EXPERT COMMENTARY

While numerous studies have investigated the risk of perinatal outcomes with advancing maternal age, the primary objective of a recent study by Lisonkova and colleagues was to examine the association between advancing maternal age and severe maternal morbidities and mortality.

Details of the study

The population-based retrospective cohort study compared age-specific rates of severe maternal morbidities and mortality among 828,269 pregnancies in Washington state between 2003 and 2013. Singleton births to women 15 to 60 years of age were included; out-of-hospital births were excluded. Information was obtained by linking the Birth Events Record Database (which includes information on maternal, pregnancy, and labor and delivery characteristics and birth outcomes), and the Comprehensive Hospital Abstract Reporting System database (which includes diagnostic and procedural codes for all hospitalizations in Washington state).

The primary objective was to examine the association between age and severe maternal morbidities. Maternal morbidities were divided into categories: antepartum hemorrhage, respiratory morbidity, thromboembolism, cerebrovascular morbidity, acute cardiac morbidity, severe postpartum hemorrhage, maternal sepsis, renal failure, obstetric shock, complications of anesthesia and obstetric interventions, and need for life-saving procedures. A composite outcome, comprised of severe maternal morbidities, intensive care unit admission, and maternal mortality, was also created.

Rates of severe morbidities were compared for age groups 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years to the referent category (25 to 29 years). Additional comparisons were also performed for ages 45 to 49 and ≥50 years for the composite and for morbidities with high incidence. Logistic regression and sensitivity analyses were used to control for demographic and prepregnancy characteristics, underlying medical conditions, assisted conception, and delivery characteristics.

Severe maternal morbidities demonstrated a J-shaped association with age: the lowest rates of morbidity were observed in women 20 to 34 years of age, and steeply increasing rates of morbidity were observed for women aged 40 and older. One notable exception was the rate of sepsis, which was increased in teen mothers compared with all other groups.

The unadjusted rate of the composite outcome of severe maternal morbidity and mortality was 2.1% in teenagers, 1.5% among women 25 to 29 years, 2.3% among those aged 40 to 44, and 3.6% among women aged 45 and older.

Although rates were somewhat attenuated after adjustment for demographic and prepregnancy characteristics, chronic medical conditions, assisted conception, and delivery characteristics, most morbidities remained significantly increased among women aged 39 years and older, including the composite outcome. Among the individual morbidities considered, increased risk was highest for renal failure, amniotic fluid embolism, cardiac morbidity, and shock, with adjusted odds ratios of 2.0 or greater for women older than 39 years.

Related article:
Reducing maternal mortality in the United States—Let’s get organized!

Study strengths and weaknesses

This study contributes substantially to the existing literature that demonstrates higher rates of pregnancy-associated morbidities in women of increasing maternal age.^1,2 Prior studies in this area focused on perinatal morbidity and mortality and on obstetric outcomes such as cesarean delivery.^3–5 This large-scale study examined the association between advancing maternal age and a variety of serious maternal morbidities. In another study, Callaghan and Berg found a similar pattern among mortalities, with high rates of mortality attributable to hemorrhage, embolism, and cardiomyopathy in women aged 40 years and older.¹

Exclusion of multiple gestations. As in any study, we must consider the methodology, and it is notable that Lisonkova and colleagues’ study excluded multiple gestations. Given the association with advanced maternal age, assisted reproductive technology, and the incidence of multiple gestations, a high rate of multiple gestations would be expected among women of advanced maternal age. (Generally, maternal age of at least 35 years is considered “advanced,” with greater than 40 years “very advanced.”) Since multiple gestations tend to be associated with increases in morbidity, excluding these pregnancies would likely bias the study results toward the null. If multiple gestations had been included, the rates of serious maternal morbidities in older women might be even higher than those demonstrated, potentially strengthening the associations reported here.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

While numerous studies have investigated the risk of perinatal outcomes with advancing maternal age, the primary objective of a recent study by Lisonkova and colleagues was to examine the association between advancing maternal age and severe maternal morbidities and mortality.

Details of the study

The population-based retrospective cohort study compared age-specific rates of severe maternal morbidities and mortality among 828,269 pregnancies in Washington state between 2003 and 2013. Singleton births to women 15 to 60 years of age were included; out-of-hospital births were excluded. Information was obtained by linking the Birth Events Record Database (which includes information on maternal, pregnancy, and labor and delivery characteristics and birth outcomes), and the Comprehensive Hospital Abstract Reporting System database (which includes diagnostic and procedural codes for all hospitalizations in Washington state).

The primary objective was to examine the association between age and severe maternal morbidities. Maternal morbidities were divided into categories: antepartum hemorrhage, respiratory morbidity, thromboembolism, cerebrovascular morbidity, acute cardiac morbidity, severe postpartum hemorrhage, maternal sepsis, renal failure, obstetric shock, complications of anesthesia and obstetric interventions, and need for life-saving procedures. A composite outcome, comprised of severe maternal morbidities, intensive care unit admission, and maternal mortality, was also created.

Rates of severe morbidities were compared for age groups 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years to the referent category (25 to 29 years). Additional comparisons were also performed for ages 45 to 49 and ≥50 years for the composite and for morbidities with high incidence. Logistic regression and sensitivity analyses were used to control for demographic and prepregnancy characteristics, underlying medical conditions, assisted conception, and delivery characteristics.

Severe maternal morbidities demonstrated a J-shaped association with age: the lowest rates of morbidity were observed in women 20 to 34 years of age, and steeply increasing rates of morbidity were observed for women aged 40 and older. One notable exception was the rate of sepsis, which was increased in teen mothers compared with all other groups.

The unadjusted rate of the composite outcome of severe maternal morbidity and mortality was 2.1% in teenagers, 1.5% among women 25 to 29 years, 2.3% among those aged 40 to 44, and 3.6% among women aged 45 and older.

Although rates were somewhat attenuated after adjustment for demographic and prepregnancy characteristics, chronic medical conditions, assisted conception, and delivery characteristics, most morbidities remained significantly increased among women aged 39 years and older, including the composite outcome. Among the individual morbidities considered, increased risk was highest for renal failure, amniotic fluid embolism, cardiac morbidity, and shock, with adjusted odds ratios of 2.0 or greater for women older than 39 years.

Related article:
Reducing maternal mortality in the United States—Let’s get organized!

Study strengths and weaknesses

This study contributes substantially to the existing literature that demonstrates higher rates of pregnancy-associated morbidities in women of increasing maternal age.^1,2 Prior studies in this area focused on perinatal morbidity and mortality and on obstetric outcomes such as cesarean delivery.^3–5 This large-scale study examined the association between advancing maternal age and a variety of serious maternal morbidities. In another study, Callaghan and Berg found a similar pattern among mortalities, with high rates of mortality attributable to hemorrhage, embolism, and cardiomyopathy in women aged 40 years and older.¹

Exclusion of multiple gestations. As in any study, we must consider the methodology, and it is notable that Lisonkova and colleagues’ study excluded multiple gestations. Given the association with advanced maternal age, assisted reproductive technology, and the incidence of multiple gestations, a high rate of multiple gestations would be expected among women of advanced maternal age. (Generally, maternal age of at least 35 years is considered “advanced,” with greater than 40 years “very advanced.”) Since multiple gestations tend to be associated with increases in morbidity, excluding these pregnancies would likely bias the study results toward the null. If multiple gestations had been included, the rates of serious maternal morbidities in older women might be even higher than those demonstrated, potentially strengthening the associations reported here.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

While numerous studies have investigated the risk of perinatal outcomes with advancing maternal age, the primary objective of a recent study by Lisonkova and colleagues was to examine the association between advancing maternal age and severe maternal morbidities and mortality.

Details of the study

The population-based retrospective cohort study compared age-specific rates of severe maternal morbidities and mortality among 828,269 pregnancies in Washington state between 2003 and 2013. Singleton births to women 15 to 60 years of age were included; out-of-hospital births were excluded. Information was obtained by linking the Birth Events Record Database (which includes information on maternal, pregnancy, and labor and delivery characteristics and birth outcomes), and the Comprehensive Hospital Abstract Reporting System database (which includes diagnostic and procedural codes for all hospitalizations in Washington state).

The primary objective was to examine the association between age and severe maternal morbidities. Maternal morbidities were divided into categories: antepartum hemorrhage, respiratory morbidity, thromboembolism, cerebrovascular morbidity, acute cardiac morbidity, severe postpartum hemorrhage, maternal sepsis, renal failure, obstetric shock, complications of anesthesia and obstetric interventions, and need for life-saving procedures. A composite outcome, comprised of severe maternal morbidities, intensive care unit admission, and maternal mortality, was also created.

Rates of severe morbidities were compared for age groups 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years to the referent category (25 to 29 years). Additional comparisons were also performed for ages 45 to 49 and ≥50 years for the composite and for morbidities with high incidence. Logistic regression and sensitivity analyses were used to control for demographic and prepregnancy characteristics, underlying medical conditions, assisted conception, and delivery characteristics.

Severe maternal morbidities demonstrated a J-shaped association with age: the lowest rates of morbidity were observed in women 20 to 34 years of age, and steeply increasing rates of morbidity were observed for women aged 40 and older. One notable exception was the rate of sepsis, which was increased in teen mothers compared with all other groups.

The unadjusted rate of the composite outcome of severe maternal morbidity and mortality was 2.1% in teenagers, 1.5% among women 25 to 29 years, 2.3% among those aged 40 to 44, and 3.6% among women aged 45 and older.

Although rates were somewhat attenuated after adjustment for demographic and prepregnancy characteristics, chronic medical conditions, assisted conception, and delivery characteristics, most morbidities remained significantly increased among women aged 39 years and older, including the composite outcome. Among the individual morbidities considered, increased risk was highest for renal failure, amniotic fluid embolism, cardiac morbidity, and shock, with adjusted odds ratios of 2.0 or greater for women older than 39 years.

Related article:
Reducing maternal mortality in the United States—Let’s get organized!

Study strengths and weaknesses

This study contributes substantially to the existing literature that demonstrates higher rates of pregnancy-associated morbidities in women of increasing maternal age.^1,2 Prior studies in this area focused on perinatal morbidity and mortality and on obstetric outcomes such as cesarean delivery.^3–5 This large-scale study examined the association between advancing maternal age and a variety of serious maternal morbidities. In another study, Callaghan and Berg found a similar pattern among mortalities, with high rates of mortality attributable to hemorrhage, embolism, and cardiomyopathy in women aged 40 years and older.¹

Exclusion of multiple gestations. As in any study, we must consider the methodology, and it is notable that Lisonkova and colleagues’ study excluded multiple gestations. Given the association with advanced maternal age, assisted reproductive technology, and the incidence of multiple gestations, a high rate of multiple gestations would be expected among women of advanced maternal age. (Generally, maternal age of at least 35 years is considered “advanced,” with greater than 40 years “very advanced.”) Since multiple gestations tend to be associated with increases in morbidity, excluding these pregnancies would likely bias the study results toward the null. If multiple gestations had been included, the rates of serious maternal morbidities in older women might be even higher than those demonstrated, potentially strengthening the associations reported here.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

From the Anne Arundel Health System Research Institute, Annapolis, MD.

Abstract

• Objective: To measure clinical outcomes associated with heparin-induced thrombocytopenia (HIT) and acquisition costs of heparin after implementing a new order set promoting unfractionated heparin (UFH) use instead of low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis.
• Methods: This was single-center, retrospective, pre-post intervention analysis utilizing pharmacy, laboratory, and clinical data sources. Subjects were patients receiving VTE thromboprophyalxis with heparin at an acute care hospital. Usage rates for UFH and LMWH, acquisition costs for heparins, number of HIT assays, best practice advisories for HIT, and confirmed cases of HIT and HIT with thrombosis were assessed.
• Results: After order set intervention, UFH use increased from 43% of all prophylaxis orders to 86%. Net annual savings in acquisition costs for VTE prophylaxis was $131,000. After the intervention, HIT best practice advisories and number of monthly HIT assays fell 35% and 15%, respectively. In the 9-month pre-intervention period, HIT and HITT occurred in zero of 6717 patients receiving VTE prophylaxis. In the 25 months of post-intervention follow-up, HIT occurred in 3 of 44,240 patients (P = 0.86) receiving VTE prophylaxis, 2 of whom had HITT, all after receiving UFH. The median duration of UFH and LMWH use was 3.0 and 3.5 days, respectively.
• Conclusion: UFH use in hospitals can be safely maintained or increased among patient subpopulations that are not at high risk for HIT. A more nuanced approach to prophylaxis, taking into account individual patient risk and expected duration of therapy, may provide desired cost savings without provoking HIT.

Key words: heparin; heparin-induced thrombocytopenia; venous thromboembolism prophylaxis; cost-effectiveness.

Heparin-induced thrombocytopenia (HIT) and its more severe clinical complication, HIT with thrombosis (HITT), complicate the use of heparin products for venous thromboembolic (VTE) prophylaxis. The clinical characteristics and time course of thrombocytopenia in relation to heparin are well characterized (typically 30%–50% drop in platelet count 5–10 days after exposure), if not absolute. Risk calculation tools help to judge the clinical probability and guide ordering of appropriate confirmatory tests [1]. The incidence of HIT is higher with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH). A meta-analysis of 5 randomized or prospective nonrandomized trials indicated a risk of 2.6% (95% CI, 1.5%–3.8%) for UFH and 0.2% (95% CI, 0.1%–0.4%) for LMWH [2], though the analyzed studies were heavily weighted by studies of orthopedic surgery patients, a high-risk group. However, not all patients are at equal risk for HIT, suggesting that LMWH may not be necessary for all patients [3]. Unfortunately, LMWH is considerably more expensive for hospitals to purchase than UFH, raising costs for a prophylactic treatment that is widely utilized. However, the higher incidence of HIT and HITT associated with UFH can erode any cost savings because of the additional cost of diagnosing HIT and need for temporary or long-term treatment with even more expensive alternative anticoagulants. Indeed, a recent retrospective study suggested that the excess costs of evaluating and treating HIT were approximately $267,000 per year in Canadian dollars [4].But contrary data has also been reported. A retrospective study of the consequences of increased prophylactic UFH use found no increase in ordered HIT assays or in the results of HIT testing or of inferred positive cases despite a growth of 71% in the number of patients receiving UFH prophylaxis [5].

In 2013, the pharmacy and therapeutics committee made a decision to encourage the use of UFH over LMWH for VTE prophylaxis by making changes to order sets to favor UFH over LMWH (enoxaparin). Given the uncertainty about excess risk of HIT, a monitoring work group was created to assess for any increase of either HIT or HITT that might follow, including any patient readmitted with thrombosis within 30 days of a discharge. In this paper, we report the impact of a hospital-wide conversion to UFH for VTE prophylaxis on the incidence of VTE, HIT, and HITT and acquisition costs of UFH and LMWH and use of alternative prophylactic anticoagulant medications.

Methods

Setting

Anne Arundel Medical Center is a 383-bed acute care hospital with about 30,000 adult admissions and 10,000 inpatient surgeries annually. The average length of stay is approximately 3.6 days with a patient median age of 59 years. Caucasians comprise 75.3% of the admitted populations and African Americans 21.4%. Most patients are on Medicare (59%), while 29.5% have private insurance, 6.6% are on Medicaid, and 4.7% self-pay. The 9 most common medical principal diagnoses are sepsis, heart failure, chronic obstructive pulmonary disease, pneumonia, myocardial infarction, ischemic stroke, urinary tract infection, cardiac arrhythmia, and other infection. The 6 most common procedures include newborn delivery (with and without caesarean section), joint replacement surgery, bariatric procedures, cardiac catheterizations, other abdominal surgeries, and thoracotomy. The predominant medical care model is internal medicine and physician assistant acute care hospitalists attending both medicine and surgical patients. Obstetrical hospitalists care for admitted obstetric patients. Patients admitted to the intensive care units had only critical care trained physician specialists as attending physicians. No trainees cared for the patients described in this study.

P&T Committee

The P&T committee is a multidisciplinary group of health care professionals selected for appointment by the chairs of the committee (chair of medicine and director of pharmacy) and approved by the president of the medical staff. The committee has oversight responsibility for all medication policies, order sets involving medications, as well as the monitoring of clinical outcomes as they regard medications.

Electronic Medical Record and Best Practice Advisory

Throughout this study period both pre-and post-intervention, the EMR in use was Epic (Verona WI), used for all ordering and lab results. A best practice advisory was in place in the EMR that alerted providers to all cases of thrombocytopenia < 100,000/mm³ when there was concurrent order for any heparin. The best practice advisory highlighted the thrombocytopenia, advised the providers to consider HIT as a diagnosis and to order confirmation tests if clinically appropriate, providing a direct link to the HIT assay order screen. The best practice advisory did not access information from prior admissions where heparin might have been used nor determine the percentage drop from the baseline platelet count.

HIT Case Definition and Assays

The 2 laboratory tests for HIT on which this study is based are the heparin-induced platelet antibody test (also known as anti-PF4) and the serotonin release assay. The heparin-induced platelet antibody test is an enzyme-linked immunosorbent assay (ELISA) that detects IgG, IgM, and IgA antibodies against the platelet factor 4 (PF4/heparin complex). This test was reported as positive if the optical density was 0.4 or higher and generated an automatic request for a serotonin release assay (SRA), which is a functional assay that measures heparin-dependent platelet activation. The decision to order the SRA was therefore a “reflex” test and not made with any knowledge of clinical characteristics of the case. The HIT assays were performed by a reference lab, Quest Diagnostics, in the Chantilly, VA facility. HIT was said to be present when both a characteristic pattern of thrombocytopenia occurring after heparin use was seen [1]and when the confirmatory SRA was positive at a level of > 20% release.

Order Set Modifications

After the P&T committee decision to emphasize UFH for VTE prophylaxis in October 2013, the relevant electronic order sets were altered to highlight the fact that UFH was the first choice for VTE prophylaxis. The order sets still allowed LMWH (enoxaparin) or alternative anticoagulants at the prescribers’ discretion but indicated they were a second choice. Doses of UFH and LMWH in the order sets were standard based upon weight and estimates of creatinine clearance and, in the case of dosing frequency for UFH, based upon the risk of VTE. Order sets for the therapeutic treatment of VTE were not changed.

