Keywords blood pressure - postpartum - severe hypertension - nifedipine - labetalol
Hypertensive disorders of pregnancy are a leading cause of maternal morbidity and
mortality worldwide, with more than 50% of hypertensive-related stroke and 50% of
eclamptic seizures occurring in the postpartum (PP) period.[1 ] Similar to a hypertensive emergency in a pregnant individual, the primary goal during
a PP hypertensive emergency is to reduce BP safely and rapidly to limit preventable
complications (e.g., eclampsia, stroke, death), and the American College of Obstetricians
and Gynecologists (ACOG) emphasizes the importance of treating severe range blood
pressure (BP) emergently within 30 to 60 minutes.[2 ] However, despite a desperate need, data from prospective studies examining treatment
strategies for PP hypertensive emergency are lacking. In the absence of PP-specific
data, current treatment protocols for PP hypertensive emergency are extrapolated from
clinical trials examining the treatment of hypertensive emergency in pregnancy and
recommend the use of either oral short-acting (SA) nifedipine or intravenous (IV)
labetalol.
Importantly, the pathophysiology of PP hypertension, which is often driven by fluid
shifts from the extravascular to intravascular space, loss of pregnancy-associated
vasodilation, and IV fluid administration,[3 ] may differ from the antepartum mechanisms that drive hypertension. Thus, the two
medication classes that are safe and effective for the treatment of a hypertensive
emergency in pregnancy may not be equally effective at rapidly treating PP severe-range
hypertension.[4 ]
[5 ] The objectives of this study were to examine which SA antihypertensive (oral SA
nifedipine or IV labetalol) better treats a PP hypertensive emergency, as defined
by: (1) shorter time in minutes to achieve therapeutic BP, (2) lower number of doses
required to achieve therapeutic BP, (3) lower incidence of crossover to the alternative
antihypertensive medication to achieve therapeutic BP, and (4) lower incidence of
recurrent severe-range hypertension after achievement of therapeutic BP.
Materials and Methods
Study Cohort
This was a retrospective cohort study of women aged ≥ 18 years who gave birth between
January 1 and December 31, 2018 at the Columbia University Irving Medical Center and
were prescribed one of two SA antihypertensives (oral SA nifedipine or IV labetalol)
for the treatment of PP severe hypertension. Severe hypertension was defined as a
systolic BP (SBP) ≥ 160 mm Hg and/or diastolic BP (DBP) ≥ 110 mm Hg in the PP period.
For this analysis, the PP period consisted of 42 days (6 weeks) beginning on the day
of delivery and qualifying severe-range BP values could occur during the delivery
hospitalization or a readmission for any indication.
Women were excluded from this analysis if the treatment of their hypertensive emergency
went off-protocol or there was no clear documentation of the timing of BP measurement
or medication administration ([Fig. 1 ]).
Fig. 1 Flow chart of patients enrolled with postpartum severe hypertension treated with
either oral short-acting (oral SA) nifedipine or intravenous (IV) labetalol.
Maternal sociodemographic characteristics and medical and surgical history were extracted
from the electronic medical record via chart review. Reported heart rate was the value
noted immediately prior to receipt of the first antihypertensive medication dose.
Exposure groups were defined according to the initial medication received, and crossover
to the other agent was allowed.
Outcomes
The primary outcome was defined as time in minutes required to achieve an initial
therapeutic BP (SBP < 160 mm Hg and DBP < 110 mm Hg). Specifically, time to achieve
an initial therapeutic BP was measured from the time of administration of the antihypertensive
agent until a therapeutic BP was achieved. Secondary outcomes included the total number
of doses required to achieve initial therapeutic BP, crossover to the alternative
agent, and the recurrence of severe hypertension (defined as at least one severe-range
BP measurement after initial BP control was achieved).
Statistical Analyses
Baseline demographic and clinical characteristics were compared between exposure groups.
