- Email: [email protected]
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends
MATERNAL FETAL MEDICINE
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends Alexandre Fillion;1 Amélie Boutin, PhD;1 Audrée Gareau-Léonard, BSc;1 Laurence Labine, MD;1 Cédric Gasse, MD, MSc;1 Caroline Gaudreau, RN;1 Suzanne Demers, MD, MSc;1,2 Emmanuel Bujold, MD MSc1,2 1
Reproduction, Mother and Child Health Unit, CHU de Québec - Université Laval Research Center, Université Laval,
Québec City, QC A. Fillion
2
Department of Gynecology, Obstetrics and Reproduction, Faculty of Medicine, Université Laval, Québec City, QC
Abstract Objectives: Antenatal corticosteroids (ACS) received within 7 days of delivery reduce perinatal morbidity and mortality associated with preterm birth. We aimed to describe the trends of ACS administration over the last decade. Methods: A cohort study of women who received ACS in 2006, 2011, and 2016 at the CHU de Québec–Université Laval was conducted. The indication, GA at ACS, and GA at birth, were collected in 150 women randomly selected in each studied year. Our main endpoints were the frequency of ACS administration within 7 days of delivery and between 48 hours and 7 days before delivery. Results: We included 447 women who received ACS at a median GA of 31.4 (range 23.6–39.0) weeks. No women received ACS after 35 weeks in 2006 and 2011. The administration of ACS for indicated delivery between 35 and 39 weeks occurred only in the last study period. Among women for whom ACS was initiated before 35 weeks, 31% received ACS in the 7 days before delivery, and only 13% received ACS between 48 hours and 7 days before birth (varying from 12% to 16%, P = 0.57). Threatened preterm labour or short cervix were the indication for ACS initiation in 39% women who received ACS before 35 weeks, but less than 5% of these women delivered between 2 and 7 days and more than 90% delivered after 14 days. Conclusions: Administration of ACS remains suboptimal. Threatened preterm labour and short cervix are poorly related to optimal use of ACS therapy.
Résumé Objectifs : L’administration de corticostéroïdes prénataux (CSP) dans les sept jours précédant l’accouchement réduit la morbidité et la mortalité périnatales associées à la naissance prématurée. Nous avons voulu étudier les tendances relatives à cette pratique au cours de la dernière décennie. Key Words: Pregnancy, antenatal corticosteroid, preterm birth Corresponding Author: Dr. Emmanuel Bujold, Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Centre Mère-Enfant du CHU de Québec - Université Laval, Québec City, QC. [email protected] Competing interests: See Acknowledgements. Received on March 26, 2018 Accepted on May 29, 2018
Méthodologie : Nous avons effectué une étude de cohorte portant sur des femmes ayant reçu des CSP en 2006, en 2011 et en 2016 au CHU de Québec–Université Laval. L’indication, l’âge gestationnel (AG) à l’administration des CSP et l’AG à la naissance ont été recueillis chez 150 femmes sélectionnées aléatoirement pour chaque année étudiée. Le principal indicateur de résultats était la fréquence d’administration des CSP dans les sept jours précédant l’accouchement et dans la période située entre les 48 heures et les sept jours précédant l’accouchement. Résultats : Nous nous sommes penchés sur 447 femmes ayant reçu des CSP à un âge gestationnel moyen de 31,4 (étendue : de 23,6 à 39,0) semaines. Aucune femme n’a reçu de CSP après 35 semaines de grossesse en 2006 et en 2011. L’administration de CSP pour les accouchements indiqués entre 35 et 39 semaines n’a eu lieu que dans la dernière période étudiée. Parmi les femmes ayant reçu des CSP avant 35 semaines, 31 % ont accouché dans les sept jours; 13 % seulement ont accouché moins de sept jours, mais plus de 48 heures après l’administration (de 12 à 16 %, P = 0,57). Des signes de travail prématuré ou un col de l’utérus court ont servi d’indication pour l’administration de CSP chez 39 % des femmes les ayant reçus avant 35 semaines, mais moins de 5 % de ces femmes ont accouché deux à sept jours plus tard, et plus de 90 % ont accouché plus de 14 jours plus tard. Conclusions : L’administration de CSP reste sous-optimale. Les signes de travail prématuré et un col de l’utérus court ne sont pas de bonnes indications pour l’utilisation optimale des CSP. Copyright © 2018 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can ■■;■■(■■):■■–■■ https://doi.org/10.1016/j.jogc.2018.06.001
INTRODUCTION
P
reterm birth is a leading cause of neonatal morbidity and mortality, with approximately one-third of all neonatal deaths being caused by prematurity in Canada and worldwide.1,2 Preterm birth increases the risk of many shortterm morbidities, including respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, ■■ JOGC ■■ ■■ • 1
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periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and retinopathy of prematurity.3 Preterm neonates are also at higher risk of long-term neurodevelopmental and behavioral sequelae, including cerebral palsy, cognitive and sensory impairment, attention deficit, and hyperactive disorder.4 Antenatal corticosteroid (ACS) therapy was introduced by Liggins et al. more than four decades ago as a treatment for reducing neonatal complications related to preterm birth.5,6 Meta-analyses of randomized trials have shown its effectiveness in reducing the risk of neonatal deaths, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and the need for mechanical ventilation and systemic infection in the first 48 hours after birth.7 However, the benefits of ACS tend to decrease as the interval between administration and birth increases, with maximal effect being observed in deliveries within 1 week of its initiation.7 Exposure to antenatal corticosteroids more than 14 days prior to delivery could shift the balance between risks and benefits towards greater harm than good.8–10 Furthermore, repeated doses or courses of ACS therapy have been associated with reduced mean head circumference at birth and potential long-term deleterious neurological effect with an increase in neurosensory disabilities and death or severe disabilities,11,12 thus stressing the importance of the timing of ACS exposure.
