Background
Antenatal corticosteroid administration is a critical fetal intervention, and the use of a rescue protocol is now standard practice. Rescue antenatal corticosteroid may improve overall accuracy of antenatal corticosteroid administration timing, but this observation and its effect on the initial course is unknown.
Objective
We sought to compare the accuracy of antenatal corticosteroid administration before and after the implementation of a rescue antenatal corticosteroid protocol.
Study Design
We performed a retrospective cohort study of patients who received a minimum of 1 dose of antenatal corticosteroid from 2006-2012 at the University of Washington Medical Center with the use of the University of Washington Medical Center Pharmacy Database. For inclusion, subjects were required to be admitted, receive the initial antenatal corticosteroid course at 24-34 weeks gestation, and deliver at University of Washington Medical Center. We designated 2 groups that were based on when rescue antenatal corticosteroid became standard practice at University of Washington Medical Center: before rescue antenatal corticosteroid (2006-2008) and after rescue antenatal corticosteroid (2009-2012). Primary outcome was delivery within any optimal antenatal corticosteroid window, which was defined as 48 hours to 7 days after the first dose or third dose. We also compared delivery within the optimal window of the initial and rescue antenatal corticosteroid courses independently and assessed antenatal corticosteroid timing by the indication for delivery. Chi squared and independent sample t -tests were used to compare results.
Results
From 2006-2012, 1356 women met inclusion criteria, 601 before and 755 after rescue antenatal corticosteroid. The study groups demonstrated similar demographics, with the exception of more white women in the group after rescue antenatal corticosteroid (47% vs 60%; P < .01) and delivered at comparable gestational ages (32.7 vs 32.6 weeks; P = .59). Availability of a second course did not increase total subjects who delivered within any optimal window (26.5% vs 28.5%; P = .41). Frequency of delivery within the initial course optimal window did not change after the introduction of the rescue course protocol (26.1% vs 26.4%; P = .92). Similarly, of the 73 subjects who received rescue antenatal corticosteroid, 24.7% delivered in the optimal window of the second course. Delivery within the optimal window varied by indication for antenatal corticosteroid, with highest accuracy among maternal indications (41.2% in any optimal window), followed by preterm premature rupture of membranes (32.1%). Lowest administration accuracy was among women with antenatal cervical shortening and advanced cervical dilation; only 2.8% and 6.3% delivered within the optimal window, respectively. Furthermore, for women with antenatal cervical shortening, the mean gestational age of delivery was 35.1 weeks, and the median interval from antenatal corticosteroid administration to delivery was 55 days (interquartile range, 34–72 days).
Conclusions
The opportunity for a second course of antenatal corticosteroid did not improve the number of women who delivered within any optimal antenatal corticosteroid window. Administration timing was similar for the initial course and the rescue course, with approximately one-quarter of women delivering within the optimal antenatal corticosteroid window. These findings likely reflect the few circumstances in which rescue antenatal corticosteroid is useful and the poor predictability of preterm birth. Future focus should be aimed at tools to predict the timing of preterm birth to optimize antenatal corticosteroid administration.
Antenatal corticosteroids (ACS) are an important intervention used to improve neonatal outcomes after preterm birth. Since the landmark study by Liggins and Howie in 1972, several studies have confirmed that treatment with ACS is associated with an overall reduction in neonatal death, respiratory distress syndrome, and intensive care admissions. ACS offer the greatest benefit to the fetus if the infant is delivered 24-48 hours after the initial dose and within 7 days of the administration. Benefits decrease after this optimal window. However, prediction of preterm birth is challenging, especially within a narrow timeframe. Although 1 strategy to improve the timing of the administration is to provide repeated courses of ACS, studies demonstrate that multiple courses carry fetal risks. More recent research demonstrates that a single rescue course of ACS may also improve neonatal outcomes, when delivered within the optimal window. In 2011 and 2012, the American College of Obstetricians and Gynecologists endorsed the administration of a single course of rescue steroids for women who remain at risk for preterm delivery, commonly known as the rescue protocol.
Studies demonstrate that most women who receive an initial dose of ACS deliver at <34 weeks gestation, but the accuracy of administration within the optimal window is low and varies by indication for delivery. The accuracy of rescue ACS administration remains unknown. Recently, studies that have demonstrated combined increased use and inaccurate timing of ACS have raised concern for long-term harmful effects on infants who are born outside of the optimal window. Furthermore, few data report on the long-term harm of a single rescue course of ACS. For these reasons, ensuring that the availability of rescue course ACS increases the number of women who receive ACS within any optimal window remains a priority. Our objective was to compare the accuracy of ACS administration before and after the availability of a rescue course protocol and to determine whether rescue ACS increase the proportion of women who deliver within any optimal ACS window.
Materials and Methods
We conducted a retrospective cohort study of women who had received ACS, comparing the proportion of patients who delivered in the optimal window of the initial ACS course before and after the availability of rescue ACS. We identified subjects using the inpatient hospital pharmacy database, capturing all women who were admitted to the labor and delivery unit. Women were included if they received at least 1 dose of ACS between January 2006 and December 2012 at the University of Washington Medical Center, a level 3-referral hospital. Data were then linked to the University of Washington Perinatal Database for additional demographic data. A single primary researcher then performed a review of each chart to confirm and obtain additional data. The Human Subjects Division at the University of Washington approved this study.
