Hypertension in Pregnancy

ISSN: 1064-1955 (Print) 1525-6065 (Online) Journal homepage: http://www.tandfonline.com/loi/ihip20

Oral labetalol compared to oral nifedipine

for postpartum hypertension: A randomized
controlled trial

Kathryn J. Sharma, Naomi Greene & Sarah J. Kilpatrick

To cite this article: Kathryn J. Sharma, Naomi Greene & Sarah J. Kilpatrick (2017) Oral
labetalol compared to oral nifedipine for postpartum hypertension: A randomized controlled trial,
Hypertension in Pregnancy, 36:1, 44-47, DOI: 10.1080/10641955.2016.1231317

To link to this article: https://doi.org/10.1080/10641955.2016.1231317

Published online: 27 Oct 2016.

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HYPERTENSION IN PREGNANCY
2017, VOL. 36, NO. 1, 44–47
http://dx.doi.org/10.1080/10641955.2016.1231317

Oral labetalol compared to oral nifedipine for postpartum hypertension: A

randomized controlled trial
Kathryn J. Sharma, Naomi Greene, and Sarah J. Kilpatrick
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA

ABSTRACT ARTICLE HISTORY

Objective: To determine whether oral labetalol is associated with a shorter time to blood pressure Received 9 May 2016
control compared to oral extended release nifedipine for management of persistent postpartum Revised 6 August 2016
Accepted 29 August 2016
hypertension. Study Design: This randomized controlled trial conducted between June 2014 and
June 2015 included women who delivered at ≥32 weeks’ gestation with persistent postpartum KEYWORDS
hypertension (sustained blood pressure ≥150/100 mmHg) requiring an oral antihypertensive agent. Hypertension; preeclampsia;
We included women with gestational hypertension, preeclampsia, or chronic hypertension not pre- randomized controlled trial
viously on medication. Women were randomized to labetalol or nifedipine, and the allocated study
drug was incrementally increased to achieve blood pressure control. The primary outcome was time
to sustained blood pressure control defined as the absence of severe hypertension for at least 12
hours. Secondary outcomes included postpartum length of stay, need for increased dosing, need for
additional oral antihypertensive agents, and patient reported side effects. Twenty women were
needed in each group as determined by the sample size calculation. Results: We randomized 25
women to oral labetalol and 25 women to oral extended release nifedipine. The time to achieve BP
control was similar between labetalol and nifedipine groups (37.6 hours versus 38.2 hours, p = 0.51).
Secondary outcomes including postpartum length of stay, need for increased dosing, and need for
additional oral antihypertensive agents were similar between groups. For women discharged on a
single agent, significantly more subjects in the labetalol group (16/21) compared to the nifedipine
group (10/22) achieved BP control with the initial starting dose (76% versus 46%, p = 0.04). No major
side effects were observed. Minor side effects were significantly more common in women taking
nifedipine compared to labetalol (48% versus 20%, p = 0.04). Conclusions: Both labetalol and nifedipine
were effective for control of persistent postpartum hypertension. However, labetalol achieved control
significantly more often with the starting dose and had fewer side effects. Clinical Trial Registration:
Oral nifedipine versus oral labetalol, NCT02168309. https://clinicaltrials.gov/ct2/show/NCT02168309?
term=labetalol+versus+nifedipine&rank=2

Introduction medications to intramuscular and immediate-release

oral medications in the treatment of postpartum hyper-
Hypertension complicating pregnancy is common
tension (2–5). However, oral labetalol and oral extended
and, when uncontrolled, can have devastating conse-
release nifedipine are the most commonly used medica-
quences (1). Persistent postpartum hypertension can
tions for postpartum hypertension, and their efficacy has
occur de novo or follow an antepartum diagnosis of
not been directly compared (6).
hypertension complicating pregnancy. While the true
Our aim was to determine whether oral labetalol is
incidence of postpartum hypertension is unknown,
associated with a shorter time to BP control com-
blood pressure (BP) is known to initially decrease
pared to oral extended release nifedipine for manage-
48 hours following delivery then peak on postpartum
ment of persistent postpartum hypertension. Our
days 3–6, likely from the mobilization of interstitial
primary outcome was time to sustained BP control
fluids following parturition (1).
defined as the absence of severe hypertension (SBP
The American College of Obstetricians and
≥160 mmHg or DBP ≥105 mmHg) for at least 12
Gynecologists (ACOG) recommends medical treatment
hours. Secondary outcomes included postpartum
of persistent postpartum hypertension, defined as systo-
length of stay, need for increased dosing, need for
lic BP (SBP) ≥150 mmHg or diastolic BP (DBP)
additional oral antihypertensive agents, and patient-
≥100 mmHg, on two or more occasions 4–6 hours
reported side effects.
apart (1). Prior studies compared intravenous