identifying numbers and selected a sample of 150 women per year. The ethics committee of the CHU de Québec– Université Laval (CHUL) approved the study. Data collection was completed using medical records of selected participants. We collected maternal age, area of residency (first three digits of the postal code), expected delivery date (estimated by first-trimester ultrasound when available), ACS characteristics (agents, dosage, and regimen; the hospital in which a dose was given; date and time of administration of any doses received in the study centre), documented indication, delivery date and time, Apgar score, and birth weight. Our primary endpoint was the latency between the first dose of ACS and delivery. Our secondary endpoints of interest were indications for ACS (as documented in the medical record), GA at initiation, use of repeated doses or courses, and GA at birth. We compared means of continuous variables between study periods using t test, or distributions using Kruskal-Wallis test. We compared proportions between the study periods using the χ2 test. We considered a two-sided type 1 error of < 0.05 as indicative of a significant difference. All analyses were conducted using SAS statistical software (version 9.3). RESULTS
The 2003 guideline of the SOGC recommends a single course of ACS for women between 24 and 34 weeks of gestation when delivery is expected to occur within 7 days,13 and the American College of Obstetricians and Gynecologists recommend the routine use of ACS from 24 0/7 to 33 6/7 weeks of gestation, also within 7 days of delivery.14 However, the prediction of GA at delivery is challenging. We aimed to describe the use of ACS therapy administration in a tertiary care centre over the last 10 years to estimate the changes in clinical practice.
We included 447 women in our analyses (Table 1); there were only 148 eligible participants in 2011, and one participant from the 150 records selected in 2016 was a duplicate. In total, 519 fetuses were exposed to ACS therapy. Thirtythree women (7%) were discharged from the study centre and delivered in another centre. Of those, delivery dates were missing for 30 women (7% of the sample). Times of administration of the first dose of ACS were missing in 5 women, and times of delivery were missing in 3 women. In those cases, a value of 12h00 (noon) was imputed. None of those cases had latencies <48 hours.
METHODS
A cohort study of pregnant women was initiated in 2005 at the CHU de Québec–Université Laval, a tertiary care centre, as part of a clinical audit. All pregnant women who received ACS prior to their transfer to or during their hospital stay at the CHU de Québec–Université Laval had a record created as part of the audit. We randomly selected 450 women who had received ACS in the calendar year of 2006, 2011, or 2016. All individual audit records were given an identifying number. For each period, using the random sampling procedure without replacement in SAS (SAS Institute Inc. Cary, NC, USA), we submitted the list of
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The majority of women (n = 365; 82%) received two doses of 12 mg of betamethasone 24 hours apart. A large proportion (89%) of women who received only one dose delivered within 24 hours of receiving the dose. Only one woman, recruited in the second study period (2011), received dexamethasone. Overall, 67 (15%) of women received their first dose of ACS in another centre before their admission to the study centre. The median GA at initiation of ACS was significantly different between study periods (Table 1). We observed a significant change in the documented indications for ACS
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends
Table 1. Characteristics of the study participants by study periods 2006 (n = 150; 174 fetuses)
2011 (n = 148; 176 fetuses)
2016 (n = 149; 169 fetuses)
P value
29.1 (4.3)
28.8 (5.4)
29.9 (5.2)
0.12
-
2 (1.4)
1 (0.7)
24 + 0 to 34 + 6 weeks
150 (100)
146 (98.7)
97 (65.1)
35 + 0 to 36 + 6 weeks
-
-
37 (24.8)
≥37 + 0 weeks
-
-
14 (9.4)
GA at birth, weeks (N = 412)
34.7 (31.7–37.4)
35.6 (33.0–38.0)
36.9 (33.6–37.6)
Characteristics Maternal age, years (N = 447)
<0.001
GA at initiation of ACS <24 weeks
0.11
Mean (standard deviation), median (IQR) or n (%).
