Hypertension, Pregnancy-Induced, Pre-eclampsia
Conditions
Keywords
ibuprofen, acetaminophen, blood pressure, post-partum, pain control, pre-eclampsia, gestational hypertension
Brief summary
To assess the effect of routine doses of ibuprofen on post-partum blood pressure control in women with gestational hypertension (gHTN) or preeclampsia without severe features (preE).
Detailed description
Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for post-partum analgesia. This use is supported by limited data on post-partum pain specifically; however, ibuprofen and other NSAIDs are superior to acetaminophen in ameliorating uterine pain and cramping in dysmenorrhea. The effect of NSAIDs on blood pressure (BP) in women post-partum is less well-known. In non-pregnant hypertensive patients NSAIDs are associated with increased BP over short courses of days to months, though effects of various NSAIDs differ. Pooled analyses suggest changes in mean BP of up to 3-6 mm Hg depending on the measurement method.There are case reports of hypertensive crises after NSAID administration post-partum in both normotensive and hypertensive women. A larger, recent retrospective cohort study found no difference in mean arterial pressure (MAP) or need for antihypertensive therapy in women with severe hypertensive disorders of pregnancy who were exposed to NSAIDs post-partum. In light of the potential for worsening blood pressure in women with hypertensive disorders of pregnancy, the Task Force on Hypertension in Pregnancy of American College of Obstetricians and Gynecologists stated that providers should be reminded of the contribution of nonsteroidal anti-inflammatory agents to increased BP. Additionally the task force recommends that NSAIDS be replaced by other analgesics in women with hypertension that persists for more than 1 day postpartum. However, provider practices since the publication of these guidelines have varied. Hypothesis: When compared to acetaminophen, ibuprofen does not increase post-partum systolic blood pressure (SBP) above baseline to a clinically relevant degree (≥10 mmHg) in women with gHTN and preE. Aim 1: To assess the mean difference in SBP during 24 hours of exposure to ibuprofen and acetaminophen. Aim 2: To assess whether ibuprofen results in higher satisfaction with pain control in the immediate post-partum period (48 hours) compared to acetaminophen. Aim 3: To prospectively assess the need for post-partum anti-hypertensive therapy and readmission for blood pressure control in women with gHTN and preE. The post-partum period is defined as delivery through 6 weeks after delivery.
Interventions
DRUGIbuprofen
At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with ibuprofen followed by acetaminophen.
DRUGAcetaminophen
At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with acetaminophen followed by ibuprofen.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Antepartum women * Diagnosis of Gestational Hypertension or Pre-eclampsia by blood pressure ≥140 systolic or ≥90 diastolic, on at least 2 measurements ≥ 4 hours apart; with or without proteinuria (urine protein-creatinine ratio ≥0.3 or 24 hour-urine protein ≥300 mg). * Taking one or fewer oral medications for blood pressure control. * Singleton gestation. * English-speaking
Exclusion criteria
* Allergy to nonsteroidal anti-inflammatory drugs, aspirin, or acetaminophen * More than 1 severe range blood pressure (≥160 systolic or ≥110 diastolic) prior to enrollment. * Neurologic symptoms attributed to hypertension (headache, visual changes) prior to enrollment. * Pulmonary edema. * Elevated AST (\>60 international units/L) or ALT (\>70 international units/L) prior to enrollment. * Low platelet count (\<100,000/microliter) prior to enrollment. * Renal insufficiency (creatinine \> 1.1 or double the baseline creatinine if known) prior to enrollment. * Chronic hypertension defined as hypertension pre-existing pregnancy or diagnosed prior to 20-weeks' gestation. * Moderate- or severe-persistent asthma. * Therapeutic anticoagulation. * Chronic opiate use during the pregnancy (opiate therapy given daily for \> 2 weeks). * Lactose intolerance or allergy due to placebo containing lactose. * Cesarean delivery. * Additional anesthesia at time of delivery (spinal anesthesia, sedation) that would change routine pain management.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Systolic Blood Pressure (SBP) | 24 hours following intervention | The adjusted mean difference in systolic blood pressure after 24 hours of exposure each to ibuprofen and acetaminophen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Self-reported Pain Score 2 Hours After First Intervention | At the time of first dose of study drug and 2 hours after | Prior to the first dose of pain medication, participants will take a brief, self-administered survey to assess abdominal and overall pain using a 0-10 scale. Two hours after the first dose of study drug, participants will repeat the self-administered survey to assess abdominal, perineal, and overall pain using a 0-10 scale. Clinical Pain Scale: 0=no pain to 10=worst pain. |
| Mean Pain Score by Nursing Assessment | 0-24 hours and 24-48 hours after initial study medication administration | Pain scores using a 0-10 scale as assessed by nursing during the 48 hours from initial study medication administration will be abstracted from the participant's medical record. Clinical Pain Scale: 0=no pain to 10=worst pain. All pain scores during the first intervention (0-24 hours) and second intervention (24-48) are included according to intention-to-treat principles. |
| Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | 24 hours and 48 hours after initial study medication administration | A brief survey on satisfaction with pain control during the first 24 hours post-partum and the second 24 hours post-partum, as well as overall during post-partum stay will be administered prior to discharge using a 1-5 Likert scale: 1=not satisfied to 5=extremely satisfied. |
Countries
United States
Participant flow
Pre-assignment details
74 women were consented prior to delivery. Women were subsequently excluded due to cesarean delivery (n=20), severe features of preeclampsia (n=7), additional anesthesia (n=2), and delivery physician preference (n=2). 43 women were randomized. Six women declined study medication and were not included in intention-to-treat analysis.