Data Collection and Analysis

The clinical research committee, the local oversight board for research and performance improvement analyses, reviewed this project and determined that it qualified as a performance improvement analysis based upon the standards of the U.S. Office of Human Research Protections. Some data were extracted from patient medical records and stored in a customized and password-protected database. Access to the database was limited to members of the analysis team and stripped of all patient identifiers under the HIPAA privacy rule standard for de-identification from 45 CFR 164.514(b) immediately following the collection of all data elements from the medical record.

An internal pharmacy database was used to determine the volume and actual acquisition cost of prophylactic anticoagulant doses administered during both pre- and post-intervention time periods. To determine if clinical suspicion for HIT increased after the intervention, a definitive listing of all ordered HIT assays was obtained from laboratory billing records for the 9 months (January 2013–September 2013) before the conversion and for 25 months after the intervention (beginning in November 2013 so as not to include the conversion month). To determine if the HIT assays were associated with a higher risk score, we identified all cases in which the HIT assay was ordered and retroactively measured the probability score known as the 4T score [1].Simultaneously, separate clinical work groups reviewed all cases of hospital-acquired thrombosis, whatever their cause, including patients readmitted with thrombosis up to 30 days after discharge and episodes of bleeding due to anti-coagulant use. A chi square analysis of the incidence of HIT pre- and post-intervention was performed.

Results

Heparin Use and Acquisition Costs

HIT Assays and Incidence of HIT and HITT

In the 9 months pre-intervention, HIT and HITT occurred in zero of 6717 patients receiving at least 1 dose of VTE prophylaxis. In the 25 months of post-intervention follow-up, 44,240 patients received prophylaxis with either heparin. HIT (clinical suspicion with positive antibody and confirmatory SRA) occurred in 3 patients, 2 of whom had HITT, all after UFH. This incidence was not statistically significant using chi square analysis (P = 0.86).

Discussion

Because the efficacy of UFH and LMWH for VTE prophylaxis are equivalent [6],choosing between them involves many factors including patient-level risk factors such as renal function, risk of bleeding, as well as other considerations such as nursing time, patient preference, risk of HIT, and acquisition cost. Indeed, the most recent version of the American College of Chest Physicians guidelines for prophylaxis against VTE note that both drugs are recommended with an evidence grade of IB [7].Cost is among the considerations considered appropriate in choosing among agents. The difference in acquisition costs of > $20 per patient per day can have a major financial impact on hospital’s pharmacy budget and may be decisive. But a focus only on acquisition cost is short sighted as the 2 medications have different complication rates with regard to HIT. Thus the need to track HIT incidence after protocol changes are made is paramount.

In our study, we did not measure thrombocytopenia as an endpoint because acquired thrombocytopenia is too common and multifactorial to be a meaningful. Rather, we used the clinical suspicion for HIT as measured by both the number of times the BPA fired warnings of low platelets in the setting of recent heparin use and the number of times clinicians suspected HIT enough to order a HIT assay. We also used actual outcomes (clinically adjudicated cases of HIT and HITT). Our data shows substantial compliance among clinicians with the voluntary conversion to UFH with an immediate and sustained shift to UFH so that UFH was used in 86% of patients. Corresponding cost savings were achieved in heparin acquisition. Unlike some prior reports, there was a minimal burden of HIT as measured by the unchanged number of BPAs, monthly HIT assays and the unchanged clinical risk 4T scores among those patients in whom the test was ordered pre and post intervention. HIT rates were not statistically different after the order set conversion took effect.

Our results and study design are similar but not identical to that of Zhou et al, who found that a campaign to increase VTE prophylaxis resulted in 71% increase of UFH use over 5 years but no increase in number of HIT assays ordered or in the distribution of HIT assay results-both surrogate endpoints [5].But not all analyses of heparin order interventions show similar results. A recent study of a heparin avoidance program in a Canadian tertiary care hospital showed a reduction of 79% and 91% in adjudicated cases of HIT and HITT respectively [4].Moreover, hospital-related expenditures for HIT decreased by nearly $267,000 (Canadian dollars) per year though the additional acquisition costs of LMWH were not stated.A small retrospective heparin avoidance protocol among orthopedic surgery patients showed a reduction of HIT incidence from 5.2% with UFH to 0% with LMWH after universal substitution of LMWH for UFH [8].A recent systematic review identified only 3 prospective studies involving over 1398 postoperative surgical patients that measured HIT and HITT as outcomes [9].The review authors, in pooled analysis, found a lower incidence of HIT and HITT with LMWH postoperatively but downgraded the evidence to “low quality” due to methodologic issues and concerns over bias.A nested case-control study of adult medical patients found that HIT was 6 times more common with UFH than with LMWH and the cost of admissions associated with HIT was 3.5 times higher than for those without HIT, though this increase in costs are not necessarily due to the HIT diagnosis itself but may be markers of patients with more severe illness [10].The duration of heparin therapy was not stated.

There are several potential reasons that our data differs from some of the previous reports described above. We used a strict definition of HIT, requiring the serotonin release assay to be positive in the appropriate clinical setting and did not rely solely upon antibody tests to make the diagnosis, a less rigorous standard found in some studies. Furthermore, our results may differ from previously reports because of differences in patient risk and duration of therapy. Our institution does not perform cardiac surgery and the very large orthopedic surgery programs do not generally use heparin. Another potentially important difference in our study from prior studies is that many of the patients treated at this institution did not receive heparin long enough to be considered at risk; only a quarter were treated for longer than 5 days, generally considered a minumum [11].This is less than half of the duration of the patients in the studies included in the meta-analysis of HIT incidence [2].

We do not contend that UFH is as safe as LMWH with regard to HIT for all populatons, but rather that the increased risk is not manifest in all patient populations and settings and so the increased cost may not be justified in low-risk patients. Indeed while variability in HIT risk among patients is well documented [3,12], the guidelines for prophylaxis do not generally take this into account when recommending particular VTE prophylaxis strategies.Clinical practice guidelines do recommend different degrees of monitoring the platelet count based on risk of HIT however.

Our study had limitations, chief of which is the retrospective nature of the analysis; however, the methodology we used was similar to those of previous publications [4,5,8].We may have missed some cases of HIT if a clinician did not order the assay in all appropriate patients but there is no reason to think that likelihood was any different pre- and post-intervention. In addition, though we reviewed every case of hospital-acquired thrombosis, it is possible that the clinical reviewers may have missed cases of HITT, especially if the thrombosis occurred before a substantial drop in the platelet count, which is rare but possible. Here too the chance of missing actual cases did not change between the pre-and post-intervention. Our study examined prophylaxis with heparin use and not therapeutic uses. Finally, while noting the acquisition cost reduction achieved with conversion to UFH, we were not able to calculate any excess expense attributed to the rare case of HIT and HITT that occurred. We believe our results are generalizable to hospitals with similar patient profiles.

The idea that patients with different risk factors might do well with different prophylaxis strategies needs to be better appreciated. Such information could be used as a guide to more individualized prophylaxis strategy aided by clinical decision support embedded within the EMR. In this way the benefit of LMWH in avoiding HIT could be reserved for those patients at greatest risk of HIT while simultaneously allowing hospitals not to overspend for prophylaxis in patients who will not benefit from LMWH. Such a strategy would need to be tested prospectively before widespread adoption.

As a result of our internal analysis we have altered our EMR-based best practice alert to conform to the 2013 American Society of Hematology guidelines [15],which is more informative than our original BPA. Specifically, the old guideline only warned if the platelet count was < 100,000/mm³ in association with heparin. The revision notified if there is a > 30% fall regardless of the absolute count and informed prescribers of the 4T score to encourage more optimum use of the HIT assay, avoiding its use for low risk scores and encouraging its use for moderate to high risk scores. We are also strengthening the emphasis that moderate to high risk 4T patients receive alternative anticoagulation until results of the HIT assay are available as we found this not to be a be a universal practice. We recommend similar self-inspection to other institutions.

Corresponding author: Barry R. Meisenberg, MD, Anne Arundel Medical Center, 2001 Medical Parkway, Annapolis, MD 21401, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JR, BRM; analysis and interpretation of data, KW, JR, BRM; drafting of article, JR, BRM; critical revision of the article, KW, JR, BRM; statistical expertise, KW, JR; administrative or technical support, JR; collection and assembly of data, KW, JR.

From the Anne Arundel Health System Research Institute, Annapolis, MD.

Abstract

• Objective: To measure clinical outcomes associated with heparin-induced thrombocytopenia (HIT) and acquisition costs of heparin after implementing a new order set promoting unfractionated heparin (UFH) use instead of low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis.
• Methods: This was single-center, retrospective, pre-post intervention analysis utilizing pharmacy, laboratory, and clinical data sources. Subjects were patients receiving VTE thromboprophyalxis with heparin at an acute care hospital. Usage rates for UFH and LMWH, acquisition costs for heparins, number of HIT assays, best practice advisories for HIT, and confirmed cases of HIT and HIT with thrombosis were assessed.
• Results: After order set intervention, UFH use increased from 43% of all prophylaxis orders to 86%. Net annual savings in acquisition costs for VTE prophylaxis was $131,000. After the intervention, HIT best practice advisories and number of monthly HIT assays fell 35% and 15%, respectively. In the 9-month pre-intervention period, HIT and HITT occurred in zero of 6717 patients receiving VTE prophylaxis. In the 25 months of post-intervention follow-up, HIT occurred in 3 of 44,240 patients (P = 0.86) receiving VTE prophylaxis, 2 of whom had HITT, all after receiving UFH. The median duration of UFH and LMWH use was 3.0 and 3.5 days, respectively.
• Conclusion: UFH use in hospitals can be safely maintained or increased among patient subpopulations that are not at high risk for HIT. A more nuanced approach to prophylaxis, taking into account individual patient risk and expected duration of therapy, may provide desired cost savings without provoking HIT.

Key words: heparin; heparin-induced thrombocytopenia; venous thromboembolism prophylaxis; cost-effectiveness.

Heparin-induced thrombocytopenia (HIT) and its more severe clinical complication, HIT with thrombosis (HITT), complicate the use of heparin products for venous thromboembolic (VTE) prophylaxis. The clinical characteristics and time course of thrombocytopenia in relation to heparin are well characterized (typically 30%–50% drop in platelet count 5–10 days after exposure), if not absolute. Risk calculation tools help to judge the clinical probability and guide ordering of appropriate confirmatory tests [1]. The incidence of HIT is higher with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH). A meta-analysis of 5 randomized or prospective nonrandomized trials indicated a risk of 2.6% (95% CI, 1.5%–3.8%) for UFH and 0.2% (95% CI, 0.1%–0.4%) for LMWH [2], though the analyzed studies were heavily weighted by studies of orthopedic surgery patients, a high-risk group. However, not all patients are at equal risk for HIT, suggesting that LMWH may not be necessary for all patients [3]. Unfortunately, LMWH is considerably more expensive for hospitals to purchase than UFH, raising costs for a prophylactic treatment that is widely utilized. However, the higher incidence of HIT and HITT associated with UFH can erode any cost savings because of the additional cost of diagnosing HIT and need for temporary or long-term treatment with even more expensive alternative anticoagulants. Indeed, a recent retrospective study suggested that the excess costs of evaluating and treating HIT were approximately $267,000 per year in Canadian dollars [4].But contrary data has also been reported. A retrospective study of the consequences of increased prophylactic UFH use found no increase in ordered HIT assays or in the results of HIT testing or of inferred positive cases despite a growth of 71% in the number of patients receiving UFH prophylaxis [5].

In 2013, the pharmacy and therapeutics committee made a decision to encourage the use of UFH over LMWH for VTE prophylaxis by making changes to order sets to favor UFH over LMWH (enoxaparin). Given the uncertainty about excess risk of HIT, a monitoring work group was created to assess for any increase of either HIT or HITT that might follow, including any patient readmitted with thrombosis within 30 days of a discharge. In this paper, we report the impact of a hospital-wide conversion to UFH for VTE prophylaxis on the incidence of VTE, HIT, and HITT and acquisition costs of UFH and LMWH and use of alternative prophylactic anticoagulant medications.

Methods

Setting

Anne Arundel Medical Center is a 383-bed acute care hospital with about 30,000 adult admissions and 10,000 inpatient surgeries annually. The average length of stay is approximately 3.6 days with a patient median age of 59 years. Caucasians comprise 75.3% of the admitted populations and African Americans 21.4%. Most patients are on Medicare (59%), while 29.5% have private insurance, 6.6% are on Medicaid, and 4.7% self-pay. The 9 most common medical principal diagnoses are sepsis, heart failure, chronic obstructive pulmonary disease, pneumonia, myocardial infarction, ischemic stroke, urinary tract infection, cardiac arrhythmia, and other infection. The 6 most common procedures include newborn delivery (with and without caesarean section), joint replacement surgery, bariatric procedures, cardiac catheterizations, other abdominal surgeries, and thoracotomy. The predominant medical care model is internal medicine and physician assistant acute care hospitalists attending both medicine and surgical patients. Obstetrical hospitalists care for admitted obstetric patients. Patients admitted to the intensive care units had only critical care trained physician specialists as attending physicians. No trainees cared for the patients described in this study.

P&T Committee

The P&T committee is a multidisciplinary group of health care professionals selected for appointment by the chairs of the committee (chair of medicine and director of pharmacy) and approved by the president of the medical staff. The committee has oversight responsibility for all medication policies, order sets involving medications, as well as the monitoring of clinical outcomes as they regard medications.

Electronic Medical Record and Best Practice Advisory

Throughout this study period both pre-and post-intervention, the EMR in use was Epic (Verona WI), used for all ordering and lab results. A best practice advisory was in place in the EMR that alerted providers to all cases of thrombocytopenia < 100,000/mm³ when there was concurrent order for any heparin. The best practice advisory highlighted the thrombocytopenia, advised the providers to consider HIT as a diagnosis and to order confirmation tests if clinically appropriate, providing a direct link to the HIT assay order screen. The best practice advisory did not access information from prior admissions where heparin might have been used nor determine the percentage drop from the baseline platelet count.

HIT Case Definition and Assays

The 2 laboratory tests for HIT on which this study is based are the heparin-induced platelet antibody test (also known as anti-PF4) and the serotonin release assay. The heparin-induced platelet antibody test is an enzyme-linked immunosorbent assay (ELISA) that detects IgG, IgM, and IgA antibodies against the platelet factor 4 (PF4/heparin complex). This test was reported as positive if the optical density was 0.4 or higher and generated an automatic request for a serotonin release assay (SRA), which is a functional assay that measures heparin-dependent platelet activation. The decision to order the SRA was therefore a “reflex” test and not made with any knowledge of clinical characteristics of the case. The HIT assays were performed by a reference lab, Quest Diagnostics, in the Chantilly, VA facility. HIT was said to be present when both a characteristic pattern of thrombocytopenia occurring after heparin use was seen [1]and when the confirmatory SRA was positive at a level of > 20% release.

Order Set Modifications

After the P&T committee decision to emphasize UFH for VTE prophylaxis in October 2013, the relevant electronic order sets were altered to highlight the fact that UFH was the first choice for VTE prophylaxis. The order sets still allowed LMWH (enoxaparin) or alternative anticoagulants at the prescribers’ discretion but indicated they were a second choice. Doses of UFH and LMWH in the order sets were standard based upon weight and estimates of creatinine clearance and, in the case of dosing frequency for UFH, based upon the risk of VTE. Order sets for the therapeutic treatment of VTE were not changed.

Data Collection and Analysis

The clinical research committee, the local oversight board for research and performance improvement analyses, reviewed this project and determined that it qualified as a performance improvement analysis based upon the standards of the U.S. Office of Human Research Protections. Some data were extracted from patient medical records and stored in a customized and password-protected database. Access to the database was limited to members of the analysis team and stripped of all patient identifiers under the HIPAA privacy rule standard for de-identification from 45 CFR 164.514(b) immediately following the collection of all data elements from the medical record.

An internal pharmacy database was used to determine the volume and actual acquisition cost of prophylactic anticoagulant doses administered during both pre- and post-intervention time periods. To determine if clinical suspicion for HIT increased after the intervention, a definitive listing of all ordered HIT assays was obtained from laboratory billing records for the 9 months (January 2013–September 2013) before the conversion and for 25 months after the intervention (beginning in November 2013 so as not to include the conversion month). To determine if the HIT assays were associated with a higher risk score, we identified all cases in which the HIT assay was ordered and retroactively measured the probability score known as the 4T score [1].Simultaneously, separate clinical work groups reviewed all cases of hospital-acquired thrombosis, whatever their cause, including patients readmitted with thrombosis up to 30 days after discharge and episodes of bleeding due to anti-coagulant use. A chi square analysis of the incidence of HIT pre- and post-intervention was performed.

Results

Heparin Use and Acquisition Costs

HIT Assays and Incidence of HIT and HITT

In the 9 months pre-intervention, HIT and HITT occurred in zero of 6717 patients receiving at least 1 dose of VTE prophylaxis. In the 25 months of post-intervention follow-up, 44,240 patients received prophylaxis with either heparin. HIT (clinical suspicion with positive antibody and confirmatory SRA) occurred in 3 patients, 2 of whom had HITT, all after UFH. This incidence was not statistically significant using chi square analysis (P = 0.86).

Discussion

Because the efficacy of UFH and LMWH for VTE prophylaxis are equivalent [6],choosing between them involves many factors including patient-level risk factors such as renal function, risk of bleeding, as well as other considerations such as nursing time, patient preference, risk of HIT, and acquisition cost. Indeed, the most recent version of the American College of Chest Physicians guidelines for prophylaxis against VTE note that both drugs are recommended with an evidence grade of IB [7].Cost is among the considerations considered appropriate in choosing among agents. The difference in acquisition costs of > $20 per patient per day can have a major financial impact on hospital’s pharmacy budget and may be decisive. But a focus only on acquisition cost is short sighted as the 2 medications have different complication rates with regard to HIT. Thus the need to track HIT incidence after protocol changes are made is paramount.