from 2006 to 2016. Although no women received ACS therapy for Caesarean delivery or induction of labour at term (≥37 weeks) or late preterm (35 + 0 to 36 + 6 weeks) in 2006 and 2011, 24% of women received ACS therapy after 34 weeks following such indications in the sample of participants from 2016. Consequently, the proportion of ACS therapy initiated at 35 weeks or later (any indication considered) increased from 0% in 2006 and 2011 to 34% in 2016 (P < 0.001). Considering this major difference in GA and clinical context of care in women receiving ACS, subsequent analyses were stratified by GA (<35 or ≥35 weeks of gestation) at initiation of antenatal corticosteroid therapy. The median latency between first dose administration and delivery decreased from 26.7 days (interquartile range [IQR]: 3.9–50.7) in 2006 and 28.5 days (IQR: 6.5–51.4) in 2011 to 6.9 days (IQR: 2.3–29.5) in 2016 (P < 0.001). After exclusion of women in whom ACS was initiated at 35 weeks of gestation or later, median latency was not significantly different between study periods, with a median latency of 22.4 days (IQR: 2.5–41.7) in 2016 (P = 0.12). The proportion of women who delivered within 7 days of their first dose of ACS was not significantly different between study periods among women with ACS initiated before 35 weeks of gestation (30% in 2006, 26% in 2011, and 38% in 2016, P = 0.17) (Table 2; Figure 1). Among women whose ACS therapy was initiated at 35 weeks or later, 82% delivered within 7 days of receiving the first dose. Median GA at birth was not significantly different between study periods (Table 1). The proportion of women who delivered at term (≥37 weeks) rose from 33.1% in 2006 to 39.6% in 2011 and to 49.7% in 2016 (P = 0.03). After exclusion of cases in which ACS therapy was initiated at 35 weeks or later, the proportions of term deliveries in 2016
was 32.6%, with no significant differences in comparison to other study periods (P = 0.77). Among women who delivered before term, latencies from initiation of ACS to delivery were ≥7 days in approximately 51%. The indications for ACS reported in medical records varied over time (Table 3). Among women in whom ACS was initiated prior to 35 weeks of gestation, threatened preterm labour (29.2%) and short cervix (9.4%) were among the most frequent indications for ACS (Figure 1). However, both indications were associated with suboptimal windows for the ACS exposure, with less than 5% delivering between 48 hours and 7 days and more than 90% delivering over 14 days after initiation of ACS (Figure 1). Finally, among women for whom ACS was prescribed before an indicated Caesarean before 39 weeks, we observed four cases (14%) in which women received ACS more than 7 days before delivery.
Table 2. Latency between initiation of ACS and delivery according to the study periods, stratified by GA at initiation Latency, n (%)
2006 (n = 150)
2011 (n = 148)
2016 (n = 149)
Initiation of ACS <35 weeks
0.29
<48 hours
23 (17.7)
21 (14.6)
20 (21.7)
48 hours to 7 days
16 (12.3)
17 (11.8)
15 (16.3)
7(5.4)
13 (9.0)
2 (2.2)
84 (64.6)
93 (64.6)
55 (59.8)
7 to 14 days ≥14 days
P value
Initiation of ACS ≥35 weeks
-
<48 hours
-
-
9 (17.7)
48 hours to 7 days
-
-
33 (64.7)
7 to 14 days
-
-
7 (13.7)
≥14 days
-
-
2 (3.9)
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Figure. Reported indications for ACS and latency between first dose and delivery. Legend: Threatened preterm labour is the most frequent indication of ACS. Threatened preterm labour (88%), short cervix (97%), placental abruption (83%), and placenta previa or vasa previa (81%) were all indications for which a high proportion of women (>80%) delivered 14 days or more after initiation of ACS. 100
Frequency
80
60
40
20
0
) ks ee w 39 ) (< ks n ee w tio s c er 39 se th n (< O n ea d ar tio te es uc ia ec Ca nd ev p i pr us al s ic sa s ed es va M r tr o is ia ld ev ta n n pr Fe tio tio ta ric es st up en re br an ac Pl br la th ta ow em en m gr ac e of Pl e rin ur te pt au a i ru tr ps e In ur am at cl ee em Pr pr m er r o et b Pr la r m bo er la et ix m Pr rv er ce et t pr or ed Sh en at re Th
Blue: 0–48 hours; green: 48 hours to 7 days; yellow: 7–14 days; red: ≥ 14 days.
DISCUSSION
We observed that administration of ACS varied among the 3 years studied. Between 2011 and 2016, ACS prophylaxis started to be given to women at 35 weeks of gestation or later. However, throughout the study period, the median latency from ACS initiation and delivery remained greater than the recommended 2 to 7 days. ACS administration based on “threatened preterm labour” and “short cervix” typically resulted in deliveries several days or weeks after the optimal time window for ACS exposure. Furthermore, in the last time period, we observed that women were given ACS in the context of CS at 35 weeks or later, an indication that was not part of the national guideline.13 Our results are comparable to those of another Canadian study: in a population-based study from Nova Scotia in 2012,
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Razaz et al. reported that 34% of women were receiving ACS prophylaxis outside the time window of 48 hours to 7 days.15 In 2002, Skoll et al. also highlighted the difficulty of correctly predicting which women will undergo preterm labour and, therefore, a potential pitfall of ACS prophylaxis.16 More recently, in Sweden, Frandberg et al. observed significant variations in the latency between ACS exposure and delivery according to the indication for the therapy.17 They observed optimal timing of ACS only in 41% of women who delivered before term. Regarding the use of ACS therapy prior to elective Caesarean; we observed that it was not unusual for ACS to be given more than 7 days before delivery. This observation may reflect suboptimal knowledge about the importance of the timing of ACS administration.