Participants by arm
| Arm | Count |
|---|---|
| Ibuprofen Followed by Acetaminophen Ibuprofen administered immediately post-partum, 600 mg (3 x 200 mg tablets) every 6 hours for 24 hours followed by acetaminophen, 650 mg (2 x 325 mg tablets) every 6 hours for 24 hours.
Ibuprofen: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with ibuprofen followed by acetaminophen.
Acetaminophen: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with acetaminophen followed by ibuprofen. | 19 |
| Acetaminophen Followed by Ibuprofen Acetaminophen administered immediately post-partum, 650 mg (2 x 325 mg tablets) every 6 hours for 24 hours followed by ibuprofen, 600 mg (3 x 200 mg tablets) every 6 hours for 24 hours.
Ibuprofen: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with ibuprofen followed by acetaminophen.
Acetaminophen: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with acetaminophen followed by ibuprofen. | 18 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (24 Hours) | Declined any study medication | 1 | 5 |
| First Intervention (24 Hours) | Discharged prior to cross-over | 0 | 2 |
| First Intervention (24 Hours) | Withdrew after receiving study drug | 2 | 6 |
| Second Intervention (24 Hours) | Discharged during second intervention | 3 | 5 |
| Second Intervention (24 Hours) | No blood pressure after cross-over | 1 | 0 |
| Second Intervention (24 Hours) | Protocol Violation | 0 | 1 |
| Second Intervention (24 Hours) | Withdrew after receiving study drug | 2 | 1 |
Baseline characteristics
| Characteristic | Ibuprofen Followed by Acetaminophen | Acetaminophen Followed by Ibuprofen | Total |
|---|---|---|---|
| Age, Continuous | 30.9 years STANDARD_DEVIATION 6.9 | 31.1 years STANDARD_DEVIATION 6.3 | 31.0 years STANDARD_DEVIATION 6.5 |
| BMI | 33.5 kg/m^2 | 31.7 kg/m^2 | 32.3 kg/m^2 |
| Gestational Age | 39.4 weeks STANDARD_DEVIATION 1.5 | 38.6 weeks STANDARD_DEVIATION 1.5 | 38.9 weeks STANDARD_DEVIATION 1.5 |
| Gestational Hypertension | 15 Participants | 17 Participants | 32 Participants |
| Insurance Commercial | 17 Participants | 14 Participants | 31 Participants |
| Insurance Public/Medicaid | 2 Participants | 4 Participants | 6 Participants |
| Marital Status Lives with partner | 1 Participants | 1 Participants | 2 Participants |
| Marital Status Married | 14 Participants | 11 Participants | 25 Participants |
| Marital Status Not reported | 0 Participants | 1 Participants | 1 Participants |
| Marital Status Single | 4 Participants | 5 Participants | 9 Participants |
| Maximum Systolic Blood Pressure Prior to Delivery | 153.2 mmHg STANDARD_DEVIATION 8.8 | 149.8 mmHg STANDARD_DEVIATION 8.6 | 151.5 mmHg STANDARD_DEVIATION 8 |
| Nulliparous | 10 Participants | 11 Participants | 21 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic White | 17 Participants | 17 Participants | 34 Participants |
| Region of Enrollment United States | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Systolic Blood Pressure | 132.5 mmHg STANDARD_DEVIATION 5.3 | 131.2 mmHg STANDARD_DEVIATION 7.3 | 131.6 mmHg STANDARD_DEVIATION 10.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 34 |
| other Total, other adverse events | 0 / 29 | 0 / 34 |
| serious Total, serious adverse events | 0 / 29 | 0 / 34 |
Outcome results
Primary
Difference in Systolic Blood Pressure (SBP)
The adjusted mean difference in systolic blood pressure after 24 hours of exposure each to ibuprofen and acetaminophen.