CONTACT Kathryn J. Sharma, MD katy.jones@gmail.com Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology,
Cedars-Sinai Medical Center, 8635 W. 3rd Street, Suite 160-W, Los Angeles, CA 90048, USA.
© 2017 Taylor & Francis
 HYPERTENSION IN PREGNANCY 45

Materials and methods Prior to initiation of our prospective trial, retrospec-

tive pilot data (from 10 patients treated each with
In this prospective randomized controlled trial, women
labetalol and nifedipine) were analyzed. The data were
who delivered at ≥32 weeks gestation with persistent
obtained from a similar patient group, managed with
postpartum hypertension (sustained SBP ≥150 or DBP
similar blood pressure criteria and goals in the post-
≥100 mmHg) requiring an oral antihypertensive agent
partum period. Analysis of this data indicated that the
were candidates for inclusion. We included women with
labetalol group had a mean of 39.0 hours ± standard
gestational hypertension, preeclampsia, or chronic
deviation of 25.9 hours and the nifedipine group had a
hypertension not previously on medication. We
mean of 41.7 ± standard deviation of 27.4 hours to
excluded women with known heart block, heart rate
achieve sustained control. Sample size calculation
<60 or >120 beats per minute, absolute contraindication
based on these times to reach the goal of successful
to nifedipine or labetalol such as allergy, significant renal
treatment with 80% power and p < 0.05 determined
disease (creatinine >1.5 mg/dL), heart failure, or moder-
that 20 patients in each group were needed to detect a
ate persistent or severe asthma.
clinically meaningful difference of 24 hours between
Participants were randomized to labetalol versus
groups. Though 24 hours is a large difference between
extended release nifedipine using a computerized ran-
groups, this difference was chosen because it was deter-
dom number generator. Group assignments were main-
mined to be a clinically meaningful time period. Five
tained inside sequentially numbered, sealed, opaque
additional patients in each study arm were recruited to
envelopes. After informed consent was obtained, study
account for loss to follow-up. Therefore, 25 women
personnel opened the assigned envelope, and the study
were planned for each group. The Cedars Sinai
drug was revealed. Neither patients nor their providers
Institutional Review Board granted study approval.
were blinded to the assigned study drug.
The trial was registered at ClinicalTrials.gov
Patient blood pressure information was reviewed every
(NCT02168309).
12 hours by the treatment team, which consisted of a
We performed distribution-appropriate statistical
primary obstetrician co-managing the blood pressure
tests to compare demographic and pregnancy charac-
medication in conjunction with a Maternal-Fetal
teristics, primary and secondary outcomes, major and
Medicine specialist. At the discretion of the treatment
minor side effects, blood pressure trends after dis-
team, the allocated study medication was incrementally
charge, and total time of post-discharge medication
increased if necessary at this time interval to achieve
use between the two treatment groups (t-tests or ana-
blood pressure control. If maximum dose of one medica-
lysis of variance for continuous variables and chi-
tion was reached without BP control, the alternative med-
square tests for categorical items). Intention-to-treat
ication was added at the lowest starting dose increasing as
analysis was performed.
needed. Labetalol was started at 200 mg PO BID and
increased up to 800 mg PO BID as needed to control
BP. Nifedipine was started at 30 mg PO daily then
increased up to 90 mg PO daily as needed to control BP. Results
The use of concomitant intravenous (IV) antihyper- Between June 2014 and June 2015, we randomized 25
tensive medication for severe hypertension as well as the women to oral labetalol and 25 women to oral
use of magnesium sulfate for seizure prophylaxis was left extended release nifedipine. Baseline maternal charac-
to the discretion of the treating medical team. Prior to teristics were similar between groups, including age,
discharge, the patient completed a written questionnaire race, body mass index (BMI), gravidity and parity, rate
to obtain information regarding medication side effects. of twins, and presence of medical comorbidities
Each patient was called 6 months after discharge to assess including chronic hypertension (Table 1). One
for total duration of antihypertensive medication use and woman in each group discontinued her initial study
the subsequent development of medical comorbidities medication secondary to maternal side effects (nausea
including cardiovascular disease. Also following dis- and emesis with labetalol and severe headache with
charge, the primary obstetrician’s office was contacted to nifedipine) and was transitioned to the alternative
obtain follow-up blood pressure information at 72 hours, study medication. These women were analyzed as
1 week, and 4–6 weeks after delivery. Variables, including intention to treat.
baseline maternal and pregnancy characteristics, were The time to achieve BP control was similar between
recorded by enrolling physician. The remaining data per- labetalol and nifedipine groups (37.6 hours versus 38.2
taining to postpartum hypertension treatment course hours, p = 0.51) (Table 2). Secondary outcomes including
were collected retrospectively following patient discharge. postpartum length of stay, the need for increased dosing,
46 K. J. SHARMA ET AL.