In our study, we did not measure thrombocytopenia as an endpoint because acquired thrombocytopenia is too common and multifactorial to be a meaningful. Rather, we used the clinical suspicion for HIT as measured by both the number of times the BPA fired warnings of low platelets in the setting of recent heparin use and the number of times clinicians suspected HIT enough to order a HIT assay. We also used actual outcomes (clinically adjudicated cases of HIT and HITT). Our data shows substantial compliance among clinicians with the voluntary conversion to UFH with an immediate and sustained shift to UFH so that UFH was used in 86% of patients. Corresponding cost savings were achieved in heparin acquisition. Unlike some prior reports, there was a minimal burden of HIT as measured by the unchanged number of BPAs, monthly HIT assays and the unchanged clinical risk 4T scores among those patients in whom the test was ordered pre and post intervention. HIT rates were not statistically different after the order set conversion took effect.

Our results and study design are similar but not identical to that of Zhou et al, who found that a campaign to increase VTE prophylaxis resulted in 71% increase of UFH use over 5 years but no increase in number of HIT assays ordered or in the distribution of HIT assay results-both surrogate endpoints [5].But not all analyses of heparin order interventions show similar results. A recent study of a heparin avoidance program in a Canadian tertiary care hospital showed a reduction of 79% and 91% in adjudicated cases of HIT and HITT respectively [4].Moreover, hospital-related expenditures for HIT decreased by nearly $267,000 (Canadian dollars) per year though the additional acquisition costs of LMWH were not stated.A small retrospective heparin avoidance protocol among orthopedic surgery patients showed a reduction of HIT incidence from 5.2% with UFH to 0% with LMWH after universal substitution of LMWH for UFH [8].A recent systematic review identified only 3 prospective studies involving over 1398 postoperative surgical patients that measured HIT and HITT as outcomes [9].The review authors, in pooled analysis, found a lower incidence of HIT and HITT with LMWH postoperatively but downgraded the evidence to “low quality” due to methodologic issues and concerns over bias.A nested case-control study of adult medical patients found that HIT was 6 times more common with UFH than with LMWH and the cost of admissions associated with HIT was 3.5 times higher than for those without HIT, though this increase in costs are not necessarily due to the HIT diagnosis itself but may be markers of patients with more severe illness [10].The duration of heparin therapy was not stated.

There are several potential reasons that our data differs from some of the previous reports described above. We used a strict definition of HIT, requiring the serotonin release assay to be positive in the appropriate clinical setting and did not rely solely upon antibody tests to make the diagnosis, a less rigorous standard found in some studies. Furthermore, our results may differ from previously reports because of differences in patient risk and duration of therapy. Our institution does not perform cardiac surgery and the very large orthopedic surgery programs do not generally use heparin. Another potentially important difference in our study from prior studies is that many of the patients treated at this institution did not receive heparin long enough to be considered at risk; only a quarter were treated for longer than 5 days, generally considered a minumum [11].This is less than half of the duration of the patients in the studies included in the meta-analysis of HIT incidence [2].

We do not contend that UFH is as safe as LMWH with regard to HIT for all populatons, but rather that the increased risk is not manifest in all patient populations and settings and so the increased cost may not be justified in low-risk patients. Indeed while variability in HIT risk among patients is well documented [3,12], the guidelines for prophylaxis do not generally take this into account when recommending particular VTE prophylaxis strategies.Clinical practice guidelines do recommend different degrees of monitoring the platelet count based on risk of HIT however.

Our study had limitations, chief of which is the retrospective nature of the analysis; however, the methodology we used was similar to those of previous publications [4,5,8].We may have missed some cases of HIT if a clinician did not order the assay in all appropriate patients but there is no reason to think that likelihood was any different pre- and post-intervention. In addition, though we reviewed every case of hospital-acquired thrombosis, it is possible that the clinical reviewers may have missed cases of HITT, especially if the thrombosis occurred before a substantial drop in the platelet count, which is rare but possible. Here too the chance of missing actual cases did not change between the pre-and post-intervention. Our study examined prophylaxis with heparin use and not therapeutic uses. Finally, while noting the acquisition cost reduction achieved with conversion to UFH, we were not able to calculate any excess expense attributed to the rare case of HIT and HITT that occurred. We believe our results are generalizable to hospitals with similar patient profiles.

The idea that patients with different risk factors might do well with different prophylaxis strategies needs to be better appreciated. Such information could be used as a guide to more individualized prophylaxis strategy aided by clinical decision support embedded within the EMR. In this way the benefit of LMWH in avoiding HIT could be reserved for those patients at greatest risk of HIT while simultaneously allowing hospitals not to overspend for prophylaxis in patients who will not benefit from LMWH. Such a strategy would need to be tested prospectively before widespread adoption.

As a result of our internal analysis we have altered our EMR-based best practice alert to conform to the 2013 American Society of Hematology guidelines [15],which is more informative than our original BPA. Specifically, the old guideline only warned if the platelet count was < 100,000/mm³ in association with heparin. The revision notified if there is a > 30% fall regardless of the absolute count and informed prescribers of the 4T score to encourage more optimum use of the HIT assay, avoiding its use for low risk scores and encouraging its use for moderate to high risk scores. We are also strengthening the emphasis that moderate to high risk 4T patients receive alternative anticoagulation until results of the HIT assay are available as we found this not to be a be a universal practice. We recommend similar self-inspection to other institutions.

Corresponding author: Barry R. Meisenberg, MD, Anne Arundel Medical Center, 2001 Medical Parkway, Annapolis, MD 21401, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JR, BRM; analysis and interpretation of data, KW, JR, BRM; drafting of article, JR, BRM; critical revision of the article, KW, JR, BRM; statistical expertise, KW, JR; administrative or technical support, JR; collection and assembly of data, KW, JR.

From the Anne Arundel Health System Research Institute, Annapolis, MD.

Abstract

• Objective: To measure clinical outcomes associated with heparin-induced thrombocytopenia (HIT) and acquisition costs of heparin after implementing a new order set promoting unfractionated heparin (UFH) use instead of low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis.
• Methods: This was single-center, retrospective, pre-post intervention analysis utilizing pharmacy, laboratory, and clinical data sources. Subjects were patients receiving VTE thromboprophyalxis with heparin at an acute care hospital. Usage rates for UFH and LMWH, acquisition costs for heparins, number of HIT assays, best practice advisories for HIT, and confirmed cases of HIT and HIT with thrombosis were assessed.
• Results: After order set intervention, UFH use increased from 43% of all prophylaxis orders to 86%. Net annual savings in acquisition costs for VTE prophylaxis was $131,000. After the intervention, HIT best practice advisories and number of monthly HIT assays fell 35% and 15%, respectively. In the 9-month pre-intervention period, HIT and HITT occurred in zero of 6717 patients receiving VTE prophylaxis. In the 25 months of post-intervention follow-up, HIT occurred in 3 of 44,240 patients (P = 0.86) receiving VTE prophylaxis, 2 of whom had HITT, all after receiving UFH. The median duration of UFH and LMWH use was 3.0 and 3.5 days, respectively.
• Conclusion: UFH use in hospitals can be safely maintained or increased among patient subpopulations that are not at high risk for HIT. A more nuanced approach to prophylaxis, taking into account individual patient risk and expected duration of therapy, may provide desired cost savings without provoking HIT.

Key words: heparin; heparin-induced thrombocytopenia; venous thromboembolism prophylaxis; cost-effectiveness.

Heparin-induced thrombocytopenia (HIT) and its more severe clinical complication, HIT with thrombosis (HITT), complicate the use of heparin products for venous thromboembolic (VTE) prophylaxis. The clinical characteristics and time course of thrombocytopenia in relation to heparin are well characterized (typically 30%–50% drop in platelet count 5–10 days after exposure), if not absolute. Risk calculation tools help to judge the clinical probability and guide ordering of appropriate confirmatory tests [1]. The incidence of HIT is higher with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH). A meta-analysis of 5 randomized or prospective nonrandomized trials indicated a risk of 2.6% (95% CI, 1.5%–3.8%) for UFH and 0.2% (95% CI, 0.1%–0.4%) for LMWH [2], though the analyzed studies were heavily weighted by studies of orthopedic surgery patients, a high-risk group. However, not all patients are at equal risk for HIT, suggesting that LMWH may not be necessary for all patients [3]. Unfortunately, LMWH is considerably more expensive for hospitals to purchase than UFH, raising costs for a prophylactic treatment that is widely utilized. However, the higher incidence of HIT and HITT associated with UFH can erode any cost savings because of the additional cost of diagnosing HIT and need for temporary or long-term treatment with even more expensive alternative anticoagulants. Indeed, a recent retrospective study suggested that the excess costs of evaluating and treating HIT were approximately $267,000 per year in Canadian dollars [4].But contrary data has also been reported. A retrospective study of the consequences of increased prophylactic UFH use found no increase in ordered HIT assays or in the results of HIT testing or of inferred positive cases despite a growth of 71% in the number of patients receiving UFH prophylaxis [5].

In 2013, the pharmacy and therapeutics committee made a decision to encourage the use of UFH over LMWH for VTE prophylaxis by making changes to order sets to favor UFH over LMWH (enoxaparin). Given the uncertainty about excess risk of HIT, a monitoring work group was created to assess for any increase of either HIT or HITT that might follow, including any patient readmitted with thrombosis within 30 days of a discharge. In this paper, we report the impact of a hospital-wide conversion to UFH for VTE prophylaxis on the incidence of VTE, HIT, and HITT and acquisition costs of UFH and LMWH and use of alternative prophylactic anticoagulant medications.

Methods

Setting

Anne Arundel Medical Center is a 383-bed acute care hospital with about 30,000 adult admissions and 10,000 inpatient surgeries annually. The average length of stay is approximately 3.6 days with a patient median age of 59 years. Caucasians comprise 75.3% of the admitted populations and African Americans 21.4%. Most patients are on Medicare (59%), while 29.5% have private insurance, 6.6% are on Medicaid, and 4.7% self-pay. The 9 most common medical principal diagnoses are sepsis, heart failure, chronic obstructive pulmonary disease, pneumonia, myocardial infarction, ischemic stroke, urinary tract infection, cardiac arrhythmia, and other infection. The 6 most common procedures include newborn delivery (with and without caesarean section), joint replacement surgery, bariatric procedures, cardiac catheterizations, other abdominal surgeries, and thoracotomy. The predominant medical care model is internal medicine and physician assistant acute care hospitalists attending both medicine and surgical patients. Obstetrical hospitalists care for admitted obstetric patients. Patients admitted to the intensive care units had only critical care trained physician specialists as attending physicians. No trainees cared for the patients described in this study.

P&T Committee

The P&T committee is a multidisciplinary group of health care professionals selected for appointment by the chairs of the committee (chair of medicine and director of pharmacy) and approved by the president of the medical staff. The committee has oversight responsibility for all medication policies, order sets involving medications, as well as the monitoring of clinical outcomes as they regard medications.

Electronic Medical Record and Best Practice Advisory

Throughout this study period both pre-and post-intervention, the EMR in use was Epic (Verona WI), used for all ordering and lab results. A best practice advisory was in place in the EMR that alerted providers to all cases of thrombocytopenia < 100,000/mm³ when there was concurrent order for any heparin. The best practice advisory highlighted the thrombocytopenia, advised the providers to consider HIT as a diagnosis and to order confirmation tests if clinically appropriate, providing a direct link to the HIT assay order screen. The best practice advisory did not access information from prior admissions where heparin might have been used nor determine the percentage drop from the baseline platelet count.

HIT Case Definition and Assays

The 2 laboratory tests for HIT on which this study is based are the heparin-induced platelet antibody test (also known as anti-PF4) and the serotonin release assay. The heparin-induced platelet antibody test is an enzyme-linked immunosorbent assay (ELISA) that detects IgG, IgM, and IgA antibodies against the platelet factor 4 (PF4/heparin complex). This test was reported as positive if the optical density was 0.4 or higher and generated an automatic request for a serotonin release assay (SRA), which is a functional assay that measures heparin-dependent platelet activation. The decision to order the SRA was therefore a “reflex” test and not made with any knowledge of clinical characteristics of the case. The HIT assays were performed by a reference lab, Quest Diagnostics, in the Chantilly, VA facility. HIT was said to be present when both a characteristic pattern of thrombocytopenia occurring after heparin use was seen [1]and when the confirmatory SRA was positive at a level of > 20% release.

Order Set Modifications

After the P&T committee decision to emphasize UFH for VTE prophylaxis in October 2013, the relevant electronic order sets were altered to highlight the fact that UFH was the first choice for VTE prophylaxis. The order sets still allowed LMWH (enoxaparin) or alternative anticoagulants at the prescribers’ discretion but indicated they were a second choice. Doses of UFH and LMWH in the order sets were standard based upon weight and estimates of creatinine clearance and, in the case of dosing frequency for UFH, based upon the risk of VTE. Order sets for the therapeutic treatment of VTE were not changed.

Data Collection and Analysis

The clinical research committee, the local oversight board for research and performance improvement analyses, reviewed this project and determined that it qualified as a performance improvement analysis based upon the standards of the U.S. Office of Human Research Protections. Some data were extracted from patient medical records and stored in a customized and password-protected database. Access to the database was limited to members of the analysis team and stripped of all patient identifiers under the HIPAA privacy rule standard for de-identification from 45 CFR 164.514(b) immediately following the collection of all data elements from the medical record.

An internal pharmacy database was used to determine the volume and actual acquisition cost of prophylactic anticoagulant doses administered during both pre- and post-intervention time periods. To determine if clinical suspicion for HIT increased after the intervention, a definitive listing of all ordered HIT assays was obtained from laboratory billing records for the 9 months (January 2013–September 2013) before the conversion and for 25 months after the intervention (beginning in November 2013 so as not to include the conversion month). To determine if the HIT assays were associated with a higher risk score, we identified all cases in which the HIT assay was ordered and retroactively measured the probability score known as the 4T score [1].Simultaneously, separate clinical work groups reviewed all cases of hospital-acquired thrombosis, whatever their cause, including patients readmitted with thrombosis up to 30 days after discharge and episodes of bleeding due to anti-coagulant use. A chi square analysis of the incidence of HIT pre- and post-intervention was performed.

Results

Heparin Use and Acquisition Costs

HIT Assays and Incidence of HIT and HITT

In the 9 months pre-intervention, HIT and HITT occurred in zero of 6717 patients receiving at least 1 dose of VTE prophylaxis. In the 25 months of post-intervention follow-up, 44,240 patients received prophylaxis with either heparin. HIT (clinical suspicion with positive antibody and confirmatory SRA) occurred in 3 patients, 2 of whom had HITT, all after UFH. This incidence was not statistically significant using chi square analysis (P = 0.86).

Discussion

Because the efficacy of UFH and LMWH for VTE prophylaxis are equivalent [6],choosing between them involves many factors including patient-level risk factors such as renal function, risk of bleeding, as well as other considerations such as nursing time, patient preference, risk of HIT, and acquisition cost. Indeed, the most recent version of the American College of Chest Physicians guidelines for prophylaxis against VTE note that both drugs are recommended with an evidence grade of IB [7].Cost is among the considerations considered appropriate in choosing among agents. The difference in acquisition costs of > $20 per patient per day can have a major financial impact on hospital’s pharmacy budget and may be decisive. But a focus only on acquisition cost is short sighted as the 2 medications have different complication rates with regard to HIT. Thus the need to track HIT incidence after protocol changes are made is paramount.

In our study, we did not measure thrombocytopenia as an endpoint because acquired thrombocytopenia is too common and multifactorial to be a meaningful. Rather, we used the clinical suspicion for HIT as measured by both the number of times the BPA fired warnings of low platelets in the setting of recent heparin use and the number of times clinicians suspected HIT enough to order a HIT assay. We also used actual outcomes (clinically adjudicated cases of HIT and HITT). Our data shows substantial compliance among clinicians with the voluntary conversion to UFH with an immediate and sustained shift to UFH so that UFH was used in 86% of patients. Corresponding cost savings were achieved in heparin acquisition. Unlike some prior reports, there was a minimal burden of HIT as measured by the unchanged number of BPAs, monthly HIT assays and the unchanged clinical risk 4T scores among those patients in whom the test was ordered pre and post intervention. HIT rates were not statistically different after the order set conversion took effect.

Our results and study design are similar but not identical to that of Zhou et al, who found that a campaign to increase VTE prophylaxis resulted in 71% increase of UFH use over 5 years but no increase in number of HIT assays ordered or in the distribution of HIT assay results-both surrogate endpoints [5].But not all analyses of heparin order interventions show similar results. A recent study of a heparin avoidance program in a Canadian tertiary care hospital showed a reduction of 79% and 91% in adjudicated cases of HIT and HITT respectively [4].Moreover, hospital-related expenditures for HIT decreased by nearly $267,000 (Canadian dollars) per year though the additional acquisition costs of LMWH were not stated.A small retrospective heparin avoidance protocol among orthopedic surgery patients showed a reduction of HIT incidence from 5.2% with UFH to 0% with LMWH after universal substitution of LMWH for UFH [8].A recent systematic review identified only 3 prospective studies involving over 1398 postoperative surgical patients that measured HIT and HITT as outcomes [9].The review authors, in pooled analysis, found a lower incidence of HIT and HITT with LMWH postoperatively but downgraded the evidence to “low quality” due to methodologic issues and concerns over bias.A nested case-control study of adult medical patients found that HIT was 6 times more common with UFH than with LMWH and the cost of admissions associated with HIT was 3.5 times higher than for those without HIT, though this increase in costs are not necessarily due to the HIT diagnosis itself but may be markers of patients with more severe illness [10].The duration of heparin therapy was not stated.

There are several potential reasons that our data differs from some of the previous reports described above. We used a strict definition of HIT, requiring the serotonin release assay to be positive in the appropriate clinical setting and did not rely solely upon antibody tests to make the diagnosis, a less rigorous standard found in some studies. Furthermore, our results may differ from previously reports because of differences in patient risk and duration of therapy. Our institution does not perform cardiac surgery and the very large orthopedic surgery programs do not generally use heparin. Another potentially important difference in our study from prior studies is that many of the patients treated at this institution did not receive heparin long enough to be considered at risk; only a quarter were treated for longer than 5 days, generally considered a minumum [11].This is less than half of the duration of the patients in the studies included in the meta-analysis of HIT incidence [2].