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends
Table 3. Reported indications for ACS according to study periods, stratified by GA at initiation 2006 (n = 150)
2011 (n = 148)
2016 (n = 149)
Threatened preterm labour
47 (31.3)
40 (27.1)
28 (28.9)
Short cervix
11 (11.3)
19 (12.9)
7 (7.2)
Preterm labour
32 (21.3)
16 (10.9)
12 (12.4)
Preterm premature rupture of membranes
18 (12.0)
24 (16.3)
9 (9.3)
Preeclampsia
17 (11.3)
18 (12.2)
11 (11.3)
Intrauterine growth restriction
10 (6.7)
3 (2.0)
7 (7.2)
Placental abruption
10 (6.7)
5 (3.4)
7 (7.2)
Placenta previa or vasa previa
3 (2.0)
8 (5.4)
11 (11.3)
Indications, n (%) Initiation of ACS <35 weeks
0.001
Fetal conditionsb
-
7 (4.8)
3 (3.1)
1 (0.7)
-
1 (1.0)
-
1 (0.7)
1 (1.0)
Others
1 (0.7)
6 (4.1)
-
Missing
-
1 (0.7)
1 (1.0)
Threatened preterm labour
-
-
1 (2.0)
Short cervix
-
-
-
Preterm labour
-
-
1 (2.0)
Preterm premature rupture of membranes
-
-
2 (3.9)
Medical labour induction (<39 weeks gestation) CS (<39 weeks gestation)
Initiation of ACS ≥35 weeks
-
Preeclampsia
-
-
6 (11.8)
Intrauterine growth restriction
-
-
3 (5.9)
Placental abruption
-
-
-
Placenta previa or vasa previa
-
-
-
b
-
-
3 (5.9)
Indicated labour induction (<39 weeks gestation)
-
-
6 (11.8)
CS (<39 weeks gestation)
-
-
29 (56.9)
Others
-
-
-
Fetal conditions
P valuea
Maximum likelihood ratio χ2 test.
a b
Fetal ascites, fetal gastroschisis, and severe oligohydramnios, among others.
Our study was limited to 3 years over a 10-year period and might not reflect all the changes experienced over the years in our centre. However, all women and fetuses who were exposed to ACS were screened, and our cohort represents a random selection of all eligible women over those years. We had few missing data, mainly related to women who delivered outside of our centre. We expect that those women would not have exhibited better timing for prophylaxis; therefore, our results may slightly underestimate the average latency. Furthermore, we selected only women who received ACS therapy, which precludes any exploration of the adequacy of ACS exposure in the general population. We did not capture data on women and fetuses who might have benefited from ACS but did not receive such therapy. Furthermore, restricting the sample to women who received ACS therapy limits the comparability of the
distribution of indications through the periods studied. The overall variation in the frequencies of the indications in the population (both women who did and who did not receive ACS therapy) through the years could affect the frequency of each indication in the study sample. However, the study informs us on changes in the characteristics of women who received ACS therapy, which might be due to changes in practice or changes in the frequency of the indications in the population, or a combination of both. CONCLUSIONS
The reported indications for ACS prophylaxis have changed over the last decade but did not result in significant improvement of optimal timing of administration, either by extending the use over questionable GAs or by exposing
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women and fetuses to ACS several weeks before birth. Women and fetuses are exposed to ACS in suboptimal conditions, limiting the benefits and raising the question of a potential increased risk of harms. Our results highlight the need for better guidance in the decision to administer ACS therapy. Acknowledgements
This study was funded by the Jeanne-et-Jean-Louis-Lévesque Perinatal Research Chair at Université Laval. Emmanuel Bujold holds a salary award from the Fonds de Recherche du Québec-Santé. REFERENCES 1. Public Health Agency of Canada. Perinatal health indicators for Canada 2017. Ottawa: Public Health Agency of Canada; 2017. 2. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016;388:3027–35.
7. Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;(3):CD004454. 8. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a “rescue course” of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009;200:e1–9. 9. Ring AM, Garland JS, Stafeil BR, et al. The effect of a prolonged time interval between antenatal corticosteroid administration and delivery on outcomes in preterm neonates: a cohort study. Am J Obstet Gynecol 2007;196:457, e1–6. 10. Lau HCQ, Tung JSZ, Wong TTC, et al. Timing of antenatal steroids exposure and its effects on neonates. Arch Gynecol Obstet 2017;296:1091–6. 11. Crowther CA, McKinlay CJ, Middleton P, et al. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev 2015;(7):CD003935. 12. Asztalos E, Willan A, Murphy K, et al. Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5). BMC Pregnancy Childbirth 2014;14:272. 13. Crane J, Armson A, Brunner M, et al. Antenatal corticosteroid therapy for fetal maturation. J Obstet Gynaecol Can 2003;25:45–52.
3. Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG 2003;110:8–16.
14. American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice, Society for Maternal-Fetal Medicine. Committee opinion no.713: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017;130:e102–9.
4. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008;371:261–9.
15. Razaz N, Skoll A, Fahey J, et al. Trends in optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroid prophylaxis. Obstet Gynecol 2015;125:288–96.
5. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515–23.
16. Skoll A, Ferreira E, Pedneault L, et al. Do we use too much antenatal betamethasone? J Obstet Gynaecol Can 2002;24:330–4.
6. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
17. Frandberg J, Sandblom J, Bruschettini M, et al. Antenatal corticosteroids: a retrospective cohort study on timing, indications and neonatal outcome. Acta Obstet Gynecol Scand 2018;97:591–7.
