Abstract
OBJECTIVE
To estimate whether the diagnosis of asthma is associated with the use of specific uterotonic and antihypertensive medications during delivery hospitalizations.
METHODS
We used Perspective, an administrative database, to determine whether women hospitalized for delivery complicated by postpartum hemorrhage or preeclampsia received uterotonics and antihypertensive medications differentially based on the absence or presence of asthma from 2006 to 2015. Given that carboprost and intravenous labetalol may be associated with asthma exacerbation adjusted models for receipt of these medications were created with adjusted risk ratios (aRR) with 95% confidence intervals (CI) as measures of effect. Risk for status asthmaticus based on receipt of carboprost and intravenous labetalol was analyzed.
RESULTS
Over the study period, a total of 5,691,178 women were analyzed, of whom 239,915 (4.2%) had preeclampsia and 139,841 postpartum hemorrhage (2.5%). Carboprost was used less frequently in patients with asthma compared with patients with no asthma (11.4% vs 18.0%) in comparison to intravenous labetalol which was used more commonly when a diagnosis of asthma was present (18.5% vs 16.7%). In unadjusted analysis, the presence of asthma was associated with a 37% decrease in likelihood of cabroprost use and an 11% increase in likelihood of labetalol use. In adjusted analysis, the presence of asthma was associated with a 32% decrease in likelihood of carboprost use (aRR 0.68, 95% CI 0.62–0.74) compared to a 7% decrease in labetalol use (aRR 0.93, 95% CI 0.90–0.97). Risk for status asthmaticus was significantly increased with use of intravenous labetalol compared to other antihypertensive medications (6.5 versus 1.7 per 1,000 delivery hospitalizations, P <0.01).
CONCLUSION
There may be an opportunity to reduce use β-blockers and carboprost among patients with asthma. Given their association with status asthmaticus, these drugs should be used cautiously in women with asthma.
INTRODUCTION
Asthma is a common medical condition encountered during 4% to 8% of pregnancies. In addition to optimizing long-term medical management of asthma, maternal risk may be reduced by avoiding agents that precipitate bronchospasm when other effective treatment options are available.1 Many commonly used medications in obstetrics may increase the risk for bronchospasm, including carboprost (15-methyl prostaglandin F2α), ergot derivatives, indomethacin, and β-blockers.1–3 For patients with asthma, the benefits of administration of these medications must be weighed against risks.
Contraindications to uterotonics and antihypertensive medications may complicate clinical decision making for patients with asthma in the context of recent major efforts to reduce severe maternal morbidity and mortality by improving management of severe range hypertension and obstetric hemorrhage.4–8 While labetalol is a first-line anti-hypertensive4 and a drug of choice for treating hypertension in pregnancy,9 both the 2013 American Congress of Obstetricians and Gynecologists’ (ACOG) Task Force on Hypertension in Pregnancy and the National Partnership for Maternal Safety bundle on severe hypertension recommend avoiding labetalol for patients with asthma because of bronchoconstriction risk.4,8 For management of hemorrhage, the ACOG Practice Bulletin on asthma in pregnancy, among other sources, notes carboprost may precipitate bronchospasm.1–3,10
Data on bronchospasm risk related to antihypertensive medications and uterotonics among obstetric patients with asthma are limited,11–13 and it is unclear to what degree clinical recommendations affect practice. Given that data on outcomes and practice patterns may be important for optimizing care for patients with asthma in regard to management of hemorrhage and hypertension, the two primary objectives of this study were: (i) to evaluate practice patterns in use of antihypertensive medications and uterotonics among patients with asthma during delivery hospitalizations, and (ii) to evaluate risk for status asthmaticus in this population.
MATERIALS AND METHODS
This analysis used the Perspective database. The Perspective database, maintained by Premier Incorporated (Charlotte, NC), includes data on patient demographics, hospital characteristics, and discharge diagnosis codes, as well as medications and devices received during acute care hospitalizations. Perspective reports on 100% of hospitalizations for individual hospitals. The data undergo 95 quality assurance and validation checks prior to being used for research.14 Perspective is routinely used for research that evaluates outcomes related to medications and medical devices.15–17 Discharges included in the Perspective database represent approximately 15% of inpatient hospital stays annually. As all data were de-identified, the Columbia University Institutional Review Board deemed the study exempt.