We do not contend that UFH is as safe as LMWH with regard to HIT for all populatons, but rather that the increased risk is not manifest in all patient populations and settings and so the increased cost may not be justified in low-risk patients. Indeed while variability in HIT risk among patients is well documented [3,12], the guidelines for prophylaxis do not generally take this into account when recommending particular VTE prophylaxis strategies.Clinical practice guidelines do recommend different degrees of monitoring the platelet count based on risk of HIT however.

Our study had limitations, chief of which is the retrospective nature of the analysis; however, the methodology we used was similar to those of previous publications [4,5,8].We may have missed some cases of HIT if a clinician did not order the assay in all appropriate patients but there is no reason to think that likelihood was any different pre- and post-intervention. In addition, though we reviewed every case of hospital-acquired thrombosis, it is possible that the clinical reviewers may have missed cases of HITT, especially if the thrombosis occurred before a substantial drop in the platelet count, which is rare but possible. Here too the chance of missing actual cases did not change between the pre-and post-intervention. Our study examined prophylaxis with heparin use and not therapeutic uses. Finally, while noting the acquisition cost reduction achieved with conversion to UFH, we were not able to calculate any excess expense attributed to the rare case of HIT and HITT that occurred. We believe our results are generalizable to hospitals with similar patient profiles.

The idea that patients with different risk factors might do well with different prophylaxis strategies needs to be better appreciated. Such information could be used as a guide to more individualized prophylaxis strategy aided by clinical decision support embedded within the EMR. In this way the benefit of LMWH in avoiding HIT could be reserved for those patients at greatest risk of HIT while simultaneously allowing hospitals not to overspend for prophylaxis in patients who will not benefit from LMWH. Such a strategy would need to be tested prospectively before widespread adoption.

As a result of our internal analysis we have altered our EMR-based best practice alert to conform to the 2013 American Society of Hematology guidelines [15],which is more informative than our original BPA. Specifically, the old guideline only warned if the platelet count was < 100,000/mm³ in association with heparin. The revision notified if there is a > 30% fall regardless of the absolute count and informed prescribers of the 4T score to encourage more optimum use of the HIT assay, avoiding its use for low risk scores and encouraging its use for moderate to high risk scores. We are also strengthening the emphasis that moderate to high risk 4T patients receive alternative anticoagulation until results of the HIT assay are available as we found this not to be a be a universal practice. We recommend similar self-inspection to other institutions.

Corresponding author: Barry R. Meisenberg, MD, Anne Arundel Medical Center, 2001 Medical Parkway, Annapolis, MD 21401, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JR, BRM; analysis and interpretation of data, KW, JR, BRM; drafting of article, JR, BRM; critical revision of the article, KW, JR, BRM; statistical expertise, KW, JR; administrative or technical support, JR; collection and assembly of data, KW, JR.

MADRID – Ninety-two percent of Spanish children sickened during the first-ever outbreak of enterovirus-associated brain stem encephalitis in western Europe survived with no long-term sequelae, Nuria Worner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

“We think that aggressive treatments should be restricted to those patients with important neurologic involvement,” declared Dr. Worner of Vall d’Hebron University Hospital in Barcelona. “We can say that no patients with milder involvement and without warning signs during the first 24 hours after onset of neurologic involvement went on to develop fulminant symptoms.”

Notable outbreaks of enterovirus A71 (EV-A71)-associated brain stem encephalitis occurred in Southeast Asia, Australia, and China in the late 1990s.

Dr. Worner reported on 196 children treated for laboratory-confirmed EV-A71–associated brain stem encephalitis at 16 Spanish hospitals in April-December 2016. Their median age was 25 months, 57% were male, and a median of 2 days of symptoms of mild viral illness transpired before neurologic symptoms arose. Prior to presenting to a hospital, 21% of the children had been diagnosed with hand-foot-and-mouth disease, and 13% with herpangina.

Initial preadmission symptoms included fever in 94% of cases, sleepiness in 86%, ataxia in 75%, tremor in 47%, myoclonus in 40%, and a rash in 26%.

Fifty-five percent of the children had EV RNA isolated from both throat and feces, 26% from the throat only, and 19% only from their feces. Eighty-seven percent of serotyped EV were EV-A71.

Ninety percent of children underwent lumbar puncture. Particularly noteworthy was the finding that EV was detected in the cerebrospinal fluid of a mere 3% of patients, although pleocytosis was present in 84%.

Brain MRI showed brain stem encephalitis along with myelitis in 50% of patients, brain stem myelitis without encephalitis in 29%, myelitis elsewhere in 2%, and normal findings in 19%.

Ground zero for the outbreak was Barcelona and the surrounding region of Catalonia; indeed, 130 of the 196 (66%) affected children came from there. The Catalan health department and pediatric infectious disease specialists quickly created standardized case severity definitions and treatment recommendations; they distributed them nationally.

Mild EV-A71–associated brain stem disease was defined as two or more of the following: tremor, myoclonus, mild ataxia, and/or significant drowsiness. The recommendation in these mild cases was for no treatment other than supportive care and careful in-hospital monitoring.

Patients with moderate involvement had to meet the definition for mild disease plus more pronounced ataxia or bulbar motor neuron involvement marked by slurred speech, drooling, dysphagia, apnea, abolition of the gag reflex, and/or an abnormal respiratory pattern. Moderately affected patients received two doses of intravenous immunoglobulin (IVIG), each dosed at 1 g/kg per 24 hours. Admission to the pediatric ICU was individualized for patients with moderate EV-A71–associated brain stem encephalitis.

Severe disease was categorized as bulbar motor neuron involvement plus neurogenic cardiorespiratory failure. Those patients were uniformly admitted to a pediatric ICU and given the two doses of IVIG. The need for systemic steroids was determined on an individual basis.

Forty percent of patients received IVIG and systemic steroids, 24% received IVIG only, 2% systemic steroids only, and 34% received no treatment other than supportive care.

Twenty-six percent of children were admitted to a pediatric ICU for a median stay of 3.5 days. Nine percent of children were placed on mechanical ventilation.

As the disease evolved, the most frequent neurologic complications included slurred speech in 15% of children, abnormal breathing pattern in 11%, seizures in 10%, acute flaccid paralysis in 9%, and cardiorespiratory failure with pulmonary edema in 9%, all occurring within the first hours after hospital admission.

The median hospital length of stay for the full study population was 6 days. The survival rate was 99.5%, with the sole death being due to cardiorespiratory failure.

With 1-6 months of follow-up since the acute episode of EV-A71–associated brain stem encephalitis, the long-term sequelae included two cases of limb paresis and two cases of paresis of a cranial nerve, one child with residual seizures, and one with hypoxic-ischemic encephalopathy.

Asked why the fatality rate in the Spanish outbreak was so much lower than in the earlier Australasian outbreaks, Dr. Worner cited Catalan physicians’ quick recognition of what was underway – and, more importantly, a difference in the EV-A71 viral subgenotype. Most of the most severe cases in Asia and Australia involved the C-4 subgenotype, while in Spain, the predominant subgenotype involved in the outbreak was C-1.

As for the curious finding that EV was detectable in the cerebrospinal fluid of a mere 3% of the Spanish children, she said the explanation is unknown. The two main possibilities are that the CNS symptoms were due to a parenchymal brain infection rather than to EV-A71 infection of meningeal tissue. Alternatively, the CNS involvement may have been a manifestation of an immunologic response to the infection, rather than being due to the virus itself.

Dr. Worner reported having no financial conflicts of interest.

[email protected]

MADRID – Ninety-two percent of Spanish children sickened during the first-ever outbreak of enterovirus-associated brain stem encephalitis in western Europe survived with no long-term sequelae, Nuria Worner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

“We think that aggressive treatments should be restricted to those patients with important neurologic involvement,” declared Dr. Worner of Vall d’Hebron University Hospital in Barcelona. “We can say that no patients with milder involvement and without warning signs during the first 24 hours after onset of neurologic involvement went on to develop fulminant symptoms.”

Notable outbreaks of enterovirus A71 (EV-A71)-associated brain stem encephalitis occurred in Southeast Asia, Australia, and China in the late 1990s.

Dr. Worner reported on 196 children treated for laboratory-confirmed EV-A71–associated brain stem encephalitis at 16 Spanish hospitals in April-December 2016. Their median age was 25 months, 57% were male, and a median of 2 days of symptoms of mild viral illness transpired before neurologic symptoms arose. Prior to presenting to a hospital, 21% of the children had been diagnosed with hand-foot-and-mouth disease, and 13% with herpangina.

Initial preadmission symptoms included fever in 94% of cases, sleepiness in 86%, ataxia in 75%, tremor in 47%, myoclonus in 40%, and a rash in 26%.

Fifty-five percent of the children had EV RNA isolated from both throat and feces, 26% from the throat only, and 19% only from their feces. Eighty-seven percent of serotyped EV were EV-A71.

Ninety percent of children underwent lumbar puncture. Particularly noteworthy was the finding that EV was detected in the cerebrospinal fluid of a mere 3% of patients, although pleocytosis was present in 84%.

Brain MRI showed brain stem encephalitis along with myelitis in 50% of patients, brain stem myelitis without encephalitis in 29%, myelitis elsewhere in 2%, and normal findings in 19%.

Ground zero for the outbreak was Barcelona and the surrounding region of Catalonia; indeed, 130 of the 196 (66%) affected children came from there. The Catalan health department and pediatric infectious disease specialists quickly created standardized case severity definitions and treatment recommendations; they distributed them nationally.

Mild EV-A71–associated brain stem disease was defined as two or more of the following: tremor, myoclonus, mild ataxia, and/or significant drowsiness. The recommendation in these mild cases was for no treatment other than supportive care and careful in-hospital monitoring.

Patients with moderate involvement had to meet the definition for mild disease plus more pronounced ataxia or bulbar motor neuron involvement marked by slurred speech, drooling, dysphagia, apnea, abolition of the gag reflex, and/or an abnormal respiratory pattern. Moderately affected patients received two doses of intravenous immunoglobulin (IVIG), each dosed at 1 g/kg per 24 hours. Admission to the pediatric ICU was individualized for patients with moderate EV-A71–associated brain stem encephalitis.

Severe disease was categorized as bulbar motor neuron involvement plus neurogenic cardiorespiratory failure. Those patients were uniformly admitted to a pediatric ICU and given the two doses of IVIG. The need for systemic steroids was determined on an individual basis.

Forty percent of patients received IVIG and systemic steroids, 24% received IVIG only, 2% systemic steroids only, and 34% received no treatment other than supportive care.

Twenty-six percent of children were admitted to a pediatric ICU for a median stay of 3.5 days. Nine percent of children were placed on mechanical ventilation.

As the disease evolved, the most frequent neurologic complications included slurred speech in 15% of children, abnormal breathing pattern in 11%, seizures in 10%, acute flaccid paralysis in 9%, and cardiorespiratory failure with pulmonary edema in 9%, all occurring within the first hours after hospital admission.

The median hospital length of stay for the full study population was 6 days. The survival rate was 99.5%, with the sole death being due to cardiorespiratory failure.

With 1-6 months of follow-up since the acute episode of EV-A71–associated brain stem encephalitis, the long-term sequelae included two cases of limb paresis and two cases of paresis of a cranial nerve, one child with residual seizures, and one with hypoxic-ischemic encephalopathy.

Asked why the fatality rate in the Spanish outbreak was so much lower than in the earlier Australasian outbreaks, Dr. Worner cited Catalan physicians’ quick recognition of what was underway – and, more importantly, a difference in the EV-A71 viral subgenotype. Most of the most severe cases in Asia and Australia involved the C-4 subgenotype, while in Spain, the predominant subgenotype involved in the outbreak was C-1.

As for the curious finding that EV was detectable in the cerebrospinal fluid of a mere 3% of the Spanish children, she said the explanation is unknown. The two main possibilities are that the CNS symptoms were due to a parenchymal brain infection rather than to EV-A71 infection of meningeal tissue. Alternatively, the CNS involvement may have been a manifestation of an immunologic response to the infection, rather than being due to the virus itself.

Dr. Worner reported having no financial conflicts of interest.

[email protected]

MADRID – Ninety-two percent of Spanish children sickened during the first-ever outbreak of enterovirus-associated brain stem encephalitis in western Europe survived with no long-term sequelae, Nuria Worner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

“We think that aggressive treatments should be restricted to those patients with important neurologic involvement,” declared Dr. Worner of Vall d’Hebron University Hospital in Barcelona. “We can say that no patients with milder involvement and without warning signs during the first 24 hours after onset of neurologic involvement went on to develop fulminant symptoms.”

Notable outbreaks of enterovirus A71 (EV-A71)-associated brain stem encephalitis occurred in Southeast Asia, Australia, and China in the late 1990s.

Dr. Worner reported on 196 children treated for laboratory-confirmed EV-A71–associated brain stem encephalitis at 16 Spanish hospitals in April-December 2016. Their median age was 25 months, 57% were male, and a median of 2 days of symptoms of mild viral illness transpired before neurologic symptoms arose. Prior to presenting to a hospital, 21% of the children had been diagnosed with hand-foot-and-mouth disease, and 13% with herpangina.

Initial preadmission symptoms included fever in 94% of cases, sleepiness in 86%, ataxia in 75%, tremor in 47%, myoclonus in 40%, and a rash in 26%.

Fifty-five percent of the children had EV RNA isolated from both throat and feces, 26% from the throat only, and 19% only from their feces. Eighty-seven percent of serotyped EV were EV-A71.

Ninety percent of children underwent lumbar puncture. Particularly noteworthy was the finding that EV was detected in the cerebrospinal fluid of a mere 3% of patients, although pleocytosis was present in 84%.

Brain MRI showed brain stem encephalitis along with myelitis in 50% of patients, brain stem myelitis without encephalitis in 29%, myelitis elsewhere in 2%, and normal findings in 19%.

Ground zero for the outbreak was Barcelona and the surrounding region of Catalonia; indeed, 130 of the 196 (66%) affected children came from there. The Catalan health department and pediatric infectious disease specialists quickly created standardized case severity definitions and treatment recommendations; they distributed them nationally.

Mild EV-A71–associated brain stem disease was defined as two or more of the following: tremor, myoclonus, mild ataxia, and/or significant drowsiness. The recommendation in these mild cases was for no treatment other than supportive care and careful in-hospital monitoring.

Patients with moderate involvement had to meet the definition for mild disease plus more pronounced ataxia or bulbar motor neuron involvement marked by slurred speech, drooling, dysphagia, apnea, abolition of the gag reflex, and/or an abnormal respiratory pattern. Moderately affected patients received two doses of intravenous immunoglobulin (IVIG), each dosed at 1 g/kg per 24 hours. Admission to the pediatric ICU was individualized for patients with moderate EV-A71–associated brain stem encephalitis.

Severe disease was categorized as bulbar motor neuron involvement plus neurogenic cardiorespiratory failure. Those patients were uniformly admitted to a pediatric ICU and given the two doses of IVIG. The need for systemic steroids was determined on an individual basis.

Forty percent of patients received IVIG and systemic steroids, 24% received IVIG only, 2% systemic steroids only, and 34% received no treatment other than supportive care.

Twenty-six percent of children were admitted to a pediatric ICU for a median stay of 3.5 days. Nine percent of children were placed on mechanical ventilation.

As the disease evolved, the most frequent neurologic complications included slurred speech in 15% of children, abnormal breathing pattern in 11%, seizures in 10%, acute flaccid paralysis in 9%, and cardiorespiratory failure with pulmonary edema in 9%, all occurring within the first hours after hospital admission.

The median hospital length of stay for the full study population was 6 days. The survival rate was 99.5%, with the sole death being due to cardiorespiratory failure.

With 1-6 months of follow-up since the acute episode of EV-A71–associated brain stem encephalitis, the long-term sequelae included two cases of limb paresis and two cases of paresis of a cranial nerve, one child with residual seizures, and one with hypoxic-ischemic encephalopathy.

Asked why the fatality rate in the Spanish outbreak was so much lower than in the earlier Australasian outbreaks, Dr. Worner cited Catalan physicians’ quick recognition of what was underway – and, more importantly, a difference in the EV-A71 viral subgenotype. Most of the most severe cases in Asia and Australia involved the C-4 subgenotype, while in Spain, the predominant subgenotype involved in the outbreak was C-1.

As for the curious finding that EV was detectable in the cerebrospinal fluid of a mere 3% of the Spanish children, she said the explanation is unknown. The two main possibilities are that the CNS symptoms were due to a parenchymal brain infection rather than to EV-A71 infection of meningeal tissue. Alternatively, the CNS involvement may have been a manifestation of an immunologic response to the infection, rather than being due to the virus itself.

Dr. Worner reported having no financial conflicts of interest.

[email protected]

Although invasive procedures like cortical stimulation mapping and the Wada test have traditionally been employed to determine the location of motor and language-related areas of the brain prior to ablative epilepsy surgery, a recent review of noninvasive procedures suggests several may have merit. Papanicolaou et al outline the value of magnetoencephalography, functional magnetic resonance imaging, and transcranial magnetic stimulation to accomplish the same purpose and explain the rationale and conditions in which these approaches may be worth considering.

Papanicolaou AC, Rezaie R, Narayana S et al. On the relative merits of invasive and non-invasive pre-surgical brain mapping: New tools in ablative epilepsy surgery [published online ahead of print July 3, 2017]. Epilepsy Res. 2017; doi: 10.1016/j.eplepsyres.2017.07.002.

Although invasive procedures like cortical stimulation mapping and the Wada test have traditionally been employed to determine the location of motor and language-related areas of the brain prior to ablative epilepsy surgery, a recent review of noninvasive procedures suggests several may have merit. Papanicolaou et al outline the value of magnetoencephalography, functional magnetic resonance imaging, and transcranial magnetic stimulation to accomplish the same purpose and explain the rationale and conditions in which these approaches may be worth considering.

Papanicolaou AC, Rezaie R, Narayana S et al. On the relative merits of invasive and non-invasive pre-surgical brain mapping: New tools in ablative epilepsy surgery [published online ahead of print July 3, 2017]. Epilepsy Res. 2017; doi: 10.1016/j.eplepsyres.2017.07.002.

Although invasive procedures like cortical stimulation mapping and the Wada test have traditionally been employed to determine the location of motor and language-related areas of the brain prior to ablative epilepsy surgery, a recent review of noninvasive procedures suggests several may have merit. Papanicolaou et al outline the value of magnetoencephalography, functional magnetic resonance imaging, and transcranial magnetic stimulation to accomplish the same purpose and explain the rationale and conditions in which these approaches may be worth considering.