The cohort included women who were admitted to labor and delivery and received at least 1 dose of betamethasone 12 mg intramuscularly, which is the ACS used almost exclusively at our and referring institutions. Patients were excluded if they received betamethasone at <24 0/7 weeks gestation or >33 6/7 weeks gestation, if they delivered at an outside institution, or if we could not confirm the administration of ACS by chart review. Some women received their first dose of ACS before transfer to our institution; they were included if ACS administration was confirmed.
Two groups were identified according to the year of initial ACS course administration. In 2009, the Maternal Fetal Medicine group at the University of Washington Medical Center developed a consensus policy that supported the use of a single rescue course of ACS. The first group received the initial ACS course between 2006 and 2008, which was before the implementation of our rescue steroid protocol; the second group received an initial ACS course between 2009 and 2012, which was after widespread use of the rescue course protocol.
We compared maternal, pregnancy, and delivery characteristics between the groups before and after the availability of rescue steroids. The potential indications for the administration of ACS were categorized as preterm labor, preterm premature rupture of membranes, antenatal cervical shortening, advanced cervical dilation, vaginal bleeding, maternal factors, and fetal factors. Preterm labor was defined as regular, painful contractions with cervical change. Antenatal cervical shortening was used to describe women who were asymptomatic but found to have a cervical length of <2 cm on transvaginal ultrasound scans. Many of these women had additional risk factors for preterm birth. Advanced cervical dilation was defined as dilation of >2 cm, and patients were given this diagnosis only if they did not meet criteria for preterm labor. If patients had >1 indication, the investigator assigned a primary indication. We compared the proportion of patients who had delivered within the optimal window before and after the availability of a rescue course protocol.
The primary outcome was delivery within the optimal window of either the initial ACS course or the rescue ACS course. The optimal window for ACS administration is defined as delivery between 48 hours and 7 days after the first dose for the initial course and between 48 hours and 7 days after the third dose for the rescue course. Although data suggest that steroid benefit can occur after 24 hours from the first dose, our institution routinely considers maximum benefit at 48 hours and uses this time point in clinical decision-making and delivery planning. The secondary outcomes included delivery within an optimal window of the rescue course and delivery within the optimal window of the initial ACS course. Additionally, we assessed delivery timing and delivery characteristics by indication for administration.
Sample size was determined by the availability of subjects who received ACS within the study time period. With our sample size of 1356 women, the assumption was that 30% of the women received ACS within the optimal window (α =.05; power of 80%; the minimal effect size detectable is 7%). Statistical analysis was completed using STATA software (version 11.1; Stata Corporation, College Station, TX). Pearson chi-squared tests were used to compare categoric variables, and independent sample t -tests were used to compare continuous variables. For all analyses, a 2-sided significance level of < .05 was considered statistically significant.
Results
We identified 1809 pregnant women for whom a pharmacy order was placed for betamethasone within the study period. After exclusions for not receiving ACS, delivering at an outside hospital, or gestational age, the final study population was 1356 subjects ( Figure 1 ). Of the total cohort, 601 women received ACS from 2006-2008 before availability of rescue protocol, and 755 women received ACS from 2009-2012 after availability of rescue protocol. Of note, similar proportions of patients were excluded from each group because of delivery at an outside institution (20.2% before rescue ACS vs 18% after rescue ACS; P = .24). However, women who were included in the study were on average 1.7 years older than those excluded for outside hospital delivery ( P < .01). Additional demographic data on the excluded group were not accessible.
Table 1 gives the maternal characteristics of our population. Study groups were similar, with the exception of racial distribution. There was a high representation of multiple gestations, transfer to higher level of care, hypertension, diabetes mellitus, and other medical comorbidities in our study group. As anticipated, there was a high proportion of preterm deliveries. The study groups delivered at similar gestational ages, with approximately 62% of the population delivering at <34 weeks gestation.
| Maternal characteristics | Group 1: before rescue availability (n = 601), n (%) | Group 2: after rescue availability (n = 755), n (%) | P value |
|---|---|---|---|
| Maternal age, y | .97 | ||
| <20 | 48 (8) | 56 (7.4) | |
| 20-34 | 418 (69.5) | 528 (70.0) | |
| ≥35 | 135 (22.5) | 171 (22.6) | |
| Race | < .01 | ||
| Black | 75 (12.5) | 100 (13.2) | |
| White | 283 (47.1) | 453 (60.0) | |
| Asian | 17 (2.8) | 17 (2.3) | |
| Hispanic | 73 (12.2) | 90 (119) | |
| Native American | 8 (1.3) | 11 (1.5) | |
| Pacific Islander | 29 (19.3) | 40 (5.8) | |
| Other | 116 (4.8) | 44 (5.3) | |
| Previous preterm delivery a | 112 (18.6) | 145 (19.2) | .74 |
| Previous cesarean delivery | 105 (17.5) | 124 (16.9) | .61 |
| Multiple gestation | 88 (14.6) | 110 (14.6) | .97 |
| Transfer from referral center | 134 (22.3) | 200 (26.5) | .07 |
| Hypertension | 93 (15.5) | 123 (16.3) | .68 |
| Diabetes mellitus | 57 (9.5) | 66 (8.7) | .64 |
| Other major medical comorbidity b | 34 (5.6) | 50 (6.6) | .46 |
| Delivery at <34 weeks gestation | 367 (62.1) | 464 (62.9) | .10 |
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