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Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends Alexandre Fillion;1 Amélie Boutin, PhD;1 Audrée Gareau-Léonard, BSc;1 Laurence Labine, MD;1 Cédric Gasse, MD, MSc;1 Caroline Gaudreau, RN;1 Suzanne Demers, MD, MSc;1,2 Emmanuel Bujold, MD MSc1,2 1
Reproduction, Mother and Child Health Unit, CHU de Québec - Université Laval Research Center, Université Laval,
Québec City, QC A. Fillion
2
Department of Gynecology, Obstetrics and Reproduction, Faculty of Medicine, Université Laval, Québec City, QC
Abstract Objectives: Antenatal corticosteroids (ACS) received within 7 days of delivery reduce perinatal morbidity and mortality associated with preterm birth. We aimed to describe the trends of ACS administration over the last decade. Methods: A cohort study of women who received ACS in 2006, 2011, and 2016 at the CHU de Québec–Université Laval was conducted. The indication, GA at ACS, and GA at birth, were collected in 150 women randomly selected in each studied year. Our main endpoints were the frequency of ACS administration within 7 days of delivery and between 48 hours and 7 days before delivery. Results: We included 447 women who received ACS at a median GA of 31.4 (range 23.6–39.0) weeks. No women received ACS after 35 weeks in 2006 and 2011. The administration of ACS for indicated delivery between 35 and 39 weeks occurred only in the last study period. Among women for whom ACS was initiated before 35 weeks, 31% received ACS in the 7 days before delivery, and only 13% received ACS between 48 hours and 7 days before birth (varying from 12% to 16%, P = 0.57). Threatened preterm labour or short cervix were the indication for ACS initiation in 39% women who received ACS before 35 weeks, but less than 5% of these women delivered between 2 and 7 days and more than 90% delivered after 14 days. Conclusions: Administration of ACS remains suboptimal. Threatened preterm labour and short cervix are poorly related to optimal use of ACS therapy.
Résumé Objectifs : L’administration de corticostéroïdes prénataux (CSP) dans les sept jours précédant l’accouchement réduit la morbidité et la mortalité périnatales associées à la naissance prématurée. Nous avons voulu étudier les tendances relatives à cette pratique au cours de la dernière décennie. Key Words: Pregnancy, antenatal corticosteroid, preterm birth Corresponding Author: Dr. Emmanuel Bujold, Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Centre Mère-Enfant du CHU de Québec - Université Laval, Québec City, QC. [email protected] Competing interests: See Acknowledgements. Received on March 26, 2018 Accepted on May 29, 2018
Méthodologie : Nous avons effectué une étude de cohorte portant sur des femmes ayant reçu des CSP en 2006, en 2011 et en 2016 au CHU de Québec–Université Laval. L’indication, l’âge gestationnel (AG) à l’administration des CSP et l’AG à la naissance ont été recueillis chez 150 femmes sélectionnées aléatoirement pour chaque année étudiée. Le principal indicateur de résultats était la fréquence d’administration des CSP dans les sept jours précédant l’accouchement et dans la période située entre les 48 heures et les sept jours précédant l’accouchement. Résultats : Nous nous sommes penchés sur 447 femmes ayant reçu des CSP à un âge gestationnel moyen de 31,4 (étendue : de 23,6 à 39,0) semaines. Aucune femme n’a reçu de CSP après 35 semaines de grossesse en 2006 et en 2011. L’administration de CSP pour les accouchements indiqués entre 35 et 39 semaines n’a eu lieu que dans la dernière période étudiée. Parmi les femmes ayant reçu des CSP avant 35 semaines, 31 % ont accouché dans les sept jours; 13 % seulement ont accouché moins de sept jours, mais plus de 48 heures après l’administration (de 12 à 16 %, P = 0,57). Des signes de travail prématuré ou un col de l’utérus court ont servi d’indication pour l’administration de CSP chez 39 % des femmes les ayant reçus avant 35 semaines, mais moins de 5 % de ces femmes ont accouché deux à sept jours plus tard, et plus de 90 % ont accouché plus de 14 jours plus tard. Conclusions : L’administration de CSP reste sous-optimale. Les signes de travail prématuré et un col de l’utérus court ne sont pas de bonnes indications pour l’utilisation optimale des CSP. Copyright © 2018 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can ■■;■■(■■):■■–■■ https://doi.org/10.1016/j.jogc.2018.06.001
INTRODUCTION
P
reterm birth is a leading cause of neonatal morbidity and mortality, with approximately one-third of all neonatal deaths being caused by prematurity in Canada and worldwide.1,2 Preterm birth increases the risk of many shortterm morbidities, including respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, ■■ JOGC ■■ ■■ • 1
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periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and retinopathy of prematurity.3 Preterm neonates are also at higher risk of long-term neurodevelopmental and behavioral sequelae, including cerebral palsy, cognitive and sensory impairment, attention deficit, and hyperactive disorder.4 Antenatal corticosteroid (ACS) therapy was introduced by Liggins et al. more than four decades ago as a treatment for reducing neonatal complications related to preterm birth.5,6 Meta-analyses of randomized trials have shown its effectiveness in reducing the risk of neonatal deaths, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and the need for mechanical ventilation and systemic infection in the first 48 hours after birth.7 However, the benefits of ACS tend to decrease as the interval between administration and birth increases, with maximal effect being observed in deliveries within 1 week of its initiation.7 Exposure to antenatal corticosteroids more than 14 days prior to delivery could shift the balance between risks and benefits towards greater harm than good.8–10 Furthermore, repeated doses or courses of ACS therapy have been associated with reduced mean head circumference at birth and potential long-term deleterious neurological effect with an increase in neurosensory disabilities and death or severe disabilities,11,12 thus stressing the importance of the timing of ACS exposure.