Continuous variables were compared using t -tests or Wilcoxon–Mann–Whitney tests, whereas binary and categorical variables were
analyzed using chi-square tests or Fisher's exact tests, as appropriate. Normality
for continuous variables was assessed using graphical methods. In addition to demographics,
the association of outcomes with the two exposure groups was also determined using
the methods above. Multivariable linear regression models were conducted for the primary
outcome, controlling for potential confounders that were chosen a priori, in a sequential
fashion across three models: unadjusted regression (Model 1); a history of chronic
and/or gestational hypertension and baseline BP (Model 2); and antihypertensive administration
antepartum, self-reported race, gestational age at delivery, insurance (commercial
vs. Medicaid), and parity (Model 3). Patients who crossed over to the second medication
before achieving BP control were analyzed based on the initial medication they received.
In addition, a Kaplan–Meier curve was plotted using the survival plot macros from
SAS, with crossovers censored at the time of the last BP measurement taken with the
starting medication. Statistical analyses were conducted using SAS version 9.4 (SAS
Institute, Inc., Cary, NC), R (R Foundation for Statistical Computing, Vienna, Austria),
and RStudio (Posit Software, PBC, Boston, MA).
Two-sided tests were conducted and p -values < 0.05 were considered significant for all analyses. As this was an exploratory
study, no adjustment for multiple comparisons was made. This study was approved by
the Institutional Review Board at the Columbia University Medical Center, with a waiver
of informed consent.
Results
We identified 99 patients with PP severe HTN, 74 were initially treated with nifedipine
and 25 with labetalol ([Fig. 1 ]). A comparison of baseline characteristics revealed that patients who received labetalol
were significantly more likely to have delivered at a later gestational age, have
a higher SBP at the time of medication administration, and have public insurance ([Table 1 ]).
Table 1
Baseline characteristics of patients with postpartum severe hypertension stratified
by initial treatment medication received
Characteristics
Overall
n = 99
Nifedipine
n = 74
Labetalol
n = 25
p -Value
Age (y)
32 ± 6
33 ± 6
32 ± 6
0.98
Race
0.02
Black
26 (26)
24 (32)
2 (8)
White
41 (41)
31 (42)
10 (41)
Asian
2 (2)
2 (3)
0 (0)
Unknown/not reported
30 (30)
17 (23)
13 (52)
Ethnicity
0.72
Hispanic/Latina
42 (42)
33 (45)
9 (36)
Not Hispanic/Latina
34 (34)
24 (32)
10 (40)
Unknown/not reported
23 (23)
17 (25)
6 (24)
Medicaid
50 (51)
34 (46)
16 (64)
0.12
Primiparity
50 (51)
37 (50)
13 (52)
0.86
Gestational age at delivery (wk)
38 [35–39]
38 [35–39]
39 [38–40]
0.01
Cesarean delivery
55 (56)
42 (57)
13 (52)
0.68
Chronic hypertension[a ]
17 (18)
13 (18)
4 (17)
>0.99
Gestational diabetes mellitus[b ]
9 (10)
7 (10)
2 (8)
>0.99
Body mass index (kg/m2 )
31 [28–37]
31 [27–37]
32 [28–36)
0.42
Initial systolic BP (mm Hg)
166 [162–173]
166 [162–172]
172 [165–177]
0.01
Initial diastolic BP (mm Hg)
97 [88–105]
96 [85–105]
100 [92–104]
0.28
Heart rate (bpm)
74 [64–86]
74 [63–87]
75 [66–86]
0.47
Abbreviations: BP, blood pressure; IQR, interquartile range; SD, standard deviation.
Note: Data presented as mean ± standard deviation, median [IQR], or n (%).
a Information only available on 97 participants.
b Information only available on 95 participants.