Time frame: 24 hours following intervention
Population: 37 women who received \>=1 dose of study drug were included in intention-to-treat analyses. 35 women had blood pressure recorded in the intended ibuprofen period; 2 excluded due to discharge prior to cross-over. 36 women had blood pressure recorded in the intended acetaminophen period; 1 excluded with no blood pressure measured after cross-over.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Difference in Systolic Blood Pressure (SBP) | Baseline systolic blood pressure | 131.8 mmHg | Standard Deviation 6.3 |
| Ibuprofen | Difference in Systolic Blood Pressure (SBP) | Systolic blood pressure after exposure | 129.1 mmHg | Standard Deviation 8.3 |
| Ibuprofen | Difference in Systolic Blood Pressure (SBP) | Observed Difference in systolic blood pressure | -2.7 mmHg | Standard Deviation 8.1 |
| Acetaminophen | Difference in Systolic Blood Pressure (SBP) | Baseline systolic blood pressure | 132.0 mmHg | Standard Deviation 6.4 |
| Acetaminophen | Difference in Systolic Blood Pressure (SBP) | Systolic blood pressure after exposure | 129.1 mmHg | Standard Deviation 8.5 |
| Acetaminophen | Difference in Systolic Blood Pressure (SBP) | Observed Difference in systolic blood pressure | -2.9 mmHg | Standard Deviation 8.6 |
95% CI: [-3.7, 5.7]
Secondary
Change in Self-reported Pain Score 2 Hours After First Intervention
Prior to the first dose of pain medication, participants will take a brief, self-administered survey to assess abdominal and overall pain using a 0-10 scale. Two hours after the first dose of study drug, participants will repeat the self-administered survey to assess abdominal, perineal, and overall pain using a 0-10 scale. Clinical Pain Scale: 0=no pain to 10=worst pain.
Time frame: At the time of first dose of study drug and 2 hours after
Population: 14 women in the ibuprofen first group and 8 women in the the acetaminophen first group completed pain surveys before and 2 hours after 1st dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Change in Self-reported Pain Score 2 Hours After First Intervention | Abdominal pain | -0.6 score on a scale | Standard Deviation 1.6 |
| Ibuprofen | Change in Self-reported Pain Score 2 Hours After First Intervention | Perineal pain | -1.1 score on a scale | Standard Deviation 1.6 |
| Ibuprofen | Change in Self-reported Pain Score 2 Hours After First Intervention | Overall pain | -0.7 score on a scale | Standard Deviation 1.8 |
| Acetaminophen | Change in Self-reported Pain Score 2 Hours After First Intervention | Abdominal pain | -0.3 score on a scale | Standard Deviation 1.2 |
| Acetaminophen | Change in Self-reported Pain Score 2 Hours After First Intervention | Perineal pain | 1.0 score on a scale | Standard Deviation 0.6 |
| Acetaminophen | Change in Self-reported Pain Score 2 Hours After First Intervention | Overall pain | -0.6 score on a scale | Standard Deviation 0.9 |
Comparison: Change in abdominal painp-value: 0.59t-test, 2 sided
Comparison: Change in perineal painp-value: 0.91t-test, 2 sided
Comparison: Change in overall painp-value: 0.88t-test, 2 sided
Secondary
Mean Pain Score by Nursing Assessment
Pain scores using a 0-10 scale as assessed by nursing during the 48 hours from initial study medication administration will be abstracted from the participant's medical record. Clinical Pain Scale: 0=no pain to 10=worst pain. All pain scores during the first intervention (0-24 hours) and second intervention (24-48) are included according to intention-to-treat principles.
Time frame: 0-24 hours and 24-48 hours after initial study medication administration
Population: Of 37 women in intention-to-treat analyses, 35 were analyzed in ibuprofen treatment; 2 of those women had no recorded nursing pain score in ibuprofen period (n=33). 36 women were analyzed in acetaminophen treatment, but 1 of those women had no recorded nursing pain score in acetaminophen period (n=35).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibuprofen | Mean Pain Score by Nursing Assessment | 2.2 score on a scale | Standard Deviation 1.1 |
| Acetaminophen | Mean Pain Score by Nursing Assessment | 2.3 score on a scale | Standard Deviation 1.3 |
p-value: 0.76t-test, 2 sided
Secondary
Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen
A brief survey on satisfaction with pain control during the first 24 hours post-partum and the second 24 hours post-partum, as well as overall during post-partum stay will be administered prior to discharge using a 1-5 Likert scale: 1=not satisfied to 5=extremely satisfied.
Time frame: 24 hours and 48 hours after initial study medication administration
Population: 11 women in the ibuprofen first group and 6 women in the the acetaminophen first group completed the satisfaction survey prior to discharge.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ibuprofen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Period 1 | 3 units on a scale |
| Ibuprofen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Period 2 | 3 units on a scale |
| Ibuprofen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Overall | 3 units on a scale |
| Acetaminophen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Period 1 | 4 units on a scale |
| Acetaminophen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Period 2 | 4.5 units on a scale |
| Acetaminophen | Satisfaction With Pain Control During 24 Hours of Exposure Each to Ibuprofen and Acetaminophen | Overall | 4.5 units on a scale |
Comparison: First intervention (24 hours)p-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: Second intervention (24 hours)p-value: 0.06Wilcoxon (Mann-Whitney)
Comparison: Overall satisfaction with pain control during study periodp-value: 0.04Wilcoxon (Mann-Whitney)