identifying numbers and selected a sample of 150 women per year. The ethics committee of the CHU de Québec– Université Laval (CHUL) approved the study. Data collection was completed using medical records of selected participants. We collected maternal age, area of residency (first three digits of the postal code), expected delivery date (estimated by first-trimester ultrasound when available), ACS characteristics (agents, dosage, and regimen; the hospital in which a dose was given; date and time of administration of any doses received in the study centre), documented indication, delivery date and time, Apgar score, and birth weight. Our primary endpoint was the latency between the first dose of ACS and delivery. Our secondary endpoints of interest were indications for ACS (as documented in the medical record), GA at initiation, use of repeated doses or courses, and GA at birth. We compared means of continuous variables between study periods using t test, or distributions using Kruskal-Wallis test. We compared proportions between the study periods using the χ2 test. We considered a two-sided type 1 error of < 0.05 as indicative of a significant difference. All analyses were conducted using SAS statistical software (version 9.3). RESULTS
The 2003 guideline of the SOGC recommends a single course of ACS for women between 24 and 34 weeks of gestation when delivery is expected to occur within 7 days,13 and the American College of Obstetricians and Gynecologists recommend the routine use of ACS from 24 0/7 to 33 6/7 weeks of gestation, also within 7 days of delivery.14 However, the prediction of GA at delivery is challenging. We aimed to describe the use of ACS therapy administration in a tertiary care centre over the last 10 years to estimate the changes in clinical practice.
We included 447 women in our analyses (Table 1); there were only 148 eligible participants in 2011, and one participant from the 150 records selected in 2016 was a duplicate. In total, 519 fetuses were exposed to ACS therapy. Thirtythree women (7%) were discharged from the study centre and delivered in another centre. Of those, delivery dates were missing for 30 women (7% of the sample). Times of administration of the first dose of ACS were missing in 5 women, and times of delivery were missing in 3 women. In those cases, a value of 12h00 (noon) was imputed. None of those cases had latencies <48 hours.
METHODS
A cohort study of pregnant women was initiated in 2005 at the CHU de Québec–Université Laval, a tertiary care centre, as part of a clinical audit. All pregnant women who received ACS prior to their transfer to or during their hospital stay at the CHU de Québec–Université Laval had a record created as part of the audit. We randomly selected 450 women who had received ACS in the calendar year of 2006, 2011, or 2016. All individual audit records were given an identifying number. For each period, using the random sampling procedure without replacement in SAS (SAS Institute Inc. Cary, NC, USA), we submitted the list of
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The majority of women (n = 365; 82%) received two doses of 12 mg of betamethasone 24 hours apart. A large proportion (89%) of women who received only one dose delivered within 24 hours of receiving the dose. Only one woman, recruited in the second study period (2011), received dexamethasone. Overall, 67 (15%) of women received their first dose of ACS in another centre before their admission to the study centre. The median GA at initiation of ACS was significantly different between study periods (Table 1). We observed a significant change in the documented indications for ACS
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends
Table 1. Characteristics of the study participants by study periods 2006 (n = 150; 174 fetuses)
2011 (n = 148; 176 fetuses)
2016 (n = 149; 169 fetuses)
P value
29.1 (4.3)
28.8 (5.4)
29.9 (5.2)
0.12
-
2 (1.4)
1 (0.7)
24 + 0 to 34 + 6 weeks
150 (100)
146 (98.7)
97 (65.1)
35 + 0 to 36 + 6 weeks
-
-
37 (24.8)
≥37 + 0 weeks
-
-
14 (9.4)
GA at birth, weeks (N = 412)
34.7 (31.7–37.4)
35.6 (33.0–38.0)
36.9 (33.6–37.6)
Characteristics Maternal age, years (N = 447)
<0.001
GA at initiation of ACS <24 weeks
0.11
Mean (standard deviation), median (IQR) or n (%).