Inclusion criteria for this analysis included delivery hospitalization from January 2006 through March 2015 for women 15 to 54 years of age. Delivery hospitalizations were identified based on billing and procedure codes using an approach that ascertains more than 95% of deliveries.18 Two cohorts of women undergoing delivery hospitalizations were analyzed: those with a diagnosis of preeclampsia and those with a diagnosis of postpartum hemorrhage. Patients with preeclampsia were identified based on ICD-9-CM codes 642.4x, 642.5x, and 642.7x. Patients with postpartum hemorrhage were identified based on ICD-9-CM codes 666.0x, 666.1x, and 666.2x. In the preeclampsia group, we analyzed whether patients received the following antihypertensive medications: oral labetalol, intravenous labetalol, nifedipine, and hydralazine. In the postpartum hemorrhage cohort we identified patients who received the following uterotonic medications: misoprostol, methylergonovine, and carboprost. Because a lower dose of misoprostol is used as a labor induction agent we used an algorithm developed by Bateman et al.19 to differentiate between induction and uterotonic-dose misoprostol use. The presence of asthma was identified based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (493, 493.0x, 493.1x, 493.2x, 493.8x, 493.9x).
We evaluated whether the presence of asthma was associated with receipt of: (i) labetalol amongst patients with preeclampsia, and (ii) carboprost amongst patients with postpartum hemorrhage. Univariate associations between clinical, hospital, and demographic variables and receipt of intravenous labetalol and carboprost were evaluated using the chi-square test. Patient demographic characteristics included maternal age, race (white, black, other), marital status, year of discharge, and payer status. Hospital characteristics included teaching status, bed size, geographic region, and urban or rural location. Adjusted risk ratios (aRR) for receipt of intravenous labetalol and carboprost with 95% confidence interval (CI) as measures of effect accounting for demographic, hospital, and asthma diagnosis were derived from fitting log-linear regression models based on the methods of generalized estimating equations that accounts for hospital clustering effects. This methodological approach allows for estimation of risk ratios which may be more clinically interpretable than odds ratios associated with logistic regression analysis. To account for the possibility of confounding by indication (i.e., a diagnosis of asthma itself being related to higher probability of treatment for severe range hypertension), we performed a sensitivity analysis and repeated the adjusted model with the same covariates evaluating receipt of intravenous labetalol restricted to preeclamptic patients requiring treatment with antihypertensive medications. We performed a similar sensitivity analysis for receipt of carboprost restricted to patients with hemorrhage receiving uterotonics to account for a possible relationship between severity of hemorrhage and asthma diagnosis. Specific preeclampsia diagnosis (severe, superimposed, or mild or unspecified) was included in the models for preeclampsia.
Risk for status asthmaticus (ICD-9-CM 493.01, 493.11, 493.21, 493.91) associated with receipt of antihypertensive medications (intravenous labetalol, oral labetalol, nifedipine, and hydralazine) and uterotonics (carboprost, misoprostol, methylergonovine) was evaluated. Because patients could receive one or more antihypertensive medications or uterotonic agents, comparisons for each medication were based on receipt of any combination of medications including the specified drug. Because of concerns regarding disclosure of personal health information categorical data with cell sizes of <10 are not presented. All analyses were performed with SAS 9.4 (SAS Institute, Cary, NC).
RESULTS
Of 5,691,178 delivery hospitalizations, 4.2% were complicated by preeclampsia (n=239,915) and 2.5% by postpartum hemorrhage (n=139,841). Overall, 5.2% of women with preeclampsia (n=12,486) and 4.0% of women with postpartum hemorrhage had asthma (n=5,633). Of patients with preeclampsia and asthma 46.8% (n=5,846) received 1 or more antihypertensive medications. Uterotonics were administered to 64.5% of women with postpartum hemorrhage and an asthma diagnosis (n=3,639).
Women with preeclampsia and asthma were younger, more likely to be black, have Medicaid insurance, deliver at a hospital in an urban location, a teaching hospital and in the Northeast and Midwest compared to the South and West, and have severe or superimposed preeclampsia than women without asthma. Women with postpartum hemorrhage with asthma were also more likely to be younger and have Medicaid insurance and deliver in a teaching hospital and in the Northeast and Midwest compared to the South and West than women without asthma (Appendix 1, available online at http://links.lww.com/xxx).
