First introduced by Liggins and Howie in 1972,1 and subsequently endorsed by the National Institutes of Health Consensus Development Conference,2 the administration of single-course antenatal corticosteroids to women at risk of preterm delivery has been shown to significantly reduce the risk of respiratory distress syndrome, intraventicular hemorrhage, necrotizing enterocolitis, infectious morbidity, need for respiratory support, neonatal intensive care unit admission, and perinatal mortality.3,4 The efficacy of such antenatal corticosteroid prophylaxis is optimal when neonates born preterm at 24–34 weeks of gestation have received a single course of corticosteroids administered 24 hours to 7 days before delivery.2–4 However, appropriate administration of antenatal corticosteroid prophylaxis is challenging, because approximately half the women who present with symptoms of preterm labor remain undelivered for weeks afterward.5–7 Nevertheless, overuse of a single course of antenatal corticosteroid prophylaxis was not a consideration in obstetric practice until recently because the efficacy of antenatal corticosteroid prophylaxis was believed to be matched with an excellent safety profile. Although follow-up studies that have tracked patients for 30 years after the original randomized trials showed no evidence of adverse cognitive, motor, or other somatic effects,8–11 the understanding that antenatal corticosteroid prophylaxis provides a useful combination of efficacious treatment and excellent safety has been contested by recent reports.
Exposure to multiple courses of corticosteroids is associated with decreased weight, length, and head circumference at birth and an increased risk of death or disability at 5 years of age.12,13 Furthermore, animal and human studies show that any prenatal exposure to corticosteroids among neonates born at term gestation is associated with a reduction in fetal size, increased and prolonged dysregulation of the hypothalamus–pituitary–adrenal axis, and changes in DNA methylation.14–17 Nevertheless, few attempts have been made to quantify population patterns of appropriate and inappropriate antenatal corticosteroid administration. We, therefore, carried out a population-based study to examine rates and temporal trends in optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroids (betamethasone or dexamethasone) for fetal benefit in a Canadian setting.
MATERIALS AND METHODS
All live births in Nova Scotia, Canada, from 1988 to 2012 were identified from the Nova Scotia Atlee Perinatal Database. This population-based, clinically focused database includes information on maternal characteristics and prenatal, labor, delivery, and neonatal events for all hospital births in Nova Scotia with a birth weight of at least 500 g or a gestational age of 20 weeks or more. Information in the database was collected from antenatal and medical charts by trained personnel using standardized data collection forms, and validation studies show that the information in the database is accurate.18
Information on receipt of antenatal corticosteroids in our data source included the timing of the first dose administered in relation to delivery and this enabled us to estimate whether a partial (one dose) or complete course (two doses) of antenatal corticosteroid was administered. We categorized receipt of antenatal corticosteroid as follows: 1) any administration of antenatal corticosteroid in the period before delivery, 2) optimal antenatal corticosteroid administration (between 24 hours and 7 days before delivery to women who delivered liveborn neonates between 24 and 34 weeks of gestation), 3) suboptimal antenatal corticosteroid administration (less than 24 hours or more than 7 days before delivery to women who delivered liveborn neonates between 24 and 34 weeks of gestation), and 4) questionably appropriate antenatal corticosteroid administration (administration to women who delivered liveborn neonates at 35 weeks of gestation or greater).2–4 Antenatal length of hospital stay was defined as the time interval between admission and delivery (in hours). Data on gestational age were based on an algorithm that combined information from the last menstrual period date, early ultrasonography (if available), and pediatric estimate. Validation studies show that this gestational age information is accurate.19
We estimated the frequency of antenatal corticosteroid administration within categories of maternal and clinical characteristics using rates, rate ratios, and 95% confidence intervals (CIs). The timespan of the study was divided into five periods (5-year intervals from 1988 to 2012) with the earliest period used as the reference, although rates were also examined by year where possible. The frequency of antenatal corticosteroid administration within specific categories of gestational age (less than 24, 24–27, 28–32, 33–34, 35–36, 37 weeks of gestation or greater) was assessed by calculating rates per 100 live births within each gestational age category. Odds ratios (ORs) were used instead of rate ratios to quantify temporal changes in receipt of antenatal corticosteroids by gestational age. Odds ratios were considered preferable in this situation because antenatal corticosteroid rates varied markedly according to gestational age and ORs (as opposed to rate ratios) are not susceptible to arbitrary effect modification given high rates.20 The frequency of antenatal corticosteroid prophylaxis was also assessed within categories of antenatal length of hospital stay and gestational age.