Papanicolaou AC, Rezaie R, Narayana S et al. On the relative merits of invasive and non-invasive pre-surgical brain mapping: New tools in ablative epilepsy surgery [published online ahead of print July 3, 2017]. Epilepsy Res. 2017; doi: 10.1016/j.eplepsyres.2017.07.002.

Study Overview

Objective. To evaluate the effectiveness of OASIS, a large-scale, statewide communication training program, on the reduction of antipsychotic use in nursing homes (NHs).

Design. Quasi-experimental longitudinal study with external controls.

Setting and participants. The participants were residents living in NHs between 1 March 2011 and 31 August 2013. The intervention group consisted of NHs in Massachusetts that were enrolled in the OASIS intervention and the control group consisted of NHs in Massachusetts and New York. The Centers for Medicare & Medicaid Services Minimum Data Set (MDS) 3.0 data was analyzed to determine medication use and behavior of residents of NHs. Residents of these NHs were excluded if they had a US Food and Drug Administration (FDA)-approved indication for antipsychotic use (eg, schizophrenia); were short-term residents (length of stay < 90 days); or had missing data on psychopharmacological medication use or behavior.

Intervention. The OASIS is an educational program that targeted both direct care and non-direct care staff in NHs to assist them in meeting the needs and challenges of caring for long-term care residents. Utilizing a train-the-trainer model, OASIS program coordinators and champions from each intervention NH participated in an 8-hour in-person training session that focused on enhancing communication skills between NH staff and residents with cognitive impairment. These trainers subsequently instructed the OASIS program to staff at their respective NHs using a team-based care approach. Addi-tional support of the OASIS educational program, such as telephone support, 12 webinars, 2 regional seminars, and 2 booster sessions, were provided to participating NHs.

Main outcome measures. The main outcome measure was facility-level prevalence of antipsychotic use in long-term NH residents captured by MDS in the 7 days preceding the MDS assessment. The secondary outcome measures were facility-level quarterly prevalence of psychotropic medications that may have been substituted for antipsychotic medications (ie, anxiolytics, antidepressants, and hypnotics) and behavioral disturbances (ie, physically abusive behavior, verbally abusive behavior, and rejecting care). All secondary outcomes were dichotomized in the 7 days preceding the MDS assessment and aggregated at the facility level for each quarter.

The analysis utilized an interrupted time series model of facility-level prevalence of antipsychotic medication use, other psychotropic medication use, and behavioral disturbances to evaluate the OASIS intervention’s effectiveness in participating facilities compared with control NHs. This methodology allowed the assessment of changes in the trend of antipsychotic use after the OASIS intervention controlling for historical trends. Data from the 18-month pre-intervention (baseline) period was compared with that of a 3-month training phase, a 6-month implementation phase, and a 3-month maintenance phase.

Main results. 93 NHs received OASIS intervention (27 with high prevalence of antipsychotic use) while 831 NHs did not (non-intervention control). The intervention NHs had a higher prevalence of antipsychotic use before OASIS training (baseline period) than the control NHs (34.1% vs. 22.7%, P < 0.001). The intervention NHs compared to controls were smaller in size (122 beds [interquartile range {IQR}, 88–152 beds] vs. 140 beds; [IQR, 104–200 beds]; P < 0.001), more likely to be for profit (77.4% vs. 62.0%, P = 0.009), had corporate ownership (93.5% vs. 74.6%, P < 0.001), and provided resident-only councils (78.5% vs. 52.9%, P < 0.001). The intervention NHs had higher registered nurse (RN) staffing hours per resident (0.8 vs. 0.7; P = 0.01) but lower certified nursing assistant (CNA) hours per resident (2.3 vs. 2.4; P = 0.04) than control NHs. There was no difference in licensed practical nurse hours per resident between groups.

All 93 intervention NHs completed the 8-hour in-person training session and attended an average of 6.5 (range, 0–12) subsequent support webinars. Thirteen NHs (14.0%) attended no regional seminars, 32 (34.4%) attended one, and 48 (51.6%) attended both. Four NHs (4.3%) attended one booster session, and 13 (14.0%) attended both. The NH staff most often trained in the OASIS training program were the directors of nursing, RNs, CNAs, and activities personnel. Support staff including housekeeping and dietary were trained in about half of the reporting intervention NHs, while physicians and nurse practitioners participated infrequently. Concurrent training programs in dementia care (Hand-in-Hand, Alzheimer Association training, MassPRO dementia care training) were implemented in 67.2% of intervention NHs.

In the intervention NHs, the prevalence of antipsych-otic prescribing decreased from 34.1% at baseline to 26.5% at the study end (7.6% absolute reduction, 22.3% relative reduction). In comparison, the prevalence of antipsychotic prescribing in control NHs decreased from 22.7% to 18.8% over the same period (3.9% absolute reduction, 17.2% relative reduction). During the OASIS implementation phase, the intervention NHs had a reduc-tion in prevalence of antipsychotic use (–1.20% [95% confidence interval {CI}, –1.85% to –0.09% per quarter]) greater than that of the control NHs (–0.23% [95% CI, –0.47% to 0.01% per quarter]), resulting in a net OASIS influence of –0.97% (95% CI, –1.85% to –0.09% per quarter; P = 0.03). The antipsychotic use reduction observed in the implementation phase was not sustained in the maintenance phase (difference of 0.93%; 95% CI, –0.66% to 2.54%; P = 0.48). No increases in other psychotropic medication use (anxiolytics, antidepressants, hypnotics) or behavioral disturbances (physically abusive behavior, verbally abusive behavior, and rejecting care) were observed during the OASIS training and implementation phases.

Conclusion. The OASIS communication training program reduced the prevalence of antipsychotic use in NHs during its implementation phase, but its effect was not sustained in the subsequent maintenance phase. The use of other psychotropic medications and behavior disturbances did not increase during the implementation of OASIS program. The findings from this study provided further support for utilizing nonpharmacologic programs to treat behavioral and psychological symptoms of dementia in older adults who reside in NHs.

Commentary

The use of both conventional and atypical antipsychotic medications is associated with a dose-related, approximately 2-fold increased risk of sudden cardiac death in older adults [1,2]. In 2006, the FDA issued a public health advisory stating that both conventional and atypical anti-psychotic medications are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. Despite this black box warning and growing recognition that antipsychotic medications are not indicated for the treatment of dementia-related psychosis, the off-label use of antipsychotic medications to treat behavioral and psychological symptoms of dementia in older adults remains a common practice in nursing homes [3]. Thus, there is an urgent need to assess and develop effective interventions that reduce the practice of antipsychotic medication prescribing in long-term care. To that effect, the study reported by Tjia et al appropriately investigated the impact of the OASIS communication training program, a nonpharmacologic intervention, on the reduction of antipsychotic use in NHs.

This study was well designed and had a number of strengths. It utilized an interrupted time series model, one of the strongest quasi-experimental approaches due to its robustness to threats of internal validity, for evaluating longitudinal effects of an intervention intended to improve the quality of medication use. Moreover, this study included a large sample size and comparison facilities from the same geographical areas (NHs in Massachusetts and New York State) that served as external controls. Several potential weaknesses of the study were identified. Because facility-level aggregate data from NHs were used for analysis, individual level (long-term care resident) characteristics were not accounted for in the analysis. In addition, while the post-OASIS intervention questionnaire response rate was 65.6% (61 of 93 intervention NHs), a higher response rate would provide better characterization of NH staff that participated in OASIS program training, program completion rate, and a more complete representation of competing dementia care training programs concurrently implemented in these NHs.

Several studies, most utilizing various provider education methods, had explored whether these interventions could curb antipsychotic use in NHs with limited success. The largest successful intervention was reported by Meador et al [4], where a focused provider education program facilitated a relative reduction in antipsychotic medication use of 23% compared to control NHs. However, the implementation of this specific program was time- and resource-intensive, requiring geropsychiatry evaluation to all physicians (45 to 60 min), nurse-educator in-service programs for NH staff (5 to 6 one-hr sessions), management specialist consultation to NH administrators (4 hr), and evening meeting for the families of NH residents. The current study by Tjia et al, the largest study to date conducted in the context of competing dementia care training programs and increased awareness of the danger of antipsychotic use in the elderly, similarly showed a meaningful reduction in antipsychotic medication use in NHs that received the OASIS communication training program. The OASIS program appears to be less resource-intensive than the provider education program modeled by Meador et al, and its train-the-trainer model is likely more adaptable to meet the limitations (eg, low staffing and staff turnover) inherent in NHs. The beneficial effect of the OASIS program on reduction of antipsychotic medication prescribing was observed despite low participation by prescribers (11.5% of physicians and 11.5% of nurse practitioners). Although it is unclear why this was observed, this finding is intriguing in that a communication training program that reframes challenging behavior of NH residents with cognitive impairment as (1) communication of unmet needs, (2) train staff to anticipate resident needs, and (3) integrate resident strengths into daily care plans can alter provider prescription behavior. The implication of this is that provider practice in managing behavioral and psychological symptoms of dementia can be improved by optimizing communication training in NH staff. Taken together, this study adds to evidence in favor of utilizing nonpharmacologic interventions to reduce antipsychotic use in long-term care.

Applications for Clinical Practice

OASIS, a communication training program for NH staff, reduces antipsychotic medication use in NHs during its implementation phase. Future studies need to investigate pragmatic methods to sustain the beneficial effect of OASIS after its implementation phase.

—Fred Ko, MD, MS, Icahn School of Medicine at Mount Sinai, New York, NY

Study Overview

Objective. To evaluate the effectiveness of OASIS, a large-scale, statewide communication training program, on the reduction of antipsychotic use in nursing homes (NHs).

Design. Quasi-experimental longitudinal study with external controls.

Setting and participants. The participants were residents living in NHs between 1 March 2011 and 31 August 2013. The intervention group consisted of NHs in Massachusetts that were enrolled in the OASIS intervention and the control group consisted of NHs in Massachusetts and New York. The Centers for Medicare & Medicaid Services Minimum Data Set (MDS) 3.0 data was analyzed to determine medication use and behavior of residents of NHs. Residents of these NHs were excluded if they had a US Food and Drug Administration (FDA)-approved indication for antipsychotic use (eg, schizophrenia); were short-term residents (length of stay < 90 days); or had missing data on psychopharmacological medication use or behavior.

Intervention. The OASIS is an educational program that targeted both direct care and non-direct care staff in NHs to assist them in meeting the needs and challenges of caring for long-term care residents. Utilizing a train-the-trainer model, OASIS program coordinators and champions from each intervention NH participated in an 8-hour in-person training session that focused on enhancing communication skills between NH staff and residents with cognitive impairment. These trainers subsequently instructed the OASIS program to staff at their respective NHs using a team-based care approach. Addi-tional support of the OASIS educational program, such as telephone support, 12 webinars, 2 regional seminars, and 2 booster sessions, were provided to participating NHs.

Main outcome measures. The main outcome measure was facility-level prevalence of antipsychotic use in long-term NH residents captured by MDS in the 7 days preceding the MDS assessment. The secondary outcome measures were facility-level quarterly prevalence of psychotropic medications that may have been substituted for antipsychotic medications (ie, anxiolytics, antidepressants, and hypnotics) and behavioral disturbances (ie, physically abusive behavior, verbally abusive behavior, and rejecting care). All secondary outcomes were dichotomized in the 7 days preceding the MDS assessment and aggregated at the facility level for each quarter.

The analysis utilized an interrupted time series model of facility-level prevalence of antipsychotic medication use, other psychotropic medication use, and behavioral disturbances to evaluate the OASIS intervention’s effectiveness in participating facilities compared with control NHs. This methodology allowed the assessment of changes in the trend of antipsychotic use after the OASIS intervention controlling for historical trends. Data from the 18-month pre-intervention (baseline) period was compared with that of a 3-month training phase, a 6-month implementation phase, and a 3-month maintenance phase.

Main results. 93 NHs received OASIS intervention (27 with high prevalence of antipsychotic use) while 831 NHs did not (non-intervention control). The intervention NHs had a higher prevalence of antipsychotic use before OASIS training (baseline period) than the control NHs (34.1% vs. 22.7%, P < 0.001). The intervention NHs compared to controls were smaller in size (122 beds [interquartile range {IQR}, 88–152 beds] vs. 140 beds; [IQR, 104–200 beds]; P < 0.001), more likely to be for profit (77.4% vs. 62.0%, P = 0.009), had corporate ownership (93.5% vs. 74.6%, P < 0.001), and provided resident-only councils (78.5% vs. 52.9%, P < 0.001). The intervention NHs had higher registered nurse (RN) staffing hours per resident (0.8 vs. 0.7; P = 0.01) but lower certified nursing assistant (CNA) hours per resident (2.3 vs. 2.4; P = 0.04) than control NHs. There was no difference in licensed practical nurse hours per resident between groups.

All 93 intervention NHs completed the 8-hour in-person training session and attended an average of 6.5 (range, 0–12) subsequent support webinars. Thirteen NHs (14.0%) attended no regional seminars, 32 (34.4%) attended one, and 48 (51.6%) attended both. Four NHs (4.3%) attended one booster session, and 13 (14.0%) attended both. The NH staff most often trained in the OASIS training program were the directors of nursing, RNs, CNAs, and activities personnel. Support staff including housekeeping and dietary were trained in about half of the reporting intervention NHs, while physicians and nurse practitioners participated infrequently. Concurrent training programs in dementia care (Hand-in-Hand, Alzheimer Association training, MassPRO dementia care training) were implemented in 67.2% of intervention NHs.

In the intervention NHs, the prevalence of antipsych-otic prescribing decreased from 34.1% at baseline to 26.5% at the study end (7.6% absolute reduction, 22.3% relative reduction). In comparison, the prevalence of antipsychotic prescribing in control NHs decreased from 22.7% to 18.8% over the same period (3.9% absolute reduction, 17.2% relative reduction). During the OASIS implementation phase, the intervention NHs had a reduc-tion in prevalence of antipsychotic use (–1.20% [95% confidence interval {CI}, –1.85% to –0.09% per quarter]) greater than that of the control NHs (–0.23% [95% CI, –0.47% to 0.01% per quarter]), resulting in a net OASIS influence of –0.97% (95% CI, –1.85% to –0.09% per quarter; P = 0.03). The antipsychotic use reduction observed in the implementation phase was not sustained in the maintenance phase (difference of 0.93%; 95% CI, –0.66% to 2.54%; P = 0.48). No increases in other psychotropic medication use (anxiolytics, antidepressants, hypnotics) or behavioral disturbances (physically abusive behavior, verbally abusive behavior, and rejecting care) were observed during the OASIS training and implementation phases.

Conclusion. The OASIS communication training program reduced the prevalence of antipsychotic use in NHs during its implementation phase, but its effect was not sustained in the subsequent maintenance phase. The use of other psychotropic medications and behavior disturbances did not increase during the implementation of OASIS program. The findings from this study provided further support for utilizing nonpharmacologic programs to treat behavioral and psychological symptoms of dementia in older adults who reside in NHs.

Commentary

The use of both conventional and atypical antipsychotic medications is associated with a dose-related, approximately 2-fold increased risk of sudden cardiac death in older adults [1,2]. In 2006, the FDA issued a public health advisory stating that both conventional and atypical anti-psychotic medications are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. Despite this black box warning and growing recognition that antipsychotic medications are not indicated for the treatment of dementia-related psychosis, the off-label use of antipsychotic medications to treat behavioral and psychological symptoms of dementia in older adults remains a common practice in nursing homes [3]. Thus, there is an urgent need to assess and develop effective interventions that reduce the practice of antipsychotic medication prescribing in long-term care. To that effect, the study reported by Tjia et al appropriately investigated the impact of the OASIS communication training program, a nonpharmacologic intervention, on the reduction of antipsychotic use in NHs.

This study was well designed and had a number of strengths. It utilized an interrupted time series model, one of the strongest quasi-experimental approaches due to its robustness to threats of internal validity, for evaluating longitudinal effects of an intervention intended to improve the quality of medication use. Moreover, this study included a large sample size and comparison facilities from the same geographical areas (NHs in Massachusetts and New York State) that served as external controls. Several potential weaknesses of the study were identified. Because facility-level aggregate data from NHs were used for analysis, individual level (long-term care resident) characteristics were not accounted for in the analysis. In addition, while the post-OASIS intervention questionnaire response rate was 65.6% (61 of 93 intervention NHs), a higher response rate would provide better characterization of NH staff that participated in OASIS program training, program completion rate, and a more complete representation of competing dementia care training programs concurrently implemented in these NHs.

Several studies, most utilizing various provider education methods, had explored whether these interventions could curb antipsychotic use in NHs with limited success. The largest successful intervention was reported by Meador et al [4], where a focused provider education program facilitated a relative reduction in antipsychotic medication use of 23% compared to control NHs. However, the implementation of this specific program was time- and resource-intensive, requiring geropsychiatry evaluation to all physicians (45 to 60 min), nurse-educator in-service programs for NH staff (5 to 6 one-hr sessions), management specialist consultation to NH administrators (4 hr), and evening meeting for the families of NH residents. The current study by Tjia et al, the largest study to date conducted in the context of competing dementia care training programs and increased awareness of the danger of antipsychotic use in the elderly, similarly showed a meaningful reduction in antipsychotic medication use in NHs that received the OASIS communication training program. The OASIS program appears to be less resource-intensive than the provider education program modeled by Meador et al, and its train-the-trainer model is likely more adaptable to meet the limitations (eg, low staffing and staff turnover) inherent in NHs. The beneficial effect of the OASIS program on reduction of antipsychotic medication prescribing was observed despite low participation by prescribers (11.5% of physicians and 11.5% of nurse practitioners). Although it is unclear why this was observed, this finding is intriguing in that a communication training program that reframes challenging behavior of NH residents with cognitive impairment as (1) communication of unmet needs, (2) train staff to anticipate resident needs, and (3) integrate resident strengths into daily care plans can alter provider prescription behavior. The implication of this is that provider practice in managing behavioral and psychological symptoms of dementia can be improved by optimizing communication training in NH staff. Taken together, this study adds to evidence in favor of utilizing nonpharmacologic interventions to reduce antipsychotic use in long-term care.