Women with preeclampsia and asthma received intravenous labetalol 1.8% more often, oral labetalol 1.6% more often, nifedipine 2.8% more often, and hydralazine 1.7% more often than those without asthma (absolute percent rate differences). Women with asthma were also 3.8% more likely to receive at least 1 type of antihypertensive medication. In contrast, although women with asthma who suffered postpartum hemorrhage were 1.0% more likely to receive misoprostol than women without asthma, 6.6% fewer received carboprost and 3.1% fewer received methylergonovine, and were overall 2.9% less likely to receive more than one medication (absolute percent rate differences, Table 1).
Table 1.
Medication receipt
| With asthma n, (%) | Without asthma n, (%) | |
|---|---|---|
| Preeclampsia | ||
|
| ||
| All preeclamptics | 12,486 (100.0%) | 227,429 (100.0%) |
| Labetalol, IV | 2,305 (18.5%) | 37,911 (16.7%) |
| Labetalol, oral | 3,565 (28.6%) | 61,281 (27.0%) |
| Nifedipine | 2,346 (18.7%) | 36,161 (15.9%) |
| Hydralazine | 2,076 (16.6%) | 33,937 (14.9%) |
| >1 medication | 2,989 (23.9%) | 47,670 (20.1%) |
|
| ||
| Postpartum hemorrhage | ||
|
| ||
| All postpartum hemorrhage | 5,633 (100.0%) | 134,208 (100.0%) |
| Misoprostol | 2,140 (38.0%) | 49,686 (37.0%) |
| Methylergonovine | 2,315 (41.1%) | 59,255 (44.2%) |
| Carboprost | 642 (11.4%) | 24,150 (18.0%) |
| >1 medication | 1,286 (22.8%) | 34,471 (25.7%) |
IV, intravenous; the table demonstrates whether patient received each of the individual medications alone or in combination with other medications.
In the adjusted model likelihood of receipt of intravenous labetalol associated with 7% lower among asthmatics (aRR 0.93, 95% CI 0.90, 0.97) (Table 2). In comparison, likelihood of receipt of carboprost was 32% with a diagnosis of asthma (aRR 0.68, 95% CI 0.62, 0.74) (Table 2). Other important factors associated with administration of intravenous labetalol included severe and superimposed preeclampsia in comparison to mild preeclampsia (aRR 3.55, 95% CI 3.34, 3.77 and aRR 3.39, 95% CI 3.18, 3.61 respectively), study year with labetalol use increasingly likely over the study, and black compared to white race (aRR 1.52, 95% CI 1.46, 1.57) (Table 3). Factors associated with increased use of carboprost included hospitals in the South compared to the Northeast (aRR 1.39, 95% CI 1.15, 1.67).
Table 2.
Unadjusted and adjusted models for receipt of carboprost
| Unadjusted model PPH n,(%) | Adjusted model Asthma n,(%) | |||
|---|---|---|---|---|
|
| ||||
| Risk ratio | 95% confidence interval | Adjusted risk ratio | 95% confidence interval | |
| Asthma | 0.63 | (0.59, 0.69) | 0.68 | (0.62, 0.74) |
| Year | ||||
| 2007 | 0.96 | (0.91, 1.02) | 0.98 | (0.92, 1.04) |
| 2008 | 0.94 | (0.89, 1.00) | 0.94 | (0.88, 1.01) |
| 2009 | 0.96 | (0.91, 1.02) | 0.93 | (0.86, 1.01) |
| 2010 | 0.96 | (0.91, 1.01) | 0.93 | (0.86, 1.00) |
| 2011 | 1.00 | (0.95, 1.06) | 0.96 | (0.88, 1.05) |
| 2012 | 0.97 | (0.92, 1.02) | 0.97 | (0.88, 1.06) |
| 2013 | 0.99 | (0.94, 1.04) | 0.97 | (0.88, 1.07) |
| 2014 | 1.02 | (0.96, 1.07) | 0.99 | (0.90, 1.09) |
| 2015 (1Q) | 1.06 | (0.98, 1.16) | 1.03 | (0.92, 1.16) |
| Hospital bed size | ||||
| Small | 1.00 | (reference) | 1.00 | (reference) |
| Medium | 0.99 | (0.96, 1.02) | 0.97 | (0.84, 1.13) |
| Large | 1.14 | (1.11, 1.18) | 0.98 | (0.83, 1.17) |
| Maternal age (years) | ||||