Temporal trends were first assessed by plotting the frequency of optimal, suboptimal, and questionably appropriate antenatal corticosteroid administration using 3-year moving averages over the 25 years of the study. The rate denominators for optimal and suboptimal administration were the total number of live births between 24 and 34 weeks of gestation. The denominator for questionably appropriate administration rates was the total number of live births at 35 weeks of gestation or greater. The linear pattern in annual rates was assessed using the Cochrane Armitage χ2 test for linear trend and also visually to identify inflections when the slope of the line changed. Statistical significance of differences was based on two-sided P values; P<.05 was considered statistically significant. Analyses were performed using SAS 9.2 andEpi Info software. This study received ethics approval from the IWK Health Centre.
Among 246,459 live births in Nova Scotia between 1988 and 2012, 2.5% received any antenatal corticosteroid prophylaxis. The rate of antenatal corticosteroid administration among all live births was 3.2% in the most recent period between 2008 and 2012. Administration of antenatal corticosteroids was significantly higher among teenage and older (35 years or older) mothers, current smokers, and women with a prepregnancy weight 70 kg or greater and varied by other maternal and obstetric characteristics as well (Table 1).
Rates of antenatal corticosteroid administration increased significantly between 1988–1992 and 2008–2012 among women delivering in each gestational age category except for those less than 24 weeks of gestation (Table 2). For instance, the rate of antenatal corticosteroid administration for women delivering at 28–32 weeks of gestation increased substantially from 39.5% in 1988–1992 to 79.3% in 2008–2012 (OR 5.8, 95% CI 4.3–7.9; Table 2); among live births at 33–34 weeks of gestation, receipt of antenatal corticosteroids increased significantly from 14.3% in 1988–1992 to 49.7% in 2008–2012 (OR 5.6, 95% CI 4.3–7.4; Table 2). Figure 1 shows temporal patterns in antenatal corticosteroid administration by 5-year period; increases between the two most recent periods were not significant in the 28–32 week gestational age category (78% in 2003–2007 to 79% in 2008–2012; OR 1.1, 95% CI 0.8–1.5), but more substantial changes were observed in the 33–34 week gestational age category (from 41.2% in 2003–2007 to 49.9% in 2008–2012; OR 1.4, 95% CI 1.1–1.8).
The rates of antenatal corticosteroid administration by antenatal length of hospital stay are shown in Table 3 for live births delivered at 28–32 weeks of gestation and 33–34 weeks of gestation. Rates of antenatal corticosteroid administration were highest among women whose antenatal length of stay was 72 hours or greater (94.5% at 28–32 weeks of gestation and 81.3% at 33–34 weeks of gestation in 2008–2012) although temporal increases in antenatal corticosteroid rates occurred among women with both shorter and longer lengths of stay (Table 3).
Temporal trends in the frequency of optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroids between 1988 and 2012 are displayed in Figure 2A. Rates of optimal antenatal corticosteroid administration increased from 10% in 1988 to 23% in 2012 (OR 2012 compared with 1988 2.7, 95% CI 1.6–4.5; P for linear trend <.001). Optimal antenatal corticosteroid administration rates were higher in women who had medically indicated preterm delivery (28.9%) than among those who had a spontaneous preterm delivery (17.1%) in 2008–2012. Rates of suboptimal administration of antenatal corticosteroids increased from 7% in 1988 to 34% in 2012 (OR 2012 compared with 1988 6.7, 95% CI 3.9–11.6; P for linear trend <.001). Figure 2B also shows temporal trends in the two subtypes of suboptimal antenatal corticosteroid administration; antenatal corticosteroid administration less than 24 hours before delivery increased steadily from 3% in 1988 to 22% in 2009 and then declined, whereas receipt of antenatal corticosteroids more than 7 days before delivery increased between 4% in 1988 to 18% in 1999 and plateaued between 27% in 2000 and 24% in 2006 followed by a small decline. The rate of questionably appropriate administration of antenatal corticosteroids also increased from 0.2% in 1988 to 1.7% in 2012 (OR 2012 compared with 1988 7.5, 95% CI 4.9–11.3; P for linear trend <.001). More than half of the neonates (52%) whose mothers received antenatal corticosteroids were born at 35 weeks of gestation or greater, a significant increase from 37% in 1988 (OR 2012 compared with 1988 1.8, 95% CI 1.1–3.1).
