changes between women treated with beta-blocker versus vasodilator and with monotherapy versus dual therapy Pre-eclampsia, pregnancy-induced hypertension, fetal growth restriction Analysis Logistic regression analysis

Severe hypertension: 9/50 (18.0%) vs 2/52 (3.8%); p =0.04 Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Results Treatment of hypertension based on results of serial hemodynamic monitoring reduced the rate of severe antenatal hypertension when compared to women who were only given labetalol monotherapy (previous phase of study) Severe hypertension: 9/50 (18.0%) vs 2/52 (3.8%); p =0.04

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Results There was a higher incidence of neonates born with a birth weight <10th percentile in the following therapy groups: Vasodilator compared to beta-blocker 58.3% vs 25.0%; p=0.04 Beta-blocker + added vasodilator compared to beta-blocker alone 58.3% vs 10.7%; p<0.001 There was no significant difference in birth weight in the group started on vasodilator therapy with subsequent addition of beta-blocker therapy compared to vasodilator therapy alone

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Results Cardiac output increased during mid-pregnancy and declined in the 3rd trimester Patients with beta-blocker (dotted line) monotherapy demonstrated the highest cardiac output Patients on vasodilators (long dashed line), in general, had the lowest cardiac output

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Results Overall, peripheral vascular resistance (PVR) fell to reach a nadir in mid-pregnancy and then rose Patients with beta-blocker monotherapy (dotted line) demonstrated the lowest PVR Patients on vasodilators (long dashed line), in general, had the highest PVR

Results There was a sustained increase in MAP during pregnancy Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Results There was a sustained increase in MAP during pregnancy Patients with beta-blocker monotherapy (dotted line) demonstrated the lowest MAP Patients on vasodilators who required the addition of beta- blockers (long dashed lined) had the highest MAP

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Conclusions Serial monitoring of maternal hemodynamics to guide antihypertensive treatment can significantly reduce the rate of severe hypertension, without accompanying decrease in birth weight Patients receiving beta-blocker monotherapy had the best maternal and fetal outcomes, suggesting this group of patients may require less intensive fetal monitoring Serial maternal hemodynamic monitoring may allow for identification of high-resistance, low-output hypertensive pregnancies that are associated with increased rates of fetal growth restriction and may benefit from dual pharmacologic therapy

Strengths Limitations Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension Stott et al., UOG 2017 Strengths Limitations Comparison of two cohorts at different time points with divergent demographic profiles Interval between hemodynamic data collection not fixed Small number of patients in each subgroup No existing literature to support power calculation for sample size Followed longitudinal changes in maternal hemodynamics over the course of gestation Use of general linear-mixed model approach to account for repeated measures and flexible time schedules Subgroup analysis to assess hemodynamic profile of both single agent and dual therapy

Discussion Points Which longitudinal maternal hemodynamic changes may explain why patients requiring vasodilatory therapy are at increased risk for fetal growth restriction? Does reduction in the rate of severe hypertension equate to reduction in adverse pregnancy outcome? How did the authors account for the fact that intervals between hemodynamic measurements were not fixed between patients? How could these prediction models potentially be clinically implemented into practice? How could an external validation study be best designed to test these prediction models?