| 15–17 | 1.11 | (1.03, 1.19) | 0.92 | (0.86, 0.97) |
| 18–24 | 1.00 | (reference) | 1.00 | (reference) |
| 25–34 | 0.96 | (0.93, 0.98) | 0.90 | (0.84, 0.96) |
| ≥35 | 1.05 | (1.01, 1.09) | 0.99 | (0.92, 1.06) |
| Insurance status | ||||
| Medicare | 0.89 | (0.77, 1.03) | 1.03 | (0.91, 1.15) |
| Medicaid | 1.03 | (1.01, 1.06) | 0.96 | (0.93, 0.99) |
| Private | 1.00 | (reference) | 1.00 | (reference) |
| Other | 1.20 | (1.12, 1.28) | 0.98 | (0.91, 1.06) |
| Uninsured | 1.12 | (1.04, 1.21) | 1.01 | (0.93, 1.10) |
| Race | ||||
| White | 1.00 | (reference) | 1.00 | (reference) |
| Black | 1.04 | (1.00, 1.08) | 1.02 | (0.97, 1.06) |
| Other | 0.98 | (0.95, 1.01) | 1.00 | (0.96, 1.03) |
| Unknown | 0.56 | (0.30, 1.04) | 0.72 | (0.41, 1.27) |
| Rural hospital | 1.05 | (1.01, 1.09) | 1.14 | (0.99, 1.31) |
| Marital Status | ||||
| Married | 1.00 | (reference) | 1.00 | (reference) |
| Unmarried | 1.02 | (0.99, 1.04) | 1.00 | (0.98, 1.03) |
| Unknown | 1.02 | (0.98, 1.07) | 0.99 | (0.91, 1.06) |
| Hospital Region | ||||
| Northeast | 1.00 | (reference) | 1.00 | (reference) |
| Midwest | 1.16 | (1.11, 1.21) | 1.07 | (0.86, 1.34) |
| South | 1.57 | (1.51, 1.63) | 1.39 | (1.15, 1.67) |
| West | 1.11 | (1.07, 1.17) | 1.04 | (0.84, 1.29) |
| Teaching hospital | 0.95 | (0.93, 0.98) | 1.05 | (0.92, 1.20) |
The adjusted model includes all of the factors in the table. The references for asthma, year, rural hospital location, hospital teaching status are absence of asthma, 2006, urban location, and non-teaching hospitals respectively.
Table 3.
Unadjusted and adjusted models for receipt of intravenous labetalol
| Unadjusted model PPH n,(%) | Adjusted model Asthma n,(%) | |||
|---|---|---|---|---|
|
| ||||
| Risk ratio | 95% confidence interval | Adjusted risk ratio | 95% confidence interval | |
| Asthma | 1.11 | (1.06, 1.16) | 0.93 | (0.90, 0.97) |
| Year | ||||
| 2007 | 1.05 | (1.00, 1.10) | 1.06 | (1.00, 1.12) |
| 2008 | 1.09 | (1.03, 1.14) | 1.07 | (0.99, 1.16) |
| 2009 | 1.14 | (1.08, 1.20) | 1.13 | (1.04, 1.23) |
| 2010 | 1.17 | (1.12, 1.23) | 1.16 | (1.05, 1.28) |
| 2011 | 1.21 | (1.15, 1.27) | 1.17 | (1.07, 1.28) |
| 2012 | 1.32 | (1.27, 1.39) | 1.29 | (1.16, 1.43) |
| 2013 | 1.43 | (1.37, 1.50) | 1.37 | (1.24, 1.52) |
| 2014 | 1.62 | (1.55, 1.69) | 1.50 | (1.35, 1.68) |
| 2015 (1Q) | 1.80 | (1.69, 1.92) | 1.61 | (1.42, 1.83) |
| Hospital bed size | ||||
| Small | 1.00 | (reference) | 1.00 | (reference) |
| Medium | 1.09 | (1.06, 1.11) | 0.96 | (0.78, 1.18) |
| Large | 1.26 | (1.23, 1.29) | 1.03 | (0.80, 1.32) |
| Maternal age (years) | ||||
| 15–17 | 0.93 | (0.88, 0.99) | 0.94 | (0.89, 0.98) |
| 18–24 | 1.00 | (reference) | 1.00 | (reference) |
| 25–34 | 1.00 | (0.97, 1.02) | 1.03 | (1.00, 1.05) |
| ≥35 | 1.23 | (1.19, 1.26) | 1.16 | (1.13, 1.20) |
| Insurance status | ||||
| Medicare | 1.48 | (1.36, 1.61) | 1.13 | (1.05, 1.22) |
| Medicaid | 1.28 | (1.25, 1.31) | 1.09 | (1.07, 1.12) |
| Private | 1.00 | (reference) | 1.00 | (reference) |
| Other | 1.11 | (1.05, 1.17) | 1.01 | (0.94, 1.09) |
| Uninsured | 1.23 | (1.15, 1.32) | 1.16 | (1.07, 1.25) |
| Race | ||||
| White | 1.00 | (reference) | 1.00 | (reference) |
| Black | 1.78 | (1.74, 1.83) | 1.52 | (1.46, 1.57) |
| Other | 1.21 | (1.18, 1.24) | 1.18 | (1.14, 1.22) |
| Unknown | 1.48 | (0.97, 2.25) | 1.02 | (0.73, 1.42) |
| Rural hospital | 0.62 | (0.59, 0.65) | 0.85 | (0.73, 0.98) |
| Marital Status | ||||