from 2006 to 2016. Although no women received ACS therapy for Caesarean delivery or induction of labour at term (≥37 weeks) or late preterm (35 + 0 to 36 + 6 weeks) in 2006 and 2011, 24% of women received ACS therapy after 34 weeks following such indications in the sample of participants from 2016. Consequently, the proportion of ACS therapy initiated at 35 weeks or later (any indication considered) increased from 0% in 2006 and 2011 to 34% in 2016 (P < 0.001). Considering this major difference in GA and clinical context of care in women receiving ACS, subsequent analyses were stratified by GA (<35 or ≥35 weeks of gestation) at initiation of antenatal corticosteroid therapy. The median latency between first dose administration and delivery decreased from 26.7 days (interquartile range [IQR]: 3.9–50.7) in 2006 and 28.5 days (IQR: 6.5–51.4) in 2011 to 6.9 days (IQR: 2.3–29.5) in 2016 (P < 0.001). After exclusion of women in whom ACS was initiated at 35 weeks of gestation or later, median latency was not significantly different between study periods, with a median latency of 22.4 days (IQR: 2.5–41.7) in 2016 (P = 0.12). The proportion of women who delivered within 7 days of their first dose of ACS was not significantly different between study periods among women with ACS initiated before 35 weeks of gestation (30% in 2006, 26% in 2011, and 38% in 2016, P = 0.17) (Table 2; Figure 1). Among women whose ACS therapy was initiated at 35 weeks or later, 82% delivered within 7 days of receiving the first dose. Median GA at birth was not significantly different between study periods (Table 1). The proportion of women who delivered at term (≥37 weeks) rose from 33.1% in 2006 to 39.6% in 2011 and to 49.7% in 2016 (P = 0.03). After exclusion of cases in which ACS therapy was initiated at 35 weeks or later, the proportions of term deliveries in 2016
was 32.6%, with no significant differences in comparison to other study periods (P = 0.77). Among women who delivered before term, latencies from initiation of ACS to delivery were ≥7 days in approximately 51%. The indications for ACS reported in medical records varied over time (Table 3). Among women in whom ACS was initiated prior to 35 weeks of gestation, threatened preterm labour (29.2%) and short cervix (9.4%) were among the most frequent indications for ACS (Figure 1). However, both indications were associated with suboptimal windows for the ACS exposure, with less than 5% delivering between 48 hours and 7 days and more than 90% delivering over 14 days after initiation of ACS (Figure 1). Finally, among women for whom ACS was prescribed before an indicated Caesarean before 39 weeks, we observed four cases (14%) in which women received ACS more than 7 days before delivery.
Table 2. Latency between initiation of ACS and delivery according to the study periods, stratified by GA at initiation Latency, n (%)
2006 (n = 150)
2011 (n = 148)
2016 (n = 149)
Initiation of ACS <35 weeks
0.29
<48 hours
23 (17.7)
21 (14.6)
20 (21.7)
48 hours to 7 days
16 (12.3)
17 (11.8)
15 (16.3)
7(5.4)
13 (9.0)
2 (2.2)
84 (64.6)
93 (64.6)
55 (59.8)
7 to 14 days ≥14 days
P value
Initiation of ACS ≥35 weeks
-
<48 hours
-
-
9 (17.7)
48 hours to 7 days
-
-
33 (64.7)
7 to 14 days
-
-
7 (13.7)
≥14 days
-
-
2 (3.9)
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Figure. Reported indications for ACS and latency between first dose and delivery. Legend: Threatened preterm labour is the most frequent indication of ACS. Threatened preterm labour (88%), short cervix (97%), placental abruption (83%), and placenta previa or vasa previa (81%) were all indications for which a high proportion of women (>80%) delivered 14 days or more after initiation of ACS. 100
Frequency
80
60
40
20
0
) ks ee w 39 ) (< ks n ee w tio s c er 39 se th n (< O n ea d ar tio te es uc ia ec Ca nd ev p i pr us al s ic sa s ed es va M r tr o is ia ld ev ta n n pr Fe tio tio ta ric es st up en re br an ac Pl br la th ta ow em en m gr ac e of Pl e rin ur te pt au a i ru tr ps e In ur am at cl ee em Pr pr m er r o et b Pr la r m bo er la et ix m Pr rv er ce et t pr or ed Sh en at re Th
Blue: 0–48 hours; green: 48 hours to 7 days; yellow: 7–14 days; red: ≥ 14 days.
DISCUSSION
We observed that administration of ACS varied among the 3 years studied. Between 2011 and 2016, ACS prophylaxis started to be given to women at 35 weeks of gestation or later. However, throughout the study period, the median latency from ACS initiation and delivery remained greater than the recommended 2 to 7 days. ACS administration based on “threatened preterm labour” and “short cervix” typically resulted in deliveries several days or weeks after the optimal time window for ACS exposure. Furthermore, in the last time period, we observed that women were given ACS in the context of CS at 35 weeks or later, an indication that was not part of the national guideline.13 Our results are comparable to those of another Canadian study: in a population-based study from Nova Scotia in 2012,
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Razaz et al. reported that 34% of women were receiving ACS prophylaxis outside the time window of 48 hours to 7 days.15 In 2002, Skoll et al. also highlighted the difficulty of correctly predicting which women will undergo preterm labour and, therefore, a potential pitfall of ACS prophylaxis.16 More recently, in Sweden, Frandberg et al. observed significant variations in the latency between ACS exposure and delivery according to the indication for the therapy.17 They observed optimal timing of ACS only in 41% of women who delivered before term. Regarding the use of ACS therapy prior to elective Caesarean; we observed that it was not unusual for ACS to be given more than 7 days before delivery. This observation may reflect suboptimal knowledge about the importance of the timing of ACS administration.
Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends
Table 3. Reported indications for ACS according to study periods, stratified by GA at initiation 2006 (n = 150)
2011 (n = 148)
2016 (n = 149)
Threatened preterm labour
47 (31.3)
40 (27.1)
28 (28.9)
Short cervix
11 (11.3)
19 (12.9)
7 (7.2)
Preterm labour
32 (21.3)
16 (10.9)
12 (12.4)
Preterm premature rupture of membranes
18 (12.0)
24 (16.3)
9 (9.3)
Preeclampsia
17 (11.3)
18 (12.2)
11 (11.3)
Intrauterine growth restriction
10 (6.7)
3 (2.0)
7 (7.2)
Placental abruption
10 (6.7)
5 (3.4)
7 (7.2)
Placenta previa or vasa previa
3 (2.0)
8 (5.4)
11 (11.3)
Indications, n (%) Initiation of ACS <35 weeks
0.001
Fetal conditionsb
-
7 (4.8)
3 (3.1)
1 (0.7)
-
1 (1.0)
-
1 (0.7)
1 (1.0)
Others
1 (0.7)
6 (4.1)
-
Missing
-
1 (0.7)
1 (1.0)
Threatened preterm labour
-
-
1 (2.0)
Short cervix
-
-
-
Preterm labour
-
-
1 (2.0)
Preterm premature rupture of membranes
-
-
2 (3.9)
Medical labour induction (<39 weeks gestation) CS (<39 weeks gestation)
Initiation of ACS ≥35 weeks
-
Preeclampsia
-
-
6 (11.8)
Intrauterine growth restriction
-
-
3 (5.9)
Placental abruption
-
-
-
Placenta previa or vasa previa
-
-
-
b
-
-
3 (5.9)
Indicated labour induction (<39 weeks gestation)
-
-
6 (11.8)
CS (<39 weeks gestation)
-
-
29 (56.9)
Others
-
-
-
Fetal conditions
P valuea
Maximum likelihood ratio χ2 test.
a b
Fetal ascites, fetal gastroschisis, and severe oligohydramnios, among others.
Our study was limited to 3 years over a 10-year period and might not reflect all the changes experienced over the years in our centre. However, all women and fetuses who were exposed to ACS were screened, and our cohort represents a random selection of all eligible women over those years. We had few missing data, mainly related to women who delivered outside of our centre. We expect that those women would not have exhibited better timing for prophylaxis; therefore, our results may slightly underestimate the average latency. Furthermore, we selected only women who received ACS therapy, which precludes any exploration of the adequacy of ACS exposure in the general population. We did not capture data on women and fetuses who might have benefited from ACS but did not receive such therapy. Furthermore, restricting the sample to women who received ACS therapy limits the comparability of the
distribution of indications through the periods studied. The overall variation in the frequencies of the indications in the population (both women who did and who did not receive ACS therapy) through the years could affect the frequency of each indication in the study sample. However, the study informs us on changes in the characteristics of women who received ACS therapy, which might be due to changes in practice or changes in the frequency of the indications in the population, or a combination of both. CONCLUSIONS
The reported indications for ACS prophylaxis have changed over the last decade but did not result in significant improvement of optimal timing of administration, either by extending the use over questionable GAs or by exposing
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women and fetuses to ACS several weeks before birth. Women and fetuses are exposed to ACS in suboptimal conditions, limiting the benefits and raising the question of a potential increased risk of harms. Our results highlight the need for better guidance in the decision to administer ACS therapy. Acknowledgements
This study was funded by the Jeanne-et-Jean-Louis-Lévesque Perinatal Research Chair at Université Laval. Emmanuel Bujold holds a salary award from the Fonds de Recherche du Québec-Santé. REFERENCES 1. Public Health Agency of Canada. Perinatal health indicators for Canada 2017. Ottawa: Public Health Agency of Canada; 2017. 2. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016;388:3027–35.
7. Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;(3):CD004454. 8. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a “rescue course” of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009;200:e1–9. 9. Ring AM, Garland JS, Stafeil BR, et al. The effect of a prolonged time interval between antenatal corticosteroid administration and delivery on outcomes in preterm neonates: a cohort study. Am J Obstet Gynecol 2007;196:457, e1–6. 10. Lau HCQ, Tung JSZ, Wong TTC, et al. Timing of antenatal steroids exposure and its effects on neonates. Arch Gynecol Obstet 2017;296:1091–6. 11. Crowther CA, McKinlay CJ, Middleton P, et al. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev 2015;(7):CD003935. 12. Asztalos E, Willan A, Murphy K, et al. Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5). BMC Pregnancy Childbirth 2014;14:272. 13. Crane J, Armson A, Brunner M, et al. Antenatal corticosteroid therapy for fetal maturation. J Obstet Gynaecol Can 2003;25:45–52.
3. Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG 2003;110:8–16.
14. American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice, Society for Maternal-Fetal Medicine. Committee opinion no.713: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017;130:e102–9.
4. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008;371:261–9.
15. Razaz N, Skoll A, Fahey J, et al. Trends in optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroid prophylaxis. Obstet Gynecol 2015;125:288–96.
5. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515–23.
16. Skoll A, Ferreira E, Pedneault L, et al. Do we use too much antenatal betamethasone? J Obstet Gynaecol Can 2002;24:330–4.
6. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
17. Frandberg J, Sandblom J, Bruschettini M, et al. Antenatal corticosteroids: a retrospective cohort study on timing, indications and neonatal outcome. Acta Obstet Gynecol Scand 2018;97:591–7.
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