Table 1. Maternal and pregnancy characteristics. Table 3. Major and minor medication side effects.
Labetalol Nifedipine Labetalol (N = 25) Nifedipine (N = 25) p-Value
(N = 25) (N = 25) p-Value Major side effects 0 (0%) 0 (0%) –
Maternal age (years) 34.0 (7.4) 33.3 (6.4) 0.71 Minor side effects
Body mass index 30.3 (4.1) 33.0 (7.8) 0.13 Any 5 (20%) 12 (45%) 0.04
Maternal race Constipation 3 (12%) 4 (16%)
White 8 (32%) 9 (36%) 0.43 Itching 1 (4%) 0 (0%)
Black 7 (28%) 11 (44%) Racing heartbeat 0 (0%) 1 (4%)
Latina 7 (28%) 4 (16%) Flushing 1 (4%) 0 (0%)
Asian 3 (12%) 1 (4%) Headache 0 (0%) 6 (24%)
Twin pregnancy 3 (12%) 2 (8%) 0.64 Loose stool 1 (4%) 0 (0%)
Primiparous 9 (36%) 9 (36%) 1.0 Data are reported as mean (SD) or n (%).
Grand multiparous 3 (12%) 4 (16%) 0.68
Medical comorbidities
None 15 (60%) 14 (56%) 0.78
Gestational diabetes 2 (8%) 3 (12%)
Thyroid disorder 1 (4%) 2 (8%)
Chronic hypertension 3 (12%) 1 (4%) Table 4. Blood pressure trends from post-discharge follow-up.
Multiple sclerosis 0 (0%) 1 (4%) Labetalol Nifedipine
Other 3 (12%) 5 (20%) (N = 25) (N = 25) p-Value
Data are reported as mean (SD) or n (%). Blood pressure at 72 hours(N = 24)
Systolic in mmHg 140 (15) 141 (27) 0.94
Diastolic in mmHg 89 (4) 87 (13) 0.70
Blood pressure at 1–2 weeks (N = 8)
Table 2. Primary and secondary outcomes. Systolic in mmHg 129 (15) 124 (10) 0.36
Labetalol Nifedipine Diastolic in mmHg 80 (10) 81 (6) 0.94
(N = 25) (N = 25) p-Value Blood pressure at 4–6 weeks (N = 10)
Systolic in mmHg 119 (9) 127 (14) 0.10
Time to control (hours) 37.6 (32.5) 38.2 (27.6) 0.51 Diastolic in mmHg 76 (10) 80 (8) 0.28
Required additional oral 3 (12%) 2 (8%) 0.64
agent for control Data are reported as mean (SD).
Discharged at starting 16/21 (76%) 10/22 (46%) 0.04
medication dosage
Required additional IV 6 (24%) 9 (36%) 0.36
medication for control Post-discharge follow-up information was available
Length of stay after 2.4 (1.3) 3.0 (2.3) 0.25
medication initiated for less than half of the women. Failure to obtain
Total postpartum length of 4.0 (1.5) 4.3 (2.3) 0.58 post-discharge follow-up data resulted from patient
stay
failure to returning the principal investigator’s multi-
Data are reported as mean (SD), median (IQR), or n (%).
ple phone calls. Blood pressure information at 72
hours, 1–2 weeks, and 4–6 weeks postpartum was
available for 24, 8, and 10 women, respectively.
the need for additional IV antihypertensive medication, Blood pressure trends at 72 hours, 1–2 weeks, and
and the need for additional oral antihypertensive agents 4–6 weeks postpartum are reported in Table 4. Blood
were also similar between groups (Table 2). pressure measurements did not differ by medication
In the labetalol group, 3 women required the addi- group. Table 5 provides information regarding the
tion of nifedipine for BP control, and 1 woman discon- proportion of women still on medication at these
tinued the labetalol altogether after starting nifedipine specified post-discharge time intervals. Total duration
due to side effects. In the nifedipine group, 2 women of use (6.4 weeks for labetalol and 8.8 weeks for
required the addition of labetalol, and 1 woman dis- nifedipine, p = 0.38) did not differ between groups.
continued the medication secondary to side effects. One woman in the labetalol group required readmis-
Therefore, 21 women were discharged on labetalol sion for uncontrolled hypertension secondary to non-
alone, and 22 women were discharged on nifedipine compliance with medical treatment. No woman
alone. For these women discharged on a single antihy- reported cardiovascular morbidity through 6 months
pertensive agent, more women in the labetalol group of follow-up.
(16/21) compared to the nifedipine group (10/22)
achieved BP control with the initial starting dose
(76% versus 46%, p = 0.04) (Table 2).
No major side effects were observed. Minor side Table 5. Total duration of post-discharge medication use.
effects were more common in women taking nifedi- Labetalol
(N = 25) Nifedipine (N = 25) p-Value
pine compared to labetalol (48% versus 20%, p =
Still required medication
0.04) (Table 3). Constipation was the most common 72 hours later (N = 24) 16 (64) 16 (64) 1.00
side effect in the labetalol group (12%). Headache 1–2 weeks later (N = 8) 14 (56) 16 (64) 0.56
4–6 weeks later (N = 10) 11 (44) 13 (52) 0.57
was the most common side effect in the nifedipine Total duration of use in weeks 6.4 (6.8) 8.8 (7.6) 0.38
group, occurring in 24% of women. Data are reported as N (%) or mean (SD).