| Married | 1.00 | (reference) | 1.00 | (reference) |
| Unmarried | 1.27 | (1.25, 1.30) | 1.09 | (1.07, 1.12) |
| Unknown | 0.95 | (0.92, 0.99) | 0.91 | (0.80, 1.03) |
| Hospital Region | ||||
| Northeast | 1.00 | (reference) | 1.00 | (reference) |
| Midwest | 1.05 | (1.02, 1.09) | 1.00 | (0.82, 1.22) |
| South | 1.10 | (1.07, 1.13) | 0.90 | (0.74, 1.10) |
| West | 1.09 | (1.06, 1.13) | 1.17 | (0.85, 1.61) |
| Teaching | 1.37 | (1.34, 1.40) | 1.20 | (0.96,1.51) |
| Preeclampsia | ||||
| Severe | 3.84 | (3.75, 3.93) | 3.55 | (3.34,3.77) |
| Mild | 1.00 | (reference) | 1.00 | (reference) |
| Superimposed | 3.99 | (3.88, 4.11) | 3.39 | (3.18,3.61) |
The adjusted model includes all of the factors in the table. The references for asthma, rural hospital location, hospital teaching status are absence of asthma, urban location, and non-teaching hospitals respectively.
The sensitivity analyses for intravenous labetalol and carboprost receipt are demonstrated in Appendix 2 and Appendix 3, available online at http://links.lww.com/xxx. Asthma was associated with a 5% lower likelihood of intravenous labetalol (aRR 0.95, 95% CI 0.92, 0.98) and a 27% lower likelihood of carboprost (aRR 0.73, 95% 0.67, 0.79). Other significant factors in the sensitivity analysis for labetalol included study year with likelihood of labetalol increasing over the study period and a diagnosis of severe or superimposed preeclampsia compared to mild preeclampsia. In the sensitivity analysis for carboprost there was decreased likelihood of drug administration as the study period progressed, and the use of the medication in the South no longer differed significantly compared to the Northeast.
Comparing risk for status asthmaticus among patients receiving labetalol and carboprost, 6.5 per 1,000 deliveries where women with asthma received IV labetalol were complicated by status asthmaticus versus 1.7 per 1,000 deliveries with other antihypertensive medications (p<0.01) (Table 4). Overall, 71.4% of status asthmaticus cases occurred amongst women receiving intravenous labetalol. In comparison, patients receiving carboprost were not significantly more likely to experience status asthmaticus than patients receiving other uterotonic medications (3.1 per 1,000 deliveries with carboprost versus 1.0 per 1,000 deliveries with other uterotonics, p=0.56). Risk for status asthmaticus was not different based on receipt of other antihypertensive medications (Appendix 4, available online at http://links.lww.com/xxx).
Table 4.
Risk for status asthmaticus for patients receiving intravenous labetalol and carboprost
| Status asthmaticus | |||
|---|---|---|---|
| Per 1,000 deliveries (95 % confidence interval) | Present (n) | Absent (n) | |
| Preeclampsia | |||
|
| |||
| ≥1 antihypertensive medication (received IV labetalol) | 6.5 (3.9–10.7) | 15 | 2290 |
| ≥1 antihypertensive medication (no IV labetalol)* | 1.7 (0.8–3.7) | 6 | 3535 |
|
| |||
| Postpartum hemorrhage | |||
|
| |||
| ≥1 uterotonic (received carboprost) | 3.1 (0.9–11.3) | 2 | 642 |
| ≥1 uterotonic (no carboprost) # | 1.0 (0.3–2.9) | 3 | 2997 |
The table demonstrates risk for status asthmaticus per 1,000 delivery hospitalizations among patients with asthma receiving uterotonic and antihypertensive medications.
p<0.01 for comparison between patients receiving ≥1 antihypertensive based on whether intravenous labetalol was administered.