Applications for Clinical Practice

OASIS, a communication training program for NH staff, reduces antipsychotic medication use in NHs during its implementation phase. Future studies need to investigate pragmatic methods to sustain the beneficial effect of OASIS after its implementation phase.

—Fred Ko, MD, MS, Icahn School of Medicine at Mount Sinai, New York, NY

Study Overview

Objective. To evaluate the effectiveness of OASIS, a large-scale, statewide communication training program, on the reduction of antipsychotic use in nursing homes (NHs).

Design. Quasi-experimental longitudinal study with external controls.

Setting and participants. The participants were residents living in NHs between 1 March 2011 and 31 August 2013. The intervention group consisted of NHs in Massachusetts that were enrolled in the OASIS intervention and the control group consisted of NHs in Massachusetts and New York. The Centers for Medicare & Medicaid Services Minimum Data Set (MDS) 3.0 data was analyzed to determine medication use and behavior of residents of NHs. Residents of these NHs were excluded if they had a US Food and Drug Administration (FDA)-approved indication for antipsychotic use (eg, schizophrenia); were short-term residents (length of stay < 90 days); or had missing data on psychopharmacological medication use or behavior.

Intervention. The OASIS is an educational program that targeted both direct care and non-direct care staff in NHs to assist them in meeting the needs and challenges of caring for long-term care residents. Utilizing a train-the-trainer model, OASIS program coordinators and champions from each intervention NH participated in an 8-hour in-person training session that focused on enhancing communication skills between NH staff and residents with cognitive impairment. These trainers subsequently instructed the OASIS program to staff at their respective NHs using a team-based care approach. Addi-tional support of the OASIS educational program, such as telephone support, 12 webinars, 2 regional seminars, and 2 booster sessions, were provided to participating NHs.

Main outcome measures. The main outcome measure was facility-level prevalence of antipsychotic use in long-term NH residents captured by MDS in the 7 days preceding the MDS assessment. The secondary outcome measures were facility-level quarterly prevalence of psychotropic medications that may have been substituted for antipsychotic medications (ie, anxiolytics, antidepressants, and hypnotics) and behavioral disturbances (ie, physically abusive behavior, verbally abusive behavior, and rejecting care). All secondary outcomes were dichotomized in the 7 days preceding the MDS assessment and aggregated at the facility level for each quarter.

The analysis utilized an interrupted time series model of facility-level prevalence of antipsychotic medication use, other psychotropic medication use, and behavioral disturbances to evaluate the OASIS intervention’s effectiveness in participating facilities compared with control NHs. This methodology allowed the assessment of changes in the trend of antipsychotic use after the OASIS intervention controlling for historical trends. Data from the 18-month pre-intervention (baseline) period was compared with that of a 3-month training phase, a 6-month implementation phase, and a 3-month maintenance phase.

Main results. 93 NHs received OASIS intervention (27 with high prevalence of antipsychotic use) while 831 NHs did not (non-intervention control). The intervention NHs had a higher prevalence of antipsychotic use before OASIS training (baseline period) than the control NHs (34.1% vs. 22.7%, P < 0.001). The intervention NHs compared to controls were smaller in size (122 beds [interquartile range {IQR}, 88–152 beds] vs. 140 beds; [IQR, 104–200 beds]; P < 0.001), more likely to be for profit (77.4% vs. 62.0%, P = 0.009), had corporate ownership (93.5% vs. 74.6%, P < 0.001), and provided resident-only councils (78.5% vs. 52.9%, P < 0.001). The intervention NHs had higher registered nurse (RN) staffing hours per resident (0.8 vs. 0.7; P = 0.01) but lower certified nursing assistant (CNA) hours per resident (2.3 vs. 2.4; P = 0.04) than control NHs. There was no difference in licensed practical nurse hours per resident between groups.

All 93 intervention NHs completed the 8-hour in-person training session and attended an average of 6.5 (range, 0–12) subsequent support webinars. Thirteen NHs (14.0%) attended no regional seminars, 32 (34.4%) attended one, and 48 (51.6%) attended both. Four NHs (4.3%) attended one booster session, and 13 (14.0%) attended both. The NH staff most often trained in the OASIS training program were the directors of nursing, RNs, CNAs, and activities personnel. Support staff including housekeeping and dietary were trained in about half of the reporting intervention NHs, while physicians and nurse practitioners participated infrequently. Concurrent training programs in dementia care (Hand-in-Hand, Alzheimer Association training, MassPRO dementia care training) were implemented in 67.2% of intervention NHs.

In the intervention NHs, the prevalence of antipsych-otic prescribing decreased from 34.1% at baseline to 26.5% at the study end (7.6% absolute reduction, 22.3% relative reduction). In comparison, the prevalence of antipsychotic prescribing in control NHs decreased from 22.7% to 18.8% over the same period (3.9% absolute reduction, 17.2% relative reduction). During the OASIS implementation phase, the intervention NHs had a reduc-tion in prevalence of antipsychotic use (–1.20% [95% confidence interval {CI}, –1.85% to –0.09% per quarter]) greater than that of the control NHs (–0.23% [95% CI, –0.47% to 0.01% per quarter]), resulting in a net OASIS influence of –0.97% (95% CI, –1.85% to –0.09% per quarter; P = 0.03). The antipsychotic use reduction observed in the implementation phase was not sustained in the maintenance phase (difference of 0.93%; 95% CI, –0.66% to 2.54%; P = 0.48). No increases in other psychotropic medication use (anxiolytics, antidepressants, hypnotics) or behavioral disturbances (physically abusive behavior, verbally abusive behavior, and rejecting care) were observed during the OASIS training and implementation phases.

Conclusion. The OASIS communication training program reduced the prevalence of antipsychotic use in NHs during its implementation phase, but its effect was not sustained in the subsequent maintenance phase. The use of other psychotropic medications and behavior disturbances did not increase during the implementation of OASIS program. The findings from this study provided further support for utilizing nonpharmacologic programs to treat behavioral and psychological symptoms of dementia in older adults who reside in NHs.

Commentary

The use of both conventional and atypical antipsychotic medications is associated with a dose-related, approximately 2-fold increased risk of sudden cardiac death in older adults [1,2]. In 2006, the FDA issued a public health advisory stating that both conventional and atypical anti-psychotic medications are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. Despite this black box warning and growing recognition that antipsychotic medications are not indicated for the treatment of dementia-related psychosis, the off-label use of antipsychotic medications to treat behavioral and psychological symptoms of dementia in older adults remains a common practice in nursing homes [3]. Thus, there is an urgent need to assess and develop effective interventions that reduce the practice of antipsychotic medication prescribing in long-term care. To that effect, the study reported by Tjia et al appropriately investigated the impact of the OASIS communication training program, a nonpharmacologic intervention, on the reduction of antipsychotic use in NHs.

This study was well designed and had a number of strengths. It utilized an interrupted time series model, one of the strongest quasi-experimental approaches due to its robustness to threats of internal validity, for evaluating longitudinal effects of an intervention intended to improve the quality of medication use. Moreover, this study included a large sample size and comparison facilities from the same geographical areas (NHs in Massachusetts and New York State) that served as external controls. Several potential weaknesses of the study were identified. Because facility-level aggregate data from NHs were used for analysis, individual level (long-term care resident) characteristics were not accounted for in the analysis. In addition, while the post-OASIS intervention questionnaire response rate was 65.6% (61 of 93 intervention NHs), a higher response rate would provide better characterization of NH staff that participated in OASIS program training, program completion rate, and a more complete representation of competing dementia care training programs concurrently implemented in these NHs.

Several studies, most utilizing various provider education methods, had explored whether these interventions could curb antipsychotic use in NHs with limited success. The largest successful intervention was reported by Meador et al [4], where a focused provider education program facilitated a relative reduction in antipsychotic medication use of 23% compared to control NHs. However, the implementation of this specific program was time- and resource-intensive, requiring geropsychiatry evaluation to all physicians (45 to 60 min), nurse-educator in-service programs for NH staff (5 to 6 one-hr sessions), management specialist consultation to NH administrators (4 hr), and evening meeting for the families of NH residents. The current study by Tjia et al, the largest study to date conducted in the context of competing dementia care training programs and increased awareness of the danger of antipsychotic use in the elderly, similarly showed a meaningful reduction in antipsychotic medication use in NHs that received the OASIS communication training program. The OASIS program appears to be less resource-intensive than the provider education program modeled by Meador et al, and its train-the-trainer model is likely more adaptable to meet the limitations (eg, low staffing and staff turnover) inherent in NHs. The beneficial effect of the OASIS program on reduction of antipsychotic medication prescribing was observed despite low participation by prescribers (11.5% of physicians and 11.5% of nurse practitioners). Although it is unclear why this was observed, this finding is intriguing in that a communication training program that reframes challenging behavior of NH residents with cognitive impairment as (1) communication of unmet needs, (2) train staff to anticipate resident needs, and (3) integrate resident strengths into daily care plans can alter provider prescription behavior. The implication of this is that provider practice in managing behavioral and psychological symptoms of dementia can be improved by optimizing communication training in NH staff. Taken together, this study adds to evidence in favor of utilizing nonpharmacologic interventions to reduce antipsychotic use in long-term care.

Applications for Clinical Practice

OASIS, a communication training program for NH staff, reduces antipsychotic medication use in NHs during its implementation phase. Future studies need to investigate pragmatic methods to sustain the beneficial effect of OASIS after its implementation phase.

—Fred Ko, MD, MS, Icahn School of Medicine at Mount Sinai, New York, NY

Patients who have seizures while asleep are more likely to experience severe and longer episodes of hypoxemia compared with seizures while awake according to an examination of 48 recorded seizures from 20 adults with epilepsy. The analysis also suggested that an increased risk of sudden death may be caused by hypoxemia from nocturnal seizures.

Latreille V, Abdennadher M, Dworetzky BA et al. Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression [published online ahead of print July 17, 2017]. Epilepsia. 2017;doi: 10.1111/epi.13841.

Patients who have seizures while asleep are more likely to experience severe and longer episodes of hypoxemia compared with seizures while awake according to an examination of 48 recorded seizures from 20 adults with epilepsy. The analysis also suggested that an increased risk of sudden death may be caused by hypoxemia from nocturnal seizures.

Latreille V, Abdennadher M, Dworetzky BA et al. Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression [published online ahead of print July 17, 2017]. Epilepsia. 2017;doi: 10.1111/epi.13841.

Patients who have seizures while asleep are more likely to experience severe and longer episodes of hypoxemia compared with seizures while awake according to an examination of 48 recorded seizures from 20 adults with epilepsy. The analysis also suggested that an increased risk of sudden death may be caused by hypoxemia from nocturnal seizures.

Latreille V, Abdennadher M, Dworetzky BA et al. Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression [published online ahead of print July 17, 2017]. Epilepsia. 2017;doi: 10.1111/epi.13841.

A combination of metabolites and genomic indicators hold promise as a noninvasive biomarker for epilepsy suggests a recent study published in Epilepsia. Wu et al found that a metabolomic-genomic signature that included reduced lactate and increased creatine plus phosphocreatine and choline was able to predict the existence of an altered metabolic state in epileptic brain regions, suggesting it may eventually be an alternative to surgically invasive approaches to diagnosis.

Wu HC, Dachet F, Ghoddoussi F, et al. Altered metabolomic-genomic signature: a potential noninvasive biomarker of epilepsy [published online ahead of print July 17, 2017]. Epilepsia. 2017; doi: 10.1111/epi.13848.

A combination of metabolites and genomic indicators hold promise as a noninvasive biomarker for epilepsy suggests a recent study published in Epilepsia. Wu et al found that a metabolomic-genomic signature that included reduced lactate and increased creatine plus phosphocreatine and choline was able to predict the existence of an altered metabolic state in epileptic brain regions, suggesting it may eventually be an alternative to surgically invasive approaches to diagnosis.

Wu HC, Dachet F, Ghoddoussi F, et al. Altered metabolomic-genomic signature: a potential noninvasive biomarker of epilepsy [published online ahead of print July 17, 2017]. Epilepsia. 2017; doi: 10.1111/epi.13848.

A combination of metabolites and genomic indicators hold promise as a noninvasive biomarker for epilepsy suggests a recent study published in Epilepsia. Wu et al found that a metabolomic-genomic signature that included reduced lactate and increased creatine plus phosphocreatine and choline was able to predict the existence of an altered metabolic state in epileptic brain regions, suggesting it may eventually be an alternative to surgically invasive approaches to diagnosis.

Wu HC, Dachet F, Ghoddoussi F, et al. Altered metabolomic-genomic signature: a potential noninvasive biomarker of epilepsy [published online ahead of print July 17, 2017]. Epilepsia. 2017; doi: 10.1111/epi.13848.

Intracranial deep brain stimulation (DBS) may offer some benefit to patients with epilepsy who do not respond to more conservative therapy, but most of the evidence comes from short-term randomized controlled trials, according to a recent review from the Cochrane Library. Experts concluded that anterior thalamic DBS, responsive ictal onset zone stimulation, and hippocampal DBS can reduce the frequency of seizures in patients with refractory epilepsy.

Sprengers M, Vonck K, Carrette E, Marson AG, Boon P. Deep brain and cortical stimulation for epilepsy. Cochrane Database Syst Rev. 2017 Jul 18;7:CD008497.

Intracranial deep brain stimulation (DBS) may offer some benefit to patients with epilepsy who do not respond to more conservative therapy, but most of the evidence comes from short-term randomized controlled trials, according to a recent review from the Cochrane Library. Experts concluded that anterior thalamic DBS, responsive ictal onset zone stimulation, and hippocampal DBS can reduce the frequency of seizures in patients with refractory epilepsy.

Sprengers M, Vonck K, Carrette E, Marson AG, Boon P. Deep brain and cortical stimulation for epilepsy. Cochrane Database Syst Rev. 2017 Jul 18;7:CD008497.

Intracranial deep brain stimulation (DBS) may offer some benefit to patients with epilepsy who do not respond to more conservative therapy, but most of the evidence comes from short-term randomized controlled trials, according to a recent review from the Cochrane Library. Experts concluded that anterior thalamic DBS, responsive ictal onset zone stimulation, and hippocampal DBS can reduce the frequency of seizures in patients with refractory epilepsy.

Sprengers M, Vonck K, Carrette E, Marson AG, Boon P. Deep brain and cortical stimulation for epilepsy. Cochrane Database Syst Rev. 2017 Jul 18;7:CD008497.

Increasingly, women with psychiatric illness are undergoing pharmacologic treatment during pregnancy. In the United States, an estimated 8% of pregnant women are prescribed antidepressants, and the number of such cases has risen over the past 15 years.¹ Women with a psychiatric diagnosis were once instructed either to discontinue all medication immediately on learning they were pregnant, or to forgo motherhood because their illness might have a negative effect on a child or because avoiding medication during pregnancy might lead to a relapse.

Fortunately, women with depression, anxiety, bipolar disorder, or schizophrenia no longer are being told that they cannot become mothers. For many women, however, stopping medication is not an option. Furthermore, psychiatric illness sometimes is diagnosed initially during pregnancy and requires treatment.

Illustration: Kimberly Martens for OBG Management

Pregnant women and their physicians need accurate information about when to taper off medication, when to start or continue, and which medications are safest. Even for clinicians with a solid knowledge base, counseling a woman who needs or may need psychotropic medication during pregnancy and breastfeeding is a daunting task. Some clinicians still recommend no drug treatment as the safest and best option, given the potential risks to the fetus.

In this review we offer a methodologic approach for decision making about pharmacologic treatment during pregnancy. As the scientific literature is constantly being updated, it is imperative to have the most current information on psychotropics and to know how to individualize that information when counseling a pregnant woman and her family. Using this framework for analyzing the risks and benefits for both mother and fetus, clinicians can avoid the unanswerable question of which medication is the “safest.”

A patient’s mental health care provider is a useful resource for information about a woman’s mental health history and current stability, but he or she may not be expert or comfortable in recommending treatment for a pregnant patient. During pregnancy, a woman’s obstetrician often becomes the “expert” for all treatment decisions.

Analyze risks and benefits of medication versus no medication

The US Food and Drug Administration (FDA) has not approved any psychotropic medication for use during pregnancy. While a clinical study would provide more scientifically rigorous safety data, conducting a double-blinded, placebo-controlled trial in pregnant women with a psychiatric disorder is unethical. Thus, the literature consists mostly of reports on case series, retrospective chart reviews, prospective naturalistic studies, and analyses of large registry databases. Each has benefits and limitations. It is important to understand the limitations when making treatment decisions.

In 1979, the FDA developed a 5-lettersystem (A, B, C, D, X) for classifying the relative safety of medications used during pregnancy.² Many clinicians and pregnant women relied on this system to decide which medications were safe. Unfortunately, the information in the system was inadequate for making informed decisions. For example, although a class B medication might have appeared safer than one in class C, the studies of risk in humans might not have been adequate to permit comparisons. Drug safety classifications were seldom changed, despite the availability of additional data.

In June 2015, the FDA changed the requirements for the Pregnancy and Lactation subsections of the labeling for human prescription drugs and biologic products. Drug manufacturers must now include in each subsection a risk summary, clinical considerations supporting patient care decisions and counseling, and detailed data. These subsections provide information on available human and animal studies, known or potential maternal or fetal adverse reactions, and dose adjustments needed during pregnancy and the postpartum period. In addition, the FDA added a subsection: Females and Males of Reproductive Potential.³

These changes acknowledge there is no list of “safe” medications. The safest medication generally is the one that works for a particular patient at the lowest effective dose. As each woman’s history of illness and effective treatment is different, the best medication may differ as well, even among women with the same illness. Therefore, medication should be individualized to the patient. A risk–benefit analysis comparing psychotropic medication treatment with no medication treatment must be performed for each patient according to her personal history and the best available data.

Read about the risks of untreated illness during pregnancy

What is the risk of untreated illness during pregnancy?

During pregnancy, women are treated for many medical disorders, including psychiatric illness. One general guideline is that, if a pregnant woman does not need a medication—whether it be for an allergy, hypertension, or another disorder—she should not take it. Conversely, if a medication is required for a patient’s well-being, her physician should continue it or switch to a safer one. This general guideline is the same for women with depression, anxiety, or a psychotic disorder.