Discussion
Our study demonstrated that both oral labetalol and
oral extended release nifedipine were effective for the
treatment of postpartum hypertension. Although time
to BP control did not differ between medication
groups, labetalol achieved control more often with the
starting dose and with fewer side effects compared to
nifedipine.
Several previous studies investigated the optimal man-
agement for postpartum hypertension. Methyldopa was
compared to timolol for postpartum BP control and both
had similar efficacy (2). However, neither medication is
commonly used postpartum for this purpose in the United
States. In another study, intramuscular hydralazine was
found to be superior to IV methyldopa to achieve goal
blood pressure, but given the parenteral route of medica-
tion administration, neither medication can be widely used
on an outpatient basis and these findings therefore have
limited clinical utility (3). Two additional studies investi-
gated severe acute elevations in BP specific to the postpar-
tum period (4, 5). One compared IV hydralazine to IV
labetalol and found no differences in persistent severe
hypertension or maternal side effects (4). The other study
compared oral nifedipine to IV labetalol and found shorter
time to achieve control with nifedipine (5). However,
neither study answers the pertinent clinical question:
which medication is superior for the management of per-
sistent postpartum hypertension? Our study addressed that
very question, and provided findings directly applicable to
an efficacious outpatient management protocol.
Our study was not without limitations. Our patients
and their providers were not blinded to medication selec-
tion. Also, though Maternal-Fetal Medicine physicians
co-managed all patients with the primary treating obste-
trician, ultimately decisions regarding medication
increases and discharge timing were subject to discretion
of the primary obstetrician, only rarely did the primary
obstetrician and Maternal-Fetal Medicine specialist differ
in opinion regarding management. Post-discharge fol-
low-up was also severely limited by the proportion of
patients who were compliant with the follow-up; there-
fore, no conclusions can be drawn about comparative
long-term management. The study’s strength, however,
is that it is the first randomized controlled trial to com-
pare the most commonly used medications for this
HYPERTENSION IN PREGNANCY 47
purpose in the United States: labetalol and nifedipine
(6). It also sheds light on a previously unexplored topic:
duration of persistent hypertension in the postpartum
period. We were able to document much longer follow-
up period than previously published reports, which have
been limited to discharge or 2–6 weeks postpartum (7).
Both oral labetalol and oral extended release nifedi-
pine are effective and well tolerated for management of
postpartum hypertension. Labetalol may be superior to
nifedipine, however, because it achieved control more
often with the starting dose and caused fewer side
effects. We suggest that in the absence of other contra-
indications to use, labetalol should be considered as
first-line treatment for persistent postpartum
hypertension.
Declaration of interest
The authors report no conflict of interest.
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