Comparisons of ≥1 uteronics based on the presence of carboprost were not significant with p=0.56 respectively.
DISCUSSION
In our analysis, patients with asthma were more than a third less likely to receive carboprost than those without the diagnosis. Use of methylergonovine maleate, which also may be associated with bronchospasm, was similarly administered less frequently amongst patients with asthma.1–3,10 In contrast, administration of intravenous labetalol was actually likelier in patients with asthma. Our studies suggest that clinical use of labetalol appears to differ from obstetric research protocols that frequently exclude patients with asthma from receiving β-blockers.20,21 Major non-obstetric guidelines recommend against administration of β-blockers to patients with asthma,22 and meta-analysis has demonstrated increased risk even when selective beta blockers are used.23 In other medical specialties risk and benefits of β-blocker administration with reactive airway disease are balanced depending on the specific clinical scenario.24–26 The 2013 ACOG Task Force on Hypertension in Pregnancy and the National Partnership for maternal safety specifically recommend avoiding labetalol because of bronchoconstriction risk.4,8
Given similar theoretical risks, why a differential exists in uterotonic but not antihypertensive management is unclear. An important factor may be that while risks among non-pregnant patients with asthma from β-blockers are well-characterized,22 risk for obstetric patients is not well documented. In comparison, there are numerous case reports of life-threatening bronchospasm associated with carboprost.12,13 While case reports can be important in highlighting risk for rare but serious outcomes, they are not representative of specific risks in large populations and, in fact, in this analysis more cases of status asthmaticus were present among women who received intravenous labetalol. While all antihypertensive medications recommended for treatment of obstetric patients may have side effects,27–29 and use of a specific agent requires weighing risks and benefits for an individual patient, our finding of an association between status asthmaticus and intravenous labetalol further support caution in using this medication in this population. In addition to research evidence, graduate medical education and society leadership likely play major roles in perceived risk, and future studies are warranted to determine whether ACOG Task Force and National Partnership recommendations are being adopted into practice.
There are several important considerations in interpreting the findings of this study. First, because the database relies on discharge diagnoses, we are unable to determine whether administration of intravenous labetalol played a causal role in individual cases of status asthmaticus and are limited to demonstrating an association. Second, because of limitations regarding granularity in administrative data and because we do not have access to outpatient records, we cannot assess how asthma severity and control on admission factored into clinical decision-making regarding use of specific uterotonic or antihypertensive medications. Specifically, we cannot determine history of prior events or symptomatology related to asthma diagnosis, nor can we account for medical management of asthma prior to delivery hospitalization admission. Third, because nifedipine can be administered for both severe-range hypertension as well as ongoing blood pressure control, we were not able to determine specific instances when it was used for hypertensive acuity. Fourth, we cannot determine the number of doses or dosage of a uterotonic or antihypertensive medication that a patient received. Fifth, while we found that risk for status asthmaticus was increased with IV labetalol the number of patients with this condition was small, precluding precise statistical estimates of number needed to harm. Similarly, because of the small number of events, we are unable to make a precise estimate risk for status asthmaticus associated with carboprost. Sixth, women could have contributed more than one delivery to this dataset and this factor could not be reliably controlled for in this data set given that patients cannot be tracked across hospitals. Seventh, we do not have actual clinical documentation as to why specific uterotonic or antihypertensive medications were selected by providers. Eighth, we elected not to evaluate asthma exacerbations short of status asthmaticus; given the cross sectional nature of this administrative data, acute exacerbations short of status asthmaticus could be both an outcome and a marker of disease severity making interpretation problematic. If providers were less likely to administer labetalol to patients with asthma presenting with an exacerbation and simultaneously patients were more likely to develop exacerbations short of status asthmaticus as a result of labetalol or carboprost treatment, the model could demonstrate an effect in either direction or no effect at all no effect at all depending on the relative contributions of the two unmeasurable scenarios. Strengths of this study include a large patient population, a long study period, and diverse clinical settings. Given the rarity of status asthmaticus among obstetric patients, further characterization of risk may require surveillance efforts from large hospital systems or statewide safety initiatives such as the California Maternal Quality Care Collaborative or New York State’s Safe Motherhood Initiative.6,7,30
In summary, given that current clinical practice involves high rates of β-blocker use among patients with preeclampsia and asthma, and that multiple other effective agents not associated with bronchospasm are available for both acute and longer-term blood pressure control, an opportunity exists to reduce use of labetalol and potential risk in this population. That an association was noted with status asthmaticus further supports that β-blockers should be used with caution in this population.