Managing hypertension during pregnancy is an example of choosing treatment when the risk of the illness to the mother and the infant outweighs the likely small risk associated with taking a medication. Blood pressure is monitored, and, when it reaches a threshold, an antihypertensive is started promptly to avoid morbidity and mortality.

Psychiatric illness carries risks for both mother and fetus as well, but no data show a clear threshold for initiating pharmacologic treatment. Therefore, in prescribing medication the most important steps are to take a complete history and perform a thorough evaluation. Important information includes the number and severity of previous episodes, prior history of hospitalization or suicidal thoughts or attempts, and any history of psychotic or manic status.

Whether to continue or discontinue medication is often decided after inquiring about other times a medication was discontinued. A patient who in the past stayed well for several years after stopping a medication may be able to taper off a medication and conceive during a window of wellness. Some women who have experienced only one episode of illness and have been stable for at least a year may be able to taper off a medication before conceiving (TABLE 1).

In the risk–benefit analysis, assess the need for pharmacologic treatment by considering the risk that untreated illness poses for both mother and fetus, the benefits of treatment for both, and the risk of medication exposure for the fetus.⁴

Mother: Risk of untreated illness versus benefit of treatment

A complete history and a current symptom evaluation are needed to assess the risk that nonpharmacologic treatment poses for the mother. Women with functional impairment, including inability to work, to perform activities of daily living, or to take care of other children, likely require treatment. Studies have found that women who discontinue treatment for a psychiatric illness around the time of conception are likely to experience a recurrence of illness during pregnancy, often in the first trimester, and must restart medication.^5,6 For some diagnoses, particularly bipolar disorder, symptoms during a relapse can be more severe and more difficult to treat, and they carry a risk for both mother and fetus.⁷ A longitudinal study of pregnant women who stopped medication for bipolar disorder found a 71% rate of relapse.⁷ In cases in which there is a history of hospitalization, suicide attempt, or psychosis, discontinuing treatment is not an option; instead, the physician must determine which medication is safest for the particular patient.

Related article:
Does PTSD during pregnancy increase the likelihood of preterm birth?

Fetus: Risk of untreated illness versus benefit of treatment

Mothers with untreated psychiatric illness are at higher risk for poor prenatal care, substance abuse, and inadequate nutrition, all of which increase the risk of negative obstetric and neonatal outcomes.⁸ Evidence indicates that untreated maternal depression increases the risk of preterm delivery and low birth weight.⁹ Children born to mothers with depression have more behavioral problems, more psychiatric illness, more visits to pediatricians, lower IQ scores, and attachment issues.¹⁰ Some of the long-term negative effects of intrauterine stress, which include hypertension, coronary heart disease, and autoimmune disorders, persist into adulthood.¹¹

Fetus: Risk of medication exposure

With any pharmacologic treatment, the timing of fetal exposure affects resultant risks and therefore must be considered in the management plan.

Before conception. Is there any effect on ovulation or fertilization?

Implantation. Does the exposure impair the blastocyst’s ability to implant in the uterine lining?

First trimester. This is the period of organogenesis. Regardless of drug exposure, there is a 2% to 4% baseline risk of a major malformation during any pregnancy. The risk of a particular malformation must be weighed against this baseline risk.

According to limited data, selective serotonin reuptake inhibitors (SSRIs) may increase the risk of early miscarriage.¹² SSRIs also have been implicated in increasing the risk of cardiovascular malformations, although the data are conflicting.^13,14

Antiepileptics such as valproate and carbamazepine are used as mood stabilizers in the treatment of bipolar disorder.¹⁵ Extensive data have shown an association with teratogenicity. Pregnant women who require either of these medications also should be prescribed folic acid 4 or 5 mg/day. Given the high risk of birth defects and cognitive delay, valproate no longer is recommended for women of reproductive potential.¹⁶

Lithium, one of the safest medications used in the treatment of bipolar disorder, is associated with a very small risk of Ebstein anomaly.¹⁷

Lamotrigine is used to treat bipolar depression and appears to have a good safety profile, along with a possible small increased risk of oral clefts.^18,19

Atypical antipsychotics (such as aripiprazole, olanzapine, quetiapine, and risperidone) are often used first-line in the treatment of psychotic disorders and bipolar disorder in women who are not pregnant. Although the safety data on use of these drugs during pregnancy are limited, a recent analysis of pregnant Medicaid enrollees found no increased risk of birth defects after controlling for potential confounding factors.²⁰ Common practice is to avoid these newer agents, given their limited data and the time needed for rare malformations to emerge (adequate numbers require many exposures during pregnancy).

Read additional fetal risks of medication exposure

Second trimester. This is a period of growth and neural development. A 2006 study suggested that SSRI exposure after pregnancy week 20 increases the risk of persistent pulmonary hypertension of the newborn (PPHN).²¹ In 2011, however, the FDA removed the PPHN warning label for SSRIs, citing inconsistent data. Whether the PPHN risk is increased with SSRI use is unclear, but the risk is presumed to be smaller than previously suggested.²² Stopping SSRIs before week 20 puts the mother at risk for relapse during pregnancy and increases her risk of developing postpartum depression. If we follow the recommendation to prescribe medication only for women who need it most, then stopping the medication at any time during pregnancy is not an option.

Third trimester. This is a period of continued growth and lung maturation.

Delivery. Is there a potential for impairment in parturition?

Neonatal adaptation. Newborns are active mainly in adapting to extrauterine life: They regulate their temperature and muscle tone and learn to coordinate sucking, swallowing, and breathing. Does medication exposure impair adaptation, or are signs or symptoms of withdrawal or toxicity present? The evidence that in utero SSRI exposure increases the risk of neonatal adaptation syndrome is consistent, but symptoms are mild and self-limited.²³ Tapering off SSRIs before delivery currently is not recommended, as doing so increases the mother’s risk for postpartum depression and, according to one study, does not prevent symptoms of neonatal adaptation syndrome from developing.²⁴

Behavioral teratogenicity. What are the long-term developmental outcomes for the child? Are there any differences in IQ, speech and language, or psychiatric illness? One study found an increased risk of autism with in utero exposure to sertraline, but the study had many methodologic flaws and its findings have not been replicated.²⁵ Most studies have not found consistent differences in speech, IQ, or behavior between infants exposed and infants not exposed to antidepressants.^26,27 By contrast, in utero exposure to anticonvulsants, particularly valproate, has led to significant developmental problems in children.²⁸ The data on atypical antipsychotics are limited.

Related article:
Do antidepressants really cause autism?
 

None of the medications used to treat depression, bipolar disorder, anxiety, or schizophrenia is considered first-line or safest therapy for the pregnant woman. For any woman who is doing well on a certain medication, but particularly for a pregnant woman, there is no compelling, data-supported reason to switch to another agent. For depression, options include all of the SSRIs, with the possible exception of paroxetine (TABLE 2). In conflicting studies, paroxetine was no different from any other SSRI in not being associated with cardiovascular defects.²⁹

One goal in treatment is to use a medication that previously was effective in the remission of symptoms and to use it at the lowest dose possible. Treating simply to maintain a low dose of drug, however, and not to effect symptom remission, exposes the fetus to both the drug and the illness. Again, the lowest effective dose is the best choice.

Read about treatment during breastfeeding

Treatment during breastfeeding

Women are encouraged to breastfeed for physical and psychological health benefits, for both themselves and their babies. Many medications are compatible with breastfeeding.³⁰ The amount of drug an infant receives through breast milk is considerably less than the amount received during the mother’s pregnancy. Breastfeeding generally is allowed if the calculated infant dose is less than 10% of the weight-adjusted maternal dose.³¹

The amount of drug transferred from maternal plasma into milk is highest for drugs with low protein binding and high lipid solubility.³² Drug clearance in infants must be considered as well. Renal clearance is decreased in newborns and does not reach adult levels until 5 or 6 months of age. In addition, liver metabolism is impaired in neonates and even more so in premature infants.³³ Drugs that require extensive first-pass metabolism may have higher bioavailability, and this factor should be considered.

Some clinicians recommend pumping and discarding breast milk when the drug in it is at its peak level; although the drug is not eliminated, the infant ingests less of it.³⁴ Most women who are anxious about breastfeeding while on medication “pump and dump” until they are more comfortable nursing and the infants are doing well. Except in cases of mother preference, most physicians with expertise in reproductive mental health generally recommend against pumping and discarding milk.

Through breast milk, infants ingest drugs in varying amounts. The amount depends on the qualities of the medication, the timing and duration of breastfeeding, and the characteristics of the infant. Few psychotropic drugs have significant effects on breastfed infants. Even lithium, previously contraindicated, is successfully used, with infant monitoring, during breastfeeding.³⁵ Given breastfeeding’s benefits for both mother and child, many more women on psychotropic medications are choosing to breastfeed.

Related article:
USPSTF Recommendations to Support Breastfeeding

Balance the pros and cons

Deciding to use medication during pregnancy and breastfeeding involves considering the risk of untreated illness versus the benefit of treatment for both mother and fetus, and the risk of medication exposure for the fetus. Mother and fetus are inseparable, and neither can be isolated from the other in treatment decisions. Avoiding psychotropic medication during pregnancy is not always the safest option for mother or fetus. The patient and her clinician and support system must make an informed decision that is based on the best available data and that takes into account the mother’s history of illness and effective treatment. Many women with psychiatric illness no longer have to choose between mental health and starting a family, and their babies will be healthy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Increasingly, women with psychiatric illness are undergoing pharmacologic treatment during pregnancy. In the United States, an estimated 8% of pregnant women are prescribed antidepressants, and the number of such cases has risen over the past 15 years.¹ Women with a psychiatric diagnosis were once instructed either to discontinue all medication immediately on learning they were pregnant, or to forgo motherhood because their illness might have a negative effect on a child or because avoiding medication during pregnancy might lead to a relapse.

Fortunately, women with depression, anxiety, bipolar disorder, or schizophrenia no longer are being told that they cannot become mothers. For many women, however, stopping medication is not an option. Furthermore, psychiatric illness sometimes is diagnosed initially during pregnancy and requires treatment.

Illustration: Kimberly Martens for OBG Management

Pregnant women and their physicians need accurate information about when to taper off medication, when to start or continue, and which medications are safest. Even for clinicians with a solid knowledge base, counseling a woman who needs or may need psychotropic medication during pregnancy and breastfeeding is a daunting task. Some clinicians still recommend no drug treatment as the safest and best option, given the potential risks to the fetus.

In this review we offer a methodologic approach for decision making about pharmacologic treatment during pregnancy. As the scientific literature is constantly being updated, it is imperative to have the most current information on psychotropics and to know how to individualize that information when counseling a pregnant woman and her family. Using this framework for analyzing the risks and benefits for both mother and fetus, clinicians can avoid the unanswerable question of which medication is the “safest.”

A patient’s mental health care provider is a useful resource for information about a woman’s mental health history and current stability, but he or she may not be expert or comfortable in recommending treatment for a pregnant patient. During pregnancy, a woman’s obstetrician often becomes the “expert” for all treatment decisions.

Analyze risks and benefits of medication versus no medication

The US Food and Drug Administration (FDA) has not approved any psychotropic medication for use during pregnancy. While a clinical study would provide more scientifically rigorous safety data, conducting a double-blinded, placebo-controlled trial in pregnant women with a psychiatric disorder is unethical. Thus, the literature consists mostly of reports on case series, retrospective chart reviews, prospective naturalistic studies, and analyses of large registry databases. Each has benefits and limitations. It is important to understand the limitations when making treatment decisions.

In 1979, the FDA developed a 5-lettersystem (A, B, C, D, X) for classifying the relative safety of medications used during pregnancy.² Many clinicians and pregnant women relied on this system to decide which medications were safe. Unfortunately, the information in the system was inadequate for making informed decisions. For example, although a class B medication might have appeared safer than one in class C, the studies of risk in humans might not have been adequate to permit comparisons. Drug safety classifications were seldom changed, despite the availability of additional data.

In June 2015, the FDA changed the requirements for the Pregnancy and Lactation subsections of the labeling for human prescription drugs and biologic products. Drug manufacturers must now include in each subsection a risk summary, clinical considerations supporting patient care decisions and counseling, and detailed data. These subsections provide information on available human and animal studies, known or potential maternal or fetal adverse reactions, and dose adjustments needed during pregnancy and the postpartum period. In addition, the FDA added a subsection: Females and Males of Reproductive Potential.³

These changes acknowledge there is no list of “safe” medications. The safest medication generally is the one that works for a particular patient at the lowest effective dose. As each woman’s history of illness and effective treatment is different, the best medication may differ as well, even among women with the same illness. Therefore, medication should be individualized to the patient. A risk–benefit analysis comparing psychotropic medication treatment with no medication treatment must be performed for each patient according to her personal history and the best available data.

Read about the risks of untreated illness during pregnancy

What is the risk of untreated illness during pregnancy?

During pregnancy, women are treated for many medical disorders, including psychiatric illness. One general guideline is that, if a pregnant woman does not need a medication—whether it be for an allergy, hypertension, or another disorder—she should not take it. Conversely, if a medication is required for a patient’s well-being, her physician should continue it or switch to a safer one. This general guideline is the same for women with depression, anxiety, or a psychotic disorder.

Managing hypertension during pregnancy is an example of choosing treatment when the risk of the illness to the mother and the infant outweighs the likely small risk associated with taking a medication. Blood pressure is monitored, and, when it reaches a threshold, an antihypertensive is started promptly to avoid morbidity and mortality.

Psychiatric illness carries risks for both mother and fetus as well, but no data show a clear threshold for initiating pharmacologic treatment. Therefore, in prescribing medication the most important steps are to take a complete history and perform a thorough evaluation. Important information includes the number and severity of previous episodes, prior history of hospitalization or suicidal thoughts or attempts, and any history of psychotic or manic status.

Whether to continue or discontinue medication is often decided after inquiring about other times a medication was discontinued. A patient who in the past stayed well for several years after stopping a medication may be able to taper off a medication and conceive during a window of wellness. Some women who have experienced only one episode of illness and have been stable for at least a year may be able to taper off a medication before conceiving (TABLE 1).

In the risk–benefit analysis, assess the need for pharmacologic treatment by considering the risk that untreated illness poses for both mother and fetus, the benefits of treatment for both, and the risk of medication exposure for the fetus.⁴

Mother: Risk of untreated illness versus benefit of treatment

A complete history and a current symptom evaluation are needed to assess the risk that nonpharmacologic treatment poses for the mother. Women with functional impairment, including inability to work, to perform activities of daily living, or to take care of other children, likely require treatment. Studies have found that women who discontinue treatment for a psychiatric illness around the time of conception are likely to experience a recurrence of illness during pregnancy, often in the first trimester, and must restart medication.^5,6 For some diagnoses, particularly bipolar disorder, symptoms during a relapse can be more severe and more difficult to treat, and they carry a risk for both mother and fetus.⁷ A longitudinal study of pregnant women who stopped medication for bipolar disorder found a 71% rate of relapse.⁷ In cases in which there is a history of hospitalization, suicide attempt, or psychosis, discontinuing treatment is not an option; instead, the physician must determine which medication is safest for the particular patient.

Related article:
Does PTSD during pregnancy increase the likelihood of preterm birth?

Fetus: Risk of untreated illness versus benefit of treatment

Mothers with untreated psychiatric illness are at higher risk for poor prenatal care, substance abuse, and inadequate nutrition, all of which increase the risk of negative obstetric and neonatal outcomes.⁸ Evidence indicates that untreated maternal depression increases the risk of preterm delivery and low birth weight.⁹ Children born to mothers with depression have more behavioral problems, more psychiatric illness, more visits to pediatricians, lower IQ scores, and attachment issues.¹⁰ Some of the long-term negative effects of intrauterine stress, which include hypertension, coronary heart disease, and autoimmune disorders, persist into adulthood.¹¹

Fetus: Risk of medication exposure

With any pharmacologic treatment, the timing of fetal exposure affects resultant risks and therefore must be considered in the management plan.

Before conception. Is there any effect on ovulation or fertilization?

Implantation. Does the exposure impair the blastocyst’s ability to implant in the uterine lining?

First trimester. This is the period of organogenesis. Regardless of drug exposure, there is a 2% to 4% baseline risk of a major malformation during any pregnancy. The risk of a particular malformation must be weighed against this baseline risk.

According to limited data, selective serotonin reuptake inhibitors (SSRIs) may increase the risk of early miscarriage.¹² SSRIs also have been implicated in increasing the risk of cardiovascular malformations, although the data are conflicting.^13,14

Antiepileptics such as valproate and carbamazepine are used as mood stabilizers in the treatment of bipolar disorder.¹⁵ Extensive data have shown an association with teratogenicity. Pregnant women who require either of these medications also should be prescribed folic acid 4 or 5 mg/day. Given the high risk of birth defects and cognitive delay, valproate no longer is recommended for women of reproductive potential.¹⁶

Lithium, one of the safest medications used in the treatment of bipolar disorder, is associated with a very small risk of Ebstein anomaly.¹⁷

Lamotrigine is used to treat bipolar depression and appears to have a good safety profile, along with a possible small increased risk of oral clefts.^18,19

Atypical antipsychotics (such as aripiprazole, olanzapine, quetiapine, and risperidone) are often used first-line in the treatment of psychotic disorders and bipolar disorder in women who are not pregnant. Although the safety data on use of these drugs during pregnancy are limited, a recent analysis of pregnant Medicaid enrollees found no increased risk of birth defects after controlling for potential confounding factors.²⁰ Common practice is to avoid these newer agents, given their limited data and the time needed for rare malformations to emerge (adequate numbers require many exposures during pregnancy).

Read additional fetal risks of medication exposure

Second trimester. This is a period of growth and neural development. A 2006 study suggested that SSRI exposure after pregnancy week 20 increases the risk of persistent pulmonary hypertension of the newborn (PPHN).²¹ In 2011, however, the FDA removed the PPHN warning label for SSRIs, citing inconsistent data. Whether the PPHN risk is increased with SSRI use is unclear, but the risk is presumed to be smaller than previously suggested.²² Stopping SSRIs before week 20 puts the mother at risk for relapse during pregnancy and increases her risk of developing postpartum depression. If we follow the recommendation to prescribe medication only for women who need it most, then stopping the medication at any time during pregnancy is not an option.