Our population-based study demonstrated a substantial temporal rise in the rates of antenatal corticosteroid administration over the past two decades. Approximately 80% of live births delivered between 28 and 32 weeks of gestation in 2008–2012 received at least a single dose of antenatal corticosteroid prophylaxis. Our study also showed a relative underutilization of antenatal corticosteroid prophylaxis among live births delivered at 33–34 weeks of gestation. Despite well-established guidelines for the administration of antenatal corticosteroids to women at risk of preterm delivery from 24 to 34 weeks of gestation,2–4,21 only 50% of live births at 33–34 weeks of gestation were exposed to antenatal corticosteroids. Specific maternal and obstetric characteristics such as preexisting and gestational diabetes, hypertension, cesarean delivery, obesity, multiple gestation, threatened preterm birth, medically indicated preterm delivery, and preterm prelabor rupture of membranes were associated with a higher likelihood of receiving antenatal corticosteroids. Among live births delivered between 24 and 34 weeks of gestation in 2012, 23% received optimally timed antenatal corticosteroids, whereas 34% received antenatal corticosteroids with suboptimal timing. More than half of the neonates (52%) whose mothers received antenatal corticosteroids in 2012 were born at 35 weeks of gestation and thus unnecessarily exposed to corticosteroids in utero. Overall, such questionably appropriate administration of antenatal corticosteroids involved 1.7% of all live births.
Previous reports suggest that it is possible to achieve an antenatal corticosteroid administration rate of 85–93% among live births at 34 weeks of gestation or less, although it is unclear if these figures refer to receipt of a partial or complete single course of antenatal corticosteroids as quantified in our study.5,22,23 Our relatively low rate of adherence at 33–34 weeks of gestation is also consistent with other literature22 and a recent study in British Columbia, Canada, indicated only 20% administration at 33–34 weeks of gestation.24 These findings highlight the importance of a continued promotion of clinical guidelines to improve administration rates of antenatal corticosteroids. It is encouraging to observe a significant increase in the administration of antenatal corticosteroids in Nova Scotia at 33–34 weeks of gestation between 2002–2007 and 2008–2012 (Fig. 1) after the recent identification of low rates of prenatal corticosteroid therapy in this subgroup.25
The challenge of accurately diagnosing preterm labor leads to suboptimal and questionably appropriate receipt of antenatal corticosteroid prophylaxis. Although only 1.7% of live births in 2012 received questionably appropriate administration of antenatal corticosteroids, approximately one in two neonates who received antenatal corticosteroid prophylaxis fell into this questionably appropriate administration category. Previous studies have demonstrated that almost half of the women who present with symptoms of preterm labor and who receive antenatal corticosteroids remain pregnant 7–14 days later.5–7,26 Uncertainty regarding the timing of delivery has been an ongoing impediment to optimal antenatal corticosteroid administration.27 With the potential for harm with unnecessary steroid therapy and long-term adverse effects being increasingly recognized,12 it is necessary to develop protocols that balance the benefits of optimal antenatal corticosteroid prophylaxis with the potential harms associated with unnecessary administration of antenatal corticosteroids. This highlights the need for research into developing multivariable prognostic models that provide an accurate probability of delivery based on symptoms and signs of preterm labor combined with pertinent biochemical and radiologic information. Current models for identifying women at risk of preterm delivery within 24 hours to 7 days show promise but need refinement and validation.28–30
The strengths of our study include the use of a previously validated and clinically focused database that included information on antenatal corticosteroid administration. Nevertheless, research findings based on information from large databases may be limited because of the potential for some transcription errors or unmeasured factors not available in the data source. The population-based nature of our study, with less than 2% missing information on gestational age and antenatal corticosteroid administration, is also a significant strength and this increases the likelihood that our findings are generalizable to other geographic regions of Canada and also to other industrialized country settings. Other limitations of our study include the lack of data on the indication for steroid use and the dosage of antenatal corticosteroid administered. Our data source captured only the timing of the earlier dose of the first course of antenatal corticosteroid administered in relation to delivery and not when or whether a second dose was administered.
In summary, our study showed that although the rate of antenatal corticosteroid administration has been on the rise in the past 25 years in Nova Scotia, approximately 20% of neonates born at 28–32 weeks of gestation and 50% of neonates born at 33–34 weeks of gestation did not receive antenatal corticosteroids. Approximately 23% of those requiring antenatal corticosteroid prophylaxis received this therapy with optimal timing, whereas another 34% received the treatment with less than optimal timing. Overall, 1.7% of neonates received antenatal corticosteroid prophylaxis that was questionably appropriate; of the women receiving antenatal corticosteroid prophylaxis, one in two delivered at 35 weeks of gestation or greater.
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