Supplementary Material
Acknowledgments
Dr. Friedman is supported by a career development award (K08HD082287) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
Footnotes
Presented at the January 2018 Society for Maternal Fetal Medicine Annual Pregnancy Meeting in Dallas, Texas
Financial Disclosure
Dr. Wright has served as a consultant for Tesaro and Clovis Oncology. The other authors did not report any potential conflicts of interest.
Each author has indicated that he or she has met the journal’s requirements for authorship.
References
- 1.Dombrowski MP, Schatz M. Asthma in pregnancy. Clinical obstetrics and gynecology. 2010;53:301–10. doi: 10.1097/GRF.0b013e3181de8906. [DOI] [PubMed] [Google Scholar]
- 2.Powrie RO, Larson L, Miller M. Managing asthma in expectant mothers. Treatments in respiratory medicine. 2006;5:1–10. doi: 10.2165/00151829-200605010-00001. [DOI] [PubMed] [Google Scholar]
- 3.Dombrowski MP, Schatz M Bulletins-Obstetrics ACoP. ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists number 90, February 2008: asthma in pregnancy. Obstetrics and gynecology. 2008;111:457–64. doi: 10.1097/AOG.0b013e3181665ff4. [DOI] [PubMed] [Google Scholar]
- 4.American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstetrics and gynecology. 2013;122:1122–31. doi: 10.1097/01.AOG.0000437382.03963.88. [DOI] [PubMed] [Google Scholar]
- 5.Main EK, Goffman D, Scavone BM, et al. National Partnership for Maternal Safety: Consensus Bundle on Obstetric Hemorrhage. Obstetrics and gynecology. 2015;126:155–62. doi: 10.1097/AOG.0000000000000869. [DOI] [PubMed] [Google Scholar]
- 6.Ananth CV, D’Alton ME. Maternal mortality and serious morbidity in New York: Recognizing the burden of the problem. Seminars in perinatology. 2016;40:79–80. doi: 10.1053/j.semperi.2015.11.010. [DOI] [PubMed] [Google Scholar]
- 7.Main EK, Cape V, Abreo A, et al. Reduction of severe maternal morbidity from hemorrhage using a state perinatal quality collaborative. American journal of obstetrics and gynecology. 2017;216:298e1–e11. doi: 10.1016/j.ajog.2017.01.017. [DOI] [PubMed] [Google Scholar]
- 8.Bernstein PS, Martin JN, Jr, Barton JR, et al. National Partnership for Maternal Safety: Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period. Obstet Gynecol. 2017;130:347–57. doi: 10.1097/AOG.0000000000002115. [DOI] [PubMed] [Google Scholar]
- 9.Caetano M, Ornstein MP, Von Dadelszen P, et al. A survey of Canadian practitioners regarding the management of the hypertensive disorders of pregnancy. Hypertension in pregnancy. 2004;23:61–74. doi: 10.1081/PRG-120028282. [DOI] [PubMed] [Google Scholar]
- 10.Schatz M, Dombrowski MP. Clinical practice. Asthma in pregnancy The New England journal of medicine. 2009;360:1862–9. doi: 10.1056/NEJMcp0809942. [DOI] [PubMed] [Google Scholar]
- 11.Martin JN, Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstetrics and gynecology. 2005;105:246–54. doi: 10.1097/01.AOG.0000151116.84113.56. [DOI] [PubMed] [Google Scholar]
- 12.Harber CR, Levy DM, Chidambaram S, Macpherson MB. Life-threatening bronchospasm after intramuscular carboprost for postpartum haemorrhage. BJOG. 2007;114:366–8. doi: 10.1111/j.1471-0528.2006.01227.x. [DOI] [PubMed] [Google Scholar]
- 13.Cooley DM, Glosten B, Roberts JR, Eppes PD, Barnes RB. Bronchospasm after intramuscular 15-methyl prostaglandin F2 alpha and endotracheal intubation in a nonasthmatic patient. Anesth Analg. 1991;73:87–9. doi: 10.1213/00000539-199107000-00016. [DOI] [PubMed] [Google Scholar]
- 14.Stulberg J, Delaney C, Neuhauser D, Aron D, Fu P, Koroukian S. Adherence to surgical care improvement project measures and the asssociation with postoperative infections. JAMA. 2010;303:2479–85. doi: 10.1001/jama.2010.841. [DOI] [PubMed] [Google Scholar]