Third trimester. This is a period of continued growth and lung maturation.

Delivery. Is there a potential for impairment in parturition?

Neonatal adaptation. Newborns are active mainly in adapting to extrauterine life: They regulate their temperature and muscle tone and learn to coordinate sucking, swallowing, and breathing. Does medication exposure impair adaptation, or are signs or symptoms of withdrawal or toxicity present? The evidence that in utero SSRI exposure increases the risk of neonatal adaptation syndrome is consistent, but symptoms are mild and self-limited.²³ Tapering off SSRIs before delivery currently is not recommended, as doing so increases the mother’s risk for postpartum depression and, according to one study, does not prevent symptoms of neonatal adaptation syndrome from developing.²⁴

Behavioral teratogenicity. What are the long-term developmental outcomes for the child? Are there any differences in IQ, speech and language, or psychiatric illness? One study found an increased risk of autism with in utero exposure to sertraline, but the study had many methodologic flaws and its findings have not been replicated.²⁵ Most studies have not found consistent differences in speech, IQ, or behavior between infants exposed and infants not exposed to antidepressants.^26,27 By contrast, in utero exposure to anticonvulsants, particularly valproate, has led to significant developmental problems in children.²⁸ The data on atypical antipsychotics are limited.

Related article:
Do antidepressants really cause autism?
 

None of the medications used to treat depression, bipolar disorder, anxiety, or schizophrenia is considered first-line or safest therapy for the pregnant woman. For any woman who is doing well on a certain medication, but particularly for a pregnant woman, there is no compelling, data-supported reason to switch to another agent. For depression, options include all of the SSRIs, with the possible exception of paroxetine (TABLE 2). In conflicting studies, paroxetine was no different from any other SSRI in not being associated with cardiovascular defects.²⁹

One goal in treatment is to use a medication that previously was effective in the remission of symptoms and to use it at the lowest dose possible. Treating simply to maintain a low dose of drug, however, and not to effect symptom remission, exposes the fetus to both the drug and the illness. Again, the lowest effective dose is the best choice.

Read about treatment during breastfeeding

Treatment during breastfeeding

Women are encouraged to breastfeed for physical and psychological health benefits, for both themselves and their babies. Many medications are compatible with breastfeeding.³⁰ The amount of drug an infant receives through breast milk is considerably less than the amount received during the mother’s pregnancy. Breastfeeding generally is allowed if the calculated infant dose is less than 10% of the weight-adjusted maternal dose.³¹

The amount of drug transferred from maternal plasma into milk is highest for drugs with low protein binding and high lipid solubility.³² Drug clearance in infants must be considered as well. Renal clearance is decreased in newborns and does not reach adult levels until 5 or 6 months of age. In addition, liver metabolism is impaired in neonates and even more so in premature infants.³³ Drugs that require extensive first-pass metabolism may have higher bioavailability, and this factor should be considered.

Some clinicians recommend pumping and discarding breast milk when the drug in it is at its peak level; although the drug is not eliminated, the infant ingests less of it.³⁴ Most women who are anxious about breastfeeding while on medication “pump and dump” until they are more comfortable nursing and the infants are doing well. Except in cases of mother preference, most physicians with expertise in reproductive mental health generally recommend against pumping and discarding milk.

Through breast milk, infants ingest drugs in varying amounts. The amount depends on the qualities of the medication, the timing and duration of breastfeeding, and the characteristics of the infant. Few psychotropic drugs have significant effects on breastfed infants. Even lithium, previously contraindicated, is successfully used, with infant monitoring, during breastfeeding.³⁵ Given breastfeeding’s benefits for both mother and child, many more women on psychotropic medications are choosing to breastfeed.

Related article:
USPSTF Recommendations to Support Breastfeeding

Balance the pros and cons

Deciding to use medication during pregnancy and breastfeeding involves considering the risk of untreated illness versus the benefit of treatment for both mother and fetus, and the risk of medication exposure for the fetus. Mother and fetus are inseparable, and neither can be isolated from the other in treatment decisions. Avoiding psychotropic medication during pregnancy is not always the safest option for mother or fetus. The patient and her clinician and support system must make an informed decision that is based on the best available data and that takes into account the mother’s history of illness and effective treatment. Many women with psychiatric illness no longer have to choose between mental health and starting a family, and their babies will be healthy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Increasingly, women with psychiatric illness are undergoing pharmacologic treatment during pregnancy. In the United States, an estimated 8% of pregnant women are prescribed antidepressants, and the number of such cases has risen over the past 15 years.¹ Women with a psychiatric diagnosis were once instructed either to discontinue all medication immediately on learning they were pregnant, or to forgo motherhood because their illness might have a negative effect on a child or because avoiding medication during pregnancy might lead to a relapse.

Fortunately, women with depression, anxiety, bipolar disorder, or schizophrenia no longer are being told that they cannot become mothers. For many women, however, stopping medication is not an option. Furthermore, psychiatric illness sometimes is diagnosed initially during pregnancy and requires treatment.

Illustration: Kimberly Martens for OBG Management

Pregnant women and their physicians need accurate information about when to taper off medication, when to start or continue, and which medications are safest. Even for clinicians with a solid knowledge base, counseling a woman who needs or may need psychotropic medication during pregnancy and breastfeeding is a daunting task. Some clinicians still recommend no drug treatment as the safest and best option, given the potential risks to the fetus.

In this review we offer a methodologic approach for decision making about pharmacologic treatment during pregnancy. As the scientific literature is constantly being updated, it is imperative to have the most current information on psychotropics and to know how to individualize that information when counseling a pregnant woman and her family. Using this framework for analyzing the risks and benefits for both mother and fetus, clinicians can avoid the unanswerable question of which medication is the “safest.”

A patient’s mental health care provider is a useful resource for information about a woman’s mental health history and current stability, but he or she may not be expert or comfortable in recommending treatment for a pregnant patient. During pregnancy, a woman’s obstetrician often becomes the “expert” for all treatment decisions.

Analyze risks and benefits of medication versus no medication

The US Food and Drug Administration (FDA) has not approved any psychotropic medication for use during pregnancy. While a clinical study would provide more scientifically rigorous safety data, conducting a double-blinded, placebo-controlled trial in pregnant women with a psychiatric disorder is unethical. Thus, the literature consists mostly of reports on case series, retrospective chart reviews, prospective naturalistic studies, and analyses of large registry databases. Each has benefits and limitations. It is important to understand the limitations when making treatment decisions.

In 1979, the FDA developed a 5-lettersystem (A, B, C, D, X) for classifying the relative safety of medications used during pregnancy.² Many clinicians and pregnant women relied on this system to decide which medications were safe. Unfortunately, the information in the system was inadequate for making informed decisions. For example, although a class B medication might have appeared safer than one in class C, the studies of risk in humans might not have been adequate to permit comparisons. Drug safety classifications were seldom changed, despite the availability of additional data.

In June 2015, the FDA changed the requirements for the Pregnancy and Lactation subsections of the labeling for human prescription drugs and biologic products. Drug manufacturers must now include in each subsection a risk summary, clinical considerations supporting patient care decisions and counseling, and detailed data. These subsections provide information on available human and animal studies, known or potential maternal or fetal adverse reactions, and dose adjustments needed during pregnancy and the postpartum period. In addition, the FDA added a subsection: Females and Males of Reproductive Potential.³

These changes acknowledge there is no list of “safe” medications. The safest medication generally is the one that works for a particular patient at the lowest effective dose. As each woman’s history of illness and effective treatment is different, the best medication may differ as well, even among women with the same illness. Therefore, medication should be individualized to the patient. A risk–benefit analysis comparing psychotropic medication treatment with no medication treatment must be performed for each patient according to her personal history and the best available data.

Read about the risks of untreated illness during pregnancy

What is the risk of untreated illness during pregnancy?

During pregnancy, women are treated for many medical disorders, including psychiatric illness. One general guideline is that, if a pregnant woman does not need a medication—whether it be for an allergy, hypertension, or another disorder—she should not take it. Conversely, if a medication is required for a patient’s well-being, her physician should continue it or switch to a safer one. This general guideline is the same for women with depression, anxiety, or a psychotic disorder.

Managing hypertension during pregnancy is an example of choosing treatment when the risk of the illness to the mother and the infant outweighs the likely small risk associated with taking a medication. Blood pressure is monitored, and, when it reaches a threshold, an antihypertensive is started promptly to avoid morbidity and mortality.

Psychiatric illness carries risks for both mother and fetus as well, but no data show a clear threshold for initiating pharmacologic treatment. Therefore, in prescribing medication the most important steps are to take a complete history and perform a thorough evaluation. Important information includes the number and severity of previous episodes, prior history of hospitalization or suicidal thoughts or attempts, and any history of psychotic or manic status.

Whether to continue or discontinue medication is often decided after inquiring about other times a medication was discontinued. A patient who in the past stayed well for several years after stopping a medication may be able to taper off a medication and conceive during a window of wellness. Some women who have experienced only one episode of illness and have been stable for at least a year may be able to taper off a medication before conceiving (TABLE 1).

In the risk–benefit analysis, assess the need for pharmacologic treatment by considering the risk that untreated illness poses for both mother and fetus, the benefits of treatment for both, and the risk of medication exposure for the fetus.⁴

Mother: Risk of untreated illness versus benefit of treatment

A complete history and a current symptom evaluation are needed to assess the risk that nonpharmacologic treatment poses for the mother. Women with functional impairment, including inability to work, to perform activities of daily living, or to take care of other children, likely require treatment. Studies have found that women who discontinue treatment for a psychiatric illness around the time of conception are likely to experience a recurrence of illness during pregnancy, often in the first trimester, and must restart medication.^5,6 For some diagnoses, particularly bipolar disorder, symptoms during a relapse can be more severe and more difficult to treat, and they carry a risk for both mother and fetus.⁷ A longitudinal study of pregnant women who stopped medication for bipolar disorder found a 71% rate of relapse.⁷ In cases in which there is a history of hospitalization, suicide attempt, or psychosis, discontinuing treatment is not an option; instead, the physician must determine which medication is safest for the particular patient.

Related article:
Does PTSD during pregnancy increase the likelihood of preterm birth?

Fetus: Risk of untreated illness versus benefit of treatment

Mothers with untreated psychiatric illness are at higher risk for poor prenatal care, substance abuse, and inadequate nutrition, all of which increase the risk of negative obstetric and neonatal outcomes.⁸ Evidence indicates that untreated maternal depression increases the risk of preterm delivery and low birth weight.⁹ Children born to mothers with depression have more behavioral problems, more psychiatric illness, more visits to pediatricians, lower IQ scores, and attachment issues.¹⁰ Some of the long-term negative effects of intrauterine stress, which include hypertension, coronary heart disease, and autoimmune disorders, persist into adulthood.¹¹

Fetus: Risk of medication exposure

With any pharmacologic treatment, the timing of fetal exposure affects resultant risks and therefore must be considered in the management plan.

Before conception. Is there any effect on ovulation or fertilization?

Implantation. Does the exposure impair the blastocyst’s ability to implant in the uterine lining?

First trimester. This is the period of organogenesis. Regardless of drug exposure, there is a 2% to 4% baseline risk of a major malformation during any pregnancy. The risk of a particular malformation must be weighed against this baseline risk.

According to limited data, selective serotonin reuptake inhibitors (SSRIs) may increase the risk of early miscarriage.¹² SSRIs also have been implicated in increasing the risk of cardiovascular malformations, although the data are conflicting.^13,14

Antiepileptics such as valproate and carbamazepine are used as mood stabilizers in the treatment of bipolar disorder.¹⁵ Extensive data have shown an association with teratogenicity. Pregnant women who require either of these medications also should be prescribed folic acid 4 or 5 mg/day. Given the high risk of birth defects and cognitive delay, valproate no longer is recommended for women of reproductive potential.¹⁶

Lithium, one of the safest medications used in the treatment of bipolar disorder, is associated with a very small risk of Ebstein anomaly.¹⁷

Lamotrigine is used to treat bipolar depression and appears to have a good safety profile, along with a possible small increased risk of oral clefts.^18,19

Atypical antipsychotics (such as aripiprazole, olanzapine, quetiapine, and risperidone) are often used first-line in the treatment of psychotic disorders and bipolar disorder in women who are not pregnant. Although the safety data on use of these drugs during pregnancy are limited, a recent analysis of pregnant Medicaid enrollees found no increased risk of birth defects after controlling for potential confounding factors.²⁰ Common practice is to avoid these newer agents, given their limited data and the time needed for rare malformations to emerge (adequate numbers require many exposures during pregnancy).

Read additional fetal risks of medication exposure

Second trimester. This is a period of growth and neural development. A 2006 study suggested that SSRI exposure after pregnancy week 20 increases the risk of persistent pulmonary hypertension of the newborn (PPHN).²¹ In 2011, however, the FDA removed the PPHN warning label for SSRIs, citing inconsistent data. Whether the PPHN risk is increased with SSRI use is unclear, but the risk is presumed to be smaller than previously suggested.²² Stopping SSRIs before week 20 puts the mother at risk for relapse during pregnancy and increases her risk of developing postpartum depression. If we follow the recommendation to prescribe medication only for women who need it most, then stopping the medication at any time during pregnancy is not an option.

Third trimester. This is a period of continued growth and lung maturation.

Delivery. Is there a potential for impairment in parturition?

Neonatal adaptation. Newborns are active mainly in adapting to extrauterine life: They regulate their temperature and muscle tone and learn to coordinate sucking, swallowing, and breathing. Does medication exposure impair adaptation, or are signs or symptoms of withdrawal or toxicity present? The evidence that in utero SSRI exposure increases the risk of neonatal adaptation syndrome is consistent, but symptoms are mild and self-limited.²³ Tapering off SSRIs before delivery currently is not recommended, as doing so increases the mother’s risk for postpartum depression and, according to one study, does not prevent symptoms of neonatal adaptation syndrome from developing.²⁴

Behavioral teratogenicity. What are the long-term developmental outcomes for the child? Are there any differences in IQ, speech and language, or psychiatric illness? One study found an increased risk of autism with in utero exposure to sertraline, but the study had many methodologic flaws and its findings have not been replicated.²⁵ Most studies have not found consistent differences in speech, IQ, or behavior between infants exposed and infants not exposed to antidepressants.^26,27 By contrast, in utero exposure to anticonvulsants, particularly valproate, has led to significant developmental problems in children.²⁸ The data on atypical antipsychotics are limited.

Related article:
Do antidepressants really cause autism?
 

None of the medications used to treat depression, bipolar disorder, anxiety, or schizophrenia is considered first-line or safest therapy for the pregnant woman. For any woman who is doing well on a certain medication, but particularly for a pregnant woman, there is no compelling, data-supported reason to switch to another agent. For depression, options include all of the SSRIs, with the possible exception of paroxetine (TABLE 2). In conflicting studies, paroxetine was no different from any other SSRI in not being associated with cardiovascular defects.²⁹

One goal in treatment is to use a medication that previously was effective in the remission of symptoms and to use it at the lowest dose possible. Treating simply to maintain a low dose of drug, however, and not to effect symptom remission, exposes the fetus to both the drug and the illness. Again, the lowest effective dose is the best choice.

Read about treatment during breastfeeding

Treatment during breastfeeding

Women are encouraged to breastfeed for physical and psychological health benefits, for both themselves and their babies. Many medications are compatible with breastfeeding.³⁰ The amount of drug an infant receives through breast milk is considerably less than the amount received during the mother’s pregnancy. Breastfeeding generally is allowed if the calculated infant dose is less than 10% of the weight-adjusted maternal dose.³¹

The amount of drug transferred from maternal plasma into milk is highest for drugs with low protein binding and high lipid solubility.³² Drug clearance in infants must be considered as well. Renal clearance is decreased in newborns and does not reach adult levels until 5 or 6 months of age. In addition, liver metabolism is impaired in neonates and even more so in premature infants.³³ Drugs that require extensive first-pass metabolism may have higher bioavailability, and this factor should be considered.

Some clinicians recommend pumping and discarding breast milk when the drug in it is at its peak level; although the drug is not eliminated, the infant ingests less of it.³⁴ Most women who are anxious about breastfeeding while on medication “pump and dump” until they are more comfortable nursing and the infants are doing well. Except in cases of mother preference, most physicians with expertise in reproductive mental health generally recommend against pumping and discarding milk.

Through breast milk, infants ingest drugs in varying amounts. The amount depends on the qualities of the medication, the timing and duration of breastfeeding, and the characteristics of the infant. Few psychotropic drugs have significant effects on breastfed infants. Even lithium, previously contraindicated, is successfully used, with infant monitoring, during breastfeeding.³⁵ Given breastfeeding’s benefits for both mother and child, many more women on psychotropic medications are choosing to breastfeed.

Related article:
USPSTF Recommendations to Support Breastfeeding

Balance the pros and cons

Deciding to use medication during pregnancy and breastfeeding involves considering the risk of untreated illness versus the benefit of treatment for both mother and fetus, and the risk of medication exposure for the fetus. Mother and fetus are inseparable, and neither can be isolated from the other in treatment decisions. Avoiding psychotropic medication during pregnancy is not always the safest option for mother or fetus. The patient and her clinician and support system must make an informed decision that is based on the best available data and that takes into account the mother’s history of illness and effective treatment. Many women with psychiatric illness no longer have to choose between mental health and starting a family, and their babies will be healthy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Title: Short periods of concurrent benzodiazepine and opioid use increase overdose risk

Clinical Question: What is the impact of concurrent benzodiazepine use in chronic versus intermittent opioid use on risk for opioid overdose?

Dr. Barrett is assistant professor in the division of hospital medicine at the University of New Mexico.

Title: Short periods of concurrent benzodiazepine and opioid use increase overdose risk

Clinical Question: What is the impact of concurrent benzodiazepine use in chronic versus intermittent opioid use on risk for opioid overdose?

Dr. Barrett is assistant professor in the division of hospital medicine at the University of New Mexico.

Title: Short periods of concurrent benzodiazepine and opioid use increase overdose risk

Clinical Question: What is the impact of concurrent benzodiazepine use in chronic versus intermittent opioid use on risk for opioid overdose?

Dr. Barrett is assistant professor in the division of hospital medicine at the University of New Mexico.