There was no significant difference in time to achieve initial therapeutic BP for
nifedipine (median: 30.5 [interquartile range, IQR: 20.0–45.0]) as compared with labetalol
(25.0 [14.0–50.0]; p = 0.82) ([Table 2 ]). This finding remained consistent after adjustment for potential confounders ([Table 3 ]). Time to initial BP control for both nifedipine and labetalol was also assessed
using Kaplan–Meier curves and analyzed using the log-rank test and demonstrated no
difference in time to event curves between treatment groups when considering crossovers
as censored ([Fig. 2 ]). We found patients initially treated with nifedipine required significantly fewer
doses of medication to reach target BP and were less likely to require crossover to
labetalol to achieve BP control. The incidence of recurrent severe hypertension (31.1
vs. 20.0%; p = 0.29) was high in patients who were treated with either nifedipine or labetalol.
Urine output was similar in both groups ([Supplementary Table S1 ], available in the online version). With respect to potential adverse medication
effects, hypotension, flushing, palpitations, nausea, and headache were similar between
patients treated with either nifedipine or labetalol, and there was no association
between having an adverse reaction and the exposure groups ([Supplementary Table S1 ], available in the online version).
Table 2
Time to initial blood pressure control and secondary outcomes stratified by initial
treatment medication
Nifedipine
n = 74
Labetalol
n = 25
p -Value
Primary outcome
Time (min) to initial BP control
30.5 [20.0–45.0]
25.0 [14.0–50.0]
0.82
Secondary outcomes
Number of doses needed to achieve therapeutic BP[a ]
1 [1–1]
1 [1–2]
<0.001
Crossover to alternative agent needed for initial BP control
0 (0)
3 (12)
0.01
Recurrence of severe hypertension
23 (31)
5 (20)
0.29
Abbreviation: BP, blood pressure; IQR, interquartile range.
Note: Data presented as median [IQR] or n (%).
a Crossovers, n = 74 for nifedipine and n = 22 for labetalol.
Table 3
Unadjusted and adjusted time to initial blood pressure control when nifedipine was
used to treat postpartum severe hypertension compared with labetalol
Time in minutes (95% CI)
p -Value
Unadjusted
−4.7 (−13.9, 4.6)
0.32
Model 2
−5.4 (−15.5, 4.8)
0.30
Model 3
−4.5 (−15.9, 6.9)
0.44
Abbreviation: CI, confidence interval.
Note: Model 2 was adjusted for baseline blood pressure and history of chronic or gestational
hypertension. Model 3 was further adjusted for antihypertensive administration antepartum
(yes or no), race, gestational age at delivery, and parity.
Fig. 2 Kaplan–Meier estimates of the cumulative time to blood pressure control among patients
receiving oral short-acting nifedipine compared with those receiving intravenous labetalol.
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Discussion
In our retrospective cohort study of PP severe hypertension, we found that there was
no difference in time to the achievement of initial therapeutic BP in individuals
who received oral SA nifedipine compared with those who received IV labetalol. Further,
our study suggests that patients who received oral SA nifedipine may require fewer
doses to achieve a therapeutic BP and are less likely to need to cross over and receive
labetalol as an alternative antihypertensive to achieve therapeutic BP. Our findings
support the continued use of both oral SA nifedipine and IV labetalol as first-line
agents for the treatment of severe PP hypertension. Historically, IV labetalol has
been a preferred agent in this setting due to concerns about time to onset of action
for an oral medication extrapolated from nonpregnant individuals. The described onset
of action is 2 to 5 minutes versus 30 to 60 minutes in nonpregnant patients treated
with IV labetalol versus oral SA nifedipine, respectively.[6 ]
[7 ] However, in our study, time to initial BP control was not significantly different
between treatment groups. This is consistent with a systematic review that found no
clear evidence as to which medication is most effective and should, therefore, be
preferentially prescribed.[8 ]
Our findings that nifedipine may have additional benefits compared with labetalol
for the treatment PP severe hypertension are also consistent with those of several
other studies performed on patients in the antepartum period with hypertensive emergencies.[9 ]
[10 ] The lower number of doses required to achieve BP control is promising, as increased
number of required doses may lead to delayed administration and related suboptimal
BP control and adverse events. Furthermore, the need to administer more doses is a
strain on nursing resources and also creates additional opportunities for medication
administration error. Importantly, the opportunity to use an oral medication has important
benefits in the acute setting for patients without IV access as is commonly encountered
in PP clinical care, as well as in lower resources settings where qualified staff
and equipment needed for administration of IV medications may be more challenging
or completely unavailable. Additionally, those with contraindications to labetalol
use (asthma, relative bradycardia) benefit from an effective alternative.