- 15.Fang M, Maselli J, Lurie J, Lindenauer P, Auerbach A. Use and outcomes of venous thromboembolism prophyalxis after spinal fusion surgery. J Thromb Haemost. 2011;9:1318–25. doi: 10.1111/j.1538-7836.2011.04326.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kulik A, Rassen JA, Myers J, et al. Comparative effectiveness of preventative therapy for venous thromboembolism after coronary artery bypass graft surgery. Circ Cardiovasc Interv. 2012;5:590–6. doi: 10.1161/CIRCINTERVENTIONS.112.968313. [DOI] [PubMed] [Google Scholar]
- 17.Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0. 9% saline compared to Plasma-Lyte. Ann Surg. 2012;255:821–9. doi: 10.1097/SLA.0b013e31825074f5. [DOI] [PubMed] [Google Scholar]
- 18.Kuklina E, Whiteman M, Hillis S, Jameieson D, Meikle S, Posner S. An enhanced method for identifying obstetric deliveries: implications for estimating maternal morbidity. Matern Child Health J. 2008;12:469–77. doi: 10.1007/s10995-007-0256-6. [DOI] [PubMed] [Google Scholar]
- 19.Bateman BT, Tsen LC, Liu J, Butwick AJ, Huybrechts KF. Patterns of second-line uterotonic use in a large sample of hospitalizations for childbirth in the United States: 2007–2011. Anesth Analg. 2014;119:1344–9. doi: 10.1213/ANE.0000000000000398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Vermillion ST, Scardo JA, Newman RB, Chauhan SP. A randomized, double-blind trial of oral nifedipine and intravenous labetalol in hypertensive emergencies of pregnancy. American journal of obstetrics and gynecology. 1999;181:858–61. doi: 10.1016/s0002-9378(99)70314-5. [DOI] [PubMed] [Google Scholar]
- 21.Raheem IA, Saaid R, Omar SZ, Tan PC. Oral nifedipine versus intravenous labetalol for acute blood pressure control in hypertensive emergencies of pregnancy: a randomised trial. BJOG. 2012;119:78–85. doi: 10.1111/j.1471-0528.2011.03151.x. [DOI] [PubMed] [Google Scholar]
- 22.British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax. 2014;69(Suppl 1):1–192. [PubMed] [Google Scholar]
- 23.Morales DR, Jackson C, Lipworth BJ, Donnan PT, Guthrie B. Adverse respiratory effect of acute beta-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials. Chest. 2014;145:779–86. doi: 10.1378/chest.13-1235. [DOI] [PubMed] [Google Scholar]
- 24.Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM. Effectiveness of beta-blocker therapy after acute myocardial infarction in elderly patients with chronic obstructive pulmonary disease or asthma. J Am Coll Cardiol. 2001;37:1950–6. doi: 10.1016/s0735-1097(01)01225-6. [DOI] [PubMed] [Google Scholar]
- 25.Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial infarction: do benefits ever outweigh risks in asthma? Cardiology. 1999;92:99–105. doi: 10.1159/000006955. [DOI] [PubMed] [Google Scholar]
- 26.Self TH, Wallace JL, Soberman JE. Cardioselective beta-blocker treatment of hypertension in patients with asthma: when do benefits outweigh risks? J Asthma. 2012;49:947–51. doi: 10.3109/02770903.2012.719252. [DOI] [PubMed] [Google Scholar]
- 27.Russell RP. Side effects of calcium channel blockers. Hypertension. 1988;11:II42–4. doi: 10.1161/01.hyp.11.3_pt_2.ii42. [DOI] [PubMed] [Google Scholar]
- 28.Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ. 2003;327:955–60. doi: 10.1136/bmj.327.7421.955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Shekhar S, Gupta N, Kirubakaran R, Pareek P. Oral nifedipine versus intravenous labetalol for severe hypertension during pregnancy: a systematic review and meta-analysis. BJOG. 2016;123:40–7. doi: 10.1111/1471-0528.13463. [DOI] [PubMed] [Google Scholar]
- 30.Chazotte C, D’Alton ME. Maternal mortality in New York--Looking back, looking forward. Seminars in perinatology. 2016;40:132–5. doi: 10.1053/j.semperi.2015.11.020. [DOI] [PubMed] [Google Scholar]
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