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) Read the free-access article here: http://onlinelibrary.wiley.com/doi/10.1002/uog.17335/full 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) Read the free-access article here: http://onlinelibrary.wiley.com/doi/10.1002/uog.17341/full Slides prepared by Dr Katherine Goetzinger (UOG Editor for Trainees)

1. 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)
Journal Club slides prepared by Dr Katherine Goetzinger
(UOG Editor for Trainees)
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)

2. 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)

3. 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

4. To examine maternal hemodynamics at presentation of hypertension
and during acute phase of treatment with labetalol in order to:
1.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
Objective
Longitudinal hemodynamics in acute phase of treatment with labetalol in
hypertensive pregnant women to predict need for vasodilatory therapy
Stott et al., UOG 2017

5. 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
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

6. 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
Methodology
Longitudinal hemodynamics in acute phase of treatment with labetalol in
hypertensive pregnant women to predict need for vasodilatory therapy
Stott et al., UOG 2017

7. Results
Longitudinal hemodynamics in acute phase of treatment with labetalol in
hypertensive pregnant women to predict need for vasodilatory therapy
Stott et al., UOG 2017
• 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

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

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

10. Results
Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive
pregnant women to predict need for vasodilatory therapy
Stott et al., UOG 2017
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

11. 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
• Independent predictors:
 maternal heart rate
 ethnicity
 mean arterial pressure
• Detection rate: 100%
• False-positive rate: 20%
AUC = 0.975

12. 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
Longitudinal hemodynamics in acute phase of treatment with labetalol in
hypertensive pregnant women to predict need for vasodilatory therapy
Stott et al., UOG 2017

13. • 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
Strengths
• 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
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

14. 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)

15. 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

16. 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
Objective
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017

17. 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
Prospective Observational Cohort Study
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017

18. 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
Methodology
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017

19. Results
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017
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

20. 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

21. Results
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017
• 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

22. Results
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017
• 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

23. Results
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017
• 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

24. 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
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017

25. Strengths
• 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
Limitations
Serial hemodynamic monitoring to guide treatment of maternal hypertension
leads to reduction in severe hypertension
Stott et al., UOG 2017
• 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

26. 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?