In addition to these therapeutic benefits of nifedipine, it offers additional potential
benefits for the management of PP hypertension. Our study suggested that patients
treated with nifedipine were less likely to need an alternative agent to achieve their
target BP. Since many of these patients will need to transition to a longer-acting
medication, use of a single medication has the potential to facilitate this transition.
Further work is needed to see if this simplified transition from short- to long-acting
medication may have the additional benefit of reducing length of stay.
Although not directly examined in our study, nifedipine has also been shown to increase
renal blood flow and improve urine output,[9 ] specifically in the PP setting.[11 ] Nifedipine related enhanced urine output is hypothesized to be secondary to the
selective renal arteriolar vasodilation, leading to increased renal perfusion. The
pathophysiology of PP preeclampsia predisposes patients to intravascular volume depletion,
and so a better understanding of mechanisms to optimize renal function in this context
warrants further exploration and possible benefits for the management of PP preeclampsia
who simultaneously require hypertensive treatment. Additionally, a study by Tolcher
et al suggests that nifedipine may also lower cerebral perfusion pressure (CPP), improving
autoregulation and potentially preventing neurovascular complications of preeclampsia.[12 ] Gaining a better understanding of medication profiles and rapidly changing maternal
physiology specific to the peripartum period will be instrumental in understanding
how to reduce maternal morbidity and mortality in this complex time. Findings from
pregnancy may not be generalizable to the PP period.
Limitations and Strengths
Limitations and Strengths
Our study has several limitations that invite follow-up studies for further exploration.
In accordance with protocol initiatives set out by the ACOG and the Safe Motherhood
Initiative, BP measurements should be taken every 10 to 20 minutes after administration
of a SA antihypertensive medication. The retrospective nature of our data meant that,
despite clinical practice and compliance of hospital protocols with these initiatives,
subsequent BP measurements were often not taken as frequently nor recorded as clearly
in the electronic medical record as is recommended. Also, our study had a relatively
small sample size, and the treatment groups were unbalanced due to local practices,
potentially limiting our power to find clinically significant results. An additional
limitation of our study is a lack of information about the concurrent use of magnesium
sulfate, a commonly used medication in the peripartum period for seizure prophylaxis
that has documented antihypertensive effects.[13 ]
Our study has several strengths. To our knowledge, it is the first to compare oral
SA nifedipine and IV labetalol in treating severe hypertension, specifically in the
PP period. Several studies have compared the efficacy of antihypertensives in the
acute management of hypertensive emergencies in pregnancy.[8 ]
[9 ] The pathophysiology of PP hypertension is thought to be uniquely related to profound
fluid shifts in the peripartum period secondary to a rise in intravascular volume
related to mobilization of extravascular fluid.[4 ]
[5 ] For this reason, the efficacy of antihypertensives in the PP period may differ.
The results of our analysis contribute to a better understanding of pharmacokinetics
of these medications unique to the PP period.
Conclusion
A call to action for timely treatment of hypertensive emergencies in the PP period
has been established to reduce maternal morbidity and mortality. However, evidence-based
guidelines demonstrating optimal drug treatment regimens have yet to be established.
Our study is the first to address this knowledge gap in the PP setting. Larger randomized
clinical trials are needed to validate these findings and further understand the trajectory
of BP reduction from drug administration. Data from this area of research will inform
clinical guidance for treatment algorithms for PP hypertensive emergencies. Further,
an optimized antihypertensive medication regimen may be associated with improved maternal
morbidity outcomes and safety, reduced lengths of maternal hospitalization, and decreased
need for readmission in the PP period.
